Sertraline 100 MG Oral Tablet [Zoloft]

WARNINGS

Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs.

placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

Such monitoring should include daily observation by families and caregivers.

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

Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that ZOLOFT is not approved for use in treating bipolar depression.

Cases of serious sometimes fatal reactions have been reported in patients receiving ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI).

Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma.

These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Therefore, ZOLOFT should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI.

Similarly, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI.

The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and – Potential for Interaction with Monoamine Oxidase Inhibitors ).

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur in treatment with SNRIs and SSRIs, including Zoloft, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

If concomitant treatment of SNRIs and SSRIs, including Zoloft, with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS – Drug Interactions ).

The concomitant use of SNRIs and SSRIs, including Zoloft, with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS – Drug Interactions ).

Neuroleptic Malignant Syndrome (NMS) or NMS-Like Reactions Rare instances of neuroleptic malignant syndrome (NMS) or NMS-like reactions have been reported when a selective serotonin reuptake inhibitor (SSRI) drug, such as sertraline, or a serotonin-norepinephrine reuptake inhibitor (SNRI) was added to antipsychotic drug therapy.

Additionally, a small number of such cases have been reported with SSRI’s and SNRI’s in the absence of antipsychotic coadministration.

These serious and sometimes fatal events can include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

It is uncertain whether these cases are serotonin syndrome which, in its most severe form, can resemble neuroleptic malignant syndrome.

As these events may result in potentially life-threatening conditions, patients should be monitored for the emergence of NMS-like signs and symptoms, especially if sertraline and an antipsychotic drug are taken concurrently.

Treatment with sertraline and any concomitant antipsychotic agent should be discontinued immediately if such events occur and supportive symptomatic treatment should be initiated.

DRUG INTERACTIONS

Drug Interactions Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins Because sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.

Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other tightly bound drugs.

In a study comparing prothrombin time AUC (0–120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50–200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT compared to a 1% decrease for placebo (p<0.02).

The normalization of prothrombin time for the ZOLOFT group was delayed compared to the placebo group.

The clinical significance of this change is unknown.

Accordingly, prothrombin time should be carefully monitored when ZOLOFT therapy is initiated or stopped.

Cimetidine In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group.

The clinical significance of these changes is unknown.

CNS Active Drugs In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).

There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a 20% decrease in the placebo group (p<0.03).

The clinical significance of these changes is unknown.

In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did not significantly alter steady-state lithium levels or the renal clearance of lithium.

Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.

In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG.

Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known.

While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT and pimozide should be contraindicated (see CONTRAINDICATIONS ).

Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.

Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of Zoloft therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.

The effect of Zoloft on valproate levels has not been evaluated in clinical trials.

In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of Zoloft therapy with appropriate adjustments to the valproate dose.

The risk of using ZOLOFT in combination with other CNS active drugs has not been systematically evaluated.

Consequently, caution is advised if the concomitant administration of ZOLOFT and such drugs is required.

There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to ZOLOFT.

Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents.

The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.

Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS .

Drugs Metabolized by P450 3A4 In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions.

The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride.

These data indicate that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.

Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).

Drugs Metabolized by P450 2D6 Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by P450 2D6.

The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide.

The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug.

There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class.

Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.

Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require lower doses than usually prescribed for the other drug.

Furthermore, whenever ZOLOFT is withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS ).

Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including Zoloft, and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including Zoloft, are coadministered with other drugs that may affect the serotonergic neutrotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.

John’s Wort (see WARNINGS-Serotonin Syndrome ).

The concomitant use of Zoloft with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS – Drug Interactions ).

Triptans There have been rare post marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan.

If concomitant treatment of SNRIs and SSRIs, including Zoloft, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome ).

Sumatriptan There have been rare post marketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan.

If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.

Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs) The extent to which SSRI–TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.

Nevertheless, caution is indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA metabolism.

Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450 2D6 under PRECAUTIONS ).

Hypoglycemic Drugs In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose.

ZOLOFT administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug.

The clinical significance of this decrease in tolbutamide clearance is unknown.

Atenolol ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.

Digoxin In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.

Microsomal Enzyme Induction Preclinical studies have shown ZOLOFT to induce hepatic microsomal enzymes.

In clinical studies, ZOLOFT was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg/day for 21 days.

This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.

Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.) Serotonin release by platelets plays an important role in hemostasis.

Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.

These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin.

Patients receiving warfarin therapy should be carefully monitored when Zoloft is initiated or discontinued.

Electroconvulsive Therapy There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and ZOLOFT.

Alcohol Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not recommended.

OVERDOSAGE

Human Experience Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999).

Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome.

The remaining 524 cases had an unknown outcome.

The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.

The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and subsequently recovered.

However, another patient who took 2.5 grams of sertraline hydrochloride alone experienced a fatal outcome.

Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor and syncope.

Overdose Management Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation and ventilation.

Monitor cardiac rhythm and vital signs.

General supportive and symptomatic measures are also recommended.

Induction of emesis is not recommended.

Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered.

Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.

No specific antidotes for sertraline are known.

In managing overdosage, consider the possibility of multiple drug involvement.

The physician should consider contacting a poison control center on the treatment of any overdose.

Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference ® (PDR ® ).

DESCRIPTION

ZOLOFT ® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral administration.

It has a molecular weight of 342.7.

Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride.

The empirical formula C 17 H 17 NCl 2 •HCl is represented by the following structural formula: Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.

ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.

ZOLOFT oral concentrate is available in a multidose 60 mL bottle.

Each mL of solution contains sertraline hydrochloride equivalent to 20 mg of sertraline.

The solution contains the following inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT).

The oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for Patients and DOSAGE AND ADMINISTRATION ).

Chemical Structure

CLINICAL STUDIES

Clinical Trials Major Depressive Disorder The efficacy of ZOLOFT as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder.

Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.

Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.

Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.

Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.

Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on ZOLOFT 50–200 mg/day.

These patients (N=295) were randomized to continuation for 44 weeks on double-blind ZOLOFT 50–200 mg/day or placebo.

A statistically significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on placebo.

The mean dose for completers was 70 mg/day.

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

Obsessive-Compulsive Disorder (OCD) The effectiveness of ZOLOFT in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1–3).

Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25.

Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day.

Patients receiving ZOLOFT experienced a mean reduction of approximately 4 points on the YBOCS total score which was significantly greater than the mean reduction of 2 points in placebo-treated patients.

Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.

Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the YBOCS total score which were significantly greater than the approximately 3 point reduction in placebo-treated patients.

Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day.

Patients receiving ZOLOFT experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients.

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and adolescents, ages 6–17).

Patients receiving ZOLOFT in this study were initiated at doses of either 25 mg/day (children, ages 6–12) or 50 mg/day (adolescents, ages 13–17), and then titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated.

The mean dose for completers was 178 mg/day.

Dosing was once a day in the morning or evening.

Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22.

Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score which was significantly greater than the 3 unit reduction for placebo patients.

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on ZOLOFT 50–200 mg/day (n=224) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response.

Response during the single-blind phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally improved).

Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient’s condition in the investigator’s judgment, to justify alternative treatment.

Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator.

Patients receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo.

This pattern was demonstrated in male and female subjects.

Panic Disorder The effectiveness of ZOLOFT in the treatment of panic disorder was demonstrated in three double-blind, placebo-controlled studies (Studies 1–3) of adult outpatients who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.

Studies 1 and 2 were 10-week flexible dose studies.

ZOLOFT was initiated at 25 mg/day for the first week, and then patients were dosed in a range of 50–200 mg/day on the basis of clinical response and toleration.

The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2.

In these studies, ZOLOFT was shown to be significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity of Illness and Global Improvement scores.

The difference between ZOLOFT and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.

Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.

Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack frequency than patients receiving placebo.

Study 3 was not readily interpretable regarding a dose response relationship for effectiveness.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender.

In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded during a 52-week open trial on ZOLOFT 50–200 mg/day (n=183) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response.

Response during the open phase was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).

Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline.

Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator.

Patients receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo.

This pattern was demonstrated in male and female subjects.

Posttraumatic Stress Disorder (PTSD) The effectiveness of ZOLOFT in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies 1–2) of adult outpatients who met DSM-III-R criteria for PTSD.

The mean duration of PTSD for these patients was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.

Studies 1 and 2 were 12-week flexible dose studies.

ZOLOFT was initiated at 25 mg/day for the first week, and patients were then dosed in the range of 50–200 mg/day on the basis of clinical response and toleration.

The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day, respectively for Studies 1 and 2.

Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance symptoms.

ZOLOFT was shown to be significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores.

In two additional placebo-controlled PTSD trials, the difference in response to treatment between patients receiving ZOLOFT and patients receiving placebo was not statistically significant.

One of these additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the second additional study was conducted in predominantly male veterans.

As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; Studies 1 and 2 combined).

Post hoc exploratory analyses revealed a significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies.

The clinical significance of this apparent gender interaction is unknown at this time.

There was insufficient information to determine the effect of race or age on outcome.

In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on ZOLOFT 50–200 mg/day (n=96) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse.

Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline.

Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3) worsening of the patient’s condition in the investigator’s judgment.

Patients receiving continued ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo.

This pattern was demonstrated in male and female subjects.

Premenstrual Dysphoric Disorder (PMDD) The effectiveness of ZOLOFT for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles.

Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV.

Patients in Study 2 met DSM-IV criteria for PMDD.

Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses.

The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies.

Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown.

Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms.

Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.

In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle.

In subsequent cycles, patients were dosed in the range of 50–150 mg/day on the basis of clinical response and toleration.

The mean dose for completers was 102 mg/day.

ZOLOFT administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.

In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses.

In subsequent cycles, patients were dosed in the range of 50–100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration.

Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle.

The mean ZOLOFT dose for completers was 74 mg/day.

ZOLOFT administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.

There was insufficient information to determine the effect of race or age on outcome in these studies.

Social Anxiety Disorder The effectiveness of ZOLOFT in the treatment of social anxiety disorder (also known as social phobia) was established in two multicenter placebo-controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.

Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50–200 mg/day) to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week.

Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety and avoidance of social and performance situations, and by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved).

ZOLOFT was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders.

Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50–200 mg/day) to placebo.

Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2.

ZOLOFT was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more responders than placebo as defined by the CGI-I.

Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.

There was insufficient information to determine the effect of race or age on outcome.

In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on ZOLOFT 50–200 mg/day were randomized to continuation of ZOLOFT or to substitution of placebo for up to 24 weeks of observation for relapse.

Relapse was defined as ≥ 2 point increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy.

Patients receiving ZOLOFT continuation treatment experienced a statistically significantly lower relapse rate over this 24-week study than patients randomized to placebo substitution.

HOW SUPPLIED

ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.

ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and on the other side scored and engraved with 25 mg.

NDC 0049-4960-30 Bottles of 30 NDC 0049-4960-50 Bottles of 50 ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and on the other side scored and engraved with 50 mg.

NDC 0049-4900-30 Bottles of 30 NDC 0049-4900-66 Bottles of 100 NDC 0049-4900-73 Bottles of 500 NDC 0049-4900-94 Bottles of 5000 NDC 0049-4900-41 Unit Dose Packages of 100 ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT and on the other side scored and engraved with 100 mg.

NDC 0049-4910-30 Bottles of 30 NDC 0049-4910-66 Bottles of 100 NDC 0049-4910-73 Bottles of 500 NDC 0049-4910-94 Bottles of 5000 NDC 0049-4910-41 Unit Dose Packages of 100 Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F)[see USP Controlled Room Temperature].

ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and 12% alcohol.

It is supplied as a 60 mL bottle with an accompanying calibrated dropper.

NDC 0049-4940-23 Bottles of 60 mL Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].

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GERIATRIC USE

Geriatric Use U.S.

geriatric clinical studies of ZOLOFT in major depressive disorder included 663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age.

No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects (see ADVERSE REACTIONS ), and other reported experience has not identified differences in safety patterns between the elderly and younger subjects.

As with all medications, greater sensitivity of some older individuals cannot be ruled out.

There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in major depressive disorder.

No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.

Other Adverse Events in Geriatric Patients.

In 354 geriatric subjects treated with ZOLOFT in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 2 and 3.

Urinary tract infection was the only adverse event not appearing in Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.

SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia ).

INDICATIONS AND USAGE

Major Depressive Disorder ZOLOFT (sertraline hydrochloride) is indicated for the treatment of major depressive disorder in adults.

The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY ).

A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately studied.

The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial.

The usefulness of the drug in patients receiving ZOLOFT for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Obsessive-Compulsive Disorder ZOLOFT is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Panic Disorder ZOLOFT is indicated for the treatment of panic disorder in adults, with or without agoraphobia, as defined in DSM-IV.

Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of ZOLOFT was established in three 10–12 week trials in adult panic disorder patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who responded during a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Posttraumatic Stress Disorder (PTSD) ZOLOFT (sertraline hydrochloride) is indicated for the treatment of posttraumatic stress disorder in adults.

The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY ).

PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror.

Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger.

A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28 weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial.

Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Premenstrual Dysphoric Disorder (PMDD) ZOLOFT is indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults.

The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY ).

The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability.

Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.

Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain.

These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others.

In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.

The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.

Therefore, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Social Anxiety Disorder ZOLOFT (sertraline hydrochloride) is indicated for the treatment of social anxiety disorder, also known as social phobia in adults.

The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of social or performance situations involving exposure to unfamiliar people or possible scrutiny by others and by fears of acting in a humiliating or embarrassing way.

Exposure to the feared social situation almost always provokes anxiety and feared social or performance situations are avoided or else are endured with intense anxiety or distress.

In addition, patients recognize that the fear is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is associated with functional impairment or marked distress.

The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-controlled trial.

Physicians who prescribe ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under CLINICAL PHARMACOLOGY ).

PEDIATRIC USE

Pediatric Use The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6–17 (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk) .

Two placebo controlled trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data were not sufficient to support a claim for use in pediatric patients.

Anyone considering the use of Zoloft in a child or adolescent must balance the potential risks with the clinical need.

The safety of ZOLOFT use in children and adolescents with OCD, ages 6–18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6–17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6–18, who had completed the initial 12-week, double-blind, placebo-controlled study.

ZOLOFT was administered at doses of either 25 mg/day (children, ages 6–12) or 50 mg/day (adolescents, ages 13–18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response.

The mean dose for completers was 157 mg/day.

In the acute 12 week pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally similar to that observed in adults.

Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of age with major depressive disorder or OCD and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight (see Pharmacokinetics under CLINICAL PHARMACOLOGY ).

Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of age have received ZOLOFT in clinical trials, both controlled and uncontrolled.

The adverse event profile observed in these patients was generally similar to that observed in adult studies with ZOLOFT (see ADVERSE REACTIONS ).

As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of ZOLOFT.

In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50–200 mg) outpatient trials for major depressive disorder (n=373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6–11) and adolescents (ages 12–17), in both cases representing a slight weight loss for sertraline compared to a slight gain for placebo.

At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo.

At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo.

There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents.

For children, about 7% had a weight loss > 7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients.

A subset of these patients who completed the randomized controlled trials (sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study.

A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials.

The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment.

Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers.

Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term.

Safety and effectiveness in pediatric patients below the age of 6 have not been established.

The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and adolescents with OCD or major depressive disorder have not been systematically assessed.

The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration and from the extrapolation of experience gained with adult patients.

In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents.

Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide Risk ).

PREGNANCY

Pregnancy–Pregnancy Category C Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively.

These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/m 2 basis.

There was no evidence of teratogenicity at any dose level.

When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m 2 basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m 2 basis) in rabbits.

When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth.

Pup body weights were also decreased during the first four days after birth.

These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m 2 basis).

The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m 2 basis).

The decrease in pup survival was shown to be due to in utero exposure to sertraline.

The clinical significance of these effects is unknown.

There are no adequate and well-controlled studies in pregnant women.

ZOLOFT (sertraline hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when ZOLOFT is administered to a nursing woman.

BOXED WARNING

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.

Anyone considering the use of Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.

Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.

Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised of the need for close observation and communication with the prescriber.

Zoloft is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD).

(See Warnings: Clinical Worsening and Suicide Risk , Precautions: Information for Patients , and Precautions: Pediatric Use )

INFORMATION FOR PATIENTS

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Zoloft and should counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions: is available for ZOLOFT.

The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZOLOFT.

Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.

Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.

Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including Zoloft, and triptans, tramadol, or other serotonergic agents.

Patients should be told that although ZOLOFT has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely.

Therefore, patients should be told that until they learn how they respond to ZOLOFT they should be careful doing activities when they need to be alert, such as driving a car or operating machinery.

Patients should be cautioned about the concomitant use of Zoloft and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Patients should be told that although ZOLOFT has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of ZOLOFT and alcohol is not advised.

Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists.

Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they are breast feeding an infant.

ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active ingredient and 12% alcohol.

ZOLOFT Oral Concentrate must be diluted before use.

Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY.

Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed.

The dose should be taken immediately after mixing.

Do not mix in advance.

At times, a slight haze may appear after mixing; this is normal.

Note that caution should be exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural rubber.

DOSAGE AND ADMINISTRATION

Initial Treatment Dosage for Adults Major Depressive Disorder and Obsessive-Compulsive Disorder ZOLOFT treatment should be administered at a dose of 50 mg once daily.

Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder ZOLOFT treatment should be initiated with a dose of 25 mg once daily.

After one week, the dose should be increased to 50 mg once daily.

While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50–200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the treatment of these indications.

Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose.

Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day.

Given the 24 hour elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.

Premenstrual Dysphoric Disorder ZOLOFT treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.

While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50–150 mg/day with dose increases at the onset of each new menstrual cycle (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle.

If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period.

ZOLOFT should be administered once daily, either in the morning or evening.

Dosage for Pediatric Population (Children and Adolescents) Obsessive-Compulsive Disorder ZOLOFT treatment should be initiated with a dose of 25 mg once daily in children (ages 6–12) and at a dose of 50 mg once daily in adolescents (ages 13–17).

While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25–200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for pediatric patients (6–17 years) with OCD.

Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day.

For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing.

Given the 24 hour elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.

ZOLOFT should be administered once daily, either in the morning or evening.

Maintenance/Continuation/Extended Treatment Major Depressive Disorder It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode.

Systematic evaluation of ZOLOFT has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50–200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL PHARMACOLOGY ).

It is not known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose needed to achieve an initial response.

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

Posttraumatic Stress Disorder It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50–200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY ).

It is not known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose needed to achieve an initial response.

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

Social Anxiety Disorder Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50–200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.

Obsessive-Compulsive Disorder and Panic Disorder It is generally agreed that OCD and Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of continuing ZOLOFT for periods of up to 28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50–200 mg/day has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL PHARMACOLOGY ).

It is not known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose needed to achieve an initial response.

Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Premenstrual Dysphoric Disorder The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.

However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient.

Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

Switching Patients to or from a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT.

In addition, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see CONTRAINDICATIONS and WARNINGS ).

Special Populations Dosage for Hepatically Impaired Patients The use of sertraline in patients with liver disease should be approached with caution.

The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied.

If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).

Treatment of Pregnant Women During the Third Trimester Neonates exposed to ZOLOFT and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS ).

When treating pregnant women with ZOLOFT during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

The physician may consider tapering ZOLOFT in the third trimester.

Discontinuation of Treatment with Zoloft Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been reported (see PRECAUTIONS ).

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.

ZOLOFT Oral Concentrate ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active ingredient and 12% alcohol.

ZOLOFT Oral Concentrate must be diluted before use.

Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY.

Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed.

The dose should be taken immediately after mixing.

Do not mix in advance.

At times, a slight haze may appear after mixing; this is normal.

Note that caution should be exercised for patients with latex sensitivity, as the dropper dispenser contains dry natural rubber.

ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

Nimodipine 30 MG Oral Capsule

WARNINGS

DEATH DUE TO INADVERTENT INTRAVENOUS ADMINISTRATION: DO NOT ADMINISTER NIMODIPINE INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES.

DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS, INCLUDING CARDIAC ARREST, CARDIOVASCULAR COLLAPSE, HYPOTENSION, AND BRADYCARDIA, HAVE OCCURRED WHEN THE CONTENTS OF NIMODIPINE CAPSULES HAVE BEEN INJECTED PARENTERALLY (SEE DOSAGE AND ADMINISTRATION ).

Reduced Efficacy with CYP3A4 Inducers: Concomitant use of strong CYP3A4 inducers (e.g.

rifampin, phenobarbital, phenytoin, carbamazepine, St John’s wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be very significantly reduced (see PRECAUTIONS, Drug Interactions ).

Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine to a lesser extent.

Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required.

Moderate and weak CYP3A4 inhibitors include, for example: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.

OVERDOSAGE

There have been no reports of overdosage from the oral administration of nimodipine.

Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension.

Clinically significant hypotension due to nimodipine overdosage may require active cardiovascular support with pressor agents.

Specific treatments for calcium channel blocker overdose should also be given promptly.

Since nimodipine is highly protein-bound, dialysis is not likely to be of benefit.

DESCRIPTION

Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers.

Nimodipine is isopropyl 2 -methoxyethyl 1,4 –dihydro -2,6 –dimethyl -4-(m-nitrophenyl) -3,5-pyridinedicarboxylate.

It has a molecular weight of 418.5 and a molecular formula of C 21 H 26 N 2 O 7 .

The structural formula is: Nimodipine is a yellow crystalline substance, practically insoluble in water.

Nimodipine capsules are formulated as soft gelatin capsules for oral administration.

Each liquid filled capsule contains 30 mg of nimodipine.

In addition the capsules contain the following inactive ingredients: gelatin, glycerin, hypromellose, iron oxide black, kosher glycerin, mannitol, peppermint oil, polyethylene glycol, propylene glycol, sorbitol, sorbitol anhydrides and titanium dioxide.

6fb8ce9c-figure-01

HOW SUPPLIED

Nimodipine Capsules 30 mg – Oblong, white opaque, soft gelatin capsules in Overbagged with 10 capsules per bag NDC 55154-4184-0 • Printed H108 in black ink.

The capsules should be stored in the manufacturer’s original package.

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Capsules should be protected from light and freezing.

Manufactured for: Heritage Pharmaceuticals Inc.

Eatontown, NJ 07724 Manufactured by: Banner Pharmacaps, Inc.

High Point, NC 27265 Distributed by: Cardinal Health Dublin, OH 43017 L51227260318 Iss.

02/2014

MECHANISM OF ACTION

Mechanism of Action Nimodipine is a calcium channel blocker.

The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents.

Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle.

In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of nimodipine-treated subarachnoid hemorrhage (SAH) patients.

The precise mechanism of action of nimodipine in humans is unknown.

Although the clinical studies described below demonstrate a favorable effect of nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that the drug either prevents or relieves the spasm of these arteries.

However, whether or not the arteriographic methodology utilized was adequate to detect a clinically meaningful effect, if any, on vasospasm is unknown.

INDICATIONS AND USAGE

Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).

BOXED WARNING

DO NOT ADMINISTER NIMODIPINE INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES.

DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS HAVE OCCURRED WHEN THE CONTENTS OF NIMODIPINE CAPSULES HAVE BEEN INJECTED PARENTERALLY (See WARNINGS and DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION

DO NOT ADMINISTER NIMODIPINE CAPSULES INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES (see WARNINGS ).

If Nimodipine is inadvertently administered intravenously, clinically significant hypotension may require cardiovascular support with pressor agents.

Specific treatments for calcium channel blocker overdose should also be given promptly.

Nimodipine is given orally in the form of soft gelatin 30 mg capsules for subarachnoid hemorrhage.

The recommended oral dose is 60 mg (two 30 mg capsules) every 4 hours for 21 consecutive days.

In general, the capsules should be swallowed whole with a little liquid, preferably not less than one hour before or two hours after meals.

Grapefruit juice is to be avoided (See PRECAUTIONS, Drug Interactions ).

Oral nimodipine therapy should commence as soon as possible within 96 hours of the onset of subarachnoid hemorrhage.

If the capsule cannot be swallowed, e.g., at the time of surgery, or if the patient is unconscious, a hole should be made in both ends of the capsule with an 18 gauge needle, and the contents of the capsule extracted into a syringe.

A parenteral syringe can be used to extract the liquid inside the capsule, but the liquid should always be transferred to a syringe that cannot accept a needle and that is designed for administration orally or via a naso-gastric tube or PEG.

To help minimize administration errors, it is recommended that the syringe used for administration be labeled “Not for IV Use”.

The contents should then be emptied into the patient’s in situ naso-gastric tube and washed down the tube with 30 mL of normal saline (0.9%).

Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first pass capacity and a reduced metabolic clearance.

The reduction in blood pressure and other adverse effects may be more pronounced in these patients.

Dosage should be reduced to one 30 mg capsule every 4 hours with close monitoring of blood pressure and heart rate; if necessary, discontinuation of the treatment should be considered.

Strong inhibitors of CYP3A4 should not be administered concomitantly with nimodipine (See CONTRAINDICATIONS ).

Strong inducers of CYP3A4 should generally not be administered with nimodipine (See WARNINGS ).

Patients on moderate and weak inducers of CYP3A4 should be closely monitored for lack of effectiveness, and a nimodipine dose increase may be required.

Patients on moderate and weak CYP3A4 inhibitors may require a nimodipine dose reduction in case of hypotension (See PRECAUTIONS, Drug Interactions )

fluticasone propionate 250 MCG/INHAL Dry Powder Inhaler, 60 Blisters

Generic Name: FLUTICASONE PROPIONATE
Brand Name: FLOVENT DISKUS
  • Substance Name(s):
  • FLUTICASONE PROPIONATE

DRUG INTERACTIONS

7 Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended.

May increase risk of systemic corticosteroid effects.

( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4.

The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur.

Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)] .

During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Ketoconazole Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

OVERDOSAGE

10 Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)] .

Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated.

Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated.

Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated.

Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

DESCRIPTION

11 FLOVENT DISKUS inhalation powder is a dry powder inhaler for oral inhalation.

The active component of FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg is fluticasone propionate, a corticosteroid having the chemical name S- (fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C 25 H 31 F 3 O 5 S.

It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT DISKUS is an orange plastic inhaler containing a foil blister strip.

Each blister on the strip contains a white powder mix of micronized fluticasone propionate (50, 100, or 250 mcg) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins).

After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, FLOVENT DISKUS delivers 46, 94, and 229 mcg of fluticasone propionate from FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

In children with asthma aged 4 and 8 years, mean PIF through FLOVENT DISKUS was 70 and 104 L/min, respectively (range: 48 to 123 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Chemical structure

CLINICAL STUDIES

14 14.1 Adult and Adolescent Subjects Aged 12 Years and Older Four randomized, double-blind, parallel-group, placebo-controlled, U.S.

clinical trials were conducted in 1,036 adult and adolescent subjects (aged 12 years and older) with asthma to assess the efficacy and safety of FLOVENT DISKUS in the treatment of asthma.

Fixed dosages of 100, 250, and 500 mcg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity.

Subjects in these trials included those inadequately controlled with bronchodilators alone and those already maintained on daily ICS.

All doses were delivered by inhalation of the contents of 1 or 2 blisters from FLOVENT DISKUS twice daily.

Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEV 1 prior to AM dose) for 3 recommended dosages of FLOVENT DISKUS (100, 250, and 500 mcg twice daily) and placebo from the four 12-week trials in adolescents and adults.

These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group.

Therefore, pulmonary function results at Endpoint (the last evaluable FEV 1 result, including most patients’ lung function data) are also displayed.

Pulmonary function, as determined by percent change from baseline in FEV 1 at recommended dosages of FLOVENT DISKUS improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone In all 4 efficacy trials, measures of pulmonary function (FEV 1 ) were statistically significantly improved as compared with placebo at all twice-daily doses.

Subjects on all dosages of FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.

In a clinical trial of 111 subjects with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 mcg twice daily was evaluated.

Both doses enabled a statistically significantly larger percentage of subjects to wean from oral prednisone as compared with placebo (75% of the subjects on 500 mcg twice daily and 89% of the subjects on 1,000 mcg twice daily as compared with 9% of subjects on placebo).

Accompanying the reduction in oral corticosteroid use, subjects treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone 14.2 Pediatric Subjects Aged 4 to 11 Years A 12-week, placebo-controlled clinical trial was conducted in 437 pediatric subjects (177 received FLOVENT DISKUS), approximately half of whom were receiving ICS at baseline.

In this trial, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV 1 (15% and 18% change from baseline at Endpoint, respectively) compared with placebo (7% change).

AM PEF was also significantly improved with doses of fluticasone propionate 50 and 100 mcg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared with placebo (14% change).

In this trial, subjects on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma).

Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric subjects with asthma, approximately half of whom were receiving ICS at baseline.

In these trials, FLOVENT DISKUS was efficacious at doses of 50 and 100 mcg twice daily when compared with placebo on major endpoints including lung function and symptom scores.

Pulmonary function improved significantly compared with placebo by the first week of treatment, and subjects treated with FLOVENT DISKUS were also less likely to discontinue trial participation due to asthma deterioration.

One hundred ninety-two (192) subjects received FLOVENT DISKUS for up to 1 year during an open-label extension.

Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.

HOW SUPPLIED

16 /STORAGE AND HANDLING FLOVENT DISKUS 50 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0600-02).

FLOVENT DISKUS 100 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0602-02).

FLOVENT DISKUS 250 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0601-02).

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature].

Store in a dry place away from direct heat or sunlight.

Keep out of reach of children.

FLOVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use.

Discard FLOVENT DISKUS 6 weeks (50-mcg strength) or 2 months (100- and 250-mcg strengths) after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first.

The inhaler is not reusable.

Do not attempt to take the inhaler apart.

GERIATRIC USE

8.5 Geriatric Use Safety data have been collected on 280 subjects (FLOVENT DISKUS n = 83, FLOVENT ROTADISK n = 197) aged 65 years and older and 33 subjects (FLOVENT DISKUS n = 14, FLOVENT ROTADISK n = 19) aged 75 years and older who have been treated with fluticasone propionate inhalation powder in U.S.

and non-U.S.

clinical trials.

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 elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation.

The strip contains fluticasone propionate 50, 100, or 250 mcg per blister.

Inhalation powder: Inhaler containing fluticasone propionate (50, 100, or 250 mcg) as a powder formulation for oral inhalation.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity.

Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide.

Data from the McKenzie vasoconstrictor assay in man are consistent with these results.

The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma.

Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate.

This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.

INDICATIONS AND USAGE

1 FLOVENT DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

Important Limitation of Use FLOVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

FLOVENT DISKUS is an inhaled corticosteroid (ICS) indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

( 1 ) Important limitation: • Not indicated for relief of acute bronchospasm.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of FLOVENT DISKUS in children aged 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)] .

The safety and effectiveness of FLOVENT DISKUS in children younger than 4 years have not been established.

Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients.

A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS.

The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known.

Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients.

In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure.

This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function.

The long‑term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.

The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown.

The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT DISKUS, should be monitored routinely (e.g., via stadiometry).

The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies.

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S.

in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years.

The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100‑mcg group (n = 89).

An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data.

A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100‑mcg group (n = 79).

In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3 rd percentile = 3.8 cm/year, 50 th percentile = 5.4 cm/year, and 97 th percentile = 7.0 cm/year; girls – 3 rd percentile = 4.2 cm/year, 50 th percentile = 5.7 cm/year, and 97 th percentile = 7.3 cm/year.

The clinical relevance of these growth data is not certain.

PREGNANCY

8.1 Pregnancy Risk Summary There are insufficient data on the use of FLOVENT DISKUS in pregnant women.

There are clinical considerations with the use of FLOVENT DISKUS in pregnant women.

(See Clinical Considerations.) In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis.

(See Data.) However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis.

(See Data.) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

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

In the U.S.

general population, the estimated 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/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Data Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species.

Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day).

The rat no observed adverse effect level (NOAEL) was observed at approximately 0.15 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day).

Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day).

The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.13 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.

The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).

Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day).

The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.2 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Candida albicans infection of the mouth and pharynx may occur.

Monitor patients periodically.

Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk.

( 5.1 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

( 5.3 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids.

Taper patients slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

( 5.4 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue FLOVENT DISKUS slowly.

( 5.5 ) • Assess for decrease in bone mineral density initially and periodically thereafter.

( 5.7 ) • Monitor growth of pediatric patients.

( 5.8 ) • Glaucoma and cataracts may occur with long-term use of ICS.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

( 5.9 ) 5.1 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT DISKUS.

When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT DISKUS continues, but at times therapy with FLOVENT DISKUS may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.2 Acute Asthma Episodes FLOVENT DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT DISKUS.

During such episodes, patients may require therapy with oral corticosteroids.

5.3 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In such children or adults who have not had these diseases or been properly immunized, 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 a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.4 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although FLOVENT DISKUS may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT DISKUS.

Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to FLOVENT DISKUS may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.5 Hypercorticism and Adrenal Suppression Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol.

Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with FLOVENT DISKUS should be observed carefully for any evidence of systemic corticosteroid effects.

Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects.

If such effects occur, FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use FLOVENT DISKUS [see Contraindications (4)] .

5.7 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

5.8 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients .

Monitor the growth of pediatric patients receiving FLOVENT DISKUS routinely (e.g., via stadiometry).

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2), Use in Specific Populations (8.4)] .

5.9 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of ICS, including fluticasone propionate.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

5.10 Paradoxical Bronchospasm As with other inhaled medicines, bronchospasm may occur with an immediate increase in wheezing after dosing.

If bronchospasm occurs following dosing with FLOVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; FLOVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted.

5.11 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] .

5.12 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions.

Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy.

These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate.

Cases of serious eosinophilic conditions have also been reported with other ICS in this clinical setting.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

A causal relationship between fluticasone propionate and these underlying conditions has not been established.

INFORMATION FOR PATIENTS

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

Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients.

If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be temporarily interrupted under close medical supervision.

Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Status Asthmaticus and Acute Asthma Symptoms Inform patients that FLOVENT DISKUS is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations.

Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol.

Instruct patients to contact their physicians immediately if there is deterioration of their asthma.

Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay.

Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression Advise patients that FLOVENT DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.

Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

Patients should discontinue FLOVENT DISKUS if such reactions occur.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take FLOVENT DISKUS.

Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including FLOVENT DISKUS, may cause a reduction in growth velocity when administered to pediatric patients.

Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Glaucoma and Cataracts Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Use Daily for Best Effect Patients should use FLOVENT DISKUS at regular intervals as directed.

Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer.

Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens.

Instruct patients not to stop use of FLOVENT DISKUS abruptly.

Patients should contact their physicians immediately if they discontinue use of FLOVENT DISKUS.

Trademarks are owned by or licensed to the GSK group of companies.

GlaxoSmithKline Durham, NC 27701 ©2023 GSK group of companies or its licensor.

FLD:16PI

DOSAGE AND ADMINISTRATION

2 • For oral inhalation only.

( 2.1 ) • Starting dosage is based on prior asthma therapy and disease severity.

( 2.2 ) • Treatment of asthma in patients aged 12 years and older: 100 mcg twice daily up to a maximum recommended dosage of 1,000 mcg twice daily.

( 2.2 ) • Treatment of asthma in patients aged 4 to 11 years: 50 mcg twice daily up to a maximum recommended dosage of 100 mcg twice daily.

( 2.2 ) 2.1 Administration Information FLOVENT DISKUS should be administered by the orally inhaled route in patients aged 4 years and older.

After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

2.2 Recommended Dosage Adult and Adolescent Patients Aged 12 Years and Older The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

The recommended starting dosage for patients aged 12 years and older who are not on an inhaled corticosteroid (ICS) is 100 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control.

The maximum recommended dosage for patients aged 12 years and older is 1,000 mcg twice daily.

Pediatric Patients Aged 4 to 11 Years The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

For patients aged 4 to 11 years not on an ICS, the recommended starting dosage is 50 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, increasing the dosage to 100 mcg twice daily may provide additional asthma control.

The maximum recommended dosage for patients aged 4 to 11 years is 100 mcg twice daily.

General Dosing Recommendations If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be used for immediate relief.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

If a dosage regimen fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength with a higher strength, initiating an ICS and long-acting beta2-agonist (LABA) combination product, or initiating oral corticosteroids, should be considered.

After asthma stability has been achieved, titrate to the lowest effective dosage to reduce the possibility of side effects.

rizatriptan 10 MG (as rizatriptan benzoate 14.53 MG) Oral Tablet

Generic Name: RIZATRIPTAN BENZOATE
Brand Name: Rizatriptan Benzoate
  • Substance Name(s):
  • RIZATRIPTAN BENZOATE

DRUG INTERACTIONS

7 7.1 Propranolol The dose of rizatriptan benzoate tablets should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .

7.2 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions.

Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and rizatriptan benzoate tablets within 24 hours is contraindicated [see Contraindications (4) ] .

7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, co-administration of rizatriptan benzoate tablets and other 5-HT 1 agonists within 24 hours of each other is contraindicated [see Contraindications (4) ] .

7.4 SSRIs/SNRIs and Serotonin Syndrome Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7) ] .

7.5 Monoamine Oxidase Inhibitors Rizatriptan benzoate tablets is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors.

A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite [see Contraindications (4) and Clinical Pharmacology (12.3) ] .

OVERDOSAGE

10 No overdoses of rizatriptan benzoate tablets were reported during clinical trials in adults.

Some adult patients who received 40 mg of rizatriptan benzoate tablets either a single dose or as two doses with a 2-hour interdose interval had dizziness and somnolence.

In a clinical pharmacology study in which 12 adult subjects received rizatriptan benzoate tablets, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence.

In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10-mg doses of rizatriptan benzoate orally disintegrating tablets within a 24-hour period.

Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea.

In addition, based on the pharmacology of rizatriptan benzoate tablets, hypertension or myocardial ischemia could occur after overdosage.

Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with rizatriptan benzoate tablets.

Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.

The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.

DESCRIPTION

11 Rizatriptan benzoate tablet, USP contains rizatriptan benzoate, a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist.

Rizatriptan benzoate is described chemically as: N,N -dimethyl-5-(1 H -1,2,4-triazol-1-ylmethyl)-1 H -indole-3-ethanamine monobenzoate and its structural formula is: Its empirical formula is C 15 H 19 N 5 •C 7 H 6 O 2 , representing a molecular weight of the free base of 269.4.

Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

Rizatriptan benzoate Tablets, USP are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively).

Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), and magnesium stearate.

rizatriptan-Structure

CLINICAL STUDIES

14 14.1 Adults The efficacy of rizatriptan benzoate tablets was established in four multicenter, randomized, placebo-controlled trials.

Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71).

Patients were instructed to treat a moderate to severe headache.

Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4).

Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated.

A second dose of rizatriptan benzoate tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2.

Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies.

In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either rizatriptan benzoate tablets 5 or 10 mg compared to those who received placebo.

In a separate study, doses of 2.5 mg were not different from placebo.

Doses greater than 10 mg were associated with an increased incidence of adverse effects.

The results from the four controlled studies are summarized in Table 2.

Table 2: Response Rates 2 Hours Following Treatment of Initial Headache in Studies 1, 2, 3, and 4 *p-value <0.05 in comparison with placebo.

† p-value <0.05 in comparison with 5 mg.

‡ Results for initial headache only.

Study Placebo Rizatriptan Benzoate Tablets 5 mg Rizatriptan Benzoate Tablets 10 mg 1 35% (n=304) 62%* (n=458) 71%* ,† (n=456) 2 ‡ 37% (n=82) — 77%* (n=320) 3 23% (n=80) 63%* (n=352) — 4 40% (n=159) 60%* (n=164) 67%* (n=385) Comparisons of drug performance based upon results obtained in different clinical trials may not be reliable.

Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

The estimated probability of achieving an initial headache response within 2 hours following treatment in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1.

Figure 1: Estimated Probability of Achieving an Initial Headache Response by 2 Hours in Pooled Studies 1, 2, 3, and 4 * * Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with rizatriptan benzoate tablets or placebo.

The averages displayed are based on pooled data from 4 placebo-controlled, outpatient trials providing evidence of efficacy (Studies 1, 2, 3, and 4).

Patients taking additional treatment or not achieving headache response prior to 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of rizatriptan benzoate tablets compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication.

The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2: Estimated Probability of Patients Taking a Second Dose of Rizatriptan benzoate Tablets, USP or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 1, 2, 3, and 4 * * This Kaplan-Meier plot is based on data obtained in 4 placebo-controlled outpatient clinical trials (Studies 1, 2, 3, and 4).

Patients not using additional treatments were censored at 24 hours.

The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose.

Remedication was not allowed within 2 hours post- dose.

Efficacy was unaffected by the presence of aura; by the gender, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral contraceptives.

In two additional similar studies, efficacy was unaffected by relationship to menses.

There were insufficient data to assess the impact of race on efficacy.

rizatriptan-Fig-1 rizatriptan-Fig-2 14.2 Pediatric Patients 6 to 17 Years of Age The efficacy of rizatriptan benzoate orally disintegrating tablets in pediatric patients 6 to 17 years was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial (Study 7).

Patients had to have at least a 6-month history of migraine attacks (with or without aura) usually lasting 3 hours or more (when untreated).

The patient population was historically non-responsive to NSAIDs and acetaminophen therapy.

Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity.

The treatment phase of the study had two stages.

Stage 1 was used to identify placebo non-responders, who then entered into Stage 2, in which patients were randomized to rizatriptan benzoate orally disintegrating tablets or placebo.

Using a weight-based dosing strategy, patients 20 kg to <40 kg (44 lb to <88 lb) received rizatriptan benzoate orally disintegrating tablets 5 mg or placebo, and patients ≥40 kg (88 lb) received rizatriptan benzoate orally disintegrating tablets10 mg or placebo.

The mean age for the studied patient population was 13 years.

Sixty-one percent of the patients were Caucasian, and fifty-six percent of the patients were female.

The percentage of patients achieving the primary efficacy endpoint of no headache pain at 2 hours after treatment was significantly greater in patients who received rizatriptan benzoate orally disintegrating tablets, compared with those who received placebo (33% vs.

24%).

Study 7 results are summarized in Table 4.

Table 4: Response Rates 2 Hours Following Treatment of Initial Headache in Pediatric Patients 6 to 17 Years of Age in Study 7 Endpoint Placebo Rizatriptan benzoate orally disintegrating tablets p-Value No headache pain at 2 hours post-dose 24% (n/m=94/388) 33% (n/m=126/382) 0.01 n = Number of evaluable patients with no headache pain at 2 hours post-dose.

m = Number of evaluable patients in population.

The observed percentage of pediatric patients achieving no headache pain within 2 hours following initial treatment with rizatriptan benzoate orally disintegrating tablets is shown in Figure 5.

Figure 5: Observed Percentage of Patients Reporting No Headache Pain by 2 Hours Post-Dose in Study 7 The prevalence of the exploratory endpoints of absence of migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not statistically significantly different between patients who received rizatriptan benzoate orally disintegrating tablets and those who received placebo.

rizatriptan-Fig-5

HOW SUPPLIED

16 /STORAGE AND HANDLING Rizatriptan benzoate tablets, USP 5 mg, are white to off-white, capsule-shaped, compressed tablets debossed “ RZT” on one side and “5” on other side.

They are supplied as follows: NDC 67877-261-30, bottle of 30 tablets.

NDC 67877-261-01, bottle of 100 tablets.

NDC 67877-261-05, bottle of 500 tablets.

NDC 67877-261-18, carton of 18 tablets NDC 67877-261-25, carton of 12 tablets Rizatriptan benzoate tablets, USP 10 mg, are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “10” on other side.

They are supplied as follows: NDC 67877-262-30, bottle of 30 tablets.

NDC 67877-262-01, bottle of 100 tablets.

NDC 67877-262-05, bottle of 500 tablets.

NDC 67877-262-18, carton of 18 tablets NDC 67877-262-25, carton of 12 tablets Storage Store rizatriptan benzoate tablets, USP at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

GERIATRIC USE

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

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range.

This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving rizatriptan benzoate tablets [see Warnings and Precautions (5.1) ] .

DOSAGE FORMS AND STRENGTHS

3 Rizatriptan benzoate Tablets, USP 5 mg tablets are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “5” on other side.

10 mg tablets are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “10” on other side.

Rizatriptan Benzoate Tablets, USP: 5 and 10 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors.

Rizatriptan benzoate tablets presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT 1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

INDICATIONS AND USAGE

1 Rizatriptan benzoate tablets are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.

Limitations of Use Rizatriptan benzoate tablets should only be used where a clear diagnosis of migraine has been established.

If a patient has no response for the first migraine attack treated with rizatriptan benzoate tablets, the diagnosis of migraine should be reconsidered before rizatriptan benzoate tablets are administered to treat any subsequent attacks.

Rizatriptan benzoate tablets are not indicated for use in the management of hemiplegic or basilar migraine [see Contraindications (4) ] .

Rizatriptan benzoate tablets are not indicated for the prevention of migraine attacks.

Safety and effectiveness of rizatriptan benzoate tablets have not been established for cluster headache.

Rizatriptan benzoate tablets are a serotonin (5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years of age( 1 ) Limitations of Use : Use only after clear diagnosis of migraine has been established ( 1 ) Not indicated for the prophylactic therapy of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients under 6 years of age have not been established.

The efficacy and safety of rizatriptan benzoate tablets in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study [see Clinical Studies ( 14.2) ] .

The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received rizatriptan benzoate tablets to those who received placebo.

The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

PREGNANCY

8.1 Pregnancy Risk Summary Available human data on the use of rizatriptan benzoate tablets in pregnant women are not sufficient to draw conclusions about drug-associated risk for major birth defects and miscarriage.

In animal studies, developmental toxicity was observed following oral administration of rizatriptan during pregnancy (decreased fetal body weight in rats) or throughout pregnancy and lactation (increased mortality, decreased body weight, and neurobehavioral impairment in rat offspring) at maternal plasma exposures greater than that expected at therapeutic doses in humans [see Animal Data].

In the U.S.

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

The reported rate of major birth defects among deliveries to women with migraine range from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which are similar to rates reported in women without migraine.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension.

Data Human Data The Pregnancy Registry for rizatriptan benzoate tablets did not identify any pattern of congenital anomalies or other adverse birth outcomes over the period of 1998 to 2018.

However, the lack of identification of any pattern should be viewed with caution, as the number of prospective reports with outcome information was low and did not provide sufficient power to detect an increased risk of individual birth defects associated with the use of rizatriptan benzoate tablets.

Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan benzoate tablets and any pattern of congenital anomalies or other adverse birth outcomes.

In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not.

Of the 157 births with first-trimester exposure to rizatriptan, 7 infants were born with malformations (relative risk 1.01 [95% CI: 0.40 to 2.08]).

A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only, compared with a population control group.

Of the 310 women who redeemed prescriptions for rizatriptan during the first trimester, 10 had infants with major congenital malformations (OR 1.03 [95% CI: 0.55 to 1.93]), while for the 271 women who redeemed prescriptions for rizatriptan before, but not during, pregnancy, 12 had infants with major congenital malformations (OR 1.48 [95% CI: 0.83 to 2.64]), each compared with the population comparison group.

Animal Data When rizatriptan (0, 2, 10, or 100 mg/kg/day) was administered orally to pregnant rats throughout organogenesis, a decrease in fetal body weight was observed at the highest doses tested.

At the mid dose (10 mg/kg/day), which was a no-effect dose for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 15 times that in humans at the maximum recommended human dose (MRHD) of 30 mg/day.

When rizatriptan (0, 5, 10, or 50 mg/kg/day) was administered orally to pregnant rabbits throughout organogenesis, no adverse fetal effects were observed.

Plasma exposure (AUC) at the highest dose tested was 115 times that in humans at the MRHD.

Placental transfer of drug to the fetus was demonstrated in both species.

Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats prior to and during mating and continuing throughout gestation and lactation resulted in reduced body weight in offspring from birth and throughout lactation at all but the lowest dose tested (2 mg/kg/day).

Plasma exposure (AUC) at the no-effect dose (2 mg/kg/day) for adverse effects on postnatal development was similar to that in humans at the MRHD.

Oral administration of rizatriptan (0, 5, 100, or 250 mg/kg/day) throughout organogenesis and lactation resulted in neonatal mortality, reduced body weight (which persisted into adulthood), and impaired neurobehavioral function in offspring at all but the lowest dose tested.

Plasma exposure (AUC) at the no-effect dose for adverse effects on postnatal development (5 mg/kg/day) was approximately 8 times that in humans at the MRHD.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) Arrhythmias: Discontinue dosing if occurs ( 5.2 ) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness; Generally not associated with myocardial ischemia; Evaluate patients at high risk ( 5.3 ) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue dosing if occurs ( 5.4 ) Gastrointestinal ischemic events, peripheral vasospastic reactions: Discontinue dosing if occurs ( 5.5 ) Medication overuse headache: Detoxification may be necessary ( 5.6 ) Serotonin syndrome: Discontinue dosing if occurs ( 5.7 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Rizatriptan benzoate tablets should not be given to patients with ischemic or vasospastic coronary artery disease.

There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of rizatriptan benzoate tablets.

Some of these reactions occurred in patients without known coronary artery disease (CAD).

5-HT 1 agonists, including rizatriptan benzoate tablets may cause coronary artery vasospasm (Prinzmetal’s Angina), even in patients without a history of CAD.

Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving rizatriptan benzoate tablets.

If there is evidence of CAD or coronary artery vasospasm, rizatriptan benzoate tablets should not be administered [see Contraindications (4) ] .

For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first rizatriptan benzoate tablets dose in a medically supervised setting and performing an electrocardiogram (ECG) immediately following rizatriptan benzoate tablets administration.

Periodic cardiovascular evaluation should be considered in intermittent long-term users of rizatriptan benzoate tablets who have cardiovascular risk factors.

5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists.

Discontinue rizatriptan benzoate tablets if these disturbances occur.

5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with rizatriptan benzoate tablets and are usually non­-cardiac in origin.

However, if a cardiac origin is suspected, patients should be evaluated.

Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5-HT 1 agonists.

5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities.

In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.

Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Discontinue rizatriptan benzoate tablets, USP if a cerebrovascular event occurs.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions.

Rizatriptan benzoate tablets should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4) ] .

5.5 Other Vasospasm Reactions 5-HT 1 agonists, including rizatriptan benzoate tablets, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome.

In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate tablets doses.

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists.

Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established.

5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache).

Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks.

Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

5.7 Serotonin Syndrome Serotonin syndrome may occur with triptans, including rizatriptan benzoate tablets particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5) ] .

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication.

Rizatriptan benzoate tablets treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.4) and Patient Counseling Information (17) ] .

5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT 1 agonists, including rizatriptan benzoate tablets.

In healthy young adult male and female patients who received maximal doses of rizatriptan benzoate tablets (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed.

Rizatriptan benzoate tablets is contraindicated in patients with uncontrolled hypertension [see Contraindications (4) ] .

INFORMATION FOR PATIENTS

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

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, and Cerebrovascular Events Inform patients that rizatriptan benzoate tablets, USP may cause serious cardiovascular side effects such as myocardial infarction or stroke.

Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms.

Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.5 )] .

Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the use of rizatriptan benzoate tablets or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7) , Drug Interactions (7.4) , and Clinical Pharmacology (12.3) ] .

Pregnancy Inform patients that rizatriptan benzoate tablets should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1) ] .

Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations ( 8.2 )].

Ability to Perform Complex Tasks Since migraines or treatment with rizatriptan benzoate tablets may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of rizatriptan benzoate tablets, USP.

Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6) ] .

Manufactured by: Alkem Laboratories Ltd., INDIA.

Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: November, 2021 Patient Information RIZATRIPTAN BENZOATE TABLETS, USP 5 mg and 10 mg Read this Patient Information before you start taking rizatriptan benzoate tablets and each time you get a refill.

There may be new information.

This information does not take the place of talking to your doctor about your medical condition or your treatment.

Unless otherwise stated, the information in this Patient Information leaflet applies to both rizatriptan benzoate tablets and to rizatriptan benzoate orally disintegrating tablets.

What is rizatriptan benzoate , USP ? Rizatriptan benzoate tablets, USP is a prescription medicine that belongs to a class of medicines called Triptans.

Rizatriptan benzoate tablets is available as a traditional tablet and as an orally disintegrating tablet.

Rizatriptan benzoate tablet are used to treat migraine attacks with or without aura in adults and in children 6 to 17 years of age.

Rizatriptan benzoate tablets is not to be used to prevent migraine attacks.

Rizatriptan benzoate tablets is not for the treatment of hemiplegic or basilar migraines.

It is not known if rizatriptan benzoate tablets is safe and effective for the treatment of cluster headaches.

It is not known if taking more than 1 dose of rizatriptan benzoate tablet in 24 hours is safe and effective in children 6 to 17 years of age.

It is not known if rizatriptan benzoate tablet is safe and effective in children under 6 years of age.

Who should not take rizatriptan benzoate tablets? Do not take rizatriptan benzoate tablets if you: have or have had heart problems have or have had a stroke or a transient ischemic attack (TIA) have or have had blood vessel problems including ischemic bowel disease have uncontrolled high blood pressure have taken other Triptan medicines in the last 24 hours have taken ergot-containing medicines in the last 24 hours have hemiplegic or basilar migraines take monoamine oxidase (MAO) inhibitor or have taken a MAO inhibitor within the last 2 weeks are allergic to rizatriptan benzoate or any of the ingredients in rizatriptan benzoate tablets, USP.

See the end of this leaflet for a complete list of ingredients in rizatriptan benzoate tablets.

Talk to your doctor before taking this medicine if you have any of the conditions listed above or if you are not sure if you take any of these medicines.

What should I tell my doctor before taking rizatriptan benzoate tablets? Before you take rizatriptan benzoate tablets, tell your doctor if you: have or have had heart problems, high blood pressure, chest pain, or shortness of breath have any risk factors for heart problems or blood vessel problems such as: high blood pressure high cholesterol smoking obesity diabetes family history of heart problems you are post menopausal you are a male over 40 have kidney or liver problems have any other medical condition are pregnant or plan to become pregnant.

It is not known if rizatriptan benzoate tablets will harm your unborn baby.

If you become pregnant while taking rizatriptan benzoate tablets, talk to your healthcare provider.

are breastfeeding or plan to breastfeed.

It is not known if rizatriptan benzoate passes into your breast milk.

Talk to your doctor about the best way to feed your baby if you take rizatriptan benzoate tablets.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Rizatriptan benzoate tablets and other medicines may affect each other causing side effects.

Rizatriptan benzoate tablets may affect the way other medicines work, and other medicines may affect how rizatriptan benzoate tablets works.

Especially tell your doctor if you take: propranolol containing medicines such as Inderal ® , Inderal ® LA, or Innopran ® XL medicines used to treat mood disorders, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take.

Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take rizatriptan benzoate tablets? Take rizatriptan benzoate tablets exactly as your doctor tells you to take it.

Your doctor will tell you how much rizatriptan benzoate tablets to take and when to take it.

If your headache comes back after your first rizatriptan benzoate tablets dose: For adults: a second dose may be taken 2 hours after the first dose.

Do not take more than 30 mg of rizatriptan benzoate tablets in a 24-hour period (for example, do not take more than 3 10-mg tablets in a 24-hour period).

For children 6 to 17 years of age: It is not known if taking more than 1 dose of rizatriptan benzoate tablets in 24 hours is safe and effective.

Talk to your doctor about what to do if your headache does not go away or comes back.

If you take too much rizatriptan benzoate tablets, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking rizatriptan benzoate tablets ? Rizatriptan benzoate tablets may cause dizziness, weakness, or fainting.

If you have these symptoms, do not drive a car, use machinery, or do anything that needs you to be alert.

What are the possible side effects of rizatriptan benzoate tablets? Rizatriptan benzoate tablets may cause serious side effects .

Call your doctor or go to the nearest hospital emergency room right away if you think you are having any of the serious side effects of rizatriptan benzoate tablets including: heart attack .

Symptoms of a heart attack may include: chest discomfort in the center of your chest that lasts for more than a few minutes or that goes away and comes back chest discomfort that feels like uncomfortable pressure, squeezing, fullness or pain pain or discomfort in your arms, back, neck, jaw or stomach shortness of breath with or without chest discomfort breaking out in a cold sweat nausea or vomiting feeling lightheaded stroke .

Symptoms of a stroke may include the following sudden symptoms: numbness or weakness in your face, arm or leg, especially on one side of your body confusion, problems speaking or understanding problems seeing in 1 or both of your eyes problems walking, dizziness, loss of balance or coordination severe headache with no known cause blood vessel problems .

Symptoms of blood vessel problems may include: stomach pain bloody diarrhea vision problems coldness and numbness of hands and feet serotonin syndrome .

A condition called serotonin syndrome can happen when Triptan medicines such as rizatriptan benzoate tablets are taken with certain other medicines.

Symptoms of serotonin syndrome may include: agitation hallucinations coma fast heartbeat fast changes in your blood pressure increased body temperature muscle spasm loss of coordination nausea, vomiting or diarrhea increased blood pressure.

The most common side effects of rizatriptan benzoate tablets in adults include: feeling sleepy or tired pain or pressure in your chest or throat dizziness Tell your doctor if you have any side effect that bothers you or that does not go away.

If you take rizatriptan benzoate tablets too often, this may result in you getting chronic headaches.

In such cases, you should contact your doctor, as you may have to stop taking rizatriptan benzoate tablets.

These are not all the possible side effects of rizatriptan benzoate tablets.

For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

How should I store rizatriptan benzoate tablets? Store rizatriptan benzoate tablets at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Safely throw away medicine that is out of date or no longer needed.

Keep rizatriptan benzoate tablets and all medicines out of the reach of children.

General Information about the safe and effective use of rizatriptan benzoate tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

Do not use rizatriptan benzoate tablets for a condition for which it was not prescribed.

Do not give rizatriptan benzoate tablets to other people, even if they have the same symptoms that you have.

It may harm them.

This Patient Information leaflet summarizes the most important information about rizatriptan benzoate tablets.

If you would like more information, talk to your doctor.

You can ask your pharmacist or doctor for information about rizatriptan benzoate tablets that is written for health professionals.

For more information contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) What are the ingredients in rizatriptan benzoate tablets ? Active ingredient in rizatriptan benzoate tablets: rizatriptan benzoate.

Inactive ingredients in rizatriptan benzoate tablets: lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), and magnesium stearate.

The brands listed are the trademarks of their respective owners.

This Patient Information has been approved by the U.S.

Food and Drug Administration.

Manufactured by: Alkem Laboratories Ltd., INDIA.

Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: November, 2021 PT 2719-05

DOSAGE AND ADMINISTRATION

2 Adults: 5 or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in a 24-hour period: 30 mg ( 2.1 ) Pediatric patients 6 to 17 years: 5 mg single dose in patients less than 40 kg (88 lb); 10 mg single dose in patients 40 kg (88 lb) or more ( 2.2 ) Adjust dose if co-administered with propranolol ( 2.4 ) 2.1 Dosing Information in Adults The recommended starting dose of rizatriptan benzoate tablets are either 5 mg or 10 mg for the acute treatment of migraines in adults.

The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions [see Clinical Studies (14.1) ] .

Redosing in Adults Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose.

The maximum daily dose should not exceed 30 mg in any 24-hour period.

The safety of treating, on average, more than four headaches in a 30-day period has not been established.

2.2 Dosing Information in Pediatric Patients (Age 6 to 17 Years) Dosing in pediatric patients is based on the patient’s body weight.

The recommended dose of rizatriptan benzoate tablets is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.

The efficacy and safety of treatment with more than one dose of rizatriptan benzoate tablet within 24 hours in pediatric patients 6 to 17 years of age have not been established.

2.4 Dosage Adjustment for Patients on Propranolol Adult Patients In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate tablets are recommended, up to a maximum of 3 doses in any 24-hour period (15 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

Pediatric Patients For pediatric patients weighing 40 kg (88 lb) or more, taking propranolol, only a single 5-mg dose of rizatriptan benzoate tablets is recommended (maximum dose of 5 mg in a 24-hour period).

Rizatriptan benzoate tablets should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg (88 lb) [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

Ketalar (ketamine hydrochloride) 10 MG/ML Injectable Solution

Generic Name: KETAMINE HYDROCHLORIDE
Brand Name: Ketalar
  • Substance Name(s):
  • KETAMINE HYDROCHLORIDE

DRUG INTERACTIONS

7 Theophylline or Aminophylline : Do not co-administer with KETALAR as concomitant use may lower the seizure threshold ( 7.1 ).

Sympathomimetics and Vasopressin : Closely monitor vital signs when co-administered with KETALAR.

Consider dose adjustment individualized to the patient’s clinical situation ( 7.2 ).

Benzodiazepines, Opioid Analgesics, or other CNS Depressants : Concomitant use may result in profound sedation, respiratory depression, coma, or death.

Concomitant use of opioid analgesics may prolong recovery time.

( 7.3 ).

7.1 Theophylline or Aminophylline Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold.

Consider using an alternative to KETALAR in patients receiving theophylline or aminophylline.

7.2 Sympathomimetics and Vasopressin Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine.

Closely monitor vital signs when KETALAR and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

7.3 Benzodiazepines, Opioid Analgesics, Or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions ( 5.8 )] .

Opioid analgesics administered concomitantly with KETALAR may prolong time to complete recovery from anesthesia.

OVERDOSAGE

10 Changes in heart rate and blood pressure, respiratory depression, and apnea may occur with overdosage or by a rapid rate of administration of KETALAR.

Monitor patients for clinically relevant changes in heart rate and blood pressure.

Assisted ventilation, including mechanical ventilation, may be required.

In cases of unintentional overdose of KETALAR (up to ten times that usually required), patients had a prolonged but complete recovery.

DESCRIPTION

11 KETALAR (ketamine hydrochloride) injection, for intravenous or intramuscular use, contains ketamine, a nonbarbiturate general anesthetic.

Ketamine hydrochloride, USP is a white crystalline powder and has a molecular formula of C 13 H 16 ClNO•HCl and a molecular weight of 274.19.

The chemical name for ketamine hydrochloride is (±)-2-( o -Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.

The chemical structure of ketamine hydrochloride is: It is formulated as a slightly acidic (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection.

Each milliliter (mL) of the multiple-dose vials contain either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) and not more than 0.10 mg/mL benzethonium chloride added as a preservative in water for injection.

The 10 mg/mL solution has been made isotonic with 6.60 mg sodium chloride.

ketamine hydrochloride

CLINICAL STUDIES

14 KETALAR has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients in 105 separate studies.

During the course of these studies, KETALAR was administered as the sole general anesthetic, as an induction agent prior to administration of other general anesthetics, or to supplement other anesthetic agents.

KETALAR has been evaluated during the following procedures: debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.

neurodiagnostic procedures such as myelograms and lumbar punctures.

diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.

sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.

extraperitoneal procedures, such as dilatation and curettage.

orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

cardiac catheterization procedures.

HOW SUPPLIED

16 /STORAGE AND HANDLING How Supplied KETALAR injection is a clear, colorless solution supplied as the hydrochloride salt in concentrations equivalent to ketamine base, as follows: Unit of sale Strength NDC 42023-113-10 Unit of 10 200 mg in 20 mL multiple- dose vial (10 mg/mL) 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride) NDC 42023-114-10 Unit of 10 500 mg in 10 mL multiple- dose vial (50 mg/mL) 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) NDC 42023-115-10 Unit of 10 500 mg in 5 mL multiple- dose vial (100 mg/mL) 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) Storage and Handling KETALAR injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] .

Protect from light.

GERIATRIC USE

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

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, 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.

DOSAGE FORMS AND STRENGTHS

3 KETALAR injection is a clear, colorless, sterile solution available in multiple-dose vials containing either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride).

200 mg/20 mL (10 mg/mL) 500 mg/10 mL (50 mg/mL) 500 mg/5 mL (100 mg/mL) Injection: 200 mg/20 mL (10 mg/mL), 500 mg/10 mL (50 mg/mL), and 500 mg/5 mL (100 mg/mL) multiple-dose vials ( 3 ).

MECHANISM OF ACTION

12.1 Mechanism of Action KETALAR, a racemic mixture of ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.

The major circulating metabolite of ketamine (norketamine) demonstrated activity at the same receptor with less affinity.

Norketamine is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat.

INDICATIONS AND USAGE

1 KETALAR (ketamine hydrochloride) injection is indicated: as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.

for the induction of anesthesia prior to the administration of other general anesthetic agents.

as a supplement to other anesthetic agents.

KETALAR is a general anesthetic indicated: as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation ( 1 ) for the induction of anesthesia prior to the administration of other general anesthetic agents ( 1 ) as a supplement to other anesthetic agents ( 1 ).

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 16 have not been established.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as KETALAR, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 ), and Nonclinical Toxicology ( 13.2 )] .

PREGNANCY

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of KETALAR in pregnant women.

In animal reproduction studies in rats developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg.

In rabbits, developmental delays and increased fetal resorptions were noted at 0.6 times the human dose.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

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 clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations KETALAR use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 ) and Nonclinical Toxicology ( 13.2 )] .

Data Animal Data Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15.

Ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups.

Pregnant rabbits were treated intramuscularly with 20 mg/kg ketamine (0.6 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15.

An increase in resorptions and skeletal hypoplasia of the fetuses were noted.

Additional pregnant rabbits were treated intramuscularly with a single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day 6 only.

Skeletal hypoplasia was reported in the fetuses.

In a study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day 18 to 21.

There was a slight increase in incidence of delayed parturition by one day in treated dams of this group.

No adverse effects on the litters or pups were noted; however, learning and memory assessments were not completed.

Three (3) pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg IM based on body surface area) twice weekly for the three weeks of the first, second, and third trimesters of pregnancy, respectively, without the development of adverse effects in the pups.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 ), and Nonclinical Toxicology ( 13.2 )] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hemodynamic Instability: Monitor vital signs and cardiac function during KETALAR administration.

( 5.1 ) Emergence Reactions: Postoperative confusional states may occur during the recovery period.

Reduce by minimizing verbal, tactile, and visual stimulation of the patient.

( 5.2 ) Risk of Respiratory Depression: May occur with overdosage or too rapid a rate of administration.

Maintain adequate oxygenation and ventilation.

( 5.3 ) Risks of KETALAR alone for Procedures of the Pharynx, Larynx, or Bronchial Tree : Pharyngeal and laryngeal reflexes are not suppressed with KETALAR when it is used alone.

Avoid use as a sole anesthetic agent in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree.

Muscle relaxants may be required.

( 5.4 ) Pediatric Neurotoxicity: Long-term cognitive deficits may occur when used for longer than 3 hours in children ≤3 years ( 5.5 ) 5.1 Hemodynamic Instability Transient increases in blood pressure, heart rate, and cardiac index are frequently observed following administration of KETALAR.

Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed.

Monitor vital signs and cardiac function during KETALAR administration.

KETALAR is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Contraindications ( 4 )] .

5.2 Emergence Reactions Emergence delirium (postoperative confusional states or agitation) has occurred in approximately 12% of patients during the recovery period, and the duration is generally a few hours.

The neuropsychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, and emergence delirium.

In some cases, these states have been accompanied by confusion, excitement, and irrational behavior, which have been recalled as unpleasant experiences.

No residual psychological effects are known to have resulted from use of KETALAR during induction and maintenance of anesthesia.

Intramuscular administration results in a lower incidence of emergence reactions.

The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using lower recommended dosages of KETALAR in conjunction with an intravenous benzodiazepine during induction and maintenance of anesthesia [see Dosage and Administration ( 2.3 )] .

Also, these reactions may be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period.

This does not preclude the monitoring of vital signs.

5.3 Respiratory Depression Respiratory depression may occur with overdosage or a rapid rate of administration of KETALAR.

Maintain adequate oxygenation and ventilation.

5.4 Risks of Ketalar Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree KETALAR does not suppress pharyngeal and laryngeal reflexes.

Avoid KETALAR administration as a sole anesthetic agent during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx.

Muscle relaxants may be required for successful completion of procedures of the pharynx, larynx, or bronchial tree.

5.5 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Use in Specific Populations ( 8.1 , 8.4 ), Nonclinical Toxicology ( 13.2 )].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

5.6 Drug-Induced Liver Injury Ketamine administration is associated with hepatobiliary dysfunction (most often a cholestatic pattern), with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications).

Biliary duct dilatation with or without evidence of biliary obstruction has also been reported with recurrent use.

Obtain baseline LFTs, including alkaline phosphatase and gamma glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing.

Monitor those receiving recurrent ketamine at periodic intervals during treatment.

5.7 Increase in Cerebrospinal Fluid Pressure An increase in intracranial pressure has been reported following administration of ketamine hydrochloride.

Patients with elevated intracranial pressure should be in a monitored setting with frequent neurologic assessments.

5.8 Drug Interactions Theophylline or Aminophylline : Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold [see Drug Interactions ( 7.1 )] .

Consider using an alternative to KETALAR in patients receiving theophylline or aminophylline.

Sympathomimetics and Vasopressin : Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine [see Drug Interactions ( 7.2 )] .

Closely monitor vital signs when KETALAR and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

Benzodiazepines, Opioid Analgesics, or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Drug Interactions ( 7.3 )] .

Closely monitor neurological status and respiratory parameters, including respiratory rate and pulse oximetry, when KETALR and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered.

Consider dose adjustment individualized to the patient’s clinical situation.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions ( 5.5 )] .

Due to the residual anesthetic effects and the potential for drowsiness, advise patients not to drive an automobile, operate hazardous machinery, or engage in hazardous activities within 24 hours of receiving KETALAR.

DOSAGE AND ADMINISTRATION

2 See Full Prescribing Information for important dosage and administration instructions.

( 2 ) Induction of anesthesia: — Intravenous route : Initially, 1 to 4.5 mg/kg administered slowly (over a period of 60 seconds).

Alternatively, administer a dose of 1 to 2 mg/kg at a rate of 0.5 mg/kg/min.

( 2.2 ) — Intramuscular route : Initially, 6.5 to 13 mg/kg.

( 2.2 ) Maintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed ( 2.2 ).

Adjust the dose according to the patient’s anesthetic needs and whether an additional anesthetic agent is employed.

( 2.2 ) Supplement to other anesthetic agents : The regimen of a reduced dose of KETALAR supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents.

( 2.2 ) 2.1 Important Dosage and Administration Information KETALAR should be administered by or under the direction of physicians experienced in the administration of general anesthetics, maintenance of a patent airway, and oxygenation and ventilation.

Continuously monitor vital signs in patients receiving KETALAR.

Emergency airway equipment must be immediately available.

Do not administer the 100 mg/mL concentration of KETALAR intravenously without proper dilution [see Dosage and Administration ( 2.3 )] .

Must be used immediately after dilution.

While some degree of airway protection may be afforded due to active laryngeal-pharyngeal reflexes, vomiting and aspiration may occur with KETALAR.

KETALAR is not recommended for use in patients who have not followed nil per os guidelines.

Due to the potential for salivation during KETALAR administration, administer an antisialagogue prior to induction of anesthesia.

In individuals with a history of chronic ketamine use for off-label indications, there have been case reports of genitourinary pain that may be related to the ketamine treatment, not the underlying condition [see Adverse Reactions ( 6 )] .

Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms.

2.2 Recommended Dosage and Administration The KETALAR dosage must be individualized and titrated to the desired clinical effect.

If a longer duration of effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia.

However, a higher total dose will result in a longer time to complete recovery.

Induction of Anesthesia Intravenous Route: The initial dose of KETALAR administered intravenously may range from 1 mg/kg to 4.5 mg/kg.

The average amount required to produce 5 to 10 minutes of surgical anesthesia within 30 seconds following injection is 2 mg/kg.

Administer KETALAR slowly (i.e., over a period of 60 seconds).

Rapid administration may result in respiratory depression and enhanced vasopressor response.

The induction dose may be administered as an intravenous infusion at a rate of 0.5 mg/kg/min.

Intramuscular Route : The initial dose of KETALAR administered intramuscularly may range from 6.5 to 13 mg/kg.

A dose of 9 to 13 mg/kg usually produces surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

Administer a benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from anesthesia.

Maintenance of Anesthesia Adjust the maintenance dose according to the patient’s anesthetic needs and whether an additional anesthetic agent is administered.

Repeat increments of one-half to the full induction dose as needed for maintenance of anesthesia.

Purposeless and tonic-clonic movements of extremities may occur during the course of ketamine anesthesia.

These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.

KETALAR given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute will maintain general anesthesia in adult patients induced with KETALAR.

Augment KETALAR with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence.

Supplement to Other Anesthetic Agents KETALAR can be administered to supplement other general and local anesthetic agents.

Continuously monitor patients for changes in respiratory and hemodynamic parameters.

A reduced dose of KETALAR can be used to produce balanced anesthesia when used in combination with other anesthetic agents.

2.3 Preparation of Dilution KETALAR is a clear, colorless sterile solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Discard if product is discolored or contains particulate matter.

Induction of Anesthesia : Do not intravenously inject the 100 mg/mL concentration of KETALAR without proper dilution.

Dilute KETALAR with an equal volume of either Sterile Water for injection, USP, 0.9% Sodium Chloride Injection, USP (Normal Saline), or 5% Dextrose in Water.

Use immediately after dilution.

Maintenance of Anesthesia : To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (Normal Saline) and mix well.

The resultant solution will contain 1 mg of ketamine per mL.

Use immediately after dilution.

When fluid restriction is required, KETALAR can be added to a 250 mL infusion as described above to provide a KETALAR concentration of 2 mg/mL.

KETALAR 10 mg/mL vials are not recommended for dilution.

Cholecalciferol 3775 UNT / folate 1 MG Oral Capsule

DESCRIPTION

Zolate is an orally-administered (capsule) prescription folate product specifically formulated for the dietary management of patients with unique nutritional needs due to medical conditions and disease states requiring increased folate levels and specific Vitamin D supplementation levels.

HOW SUPPLIED

Zolate are clear gelatin capsules, and are supplied in bottles of 30 capsules.

INDICATIONS AND USAGE

Zolate is indicated for the distinct nutritional requirements of patients in need of folate and Vitamin D supplementation as determined by a licensed medical practitioner.

Zolate should be administered under the supervision of a licensed medical practitioner.

WARNING AND CAUTIONS

WARNINGS AND PRECAUTIONS Caution is recommended in patients with a history of bipolar illness, as mood elevation is possible in this population.

Patients taking anticonvulsant medications should also exercise caution before taking this product, as folate may (i) interfere with anticonvulsant medication, and/or (ii) lower seizure threshold.

Conversely, anticonvulsant medications may interfere with folate metabolism, although the exact mechanism of action is not clear or well understood.

Patients undergoing cancer treatment should consult their licensed medical practitioner for advice.

Folate alone is improper therapy in the treatment of pernicious anemia and other megaloblastic anemias where vitamin B12 is deficient.

Folate in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission may occur while neurological manifestations progress.

DOSAGE AND ADMINISTRATION

One (1) capsule daily or as directed by a licensed medical practitioner.

Ritonavir 100 MG Oral Capsule

DRUG INTERACTIONS

7 When co-administering NORVIR with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.

Co-administration of NORVIR can alter the concentrations of other drugs.

The potential for drug-drug interactions must be considered prior to and during therapy.

(4, 5.1, 7, 12.3) 7.1 Potential for NORVIR to Affect Other Drugs Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A.

Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir.

Thus, co-administration of NORVIR with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.

Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 3 .

Ritonavir also inhibits CYP2D6 to a lesser extent.

Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction.

Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir.

The healthcare provider should consult appropriate references for comprehensive information.

7.2 Established and Other Potentially Significant Drug Interactions Table 3 provides a list of established or potentially clinically significant drug interactions.

Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 )] for magnitude of interaction.

Table 3.

Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comments HIV-Antiviral Agents HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir ↑ amprenavir ↑ atazanavir ↑ darunavir See the complete prescribing information for fosamprenavir, atazanavir, darunavir, for details on co-administration with ritonavir.

HIV-1 Protease Inhibitor: indinavir ↑ indinavir Appropriate doses for this combination, with respect to efficacy and safety, have not been established.

HIV-1 Protease Inhibitor: saquinavir ↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir.

Saquinavir/ritonavir in combination with rifampin is not recommended, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.

HIV-1 Protease Inhibitor: tipranavir ↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.

Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine ↑ ritonavir Appropriate doses of this combination with respect to safety and efficacy have not been established.

HIV-1 CCR5 – antagonist: maraviroc ↑ maraviroc See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.

Integrase Inhibitor: raltegravir ↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.

Other Agents Alpha 1- Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Contraindicated due to potential hypotension [see Contraindications (4) ] .

Antianginal: ranolazine ↑ ranolazine Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ] .

Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl ↑ analgesics ↓ methadone ↑ fentanyl A dose decrease may be needed for these drugs when co-administered with ritonavir.

Dosage increase of methadone may be considered.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.

Anesthetic: meperidine ↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).

Antialcoholics: disulfiram/metronidazole Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine ↑ antiarrhythmics Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4) ].

Antiarrhythmics: disopyramide, lidocaine, mexiletine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications (4) ] .

Avoid co-administration of encorafenib or ivosidenib with NORVIR due to potential risk of serious adverse events such as QT interval prolongation.

If co-administration of encorafenib with NORVIR cannot be avoided, modify dose as recommended in encorafenib USPI.

If co-administration of ivosidenib with NORVIR cannot be avoided, reduce ivosidenib dose to 250 mg once daily.

Avoid use of neratinib, venetoclax or ibrutinib with NORVIR.

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine.

Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR.

Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Anticoagulant: warfarin ↑↓ warfarin Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.

Anticoagulant: rivaroxaban ↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir.

Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.

Anticonvulsants: carbamazepine, clonazepam, ethosuximide ↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Anticonvulsants: divalproex, lamotrigine, phenytoin ↓ anticonvulsants A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g.

fluoxetine, paroxetine, tricyclics: e.g.

amitriptyline, nortriptyline ↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir.

Antidepressant: bupropion ↓ bupropion ↓ active metabolite, hydroxybupropion Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Antidepressant: desipramine ↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended.

Antidepressant: trazodone ↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR.

A lower dose of trazodone should be considered.

Antiemetic: dronabinol ↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir.

Antifungal: ketoconazole itraconazole voriconazole ↑ ketoconazole ↑ itraconazole ↓ voriconazole High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated due to the potential for loss of antifungal response [see Contraindications (4) ] .

Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Anti-gout: colchicine ↑ colchicine Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4) ] .

For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later.

Dose to be repeated no earlier than three days.

Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Anti-infective: clarithromycin ↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: For patients with CL CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.

For patients with CL CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.

Antimycobacterial: bedaquiline ↑ bedaquiline Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.

Antimycobacterial: rifabutin ↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week).

Further dosage reduction may be necessary.

Antimycobacterial: rifampin ↓ ritonavir May lead to loss of virologic response.

Alternate antimycobacterial agents such as rifabutin should be considered.

Antiparasitic: atovaquone ↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed.

Antiparasitic: quinine ↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir.

Antipsychotics: lurasidone pimozide ↑ lurasidone ↑ pimozide Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ] .

Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] .

Antipsychotics: perphenazine, risperidone, thioridazine ↑ antipsychotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

Antipsychotics: quetiapine ↑ quetiapine Initiation of NORVIR in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures.

If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.

Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking NORVIR: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

β-Blockers: metoprolol, timolol ↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended.

A dose decrease may be needed for these drugs when co-administered with ritonavir.

Bronchodilator: theophylline ↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered.

Calcium channel blockers: diltiazem, nifedipine, verapamil ↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.

A dose decrease may be needed for these drugs when co-administered with ritonavir.

Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels.

Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.

Endothelin receptor antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on ritonavir: In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

GnRH Receptor Antagonists: elagolix ↑ elagolix ↓ ritonavir Concomitant use of elagolix 200 mg twice daily and NORVIR for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations.

Limit concomitant use of elagolix 150 mg once daily and NORVIR to 6 months.

Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4) ] .

GI Motility Agent: cisapride ↑ cisapride Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4) ] .

Hepatitis C direct acting antiviral: glecaprevir/pibrentasvir simeprevir ↑ glecaprevir ↑ pibrentasvir ↑simeprevir It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir.

Herbal Products: St.

John’s Wort (hypericum perforatum) ↓ ritonavir Contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications (4) ] .

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4) ] .

Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.

If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.

Lomitapide is a sensitive substrate for CYP3A4 metabolism.

CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold.

Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications (4) ] .

Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.

Kinase Inhibitors: fostamatinib (also see anticancer agents above) ↑ fostamatinib metabolite R406 Monitor for toxicities of R406 such as hepatotoxicity and neutropenia.

Fostamatinib dose reduction may be required.

Long-acting beta- adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended.

The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Oral Contraceptives or Patch Contraceptives: ethinyl estradiol ↓ ethinyl estradiol Alternate methods of contraception should be considered.

PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil ↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio ® ) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications (4) ] .

Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir.

Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ® ) is contraindicated [see Contraindications (4) ] .

The following dose adjustments are recommended for use of tadalafil (Adcirca ® ) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir.

Stop ADCIRCA at least 24 hours prior to starting ritonavir.

After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4) ] .

Sedative/hypnotics: Parenteral midazolam ↑ midazolam Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Stimulant: methamphetamine ↑ methamphetamine Use with caution.

A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.

# refers to interaction with apalutamide.

OVERDOSAGE

10 Acute Overdosage – Human Overdose Experience Human experience of acute overdose with NORVIR is limited.

One patient in clinical trials took NORVIR 1500 mg per day for two days.

The patient reported paresthesias which resolved after the dose was decreased.

A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.

The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.

Management of Overdosage Treatment of overdose with NORVIR consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

There is no specific antidote for overdose with NORVIR.

If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.

Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.

Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.

A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with NORVIR.

DESCRIPTION

11 NORVIR (ritonavir) is an inhibitor of HIV-1 protease with activity against the Human Immunodeficiency Virus (HIV) type 1.

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)].

Its molecular formula is C 37 H 48 N 6 O 5 S 2 , and its molecular weight is 720.95.

Ritonavir has the following structural formula: Ritonavir is a white-to-light-tan powder.

Ritonavir has a bitter metallic taste.

It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

NORVIR soft gelatin capsules are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: Butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid, polyoxyl 35 castor oil, and titanium dioxide.

Chemical structure for ritonavir.

CLINICAL STUDIES

14 The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.

14.1 Advanced Patients with Prior Antiretroviral Therapy Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-1 infected patients with at least nine months of prior antiretroviral therapy and baseline CD 4 cell counts less than or equal to 100 cells per µL.

NORVIR 600 mg twice-daily or placebo was added to each patient’s baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents.

The study accrued 1090 patients, with mean baseline CD 4 cell count at study entry of 32 cells per µL.

After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period.

Median duration of double-blind therapy with NORVIR and placebo was 6 months.

The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.

The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% (140/543) for patients initially randomized to NORVIR compared to 42% (229/547) for patients initially randomized to placebo.

This difference in rates was statistically significant.

Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to NORVIR compared to 26% (142/547) for patients initially randomized to placebo.

This difference in rates was statistically significant.

However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated.

During the double-blind phase of Study 247, CD 4 cell counts increases from baseline for patients randomized to NORVIR at Week 2 and Week 4 were observed.

From Week 4 and through Week 24, mean CD 4 cell counts for patients randomized to NORVIR appeared to plateau.

In contrast, there was no apparent change in mean CD 4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.

14.2 Patients without Prior Antiretroviral Therapy In Study 245, 356 antiretroviral-naive HIV-1 infected patients (mean baseline CD 4 = 364 cells/µL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs.

During the double-blind phase of study 245, greater mean CD 4 cell count increases were observed from baseline to Week 12 in the NORVIR-containing arms compared to the zidovudine arms.

Mean CD 4 cell count changes subsequently appeared to plateau through Week 24 in the NORVIR arm, whereas mean CD 4 cell counts gradually diminished through Week 24 in the zidovudine and NORVIR plus zidovudine arms.

Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the NORVIR-containing arms compared to the zidovudine arm.

After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the NORVIR and zidovudine arms or gradually rebounded toward baseline in the NORVIR plus zidovudine arm.

HOW SUPPLIED

16 /STORAGE AND HANDLING The package sizes, strengths, and storage and handling recommendations for NORVIR (ritonavir) soft gelatin capsules are shown in the table below.

NORVIR Capsules, Soft Gelatin, 100 mg Ritonavir Presentation White capsules imprinted with the “a” logo, 100 and the code DS Packaging Size Bottles containing 120 capsules Bottles containing 30 capsules NDC Number 0074-3333-30 0074-6633-30 Recommended Storage Store NORVIR soft gelatin capsules in the refrigerator between 2°-8°C (36°-46°F) until dispensed.

Refrigeration of NORVIR soft gelatin capsules by the patient is recommended, but not required if used within 30 days and stored below 25°C (77°F).

Protect from light.

Avoid exposure to excessive heat.

Product should be stored and dispensed in the original container.

Keep cap tightly closed.

RECENT MAJOR CHANGES

Contraindications ( 4 ) 12/2019

GERIATRIC USE

8.5 Geriatric Use Clinical studies of NORVIR 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 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.

DOSAGE FORMS AND STRENGTHS

3 NORVIR (ritonavir) capsules, soft gelatin White soft gelatin capsules imprinted with the “a” logo, 100 and the code DS, providing 100 mg of ritonavir.

Capsule, Soft Gelatin: 100 mg.

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MECHANISM OF ACTION

12.1 Mechanism of Action Ritonavir is an antiretroviral drug [see Microbiology (12.4) ] .

INDICATIONS AND USAGE

1 NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

NORVIR is an HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

(1)

PEDIATRIC USE

8.4 Pediatric Use In HIV-1 infected patients age greater than 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NORVIR during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263.

Risk Summary Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage.

Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S.

reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data ].

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits.

During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose.

In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on a body surface area conversion factor [see Data].

The 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 clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Human Data Based on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S.

reference population of the MACDP.

The prevalence of birth defects in live births was 2.3% (95% CI: 1.7%-2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3%-3.5%) following second and third trimester exposure to ritonavir-containing regimens.

While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.

Animal Data Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day), and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days 6 through 17 and 6 through 19, respectively).

No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose.

Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dose at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose.

A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose.

Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic dosage equivalent to 1.8 times higher than the recommended daily dose, based on a body surface area conversion factor.

In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day 6 through postnatal day 20.

At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 1/2 of the recommended daily dose, based on a body surface area conversion factor.

NUSRING MOTHERS

8.3 Females and Males of Reproductive Potential Contraception Use of NORVIR may reduce the efficacy of combined hormonal contraceptives.

Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.2) ] .

BOXED WARNING

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS Co-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs.

Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR [see Contraindications (4) , Warnings and Precautions (5.1) .

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS See full prescribing information for complete boxed warning Co-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs.

Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR (4 , 5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS The following have been observed in patients receiving NORVIR: The concomitant use of NORVIR and certain other drugs may result in known or potentially significant drug interactions.

Consult the full prescribing information prior to and during treatment for potential drug interactions.

(5.1, 7.2) Hepatotoxicity: Fatalities have occurred.

Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations.

(5.2, 8.6) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate.

(5.3) Allergic Reactions/Hypersensitivity: Allergic reactions have been reported and include anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, bronchospasm and angioedema.

Discontinue treatment if severe reactions develop.

(5.4, 6.2) PR interval prolongation may occur in some patients.

Cases of second and third degree heart block have been reported.

Use with caution with patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval.

(5.5, 12.3) Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter.

(5.6) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia.

(5.7) Patients may develop immune reconstitution syndrome.

(5.8) Patients may develop redistribution/accumulation of body fat.

(5.9) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required.

(5.10) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of NORVIR, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving NORVIR, may increase plasma concentrations of medications metabolized by CYP3A.

Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of NORVIR, respectively.

These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.

Clinically significant adverse reactions from greater exposures of NORVIR.

Loss of therapeutic effect of NORVIR and possible development of resistance.

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions.

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] .

Consider the potential for drug interactions prior to and during NORVIR therapy; review concomitant medications during NORVIR therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ] .

5.2 Hepatotoxicity Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs (see Table 2).

There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C.

Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.

Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment [see Use In Specific Populations (8.6) ] .

There have been postmarketing reports of hepatic dysfunction, including some fatalities.

These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

5.3 Pancreatitis Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia.

In some cases fatalities have been observed.

Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis [see Warnings and Precautions (5.8) ] .

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur.

Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

5.4 Allergic Reactions/Hypersensitivity Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported.

Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported.

Discontinue treatment if severe reactions develop.

5.5 PR Interval Prolongation Ritonavir prolongs the PR interval in some patients.

Post marketing cases of second or third degree atrioventricular block have been reported in patients.

NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated.

As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A.

Clinical monitoring is recommended [see Drug Interactions (7) , and Clinical Pharmacology (12.3) ] .

5.6 Lipid Disorders Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1) ] .

Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy.

Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors [see Contraindications (4) , and Drug Interactions (7) ] .

5.7 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy.

Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events.

In some cases, diabetic ketoacidosis has occurred.

In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases.

Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with NORVIR.

5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including NORVIR.

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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

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 Fat Redistribution 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 antiretroviral therapy.

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

A causal relationship has not been established.

5.10 Patients with Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors.

In some patients additional factor VIII was given.

In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced.

A causal relationship between protease inhibitor therapy and these events has not been established.

5.11 Resistance/Cross-resistance Varying degrees of cross-resistance among protease inhibitors have been observed.

Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4) ] .

5.12 Laboratory Tests Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid.

Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient information).

General Administration Information [see Dosage and Administration ( 2 )] : Advise patients and caregivers to pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of NORVIR.

Advise caregivers to inform their healthcare provider if their child’s weight changes in order to make sure that the child’s NORVIR dose is adjusted as needed.

Advise patients to take NORVIR with meals.

For adult patients taking NORVIR capsules, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded.

Advise patients to remain under the care of a physician while using NORVIR and to take NORVIR and other concomitant antiretroviral therapy every day as prescribed.

NORVIR must always be used in combination with other antiretroviral drugs.

Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider.

If a dose of NORVIR is missed patients should take the dose as soon as possible and then return to their normal schedule.

However, if a dose is skipped the patient should not double the next dose.

Continued NORVIR therapy at a dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

NORVIR 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 NORVIR.

Drug Interactions NORVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St.

John’s Wort.

Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with NORVIR because hormonal levels may decrease [see Drug Interactions (7.2) , Use in Specific Populations (8.3) ].

Hepatotoxicity Pre-existing liver disease including Hepatitis B or C can worsen with use of NORVIR.

This can be seen as worsening of transaminase elevations or hepatic decompensation.

Advise patients that their liver function tests will need to be monitored closely especially during the first several months of NORVIR treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin [see Warnings and Precautions (5.3) ] .

Pancreatitis Pancreatitis, including some fatalities, has been observed in patients receiving NORVIR therapy.

Advise patients to notify their healthcare provider of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis [see Warnings and Precautions (5.4) ] .

Allergic Reactions/Hypersensitivity Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving NORVIR.

Advise patients to contact their healthcare provider if they develop a rash while taking NORVIR [see Warnings and Precautions (5.5) ] .

PR Interval Prolongation NORVIR may produce changes in the electrocardiogram (e.g., PR prolongation).

Advise patients to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness [see Warnings and Precautions (5.6) ] .

Lipid Disorders Advise patients that treatment with NORVIR therapy can result in substantial increases in the concentration of total cholesterol and triglycerides [see Warnings and Precautions (5.7) ] .

Diabetes Mellitus/Hyperglycemia Advise patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported and to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on NORVIR as they may require a change in their diabetes treatment or new treatment [see Warnings and Precautions (5.7) ] .

Immune Reconstitution Syndrome Advise patients that immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including NORVIR [see Warnings and Precautions (5.9) ] .

Fat Redistribution Advise patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time [see Warnings and Precautions (5.10) ] .

Patients with Hemophilia Advise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as NORVIR [see Warnings and Precautions (5.11) ] .

Pregnancy Exposure Registry Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to NORVIR [see Use in Specific Populations (8.1) ] .

Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2) ] .

NORVIR 100 mg soft gelatin capsules are manufactured for: AbbVie Inc.

North Chicago, IL 60064 USA ©2020 AbbVie Inc.

All rights reserved.

DOSAGE AND ADMINISTRATION

2 Dose modification for NORVIR is necessary when used with other protease inhibitors.

(2) Adult patients: 600 mg twice-daily with meals if possible.

(2.2) Pediatrics patients: The recommended twice daily dose for children greater than one month of age is based on body surface area and should not exceed 600 mg twice daily with meals.

(2.3) 2.1 General Administration Recommendations NORVIR must be used in combination with other antiretroviral agents.

NORVIR is administered orally in combination with other antiretroviral agents.

It is recommended that NORVIR be taken with meals.

General Dosing Guidelines Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued.

2.2 Dosage Recommendations in Adults Recommended Dosage for treatment of HIV-1 The recommended dosage of NORVIR is 600 mg twice daily by mouth.

Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels.

NORVIR should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily.

The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

2.3 Dosage Recommendations in Pediatric Patients NORVIR must be used in combination with other antiretroviral agents [see Dosage and Administration (2) ] .

The recommended dosage of NORVIR in pediatric patients older than 1 month is 350 to 400 mg per m 2 twice daily by mouth and should not exceed 600 mg twice daily.

NORVIR should be started at 250 mg per m 2 twice daily and increased at 2 to 3 day intervals by 50 mg per m 2 twice daily.

If patients do not tolerate 400 mg per m 2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered.

The use of NORVIR oral solution is recommended for children greater than 1 month who cannot swallow capsules.

Please refer to the NORVIR oral solution full prescribing information for pediatric dosage and administration.

5-5-fluorouracil 50 MG/ML Injectable Solution

WARNINGS

THE DAILY DOSE OF FLUOROURACIL IS NOT TO EXCEED 800 MG.

IT IS RECOMMENDED THAT PATIENTS BE HOSPITALIZED DURING THEIR FIRST COURSE OF TREATMENT.

Fluorouracil should be used with extreme caution in poor risk patients with a history of high-dose pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal function.

Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase activity.

1 A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with worse morbidity.

Absence of this catabolic enzyme appears to result in prolonged clearance of 5-fluorouracil.

Pregnancy Teratogenic Effects – Pregnancy Category D Fluorouracil may cause fetal harm when administered to a pregnant woman.

Fluorouracil has been shown to be teratogenic in laboratory animals.

Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on day 10 or 12 of gestation.

Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg given to hamsters between days 8 and 11 of gestation were teratogenic.

Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails.

The dosages which were teratogenic in animals are 1 to 3 times the maximum recommended human therapeutic dose.

In monkeys, divided doses of 40 mg/kg given between days 20 and 24 of gestation were not teratogenic.

There are no adequate and well-controlled studies with fluorouracil in pregnant women.

While there is no evidence of teratogenicity in humans due to fluorouracil, it should be kept in mind that other drugs which inhibit DNA synthesis ( e.g.

, methotrexate and aminopterin) have been reported to be teratogenic in humans.

Women of childbearing potential should be advised to avoid becoming pregnant.

If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be told of the potential hazard to the fetus.

Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Combination Therapy Any form of therapy which adds to the stress of the patient, interferes with nutrition or depresses bone marrow function will increase the toxicity of Fluorouracil.

DRUG INTERACTIONS

Drug Interactions Leucovorin calcium may enhance the toxicity of fluorouracil.

Also see WARNINGS section.

OVERDOSAGE

The possibility of overdosage with fluorouracil is unlikely in view of the mode of administration.

Nevertheless, the anticipated manifestations would be nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis).

No specific antidotal therapy exists.

Patients who have been exposed to an overdose of Fluorouracil should be monitored hematologically for at least four weeks.

Should abnormalities appear, appropriate therapy should be utilized.

The acute intravenous toxicity of fluorouracil is as follows: Species LD 50 (mg/kg ±S.E.) Mouse 340 ± 17 Rat 165 ± 26 Rabbit 27 ± 5.1 Dog 31.5 ± 3.8

DESCRIPTION

Fluorouracil Injection, USP an antineoplastic antimetabolite, is a colorless to yellow aqueous sterile, nonpyrogenic injectable solution for intravenous administration.

Each mL contains: 50 mg of fluorouracil; pH is adjusted to approximately 9.2 with sodium hydroxide.

Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1 H ,3 H )-pyrimidinedione.

It is a white to practically white crystalline powder which is sparingly soluble in water.

The molecular weight is 130.08 and the structural formula is: C 4 H 3 FN 2 O 2 .

A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses.

The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion or the filling of empty sterile syringes for patients with individualized dosing requirements.

Chemical Structure

HOW SUPPLIED

NDC 66758-054-01: 50 mg/mL in a 50 mL flip-top Pharmacy Bulk Package vial, individually packaged.

NDC 66758-054-02: 50 mg/mL in a 100 mL flip-top Pharmacy Bulk Package vial, individually packaged.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

DO NOT FREEZE.

PROTECT FROM LIGHT .

Vial stoppers do not contain natural rubber latex.

For Sandoz Inc.

Customer Service, call 1-800-525-8747.

Manufactured for: SANDOZ Princeton, NJ 08540 Manufactured by: Ebewe PHARMA A-4866 Unterach, AUSTRIA April 2011

INDICATIONS AND USAGE

Fluorouracil is effective in the palliative management of carcinoma of the colon, rectum, breast, stomach and pancreas.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in children have not been established.

PREGNANCY

Pregnancy Teratogenic Effects – Pregnancy Category D Fluorouracil may cause fetal harm when administered to a pregnant woman.

Fluorouracil has been shown to be teratogenic in laboratory animals.

Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on day 10 or 12 of gestation.

Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg given to hamsters between days 8 and 11 of gestation were teratogenic.

Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails.

The dosages which were teratogenic in animals are 1 to 3 times the maximum recommended human therapeutic dose.

In monkeys, divided doses of 40 mg/kg given between days 20 and 24 of gestation were not teratogenic.

There are no adequate and well-controlled studies with fluorouracil in pregnant women.

While there is no evidence of teratogenicity in humans due to fluorouracil, it should be kept in mind that other drugs which inhibit DNA synthesis ( e.g.

, methotrexate and aminopterin) have been reported to be teratogenic in humans.

Women of childbearing potential should be advised to avoid becoming pregnant.

If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be told of the potential hazard to the fetus.

Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers It is not known whether fluorouracil is excreted in human milk.

Because fluorouracil inhibits DNA, RNA and protein synthesis, mothers should not nurse while receiving this drug.

BOXED WARNING

PHARMACY BULK PACKAGE – Not For Direct Infusion WARNING It is recommended that FLOUROURACIL be given only by or under the supervision of a qualified physician who is experienced in cancer chemotherapy and who is well versed in the use of potent antimetabolites.

Because of the possibility of severe toxic reactions, it is recommended that patients be hospitalized at least during the initial course of therapy.

INFORMATION FOR PATIENTS

Information for Patients Patients should be informed of expected toxic effects, particularly oral manifestations.

Patients should be alerted to the possibility of alopecia as a result of therapy and should be informed that it is usually a transient effect.

DOSAGE AND ADMINISTRATION

General Instructions Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.

No dilution is required.

All dosages are based on the patient’s actual weight.

However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

Dosage 12 mg/kg are given intravenously once daily for 4 successive days.

The daily dose should not exceed 800 mg.

If no toxicity is observed , 6 mg/kg are given on the 6 th , 8 th , 10 th and 12 th days unless toxicity occurs .

No therapy is given on the 5 th , 7 th , 9 th or 11 th days.

Therapy is to be discontinued at the end of the 12 th day, even if no toxicity has become apparent.

(See WARNINGS and PRECAUTIONS .) Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.

If no toxicity is observed , 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.

No therapy is given on the 4 th , 6 th or 8 th days.

The daily dose should not exceed 400 mg.

A sequence of injections on either schedule constitutes a “course of therapy.” Maintenance Therapy In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules: 1.

Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

2.

When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.

Do not exceed 1 gm per week.

The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.

Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

Procedures for proper handling and disposal of anticancer drugs should be considered.

Several guidelines on this subject have been published.

2-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropiate.

Note Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.

If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

DIRECTION FOR PROPER USE OF PHARMACY BULK PACKAGE Pharmacy Bulk Packages are for use in a Pharmacy Admixture Service only in a vertical laminar flow hood.

The container closure should be penetrated only one time utilizing a suitable sterile dispensing set or transfer device which allows measured distribution of the contents.

Swab vial stopper with an antiseptic solution.

Insert the device/set into the vial using aseptic technique.

Once the sterile dispensing set or transfer device has been inserted into the container, withdrawal of the contents should be accomplished without delay.

However, if this is not possible, a maximum time of 4 hours from the initial entry may be allowed to complete fluid aliquoting/transferring operations.

The transferred drug solution should be used promptly.

Discard the contents no later than 4 hours after initial closure puncture.

Olmesartan medoxomil 20 MG Oral Tablet [Benicar]

DRUG INTERACTIONS

7 No significant drug interactions were reported in studies in which Benicar was co-administered with digoxin or warfarin in healthy volunteers.

The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH) 3 /Mg(OH) 2 ].

Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.

Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Closely monitor blood pressure, renal function and electrolytes in patients on Benicar and other agents that affect the RAS.

Do not co-administer aliskiren with Benicar in patients with diabetes [see Contraindications (4) ].

Avoid use of aliskiren with Benicar in patients with renal impairment (GFR <60 ml/min).

Colesevelam hydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan.

Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect.

Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3) ] .

NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect (7) .

Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7) .

Colesevelam hydrochloride: Consider administering olmesartan at least 4 hours before colesevelam hydrochloride dose (7)

OVERDOSAGE

10 Limited data are available related to overdosage in humans.

The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs.

If symptomatic hypotension occurs, initiate supportive treatment.

The dialyzability of olmesartan is unknown.

DESCRIPTION

11 Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.

Olmesartan is a selective AT 1 subtype angiotensin II receptor antagonist.

Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 hydroxy-1-methylethyl)-2-propyl-1-[ p -( o -1H-tetrazol-5-ylphenyl)benzyl]imidazole-5 carboxylate, cyclic 2,3-carbonate.

Its empirical formula is C 29 H 30 N 6 O 6 and its structural formula is: Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.59.

It is practically insoluble in water and sparingly soluble in methanol.

Benicar is available for oral use as film-coated tablets containing 5 mg, 20 mg, or 40 mg of olmesartan medoxomil and the following inactive ingredients: hydroxypropyl cellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, and (5 mg only) yellow iron oxide.

Structural formula for olmesartan medoxomil

CLINICAL STUDIES

14 14.1 Adult Hypertension The antihypertensive effects of Benicar have been demonstrated in seven placebo controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure.

A total of 2693 patients (2145 Benicar; 548 placebo) with essential hypertension were studied.

Benicar once daily lowered diastolic and systolic blood pressure.

The response was dose-related, as shown in the following graph.

A Benicar dose of 20 mg daily produces a trough sitting BP reduction over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting BP reduction over placebo of about 12/7 mmHg.

Benicar doses greater than 40 mg had little additional effect.

The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2 weeks.

Data above are from seven placebo-controlled studies (2145 Benicar patients, 548 placebo patients).

The blood pressure lowering effect was maintained throughout the 24-hour period with Benicar once daily, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%.

The blood pressure lowering effect of Benicar, with and without hydrochlorothiazide, was maintained in patients treated for up to 1 year.

There was no evidence of tachyphylaxis during long-term treatment with Benicar or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1 year of treatment.

The antihypertensive effect of Benicar was similar in men and women and in patients older and younger than 65 years.

The effect was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers.

Benicar had an additional blood pressure lowering effect when added to hydrochlorothiazide.

There are no trials of Benicar demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

Benicar Dose Response: Placebo-adjusted Reduction in Blood Pressure (mm Hg) 14.2 Pediatric Hypertension The antihypertensive effects of Benicar in the pediatric population were evaluated in a randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years.

The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks.

The etiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort).

Patients who weighed 20 to <35 kg were randomized to 2.5 or 20 mg of Benicar once daily and patients who weighed ≥35 kg were randomized to 5 or 40 mg of Benicar once daily.

At the end of 3 weeks, patients were re-randomized to continuing Benicar or to taking placebo for up to 2 weeks.

During the initial dose-response phase, Benicar significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner.

Overall, the two dose levels of Benicar (low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively.

These reductions in systolic blood pressure included both drug and placebo effect.

During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2 mmHg lower and mean diastolic blood pressure at trough was 2.8 mmHg lower in patients continuing Benicar than in patients withdrawn to placebo.

These differences were statistically different.

As observed in adult populations, the blood pressure reductions were smaller in black patients.

In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of Benicar once daily for three weeks in an open label phase and then were randomized to receiving Benicar or placebo in a double-blind phase.

At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to Benicar; this difference in blood pressure was not statistically significant (95% C.I.

-2 to 7/-1 to 7).

HOW SUPPLIED

16 /STORAGE AND HANDLING Benicar is supplied as yellow, round, film-coated, non-scored tablets containing 5 mg of olmesartan medoxomil, as white, round, film-coated, non-scored tablets containing 20 mg of olmesartan medoxomil, and as white, oval-shaped, film-coated, non-scored tablets containing 40 mg of olmesartan medoxomil.

Tablets are debossed with Sankyo on one side and C12, C14, or C15 on the other side of the 5, 20, and 40 mg tablets, respectively.

Tablets are supplied as follows: 5 mg 20 mg 40 mg Bottle of 30 NDC 51138-211-30 NDC 51138-212-30 NDC 51138-213-30 Storage Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature] .

RECENT MAJOR CHANGES

Boxed Warning 3/2012 Indications and Usage (1) 2/2012 Contraindications (4) 9/2012 Dosage and Administration: Pediatric Hypertension (6 to 16 years of age) (2.2) 2/2012 Warnings and Precautions: Pregnancy (5.1) 3/2012 Morbidity in Infants (5.2) 2/2012

GERIATRIC USE

8.5 Geriatric Use Of the total number of hypertensive patients receiving Benicar in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older.

No overall differences in effectiveness or safety were observed between elderly patients and younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) ] .

DOSAGE FORMS AND STRENGTHS

3 5 mg yellow, round, film-coated, non-scored tablets debossed with Sankyo on one side and C12 on the other side 20 mg white, round, film-coated, non-scored tablets debossed with Sankyo on one side and C14 on the other side 40 mg white, oval-shaped, film-coated, non-scored tablets debossed with Sankyo on one side and C15 on the other side Tablets: 5 mg, 20 mg, and 40 mg (3) .

MECHANISM OF ACTION

12.1 Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II).

Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium.

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in vascular smooth muscle.

Its action is, therefore, independent of the pathways for angiotensin II synthesis.

An AT 2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis.

Olmesartan has more than a 12,500-fold greater affinity for the AT 1 receptor than for the AT 2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension.

ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE.

Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin.

Whether this difference has clinical relevance is not yet known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

INDICATIONS AND USAGE

1 Benicar is indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

There are no controlled trials demonstrating risk reduction with Benicar.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

It may be used alone or in combination with other antihypertensive agents.

Benicar is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1) .

PEDIATRIC USE

8.4 Pediatric Use Neonates with a history of in utero exposure to Benicar: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The antihypertensive effects of Benicar were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see Clinical Studies (14.2) ] .

The pharmacokinetics of Benicar were evaluated in pediatric patients 1 to 16 years of age [see Clinical Pharmacology (12.3) ] .

Benicar was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults.

Benicar has not been shown to be effective for hypertension in children <6 years of age.

Children <1 year of age must not receive Benicar for hypertension [see Warnings and Precautions (5.2) ].

The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development.

RAAS blockade has been shown to lead to abnormal kidney development in very young mice.

Administering drugs that act directly on the renin- angiotensin aldosterone system (RAAS) can alter normal renal development.

PREGNANCY

8.1 Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue Benicar as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue Benicar, unless it is considered lifesaving for the mother.

Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to Benicar for hypotension, oliguria, and hyperkalemia [ see Use in Specific Populations ( 8.4 )] .

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats.

Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Benicar as soon as possible [see Warnings and Precautions ( 5.1 )].

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions ( 5.1 )].

WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue Benicar as soon as possible (5.1) .

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1) .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Avoid fetal (in utero) exposure (5.1) .

Children <1 year of age must not receive Benicar for hypertension (5.2) .

Observe for signs and symptoms of hypotension in volume- or salt-depleted patients with treatment initiation (5.3) .

Monitor for worsening renal function in patients with renal impairment (5.4) .

5.1 Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue Benicar as soon as possible [ see Use in specific Populations ( 8.1 )] .

5.2 Morbidity in Infants Children <1 year of age must not receive Benicar for hypertension.

Drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of immature kidneys [see Use in Specific Populations (8.4) ] .

5.3 Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin aldosterone system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with Benicar.

Initiate treatment under close medical supervision.

If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline [see Dosage and Administration (2.1) ] .

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.4 Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Benicar.

In patients whose renal function may depend upon the activity of the renin angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

Similar results may be anticipated in patients treated with Benicar [see Dosage and Administration (2.1) , Drug Interactions (7) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported.

There has been no long-term use of Benicar in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Benicar during pregnancy.

Discuss treatment options with women planning to become pregnant.

Patients should be asked to report pregnancies to their physicians as soon as possible.

Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054 Rx Only Copyright © Daiichi Sankyo, Inc.

2009.

All rights reserved.

Repackaged By: Med-Health Pharma, LLC North Las Vegas, NV 89032 SP-60060 Rev06

DOSAGE AND ADMINISTRATION

2 Indication Starting dose Dose Range Adult Hypertension (2.1) 20 mg once daily 20 – 40 mg once daily Pediatric Hypertension (6 – 16 years) (2.2) 20 to <35 kg 10 mg once daily ≥35 kg 20 mg once daily 20 to <35 kg 10 – 20 mg once daily ≥35 kg 20 – 40 mg once daily Benicar may be administered with or without food.

If blood pressure is not controlled by Benicar alone, a diuretic may be added.

Benicar may be administered with other antihypertensive agents.

2.1 Adult Hypertension Dosage must be individualized.

The usual recommended starting dose of Benicar is 20 mg once daily when used as monotherapy in patients who are not volume-contracted.

For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Benicar may be increased to 40 mg.

Doses above 40 mg do not appear to have greater effect.

Twice-daily dosing offers no advantage over the same total dose given once daily.

No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min) or with moderate to marked hepatic dysfunction [see Warnings and Precautions (5.4) , Use in Specific Populations ( 8.5 , 8.6 , 8.7 ) and Clinical Pharmacology (12.3) ] .

For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Benicar under close medical supervision and give consideration to use of a lower starting dose [see Warnings and Precautions (5.3) ] .

Benicar may be administered with or without food.

If blood pressure is not controlled by Benicar alone, a diuretic may be added.

Benicar may be administered with other antihypertensive agents.

2.2 Pediatric Hypertension (6 to 16 years of age) Dosage must be individualized.

For children who can swallow tablets, the usual recommended starting dose of Benicar is 10 mg once daily for patients who weigh 20 to <35 kg (44 to 77 lb), or 20 mg once daily for patients who weigh ≥35 kg.

For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Benicar may be increased to a maximum of 20 mg once daily for patients who weigh <35 kg or 40 mg once daily for patients who weigh ≥35 kg.

Children <1 year of age must not receive Benicar for hypertension.

For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below [see Clinical Pharmacology (12.3) ] .

Follow the suspension preparation instructions below to administer Benicar as a suspension.

Preparation of Suspension (for 200 mL of a 2 mg/mL suspension) Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty Benicar 20 mg tablets and allow to stand for a minimum of 5 minutes.

Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute.

Repeat 1-minute shaking and 1-minute standing for four additional times.

Add 100 mL of Ora-Sweet ® * and 50 mL of Ora-Plus ® * to the suspension and shake well for at least 1 minute.

The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks.

Shake the suspension well before each use and return promptly to the refrigerator.

* Ora-Sweet ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc.

WARNINGS

Fluoroquinolones, including ciprofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.

This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair.

Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.

Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis.

Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors.

Inflammation and tendon rupture can occur, sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported.

Ciprofloxacin should be used with caution in patients with a history of tendon disorders.

Ciprofloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon.

Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Fluoroquinolones, including ciprofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.

Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis.

Avoid ciprofloxacin in patients with known history of myasthenia gravis.

(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Post-Marketing Adverse Event Reports.

) THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.

(See PRECAUTIONS: Pregnancy , and Nursing Mothers subsections.) Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy.

Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.

Only a few patients had a history of hypersensitivity reactions.

Serious anaphylactic reactions require immediate emergency treatment with epinephrine.

Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

Other Serious and Sometimes Fatal Reactions Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including ciprofloxacin.

These events may be severe and generally occur following the administration of multiple doses.

Clinical manifestations may include one or more of the following: Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome); Vasculitis; arthralgia; myalgia; serum sickness; Allergic pneumonitis; Interstitial nephritis; acute renal insufficiency or failure; Hepatitis; jaundice; acute hepatic necrosis or failure; Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS ).

Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin.

Acute liver injury is rapid in onset (range 1-39 days), and is often associated with hypersensitivity.

The pattern of injury can be hepatocellular, cholestatic or mixed.

Most patients with fatal outcomes were older than 55 years old.

In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued immediately (see ADVERSE REACTIONS ).

There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin (see ADVERSE REACTIONS ).

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND THEOPHYLLINE.

These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure.

Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated.

If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones, including ciprofloxacin.

Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, psychotic reactions have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide.

These reactions may occur following the first dose.

If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued, patients should be advised to inform their healthcare provider immediately and appropriate measures instituted.

Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold.

As with all fluoroquinolones, ciprofloxacin should be used with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction).

Ciprofloxacin should only be used where the benefits of treatment exceed the risks, since these patients are endangered because of possible undesirable CNS side effects.

Cases of status epilepticus have been reported.

If seizures occur, ciprofloxacin should be discontinued.

(See PRECAUTIONS: General , Information for Patients , Drug Interactions and ADVERSE REACTIONS .

) Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile.

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing isolates of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including ciprofloxacin.

Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Patients treated with ciprofloxacin should be advised to inform their healthcare provider prior to continuing treatment if symptoms of neuropathy develop.

Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in the INDICATIONS AND USAGE section.

An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed.

(See ADVERSE REACTIONS .

) In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.

Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage.

Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.

(See ANIMAL PHARMACOLOGY .

) Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia.

Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin.

Ciprofloxacin should be avoided in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example, congenital long QT syndrome , uncorrected electrolyte imbalance, such as hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics.

Elderly patients may also be more susceptible to drug-associated effects on the QT interval.

(See PRECAUTIONS , Drug Interactions and Geriatric Use ).

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.

Coadministration of ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug (See PRECAUTIONS , Drug Interactions ) .

Ciprofloxacin has not been shown to be effective in the treatment of syphilis.

Antimicrobial agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis.

All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis.

Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after three months.

OVERDOSAGE

In the event of acute overdosage, reversible renal toxicity has been reported in some cases.

The stomach should be emptied by inducing vomiting or by gastric lavage.

The patient should be carefully observed and given supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum, or calcium containing antacids, which can reduce the absorption of ciprofloxacin.

Adequate hydration must be maintained.

Only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.

Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats, and dogs.

No deaths occurred within a 14-day post treatment observation period at the highest oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog.

Clinical signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs.

In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg.

Mortality was delayed in these animals, occurring 10-14 days after dosing.

In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.

DESCRIPTION

Ciprofloxacin hydrochloride tablets are synthetic broad spectrum antimicrobial agents for oral administration.

Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.

It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8.

Its empirical formula is C 17 H 18 FN 3 O 3 • HCl • H 2 O and its chemical structure is as follows: Ciprofloxacin tablets are film-coated and white in color.

Each tablet, for oral administration, contains ciprofloxacin hydrochloride equivalent to 100 mg, 250 mg, 500 mg or 750 mg ciprofloxacin.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, sodium starch glycolate, corn starch and titanium dioxide.

MM1

CLINICAL STUDIES

NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues.

Ciprofloxacin, administered IV and/or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years).

The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany.

The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days).

The primary objective of the study was to assess musculoskeletal and neurological safety.

Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC).

The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).

The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown below.

Ciprofloxacin Comparator Randomized Patients 337 352 Per Protocol Patients 211 231 Clinical Response at 5 to 9 Days Post-Treatment 95.7% (202/211) 92.6% (214/231) 95% CI [-1.3%, 7.3%] Bacteriologic Eradication byPatient at 5 to 9 DaysPost-Treatment* 84.4% (178/211) 78.3% (181/231) 95% CI [-1.3%, 13.1%] Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days Post-Treatment Escherichia coli 156/178 (88%) 161/179 (90%) * Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients.

There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections.

HOW SUPPLIED

Ciprofloxacin Tablets USP 100 mg are white, oval shaped film-coated tablets debossed with “R” on one side and “125” on other side and supplied in a cystitis pack containing 6 tablets for use only in female patients with acute uncomplicated cystitis.

Cystitis package of 6 NDC 55111-125-06 Ciprofloxacin Tablets USP 250 mg are white, oval shaped film-coated tablets debossed with “R” on one side and “126” on other side and are supplied in bottles of 50, 100, 500 and unit dose packages of 10 × 10.

Bottles of 50 NDC 55111-126-50 Bottles of 100 NDC 55111-126-01 Bottles of 500 NDC 55111-126-05 Unit dose package of 10 × 10 NDC 55111-126-78 Ciprofloxacin Tablets USP 500 mg are white, oval shaped film-coated tablets debossed with “R” on one side and “127” on other side and are supplied in bottles of 50, 100, 500 and unit dose packages of 10 × 10.

Bottles of 50 NDC 55111-127-50 Bottles of 100 NDC 55111-127-01 Bottles of 500 NDC 55111-127-05 Unit dose package of 10 × 10 NDC 55111-127-78 Ciprofloxacin Tablets USP 750 mg are white, modified capsule shaped film-coated tablets debossed with “R” on one side and “128” on other side and are supplied in bottles of 50, 100, 500 and unit dose packages of 10 × 10.

Bottles of 50 NDC 55111-128-50 Bottles of 100 NDC 55111-128-01 Bottles of 500 NDC 55111-128-05 Unit dose package of 10 × 10 NDC 55111-128-78 Store below 86°F (30°C).

INDICATIONS AND USAGE

INDICATIONS & USAGE Ciprofloxacin tablets are indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below.

Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter koseri (diversus), Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or vancomycin-susceptible Enterococcus faecalis.

Acute Uncomplicated Cystitis in Females caused by Escherichia coli or Staphylococcus saprophyticus.

Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.

Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae.

* Also, Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.

*Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae .

Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis.

Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible, Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.

Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.

Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.

Infectious Diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii *, Shigella dysenteriae, Shigella flexneri or Shigella sonnei * when antibacterial therapy is indicated.

* Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients.

Typhoid Fever (Enteric Fever) caused by Salmonella typhi.

NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated.

Uncomplicated Cervical and Urethral Gonorrhea due to Neisseria gonorrhoeae.

Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli .

NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues.

(See WARNINGS , PRECAUTIONS, Pediatric Use , ADVERSE REACTIONS and CLINICAL STUDIES .) Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.

(See ANIMAL PHARMACOLOGY .) Inhalational Anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication.

5 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001.

(See also, INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION ).

If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin.

Therapy with ciprofloxacin hydrochloride may be initiated before results of these tests are known; once results become available appropriate therapy should be continued.

As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin.

Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin tablets and other antibacterial drugs, ciprofloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

BOXED WARNING

WARNING: Fluoroquinolones, including ciprofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.

This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (See WARNINGS ).

Fluoroquinolones, including ciprofloxacin, may exacerbate muscle weakness in persons with myasthenia gravis.

Avoid ciprofloxacin in patients with known history of myasthenia gravis (see WARNINGS ).