Loperamide Hydrochloride 2 MG Oral Tablet [Imodium]

Generic Name: LOPERAMIDE HYDROCHLORIDE
Brand Name: Imodium A-D
  • Substance Name(s):
  • LOPERAMIDE HYDROCHLORIDE

WARNINGS

Warnings Allergy alert Do not use if you have ever had a rash or other allergic reaction to loperamide HCl Heart alert Taking more than directed can cause serious heart problems or death Do not use if you have bloody or black stool Ask a doctor before use if you have fever mucus in the stool a history of liver disease a history of abnormal heart rhythm Ask a doctor or pharmacist before use if you are taking a prescription drug.

Loperamide may interact with certain prescription drugs.

When using this product tiredness, drowsiness or dizziness may occur.

Be careful when driving or operating machinery.

Stop use and ask a doctor if symptoms get worse diarrhea lasts for more than 2 days you get abdominal swelling or bulging.

These may be signs of a serious condition.

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

INDICATIONS AND USAGE

Use controls symptoms of diarrhea, including Travelers’ Diarrhea

INACTIVE INGREDIENTS

Inactive ingredients anhydrous lactose, carnauba wax, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch

PURPOSE

Purpose Anti-diarrheal

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

ASK DOCTOR

Ask a doctor before use if you have fever mucus in the stool a history of liver disease a history of abnormal heart rhythm

DOSAGE AND ADMINISTRATION

Directions drink plenty of clear fluids to help prevent dehydration caused by diarrhea find right dose on chart.

If possible, use weight to dose; otherwise, use age.

adults and children 12 years and over 2 caplets after the first loose stool; 1 caplet after each subsequent loose stool; but no more than 4 caplets in 24 hours children 9-11 years (60-95 lbs) 1 caplet after the first loose stool; 1/2 caplet after each subsequent loose stool; but no more than 3 caplets in 24 hours children 6-8 years (48-59 lbs) 1 caplet after the first loose stool; 1/2 caplet after each subsequent loose stool; but no more than 2 caplets in 24 hours children 2-5 years (34 to 47 lbs) ask a doctor children under 2 years (up to 33 lbs) do not use

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

Do not use if you have bloody or black stool

STOP USE

Stop use and ask a doctor if symptoms get worse diarrhea lasts for more than 2 days you get abdominal swelling or bulging.

These may be signs of a serious condition.

ACTIVE INGREDIENTS

Active ingredient (in each caplet) Loperamide HCl 2 mg

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking a prescription drug.

Loperamide may interact with certain prescription drugs.

OLANZapine 15 MG Disintegrating Oral Tablet

DRUG INTERACTIONS

7 The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies.

Diazepam: May potentiate orthostatic hypotension.

( 7.1 , 7.2 ) Alcohol: May potentiate orthostatic hypotension.

( 7.1 ) Carbamazepine: Increased clearance of olanzapine.

( 7.1 ) Fluvoxamine: May increase olanzapine levels.

( 7.1 ) Olanzapine and Fluoxetine in Combination: Also refer to the Drug Interactions section of the package insert for Symbyax.

( 7.1 ) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs and alcohol.

( 7.2 ) Antihypertensive Agents: Enhanced antihypertensive effect.

( 7.2 ) Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists.

( 7.2 ) Other Concomitant Drug Therapy: When using olanzapine in combination with lithium or valproate, refer to the Drug Interactions sections of the package insert for those products.

( 7.2 ) 7.1 Potential for Other Drugs to Affect Olanzapine Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [ see Drug Interactions (7.2) ] .

Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of olanzapine.

Inducers of CYP1A2 — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine.

This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity.

Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics.

The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)].

Inhibitors of CYP1A2 Fluvoxamine: Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine.

This results in a mean increase in olanzapine C max following fluvoxamine of 54% in female nonsmokers and 77% in male smokers.

The mean increase in olanzapine AUC is 52% and 108%, respectively.

Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

Inhibitors of CYP2D6 Fluoxetine: Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance.

The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.

When using olanzapine and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [ see Drug Interactions (7.2) ] .

Inducers of CYP1A2 or Glucuronyl Transferase — Omeprazole and rifampin may cause an increase in olanzapine clearance.

Charcoal — The administration of activated charcoal (1 g) reduced the C max and AUC of oral olanzapine by about 60%.

As peak olanzapine levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.

Anticholinergic Drugs — Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility.

Olanzapine should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.14)] .

7.2 Potential for Olanzapine to Affect Other Drugs CNS Acting Drugs — Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol.

Antihypertensive Agents — Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium.

Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium [see Warnings and Precautions (5.16)] .

Valproate — Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate.

Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate [see Warnings and Precautions (5.16)].

Effect of Olanzapine on Drug Metabolizing Enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Imipramine — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Warfarin — Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug Interactions (7.1)] .

Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam.

However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Drug Interactions (7.1)] .

Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions (7.1)] .

Biperiden — Multiple doses of olanzapine did not influence the kinetics of biperiden.

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

OVERDOSAGE

10 10.1 Human Experience In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in 67 patients.

In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech.

In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG.

Vital signs were usually within normal limits following overdoses.

In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases.

In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.

Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension.

Reports of fatality in association with overdose of olanzapine alone have been received.

In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

10.2 Management of Overdose There is no specific antidote to an overdose of olanzapine.

The possibility of multiple drug involvement should be considered.

Establish and maintain an airway and ensure adequate oxygenation and ventilation.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).

For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the prescribing information for those products.

For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax prescribing information.

DESCRIPTION

11 Olanzapine, USP is an atypical antipsychotic that belongs to the thienobenzodiazepine class.

The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H -thieno[2,3- b ] [1,5]benzodiazepine.

The molecular formula is C 17 H 20 N 4 S, which corresponds to a molecular weight of 312.44.

The chemical structure is: Olanzapine, USP is a yellow crystalline solid, which is soluble in n-propanol; sparingly soluble in acetonitrile; slightly soluble in methanol and in dehydrated alcohol; practically insoluble in water.

Olanzapine orally disintegrating tablets, USP are intended for oral administration only.

Each orally disintegrating tablet contains olanzapine, USP equivalent to 5 mg, 10 mg, 15 mg or 20 mg.

It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid.

Olanzapine orally disintegrating tablets, USP also contain the following inactive ingredients: aspartame, colloidal silicon dioxide, low-substituted hydroxyl propyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose and strawberry flavor 52311 AP 0551 which contains artificial flavors, benzyl alcohol, maltodextrin, propylene glycol and triethyl citrate.

Olanzapine orally disintegrating tablets meets USP Disintegration Test 2.

CLINICAL STUDIES

14 When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

14.1 Schizophrenia Adults The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of adult inpatients who met DSM III-R criteria for schizophrenia.

A single haloperidol arm was included as a comparative treatment in 1 of the 2 trials, but this trial did not compare these 2 drugs on the full range of clinically relevant doses for both.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.

The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.

A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

In addition, 2 more recently developed scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS).

The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity.

The results of the trials follow: (1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of 1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity.

(2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on a once daily schedule, the 2 highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS.

There was no clear advantage for the high-dose group over the medium-dose group.

(3) In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open-label treatment for at least 8 weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to placebo.

The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study.

Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months.

Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

Adolescents The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17 years) was established in a 6-week double-blind, placebo-controlled, randomized trial of inpatients and outpatients with schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL).

The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) total score.

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 12.5 mg/day, mean dose of 11.1 mg/day) was more effective than placebo in the treatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients in the olanzapine treatment group than in the placebo group.

While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.

It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Patients should be periodically reassessed to determine the need for maintenance treatment.

14.2 Bipolar I Disorder (Manic or Mixed Episodes) Adults Monotherapy — The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes.

These trials included patients with or without psychotic features and with or without a rapid-cycling course.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).

The primary outcome in these trials was change from baseline in the Y-MRS total score.

The results of the trials follow: (1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5 to 20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.

In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.

(2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5 to 20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.

(3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse.

Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment.

Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8.

Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression.

In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse.

Adjunct to Lithium or Valproate — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes.

These trials included patients with or without psychotic features and with or without a rapid-cycling course.

The results of the trials follow: (1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy.

Olanzapine (in a dose range of 5 to 20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 mcg/mL to 125 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

(2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy.

Olanzapine (in a dose range of 5 to 20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 mcg/mL to 125 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

Adolescents Acute Monotherapy — The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161).

Diagnosis was confirmed by the K-SADS-PL.

The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score.

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.

While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.

It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Patients should be periodically reassessed to determine the need for maintenance treatment.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Olanzapine orally disintegrating tablets, USP are yellow colored, round, flat face beveled edge, debossed tablets with characteristic flavour.

The tablets are available as follows: TABLET STRENGTH Olanzapine orally disintegrating tablets, USP 5 mg 10 mg 15 mg 20 mg Debossed D5; CO D10; CO D15; CO D20; CO NDC Codes: child-resistant blisters of 10 tablets 59746-306-12 59746-307-12 59746-308-12 59746-309-12 NDC Codes: Carton of 30 tablets (3 x 10 unit-dose) 59746-306-32 59746-307-32 59746-308-32 59746-309-32 16.2 Storage and Handling Store at 20ºC to 25°C (68ºF to 77ºF); excursions permitted to 15°C to 30°C (59ºF to 86ºF) [See USP Controlled Room Temperature].

The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20°C to 25°C (68°F to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15°C and 30°C (59°F and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Protect olanzapine orally disintegrating tablets from light and moisture.

RECENT MAJOR CHANGES

Warnings and Precautions, Tardive Dyskinesia ( 5.6 ) 10/2019 Warnings and Precautions, Use in Patients with Concomitant Illness ( 5.14 ) Removed 4/2020 Warnings and Precautions, Anticholinergic (antimuscarinic) Effects ( 5.14 ) 4/2020

GERIATRIC USE

8.5 Geriatric Use Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over.

In patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared to younger patients.

Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia.

Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo.

In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo.

In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations.

The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%).

Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17)].

Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.1)] .

Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.

DOSAGE FORMS AND STRENGTHS

3 Olanzapine orally disintegrating tablets, USP are yellow colored, round, flat face beveled edge, debossed tablets with characteristic flavour.

Tablets are not scored.

The tablets are available as follows: TABLET STRENGTH Olanzapine Orally Disintegrating Tablets 5 mg 10 mg 15 mg 20 mg Debossed D5;CO D10;CO D15;CO D20;CO Orally Disintegrating Tablets (not scored): 5 mg, 10 mg, 15 mg, 20 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of olanzapine, in the listed indications is unclear.

However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism.

INDICATIONS AND USAGE

1 Olanzapine orally disintegrating tablets are atypical antipsychotic indicated: As oral formulation for the: Treatment of schizophrenia.

( 1.1 ) Adults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial.

( 14.1 ) Adolescents (ages 13 to 17): Efficacy was established in one 6-week trial in patients with schizophrenia ( 14.1 ).

The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents.

( 1.1 ) Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder.

( 1.2 ) Adults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one maintenance trial.

( 14.2 ) Adolescents (ages 13 to 17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar I disorder ( 14.2 ).

The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents.

( 1.2 ) Medication therapy for pediatric patients with schizophrenia or bipolar I disorder should be undertaken only after a thorough diagnostic evaluation and with careful consideration of the potential risks.

( 1.3 ) Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder.

( 1.2 ) Efficacy was established in two 6-week clinical trials in adults ( 14.2 ).

Maintenance efficacy has not been systematically evaluated.

As O lanzapine and Fluoxetine in Combination for the: Treatment of depressive episodes associated with bipolar I disorder.

( 1.5 ) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax.

Treatment of treatment resistant depression.

( 1.6 ) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.

1.1 Schizophrenia Olanzapine orally disintegrating tablets are indicated for the treatment of schizophrenia.

Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial.

In adolescent patients with schizophrenia (ages 13 to 17), efficacy was established in one 6-week trial [ see Clinical Studies (14.1 )] .

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia.

Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5) ] .

1.2 Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy — Olanzapine orally disintegrating tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder.

Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial.

In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13 to 17), efficacy was established in one 3-week trial [ see Clinical Studies (14.2)] .

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia.

Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5) ] .

Adjunctive Therapy to Lithium or Valproate — Olanzapine orally disintegrating tablets are indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate.

Efficacy was established in two 6-week clinical trials in adults.

The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical Studies (14.2)] .

1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging.

For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms.

It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment.

Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

1.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder Olanzapine and fluoxetine in combination are indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies.

When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

1.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression Oral Olanzapine and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients.

When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of treatment resistant depression.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term studies in adolescents (ages 13 to 17 years).

Use of olanzapine in adolescents is supported by evidence from adequate and well-controlled studies of olanzapine in which 268 adolescents received olanzapine in a range of 2.5 to 20 mg/day [see Clinical Studies (14.1, 14.2)].

Recommended starting dose for adolescents is lower than that for adults [see Dosage and Administration (2.1, 2.2)] .

Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels [see Warnings and Precautions (5.5, 5.15, 5.17) and Adverse Reactions (6.1)] .

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia.

Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Indications and Usage (1.1, 1.2)] .

Safety and effectiveness of olanzapine in children <13 years of age have not been established [see Patient Counseling Information (17)] .

Safety and efficacy of olanzapine and fluoxetine in combination in children and adolescents (10 to 17 years of age) have been established for the acute treatment of depressive episodes associated with bipolar I disorder.

Safety and effectiveness of olanzapine and fluoxetine in combination in children < 10 years of age have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy.

Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary Neonates exposed to antipsychotic drugs, including olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations).

Overall available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including olanzapine, during pregnancy (see Clinical Considerations).

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m 2 body surface area; some fetal toxicities were observed at these doses ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide.

Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy.

These symptoms have varied in severity.

Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data Human Data Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy.

The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects.

A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based on mg/m 2 body surface area, respectively), no evidence of teratogenicity was observed.

In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m 2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m 2 body surface area).

In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m 2 body surface area).

BOXED WARNING

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear .

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1) , Use in Specific Populations (8.5 ), and Patient Counseling Information (17) ] .

When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

( 5.1 , 8.5 , 17 ) When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS When using olanzapine and fluoxetine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack).

( 5.1 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine, also refer to the Boxed Warning and Warnings and Precautions sections of the package insert for Symbyax.

( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring.

( 5.3 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected.

( 5.4) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain.

( 5.5 ) Hyperglycemia a nd Diabetes Mellitus : In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine.

Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment.

( 5.

5) Dyslipidemia: Undesirable alterations in lipids have been observed.

Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment.

( 5.5 ) Weight Gain: Potential consequences of weight gain should be considered.

Patients should receive regular monitoring of weight.

( 5.5 ) Tardive Dyskinesia: Discontinue if clinically appropriate.

( 5.6 ) Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration.

Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses.

( 5.

7) Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine.

Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

( 5.

11) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Use caution when operating machinery.

( 5.1 2) Anticholinergic (antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions.

( 5.14 ) Hyperprolactinemia: May elevate prolactin levels.

( 5.1 5) Use in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or valproate.

( 5.16 ) Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment.

( 5.1 7) 5.1 Elderly Patients with Dementia-Related Psychosis Increased Mortality — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5) , and Patient Counseling Information (17)] .

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis.

In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17 )] .

5.2 Suicide The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy.

Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia).

Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17) ] .

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure.

DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.

DRESS is sometimes fatal.

Discontinue olanzapine if DRESS is suspected [ see Patient Counseling Information (17 )] .

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain.

Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk.

Olanzapine’s specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, nonfasting 140 to 200 mg/dL).

Patients taking olanzapine should be monitored regularly for worsening of glucose control.

Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling Information (17) ] .

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).

The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL.

Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL).

The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL).

Olanzapine-treated patients had a greater mean HbA 1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA 1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599).

Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 48 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Olanzapine 543 2.2% 345 12.8% Placebo 293 3.4% NA a NA a Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Olanzapine 178 17.4% 127 26% Placebo 96 11.5% NA a NA a a Not Applicable.

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487).

In analyses of patients who completed 9 to 12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL).

The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121).

Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 24 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Olanzapine 124 0% 108 0.9% Placebo 53 1.9% NA a NA a Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Olanzapine 14 14.3% 13 23.1% Placebo 13 0% NA a NA a a Not Applicable.

Dyslipidemia Undesirable alterations in lipids have been observed with olanzapine use.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17)].

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use.

Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients.

For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients.

Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL.

In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies.

Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 48 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Triglycerides Increase by ≥50 mg/dL Olanzapine 745 39.6% 487 61.4% Placebo 402 26.1% NA a NA a Normal to High (<150 mg/dL to ≥200 mg/dL) Olanzapine 457 9.2% 293 32.4% Placebo 251 4.4% NA a NA a Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL) Olanzapine 135 39.3% 75 70.7% Placebo 65 20% NA a NA a Fasting Total Cholesterol Increase by ≥40 mg/dL Olanzapine 745 21.6% 489 32.9% Placebo 402 9.5% NA a NA a Normal to High (<200 mg/dL to ≥240 mg/dL) Olanzapine 392 2.8% 283 14.8% Placebo 207 2.4% NA a NA a Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL) Olanzapine 222 23% 125 55.2% Placebo 112 12.5% NA a NA a Fasting LDL Cholesterol Increase by ≥30 mg/dL Olanzapine 536 23.7% 483 39.8% Placebo 304 14.1% NA a NA a Normal to High (<100 mg/dL to ≥160 mg/dL) Olanzapine 154 0% 123 7.3% Placebo 82 1.2% NA a NA a Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL) Olanzapine 302 10.6% 284 31% Placebo 173 8.1% NA a NA a a Not Applicable.

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL.

In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents.

For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL.

Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies Up to 6 weeks exposure At least 24 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Triglycerides Increase by ≥50 mg/dL Olanzapine 138 37% 122 45.9% Placebo 66 15.2% NA a NA a Normal to High (130 mg/dL) Olanzapine 67 26.9% 66 36.4% Placebo 28 10.7% NA a NA a Borderline to High (≥90 mg/dL and ≤130 mg/dL to >130 mg/dL) Olanzapine 37 59.5% 31 64.5% Placebo 17 35.3% NA a NA a Fasting Total Cholesterol Increase by ≥40 mg/dL Olanzapine 138 14.5% 122 14.8% Placebo 66 4.5% NA a NA a Normal to High (<170 mg/dL to ≥200 mg/dL) Olanzapine 87 6.9% 78 7.7% Placebo 43 2.3% NA a NA a Borderline to High (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL) Olanzapine 36 38.9% 33 57.6% Placebo 13 7.7% NA a NA a Fasting LDL Cholesterol Increase by ≥30 mg/dL Olanzapine 137 17.5% 121 22.3% Placebo 63 11.1% NA a NA a Normal to High (<110 mg/dL to ≥130 mg/dL) Olanzapine 98 5.1% 92 10.9% Placebo 44 4.5% NA a NA a Borderline to High (≥110 mg/dL and <130 mg/dL to ≥130 mg/dL) Olanzapine 29 48.3% 21 47.6% Placebo 9 0% NA a NA a a Not Applicable.

Weight Gain Potential consequences of weight gain should be considered prior to starting olanzapine.

Patients receiving olanzapine should receive regular monitoring of weight [see Patient Counseling Information (17) ] .

Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks.

Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories.

Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021).

The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively.

Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials.

The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults Amount Gained kg (lb) 6 Weeks (N=7465) (%) 6 Months (N=4162) (%) 12 Months (N=1345) (%) 24 Months (N=474) (%) 36 Months (N=147) (%) ≤0 26.2 24.3 20.8 23.2 17 0 to ≤5 (0-11 lb) 57 36 26 23.4 25.2 >5 to ≤10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4 >10 to ≤15 (22-33 lb) 1.8 10.9 14.9 11.4 17 >15 to ≤20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6 >20 to ≤25 (44-55 lb) 0 0.9 3.3 5.1 4.1 >25 to ≤30 (55-66 lb) 0 0.2 1.4 2.3 4.8 >30 (>66 lb) 0 0.1 0.8 1.2 2 Dose group differences with respect to weight gain have been observed.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy in Adolescents – The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

Mean increase in weight in adolescents was greater than in adults.

In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials Olanzapine-treated patients Placebo-treated patients Mean change in body weight from baseline (median exposure = 3 weeks) 4.6 kg (10.1 lb) 0.3 kg (0.7 lb) Percentage of patients who gained at least 7% of baseline body weight 40.6% (median exposure to 7% = 4 weeks) 9.8% (median exposure to 7% = 8 weeks) Percentage of patients who gained at least 15% of baseline body weight 7.1% (median exposure to 15% = 19 weeks) 2.7% (median exposure to 15% = 8 weeks) In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179).

The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively.

Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17).

Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials.

The data in each column represent data for those patients who completed treatment periods of the durations specified.

Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents Amount Gained kg (lb) 6 Weeks (N=243) (%) 6 Months (N=191) (%) ≤0 2.9 2.1 0 to ≤5 (0-11 lb) 47.3 24.6 >5 to ≤10 (11-22 lb) 42.4 26.7 >10 to ≤15 (22-33 lb) 5.8 22.0 >15 to ≤20 (33-44 lb) 0.8 12.6 >20 to ≤25 (44-55 lb) 0.8 9.4 >25 to ≤30 (55-66 lb) 0 2.1 >30 to ≤35 (66-77 lb) 0 0 >35 to ≤40 (77-88 lb) 0 0 >40 (>88 lb) 0 0.5 5.6 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered.

However, some patients may require treatment with olanzapine despite the presence of the syndrome.

For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products.

5.7 Orthostatic Hypotension Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonistic properties [see Patient Counseling Information (17) ] .

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD [see Dosage and Administration (2) ] .

A more gradual titration to the target dose should be considered if hypotension occurs.

Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies.

The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7) ] .

5.8 Falls Olanzapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis Class Effect — In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine.

Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia.

Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue olanzapine and have their WBC followed until recovery.

5.10 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease.

Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

5.11 Seizures During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients.

There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia.

Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.12 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients.

This adverse reaction was also dose related.

Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Patient Counseling Information (17) ] .

5.13 Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing olanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see Patient Counseling Information (17) ].

5.14 Anticholinergic (antimuscarinic) Effects Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2 ] .

In premarketing clinical trials, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism.

Such adverse reactions were not often the basis for discontinuations, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions.

In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1 )].

5.15 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer.

As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1) ] .

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo.

In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (2% [49/3240] of females), sexual function-related events 2 (2% [150/8136] of females and males), and breast-related events 3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine­-treated patients compared to 7% of placebo-treated patients.

In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (1% [2/168] of females), sexual function-related events 2 (0.7% [3/454] of females and males), and breast-related events 3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4) ] .

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3 Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

5.16 Use in Combination with Fluoxetine, Lithium, or Valproate When using olanzapine and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for Symbyax.

When using olanzapine in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate [see Drug Interactions (7) ].

5.17 Laboratory Tests Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.5) and Patient Counseling Information (17 )].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) for the oral formulations.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking olanzapine as monotherapy or in combination with fluoxetine.

If you do not think you are getting better or have any concerns about your condition while taking olanzapine, call your doctor.

When using olanzapine and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo.

Olanzapine is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)] .

Neuroleptic Malignant Syndrome (NMS) Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine.

Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)] .

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)] .

Hyperglycemia and Diabetes Mellitus Patients should be advised of the potential risk of hyperglycemia-related adverse reactions.

Patients should be monitored regularly for worsening of glucose control.

Patients who have diabetes should follow their doctor’s instructions about how often to check their blood sugar while taking olanzapine [see Warnings and Precautions (5.5)] .

Dyslipidemia Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine.

Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.5)] .

Weight Gain Patients should be counseled that weight gain has occurred during treatment with olanzapine.

Patients should have their weight monitored regularly [see Warnings and Precautions (5.5)] .

Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions (5.7) and Drug Interactions (7)] .

Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better.

Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting.

Potential for Cognitive and Motor Impairment Because olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Warnings and Precautions (5.12)] .

Body Temperature Regulation Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions (5.13)] .

Concomitant Medication Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax.

Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions (7)] .

Alcohol Patients should be advised to avoid alcohol while taking olanzapine [see Drug Interactions (7)] .

Phenylketonurics Olanzapine orally disintegrating tablets contain phenylalanine (1.12, 2.24, 3.36, or 4.48 mg per 5, 10, 15, or 20 mg tablet, respectively) [see Description (11)].

Use in Specific Populations Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine.

Advise patients that olanzapine may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine during pregnancy [see Use in Specific Populations (8.1)] .

Lactation — Advise breastfeeding women using olanzapine to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs.

[see Use in Specific Populations (8.3)] .

Infertility — Advise females of reproductive potential that olanzapine may impair fertility due to an increase in serum prolactin levels.

The effects on fertility are reversible [see Use in Specific Populations (8.3)].

Pediatric Use — Olanzapine is indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents 13 to 17 years of age.

Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels.

Patients should be counseled about the potential long-term risks associated with olanzapine and advised that these risks may lead them to consider other drugs first [see Indications and Usage (1.1, 1.2)] .

Safety and effectiveness of olanzapine in patients under 13 years of age have not been established.

Safety and efficacy of olanzapine and fluoxetine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar I disorder.

Safety and effectiveness of olanzapine and fluoxetine in combination in patients <10 years of age have not been established [see Warnings and Precautions (5.5) and Use in Specific Populations (8.4)] .

Need for Comprehensive Treatment Program in Pediatric Patients Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder.

Effectiveness and safety of olanzapine have not been established in pediatric patients less than 13 years of age.

Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders.

Appropriate educational placement is essential and psychosocial intervention is often helpful.

The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider’s assessment of the chronicity and severity of the patient’s symptoms [see Indications and Usage (1.3)] .

All trademark names are the property of their respective owners.

Rx Only Manufactured by: Jubilant Generics Limited Roorkee – 247661, India Marketed by: Jubilant Cadista Pharmaceuticals Inc.

Salisbury, MD 21801, USA Revision: 07/2020

DOSAGE AND ADMINISTRATION

2 Schizophrenia in adults (2.1) Oral: Start at 5 to 10 mg once daily; Target: 10 mg/day within several days Schizophrenia in adolescents ( 2.1 ) Oral: Start at 2.5 to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) in adults (2.2) Oral: Start at 10 or 15 mg once daily Bipolar I Disorder (manic or mixed episodes) in adolescents (2.2) Oral: Start at 2.5 to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) with lithium or valproate in adults (2.2) Oral: Start at 10 mg once daily Depressive Episodes associated with Bipolar I Disorder in adults (2.5) Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Depressive Episodes associated with Bipolar I Disorder in children and adolescents (2.5) Oral in combination with fluoxetine: Start at 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily Treatment Resistant Depression in adults ( 2.6) Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Lower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism.

( 2.1 ) Olanzapine may be given without regard to meals.

( 2.1 ) Olanzapine and Fluoxetine in Combination: Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

( 2.5, 2.6 ) Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or treatment resistant depression.

( 2.5, 2.6 ) Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults.

( 2.5, 2.6 ) Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17.

(2.5) 2.1 Schizophrenia Adults Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days.

Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient.

When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials.

However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose.

An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment.

Olanzapine is not indicated for use in doses above 20 mg/day.

Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7) , and Clinical Pharmacology (12.3) ] .

When indicated, dose escalation should be performed with caution in these patients.

Maintenance Treatment — The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine orally disintegrating tablets for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies (14.1) ] .

The healthcare provider who elects to use olanzapine orally disintegrating tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Adolescents Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day.

Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day).

When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [ see Clinical Studies (14.1)] .

Maintenance Treatment — The efficacy of olanzapine orally disintegrating tablets for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.

Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Patients should be periodically reassessed to determine the need for maintenance treatment.

2.2 Bipolar I Disorder (Manic or Mixed Episodes) Adults Dose Selection for Monotherapy — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg.

Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials.

When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials.

The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies (14.2)].

Maintenance Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with olanzapine orally disintegrating tablets at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [ see Clinical Studies (14.2) ] .

The healthcare provider who elects to use olanzapine orally disintegrating tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals.

Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies (14.2)] .

The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Adolescents Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day.

Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day).

When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies (14.2)] .

Maintenance Treatment — The efficacy of olanzapine orally disintegrating tablets for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.

Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Patients should be periodically reassessed to determine the need for maintenance treatment.

2.3 Administration of Olanzapine Orally Disintegrating Tablets Peel back foil on blister.

Do not push tablet through foil.

Immediately upon opening the blister, using dry hands, remove tablet and place entire olanzapine orally disintegrating tablet in the mouth.

Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.

2.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Adults Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg.

Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg.

Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Children and Adolescents (10 to 17 years of age) Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability.

Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.

Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine).

Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day.

The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax.

Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

Table 1: Approximate Dose Correspondence Between Symbyax a and the Combination of Olanzapine and Fluoxetine For Symbyax (mg/day) Use in Combination Olanzapine (mg/day) Fluoxetine (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine.

While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment.

The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

2.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg.

Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg.

Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine).

Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day.

Table 1 above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax.

Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment.

The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Olanzapine orally disintegrating tablets monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).

2.7 Olanzapine and Fluoxetine in Combination: Dosing in Special Populations The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine.

Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism.

When indicated, dose escalation should be performed with caution in these patients.

Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under 10 years of age [see Warnings and Precautions (5.14) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] .

tenofovir 136 MG Oral Tablet

DRUG INTERACTIONS

7 This section describes clinically relevant drug interactions with VIREAD.

Drug interactions trials are described elsewhere in the labeling [See ].

Clinical Pharmacology (12.3) Didanosine: Coadministration increases didanosine concentrations.

Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy).

Consider dose reductions or discontinuations of didanosine if warranted.

( ) 7.1 HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations.

When coadministered with VIREAD, use atazanavir given with ritonavir.

Coadministration of VIREAD with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations.

Monitor for evidence of tenofovir toxicity.

( ) 7.2 7.1 Didanosine Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions.

Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.

When administered with VIREAD, C and AUC of didanosine increased significantly .

The mechanism of this interaction is unknown.

Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy.

Suppression of CD4 cell counts has been observed in patients receiving VIREAD with didanosine 400 mg daily.

max [See ] Clinical Pharmacology (12.3) + In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD.

In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD.

When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).

For additional information on coadministration of VIREAD and didanosine, please refer to the full prescribing information for didanosine.

7.2 HIV-1 Protease Inhibitors VIREAD decreases the AUC and C of atazanavir .

When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg.

VIREAD should not be coadministered with atazanavir without ritonavir.

min [See ] Clinical Pharmacology (12.3) Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations .

Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters.

When tenofovir disoproxil fumarate is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.

Patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for VIREAD-associated adverse reactions.

VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.

[See ] Clinical Pharmacology (12.3) 7.3 Hepatitis C Antiviral Agents Coadministration of tenofovir disoproxil fumarate and HARVONI (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure .

[See ] Clinical Pharmacology (12.3) In patients receiving VIREAD concomitantly with HARVONI without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir disoproxil fumarate.

In patients receiving VIREAD concomitantly with HARVONI and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established.

If coadministration is necessary, monitor for adverse reactions associated with tenofovir disoproxil fumarate.

7.4 Drugs Affecting Renal Function Since tenofovir is primarily eliminated by the kidneys , coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs.

Some examples include, but are not limited to, cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs .

[See ] Clinical Pharmacology (12.3) [See ] Warnings and Precautions (5.3) In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

OVERDOSAGE

10 Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available.

In Study 901, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days.

No severe adverse reactions were reported.

The effects of higher doses are not known.

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

DESCRIPTION

11 VIREAD is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir.

tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

Tenofovir exhibits activity against HIV-1 reverse transcriptase.

In vivo The chemical name of tenofovir disoproxil fumarate is 9-[( )-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1).

It has a molecular formula of C H N O P • C H O and a molecular weight of 635.52.

It has the following structural formula: R 19 30 5 10 4 4 4 Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C.

It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.

VIREAD is available as tablets or as an oral powder.

VIREAD tablets are for oral administration in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil, respectively.

Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

The 300 mg tablets are coated with Opadry II Y-30-10671-A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

The 150, 200, and 250 mg tablets are coated with Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

VIREAD oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil.

The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.

In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.

Chemical Structure Figure

CLINICAL STUDIES

14 14.1 Clinical Efficacy in Adults with HIV-1 Infection Treatment-Naïve Adult Patients Study 903 Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing VIREAD (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects.

Subjects had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black.

The mean baseline CD4 cell count was 279 cells/mm (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000).

Subjects were stratified by baseline HIV-1 RNA and CD4 cell count.

Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4 cell counts <200 cells/mm .

Treatment outcomes through 48 and 144 weeks are presented in Table 17.

+ 3 + + 3 Table 17 Outcomes of Randomized Treatment at Week 48 and 144 (Study 903) At Week 48 At Week 144 Outcomes VIREAD+3TC +EFV (N=299) d4T+3TC +EFV (N=301) VIREAD+3TC +EFV (N=299) d4T+3TC +EFV (N=301) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144.

79% 82% 68% 62% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144.

6% 4% 10% 8% Rebound 5% 3% 8% 7% Never suppressed 0% 1% 0% 0% Added an antiretroviral agent 1% 1% 2% 1% Death <1% 1% <1% 2% Discontinued due to adverse event 6% 6% 8% 13% Discontinued for other reasons Includes lost to follow-up, subject's withdrawal, noncompliance, protocol violation and other reasons.

8% 7% 14% 15% Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4 cell count (< or ≥200 cells/mm ).

Through 144 weeks of therapy, 62% and 58% of subjects in the VIREAD and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL.

The mean increase from baseline in CD4 cell count was 263 cells/mm for the VIREAD arm and 283 cells/mm for the stavudine arm.

+ 3 + 3 3 Through 144 weeks, 11 subjects in the VIREAD group and 9 subjects in the stavudine group experienced a new CDC Class C event.

Study 934 Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects.

From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + VIREAD with efavirenz.

Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black.

The mean baseline CD4 cell count was 245 cells/mm (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log copies/mL (range 3.56–6.54).

Subjects were stratified by baseline CD4 cell count (< or ≥200 cells/mm ); 41% had CD4 cell counts 100,000 copies/mL.

Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.

+ 3 10 + 3 + 3 Table 18 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934) Outcomes At Week 48 At Week 144 FTC +VIREAD +EFV (N=244) AZT/3TC +EFV (N=243) FTC +VIREAD +EFV (N=227) Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue the trial after Week 48 or Week 96 were excluded from analysis.

AZT/3TC +EFV (N=229) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.

84% 73% 71% 58% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144.

2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.

10% 14% 20% 22% Through Week 48, 84% and 73% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144).

The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial.

In addition, 80% and 70% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144).

The mean increase from baseline in CD4 cell count was 190 cells/mm in the EMTRIVA + VIREAD group and 158 cells/mm in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm at Week 144).

+ 3 3 3 Through 48 weeks, 7 subjects in the emtricitabine + VIREAD group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Treatment-Experienced Adult Patients Study 907 Study 907 was a 24-week, double-blind placebo-controlled multicenter trial of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects.

After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label VIREAD for an additional 24 weeks.

Subjects had a mean baseline CD4 cell count of 427 cells/mm (range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years.

Mean age of the subjects was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

+ 3 The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.

Table 19 Outcomes of Randomized Treatment (Study 907) Outcomes 0–24 weeks 0–48 weeks 24–48 weeks VIREAD (N=368) Placebo (N=182) VIREAD (N=368) Placebo Crossover to VIREAD (N=170) HIV-1 RNA <400 copies/mL Subjects with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively.

40% 11% 28% 30% Virologic failure Subjects with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively.

53% 84% 61% 64% Discontinued due to adverse event 3% 3% 5% 5% Discontinued for other reasons Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.

3% 3% 5% 1% At 24 weeks of therapy, there was a higher proportion of subjects in the VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively).

Mean change in absolute CD4 cell counts by Week 24 was +11 cells/mm for the VIREAD group and -5 cells/mm for the placebo group.

Mean change in absolute CD4 cell counts by Week 48 was +4 cells/mm for the VIREAD group.

+ 3 3 + 3 Through Week 24, one subject in the VIREAD group and no subjects in the placebo arm experienced a new CDC Class C event.

14.2 Clinical Efficacy in Adults with Chronic Hepatitis B HBeAg-Negative Chronic Hepatitis B Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve.

The mean age of subjects was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience).

At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log copies/mL; and mean serum ALT was 140 U/L.

10 HBeAg-Positive Chronic Hepatitis B Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function.

The mean age of subjects was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced.

At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log copies /mL; and mean serum ALT was 147 U/L.

10 The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.

The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL (69 IU/mL) and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).

Table 20 Histological, Virological, Biochemical, and Serological Response at Week 48 0102 (HBeAg-) 0103 (HBeAg+) VIREAD (N=250) HEPSERA (N=125) VIREAD (N=176) HEPSERA (N=90) Complete Response 71% 49% 67% 12% Histology Histological Response Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.

72% 69% 74% 68% <400 copies/mL (<69 IU/mL) HBV DNA 93% 63% 76% 13% Normalized ALT ALT The population used for analysis of ALT normalization included only subjects with ALT above ULN at baseline.

76% 77% 68% 54% HBeAg Loss/Seroconversion Serology NA NA = Not Applicable NA 20%/19% 16%/16% HBsAg Loss/Seroconversion 0/0 0/0 3%/1% 0/0 Treatment Beyond 48 Weeks In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to VIREAD and HEPSERA, respectively) were eligible to roll over to open-label VIREAD with no interruption in treatment.

In Study 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the study through Week 384.

Among subjects randomized to VIREAD followed by open-label treatment with VIREAD, 73% had HBV DNA <400 copies/ml (69 IU/ml), and 63% had ALT normalization at Week 384.

Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 80% had HBV DNA <400 copies/mL (69 IU/mL) and 70% had ALT normalization through Week 384.

At Week 384, both HBsAg loss and seroconversion were approximately 1% in both treatment groups.

In Study 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the study through Week 384.

Among subjects randomized to VIREAD, 49% had HBV DNA <400 copies/mL (69 IU/mL), 42% had ALT normalization, and 20% had HBeAg loss (13% seroconversion to anti-HBe antibody) through Week 384.

Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 56% had HBV DNA <400 copies/mL (69 IU/mL), 50% had ALT normalization, and 28% had HBeAg loss (19% seroconversion to anti-HBe antibody) through Week 384.

At Week 384, HBsAg loss and seroconversion were 11% and 8% respectively, in subjects initially randomized to VIREAD and 12% and 10%, respectively, in subjects initially randomized to HEPSERA.

Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with VIREAD monotherapy were available for analysis at baseline, Week 48 and Week 240.

There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label VIREAD without biopsy data that would be expected to affect histological outcomes at Week 240.

Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively.

In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively.

In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively.

Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points.

No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.

Patients with Lamivudine-Resistant Chronic Hepatitis B Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of VIREAD compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥ 1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M).

One hundred forty-one adult subjects were randomized to the VIREAD treatment arm.

The mean age of subjects randomized to VIREAD was 47 years (range 18–73), 74% were male, 59% were Caucasian, and 37% were Asian.

At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT.

Subjects had a mean HBV DNA of 6.4 log copies/mL and mean serum ALT of 71 U/L at baseline.

10 After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to VIREAD had HBV DNA < 400 copies/mL (69 IU/mL), and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization.

Among the HBeAg-positive subjects randomized to VIREAD, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96.

The proportion of subjects with HBV DNA concentrations below 400 copies/mL (69 IU/mL) at Week 96 was similar between the VIREAD monotherapy and the comparator arms.

Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.

Patients with Chronic Hepatitis B and Decompensated Liver Disease VIREAD was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of VIREAD compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).

Forty-five adult subjects (37 males and 8 females) were randomized to the VIREAD treatment arm.

At baseline, 69% subjects were HBeAg-negative, and 31% were HBeAg-positive.

Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log copies/mL and mean serum ALT of 61 U/L at baseline.

Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphorus of < 2 mg/dL .

10 [See ] Adverse Reactions (6.1) At 48 weeks, 31/44 (70%) and 12/26 (46%) Viread-treated subjects achieved an HBV DNA < 400 copies/mL (69 IU/mL), and normalized ALT, respectively.

The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.

HOW SUPPLIED

16 /STORAGE AND HANDLING NDC:54569-5334-0 in a BOTTLE of 30 TABLET, COATEDS Tablets VIREAD tablets, 150 mg, are triangle-shaped, white, film-coated tablets containing 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil, are debossed with “GSI” on one side and with “150” on the other side.

Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.

(NDC 61958-0404-1) VIREAD tablets, 200 mg, are round-shaped, white, film-coated tablets containing 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil, are debossed with “GSI” on one side and with “200” on the other side.

Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.

(NDC 61958-0405-1) VIREAD tablets, 250 mg, are capsule-shaped, white, film-coated tablets containing 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil, are debossed with “GSI” on one side and with “250” on the other side.

Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.

(NDC 61958-0406-1) VIREAD tablets, 300 mg, are almond-shaped, light blue, film-coated tablets containing 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, are debossed with “GILEAD” and “4331” on one side and with “300” on the other side.

Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.

(NDC 61958-0401-1) Oral Powder VIREAD oral powder consists of white, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per gram of powder and is available in multi-use bottles containing 60 grams of oral powder, closed with a child-resistant closure, and co-packaged with a dosing scoop.

(NDC 61958-0403-1) Store VIREAD tablets and oral powder at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).

Keep the bottle tightly closed.

Dispense only in original container.

Do not use if seal over bottle opening is broken or missing.

GERIATRIC USE

8.5 Geriatric Use Clinical trials of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 VIREAD is available as tablets or as an oral powder.

VIREAD tablets 150 mg contain 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil.

The tablets are triangle-shaped, white, film-coated, and debossed with “GSI” on one side and “150” on the other side.

VIREAD tablets 200 mg contain 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil.

The tablets are round-shaped, white, film-coated, and debossed with “GSI” on one side and “200” on the other side.

VIREAD tablets 250 mg contain 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil.

The tablets are capsule-shaped, white, film-coated, and debossed with “GSI” on one side and “250” on the other side.

VIREAD tablets 300 mg contain 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil.

The tablets are almond-shaped, light blue, film-coated, and debossed with “GILEAD” and “4331” on one side and with “300” on the other side.

The oral powder consists of white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per level scoop.

Each level scoop contains 1 gram of oral powder.

Tablets: 150, 200, 250 and 300 mg ( ) 3 Oral Powder: 40 mg per 1 g of oral powder ( ) 3

MECHANISM OF ACTION

12.1 Mechanism of Action Tenofovir disoproxil fumarate is an antiviral drug [See ].

Microbiology (12.4)

INDICATIONS AND USAGE

1 VIREAD is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor.

VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.

( ) 1 VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.

( ) 1 1.1 HIV-1 Infection VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.

The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection: VIREAD should not be used in combination with ATRIPLA , COMPLERA , STRIBILD , or TRUVADA .

® ® ® ® [See ] Warnings and Precautions (5.4) 1.2 Chronic Hepatitis B VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older .

The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine.

Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease [See ].

Clinical Studies (14.2) VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease .

[See , ] Adverse Reactions (6.1) Clinical Studies (14.2) The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy [See , ].

Microbiology (12.4) Clinical Studies (14.2)

PEDIATRIC USE

8.4 Pediatric Use Pediatric Patients 2 Years of Age and Older with HIV-1 infection The safety of VIREAD in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which VIREAD was administered to HIV-1 infected treatment-experienced subjects.

In addition, the pharmacokinetic profile of tenofovir in patients 2 to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials .

[See ] Clinical Pharmacology (12.3) In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with VIREAD (N = 44) or continue their original regimen (N = 48) for 48 weeks.

Five additional subjects over the age of 12 were enrolled and randomized (VIREAD N=4, original regimen N=1) but are not included in the efficacy analysis.

After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label VIREAD.

At Week 48, 89% of subjects in the VIREAD treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL.

During the 48 week randomized phase of the study, 1 subject in the VIREAD group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the VIREAD group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.

In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with VIREAD (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks.

The mean baseline CD4 cell count was 374 cells/mm and the mean baseline plasma HIV-1 RNA was 4.6 log copies/mL.

At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates.

Overall, the trial failed to show a difference in virologic response between the VIREAD and placebo treatment groups.

Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to VIREAD and OBR.

3 10 Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of VIREAD in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to VIREAD.

[See , , and ].

Warnings and Precautions (5.6) Adverse Reactions (6.1) Clinical Pharmacology (12.3) Safety and effectiveness of VIREAD in pediatric patients younger than 2 years of age with HIV-1 infection have not been established.

Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with VIREAD 300 mg (N = 52) or placebo (N = 54) for 72 weeks.

At study entry, the mean HBV DNA was 8.1 log copies/mL and mean ALT was 101 U/L.

Of 52 subjects treated with VIREAD, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced.

Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience.

At Week 72, 88% (46/52) of subjects in the VIREAD group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL).

Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving VIREAD had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group.

One VIREAD-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.

10 Safety and effectiveness of VIREAD in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed.

: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established.

Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Antiretroviral Pregnancy Registry Risk Summary Animal Data Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

NUSRING MOTHERS

8.3 Nursing Mothers Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk.

The impact of this exposure in breastfed infants is unknown.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

mothers should be instructed not to breastfeed if they are receiving VIREAD.

BOXED WARNING

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals .

[See ] Warnings and Precautions (5.1) Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD.

Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD.

If appropriate, resumption of anti-hepatitis B therapy may be warranted .

[See ] Warnings and Precautions (5.2) WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS See full prescribing information for complete boxed warning.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD.

( ) 5.1 Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD.

Hepatic function should be monitored closely in these patients.

If appropriate, resumption of anti-hepatitis B therapy may be warranted.

( ) 5.2

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome.

Assess estimated creatinine clearance before initiating treatment with VIREAD.

In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with VIREAD and periodically during treatment.

Avoid administering VIREAD with concurrent or recent use of nephrotoxic drugs.

( ) 5.3 Coadministration with Other Products: Do not use with other tenofovir-containing products (e.g., ATRIPLA, COMPLERA, STRIBILD and TRUVADA).

Do not administer in combination with HEPSERA.

( ) 5.4 HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD.

VIREAD should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection.

( ) 5.5 Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss.

( ) 5.6 Redistribution/accumulation of body fat: Observed in HIV-infected patients receiving antiretroviral combination therapy.

( ) 5.7 Immune reconstitution syndrome: Observed in HIV-infected patients.

May necessitate further evaluation and treatment.

( ) 5.8 Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients.

Monitor carefully and consider treatment modification.

( ) 5.9 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals.

A majority of these cases have been in women.

Obesity and prolonged nucleoside exposure may be risk factors.

Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.

Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.2 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis.

Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

If appropriate, resumption of anti-hepatitis B therapy may be warranted.

5.3 New Onset or Worsening Renal Impairment Tenofovir is principally eliminated by the kidney.

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD .

[See ] Adverse Reactions (6.2) It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD.

In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA , it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIREAD, and periodically during VIREAD therapy.

® Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min .

No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.

[See ] Dosage and Administration (2.3) VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) .

Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF.

Some patients required hospitalization and renal replacement therapy.

Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

[See ] Drug Interactions (7.4) Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

5.4 Coadministration with Other Products VIREAD should not be used in combination with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, or TRUVADA since tenofovir disoproxil fumarate is a component of these products.

VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil) [See ].

Drug Interactions (7.4) 5.5 Patients Coinfected with HIV-1 and HBV Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.

HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD.

It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.

5.6 Bone Effects Bone Mineral Density: In clinical trials in HIV-1 infected adults, VIREAD was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators.

Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD .

[See ] Adverse Reactions (6.1) Clinical trials evaluating VIREAD in pediatric and adolescent subjects were conducted.

Under normal circumstances, BMD increases rapidly in pediatric patients.

In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover.

Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups.

Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years.

In all pediatric trials, skeletal growth (height) appeared to be unaffected .

[See ] Adverse Reactions (6.1) The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.

Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD .

Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy.

Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF .

[See ] Adverse Reactions (6.2) [See ] Warnings and Precautions (5.3) 5.7 Fat Redistribution In HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving combination antiretroviral therapy.

The mechanism and long-term consequences of these events are currently unknown.

A causal relationship has not been established.

5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD.

During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as infection, cytomegalovirus, pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Mycobacterium avium Pneumocystis jirovecii Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.9 Early Virologic Failure Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor.

In particular, early virological failure and high rates of resistance substitutions have been reported.

Triple nucleoside regimens should therefore be used with caution.

Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

VIREAD is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.

Patients should remain under the care of a physician when using VIREAD.

Patients should avoid doing things that can spread HIV or HBV to others.

Do not share needles or other injection equipment.

Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.

Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Do not have any kind of sex without protection.

Tenofovir is excreted in breast milk and it is not known whether it can harm the baby.

Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Do not breastfeed.

The long-term effects of VIREAD are unknown.

VIREAD tablets and oral powder are for oral ingestion only.

VIREAD should not be discontinued without first informing their physician.

If you have HIV-1 infection, with or without HBV coinfection, it is important to take VIREAD with combination therapy.

It is important to take VIREAD on a regular dosing schedule and to avoid missing doses.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported.

Treatment with VIREAD should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) .

[See ] Warnings and Precautions (5.1) Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued VIREAD .

[See ] Warnings and Precautions (5.2) Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported.

VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) .

Dosing interval of VIREAD may need adjustment in patients with renal impairment .

[See ] Warnings and Precautions (5.3) [See ] Dosage and Administration (2.3) VIREAD should not be coadministered with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, and TRUVADA since it is a component of these products .

[See ] Warnings and Precautions (5.4) VIREAD should not be administered in combination with HEPSERA .

[See ] Warnings and Precautions (5.4) Patients with HIV-1 should be tested for Hepatitis B virus (HBV) before initiating antiretroviral therapy .

[See ] Warnings and Precautions (5.5) In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating VIREAD [See ].

Warnings and Precautions (5.5) Decreases in bone mineral density have been observed with the use of VIREAD.

Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia .

[See ] Warnings and Precautions (5.6) In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.

The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.

DOSAGE AND ADMINISTRATION

2 Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults and pediatric patients 12 years of age and older (35 kg or more): 300 mg once daily taken orally without regard to food.

( ) 2.1 Recommended dose for the treatment of HIV-1 in pediatric patients (2 to less than 12 years of age): Tablets: for pediatric patients weighing greater than or equal to 17 kg who can swallow an intact tablet, one VIREAD tablet (150, 200, 250 or 300 mg based on body weight) once daily taken orally without regard to food.

( ) Oral powder: 8 mg/kg VIREAD oral powder (up to a maximum of 300 mg) once daily with food.

( ) 2.2 2.2 Dose recommended in renal impairment in adults: Creatinine clearance 30–49 mL/min: 300 mg every 48 hours.

( ) Creatinine clearance 10–29 mL/min: 300 mg every 72 to 96 hours.

( ) Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis.

( ) 2.3 2.3 2.3 2.1 Recommended Dose in Adults and Pediatric Patients 12 Years of Age and Older (35 kg or more) For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.

For patients unable to swallow VIREAD tablets, the oral powder formulation (7.5 scoops) may be used.

In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.

Safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been established.

2.2 Recommended Dose in Pediatric Patients 2 Years to Less than 12 Years of Age HIV-1 Infection For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of VIREAD is 8 mg of tenofovir disoproxil fumarate per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.

VIREAD oral powder should be measured only with the supplied dosing scoop.

One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate.

VIREAD oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt).

The entire mixture should be ingested immediately to avoid a bitter taste.

Do not administer VIREAD oral powder in a liquid as the powder may float on top of the liquid even after stirring.

Further patient instructions on how to administer VIREAD oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information).

VIREAD is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets.

The dose is one tablet once daily taken orally, without regard to food.

Tables 1 and 2 contain dosing recommendations for VIREAD oral powder and tablets based on body weight.

Weight should be monitored periodically and the VIREAD dose adjusted accordingly.

Table 1 Dosing Recommendations for Pediatric Patients ≥2 Years of Age Using VIREAD Oral Powder Body Weight Kilogram (kg) Oral Powder Once Daily Scoops of Powder 10 to <12 2 12 to <14 2.5 14 to <17 3 17 to <19 3.5 19 to <22 4 22 to <24 4.5 24 to <27 5 27 to <29 5.5 29 to <32 6 32 to <34 6.5 34 to <35 7 ≥35 7.5 Table 2 Dosing Recommendations for Pediatric Patients ≥2 Years of Age and Weighing ≥17 kg Using VIREAD Tablets Body Weight Kilogram (kg) Tablets Once Daily 17 to <22 150 mg 22 to <28 200 mg 28 to <35 250 mg ≥35 300 mg Chronic Hepatitis B Safety and efficacy of VIREAD in patients younger than 12 years of age have not been established.

2.3 Dose Adjustment for Renal Impairment in Adults Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment .

Therefore, the dosing interval of VIREAD tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 3.

These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis.

The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients .

There are no data to recommend use of VIREAD tablets 150, 200 or 250 mg or VIREAD oral powder in patients with renal impairment.

[See ] Clinical Pharmacology (12.3) [See ] Warnings and Precautions (5.3) No dose adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min).

Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment .

[See ] Warnings and Precautions (5.3) Table 3 Dosage Adjustment for Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) Calculated using ideal (lean) body weight.

≥50 30–49 10–29 Hemodialysis Patients Recommended 300 mg Dosing Interval Every 24 hours Every 48 hours Every 72 to 96 hours Every 7 days or after a total of approximately 12 hours of dialysis Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration.

VIREAD should be administered following completion of dialysis.

The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance below 10 mL/min; therefore, no dosing recommendation is available for these patients.

No data are available to make dose recommendations in pediatric patients with renal impairment.

Gleevec 400 MG Oral Tablet

Generic Name: IMATINIB MESYLATE
Brand Name: Gleevec
  • Substance Name(s):
  • IMATINIB MESYLATE

DRUG INTERACTIONS

7 CYP3A4 inducers may decrease Gleevec C max and area under curve (AUC).

( 2.12 , 7.1 , 12.3 ) CYP3A4 inhibitors may increase Gleevec C max and AUC.

( 7.2 , 12.3 ) Gleevec is an inhibitor of CYP3A4 and CYP2D6 which may increase the C max and AUC of other drugs.

( 7.3 , 7.4 , 12.3 ) Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin.

( 7.3 ) 7.1 Agents Inducing CYP3A Metabolism Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12.3)].

7.2 Agents Inhibiting CYP3A Metabolism Concomitant administration of Gleevec and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase.

Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology (12.3)] .

7.3 Interactions With Drugs Metabolized by CYP3A4 Gleevec will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

Use caution when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window.

Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation [see Clinical Pharmacology (12.3)] .

7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

OVERDOSAGE

10 Experience with doses greater than 800 mg is limited.

Isolated cases of Gleevec overdose have been reported.

In the event of overdosage, observe the patient and give appropriate supportive treatment.

Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain.

6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.

8 to 10 g (single dose): Vomiting and GI pain have been reported.

A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Gleevec daily for 6 days.

Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week.

Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions.

Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days.

Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed.

Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2.

Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.

Pediatric Overdose One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia; and another 3 year old male exposed to a single dose of 980 mg experienced decreased white blood cell (WBC) count and diarrhea.

DESCRIPTION

11 Imatinib is a small molecule kinase inhibitor.

Gleevec film-coated tablets are supplied as 100 mg and 400 mg tablets for oral administration.

Each 100 mg tablet contains 119.5 mg of imatinib mesylate equivalent to 100 mg of imatinib free base.

Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base.

Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is: Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder.

Its molecular formula is C 29 H 31 N 7 O • CH 4 SO 3 and its molecular weight is 589.7 g/mol.

Imatinib mesylate is soluble in aqueous buffers less than or equal to pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers.

In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile.

Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); hydroxypropyl methylcellulose (USP); magnesium stearate (NF); and microcrystalline cellulose (NF).

Tablet coating: ferric oxide, red (NF); ferric oxide, yellow (NF); hydroxypropyl methylcellulose (USP); polyethylene glycol (NF), and talc (USP).

Imatinib structural formula

CLINICAL STUDIES

14 Figure 1 Progression Free Survival (ITT Principle) Figure 2 Time to Progression to AP or BC (ITT Principle) Figure 3: Study 1 Recurrence-Free Survival (ITT Population) Figure 4: Study 2 Recurrence-Free Survival (ITT Population) Figure 5: Study 2 Overall Survival (ITT Population) 14.1 Chronic Myeloid Leukemia Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study (Gleevec versus IFN+Ara-C) has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.

This study compared treatment with either single-agent Gleevec or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C).

Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR.

Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC).

In the Gleevec arm, patients were treated initially with 400 mg daily.

Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily.

In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m 2 /day subcutaneously in combination with subcutaneous Ara-C 20 mg/m 2 /day for 10 days/month.

A total of 1106 patients were randomized from 177 centers in 16 countries, 553 to each arm.

Baseline characteristics were well balanced between the two arms.

Median age was 51 years (range, 18 to 70 years), with 21.9% of patients greater than or equal to 60 years of age.

There were 59% males and 41% females; 89.9% Caucasian and 4.7% black patients.

At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the Gleevec and IFN arm, respectively.

The median duration of second-line treatment with Gleevec was 64 months.

Sixty percent of patients randomized to Gleevec are still receiving first-line treatment.

In these patients, the average dose of Gleevec was 403 mg ± 57 mg.

Overall, in patients receiving first line Gleevec, the average daily dose delivered was 406 mg ± 76 mg.

Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment.

In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Gleevec arm was severe intolerance to treatment (26%) and progression (14%).

The primary efficacy endpoint of the study was progression-free survival (PFS).

Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management.

The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Gleevec were compared with patients randomized to receive IFN.

Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment.

The estimated rate of progression-free survival at 84 months in the ITT population was 81.2% [95% CI: 78, 85] in the Gleevec arm and 60.6% [56, 65] in the IFN arm (p less than 0.0001, log-rank test), (Figure 1).

With 7 years follow up there were 93 (16.8%) progression events in the Gleevec arm: 37 (6.7%) progression to AP/BC, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and 10 (1.8%) CML unrelated deaths.

In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C.

The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92.5% [90, 95] in the Gleevec arm compared to the 85.1%, [82, 89] (p less than or equal to 0.001) in the IFN arm, (Figure 2).

The annual rates of any progression events have decreased with time on therapy.

The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in CCyR but without a major molecular response and 70% in patients who were not in CCyR at this time point (p less than 0.001).

Figure 1: Progression Free Survival (ITT Principle) Figure 2: Time to Progression to AP or BC (ITT Principle) A total of 71 (12.8%) and 85 (15.4%) patients died in the Gleevec and IFN+Ara-C group, respectively.

At 84 months the estimated overall survival is 86.4% (83, 90) vs 83.3% (80, 87) in the randomized Gleevec and the IFN+Ara-C group, respectively (p = 0.073 log-rank test).

The hazard ratio is 0.750 with 95% CI 0.547-1.028.

This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to Gleevec.

Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints.

Response data are shown in Table 18.

Complete hematologic response, major cytogenetic response and CCyR were also statistically significantly higher in the Gleevec arm compared to the IFN + Ara-C arm (no cross-over data considered for evaluation of responses).

Median time to CCyR in the 454 responders was 6 months (range, 2 to 64 months, 25 th to 75 th percentiles = 3 to 11 months) with 10% of responses seen only after 22 months of therapy.

Table 18: Response in Newly Diagnosed CML Study (84-Month Data) *p less than 0.001, Fischer’s exact test.

1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): WBC less than 10 x 10 9 /L, platelet less than 450 x 10 9 /L, myelocyte + metamyelocyte less than 5% in blood, no blasts and promyelocytes in blood, no extramedullary involvement.

2 Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1%-35%).

A major response (0%-35%) combines both complete and partial responses.

3 Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.

Best response rate Gleevec n = 553 IFN+Ara−C n = 553 Hematologic response 1 CHR rate n (%) 534 (96.6%)* 313 (56.6%)* [95% CI] [94.7%, 97.9%] [52.4%, 60.8%] Cytogenetic response 2 Major cytogenetic response n (%) 472 (85.4%)* 93 (16.8%)* [95% CI] [82.1%, 88.2%] [13.8%, 20.2%] Unconfirmed 3 88.6%* 23.3%* Complete cytogenetic response n (%) 413 (74.7%)* 36 (6.5%)* [95% CI] [70.8, 78.3] [4.6, 8.9] Unconfirmed 3 82.5%* 11.6%* Molecular response was defined as follows: in the peripheral blood, after 12 months of therapy, reduction of greater than or equal to 3 logarithms in the amount of BCR-ABL transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline.

Molecular response was only evaluated in a subset of patients who had a CCyR by 12 months or later (N = 333).

The molecular response rate in patients who had a CCyR in the Gleevec arm was 59% at 12 months and 72% at 24 months.

Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy – Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase.

After one month of therapy to 6 months of therapy, there was a 13% to 21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity.

There was no apparent change from baseline in median index for patients treated with Gleevec.

An open-label, multicenter, randomized trial (Gleevec versus nilotinib) was conducted to determine the efficacy of Gleevec versus nilotinib in adult patients with cytogenetically confirmed, newly diagnosed Ph+ CML-CP.

Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide.

Efficacy was based on a total of 846 patients: 283 patients in the Gleevec 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group.

Median age was 46 years in the Gleevec group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients greater than or equal to 65 years of age in Gleevec 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively.

There were slightly more male than female patients in all groups (56%, 56%, and 62% in Gleevec 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice-daily treatment groups, respectively).

More than 60% of all patients were Caucasian, and 25% were Asian.

The primary data analysis was performed when all 846 patients completed 12 months of treatment or discontinued earlier.

Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of treatment or discontinued earlier.

The median time on treatment was approximately 61 months in all three treatment groups.

The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication.

MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline.

Efficacy endpoints are summarized in Table 19.

Twelve patients in the Gleevec arm progressed to either accelerated phase or blast crises (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months) while two patients on the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment).

Table 19: Efficacy (MMR and CCyR) of Gleevec Compared to Nilotinib in Newly Diagnosed Ph+ CML-CP Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response; Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase.

a CMH test stratified by Sokal risk group.

b CCyR: 0% Ph+ metaphases.

Cytogenetic responses were based on the percentage of Ph-positive metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample.

Gleevec 400 mg once daily Nilotinib 300 mg twice daily N = 283 N = 282 MMR at 12 months (95% CI) 22% (17.6, 27.6) 44% (38.4, 50.3) P-Value a < 0.0001 CCyR b by 12 months (95% CI) 65% (59.2, 70.6) 80% (75.0, 84.6) MMR at 24 months (95% CI) 38% (31.8, 43.4) 62% (55.8, 67.4) CCyR b by 24 months (95% CI) 77% (71.7, 81.8) 87% (82.4, 90.6) By 60 months, MMR was achieved by 60% of patients on Gleevec and 77% of patients on nilotinib.

Median overall survival was not reached in either arm.

At the time of the 60-month final analysis, the estimated survival rate was 91.7% for patients on Gleevec and 93.7% for patients on nilotinib.

Late Chronic Phase CML and Advanced Stage CML : Three international, open-label, single-arm Phase 2 studies were conducted to determine the safety and efficacy of Gleevec in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis.

About 45% of patients were women and 6% were black.

In clinical studies, 38% to 40% of patients were greater than or equal to 60 years of age and 10% to 12% of patients were greater than or equal to 70 years of age.

Chronic Phase, Prior Interferon-Alpha Treatment: 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed.

The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%).

Patients had received a median of 14 months of prior IFN therapy at doses greater than or equal to 25 x 10 6 units/week and were all in late chronic phase, with a median time from diagnosis of 32 months.

Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or CCyR (0% Ph+ metaphases).

Median duration of treatment was 29 months with 81% of patients treated for greater than or equal to 24 months (maximum = 31.5 months).

Efficacy results are reported in Table 20.

Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%).

Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients.

Accelerated Phase: 235 patients with accelerated phase disease were enrolled.

These patients met one or more of the following criteria: greater than or equal to 15% – less than 30% blasts in PB or BM; greater than or equal to 30% blasts + promyelocytes in PB or BM; greater than or equal to 20% basophils in PB; and less than 100 x 10 9 /L platelets.

The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg.

Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML.

Cytogenetic responses were also evaluated.

Median duration of treatment was 18 months with 45% of patients treated for greater than or equal to 24 months (maximum = 35 months).

Efficacy results are reported in Table 20.

Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs 64%), confirmed and unconfirmed major cytogenetic response (31% vs 19%).

Myeloid Blast Crisis: 260 patients with myeloid blast crisis were enrolled.

These patients had greater than or equal to 30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”).

The first 37 patients were started at 400 mg; the remaining 223 patients were started at 600 mg.

Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase.

Cytogenetic responses were also assessed.

Median duration of treatment was 4 months with 21% of patients treated for greater than or equal to 12 months and 10% for greater than or equal to 24 months (maximum = 35 months).

Efficacy results are reported in Table 20.

The hematologic response rate was higher in untreated patients than in treated patients (36% vs 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs 16%).

The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600-mg dose group than for the 400-mg dose group (17% vs 8%).

Table 20: Response in Chronic Myeloid Leukemia Studies Abbreviations: BM, bone marrow; PB, peripheral blood.

1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): CHR: Chronic phase study [WBC less than 10 x 10 9 /L, platelet less than 450 x 10 9 /L, myelocytes + metamyelocytes less than 5% in blood, no blasts and promyelocytes in blood, basophils less than 20%, no extramedullary involvement] and in the accelerated and blast crisis studies [absolute neutrophil count (ANC) greater than or equal to 1.5 x 10 9 /L, platelets greater than or equal to 100 x 10 9 /L, no blood blasts, BM blasts less than 5% and no extramedullary disease].

NEL: Same criteria as for CHR but ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L (accelerated and blast crisis studies).

RTC: less than 15% blasts BM and PB, less than 30% blasts + promyelocytes in BM and PB, less than 20% basophils in PB, no extramedullary disease other than spleen and liver (accelerated and blast crisis studies).

2 Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1%-35%).

A major response (0%-35%) combines both complete and partial responses.

3 Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.

4 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least 1 month after the initial bone marrow study.

Chronic phase IFN failure (n = 532) Accelerated phase (n = 235) Myeloid blast crisis (n = 260) 600 mg n = 158 600 mg n = 223 400 mg 400 mg n = 77 400 mg n = 37 % of patients [CI 95% ] Hematologic response 1 95% [92.3−96.3] 71% [64.8−76.8] 31% [25.2−36.8] Complete hematologic response (CHR) 95% 38% 7% No evidence of leukemia (NEL) Not applicable 13% 5% Return to chronic phase (RTC) Not applicable 20% 18% Major cytogenetic response 2 60% [55.3−63.8] 21% [16.2−27.1] 7% [4.5−11.2] (Unconfirmed 3 ) (65%) (27%) (15%) Complete 4 (Unconfirmed 3 ) 39% (47%) 16% (20%) 2% (7%) The median time to hematologic response was 1 month.

In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response.

After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% [88.3, 93.2].

In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg).

An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response.

The median survival was 20.9 [13.1, 34.4] months for the 400 mg group and was not yet reached for the 600 mg group (p = 0.0097).

An estimated 46.2% [34.7, 57.7] vs 65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in the 400 mg vs 600 mg dose groups, respectively.

In blast crisis, the estimated median duration of hematologic response is 10 months.

An estimated 27.2% [16.8, 37.7] of hematologic responders maintained their response 2 years after achieving their initial response.

Median survival was 6.9 [5.8, 8.6] months, and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were alive 2 years after start of study.

Efficacy results were similar in men and women and in patients younger and older than age 65.

Responses were seen in black patients, but there were too few black patients to allow a quantitative comparison.

14.2 Pediatric CML A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single-arm Phase 2 trial.

Patients were treated with Gleevec 340 mg/m 2 /day, with no interruptions in the absence of dose limiting toxicity.

Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy.

The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults.

Additionally, partial cytogenetic response (PCyR) was observed in 16%.

The majority of patients who achieved a CCyR developed the CCyR between Months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months.

Patients were allowed to be removed from protocol therapy to undergo alternative therapy, including hematopoietic stem cell transplantation.

Thirty-one children received stem cell transplantation.

Of the 31 children, 5 were transplanted after disease progression on study and 1 withdrew from study during first week treatment and received transplant approximately 4 months after withdrawal.

Twenty-five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range, 4 to 24).

Of the 25 patients 13 (52%) had CCyR and 5 (20%) had PCyR at the end of protocol therapy.

One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy.

These patients had not previously received Gleevec and ranged in age from 3 to 20 years old; 3 were 3 to 11 years old, 9 were 12 to 18 years old, and 2 were greater than 18 years old.

Patients were treated at doses of 260 mg/m 2 /day (n = 3), 340 mg/m 2 /day (n = 4), 440 mg/m 2 /day (n = 5) and 570 mg/m 2 /day (n = 2).

In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a CCyR, and 2 had a minimal cytogenetic response.

In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a CCyR at doses of 242 and 257 mg/m 2 /day.

14.3 Acute Lymphoblastic Leukemia A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended Gleevec dose of 600 mg/day.

In addition 2 patients with relapsed/refractory Ph+ ALL received Gleevec 600 mg/day in a Phase 1 study.

Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ ALL Phase 2 study patients and for the 2 Phase 1 patients are shown in Table 21.

The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months.

Table 21: Effect of Gleevec on Relapsed/Refractory Ph+ ALL Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response; NEL, no evidence of leukemia; PCyR, partial cytogenic response; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; PHR, partial hematologic response; RTC, return to chronic phase.

Phase 2 study (N = 43) n (%) Phase 1 study (N = 2) n (%) CHR 8 (19) 2 (100) NEL 5 (12) RTC/PHR 11 (26) MCyR 15 (35) CCyR 9 (21) PCyR 6 (14) 14.4 Pediatric ALL Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5-year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol.

The safety and effectiveness of Gleevec (340 mg/m 2 /day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL.

The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor.

There were 92 eligible patients with Ph+ ALL enrolled.

The median age was 9.5 years (1 to 21 years: 2.2% between 1 and less than 2 years, 56.5% between 2 and less than 12 years, 34.8% between 12 and less than 18 years, and 6.5% between 18 and 21 years).

Sixty-four percent were male, 75% were white, 9% were Asian/Pacific Islander, and 5% were black.

In 5 successive cohorts of patients, Gleevec exposure was systematically increased by earlier introduction and prolonged duration.

Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of Gleevec exposure.

There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received Gleevec plus chemotherapy; 30 were treated exclusively with chemotherapy and Gleevec and 20 received chemotherapy plus Gleevec and then underwent hematopoietic stem cell transplant, followed by further Gleevec treatment.

Patients in cohort 5 treated with chemotherapy received continuous daily exposure to Gleevec beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy.

During maintenance cycles 5 through 12, Gleevec was administered 28 days out of the 56 day cycle.

Patients who underwent hematopoietic stem cell transplant received 42 days of Gleevec prior to HSCT, and 28 weeks (196 days) of Gleevec after the immediate post transplant period.

The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81).

The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months.

14.5 Myelodysplastic/Myeloproliferative Diseases An open-label, multicenter, Phase 2 clinical trial was conducted testing Gleevec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 7 patients with MDS/MPD.

These patients were treated with Gleevec 400 mg daily.

The ages of the enrolled patients ranged from 20 to 86 years.

A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study.

These patients also received Gleevec at a dose of 400 mg daily with the exception of three patients who received lower doses.

Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a CCyR).

Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement.

All of these patients responded hematologically (13 completely).

Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely).

Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response.

A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly.

Median duration of therapy was 12.9 months (0.8 to 26.7) in the 7 patients treated within the Phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature.

Results are provided in Table 22.

Response durations of Phase 2 study patients ranged from 141+ days to 457+ days.

Table 22: Response in MDS/MPD Abbreviations: NE, not evaluable; MDS/MPD, myelodysplastic/myeloproliferative disease.

Number of patients Complete hematologic response Major cytogenetic response N N (%) N (%) Overall population 31 14 (45) 12 (39) Chromosome 5 translocation 14 11 (79) 11 (79) Chromosome 4 translocation 2 2 (100) 1 (50) Others/no translocation 14 1 (7) 0 Molecular relapse 1 NE NE 14.6 Aggressive Systemic Mastocytosis One open-label, multicenter, Phase 2 study was conducted testing Gleevec in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 5 patients with ASM treated with 100 mg to 400 mg of Gleevec daily.

These 5 patients ranged from 49 to 74 years of age.

In addition to these 5 patients, 10 published case reports and case series describe the use of Gleevec in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of Gleevec daily.

Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with Gleevec from the published reports and in the Phase 2 study.

Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion).

Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease.

Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to Gleevec), one with concomitant CML.

Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (PHR) (61% overall response rate).

Median duration of Gleevec therapy for the 5 ASM patients in the Phase 2 study was 13 months (range, 1.4 to 22.3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature.

A summary of the response rates to Gleevec in ASM is provided in Table 23.

Response durations of literature patients ranged from 1+ to 30+ months.

Table 23: Response in ASM Abbreviations: ASM, aggressive systemic mastocytosis; PDGFR, platelet-derived growth factor receptor.

*Patient had concomitant chronic myeloid leukemia CML and ASM.

Cytogenetic abnormality Number of patients N Complete hematologic response N (%) Partial hematologic response N (%) FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion) 7 7 (100) 0 Juxtamembrane mutation 2 0 2 (100) Unknown or no cytogenetic abnormality detected 15 0 7 (44) D816V mutation 4 1* (25) 0 Total 28 8 (29) 9 (32) Gleevec has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM).

Gleevec is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma.

Patients that harbor the D816V mutation of c-Kit are not sensitive to Gleevec and should not receive Gleevec.

14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia One open-label, multicenter, Phase 2 study was conducted testing Gleevec in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL).

HES patients were treated with 100 mg to 1,000 mg of Gleevec daily.

The ages of these patients ranged from 16 to 64 years.

A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series.

These patients received Gleevec at doses of 75 mg to 800 mg daily.

Hematologic response rates are summarized in Table 24.

Response durations for literature patients ranged from 6+ weeks to 44 months.

Table 24: Response in HES/CEL Abbreviations: CEL, chronic eosinophilic leukemia; HES, hypereosinophilic syndrome; PDGFR, platelet-derived growth factor receptor.

Cytogenetic abnormality Number of patients Complete hematological response N (%) Partial hematological response N (%) Positive FIP1L1-PDGFRα fusion kinase 61 61 (100) 0 Negative FIP1L1-PDGFRα fusion kinase 56 12 (21) 9 (16) Unknown cytogenetic abnormality 59 34 (58) 7 (12) Total 176 107 (61) 23 (13) 14.8 Dermatofibrosarcoma Protuberans Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma.

It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene.

An open-label, multicenter, Phase 2 study was conducted testing Gleevec in a diverse population of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 12 patients with DFSP who were treated with Gleevec 800 mg daily (age range, 23 to 75 years).

DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry.

A further 6 DFSP patients treated with Gleevec are reported in 5 published case reports, their ages ranging from 18 months to 49 years.

The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease.

The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) Gleevec daily.

A single pediatric patient received 400 mg/m 2 /daily, subsequently increased to 520 mg/m 2 /daily.

Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities.

Responses to treatment are described in Table 25.

Table 25: Response in DFSP Number of patients (n = 18) % Complete response 7 39 Partial response* 8 44 Total responders 15 83 *5 patients made disease free by surgery.

Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%.

A further 3 patients achieved a partial response, for an overall response rate of 83%.

Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%).

For the 10 study patients with the PDGF B gene rearrangement, there were 4 complete and 6 partial responses.

The median duration of response in the Phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months.

14.9 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant GIST.

The two study designs were similar allowing a predefined combined analysis of safety and efficacy.

A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity.

Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily.

The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups.

Median age at patient entry was 60 years.

Males comprised 58% of the patients enrolled.

All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST.

The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study.

A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted.

Results from this combined analysis are shown in Table 26.

Table 26: Overall Survival, Progression-Free Survival and Tumor Response Rates in the Phase 3 GIST Trials Abbreviation: GIST, gastrointestinal stromal tumors.

Gleevec 400 mg N = 818 Gleevec 800 mg N = 822 Progression-free survival (months) Median 18.9 23.2 95% CI 17.4–21.2 20.8–24.9 Overall survival (months) 49.0 48.7 95% CI 45.3–60.0 45.3–51.6 Best overall tumor response Complete response Partial response 43 (5.3%) 377 (46.1%) 41 (5.0%) 402 (48.9%) Median follow up for the combined studies was 37.5 months.

There were no observed differences in overall survival between the treatment groups (p = 0.98).

Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n = 347) had a 3.4 month median and a 7.7 month mean exposure to Gleevec following crossover.

One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST.

In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally every day for up to 36 months.

The primary outcome of the study was objective response rate.

Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria.

There were no differences in response rates between the 2 dose groups.

The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group.

The median time to response was 12 weeks (range was 3 to 98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached).

Adjuvant Treatment of GIST In the adjuvant setting, Gleevec was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1).

Patients were randomized one to one to Gleevec at 400 mg/day or matching placebo for 12 months.

The ages of these patients ranged from 18 to 91 years.

Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size greater than or equal to 3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration.

Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause.

In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month Gleevec arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p less than 0.0001.

After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month Gleevec arm.

Seventy-two of these 79 patients subsequently crossed over to Gleevec therapy.

In an updated analysis, the median follow-up for patients without a RFS event was 50 months.

There were 74 (21%) RFS events in the 12-month Gleevec arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3).

The median follow-up for OS in patients still living was 61 months.

There were 26 (7%) and 33 (9%) deaths in the 12-month Gleevec and placebo arms, respectively with a hazard ratio of 0.816 (95% CI: 0.488-1.365).

Figure 3: Study 1 Recurrence-Free Survival (ITT Population) A second randomized, multicenter, open-label, Phase 3 trial in the adjuvant setting (Study 2) compared 12 months of Gleevec treatment to 36 months of Gleevec treatment at 400 mg/day in adult patients with KIT (CD117) positive GIST after surgical resection with one of the following: tumor diameter greater than 5 cm and mitotic count greater than 5/50 high power fields (HPF), or tumor diameter greater than 10 cm and any mitotic count, or tumor of any size with mitotic count greater than 10/50 HPF, or tumors ruptured into the peritoneal cavity.

There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm.

The median age was 61 years (range, 22 to 84 years).

RFS was defined as the time from date of randomization to the date of recurrence or death from any cause.

The median follow-up for patients without a RFS event was 42 months.

There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm.

Thirty-six months of Gleevec treatment significantly prolonged RFS compared to 12 months of Gleevec treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p less than 0.0001 (Figure 4).

The median follow-up for overall survival (OS) in patients still living was 48 months.

There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm.

Thirty-six months of Gleevec treatment significantly prolonged OS compared to 12 months of Gleevec treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p = 0.0187 (Figure 5).

Figure 4: Study 2 Recurrence-Free Survival (ITT Population) Figure 5: Study 2 Overall Survival (ITT Population)

HOW SUPPLIED

16 /STORAGE AND HANDLING Gleevec film-coated tablets are supplied as 100 mg and 400 mg tablets for oral administration.

Each 100 mg tablet contains 119.5 mg of imatinib mesylate equivalent to 100 mg of imatinib free base.

Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base.

100-mg tablets Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side.

Bottles of 90 tablets…………………………………NDC 0078-0401-34 400-mg tablets Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “gleevec” on one side and score on the other side.

Unit Dose (blister pack of 30) ………………………NDC 0078-0649-30 Unit Dose (carton box including 3 blister packs of 10)…………NDC 0078-0649-13 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Protect from moisture.

Dispense in a tight container, USP.

Do not crush Gleevec tablets.

Avoid direct contact of crushed tablets with the skin or mucous membranes.

If such contact occurs, wash thoroughly as outlined in the references.

Avoid exposure to crushed tablets.

GERIATRIC USE

8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years.

In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years.

The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5.1)] .

The efficacy of Gleevec was similar in older and younger patients.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years.

No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant GIST study, 221 patients (31%) were older than 65 years.

No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema.

The efficacy of Gleevec was similar in patients older than 65 years and younger patients.

DOSAGE FORMS AND STRENGTHS

3 100 mg film coated tablets Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side 400 mg film coated tablets Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “gleevec” on one side and score on the other side.

Tablets (scored): 100 mg and 400 mg

MECHANISM OF ACTION

12.1 Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML.

Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.

Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients.

In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis.

Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events.

In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.

INDICATIONS AND USAGE

1 Gleevec is a kinase inhibitor indicated for the treatment of: Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

( 1.1 ) Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy.

( 1.2 ) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

( 1.3 ) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

( 1.4 ) Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

( 1.5 ) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.

( 1.6 ) Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

( 1.7 ) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

( 1.8 ) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).

( 1.9 ) Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST.

( 1.10 ) 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of Gleevec have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14.2, 14.4)].

There are no data in children under 1 year of age.

PREGNANCY

8.1 Pregnancy Risk Summary Gleevec can cause fetal harm when administered to a pregnant woman based on human and animal data.

There are no clinical studies regarding use of Gleevec in pregnant women.

There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to Gleevec during pregnancy.

Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA.

Advise women to avoid pregnancy when taking Gleevec.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S.

general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%.

Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.

In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones.

Lower mean fetal body weights were associated with retarded skeletal ossifications.

In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed.

The examinations of the fetuses did not reveal any drug related morphological changes.

In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day.

Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss.

Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4.

In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased.

There were no other significant effects in developmental parameters or behavioral testing.

F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses.

The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Edema and severe fluid retention have occurred.

Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics.

( 5.1 , 6.1 ) Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred.

Manage with dose reduction, dose interruption, or discontinuation of treatment.

Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter.

( 5.2 ) Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors.

Monitor and treat patients with cardiac disease or risk factors for cardiac failure.

( 5.3) Severe hepatotoxicity, including fatalities may occur.

Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated.

Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction.

( 5.4 ) Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST.

GI tumor sites may be the source of GI bleeds in GIST.

( 5.5 ) Gastrointestinal (GI) perforations, some fatal, have been reported.

( 5.6 ) Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Gleevec in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD, and ASM).

( 5.7 ) Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Gleevec.

( 5.8 ) Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement.

Closely monitor TSH levels in such patients.

( 5.9 ) Fetal harm can occur when administered to a pregnant woman.

Apprise women of the potential harm to the fetus, and to use effective contraception.

( 5.10 , 8.1 ) Growth retardation occurring in children and pre-adolescents receiving Gleevec has been reported.

Close monitoring of growth in children under Gleevec treatment is recommended.

( 5.11 , 6.2 ) Tumor Lysis Syndrome.

Close monitoring is recommended.

( 5.12 ) Reports of motor vehicle accidents have been received in patients receiving Gleevec.

Caution patients about driving a car or operating machinery.

( 5.13 ) Renal Toxicity.

A decline in renal function may occur in patients receiving Gleevec.

Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction.

( 5.14 ) 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1)] .

Weigh and monitor patients regularly for signs and symptoms of fluid retention.

Investigate unexpected rapid weight gain carefully and provide appropriate treatment.

The probability of edema was increased with higher Gleevec dose and age greater than 65 years in the CML studies.

Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2% to 6% of other adult CML patients taking Gleevec.

In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2% to 6% of other adult CML patients taking Gleevec.

Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.1)] .

In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Gleevec and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving Gleevec and in 3.9% of patients receiving nilotinib 300 mg twice daily.

Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the Gleevec arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm.

5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia.

Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 3 months).

In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML.

In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia.

These generally occur within the first several months of therapy [see Dosage and Administration (2.14)] .

5.3 Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have been reported in patients taking Gleevec.

Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease.

In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C.

In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared Gleevec and nilotinib, cardiac failure was observed in 1.1% of patients in the Gleevec arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group.

Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure.

Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.1)] .

Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec.

Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated.

Manage laboratory abnormalities with Gleevec interruption and/or dose reduction [see Dosage and Administration (2.13)] .

When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed.

Additionally, there have been reports of acute liver failure.

Monitoring of hepatic function is recommended.

5.5 Hemorrhage In a trial of Gleevec versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage.

In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site.

In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient).

Gastrointestinal tumor sites may have been the source of GI hemorrhages.

In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Gleevec and nilotinib, GI hemorrhage occurred in 1.4% of patients in the Gleevec arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm.

None of these events were Grade 3 or 4 in the Gleevec arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm.

In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation.

Gleevec should be taken with food and a large glass of water to minimize this problem.

There have been rare reports, including fatalities, of GI perforation.

5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Gleevec therapy.

The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec.

Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels.

Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels.

If either is abnormal, consider prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec at the initiation of therapy.

5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec.

In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge.

Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction.

In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec.

Monitor TSH levels in such patients.

5.10 Embryo-Fetal Toxicity Gleevec can cause fetal harm when administered to a pregnant woman.

Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area (BSA).

Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on BSA.

Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Gleevec and for 14 days after stopping Gleevec.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .

5.11 Growth Retardation in Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving Gleevec.

The long-term effects of prolonged treatment with Gleevec on growth in children are unknown.

Therefore, monitor growth in children under Gleevec treatment [see Adverse Reactions (6.1)].

5.12 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving Gleevec.

The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment.

Monitor these patients closely and take appropriate precautions.

Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of Gleevec.

5.13 Impairments Related to Driving and Using Machinery Motor vehicle accidents have been reported in patients receiving Gleevec.

Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with Gleevec.

Recommend caution when driving a car or operating machinery.

5.14 Renal Toxicity A decline in renal function may occur in patients receiving Gleevec.

Median estimated glomerular filtration rate (eGFR) values in patients on Gleevec 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 mL/min/1.73 m 2 (N = 1190) to 75 mL/min/1.73 m 2 at 12 months (N = 1082) and 69 mL/min/1.73 m 2 at 60 months (N = 549).

Evaluate renal function prior to initiating Gleevec and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Dosing and Administration Advise patients to take Gleevec exactly as prescribed, not to change their dose or to stop taking Gleevec unless they are told to do so by their doctor.

If the patient missed a dose of Gleevec, the patient should take the next scheduled dose at its regular time.

The patient should not take two doses at the same time.

Advise patients to take Gleevec with a meal and a large glass of water [see Dosage and Administration (2.1)] .

Fluid Retention and Edema Inform patients of the possibility of developing edema and fluid retention.

Advise patients to contact their health care provider if unexpected rapid weight gain occurs [see Warnings and Precautions (5.1)] .

Hepatotoxicity Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity.

Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding, or bruising [see Warnings and Precautions (5.4)] .

Pregnancy and Breastfeeding Advise patients to inform their doctor if they are or think they may be pregnant.

Advise women of reproductive potential to avoid becoming pregnant while taking Gleevec.

Female patients of reproductive potential taking Gleevec should use highly effective contraception during treatment and for fourteen days after stopping treatment with Gleevec [see Use in Specific Populations (8.3)] .

Avoid breastfeeding during treatment and for 1 month after the last dose [see Use in Specific Populations (8.2)] .

Drug Interactions Gleevec and certain other medicines, such as warfarin, erythromycin, and phenytoin, including over-the-counter medications, such as herbal products, can interact with each other.

Advise patients to tell their doctor if they are taking or plan to take iron supplements.

Avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking Gleevec [see Drug Interactions (7)] .

Pediatric Advise patients that growth retardation has been reported in children and pre-adolescents receiving Gleevec.

The long term effects of prolonged treatment with Gleevec on growth in children are unknown.

Therefore, closely monitor growth in children under Gleevec treatment [see Warnings and Precautions (5.11)] .

Driving and Using Machines Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with Gleevec.

Therefore, caution patients about driving a car or operating machinery [see Warnings and Precautions (5.13)] .

Distributed by Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2024-18

DOSAGE AND ADMINISTRATION

2 Adults with Ph+ CML CP ( 2.2 ): 400 mg/day Adults with Ph+ CML AP or BC ( 2.2 ): 600 mg/day Pediatrics with Ph+ CML CP ( 2.3 ): 340 mg/m 2 /day Adults with Ph+ ALL ( 2.4 ): 600 mg/day Pediatrics with Ph+ ALL ( 2.5 ): 340 mg/m 2 /day Adults with MDS/MPD ( 2.6 ): 400 mg/day Adults with ASM ( 2.7 ): 100 mg/day or 400 mg/day Adults with HES/CEL ( 2.8 ): 100 mg/day or 400 mg/day Adults with DFSP ( 2.9 ): 800 mg/day Adults with metastatic and/or unresectable GIST ( 2.10 ): 400 mg/day Adjuvant treatment of adults with GIST ( 2.11 ): 400 mg/day Patients with mild to moderate hepatic impairment ( 2.12 ): 400 mg/day Patients with severe hepatic impairment ( 2.12 ): 300 mg/day All doses of Gleevec should be taken with a meal and a large glass of water.

Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

Gleevec can be dissolved in water or apple juice for patients having difficulty swallowing.

Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

2.1 Drug Administration The prescribed dose should be administered orally, with a meal and a large glass of water.

Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice.

The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100-mg tablet, and 200 mL for a 400-mg tablet) and stirred with a spoon.

The suspension should be administered immediately after complete disintegration of the tablet(s).

For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dose of Gleevec is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

2.3 Pediatric Patients With Ph+ CML CP The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (not to exceed 600 mg).

Gleevec treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the morning and one portion in the evening.

There is no experience with Gleevec treatment in children under 1 year of age.

2.4 Adult Patients With Ph+ ALL The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.

2.5 Pediatric Patients With Ph+ ALL The recommended dose of Gleevec to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg).

Gleevec treatment can be given as a once daily dose.

2.6 Adult Patients With MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment.

The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.

2.7 Adult Patients With ASM Determine D816V c-Kit mutation status prior to initiating treatment.

The recommended dose of Gleevec is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation.

If c-Kit mutational status is not known or unavailable, treatment with Gleevec 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies.

For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended.

Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

2.8 Adult Patients With HES/CEL The recommended dose of Gleevec is 400 mg/day for adult patients with HES/CEL.

For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended.

Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

2.9 Adult Patients With DFSP The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP.

2.10 Adult Patients With Metastatic and/or Unresectable GIST The recommended dose of Gleevec is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST.

A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

2.11 Adult Patients With Adjuvant GIST The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST.

In clinical trials, one year of Gleevec and three years of Gleevec were studied.

In the patient population defined in Study 2, three years of Gleevec is recommended [see Clinical Studies (14.8)] .

The optimal treatment duration with Gleevec is not known.

2.12 Dose Modification Guidelines Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital).

If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Gleevec should be increased by at least 50%, and clinical response should be carefully monitored [see Drug Interactions (7.1)].

Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose.

A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment [see Use in Specific Populations (8.6)] .

Renal Impairment: Patients with moderate renal impairment (creatinine clearance [CrCL] = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated.

Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min).

For patients with moderate renal impairment doses greater than 400 mg are not recommended.

Imatinib should be used with caution in patients with severe renal impairment.

A dose of 100 mg/day was tolerated in two patients with severe renal impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.7)].

2.13 Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, Gleevec should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN.

In adults, treatment with Gleevec may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg).

In children, daily doses can be reduced under the same circumstances from 340 mg/m 2 /day to 260 mg/m 2 /day.

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Gleevec should be withheld until the event has resolved.

Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

2.14 Dose Adjustment for Hematologic Adverse Reactions Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.

Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD, myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia.

ASM associated with eosinophilia (starting dose 100 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Gleevec until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Gleevec until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction) Chronic Phase CML (starting dose 400 mg) MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Gleevec until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Gleevec at the original starting dose of 400 mg If recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume Gleevec at a reduced dose of 300 mg Ph+ CML: Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg) ANC less than 0.5 x 10 9 /L and/or platelets less than 10 x 10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy) If cytopenia is unrelated to leukemia, reduce dose of Gleevec to 400 mg If cytopenia persists 2 weeks, reduce further to 300 mg If cytopenia persists 4 weeks and is still unrelated to leukemia, stop Gleevec until ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L and then resume treatment at 300 mg DFSP (starting dose 800 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Gleevec until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Gleevec at 600 mg In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume Gleevec at reduced dose of 400 mg Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m 2 ) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop Gleevec until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction) In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume Gleevec at reduced dose of 260 mg/m 2

pregabalin 300 MG Oral Capsule [Lyrica]

DRUG INTERACTIONS

7 Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement.

In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions.

Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate.

Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs [see Clinical Pharmacology (12) ] .

Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol.

Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs.

No clinically important effects on respiration were seen.

OVERDOSAGE

10 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA.

The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences.

In the postmarketing experience, the most commonly reported adverse events observed when LYRICA was taken in overdose included affective disorder, somnolence, confusional state, depression, agitation, and restlessness.

Seizures were also reported.

Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA.

If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway.

General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.

Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA.

Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

DESCRIPTION

11 Pregabalin is described chemically as ( S )-3-(aminomethyl)-5-methylhexanoic acid.

The molecular formula is C 8 H 17 NO 2 and the molecular weight is 159.23.

The chemical structure of pregabalin is: Pregabalin is a white to off-white, crystalline solid with a pK a1 of 4.2 and a pK a2 of 10.6.

It is freely soluble in water and both basic and acidic aqueous solutions.

The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.

LYRICA (pregabalin) Capsules are administered orally and are supplied as imprinted hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as inactive ingredients.

The capsule shells contain gelatin and titanium dioxide.

In addition, the orange capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide.

Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells.

The imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide.

LYRICA (pregabalin) oral solution, 20 mg/mL, is administered orally and is supplied as a clear, colorless solution contained in a 16 fluid ounce white HDPE bottle with a polyethylene-lined closure.

The oral solution contains 20 mg/mL of pregabalin, along with methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water as inactive ingredients.

Chemical Structure

CLINICAL STUDIES

14 14.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose.

Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years.

A total of 89% of patients completed Studies DPN 1 and DPN 2.

The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

The baseline mean pain scores across the two studies ranged from 6.1 to 6.7.

Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.

Patients recorded their pain daily in a diary.

Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo.

Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions [see Adverse Reactions (6.1) ] .

For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 1: Patients Achieving Various Levels of Improvement in Pain Intensity – Study DPN 1 Figure 1 Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo.

Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 2: Patients Achieving Various Levels of Improvement in Pain Intensity– Study DPN 2 Figure 2 14.2 Postherpetic Neuralgia The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies.

These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

Seventy-three percent of patients completed the studies.

The baseline mean pain scores across the 3 studies ranged from 6 to 7.

Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.

Patients recorded their pain daily in a diary.

Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo.

Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily.

Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily.

In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 3: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 1 Figure 3 Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance.

Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily.

Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 4: Patients Achieving Various Levels of Improvement in Pain Intensity – Study PHN 2 Figure 4 Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance.

Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 5: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 3 Figure 5 14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients.

Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs).

Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline.

During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks.

The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively.

Approximately half of the patients were taking 2 concurrent AEDs at baseline.

Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.

Table 8 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.

Table 8.

Seizure Response in Controlled, Add-On Epilepsy Studies Daily Dose of Pregabalin Dosing Regimen N Baseline Seizure Frequency/mo Median % Change from Baseline p-value, vs.

placebo Study E1 Placebo BID 100 9.5 0 50 mg/day BID 88 10.3 -9 0.4230 150 mg/day BID 86 8.8 -35 0.0001 300 mg/day BID 90 9.8 -37 0.0001 600 mg/day BID 89 9.0 -51 0.0001 Study E2 Placebo TID 96 9.3 1 150 mg/day TID 99 11.5 -17 0.0007 600 mg/day TID 92 12.3 -43 0.0001 Study E3 Placebo BID/TID 98 11 -1 600 mg/day BID 103 9.5 -36 0.0001 600 mg/day TID 111 10 -48 0.0001 In the first study (E1), there was evidence of a dose-response relationship for total daily doses of Lyrica between 150 and 600 mg/day; a dose of 50 mg/day was not effective.

In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing).

In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing).

In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing).

While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant.

A secondary outcome measure included the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency).

The following figure displays responder rate by dose for two of the studies.

Figure 6: Responder rate by add-on epilepsy study Figure 7: Seizure Reduction by Dose (All Partial Onset Seizures) for Studies E1, E2, and E3 Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically important differences as a function of age, gender, or race.

Figure 6 Figure 7 14.4 Management of Fibromyalgia The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2).

Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites).

The studies showed a reduction in pain by visual analog scale.

In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).

Study F1 : This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo.

Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS).

The baseline mean pain score in this trial was 6.7.

Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study.

A total of 64% of patients randomized to LYRICA completed the study.

There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions [ see Adverse Reactions (6.1) ].

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

The results are summarized in Figure 8 and Table 9.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that level of improvement.

The figure is cumulative.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 8: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1 Table 9.

Patient Global Response in Fibromyalgia Study F1 Patient Global Impression of Change Treatment Group (mg/day) % Any Improvement 95% CI PGB = Pregabalin Placebo 47.6 (40.0,55.2) PGB 300 68.1 (60.9, 75.3) PGB 450 77.8 (71.5, 84.0) PGB 600 66.1 (59.1, 73.1) Figure 8 Study F2 : This randomized withdrawal study compared LYRICA with placebo.

Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg.

Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as “much improved” or “very much improved.” Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo.

Patients were treated for up to 6 months following randomization.

Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment.

Fifty-four percent of patients were able to titrate to an effective and tolerable dose of LYRICA during the 6-week open-label phase.

Of the patients entering the randomized treatment phase assigned to remain on LYRICA, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.

When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo.

Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study.

Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ Time to worsening of the FIQ was defined as the time to a 1-point increase from double-blind baseline in each of the subscales, and a 5-point increase from double-blind baseline evaluation for the FIQ total score.

, and longer time to loss of overall assessment of patient status, as measured by the PGIC Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than “much improvement.” .

Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis) Figure 9 14.5 Management of Neuropathic Pain Associated with Spinal Cord Injury The efficacy of LYRICA for the management of neuropathic pain associated with spinal cord injury was established in two double-blind, placebo-controlled, multicenter studies.

Patients were enrolled with neuropathic pain associated with spinal cord injury that persisted continuously for at least three months or with relapses and remissions for at least six months.

A total of 63% of patients completed study 1 and 84% completed study 2.

The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

The baseline mean pain scores across the two studies ranged from 6.5 to 6.7.

Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and antidepressant drugs if the dose was stable for 30 days prior to screening.

Patients were allowed to take acetaminophen and nonsteroidal anti-inflammatory drugs during the studies.

Study SCI 1 : This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose (150–600 mg/day) study compared pregabalin with placebo.

The 12-week study consisted of a 3-week dose adjustment phase and a 9-week dose maintenance phase.

Treatment with LYRICA 150–600 mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline.

The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is presented in Figure 10.

Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure 10 : Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1 Figure 10 Study SCI 2 : This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible dose (150–600 mg/day, in increments of 150 mg) study compared the efficacy, safety and tolerability of pregabalin with placebo.

The 16-week study consisted of a 4-week dose adjustment phase and a 12-week dose maintenance phase.

Treatment with LYRICA statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline.

The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 16 is presented in Figure 11.

Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure 11 : Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2 Figure 11

HOW SUPPLIED

16 /STORAGE AND HANDLING Product: 63629-4995 NDC: 63629-4995-1 30 CAPSULE in a BOTTLE NDC: 63629-4995-2 60 CAPSULE in a BOTTLE NDC: 63629-4995-3 90 CAPSULE in a BOTTLE

GERIATRIC USE

8.5 Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.

In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.

In controlled clinical studies of LYRICA in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older.

No overall differences in safety and efficacy were observed between these patients and younger patients.

In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older.

Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.

LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function.

Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.6) ] .

DOSAGE FORMS AND STRENGTHS

3 Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg Oral Solution: 20 mg/mL [see Description (11) and How Supplied/Storage and Handling (16) ].

Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg.

( 3 ) Oral Solution: 20 mg/ mL.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action LYRICA (pregabalin) binds with high affinity to the alpha 2 -delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues.

Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha 2 -delta subunit may be involved in pregabalin’s anti-nociceptive and antiseizure effects in animals.

In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha 2 -delta containing-calcium channel trafficking and/or reducing calcium currents.

Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.

While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA A , GABA B , or benzodiazepine receptors, does not augment GABA A responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation.

However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.

Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity.

It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.

INDICATIONS AND USAGE

1 LYRICA is indicated for: Management of neuropathic pain associated with diabetic peripheral neuropathy Management of postherpetic neuralgia Adjunctive therapy for adult patients with partial onset seizures Management of fibromyalgia Management of neuropathic pain associated with spinal cord injury LYRICA is indicated for: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) ( 1 ) Postherpetic neuralgia (PHN) ( 1 ) Adjunctive therapy for adult patients with partial onset seizures ( 1 ) Fibromyalgia ( 1 ) Neuropathic pain associated with spinal cord injury ( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established.

Fibromyalgia A 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at LYRICA total daily doses of 75–450 mg per day.

The primary efficacy endpoint of change from baseline to Week 15 in mean pain intensity (derived from an 11-point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance.

The most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue.

The overall safety profile in adolescents was similar to that observed in adults with fibromyalgia.

Juvenile Animal Data In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg.

The neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects.

The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day.

A no-effect dose was not established.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYRICA during pregnancy.

To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.

This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.

Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Risk Summary There are no adequate and well-controlled studies with LYRICA in pregnant women.

However, in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal to 16 times human exposure at the maximum recommended dose (MRD) of 600 mg/day [see Data ] .

In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation.

The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD.

The background risk of major birth defects and miscarriage for the indicated populations are unknown.

However, the background risk in the U.S.

general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.

Advise pregnant women of the potential risk to a fetus.

Data Animal Data When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses.

Fetal body weights were decreased at the highest dose.

The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day.

A no-effect dose for rat embryo-fetal developmental toxicity was not established.

When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose.

The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD.

In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg.

The effect on offspring survival was pronounced at doses greater than or equal to 1250 mg/kg, with 100% mortality in high-dose litters.

When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg.

The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.

In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC (0–24) of 123 µg∙hr/mL) at theMRD.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Angioedema (e.g., swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment.

Discontinue LYRICA immediately in these cases.

( 5.1 ) Hypersensitivity reactions (e.g.

hives, dyspnea, and wheezing) can occur.

Discontinue LYRICA immediately in these patients.

( 5.2 ) Increased seizure frequency may occur in patients with seizure disorders if LYRICA is rapidly discontinued.

Withdraw LYRICA gradually over a minimum of 1 week.

( 5.3 ) Antiepileptic drugs, including LYRICA, increase the risk of suicidal thoughts or behavior.

( 5.4 ) LYRICA may cause peripheral edema.

Exercise caution when co-administering LYRICA and thiazolidinedione antidiabetic agents.

( 5.5 ) LYRICA may cause dizziness and somnolence and impair patients’ ability to drive or operate machinery.( 5.6 ) 5.1 Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA.

Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx).

There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment.

Discontinue LYRICA immediately in patients with these symptoms.

Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema.

In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema.

5.2 Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA.

Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing.

Discontinue LYRICA immediately in patients with these symptoms.

5.3 Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders.

If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week.

5.4 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2.

Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Report behaviors of concern immediately to healthcare providers.

5.5 Peripheral Edema LYRICA treatment may cause peripheral edema.

In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure.

Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group.

In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema.

Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone.

The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy.

In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents.

Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs.

As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents.

Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients.

5.6 Dizziness and Somnolence LYRICA may cause dizziness and somnolence.

Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient Counseling Information (17.5) ] .

In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients.

Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses.

Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies.

In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients [see Drug Interactions (7) ] .

5.7 Weight Gain LYRICA treatment may cause weight gain.

In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients.

Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain.

LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age.

Weight gain was not limited to patients with edema [see Warnings and Precautions (5.5) ] .

Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown.

Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients.

In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg.

While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA 1C ).

5.8 Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea.

Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly.

5.9 Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology (13.1) ] .

The clinical significance of this finding is unknown.

Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients greater than 12 years of age, new or worsening-preexisting tumors were reported in 57 patients.

Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.

5.10 Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing.

Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision).

Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients.

In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients.

Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients.

Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients.

Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur.

If visual disturbance persists, consider further assessment.

Consider more frequent assessment for patients who are already routinely monitored for ocular conditions [see Patient Counseling Information (17.8) ] .

5.11 Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations.

Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients.

In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal.

Three LYRICA treated subjects had events reported as rhabdomyolysis in premarketing clinical trials.

The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events.

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever.

Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

5.12 Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count.

LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 × 10 3 /µL, compared to 11 × 10 3 /µL in placebo patients.

In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 × 10 3 /µL.

A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 × 10 3 / µL.

In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions.

5.13 PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation.

In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses greater than or equal to 300 mg/day.

This mean change difference was not associated with an increased risk of PR increase greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR greater than 200 msec, or an increased risk of adverse reactions of second or third degree AV block.

Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications.

However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION 17.1 Medication Guide Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking LYRICA.

Instruct patients to take LYRICA only as prescribed.

17.2 Angioedema Advise patients that LYRICA may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise.

Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms [ see Warnings and Precautions (5.1) ].

17.3 Hypersensitivity Advise patients that LYRICA has been associated with hypersensitivity reactions such as wheezing, dyspnea, rash, hives, and blisters.

Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.2) ].

17.4 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including LYRICA, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.4) ] .

17.5 Dizziness and Somnolence Counsel patients that LYRICA may cause dizziness, somnolence, blurred vision and other CNS signs and symptoms.

Accordingly, advise patients not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on LYRICA to gauge whether or not it affects their mental, visual, and/or motor performance adversely.

[see Warnings and Precautions (5.6) ] .

17.6 Weight Gain and Edema Counsel patients that LYRICA may cause edema and weight gain.

Advise patients that concomitant treatment with LYRICA and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain.

For patients with preexisting cardiac conditions, this may increase the risk of heart failure.

[see Warnings and Precautions (5.5 and 5.7) ] .

17.7 Abrupt or Rapid Discontinuation Advise patients to take LYRICA as prescribed.

Abrupt or rapid discontinuation may result in insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea.

[see Warnings and Precautions (5.8) ] .

17.8 Ophthalmological Effects Counsel patients that LYRICA may cause visual disturbances.

Inform patients that if changes in vision occur, they should notify their physician [see Warnings and Precautions (5.10) ] .

17.9 Creatine Kinase Elevations Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

[see Warnings and Precautions (5.11) ] .

17.10 CNS Depressants Inform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as somnolence [see Warnings and Precautions (5.6) and Drug Interactions (7) ] .

17.11 Alcohol Tell patients to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedating effects of alcohol.

17.12 Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYRICA during pregnancy [see Use in Specific Populations (8.1) ] .

17.13 Lactation Advise nursing mothers that breastfeeding is not recommended during treatment with LYRICA [ see Use in Specific Populations (8.2) ] .

17.14 Male Fertility Inform men being treated with LYRICA who plan to father a child of the potential risk of male-mediated teratogenicity.

In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity.

The clinical significance of this finding is uncertain [see Nonclinical Toxicology (13.1) and Use in specific populations (8.3) ] .

17.15 Dermatopathy Instruct diabetic patients to pay particular attention to skin integrity while being treated with LYRICA.

Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with LYRICA was observed in clinical trials [see Nonclinical Toxicology (13.2) ] .

DOSAGE AND ADMINISTRATION

2 LYRICA is given orally with or without food.

When discontinuing LYRICA, taper gradually over a minimum of 1 week.

For all indications, begin dosing at 150 mg/day.

( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 ) Dosing recommendations: INDICATION Dosing Regimen Maximum Dose DPN Pain ( 2.1 ) 3 divided doses per day 300 mg/day within 1 week PHN ( 2.2 ) 2 or 3 divided doses per day 300 mg/day within 1 week.

Maximum dose of 600 mg/day.

Adjunctive Therapy for Adult Patients with Partial Onset Seizures ( 2.3 ) 2 or 3 divided doses per day Maximum dose of 600 mg/day.

Fibromyalgia ( 2.4 ) 2 divided doses per day 300 mg/day within 1 week.

Maximum dose of 450 mg/day.

Neuropathic Pain Associated with Spinal Cord Injury ( 2.5 ) 2 divided doses per day 300 mg/day within 1 week.

Maximum dose of 600 mg/day.

Dose should be adjusted in patients with reduced renal function.

( 2.6 ) Oral Solution Concentration and Dispensing ( 2.7 ) 2.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min.

Begin dosing at 50 mg three times a day (150 mg/day).

The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6) ] .

Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated.

In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended [see Adverse Reactions (6.1) ] .

2.2 Postherpetic Neuralgia The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min.

Begin dosing at 75 mg two times a day, or 50 mg three times a day (150 mg/day).

The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6) ] .

Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day, and who are able to tolerate LYRICA, may be treated with up to 300 mg two times a day, or 200 mg three times a day (600 mg/day).

In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily [see Adverse Reactions (6.1) ] .

2.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults.

Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related.

Administer the total daily dose in two or three divided doses.

In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day).

Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6) ] .

The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied.

The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials.

Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.

2.4 Management of Fibromyalgia The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day.

Begin dosing at 75 mg two times a day (150 mg/day).

The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability.

Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day).

Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated.

In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended [see Adverse Reactions (6.1) ] .

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6) ] .

2.5 Neuropathic Pain Associated with Spinal Cord Injury The recommended dose range of LYRICA for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day.

The recommended starting dose is 75 mg two times a day (150 mg/day).

The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability.

Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate LYRICA may be treated with up to 300 mg two times a day [see Clinical Studies (14.5) ] .

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6) ] .

2.6 Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.

Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1.

To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed.

CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr greater than or equal to 60 mL/min).

Then refer to Table 1 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr greater than or equal to 60 mL/min), receives a total daily dose of 150 mg/day pregabalin.

Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.) For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function.

In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1 ).

Table 1.

Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance (CLcr) (mL/min) Total Pregabalin Daily Dose (mg/day) Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.

Dose Regimen TID= Three divided doses; BID = Two divided doses; QD = Single daily dose.

≥60 150 300 450 600 BID or TID 30–60 75 150 225 300 BID or TID 15–30 25–50 75 100–150 150 QD or BID <15 25 25–50 50–75 75 QD Supplementary dosage following hemodialysis (mg) Supplementary dose is a single additional dose.

Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg Cockcroft and Gault equation 2.7 Oral Solution Concentration and Dispensing The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in milligrams (mg).

The pharmacist will calculate the applicable dose in mL for dispensing (e.g., 150 mg equals 7.5 mL oral solution).

Pramipexole dihydrochloride 0.5 MG Oral Tablet

WARNINGS

Falling Asleep During Activities of Daily Living Patients treated with pramipexole dihydrochloride tablets have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents.

Although many of these patients reported somnolence while on pramipexole dihydrochloride tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Some of these events had been reported as late as one year after the initiation of treatment.

Somnolence is a common occurrence in patients receiving pramipexole dihydrochloride tablets at doses above 1.5 mg/day (0.5 mg TID) for Parkinson’s disease.

Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history.

For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment.

Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with pramipexole dihydrochloride tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with pramipexole dihydrochloride tablets such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine – see PRECAUTIONS, Drug Interactions ).

If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride tablets should ordinarily be discontinued.

If a decision is made to continue pramipexole dihydrochloride tablets, patients should be advised to not drive and to avoid other potentially dangerous activities.

While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Symptomatic Hypotension Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation.

Parkinson’s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge.

For these reasons, both Parkinson’s disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk (see PRECAUTIONS, Information for Patients (also see Patient Package Insert) ).

In clinical trials of pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole dihydrochloride tablets than among those assigned to placebo.

This result, especially with the higher doses used in Parkinson’s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.

While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials.

Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded.

Hallucinations In the three double-blind, placebo-controlled trials in early Parkinson’s disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo.

In the four double-blind, placebo-controlled trials in advanced Parkinson’s disease, where patients received pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo.

Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson’s disease patients and 2.7% of the advanced Parkinson’s disease patients compared with about 0.4% of placebo patients in both populations.

Age appears to increase the risk of hallucinations attributable to pramipexole.

In the early Parkinson’s disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years.

In the advanced Parkinson’s disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.

DRUG INTERACTIONS

Drug Interactions Carbidopa/levodopa Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10).

Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa C max by about 40% and a decrease in T max from 2.5 to 0.5 hours.

Selegiline In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.

Amantadine Population pharmacokinetic analysis suggest that amantadine may slightly decrease the oral clearance of pramipexole.

Cimetidine Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).

Probenecid Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).

OVERDOSAGE

There is no clinical experience with massive overdosage.

One patient, with a 10 year history of schizophrenia, took 11 mg/day of pramipexole for 2 days in a clinical trial to evaluate the effect of pramipexole in schizophrenic patients.

No adverse events were reported related to the increased dose.

Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute.

The patient withdrew from the study at the end of week 2 due to lack of efficacy.

There is no known antidote for overdosage of a dopamine agonist.

If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed.

Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

DESCRIPTION

Pramipexole dihydrochloride tablets contain pramipexole, a nonergot dopamine agonist.

The chemical name of pramipexole dihydrochloride is ( S )-2-amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole dihydrochloride monohydrate.

The structural formula is: C 10 H 17 N3 S · 2HCl · H2O Molecular Weight: 302.27 Pramipexole dihydrochloride is a white to off-white powder substance.

Melting occurs in the range of 296°C to 301°C, with decomposition.

Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.

Pramipexole dihydrochloride tablets, for oral administration, contain 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate.

Inactive ingredients consist of corn starch, hydrogenated vegetable oil, mannitol, povidone and pregelatinized corn starch.

Chemical Structure 1

CLINICAL STUDIES

Parkinson’s Disease The effectiveness of pramipexole dihydrochloride tablets in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials.

Three were conducted in patients with early Parkinson’s disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson’s disease who were receiving concomitant levodopa.

Among these seven studies, three studies provide the most persuasive evidence of pramipexole’s effectiveness in the management of patients with Parkinson’s disease who were and were not receiving concomitant levodopa.

Two of these three trials enrolled patients with early Parkinson’s disease (not receiving levodopa), and one enrolled patients with advanced Parkinson’s disease who were receiving maximally tolerated doses of levodopa.

In all studies, the Unified Parkinson’s Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure.

The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).

Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52.

Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II.

It is designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.

Studies in Patients with Early Parkinson’s Disease Patients (N=599) in the two studies of early Parkinson’s disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the “on-off” phenomenon and dyskinesia characteristic of later stages of the disease.

One of the two early Parkinson’s disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose escalation period and a 6 month maintenance period.

Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine.

Patients were randomized to pramipexole dihydrochloride tablets or placebo.

Patients treated with pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses.

At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant.

The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant.

A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).

The second early Parkinson’s disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6 week dose-escalation period and a 4 week maintenance period.

Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products.

Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride tablets (1.5 mg, 3 mg, 4.5 mg, or 6 mg per day) or placebo.

At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients.

The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with pramipexole dihydrochloride tablets and 0.6 in placebo treated patients.

No dose-response relationship was demonstrated.

The between treatment differences on both parts of the UPDRS were statistically significant in favor of pramipexole dihydrochloride tablets for all doses.

No differences in effectiveness based on age or gender were detected.

There were too few non- caucasian patients to evaluate the effect of race.

Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.

Studies in Patients with Advanced Parkinson’s Disease In the advanced Parkinson’s disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of “on” and “off” time.

Patients in the advanced Parkinson’s disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had “on-off” periods.

The advanced Parkinson’s disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose-escalation period and a 6 month maintenance period.

Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination.

Patients treated with pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses.

At selected times during the 6 month maintenance period, patients were asked to record the amount of “off,” “on,” or “on with dyskinesia” time per day for several sequential days.

At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant.

The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant.

A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day).

Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with pramipexole dihydrochloride tablets versus 54% of placebo patients.

On average, the levodopa dose was reduced 27%.

The mean number of “off” hours per day during baseline was 6 hours for both treatment groups.

Throughout the trial, patients treated with pramipexole dihydrochloride had a mean of 4 “off” hours per day, while placebo-treated patients continued to experience 6 “off” hours per day.

No differences in effectiveness based on age or gender were detected.

There were too few non-caucasian patients to evaluate the effect of race.

HOW SUPPLIED

Pramipexole Dihydrochloride tablets are available as follows: 0.125 mg: White, round unscored tablet.

Debossed with stylized b on one side and C2 on the other side.

Available in bottles of: 63 Tablets NDC 0555-0617-62 0.25 mg: White, oval tablet scored on both sides.

Debossed with stylized b on one side and C|3 on the other side.

Available in bottles of: 90 Tablets NDC 0555-0612-14 0.5 mg: White, oval tablet scored on both sides.

Debossed with stylized b on one side and C|4 on the other side.

Available in bottles of: 90 Tablets NDC 0555-0613-14 1 mg: White, round tablet scored on both sides.

Debossed with stylized b on one side and C|5 on the other side.

Available in bottles of: 90 Tablets NDC 0555-0614-14 1.5 mg: White, round tablet scored on both sides.

Debossed with stylized b on one side and C|6 on the other side.

Available in bottles of: 90 Tablets NDC 0555-0615-14 KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

Protect from light.

PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET

GERIATRIC USE

Geriatric Use Pramipexole total oral clearance was approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function.

This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours.

In clinical studies with Parkinson’s disease patients, 38.7% of patients were older than 65 years.

There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of pramipexole dihydrochloride tablets was increased in the elderly.

MECHANISM OF ACTION

Mechanism of Action Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D 2 subfamily of dopamine receptors, binding with higher affinity to D 3 than to D 2 or D 4 receptor subtypes.

Parkinson’s Disease: The precise mechanism of action of pramipexole as a treatment for Parkinson’s disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum.

This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.

The relevance of D 3 receptor binding in Parkinson’s disease is unknown.

INDICATIONS AND USAGE

Parkinson’s Disease Pramipexole dihydrochloride tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.

The effectiveness of pramipexole dihydrochloride tablets was demonstrated in randomized, controlled trials in patients with early Parkinson’s disease who were not receiving concomitant levodopa therapy as well as in patients with advanced disease on concomitant levodopa (see CLINICAL STUDIES ).

PEDIATRIC USE

Pediatric Use The safety and efficacy of pramipexole dihydrochloride tablets in pediatric patients has not been established.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day (5 times the maximum recommended human dose (MRHD) on a mg/m 2 basis).

Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos.

The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD.

These findings are thought to be due to the prolactin lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans).

Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated.

There was no evidence of adverse effects on embryo fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 71 times that in humans at the MRHD).

Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m 2 basis) or greater during the latter part of pregnancy and throughout lactation.

There are no studies of pramipexole in human pregnancy.

Because animal reproduction studies are not always predictive of human response, pramipexole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers A single-dose, radio-labeled study showed that drug-related materials were excreted into the breast milk of lactating rats.

Concentrations of radioactivity in milk were three to six times higher than concentrations in plasma at equivalent time points.

Other studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

INFORMATION FOR PATIENTS

Information for Patients (also see Patient Package Insert) Patients should be instructed to take pramipexole dihydrochloride tablets only as prescribed.

Patients should be alerted to the potential sedating effects associated with pramipexole dihydrochloride tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living.

Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with pramipexole dihydrochloride tablets to gauge whether or not it affects their mental and/or motor performance adversely.

Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.

Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with pramipexole dihydrochloride tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).

Patients should be informed that hallucinations can occur and that the elderly are at a higher risk than younger patients with Parkinson’s disease.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including pramipexole dihydrochloride.

Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped.

Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with pramipexole dihydrochloride.

Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking pramipexole dihydrochloride.

Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride.

Patients may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating.

Hypotension may occur more frequently during initial therapy.

Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with pramipexole dihydrochloride tablets.

Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, Pregnancy ).

Because of the possibility that pramipexole may be excreted in breast milk, patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.

If patients develop nausea, they should be advised that taking pramipexole with food may reduce the occurrence of nausea.

DOSAGE AND ADMINISTRATION

Parkinson’s Disease In all clinical studies, dosage was initiated at a subtherapeutic level to avoid intolerable adverse effects and orthostatic hypotension.

Pramipexole dihydrochloride tablets should be titrated gradually in all patients.

The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of dyskinesia, hallucinations, somnolence, and dry mouth.

Dosing in Patients With Normal Renal Function Initial Treatment Dosages should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days.

A suggested ascending dosage schedule that was used in clinical studies is shown in the following table: Table 3: Ascending Dosage Schedule of Pramipexole Dihydrochloride Tablets for Parkinson’s Disease Week Dosage (mg) Total Daily Dose (mg) 1 0.125 tid 0.375 2 0.25 tid 0.75 3 0.5 tid 1.50 4 0.75 tid 2.25 5 1 tid 3 6 1.25 tid 3.75 7 1.5 tid 4.50 Maintenance Treatment Pramipexole dihydrochloride tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).

In a fixed-dose study in early Parkinson’s disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of pramipexole dihydrochloride tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day.

However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence, and amnesia.

The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day.

The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo.

When pramipexole dihydrochloride tablets are used in combination with levodopa, a reduction of the levodopa dosage should be considered.

In a controlled study in advanced Parkinson’s disease, the dosage of levodopa was reduced by an average of 27% from baseline.

Dosing in Patients With Renal Impairment Table 4: Pramipexole Dosage in Parkinson’s Disease Patients With Renal Impairment Renal Status Starting Dose (mg) Maximum Dose (mg) Normal to mild impairment (creatinine Cl > 60 mL/min) 0.125 tid 1.5 tid Moderate impairment (creatinine Cl = 35 to 59 mL/min) 0.125 bid 1.5 bid Severe impairment (creatinine Cl = 15 to 34 mL/min) 0.125 qd 1.5 qd Very severe impairment (creatinine Cl < 15 mL/min and hemodialysis patients) The use of pramipexole dihydrochloride tablets has not been adequately studied in this group of patients.

Discontinuation of Treatment It is recommended that pramipexole dihydrochloride tablets be discontinued over a period of 1 week; in some studies, however, abrupt discontinuation was uneventful.

escitalopram oxalate 10 MG Oral Tablet

Generic Name: ESCITALOPRAM OXALATE
Brand Name: escitalopram oxalate
  • Substance Name(s):
  • ESCITALOPRAM OXALATE

DRUG INTERACTIONS

7 • Concomitant use with SSRIs, SNRIs or Tryptophan is not recommended ( 7 ) • Use caution when concomitant use with drugs that affect Hemostasis (NSAIDs, Aspirin, Warfarin) ( 7 ) Table 6 presents clinically important drug interactions with escitalopram.

TABLE 6 Clinically Important Drug Interactions with Escitalopram Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Concomitant use of SSRIs, including Escitalopram, and MAOIs increases the risk of serotonin syndrome.

Intervention: Escitalopram is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.7 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )] .

Pimozide Clinical Impact: Concomitant use of racemic citalopram with pimozide increases plasma concentrations of pimozide, a drug with a narrow therapeutic index, and may increase the risk of QT prolongation and/or ventricular arrhythmias compared to use of racemic citalopram alone [see Clinical Pharmacology ( 12.3 )] .

Intervention: Escitalopram is contraindicated in patients taking pimozide [see Contraindications ( 4 )] .

Other Serotonergic Drugs Clinical Impact: Concomitant use of escitalopram and other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St.

John’s Wort) increases the risk of serotonin syndrome.

Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during Escitalopram initiation and dosage increases.

If serotonin syndrome occurs, consider discontinuation of Escitalopram and/or concomitant serotonergic drugs [see Warning and Precautions ( 5.2 )] .

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) Clinical Impact: Concomitant use of Escitalopram and an antiplatelet or anticoagulant may potentiate the risk of bleeding.

Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of Escitalopram and antiplatelet agents and anticoagulants.

For patients taking warfarin, carefully monitor the international normalized ratio [see Warning and Precautions ( 5.7 )] .

Sumatriptan Clinical Impact: There have been postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan.

Intervention: If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised [see Warning and Precautions ( 5.2 )] .

Carbamazepine Clinical Impact: Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate.

Intervention: Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered.

Drugs Metabolized by CYP2D6 Clinical Impact: Coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine.

Intervention: The clinical significance of this finding is unknown.

Exercise caution during coadministration of escitalopram and drugs metabolized by CYP2D6.

OVERDOSAGE

10 The following have been reported with escitalopram tablet overdosage: Seizures, which may be delayed, and altered mental status including coma.

Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes.

Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.

Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk).

Prolonged cardiac monitoring is recommended in escitalopram tablets overdosage ingestions due to the arrhythmia risk.

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a escitalopram overdose.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

DESCRIPTION

11 Escitalopram tablets contain escitalopram a selective serotonin reuptake inhibitor (SSRI), present as escitalopram oxalate salt.

Escitalopram is the pure S- enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram.

Escitalopram oxalate is designated S-(+)-1- [3-(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula: The molecular formula is C 20 H 21 FN 2 O • C 2 H 2 O 4 and the molecular weight is 414.40.

Escitalopram oxalate, USP occurs as a fine, white to slightly-yellow powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.

Escitalopram tablets, USP are white to off-white, round, biconvex, film-coated tablets containing 6.38 mg, 12.75 mg and 25.55 mg escitalopram oxalate in strengths equivalent to 5 mg, 10 mg, and 20 mg, respectively, of escitalopram base.

The 10 and 20 mg tablets are scored.

The tablets also contain the following inactive ingredients: cellulose microcrystalline, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, povidone and talc.

The film coating contains hypromellose, polyethylene glycol 400 and titanium dioxide.

Meets USP Dissolution Test 2.

1

CLINICAL STUDIES

14 14.1 Major Depressive Disorder Adults The efficacy of escitalopram as a treatment for major depressive disorder was established in three, 8-week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for major depressive disorder.

The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS).

A fixed-dose study compared 10 mg daily escitalopram and 20 mg daily escitalopram to placebo and 40 mg daily citalopram.

The 10 mg daily and 20 mg daily escitalopram treatment groups showed statistically significant greater mean improvement compared to placebo on the MADRS.

The 10 mg and 20 mg escitalopram groups were similar on this outcome measure.

In a second fixed-dose study of 10 mg daily escitalopram and placebo, the 10 mg daily escitalopram treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.

In a flexible-dose study, comparing escitalopram, titrated between 10 mg and 20 mg daily, to placebo and citalopram, titrated between 20 mg and 40 mg daily, the escitalopram treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.

Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

In a longer-term trial, 274 patients meeting (DSM-IV) criteria for major depressive disorder, who had responded during an initial 8-week, open-label treatment phase with escitalopram 10 mg or 20 mg daily, were randomized to continuation of escitalopram at their same dose, or to placebo, for up to 36 weeks of observation for relapse.

Response during the open-label phase was defined by having a decrease of the MADRS total score to ≤ 12.

Relapse during the double-blind phase was defined as an increase of the MADRS total score to ≥ 22, or discontinuation due to insufficient clinical response.

Patients receiving continued escitalopram experienced a statistically significant longer time to relapse compared to those receiving placebo.

Pediatric Patients 12 years of age and older The efficacy of escitalopram as a treatment for major depressive disorder in pediatric patients 12 to 17 years was established in an 8-week, flexible-dose, placebo-controlled study that compared escitalopram tablets (10 mg to 20 mg daily) to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder (MDD).

The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale – Revised (CDRS-R).

In this study, escitalopram showed statistically significant greater mean improvement compared to placebo on the CDRS-R.

The efficacy of escitalopram in the treatment of major depressive disorder in pediatric patients 12 to 17 years was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20 mg to 40 mg daily.

In this outpatient study in pediatric patients 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the 12 to 17 year subgroup.

Two additional flexible-dose, placebo-controlled MDD studies (one escitalopram study in patients ages 7 to 17 years and one citalopram study patients 13 to 18 years) did not demonstrate efficacy.

The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD.

14.2 Generalized Anxiety Disorder Adults The efficacy of escitalopram in the treatment of generalized anxiety disorder (GAD) in adults was demonstrated in three, 8-week, multicenter, flexible-dose, placebo-controlled studies that compared escitalopram tablets (10 mg to 20 mg daily) to placebo in outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD.

In all three studies, escitalopram showed statistically significant greater mean improvement compared to placebo on the Hamilton Anxiety Scale (HAM-A).

There were too few patients in differing ethnic and age groups to adequately assess whether or not escitalopram has differential effects in these groups.

There was no difference in response to escitalopram between men and women.

Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO (escitalopram) tablets.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

HOW SUPPLIED

16 /STORAGE AND HANDLING How Supplied Escitalopram tablets, USP 5 mg are white to off-white, round, biconvex, film coated tablets debossed with ‘135’ on one side and ‘5’ on other side.

Bottles of 30 NDC 13668-135-30 Bottles of 100 NDC 13668-135-01 Bottles of 500 NDC 13668-135-05 Bottles of 1000 NDC 13668-135-10 Bottles of 4000 NDC 13668-135-40 Escitalopram tablets, USP 10 mg are white to off-white, round, biconvex, film coated tablets debossed with break line on one side, separating ’11’ and ’36’ on one side, and ’10’ on other side.

Bottles of 30 NDC 13668-136-30 Bottles of 100 NDC 13668-136-01 Bottles of 500 NDC 13668-136-05 Bottles of 1000 NDC 13668-136-10 Bottles of 3000 NDC 13668-136-43 Escitalopram tablets, USP 20 mg are white to off-white, round, biconvex, film coated tablets debossed with break line on one side, separating ’11’ and ’37’ on one side, and ’20’ on other side.

Bottles of 30 NDC 13668-137-30 Bottles of 100 NDC 13668-137-01 Bottles of 500 NDC 13668-137-05 Bottles of 1000 NDC 13668-137-10 Bottles of 2000 NDC 13668-137-20 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Indications ( 1 ) 5/2023 Dosage and Administration ( 2.2 , 2.3 , 2.5 ) 5/2023 Dosage and Administration, Use of Escitalopram with Other MAOIs such as Linezolid or Methylene Blue ( 2.7 ) – Removed 5/2023 Warnings and Precautions ( 5.2 , 5.7 ) 8/2023

GERIATRIC USE

8.5 Geriatric Use Approximately 69 patients (6%) of the 1,144 patients receiving escitalopram in controlled trials of escitalopram in major depressive disorder and GAD were 60 years of age or older [see Clinical Studies ( 14.1 , 14.2 )] .

The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age.

Nevertheless, greater sensitivity of some elderly individuals to effects of escitalopram cannot be ruled out.

In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in subjects 65 years and older as compared to young subjects and C max was unchanged [see Clinical Pharmacology ( 12.3 )] .

The recommended dosage of escitalopram tablets for elderly patients is 10 mg daily [see Dosage and Administration ( 2.5 )] .

SSRIs, including escitalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5.6 )] .

Of 4,422 patients in clinical studies of racemic citalopram, 1,357 were 60 and over, 1,034 were 65 and over, and 457 were 75 and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the geriatric and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Tablets: 5 mg, 10 mg (scored), and 20 mg (scored) Escitalopram tablets, USP are film-coated, round tablets containing escitalopram oxalate in strengths equivalent to 5 mg, 10 mg and 20 mg escitalopram base.

The 10 and 20 mg tablets are scored.

5 mg tablets are debossed with ‘135’ on one side and ‘5’ on other side.

10 mg tablets are debossed with break line on one side, separating ’11’ and ’36’ on one side, and ’10’ on other side.

20 mg tablets are debossed with break line on one side, separating ’11’ and ’37’ on one side, and ’20’ on other side.

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

INDICATIONS AND USAGE

1 Escitalopram is a selective serotonin reuptake inhibitor (SSRI) indicated for the: • treatment of major depressive disorder (MDD) in adults and pediatric patients 12 years of age and older ( 1 ) • treatment of generalized anxiety disorder (GAD) in adults ( 1 ) Escitalopram tablets are indicated for the treatment of: • major depressive disorder (MDD) in adults and pediatric patients 12 years of age and older.

• generalized anxiety disorder (GAD) in adults Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO (escitalopram) tablets.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

PEDIATRIC USE

8.4 Pediatric Use Major Depressive Disorder The safety and effectiveness of escitalopram for the treatment of major depressive disorder have been established in pediatric patients 12 years of age and older.

Use of escitalopram for this indication is supported by evidence from adequate and well-controlled studies in adults with additional evidence from an 8-week, flexible-dose, placebo-controlled study that compared escitalopram tablets 10 mg to 20 mg once daily to placebo in pediatric patients 12 to 17 years of age with major depressive disorder [see Clinical Studies ( 14.1 )] .

The safety of escitalopram was similar to adult patients with MDD [see Adverse Reactions ( 6.1 )] .

The safety and effectiveness of escitalopram for the treatment of major depressive disorder have not been established in pediatric patients younger than 12 years of age.

In a 24-week, open-label safety study in 118 pediatric patient (aged 7 to 11 years) who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for escitalopram.

Generalized Anxiety Disorder The safety and effectiveness of escitalopram for the treatment of generalized anxiety disorder have not been established in pediatric patients younger than 7 years of age.

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Precautions ( 5.1 )] .

Decreased appetite and weight loss have been observed in association with the use of SSRIs.

Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as escitalopram.

Juvenile Animal Toxicity Data In a juvenile animal study, male and female rats were administered escitalopram at 5, 40, or 80 mg/kg/day by oral gavage from postnatal day (PND) 21 to PND 69.

A delay in sexual maturation was observed in both males and females at ≥ 40 mg/kg/day with a No Observed Adverse Effect Level (NOAEL) of 5 mg/kg/day.

This NOAEL was associated with plasma AUC levels less than those measured at the maximum recommended dose (MRHD) in pediatrics (20 mg).

However, there was no effect on reproductive function.

Increased motor activity (both ambulatory and fine movements) was observed in females prior to daily dosing at ≥ 40 mg/kg/day (3.5 times the MRHD based on AUC levels).

A reversible disruption of learning and memory function was observed in males at 80 mg/kg/day with a NOAEL of 40 mg/kg/day, which was associated with an AUC level 3.5 times those measured at the MRHD in pediatrics.

There was no effect on learning and memory function in treated female rats.

Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO (escitalopram) tablets.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.7 ) and Clinical Considerations] .

Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage.

There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation (see Clinical Considerations), with exposure to selective serotonin reuptake inhibitors (SSRIs), including escitalopram, during pregnancy.

There are risks associated with untreated depression in pregnancy (see Clinical Considerations).

In animal reproduction studies, both escitalopram and racemic citalopram have been shown to have adverse effects on embryo/fetal and postnatal development, including fetal structural abnormalities, when administered at doses greater than human therapeutic doses (see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Disease-associated maternal risk and/or embryo/fetal risk Women who discontinue antidepressants are more likely to experience a relapse of major depression than women who continue antidepressants.

This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depression, who were euthymic and taking antidepressants at the beginning of pregnancy.

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Maternal Adverse Reactions Use of escitalopram tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.7 )].

Fetal/Neonatal adverse reactions Neonates exposed to SSRIs or SNRIs, including escitalopram, late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.

It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.2 )] .

Data Human Data Exposure to SSRIs, particularly later in pregnancy, may increase the risk for PPHN.

PPHN occurs in 1 to 2 per 1,000 live births in the general populations and is associated with substantial neonatal morbidity and mortality.

Animal Data In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses [approximately ≥ 55 times the maximum recommended human dose (MRHD) of 20 mg/day on a mg/m 2 basis].

Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels.

The developmental no-effect dose of 56 mg/kg/day is approximately 27 times the MRHD of 20 mg on a mg/m 2 basis.

No malformations were observed at any of the doses tested (as high as 73 times the MRHD on a mg/m 2 basis).

When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 23 times the MRHD of 20 mg on a mg/m 2 basis.

Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose.

Slightly increased offspring mortality was also seen at 24 mg/kg/day.

The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD of 20 mg on a mg/m 2 basis.

In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a mg/m 2 basis.

This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain).

The developmental no-effect dose was 56 mg/kg/day is approximately 9 times the MRHD on a mg/m 2 basis.

In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m 2 basis.

Thus, developmental effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit.

When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD of 60 mg on a mg/m 2 basis.

The no-effect dose was 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m 2 basis.

Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m 2 basis.

A no-effect dose was not determined in that study.

BOXED WARNING

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning .

Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants.

Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1 ).

Escitalopram tablets are not approved for use in pediatric patients less than 7 years of age ( 8.4 ).

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies.

Closely monitor all antidepressant -treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions ( 5.1 )].

Escitalopram tablets is not approved for use in pediatric patients less than 7 years of age [see Use in Specific Populations ( 8.4) ].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents but also when taken alone.

If it occurs, discontinue Escitalopram and serotonergic agents and initiate supportive treatment ( 4 , 5.2 ) • Discontinuation syndrome: When discontinuing Escitalopram, reduce dosage gradually whenever possible, and monitor for discontinuation symptoms ( 5.3 ) • Seizures: Use with caution in patients with a history of seizure ( 5.4 ) • Activation of Mania/Hypomania: Screen patients for bipolar disorder.

( 5.5 ) • Hyponatremia: Can occur in association with syndrome of inappropriate antidiuretic hormone secretion ( 5.6 ) • Increased Risk of Bleeding: Concomitant use of nonsteroidal anti-inflammatory drugs, aspirin, other antiplatelet drugs, warfarin and other drugs that affect coagulation may increase risk ( 5.7 ) • Interference with Cognitive and Motor Performance: Use caution when operating machinery ( 5.8 ) • Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.9 ) • Use in Patients with Concomitant Illness: Use caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses ( 5.10 ) • Sexual Dysfunction: Escitalopram may cause symptoms of sexual dysfunction ( 5.11 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.

The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.

Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider.

Consider changing the therapeutic regimen, including possibly discontinuing escitalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome SSRIs, including escitalopram tablets, can precipitate serotonin syndrome, a potentially life-threatening condition.

The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 )] .

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination) seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of escitalopram with MAOIs is contraindicated.

In addition, do not initiate Escitalopram in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection).

If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Escitalopram, discontinue Escitalopram before initiating treatment with the MAOI [see Contraindications (4) and Dosage and Administration ( 2.7 )] .

Monitor all patients taking escitalopram tablets for the emergence of serotonin syndrome.

Discontinue treatment with escitalopram tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of escitalopram with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Discontinuation Syndrome During marketing of escitalopram tablets and other SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Monitor for these symptoms when discontinuing treatment with escitalopram.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration ( 2.6 )] .

5.4 Seizures Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram has not been systematically evaluated in patients with a seizure disorder.

These patients were excluded from clinical studies during the product’s premarketing testing.

In clinical trials of escitalopram, cases of convulsion have been reported in association with escitalopram treatment.

Like other drugs effective in the treatment of major depressive disorder, escitalopram tablets should be introduced with care in patients with a history of seizure disorder.

5.5 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with escitalopram or another antidepressant may precipitate a mixed/manic episode.

In placebo-controlled trials of escitalopram in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with escitalopram and in none of the 592 patients treated with placebo.

One additional case of hypomania has been reported in association with escitalopram treatment.

Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder.

Prior to initiating treatment with escitalopram, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.4 )] .

5.6 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs , including escitalopram.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when escitalopram was discontinued.

Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.

Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations ( 8.5 )] .

Consider discontinuation of escitalopram in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.7 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including escitalopram, increase the risk of bleeding events.

Concomitant use of aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to the risk.

Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.

Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )].

Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of escitalopram and antiplatelet agents or anticoagulants.

For patients taking warfarin, carefully monitor the international normalized ratio [see Drug Interactions ( 7 )] .

5.8 Interference with Cognitive and Motor Performance In a study in normal volunteers, escitalopram 10 mg daily did not produce impairment of intellectual function or psychomotor performance.

Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram tablets therapy does not affect their ability to engage in such activities.

5.9 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including escitalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.10 Use in Patients with Concomitant Illness Clinical experience with escitalopram in patients with certain concomitant systemic illnesses is limited.

Caution is advisable in using escitalopram tablets in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.

Escitalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.

In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased.

The recommended dose of escitalopram tablets in hepatically impaired patients is 10 mg daily [see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.6)] .

Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination.

Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with escitalopram tablets, however, it should be used with caution in such patients [see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.7)] .

5.11 Sexual Dysfunction Use of SSRIs, including escitalopram, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )] .

In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.

In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of escitalopram and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.

When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.

Discuss potential management strategies to support patients in making informed decisions about treatment.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors Advise patients, their families and caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to their healthcare provider [see Boxed Warning and Warnings and Precautions ( 5.1 )].

Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the with the concomitant use of escitalopram with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St.

John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid).

Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )].

Discontinuation Syndrome Advise patients not to abruptly discontinue escitalopram tablets and to discuss any tapering regimen with their healthcare provider.

Inform patients that adverse reactions can occur when escitalopram tablets are discontinued [see Warnings and Precautions ( 5.3 )] .

Activation of Mania or Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions ( 5.5 )].

Increased Risk of Bleeding Inform patients about the concomitant use of escitalopram with NSAIDs, aspirin, warfarin, other antiplatelet drugs, or other anticoagulants because the combined use has been associated with an increased risk of bleeding.

Advise patients to inform their healthcare providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions ( 5.7 )] .

Angle Closure Glaucoma Advise patients that taking escitalopram tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma.

Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy.

Open-angle glaucoma is not a risk factor for angle closure glaucoma.

Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions ( 5.9 )] .

Sexual Dysfunction Advise patients that use of escitalopram may cause symptoms of sexual dysfunction in both male and female patients.

Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions ( 5.11 )] .

Concomitant Medications Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered.

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.

Interference with Psychomotor Performance Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram tablets therapy does not affect their ability to engage in such activities.

Alcohol Patients should be told that, although escitalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of escitalopram and alcohol in depressed patients is not advised.

Pregnancy Advise pregnant women to notify their healthcare providers if they become pregnant or intend to become pregnant during treatment with escitalopram tablets.

Advise patients that escitalopram use later in pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension (PPHN) of the newborn [see Use in Specific Populations ( 8.1 )].

Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to escitalopram during pregnancy [see Use in Specific Populations ( 8.1 )].

Lactation Advise breastfeeding women using escitalopram to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )].

Manufactured by: TORRENT PHARMACEUTICALS LTD., INDIA.

8094551 Revised: October 2023 Or VKT Pharma Private Limited, Srikakulam-532409, India.

8094553 Revised: October 2023 800204 Manufactured for: TORRENT PHARMA INC., Basking Ridge, NJ 07920.

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DOSAGE AND ADMINISTRATION

2 Indication and Population Recommended Dosage MDD in Adults ( 2.1 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily MDD in Pediatric Patients 12 years and older ( 2.1 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily GAD in Adults ( 2.2 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily • No additional benefits were seen at 20 mg once daily ( 2.1 ) • Administer once daily, morning or evening, with or without food ( 2.3 ) • Elderly patients: recommended dosage is 10 mg once daily ( 2.4 ) • Hepatic impairment: recommended dosage is 10 mg once daily ( 2.4 , 8.6 ) • When discontinuing Escitalopram tablets, reduce dose gradually whenever possible ( 2.5 ) 2.1 Major Depressive Disorder Adults The recommended dosage of escitalopram tablets in adults is 10 mg once daily.

A fixed-dose trial of escitalopram tablets demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram tablets, but failed to demonstrate a greater benefit of 20 mg over 10 mg [see Clinical Studies (14.1)].

Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 1 week.

Pediatric Patients 12 years of age and older The recommended dosage of escitalopram tablets in pediatric patients 12 years of age and older is 10 mg once daily.

Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 3 weeks.

2.2 Generalized Anxiety Disorder Adults The recommended starting dosage of escitalopram tablets in adults is 10 mg once daily.

Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 1 week.

Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO (escitalopram) tablets.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.3 Administration Information Administer escitalopram tablets orally once daily, in the morning or evening, with or without food.

2.4 Screen for Bipolar Disorder Prior to Starting Escitalopram Tablets Prior to initiating treatment with escitalopram tablets or another antidepressant, screen patients for a personal family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.5 )] .

2.5 Recommended Dosage for Specific Populations The recommended dosage for most elderly patients and patients with hepatic impairment is 10 mg once daily [see Use in Specific Populations ( 8.5 , 8.6 )] .

The recommended dosage for escitalopram tablets in adults with a creatinine clearance less than 20 mL/minute has not been determined.

No dosage adjustment is necessary for patients with mild or moderate renal impairment [see Use in Specific Populations ( 8.7 )] .

2.6 Discontinuation of Treatment with Escitalopram Tablets Symptoms associated with discontinuation of escitalopram tablets and other SSRIs and SNRIs have been reported [see Warnings and Precautions ( 5.3 )] .

Patients should be monitored for these symptoms when discontinuing treatment.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

2.7 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with escitalopram tablets.

Conversely, at least 14 days should be allowed after stopping escitalopram tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4 )] .

buprenorphine HCl 2 MG / naloxone HCl 0.5 MG Sublingual Tablet

DRUG INTERACTIONS

7 Table 4 Includes clinically significant drug interactions with SUBOXONE.

Table 4.

Clinically Significant Drug Interactions Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

Intervention: Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use.

In some cases, monitoring in a higher level of care for taper may be appropriate.

In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions ( 5.2 , 5.3 )] .

Examples: Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.

Inhibitors of CYP3A4 Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of SUBOXONE sublingual film is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.

Intervention: If concomitant use is necessary, consider dosage reduction of SUBOXONE sublingual film until stable drug effects are achieved.

Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the SUBOXONE sublingual film dosage until stable drug effects are achieved.

Monitor for signs of opioid withdrawal.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.

ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology ( 12.3 )] , potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.

Intervention: If concomitant use is necessary, consider increasing the SUBOXONE sublingual film dosage until stable drug effects are achieved.

Monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider SUBOXONE sublingual film dosage reduction and monitor for signs of respiratory depression.

Examples: Rifampin, carbamazepine, phenytoin Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4.

Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor.

Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.

Intervention: Patients who are on chronic SUBOXONE sublingual film treatment should have their dose monitored if NNRTIs are added to their treatment regimen.

Examples: efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects.

Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation.

Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.

Intervention: Monitor patients taking SUBOXONE sublingual film and atazanavir with and without ritonavir, and reduce dose of SUBOXONE sublingual film if warranted.

Examples: atazanavir, ritonavir Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.

Intervention: None Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.

Discontinue SUBOXONE sublingual film sublingual film if serotonin syndrome is suspected.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Intervention: The use of SUBOXONE sublingual film is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Examples: phenelzine, tranylcypromine, linezolid Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention: Monitor patients receiving muscle relaxants and SUBOXONE sublingual film for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBOXONE sublingual film and/or the muscle relaxant as necessary.

Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when SUBOXONE sublingual film is used concomitantly with anticholinergic drugs.

Benzodiazepines: Use caution in prescribing SUBOXONE sublingual film for patients receiving benzodiazepines or other CNS depressants and warn patients against concomitant self-administration/misuse.

( 7 ) CYP3A4Inhibitors and Inducers: Monitor patients starting or ending CYP3A4 inhibitors or inducers for potential over- or under- dosing.

( 7 ) Antiretrovirals: Patients who are on chronic buprenorphine treatment should have their dose monitored if NNRTIs are added to their treatment regimen.

Monitor patients taking buprenorphine and atazanavir with and without ritonavir.

Dose reduction of buprenorphine may be warranted ( 7 ).

Serotonergic Drugs: Concomitant use may result in serotonin syndrome.

Discontinue SUBOXONE sublingual film if serotonin syndrome is suspected.

( 7 )

OVERDOSAGE

10 Clinical Presentation The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression, and death.

Treatment of Overdose In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully.

When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation.

Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.

In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required.

Naloxone may be of value for the management of buprenorphine overdose.

Higher than normal doses and repeated administration may be necessary.

The long duration of action of SUBOXONE sublingual film should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose.

Insufficient duration of monitoring may put patients at risk.

DESCRIPTION

11 SUBOXONE® (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo identifying the product and strength in white ink.

It contains buprenorphine HCl, a mu-opioid receptor partial agonist, and a kappa- opioid receptor antagonist, and naloxone HCl dihydrate, an opioid antagonist, at a ratio of 4:1 (ratio of free bases).

It is intended for sublingual or buccal administration and is available in four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone and 12 mg buprenorphine with 3 mg naloxone.

Each film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink.

Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14- ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride.

It has the following chemical structure: Buprenorphine HCl has the molecular formula C 29 H 41 NO 4 • HCl and the molecular weight is 504.10.

It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane.

Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride dihydrate.

It has the following chemical structure: Naloxone hydrochloride dihydrate has the molecular formula C 19 H 21 NO 4 • HCl • 2H 2 O and the molecular weight is 399.87.

It is a white to slightly off-white powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether.

Figure Figure

HOW SUPPLIED

16 / STORAGE AND HANDLING Product: 63629-4028

RECENT MAJOR CHANGES

Dosage and Administration ( 2.2 , 2.3 , 2.5 , 2.8 ) 09/2017 Warnings and Precautions ( 5.2 , 5.3 ) 02/2018

GERIATRIC USE

8.5 Geriatric Use Clinical studies of SUBOXONE sublingual film, SUBOXONE sublingual tablets, or SUBUTEX sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Due to possible decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe SUBOXONE sublingual film should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

DOSAGE FORMS AND STRENGTHS

3 SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four dosage strengths: Buprenorphine 2 mg/naloxone 0.5 mg, Buprenorphine 4 mg/naloxone 1 mg, Buprenorphine 8 mg/naloxone 2 mg and Buprenorphine 12 mg/naloxone 3 mg Sublingual film: buprenorphine 2 mg/ naloxone, 4 0.5 mg , buprenorphine 4 mg/ naloxone, 8 1 mg , buprenorphine 8 mg/ naloxone 2 mg and buprenorphine 12 mg/ naloxone 3 mg.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action SUBOXONE sublingual film contains buprenorphine and naloxone.

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

Naloxone is a potent antagonist at mu opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.

INDICATIONS AND USAGE

1 SUBOXONE sublingual film is indicated for treatment of opioid dependence .

SUBOXONE sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.

SUBOXONE® sublingual film contains buprenorphine, a partial‐opioid agonist, and naloxone, an opioid antagonist, and is indicated for treatment of opioid dependence.

( 1 ) SUBOXONE sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric patients.

This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist.

PREGNANCY

8.1 Pregnancy Risk Summary The data on use of buprenorphine, one of the active ingredients in SUBOXONE sublingual film, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure.

There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see Data ].

Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [ see Data ].

The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk.

Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses.

Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine.

Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine.

No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine.

However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively.

In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data ].

Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Disease – associated maternal and embryo – fetal risk Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death.

In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dose Adjustment during Pregnancy and the Postpartum Period Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy.

Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary.

Fetal/neonatal adverse reactions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with SUBOXONE sublingual film.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight.

Signs of neonatal withdrawal usually occur in the first days after birth.

The duration and severity of neonatal opioid withdrawal syndrome may vary.

Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )] .

Labor or Delivery Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.

Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy.

Limited data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine.

Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances.

Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison.

Rather, women on another form of opioid medication- assisted treatment, or women in the general population are generally used as the comparison group.

However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes.

In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups.

A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.

Among women who remained in treatment until delivery, there was no difference between buprenorphine- treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS.

Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs.

10.4 mg), had shorter hospital stays (10.0 days vs.

17.5 days), and shorter duration of treatment for NOWS (4.1 days vs.

9.9 days) compared to the methadone-exposed group.

There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events.

The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known.

Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret.

Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m 2 ) to the human sublingual dose of 16 mg buprenorphine via SUBOXONE sublingual tablets.

Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone during the period of organogenesis.

Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg) in the presence of maternal toxicity (mortality).

Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times, the human sublingual dose of 16 mg) in the absence of clear maternal toxicity.

No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg).

Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits.

Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group.

Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed.

Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of 16 mg).

In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.

Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.

Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human daily sublingual dose of 16 mg).

Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg/day.

Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human daily sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) were not statistically significant.

In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the human daily sublingual dose of 16 mg).

No maternal toxicity was noted at doses causing post-implantation loss in this study.

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg).

Fertility, pre- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human daily sublingual dose of 16 mg), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg).

An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices.

Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the human sublingual dose of 16 mg).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: Buprenorphine can be abused in a similar manner to other opioids.

l Monitor patients for conditions indicative of ldiversion or progression of opioid dependence and addictive behaviors.

Multiple refills should not be prescribed early in treatment or without appropriate patient follow‐up visits.

( 5.1 ) Respiratory Depression: Life‐threatening respiratory depression and death have occurred in association with buprenorphine, use.

Warn patients of the potential danger of self‐administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual film, or both in situations of concomitant.

( 5.2 , 5.3 ) Unintentional Pediatric Exposure: Store SUBOXONE sublingual film safely out of the sight and reach of children.

Buprenorphine can cause severe, possibly fatal, respiratory depression in children.

( 5.4 ) Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy ( 5.5 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.

( 5.6 ) Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately.

( 5.7 ) Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events.

( 5.8 ) Precipitation of Opioid Withdrawal Signs and Symptoms: An opioid withdrawal syndrome is likely to occur with parenteral misuse of SUBOXONE sublingual film by individuals physically dependent on full opioid agonists, or by sublingual or buccal administration before the agonist effects of other opioids have subsided.

( 5.10 ) Risk of Overdose in Opioid‐Naïve Patients: SUBOXONE sublingual film is not appropriate as an analgesic.

There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose.

( 5.11 ) 5.1 Addiction, Abuse , and Misuse SUBOXONE sublingual film contains buprenorphine, a schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit.

Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home.

Clinical monitoring appropriate to the patient’s level of stability is essential.

Multiple refills should not be prescribed early in treatment or without appropriate patient follow‐up visits [see Drug Abuse and Dependence ( 9.2 )] .

5.2 Risk of Respiratory and Central Nervous System (CNS) Depression Buprenorphine has been associated with life‐threatening respiratory depression and death.

Many, but not all, post‐marketing reports regarding coma and death involved misuse by self‐injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol.

Warn patients of the potential danger of self‐administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual film [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )].

Use SUBOXONE sublingual film with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre‐existing respiratory depression).

5.3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants Concomitant use of buprenorphine and benzodiazepines or other CNS depressants (increases the risk of adverse reactions including overdose and death.

Medication‐assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs.

Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment.

Adjustments to induction procedures and additional monitoring may be required.

There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine‐treated patients.

However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use.

In some cases, monitoring in a higher level of care for taper may be appropriate.

In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia.

Before co‐prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non‐pharmacologic treatments to address anxiety or insomnia.

Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs.

Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions ( 7 )].

5.4 Unintentional Pediatric Exposure Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

Store buprenorphine‐containing medications safely out of the sight and reach of children.

and destroy any unused medication appropriately [see Patient Counseling Information ( 17 ) ].

5.5 Neonatal Opioid Withdrawal Syndrome Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically‐authorized or illicit.

Unlike opioid withdrawal syndrome in adults, NOWS may be life‐threatening if not recognized and treated in the neonate.

Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see Use in Specific Populations ( 8.1 )] .

Advise pregnant women receiving opioid addiction treatment with SUBOXONE sublingual film of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1 )] .

This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes.

Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

5.6 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Presentation of adrenal insufficiency may include non‐specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.

If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.

Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.

The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.7 Risk of Opioid Withdrawal with Abrupt Discontinuation Buprenorphine is a partial agonist at the mu‐opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper.

The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence ( 9.3 )] .

When discontinuing SUBOXONE sublingual film, gradually taper the dosage [see Dosage and Administration ( 2.8 )] .

5.8 Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post‐marketing adverse event reports.

The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.

In many cases, the presence of pre‐existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role.

In other cases, insufficient data were available to determine the etiology of the abnormality.

Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary.

The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases.

Liver function tests, prior to initiation of treatment, are recommended to establish a baseline.

Periodic monitoring of liver function during treatment is also recommended.

A biological and etiological evaluation is recommended when a hepatic event is suspected.

Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.

5.9 Hypersensitivity Reactions Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post‐marketing experience.

Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported.

The most common signs and symptoms include rashes, hives, and pruritus.

A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of SUBOXONE sublingual film.

5.10 Precipitation of Opioid Withdrawal Signs and Symptoms Because it contains naloxone, SUBOXONE sublingual film is likely to produce withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone.

Because of the partial agonist properties of buprenorphine, SUBOXONE sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered before the agonist effects of the opioid have subsided.

5.11 Risk of Overdose in Opioid Naïve Patients There have been reported deaths of opioid ‐naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia.

SUBOXONE sublingual film is not appropriate as an analgesic.

5.12 Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment.

The doses of buprenorphine and naloxone in this fixed‐dose combination product cannot be individually titrated., and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine.

Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function.

This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment.

In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment.

However, buprenorphine/naloxone products are not recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal.

Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone.

However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy [see Use in Specific Populations ( 8.6 )].

5.13 Impairment of Ability to Drive or Operate Machinery SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment.

Caution patients about driving or operating hazardous machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely affect his or her ability to engage in such activities.

5.14 Orthostatic Hypotension Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory patients.

5.15 Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased.

Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

5.16 Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

5.17 Effects in Acute Abdominal Conditions As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling ( Medication Guide ).

Safe Use Before initiating treatment with SUBOXONE sublingual film, explain the points listed below to caregivers and patients.

Instruct patients to read the Medication Guide each time SUBOXONE sublingual film is dispensed because new information may be available.

SUBOXONE sublingual film must be administered whole.

Advise patients not to cut, chew, or swallow SUBOXONE sublingual film.

Inform patients and caregivers that potentially fatal additive effects may occur if SUBOXONE sublingual film is used with benzodiazepines or other CNS depressants , including alcohol.

Counsel patients that such medications should not be used concomitantly unless supervised bya health care provider [see Warnings and Precautions ( 5.2 , 5.3 ), Drug Interactions ( 7 )].

Advise patients that SUBOXONE sublingual film contains an opioid that can be a target for people who abuse prescription medications or street drugs.

Caution patients to keep their films in a safe place, and to protect them from theft.

Instruct patients to keep SUBOXONE sublingual film in a secure place, out of the sight and reach of children.

Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death.

Advise patients to seek medical attention immediately if a child is exposed to SUBOXONE sublingual film.

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs.

Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.

Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Drug Interactions ( 7 )] .

Inform patients that opioids could cause adrenal insufficiency, a potentially life- threatening condition.

Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.6 )] .

Advise patients to never give SUBOXONE sublingual film to anyone else, even if he or she has the same signs and symptoms.

It may cause harm or death.

Advise patients that selling or giving away this medication is against the law.

Caution patients that SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery.

Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities [see Warnings and Precautions ( 5.13 )].

Advise patients not to change the dosage of SUBOXONE sublingual film without consulting their healthcare provider.

Advise patients to take SUBOXONE sublingual film once a day.

Advise patients that if they miss a dose of SUBOXONE sublingual film they should take it as soon as they remember.

If it is almost time for the next dose, they should skip the missed dose and take the next dose at the regular time.

Inform patients that SUBOXONE sublingual film can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.

Advise patients seeking to discontinue treatment with buprenorphine for opioid dependence to work closely with their healthcare provider on a tapering schedule and inform them of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.

Advise patients that, like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions ( 5.14 )].

Advise patients to inform their healthcare provider if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used [see Drug Interactions ( 7 )].

Advise women that if they are pregnant while being treated with SUBOXONE sublingual film, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 )].

Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see Use in Specific Populations ( 8.2 )].

Inform patients that chronic use of opioids may cause reduced fertility.

It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )].

Advise patients to inform their family members that, in the event of emergency, the treating healthcare provider or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with SUBOXONE sublingual film.

Disposal of Unused SUBOXONE Sublingual Films Unused SUBOXONE sublingual films should be disposed of as soon as they are no longer needed.

Unused films should be flushed down the toilet.

Manufactured for Indivior Inc.

North Chesterfield, VA 23235 by: Aquestive Therapeutics, Warren, NJ 07059 Distributed by: Indivior Inc.

North Chesterfield, VA 23235 SUBOXONE ® and SUBUTEX ® are registered trademarks of Indivior UK Ltd.

DOSAGE AND ADMINISTRATION

2 Prescription use of this product is limited under the Drug Addiction Treatment Act.

( 2.1 ) Administer SUBOXONE sublingual film as a single daily dose.

( 2.2 ) To avoid precipitating withdrawal, induction with SUBOXONE sublingual film should be undertaken when objective and clear signs of withdrawal are evident and SUBOXONE sublingual film should be administered in divided doses when used as initial treatment.

( 2.3 ) For patients dependent on short‐acting opioid products who are in opioid withdrawal; on Day 1, administer up to 8 mg/2 mg SUBOXONE sublingual film (in divided doses).

On Day 2, administer up to 16 mg/4 mg of SUBOXONE sublingual film as a single dose.

( 2.3 ) For patients dependent on methadone or long‐acting opioid products, induction onto sublingual buprenorphine monotherapy is recommended on Days 1 and 2 of treatment.

( 2.3 ) For maintenance treatment, the target dosage of SUBOXONE sublingual film is usually 16 mg/4 mg as a single daily dose.

( 2.4 ) Sublingual Administration: Place one film under the tongue, close to the base on the left or right side, and allow to completely dissolve.

Buccal Administration: Place one film on the inside of the left or right cheek and allow to completely dissolve.

( 2.5 ) SUBOXONE sublingual film must be administered whole.

Do not cut, chew, or swallow SUBOXONE sublingual film ( 2.5 ) When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal.

( 2.8 ) 2.1 Drug Addiction and Treatment Act Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C.

823(g), prescription use of this product in the treatment of opioid dependence is limited to healthcare providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

2.2 Important Dosage and Administration Information SUBOXONE sublingual film is administered sublingually or buccally as a single daily dose.

Medication should be prescribed in consideration of the frequency of visits.

Provision of multiple refills is not advised early in treatment or without appropriate patient follow‐up visits.

2.3 Induction Prior to induction, consideration should be given to the type of opioid dependence (i.e., long‐ or short‐acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.

Patients dependent on heroin or other short‐acting opioid products Patients dependent on heroin or other short‐acting opioid products may be inducted with either SUBOXONE sublingual film or with sublingual buprenorphine monotherapy.

At treatment initiation, the first dose of SUBOXONE sublingual film should be administered when objective signs of moderate opioid withdrawal appear, not less than six hours after the patient last used opioids.

It is recommended that an adequate treatment dose, titrated to clinical effectiveness, be achieved as rapidly as possible.

In some studies, a too‐gradual induction over several days led to a high rate of drop‐out of buprenorphine patients during the induction period.

On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE sublingual film is recommended.

Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2‐hour intervals, under supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal symptoms.

On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.

Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, it is recommended that the sublingual site of administration be used during induction to minimize exposure to naloxone, to reduce the risk of precipitated withdrawal.

Patients dependent on methadone or long‐acting opioid products Patients dependent upon methadone or long‐acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short‐acting opioid products.

Buprenorphine/naloxone combination products have not been evaluated in adequate and well‐controlled studies for induction in patients who are physically dependent on long‐acting opioid products, and the naloxone in these combination products is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged withdrawal.

For this reason, buprenorphine monotherapy is recommended in patients taking long‐acting opioids when used according to approved administration instructions.

Following induction, the patient may then be transitioned to once‐daily SUBOXONE sublingual film.

2.4 Maintenance For maintenance, SUBOXONE sublingual film may be administered buccally or sublingually.

The dosage of SUBOXONE sublingual film from Day 3 onwards should be progressively adjusted in increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.

After treatment induction and stabilization, the maintenance dose of SUBOXONE sublingual film is generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day depending on the individual patient and clinical response.

The recommended target dosage of SUBOXONE sublingual film during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose.

Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical advantage.

When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take‐home medication.

There is no maximum recommended duration of maintenance treatment.

Patients may require treatment indefinitely and should continue for as long as patients are benefiting and the use of SUBOXONE sublingual film contributes to the intended treatment goals.

2.5 Method of Administration SUBOXONE sublingual film must be administered whole.

Do not cut, chew, or swallow SUBOXONE sublingual film.

Advise patients not to eat or drink anything until the film is completely dissolved.

Sublingual Administration Place one film under the tongue, close to the base on the left or right side.

If an additional film is necessary to achieve the prescribed dose, place an additional film sublingually on the opposite side from the first film.

Place the film in a manner to minimize overlapping as much as possible.

The film must be kept under the tongue until the film is completely dissolved.

If a third film is necessary to achieve the prescribed dose, place it under the tongue on either side after the first 2 films have dissolved.

Buccal Administration Place one film on the inside of the right or left cheek.

If an additional film is necessary to achieve the prescribed dose, place an additional film on the inside of the opposite cheek.

The film must be kept on the inside of the cheek until the film is completely dissolved.

If a third film is necessary to achieve the prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved.

SUBOXONE sublingual film should NOT be moved after placement.

To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.

Proper administration technique should be demonstrated to the patient.

2.6 Clinical Supervision Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits.

SUBOXONE sublingual film is subject to diversion and abuse.

When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take‐home medication.

Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient.

Medication should be prescribed in consideration of the frequency of visits.

Provision of multiple refills is not advised early in treatment or without appropriate patient follow‐up visits.

Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.

Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow‐up visits may be appropriate.

A once‐monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives.

Continuation or modification of pharmacotherapy should be based on the healthcare provider’s evaluation of treatment outcomes and objectives such as: Absence of medication toxicity.

Absence of medical or behavioral adverse effects.

Responsible handling of medications by the patient.

Patient’s compliance with all elements of the treatment plan (including recovery‐oriented activities, psychotherapy, and/or other psychosocial modalities).

Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).

If treatment goals are not being achieved, the healthcare provider should re‐evaluate the appropriateness of continuing the current treatment.

2.7 Unstable Patients Healthcare providers will need to decide when they cannot appropriately provide further management for particular patients.

For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the healthcare provider does not feel that he/she has the expertise to manage the patient.

In such cases, the healthcare provider may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment.

Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.

Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.

2.8 Discontinuing Treatment The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be made as part of a comprehensive treatment plan.

Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication‐assisted treatment.

Taper patients to reduce the occurrence of opioid withdrawal signs and symptoms.

[See Warnings and Precautions ( 5.7 )] .

2.9 Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and SUBOXONE Sublingual Film Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets and SUBOXONE sublingual film should be started on the same dosage of the previously administered product.

However, dosage adjustments may be necessary when switching between buprenorphine products.

Not all strengths and combinations of the SUBOXONE sublingual films are bioequivalent to SUBOXONE® sublingual tablets as observed in pharmacokinetic studies [see Clinical Pharmacology ( 12.3 )] .

Therefore, systemic exposures of buprenorphine and naloxone may be different when patients are switched from tablets to film or vice‐versa.

Patients should be monitored for symptoms related to over‐dosing or under‐dosing.

2.10 Switching Between SUBOXONE Sublingual Film Strengths As indicated in Table 1 , the sizes and the compositions of the four units of SUBOXONE sublingual films, i.e., mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg and the 12 mg/3 mg units, are different from one another.

If patients switch between various combinations of lower and higher strength units of SUBOXONE sublingual films to obtain the same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg unit, or vice‐versa), systemic exposures of buprenorphine and naloxone may be different and patients should be monitored for over‐dosing or under‐dosing.

For this reason, pharmacist should not substitute one or more film strengths for another without approval of the prescriber.

Table 1.

Comparison of Available SUBOXONE Sublingual Film Strengths by Dimensions and Drug Concentrations.

SUBOXONE sublingual film unit strength (buprenorphine/naloxone) SUBOXONE sublingual film unit dimensions Buprenorphine Concentration % (w/w) Naloxone Concentration % (w/w) 2 mg/0.5 mg 22.0 mm x 12.8 mm 5.4 1.53 4 mg/1 mg (2 times the length of the 2 mg/0.5 mg unit) 22.0 mm x 25.6 mm 5.4 1.53 8 mg/2 mg 22.0 mm x 12.8 mm 17.2 4.88 12 mg/3 mg (1.5 times the length of the 8 mg/2 mg unit) 22.0 mm X 19.2 mm 17.2 4.88 2.11 Switching Between Sublingual and Buccal Sites of Administration The systemic exposure of buprenorphine between buccal and sublingual administration of SUBOXONE sublingual film is similar.

Therefore, once induction is complete, patients can switch between buccal and sublingual administration without significant risk of under or overdosing.

prednisolone 1 MG/ML Oral Solution

WARNINGS

General In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.

Cardio-renal Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium.

These effects are less likely to occur with the synthetic derivatives except when used in large doses.

Dietary salt restriction and potassium supplementation may be necessary.

All corticosteroids increase calcium excretion.

Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients.

Changes in thyroid status of the patient may necessitate adjustment in dosage.

Infections (General) Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals.

There may be decreased resistance and inability to localize infection when corticosteroids are used.

Infection with any pathogen including viral, bacterial, fungal, protozoan or helminthic infection, in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect humoral or cellular immunity, or neutrophil function.

These infections may be mild to severe, and, with increasing doses of corticosteroids, the rate of occurance of infectious complications increases.

Corticosteroids may also mask some signs of infection after it has already started.

Infections (Viral) Chicken pox and measles, for example, can have a more serious or even fatal course in nonimmune children or adults on corticosteroids.

In such children or adults who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information).

If chicken pox develops, treatment with antiviral agents should be considered.

Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi or viruses.

The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

Corticosteroids should not be used in active ocular herpes simplex.

Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Candida, Mycobacterium, Ameba, Toxoplasma, Pneumocystis, Cryptococus, Nocardia, etc.

Corticosteroids may activate latent amebiasis.

Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patient with known or suspected Strongyloides (threadworm) infestation.

In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

Tuberculosis The use of prednisolone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur.

During prolonged corticosteroid therapy these patients should receive chemoprophylaxis.

Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

Killed or inactivated vaccines may be administered, however, the response to such vaccines can not be predicted.

Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease.

DRUG INTERACTIONS

Drug Interactions Drugs such as barbiturates, phenytoin, ephedrine, and rifampin, which induce hepatic microsomal drug metabolizing enzyme activity may enhance metabolism of prednisolone and require that the dosage of prednisolone sodium phosphate oral solution be increased.

Increased activity of both cyclosporin and corticosteroids may occur when the two are used concurrently.

Convulsions have been reported with this concurrent use.

Estrogens may decrease the hepatic metabolism of certain corticosteroids thereby increasing their effect.

Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects.

Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports.

Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Concomitant use of aspirin (or other non-steroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects.

Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

The clearance of salicylates may be increased with concurrent use of corticosteroids.

When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., diuretics, amphotericin-B), patients should be observed closely for development of hypokalemia.

Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis.

If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Due to inhibition of antibody response, patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines.

Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines.

If possible, routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued.

Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Corticosteroids may suppress reactions to skin tests.

OVERDOSAGE

The effects of accidental ingestion of large quantities of prednisolone over a very short period of time have not been reported, but prolonged use of the drug can produce mental symptoms, moon face, abnormal fat deposits, fluid retention, excessive appetite, weight gain, hypertrichosis, acne, striae, ecchymosis, increased sweating, pigmentation, dry scaly skin, thinning scalp hair, increased blood pressure, tachycardia, thrombophlebitis, decreased resistance to infection, negative nitrogen balance with delayed bone and wound healing, headache, weakness, menstrual disorders, accentuated menopausal symptoms, neuropathy, fractures, osteoporosis, peptic ulcer, decreased glucose tolerance, hypokalemia, and adrenal insufficiency.

Hepatomegaly and abdominal distention have been observed in children.

Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive and symptomatic therapy.

For chronic overdosage in the face of severe disease requiring continuous steroid therapy the dosage of prednisolone may be reduced only temporarily, or alternate day treatment may be introduced.

DESCRIPTION

Prednisolone Sodium Phosphate Oral Solution is a dye free, clear, raspberry flavored solution.

Each 5 mL (teaspoonful) of prednisolone sodium phosphate oral solution contains 6.7 mg prednisolone sodium phosphate (5 mg prednisolone base) in a palatable, aqueous vehicle.

Inactive Ingredients: artificial raspberry flavor, dibasic sodium phosphate, USP, methylparaben, monobasic sodium phosphate, purified water, USP, sodium benzoate, NF and sorbitol solution, USP.

Prednisolone sodium phosphate occurs as white or slightly yellow, friable granules or powder.

It is freely soluble in water; soluble in methanol; slightly soluble in alcohol and in chloroform; and very slightly soluble in acetone and in dioxane.

The chemical name of prednisolone sodium phosphate is 11β,17,21-Trihydroxypregna-1,4-diene-3,20-dione 21-(disodium phosphate).

The molecular formula is C 21 H 27 Na 2 O 8 P; the molecular weight is 484.40.

Its chemical structure is: Pharmacological Category: Glucocorticoid prednisolone-01

HOW SUPPLIED

Prednisolone Sodium Phosphate Oral Solution is a clear, raspberry flavored solution containing 6.7 mg prednisolone sodium phosphate (5 mg prednisolone base) per 5 mL (teaspoonful) available in 4 fl oz (118 mL) bottles.

RECOMMENDED STORAGE Store at 4 °–25 °C (39 °–77 °F).

May be refrigerated.

Keep tightly closed and out of the reach of children.

GERIATRIC USE

Geriatric Use Clinical studies of prednisolone sodium phosphate oral solution did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience with prednisolone sodium phosphate has not identified differences in responses between the elderly and younger patients.

However, the incidence of corticosteroid-induced side effects may be increased in geriatric patients and appear to be dose-related.

Osteoporosis is the most frequently encountered complication, which occurs at a higher incidence rate in corticosteroid-treated geriatric patients as compared to younger populations and in age-matched controls.

Losses of bone mineral density appear to be greatest early on in the course of treatment and may recover over time after steroid withdrawal or use of lower doses (i.e., ≤5 mg/day).

Prednisolone doses of 7.5 mg/day or higher have been associated with an increased relative risk of both vertebral and nonvertebral fractures, even in the presence of higher bone density compared to patients with involutional osteoporosis.

Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of prednisolone indication should be undertaken to minimize complications and keep the prednisolone dose at the lowest acceptable level.

Coadministration of bisphosphonates has been shown to retard the rate of bone loss in corticosteroid-treated males and postmenopausal females, and these agents are recommended in the prevention and treatment of corticosteroid-induced osteoporosis.

It has been reported that equivalent weight-based doses yield higher total and unbound prednisolone plasma concentrations and reduced renal and non-renal clearance in elderly patients compared to younger populations.

However, it is not clear whether dosing reductions would be necessary in elderly patients, since these pharmacokinetic alterations may be offset by age-related differences in responsiveness of target organs and/or less pronounced suppression of adrenal release of cortisol.

Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY ).

INDICATIONS AND USAGE

Prednisolone sodium phosphate oral solution is indicated in the following conditions: 1.

Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in adult and pediatric populations with: seasonal or perennial allergic rhinitis; asthma; contact dermatitis; atopic dermatitis; serum sickness; drug hypersensitivity reactions.

2.

Dermatologic Diseases Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme (Stevens-Johnson syndrome); exfoliative erythroderma; mycosis fungoides.

3.

Edematous States To induce diuresis or remission of proteinuria in nephrotic syndrome in adults with lupus erythematosus and in adults and pediatric populations, with idiopathic nephrotic syndrome, without uremia.

4.

Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia; hypercalcemia associated with cancer; nonsuppurative thyroiditis.

5.

Gastrointestinal Diseases To tide the patient over a critical period of the disease in: ulcerative colitis; regional enteritis.

6.

Hematologic Disorders Idiopathic thrombocytopenic purpura in adults; selected cases of secondary thrombocytopenia; acquired (autoimmune) hemolytic anemia; pure red cell aplasia; Diamond-Blackfan anemia.

7.

Neoplastic Diseases For the treatment of acute leukemia and aggressive lymphomas in adults and children.

8.

Nervous System Acute exacerbations of multiple sclerosis.

9.

Ophthalmic Diseases Uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids; temporal arteritis; sympathetic ophthalmia.

10.

Respiratory Diseases Symptomatic sarcoidosis; idiopathic eosinophilic pneumonias; fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy; asthma (as distinct from allergic asthma listed above under ” Allergic States “), hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, acute exacerbations of chronic obstructive pulmonary disease (COPD), and Pneumocystis carinii pneumonia (PCP) associated with hypoxemia occurring in an HIV (+) individual who is also under treatment with appropriate anti-PCP antibiotics.

Studies support the efficacy of systemic corticosteroids for the treatment of these conditions: allergic bronchopulmonary aspergillosis, idiopathic bronchiolitis obliterans with organizing pneumonia.

11.

Rheumatic Disorders As adjunctive therapy for short term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low dose maintenance therapy); ankylosing spondylitis; acute and subacute bursitis; acute nonspecific tenosynovitis; acute gouty arthritis; epicondylitis.

For the treatment of systemic lupus erythematosus, dermatomyositis (polymyositis), polymyalgia rheumatica, Sjogren’s syndrome, relapsing polychrondritis, and certain cases of vasculitis.

12.

Miscellaneous Tuberculous meningitis with subarachnoid block or impending block, tuberculosis with enlarged mediastinal lymph nodes causing respiratory difficulty, and tuberculosis with pleural or pericardial effusion (appropriate antituberculous chemotherapy must be used concurrently when treating any tuberculosis complications); Trichinosis with neurologic or myocardial involvement; acute or chronic solid organ rejection (with or without other agents).

PEDIATRIC USE

Pediatric Use The efficacy and safety of prednisolone in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations.

Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age).

However, some of these conclusions and other indications for pediatric use of corticosteroid, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of prednisolone in pediatric patients are similar to those in adults (see ADVERSE REACTIONS ).

Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis.

Children who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity.

This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels).

Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function.

The linear growth of children treated with corticosteroids by any route should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives.

In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

PREGNANCY

Pregnancy Teratogenic effects Pregnancy Category C Prednisolone has been shown to be teratogenic in many species when given in doses equivalent to the human dose.

Animal studies in which prednisolone has been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring.

There are no adequate and well-controlled studies in pregnant women.

Prednisolone sodium phosphate oral solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

NUSRING MOTHERS

Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

Caution should be exercised when prednisolone sodium phosphate oral solution is administered to a nursing woman.

INFORMATION FOR PATIENTS

Information for Patients Patients should be warned not to discontinue the use of prednisolone sodium phosphate oral solution abruptly or without medical supervision, to advise any medical attendants that they are taking it and to seek medical advice at once should they develop fever or other signs of infection.

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles.

Patients should also be advised that if they are exposed, medical advice should be sought without delay.

DOSAGE AND ADMINISTRATION

The initial dosage of prednisolone sodium phosphate oral solution, 5 mg (base/5 mL) may vary from 5 mL to 60 mL (5 to 60 mg prednisolone base) per day depending on the specific disease entity being treated.

In situations of less severity, lower doses will generally suffice while in selected patients higher initial doses may be required.

The initial dosage should be maintained or adjusted until a satisfactory response is noted.

If after a reasonable period of time, there is a lack of satisfactory clinical response, prednisolone sodium phosphate oral solution should be discontinued and the patient placed on other appropriate therapy.

IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached.

It should be kept in mind that constant monitoring is needed in regard to drug dosage.

Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of prednisolone sodium phosphate oral solution for a period of time consistent with the patient’s condition.

If after long term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

In the treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day or 4 to 8 mg dexamethasone every other day for one month have been shown to be effective.

In pediatric patients, the initial dose of prednisolone sodium phosphate oral solution may vary depending on the specific disease entity being treated.

The range of initial doses is 0.14 to 2 mg/kg/day in three or four divided doses (4 to 60 mg/m 2 bsa/day).

The standard regimen used to treat nephrotic syndrome in pediatric patients is 60 mg/m 2 /day given in three divided doses for 4 weeks, followed by 4 weeks of single dose alternate-day therapy at 40 mg/m 2 /day.

The National Heart, Lung, and Blood Institute (NHLBI) recommended dosing for systemic prednisone, prednisolone or methylprednisolone in children whose asthma is uncontrolled by inhaled corticosteroids and long-acting bronchodilators is 1–2 mg/kg/day in single or divided doses.

It is further recommended that short course, or “burst” therapy, be continued until a child achieves a peak expiratory flow rate of 80% of his or her personal best or symptoms resolve.

This usually requires 3 to 10 days of treatment, although it can take longer.

There is no evidence that tapering the dose after improvement will prevent relapse.

For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds.

When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

Glycopyrrolate 2 MG Oral Tablet

Generic Name: GLYCOPYRROLATE
Brand Name: Glycopyrrolate
  • Substance Name(s):
  • GLYCOPYRROLATE

WARNINGS

In the presence of a high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of glycopyrrolate.

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomyor colostomy .

In this instance treatment with this drug would be inappropriate and possibly harmful.

Glycopyrrolate may produce drowsiness and blurred vision.

In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or performing hazardous work while taking this drug.

Theoretically, with overdosage, a curare-like action may occur, i.e., neuro-muscular blockade leading to muscular weakness and possible paralysis.

Pregnancy The safety of this drug during pregnancy has not been established.

The use of any drug during pregnancy requires that potential benefits of the drug be weighed against possible hazards to mother and child.

Reproduction studies in rats revealed no teratogenic effects from glycopyrrolate; however, the potent anticholinergic action of this agent resulted in diminished rates of conception and of survival at weaning, in a dose-related manner.

Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.

Information on possible adverse effects in the pregnant female is limited to uncontrolled data derived from marketing experience.

Such experience has revealed no reports of teratogenic or other fetus-damaging potential.

No controlled studies to establish the safety of the drug in pregnancy have been performed.

Nursing Mothers It is not known whether this drug is excreted in human milk.

As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

Pediatric Use Since there is no adequate experience in pediatric patients who have received this drug, safety and efficacy in pediatric patients have not been established.

DRUG INTERACTIONS

There are no known drug interactions.

OVERDOSAGE

The symptoms of overdosage of glycopyrrolate are peripheral in nature rather than central.

To guard against further absorption of the drug-use gastric lavage, cathartics and/or enemas.

To combat peripheral anticholinergic effects (residual mydriasis, dry mouth, etc.)-utilize a quaternary ammonium anticholinesterase, such as neostigmine methylsulfate.

To combat hypotension-use pressor amines (norepinephrine, metaraminol) i.v.; and supportive care.

To combat respiratory depression-administer oxygen; utilize a respiratory stimulant such as Dopram®* i.v.; artificial respiration.

DESCRIPTION

Glycopyrrolate tablets contain the synthetic anticholinergic glycopyrrolate.

Glycopyrrolate is a quaternary ammonium compound with the following chemical name: 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

Its empirical formula is C 19 H 28 BrNO 3 , its molecular weight is 398.33, and its structural formula is: Each 1 mg tablet contains: Glycopyrrolate, USP 1mg Each 2 mg tablet contains: Glycopyrrolate, USP 2mg Inactive Ingredients: Dibasic Calcium Phosphate, Lactose, Magnesium Stearate, Povidone, Sodium Starch Glycolate this is the structure

HOW SUPPLIED

Glycopyrrolate tablets 1 mg are bisected, compressed white, round tablets debossed “K” above the bisect and “400” below the bisect on one side of the tablet, and plain on the other side.

Available in bottles of 100 (NDC 49884-065-01).

Glycopyrrolate tablets 2 mg are bisected, compressed white, round tablets debossed “K” above the bisect and “401” below the bisect on one side of the tablet, and plain on the other side.

Available in bottles of 100 (NDC 49884-066-01).

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Dispense in tight container.

Rx only * Dopram ® is a registered trademark of Baxter Healthcare Corporation.

Manufactured by: Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977 Rev: 07/2010 OS065-01-1-02

INDICATIONS AND USAGE

For use as adjunctive therapy in the treatment of peptic ulcer.

PEDIATRIC USE

Pediatric Use Since there is no adequate experience in pediatric patients who have received this drug, safety and efficacy in pediatric patients have not been established.

PREGNANCY

Pregnancy The safety of this drug during pregnancy has not been established.

The use of any drug during pregnancy requires that potential benefits of the drug be weighed against possible hazards to mother and child.

Reproduction studies in rats revealed no teratogenic effects from glycopyrrolate; however, the potent anticholinergic action of this agent resulted in diminished rates of conception and of survival at weaning, in a dose-related manner.

Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.

Information on possible adverse effects in the pregnant female is limited to uncontrolled data derived from marketing experience.

Such experience has revealed no reports of teratogenic or other fetus-damaging potential.

No controlled studies to establish the safety of the drug in pregnancy have been performed.

NUSRING MOTHERS

Nursing Mothers It is not known whether this drug is excreted in human milk.

As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

DOSAGE AND ADMINISTRATION

The dosage of glycopyrrolate should be adjusted to the needs of the individual patient to assure symptomatic control with a minimum of adverse reactions.

The presently recommended maximum daily dosage of glycopyrrolate is 8 mg.

Glycopyrrolate Tablets 1 mg.

The recommended initial dosage of glycopyrrolate for adults is one tablet three times daily (in the morning, early afternoon, and at bedtime).

Some patients may require two tablets at bedtime to assure overnight control of symptoms.

For maintenance, a dosage of one tablet twice a day is frequently adequate.

Glycopyrrolate Tablets 2 mg.

The recommended dosage of glycopyrrolate for adults is one tablet two or three times daily at equally spaced intervals.

Glycopyrrolate tablets are not recommended for use in pediatric patients under the age of 12 years.