Drug Intercation

lacosamide 50 MG Oral Tablet

DRUG INTERACTIONS

7 Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between VIMPAT and carbamazepine, valproate, digoxin, metformin, omeprazole, or an oral contraceptive containing ethinylestradiol and levonorgestrel.

There was no evidence for any relevant drug-drug interaction of VIMPAT with common AEDs in the placebo-controlled clinical trials in patients with partial-onset seizures [see Clinical Pharmacology (12.3) ].

The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system.

OVERDOSAGE

10 10.1 Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans There is limited clinical experience with VIMPAT overdose in humans.

The highest reported accidental overdose of VIMPAT during clinical development was 1200 mg/day which was non-fatal.

The types of adverse events experienced by patients exposed to supratherapeutic doses during the trials were not clinically different from those of patients administered recommended doses of VIMPAT.

There has been a single case of intentional overdose by a patient who self-administered 12 grams VIMPAT along with large doses of zonisamide, topiramate, and gabapentin.

The patient presented in a coma and was hospitalized.

An EEG revealed epileptic waveforms.

The patient recovered 2 days later.

10.2 Treatment or Management of Overdose There is no specific antidote for overdose with VIMPAT.

Standard decontamination procedures should be followed.

General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient.

A Certified Poison Control Center should be contacted for up to date information on the management of overdose with VIMPAT.

Standard hemodialysis procedures result in significant clearance of VIMPAT (reduction of systemic exposure by 50% in 4 hours).

Hemodialysis has not been performed in the few known cases of overdose, but may be indicated based on the patient’s clinical state or in patients with significant renal impairment.

DESCRIPTION

11 The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC).

Lacosamide is a functionalized amino acid.

Its molecular formula is C 13 H 18 N 2 O 3 and its molecular weight is 250.30.

The chemical structure is: Lacosamide is a white to light yellow powder.

It is sparingly soluble in water and slightly soluble in acetonitrile and ethanol.

Chemical Structure 11.1 VIMPAT Tablets VIMPAT tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and dye pigments as specified below: VIMPAT tablets are supplied as debossed tablets and contain the following coloring agents: 50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake 100 mg tablets: yellow iron oxide 150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide 200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake 11.2 VIMPAT Injection VIMPAT injection is a clear, colorless, sterile solution containing 10 mg lacosamide per mL for intravenous infusion.

One 20-mL vial contains 200 mg of lacosamide drug substance.

The inactive ingredients are sodium chloride and water for injection.

Hydrochloric acid is used for pH adjustment.

VIMPAT injection has a pH of 3.5 to 5.0.

11.3 VIMPAT Oral Solution VIMPAT oral solution contains 10 mg of lacosamide per mL.

The inactive ingredients are purified water, sorbitol solution, glycerin, polyethylene glycol, carboxymethylcellulose sodium, acesulfame potassium, methylparaben, flavoring (including natural and artificial flavors, propylene glycol, aspartame, and maltol), anhydrous citric acid and sodium chloride.

CLINICAL STUDIES

14 14.1 Effectiveness in Partial-Onset Seizures The efficacy of VIMPAT as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter trials in adult patients.

Patients enrolled had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs.

During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days.

In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days.

84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.

Study 1 compared doses of VIMPAT 200, 400, and 600 mg/day with placebo.

Study 2 compared doses of VIMPAT 400 and 600 mg/day with placebo.

Study 3 compared doses of VIMPAT 200 and 400 mg/day with placebo.

In all three trials, following an 8-week Baseline Phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose (a 1-step back-titration of VIMPAT 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the Titration Phase).

During the Titration Phase in all 3 trials, treatment was initiated at 100 mg/day (50 mg given twice daily) and increased in weekly increments of 100 mg/day to the target dose.

The Titration Phase lasted 6 weeks in Study 1 and Study 2 and 4 weeks in Study 3.

In all three trials, the Titration Phase was followed by a Maintenance Phase that lasted 12 weeks, during which patients were to remain on a stable dose of VIMPAT.

A reduction in 28 day seizure frequency (Baseline to Maintenance Phase) as compared to the placebo group was the primary variable in all three trials.

The criteria for statistical significance was p<0.05.

A statistically significant effect was observed with VIMPAT treatment (Figure 1) at doses of 200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2).

Subset evaluations of VIMPAT demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial seizure frequency (responder rate) from Baseline to the Maintenance phase at least as great as that represented on the Y-axis.

A positive value on the Y-axis indicates an improvement from Baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from Baseline (ie., an increase in seizure frequency).

Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo.

The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the VIMPAT groups compared to the placebo group.

For example, 40% of patients randomized to VIMPAT (400 mg/day) experienced a 50% or greater reduction in seizure frequency, compared to 23% of patients randomized to placebo.

Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.

Figure Figure

HOW SUPPLIED

16 /STORAGE AND HANDLING VIMPAT (lacosamide) Tablets 50 mg are pink, oval, film-coated tablets debossed with “SP” on one side and “50” on the other.

They are supplied as follows: Bottles of 60 NDC54868-6077-0 16.1 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).

[See USP Controlled Room Temperature].

Do not freeze Vimpat injection or oral solution.

Discard any unused Vimpat oral solution remaining after seven (7) weeks of first opening the bottle.

GERIATRIC USE

8.5 Geriatric Use There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately assess the effectiveness of VIMPAT in this population.

In healthy subjects, the dose and body weight normalized pharmacokinetic parameters AUC and C max were approximately 20% higher in elderly subjects compared to young subjects.

The slightly higher lacosamide plasma concentrations in elderly subjects are possibly caused by differences in total body water (lean body weight) and age-associated decreased renal clearance.

No VIMPAT dose adjustment based on age is considered necessary.

Caution should be exercised for dose titration in elderly patients.

DOSAGE FORMS AND STRENGTHS

3 50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), and 200 mg (blue) film-coated tablets 200 mg/20mL injection 10 mg/mL oral solution 50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), 200 mg (blue) film-coated tablets (3) 200 mg/20 mL single-use vial for intravenous use (3) 10 mg/mL oral solution (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The precise mechanism by which VIMPAT exerts its antiepileptic effects in humans remains to be fully elucidated.

In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

Lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth.

The role of CRMP-2 binding in seizure control is unknown.

INDICATIONS AND USAGE

1 VIMPAT is indicated for: Partial-onset seizures ( 1.1 ): Tablets and oral solution are indicated for adjunctive therapy in patients ≥17 years.

Injection is indicated as short term replacement when oral administration is not feasible in these patients.

1.1 Partial-Onset Seizures VIMPAT (lacosamide) tablets and oral solution are indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged 17 years and older.

VIMPAT (lacosamide) injection for intravenous use is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged 17 years and older when oral administration is temporarily not feasible.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of VIMPAT in pediatric patients <17 years have not been established.

Lacosamide has been shown in vitro to interfere with the activity of CRMP-2, a protein involved in neuronal differentiation and control of axonal outgrowth.

Potential adverse effects on CNS development can not be ruled out.

Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).

The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (AUC) approximately 0.5 times the human plasma AUC at the maximum recommended human dose of 400 mg/day.

PREGNANCY

8.1 Pregnancy Pregnancy Category C Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy.

Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy.

These effects were observed at doses associated with clinically relevant plasma exposures.

Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.

Potential adverse effects on CNS development can not be ruled out.

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

VIMPAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any teratogenic effects.

However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats.

These doses were associated with maternal plasma lacosamide exposures [area under the plasma-time concentration curve; (AUC)] ≈2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

When lacosamide (25, 70, or 200 mg/kg/day) was orally administered to rats throughout gestation, parturition, and lactation, increased perinatal mortality and decreased body weights were observed in the offspring at the highest dose.

The no-effect dose for pre- and post-natal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC approximately equal to that in humans at the MRHD.

Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).

The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development.

The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC approximately 0.5 times that in humans at the MRHD.

Pregnancy Registry UCB, Inc.

has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with VIMPAT.

To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling 1-888-537-7734 (toll free).

Physicians are also advised to recommend that pregnant patients taking VIMPAT enroll in the North American Antiepileptic Drug Pregnancy Registry.

This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.

Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

NUSRING MOTHERS

8.3 Nursing Mothers Studies in lactating rats have shown that lacosamide and/or its metabolites are excreted in milk.

It is not known whether VIMPAT is excreted in human milk.

Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue VIMPAT, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation (5.1) Patients should be advised that VIMPAT may cause dizziness and ataxia.

(5.2) Caution is advised for patients with known cardiac conduction problems [e.g., second-degree atrioventricular (AV) block], who are taking drugs known to induce PR interval prolongation, or with severe cardiac disease such as myocardial ischemia or heart failure.

(5.3) Patients should be advised that VIMPAT may cause syncope.

(5.4) In patients with seizure disorders, VIMPAT should be gradually withdrawn to minimize the potential of increased seizure frequency.

(5.5) Multiorgan Hypersensitivity Reactions (5.6) Phenylketonurics (5.7) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VIMPAT, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.

Anyone considering prescribing VIMPAT or any other AED must balance this risk with the risk of untreated illness.

Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.2 Dizziness and Ataxia Patients should be advised that VIMPAT may cause dizziness and ataxia.

Accordingly, they should be advised not to drive a car or to operate other complex machinery until they are familiar with the effects of VIMPAT on their ability to perform such activities.

In patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%).

Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared to 2% of placebo patients).

The onset of dizziness and ataxia was most commonly observed during titration.

There was a substantial increase in these adverse events at doses higher than 400 mg/day.

[see Adverse Reactions/ Table 2 (6.1) ] 5.3 Cardiac Rhythm and Conduction Abnormalities PR interval prolongation Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in patients and in healthy volunteers.

[see Clinical Pharmacology (12.2) ] In clinical trials in patients with partial-onset epilepsy, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT and 0% (0/364) of patients randomized to receive placebo.

In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of patients receiving VIMPAT and 0% (0/291) of patients receiving placebo.

Second degree or higher AV block has been reported in postmarketing experience in epilepsy patients.

When VIMPAT is given with other drugs that prolong the PR interval, further PR prolongation is possible.

Patients should be made aware of the symptoms of second-degree or higher AV block (e.g.

slow or irregular pulse, feeling of lightheadedness and fainting) and told to contact their physician should any of these occur.

VIMPAT should be used with caution in patients with known conduction problems (e.g.

marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), or with severe cardiac disease such as myocardial ischemia or heart failure.

In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state, is recommended.

Atrial fibrillation and Atrial flutter In the short-term investigational trials of VIMPAT in epilepsy patients, there were no cases of atrial fibrillation or flutter, however, both have been reported in open label epilepsy trials and in postmarketing experience.

In patients with diabetic neuropathy, 0.5% of patients treated with VIMPAT experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients.

VIMPAT administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.

Patients should be made aware of the symptoms of atrial fibrillation and flutter (e.g., palpitations, rapid pulse, shortness of breath) and told to contact their physician should any of these symptoms occur.

5.4 Syncope In the short-term controlled trials of VIMPAT in epilepsy patients with no significant system illnesses, there was no increase in syncope compared to placebo.

In the short-term controlled trials of VIMPAT in patients with diabetic neuropathy, 1.2% of patients who were treated with VIMPAT reported an adverse reaction of syncope or loss of consciousness, compared to 0% of placebo-treated patients with diabetic neuropathy.

Most of the cases of syncope were observed in patients receiving doses above 400 mg/day.

The cause of syncope was not determined in most cases.

However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia.

5.5 Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, VIMPAT should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.

5.6 Multiorgan Hypersensitivity Reactions One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to VIMPAT during clinical development.

The event occurred in a healthy volunteer, 10 days after stopping VIMPAT treatment.

The subject was not taking any concomitant medication and potential known viral etiologies for hepatitis were ruled out.

The subject fully recovered within a month, without specific treatment.

The case is consistent with a delayed multiorgan hypersensitivity reaction.

Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology.

Multiorgan hypersensitivity reactions (also known as D rug R eaction with E osinophilia and S ystemic S ymptoms, or DRESS) have been reported with other anticonvulsants and typically, although not exclusively, present with fever and rash associated with other organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis.

Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur.

If this reaction is suspected, VIMPAT should be discontinued and alternative treatment started.

5.7 Phenylketonurics VIMPAT oral solution contains aspartame, a source of phenylalanine.

A 200 mg dose of VIMPAT oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION [See Medication Guide ] Patients should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking VIMPAT.

Patients should be instructed to take VIMPAT only as prescribed.

17.1 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including VIMPAT, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

17.2 Dizziness and Ataxia Patients should be counseled that VIMPAT use may cause dizziness, double vision, abnormal coordination and balance, and somnolence.

Patients taking VIMPAT should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with VIMPAT.

17.3 Cardiac Rhythm and Conduction Abnormalities Patients should be counseled that VIMPAT is associated with electrocardiographic changes that may predispose to irregular beat and syncope, particularly in patients with underlying cardiovascular disease, with heart conduction problems or who are taking other medications that affect the heart.

Patients who develop syncope should lay down with raised legs until recovered and contact their health care provider.

17.4 Multiorgan Hypersensitivity Reactions Patients should be aware that VIMPAT may cause serious hypersensitivity reactions affecting multiple organs such as the liver and kidney.

VIMPAT should be discontinued if a serious hypersensitivity reaction is suspected.

Patients should also be instructed to report promptly to their physicians any symptoms of liver toxicity (e.g.

fatigue, jaundice, dark urine).

17.5 Pregnancy Registry UCB, Inc.

has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with VIMPAT.

To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling 1-888-537-7734 (toll free).

Patients should also be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant.

This Registry is collecting information about the safety of AEDs during pregnancy.

To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1) ].

DOSAGE AND ADMINISTRATION

2 VIMPAT may be taken with or without food.

When using VIMPAT oral solution, it is recommended that a calibrated measuring device be obtained and used.

A household teaspoon or tablespoon is not an adequate measuring device.

Healthcare providers should recommend a device that can measure and deliver the prescribed dose accurately, and provide instructions for measuring the dosage.

Partial-onset seizures (2.1) : Initially, give 50 mg twice daily (100 mg/day).

The dose may be increased, based on clinical response and tolerability, at weekly intervals by 100 mg/day given as two divided doses to a daily dose of 200 to 400 mg/day.

VIMPAT injection may be given without further dilution or mixed in compatible diluent and should be administered intravenously over a period of 30 to 60 minutes.

(2.1) Oral-Intravenous Replacement therapy (2.1) : When switching from oral VIMPAT, the initial total daily intravenous dosage of VIMPAT should be equivalent to the total daily dosage and frequency of oral VIMPAT.

At the end of the intravenous treatment period, the patient may be switched to VIMPAT oral administration at the equivalent daily dosage and frequency of the intravenous administration.

See full prescribing information for compatibility and stability (2.1) and dosing in patients with renal impairment (2.2) and hepatic impairment (2.3) .

2.1 Partial-Onset Seizures VIMPAT can be initiated with either oral or intravenous administration.

The initial dose should be 50 mg twice daily (100 mg per day).

VIMPAT can be increased at weekly intervals by 100 mg/day given as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient response and tolerability.

In clinical trials, the 600 mg daily dose was not more effective than the 400 mg daily dose, and was associated with a substantially higher rate of adverse reactions.

[see Clinical Studies (14.1) ] Switching from Oral to Intravenous Dosing When switching from oral VIMPAT, the initial total daily intravenous dosage of VIMPAT should be equivalent to the total daily dosage and frequency of oral VIMPAT and should be infused intravenously over a period of 30 to 60 minutes.

There is experience with twice daily intravenous infusion for up to 5 days.

Switching from Intravenous to Oral Dosing At the end of the intravenous treatment period, the patient may be switched to VIMPAT oral administration at the equivalent daily dosage and frequency of the intravenous administration.

Compatibility and Stability VIMPAT injection can be administered intravenously without further dilution or may be mixed with diluents.

VIMPAT injection was found to be physically compatible and chemically stable when mixed with the following diluents for at least 24 hours and stored in glass or polyvinyl chloride (PVC) bags at ambient room temperature 15-30°C (59-86°F).

Diluents: Sodium Chloride Injection 0.9% (w/v) Dextrose Injection 5% (w/v) Lactated Ringer’s Injection The stability of VIMPAT injection in other infusion solutions has not been evaluated.

Product with particulate matter or discoloration should not be used.

Any unused portion of VIMPAT injection should be discarded.

2.2 Patients with Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment.

A maximum dose of 300 mg/day VIMPAT is recommended for patients with severe renal impairment [creatinine clearance (CL CR ) ≤30mL/min] and in patients with endstage renal disease.

VIMPAT is effectively removed from plasma by hemodialysis.

Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.

In all renally impaired patients, the dose titration should be performed with caution.

[see Use in Specific Populations (8.6) ] 2.3 Patients with Hepatic Impairment The dose titration should be performed with caution in patients with hepatic impairment.

A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.

VIMPAT use is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ].

etodolac 600 MG 24 HR Extended Release Oral Tablet

Generic Name: ETODOLAC

Brand Name: Etodolac

Substance Name(s):
ETODOLAC

BICILLIN L-A 1,200,000 UNT in 2 ML Prefilled Syringe

Generic Name: PENICILLIN G BENZATHINE

Brand Name: BICILLIN L-A

Substance Name(s):
PENICILLIN G BENZATHINE

WARNINGS

WARNING NOT FOR INTRAVENOUS USE.

DO NOT INJECT INTRAVENOUSLY OR ADMIX WITH OTHER INTRAVENOUS SOLUTIONS.

THERE HAVE BEEN REPORTS OF INADVERTENT INTRAVENOUS ADMINISTRATION OF PENICILLIN G BENZATHINE WHICH HAS BEEN ASSOCIATED WITH CARDIORESPIRATORY ARREST AND DEATH.

Prior to administration of this drug, carefully read the , ADVERSE REACTIONS , and DOSAGE AND ADMINISTRATION sections of the labeling.

Penicillin G benzathine should only be prescribed for the indications listed in this insert.

Anaphylaxis SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY.

THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS.

THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS.

BEFORE INITIATING THERAPY WITH BICILLIN L-A, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS.

IF AN ALLERGIC REACTION OCCURS, BICILLIN L-A SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED.

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE.

OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

Severe cutaneous adverse reactions Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients taking penicillin G (the active moiety in Bicillin L-A).

When SCAR is suspected, Bicillin L-A should be discontinued immediately and an alternative treatment should be considered.

Clostridioides difficile Associated Diarrhea Clostridioides difficile associated-diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Bicillin L-A, 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 .

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains 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 antibacterial 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.

Method of Administration Do not inject into or near an artery or nerve.

See administration instructions below.

Injection into or near a nerve may result in permanent neurological damage.

Inadvertent intravascular administration, including inadvertent direct intra-arterial injection or injection immediately adjacent to arteries, of Bicillin L-A and other penicillin preparations has resulted in severe neurovascular damage, including transverse myelitis with permanent paralysis, gangrene requiring amputation of digits and more proximal portions of extremities, and necrosis and sloughing at and surrounding the injection site consistent with the diagnosis of Nicolau syndrome.

Such severe effects have been reported following injections into the buttock, thigh, and deltoid areas.

Other serious complications of suspected intravascular administration which have been reported include immediate pallor, mottling, or cyanosis of the extremity both distal and proximal to the injection site, followed by bleb formation; severe edema requiring anterior and/or posterior compartment fasciotomy in the lower extremity.

The above-described severe effects and complications have most often occurred in infants and small children.

Prompt consultation with an appropriate specialist is indicated if any evidence of compromise of the blood supply occurs at, proximal to, or distal to the site of injection.

1–9 (See PRECAUTIONS , and DOSAGE AND ADMINISTRATION sections.) FOR DEEP INTRAMUSCULAR INJECTION ONLY.

There have been reports of inadvertent intravenous administration of penicillin G benzathine which has been associated with cardiorespiratory arrest and death.

Therefore, do not inject intravenously or admix with other intravenous solutions.

(See DOSAGE AND ADMINISTRATION section.) Administer by DEEP INTRAMUSCULAR INJECTION ONLY in the upper, outer quadrant of the buttock (dorsogluteal) or the ventrogluteal site.

Quadriceps femoris fibrosis and atrophy have been reported following repeated intramuscular injections of penicillin preparations into the anterolateral thigh.

Because of these adverse effects and the vascularity of this region, administration in the anterolateral thigh is not recommended.

DRUG INTERACTIONS

Drug Interactions Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of penicillin, and concurrent use of these drugs should be avoided.

Concurrent administration of penicillin and probenecid increases and prolongs serum penicillin levels by decreasing the apparent volume of distribution and slowing the rate of excretion by competitively inhibiting renal tubular secretion of penicillin.

OVERDOSAGE

Penicillin in overdosage has the potential to cause neuromuscular hyperirritability or convulsive seizures.

DESCRIPTION

Description Bicillin L-A (penicillin G benzathine injectable suspension) is available for deep intramuscular injection.

Penicillin G benzathine is prepared by the reaction of dibenzylethylene diamine with two molecules of penicillin G.

It is chemically designated as (2 S , 5 R , 6 R )-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compound with N,N’ – dibenzylethylenediamine (2:1), tetrahydrate.

It occurs as a white, crystalline powder and is very slightly soluble in water and sparingly soluble in alcohol.

Its chemical structure is as follows: Bicillin L-A contains penicillin G benzathine in aqueous suspension with sodium citrate buffer and, as w/v, approximately 0.65% sodium citrate, 0.59% povidone, 0.54% carboxymethylcellulose sodium, 0.53% lecithin, 0.12% methylparaben, and 0.013% propylparaben.

Bicillin L-A contains approximately 0.11 mEq of sodium per 600,000 units of penicillin G (approximately 2.59 mg of sodium per 600,000 units of penicillin G).

Bicillin L-A suspension in the disposable-syringe formulation is viscous and opaque.

It is available in a 1 mL, 2 mL, and 4 mL sizes containing the equivalent of 600,000 (actual volume of 1.17 mL contains 620,100), 1,200,000 (actual volume of 2.34 mL contains 1,240,200), and 2,400,000 (actual volume of 4.67 mL contains 2,475,100) units respectively of penicillin G as the benzathine salt.

Read CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections prior to use.

Chemical Structure

HOW SUPPLIED

Bicillin L-A (penicillin G benzathine injectable suspension) is supplied in packages of 10 disposable syringes as follows: 1 mL size, containing 600,000 units per syringe, (21 gauge, thin-wall 1-inch needle for pediatric use), with 0.11 mEq of sodium per 600,000 units of penicillin G (2.59 mg of sodium per 600,000 units of penicillin G), NDC 60793-700-10.

2 mL size, containing 1,200,000 units per syringe, (21 gauge, thin-wall 1-1/2-inch needle), with 0.22 mEq of sodium per 1,200,000 units of penicillin G (5.17 mg of sodium per 1,200,000 units of penicillin G), NDC 60793-701-10.

4 mL size, containing 2,400,000 units per syringe (18 gauge, × 1–1/2-inch needle), with 0.45 mEq of sodium per 2,400,000 units of penicillin G (10.32 mg of sodium per 2,400,000 units of penicillin G), NDC 60793-702-10.

Store in a refrigerator, 2° to 8°C (36° to 46°F).

Keep from freezing.

GERIATRIC USE

Geriatric Use Clinical studies of penicillin G benzathine 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.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

(See CLINICAL PHARMACOLOGY .) Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

MECHANISM OF ACTION

Mechanism of Action Penicillin G exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication.

It acts through the inhibition of biosynthesis of cell-wall peptidoglycan, rendering the cell wall osmotically unstable.

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bicillin L-A and other antibacterial drugs, Bicillin L-A should be used only to treat or prevent infections that are proven or strongly suspected to be caused by 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.

Intramuscular penicillin G benzathine is indicated in the treatment of infections due to penicillin-G-sensitive microorganisms that are susceptible to the low and very prolonged serum levels common to this particular dosage form.

Therapy should be guided by bacteriological studies (including sensitivity tests) and by clinical response.

The following infections will usually respond to adequate dosage of intramuscular penicillin G benzathine: Mild-to-moderate infections of the upper-respiratory tract due to susceptible streptococci.

Venereal infections —Syphilis, yaws, bejel, and pinta.

Medical Conditions in which Penicillin G Benzathine Therapy is indicated as Prophylaxis: Rheumatic fever and/or chorea —Prophylaxis with penicillin G benzathine has proven effective in preventing recurrence of these conditions.

It has also been used as follow-up prophylactic therapy for rheumatic heart disease and acute glomerulonephritis.

PEDIATRIC USE

Pediatric Use (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections.)

PREGNANCY

Pregnancy Teratogenic effects Pregnancy Reproduction studies performed in the mouse, rat, and rabbit have revealed no evidence of impaired fertility or harm to the fetus due to penicillin G.

Human experience with the penicillins during pregnancy has not shown any positive evidence of adverse effects on the fetus.

There are, however, no adequate and well-controlled studies in pregnant women showing conclusively that harmful effects of these drugs on the fetus can be excluded.

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

NUSRING MOTHERS

Nursing Mothers Soluble penicillin G (the hydrolysate of penicillin G benzathine) is excreted in breast milk.

Caution should be exercised when penicillin G benzathine is administered to a nursing woman.

BOXED WARNING

WARNING NOT FOR INTRAVENOUS USE.

DO NOT INJECT INTRAVENOUSLY OR ADMIX WITH OTHER INTRAVENOUS SOLUTIONS.

THERE HAVE BEEN REPORTS OF INADVERTENT INTRAVENOUS ADMINISTRATION OF PENICILLIN G BENZATHINE WHICH HAS BEEN ASSOCIATED WITH CARDIORESPIRATORY ARREST AND DEATH.

Prior to administration of this drug, carefully read the WARNINGS , ADVERSE REACTIONS , and DOSAGE AND ADMINISTRATION sections of the labeling.

INFORMATION FOR PATIENTS

Information for Patients Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

Patients should be counseled that antibacterial drugs including Bicillin L-A should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When Bicillin L-A is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bicillin L-A or other antibacterial drugs in the future.

DOSAGE AND ADMINISTRATION

Streptococcal (Group A) Upper Respiratory Infections (for example, pharyngitis) Adults—a single injection of 1,200,000 units; older pediatric patients—a single injection of 900,000 units; infants and pediatric patients under 60 lbs.—300,000 to 600,000 units.

Syphilis Primary, secondary, and latent—2,400,000 units (1 dose).

Late (tertiary and neurosyphilis)—2,400,000 units at 7-day intervals for three doses.

Congenital—under 2 years of age: 50,000 units/kg/body weight; ages 2 to 12 years: adjust dosage based on adult dosage schedule.

Yaws, Bejel, and Pinta —1,200,000 units (1 injection).

Prophylaxis —for rheumatic fever and glomerulonephritis.

Following an acute attack, penicillin G benzathine (parenteral) may be given in doses of 1,200,000 units once a month or 600,000 units every 2 weeks.

METHOD OF ADMINISTRATION BICILLIN L-A IS INTENDED FOR INTRAMUSCULAR INJECTION ONLY.

DO NOT INJECT INTO OR NEAR AN ARTERY OR NERVE, OR INTRAVENOUSLY OR ADMIX WITH OTHER INTRAVENOUS SOLUTIONS.

(SEE WARNINGS SECTION.) Administer by DEEP INTRAMUSCULAR INJECTION in the upper, outer quadrant of the buttock (dorsogluteal) or the ventrogluteal site.

In neonates, infants and small children, the midlateral aspect of the thigh may be preferable.

Administration in the anterolateral thigh is not recommended due to the adverse effects observed (see WARNINGS section), and vascularity of this region.

When doses are repeated, vary the injection site.

Because of the high concentration of suspended material in this product, the needle may be blocked if the injection is not made at a slow, steady rate.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

prazosin HCl 1 MG Oral Capsule

WARNINGS

As with all alpha-blockers, prazosin hydrochloride may cause syncope with sudden loss of consciousness.

In most cases, this is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe tachycardia with heart rates of 120 to 160 beats per minute.

Syncopal episodes have usually occurred within 30 to 90 minutes of the initial dose of the drug; occasionally, they have been reported in association with rapid dosage increases or the introduction of another antihypertensive drug into the regimen of a patient taking high doses of prazosin hydrochloride.

The incidence of syncopal episodes is approximately 1% in patients given an initial dose of 2 mg or greater.

Clinical trials conducted during the investigational phase of this drug suggest that syncopal episodes can be minimized by limiting the initial dose of the drug to 1 mg, by subsequently increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient’s regimen with caution (see DOSAGE AND ADMINISTRATION).

Hypotension may develop in patients given prazosin hydrochloride who are also receiving a beta-blocker such as propranolol.

If syncope occurs, the patient should be placed in the recumbent position and treated supportively as necessary.

This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration.

Patients should always be started on the prazosin hydrochloride capsules, 1 mg.

The 2 and 5 mg capsules are not indicated for initial therapy.

More common than loss of consciousness are the symptoms often associated with lowering of the blood pressure, namely, dizziness and lightheadedness.

The patient should be cautioned about these possible adverse effects and advised what measures to take should they develop.

The patient should also be cautioned to avoid situations where injury could result should syncope occur during the initiation of prazosin hydrochloride therapy.

Priapism Prolonged erections and priapism have been reported with alpha-1 blockers including prazosin in postmarketing experience.

In the event of an erection that persists longer than 4 hours, seek immediate medical assistance.

If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

DRUG INTERACTIONS

Drug Interactions Prazosin hydrochloride has been administered without any adverse drug interaction in limited clinical experience to date with the following: (1) cardiac glycosides – digitalis and digoxin; (2) hypoglycemics – insulin, chlorpropamide, phenformin, tolazamide, and tolbutamide; (3) tranquilizers and sedatives – chlordiazepoxide, diazepam, and phenobarbital; (4) antigout – allopurinol, colchicine, and probenecid; (5) antiarrhythmics – procainamide, propranolol (see however), and quinidine; and (6) analgesics, antipyretics and anti-inflammatories – propoxyphene, aspirin, indomethacin, and phenylbutazone.

WARNINGS Addition of a diuretic or other antihypertensive agent to prazosin hydrochloride has been shown to cause an additive hypotensive effect.

This effect can be minimized by reducing the prazosin hydrochloride dose to 1 to 2 mg three times a day, by introducing additional antihypertensive drugs cautiously, and then by retitrating prazosin hydrochloride based on clinical response.

Concomitant administration of prazosin hydrochloride with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see ).

DOSAGE AND ADMINISTRATION

OVERDOSAGE

Accidental ingestion of at least 50 mg of prazosin in a two-year-old child resulted in profound drowsiness and depressed reflexes.

No decrease in blood pressure was noted.

Recovery was uneventful.

Should overdosage lead to hypotension, support of the cardiovascular system is of first importance.

Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position.

If this measure is inadequate, shock should first be treated with volume expanders.

If necessary, vasopressors should then be used.

Renal function should be monitored and supported as needed.

Laboratory data indicate prazosin hydrochloride is not dialyzable because it is protein bound.

DESCRIPTION

Prazosin hydrochloride, USP a quinazoline derivative, is the first of a new chemical class of antihypertensives.

It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is: C H N O •HCl M.W.

419.87 19 21 5 4 It is a white, crystalline substance, slightly soluble in water and isotonic saline.

Each capsule for oral administration, contains prazosin hydrochloride, USP equivalent to 1 mg, 2 mg or 5 mg of prazosin.

Inactive ingredients include: anhydrous lactose, magnesium stearate, and pregelatinized starch.

Additional inactive ingredients for the gelatin capsule include: 1 mg (Ivory): D&C Yellow No.

10 and titanium dioxide; 2 mg (Pink): FD&C Blue No.

1, FD&C Red No.

40, D&C Red No.

28, and titanium dioxide; 5 mg (Light Blue): FD&C Blue No.

1 and titanium dioxide.

prazosin hydrochloride capsules structural formula

HOW SUPPLIED

NDC:54569-2583-1 in a BOTTLE of 30 CAPSULES

INDICATIONS AND USAGE

Prazosin hydrochloride capsules USP are 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 this drug.

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 some other 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 to 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.

Prazosin hydrochloride capsules USP can be used alone or in combination with other antihypertensive drugs such as diuretics or beta-adrenergic blocking agents.

PEDIATRIC USE

Usage in Children Safety and effectiveness in children have not been established.

PREGNANCY

Usage in Pregnancy Teratogenic Effects Pregnancy category C Prazosin hydrochloride has been shown to be associated with decreased litter size at birth, 1, 4, and 21 days of age in rats when given doses more than 225 times the usual maximum recommended human dose.

No evidence of drug-related external, visceral, or skeletal fetal abnormalities were observed.

No drug-related external, visceral, or skeletal abnormalities were observed in fetuses of pregnant rabbits and pregnant monkeys at doses more than 225 times and 12 times the usual maximum recommended human dose, respectively.

The use of prazosin and a beta-blocker for the control of severe hypertension in 44 pregnant women revealed no drug-related fetal abnormalities or adverse effects.

Therapy with prazosin was continued for as long as 14 weeks.

1 Prazosin has also been used alone or in combination with other hypotensive agents in severe hypertension of pregnancy by other investigators.

No fetal or neonatal abnormalities have been reported with the use of prazosin.

2 There are no adequate and well controlled studies which establish the safety of prazosin hydrochloride in pregnant women.

Prazosin hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

NUSRING MOTHERS

Nursing Mothers Prazosin hydrochloride has been shown to be excreted in small amounts in human milk.

Caution should be exercised when prazosin hydrochloride is administered to a nursing woman.

INFORMATION FOR PATIENTS

Information for Patients Dizziness or drowsiness may occur after the first dose of this medicine.

Avoid driving or performing hazardous tasks for the first 24 hours after taking this medicine or when the dose is increased.

Dizziness, lightheadedness, or fainting may occur, especially when rising from a lying or sitting position.

Getting up slowly may help lessen the problem.

These effects may also occur if you drink alcohol, stand for long periods of time, exercise, or if the weather is hot.

While taking prazosin hydrochloride, be careful in the amount of alcohol you drink.

Also, use extra care during exercise or hot weather, or if standing for long periods.

Check with your physician if you have any questions.

DOSAGE AND ADMINISTRATION

The dose of prazosin hydrochloride capsules USP should be adjusted according to the patient’s individual blood pressure response.

The following is a guide to its administration: Initial Dose 1 mg two or three times a day (see ).

WARNINGS Maintenance Dose Dosage may be slowly increased to a total daily dose of 20 mg given in divided doses.

The therapeutic dosages most commonly employed have ranged from 6 mg to 15 mg daily given in divided doses.

Doses higher than 20 mg usually do not increase efficacy, however a few patients may benefit from further increases up to a daily dose of 40 mg given in divided doses.

After initial titration some patients can be maintained adequately on a twice daily dosage regimen.

Use With Other Drugs When adding a diuretic or other antihypertensive agent, the dose of prazosin hydrochloride capsules USP should be reduced to 1 mg or 2 mg three times a day and retitration then carried out.

Concomitant administration of prazosin hydrochloride capsules USP with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking prazosin hydrochloride capsules USP.

Fosinopril Sodium 20 MG Oral Tablet

WARNINGS

Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including fosinopril sodium) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors.

If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.

If laryngeal stridor or angioedema of the face, lips mucous membranes, tongue, glottis or extremities occurs, treatment with fosinopril sodium should be discontinued and appropriate therapy instituted immediately.

Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see PRECAUTIONS: Information for Patients and ADVERSE REACTIONS ).

Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.

These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.

The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hypotension Fosinopril sodium can cause symptomatic hypotension.

Like other ACE inhibitors, fosinopril has been only rarely associated with hypotension in uncomplicated hypertensive patients.

Symptomatic hypotension is most likely to occur in patients who have been volume-and /or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

Volume and/or salt depletion should be corrected before initiating therapy with fosinopril sodium.

In patients with heart failure, with our without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death.

In such patients, fosinopril sodium therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased.

Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatremic.

If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline.

Fosinopril sodium treatment usually can be continued following restoration of blood pressure and volume.

Neutropenia / Agranulocytosis Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma.

Available data from clinical trials of fosinopril are insufficient to show that fosinopril does not cause agranulocytosis at similar rates.

Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

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 fosinopril 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 fosinopril, 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 fosinopril for hypotension, oliguria, and hyperkalemia (see Precautions , Pediatric Use ).

No teratogenic effects of fosinopril were seen in studies of pregnant rats and rabbits.

On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose.

DRUG INTERACTIONS

Drug Interactions 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 fosinopril and other agents that affect the RAS.

Do not co-administer aliskiren with fosinopril in patients with diabetes.

Avoid use of aliskiren with fosinopril in patients with renal impairment (GFR <60 mL/min).

With diuretics: Patients on diuretics, especially those with intravascular volume depletion, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with fosinopril sodium.

The possibility of hypotensive effects with fosinopril sodium can be minimized by either discontinuing the diuretic or increasing salt intake prior to initiation of treatment with fosinopril sodium.

If this is not possible, the starting dose should be reduced and the patient should be observed closely for several hours following an initial dose and until blood pressure has stabilized.

(see DOSAGE AND ADMINISTRATION ).

With potassium supplements and potassium-sparing diuretics: Fosinopril sodium can attenuate potassium loss caused by thiazide diuretics.

Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia.

Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.

With lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium.

These drugs should be co administered with caution, and frequent monitoring of serum lithium levels is recommended.

If a diuretic is also used, the risk of lithium toxicity may be increased.

With antacids: In a clinical pharmacology study, coadministration of an antacid (aluminum hydroxide, magnesium hydroxide, and simethicone) with fosinopril reduced serum levels and urinary excretion of fosinoprilat as compared with fosinopril administrated alone, suggesting that antacids may impair absorption of fosinopril.

Therefore, if concomitant and administration of these agents is indicated, dosing should be separated by 2 hours.

Other: Neither fosinopril sodium nor its metabolites have been found to interact with food.

In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.

In study with concomitant administration of aspirin and fosinopril sodium.

The bioavailability of unbound fosinoprilat was not altered.

In a pharmacokinetic interaction study with warfarin, bioavailability parameters, the degree of protein binding, and the anticoagulant effect (measured by prothrombin time) of warfarin were not significantly changed.

OVERDOSAGE

Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality.

Human overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril over dosage is likely to hypotension.

Laboratory determination of serum levels of fosinoprilat and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of fosinopril overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of fosinopril and its metabolites.

Fosinoprilat is poorly removed from the body by both hemodialysis and peritoneal dialysis.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of fosinopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities.

Because the hypotensive effect of fosinopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat fosinopril overdose by infusion of normal saline solution.

There is published report of a 20 month-old female, weighing 12 kg, who ingested approximately 200 mg MONOPRIL.

After receiving gastric lavage and activated charcoal within one hour of the ingestion, she made an eventful recovery.

Information from clinical studies of fosinopril sodium administered as a single dose greater than the approved dose in the treatment of hypertension in the pediatric patients is available in the approved labeling for Bristol-Myers Squibb Company’s fosinopril sodium drug products.

However, due to Bristol-Myer Squibb’s marketing exclusively rights, this drug product is not labeled for pediatric use.

DESCRIPTION

Fosinopril sodium tablet, USP is the sodium salt of fosinopril USP, the ester prodrug of an angiotensin converting enzyme (ACE) inhibitor, fosinoprilat.

It contains a phosphinate group capable of specific binding to the active site of angiotensin converting enzyme.

Fosinopril sodium, USP is designated chemically as:L-proline,4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4- phenylbutyl)phosphinyl]acetyl]-, sodium salt, trans-.

Fosinopril sodium,USP is a white to off-white crystalline powder.

It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane.

Its structural formula is: Its empirical formula is C 30 H 45 NNaO 7 P, and its molecular weight is 585.65.

Fosinopril Sodium, USP is available for oral administrations as 10 mg, 20 mg, and 40 mg tablets.

Inactive ingredients include: crospovidone, lactose, microcrystalline cellulose, magnesium stearate, and povidone.

Chemical Structure

HOW SUPPLIED

Repackaged by Aphena Pharma Solutions – TN.

See Repackaging Information for available configurations.

Fosinopril Sodium Tablets, USP 10 mg tablets: White, round, biconvex partially scored tablets debossed with “IG”on one side and “200” on other side.

They are supplied in bottles of 90 (NDC 76282-200-90) and 1000 (NDC 76282-200-10).

Bottles contain a desiccant canister.

20 mg tablets: White, round, biconvex tablets debossed with “IG” on one side and “201” on other side.

They are supplied in bottles of 90 (NDC 76282-201-90) and 1000 (NDC 76282-201-10).

Bottles contain a desiccant canister.

40 mg tablets: White, round, biconvex tablets debossed with “IG” on one side and “202” on other side.

They are supplied in bottles of 90 (NDC 76282-202-90) and 1000 (NDC 76282-202-10).

Bottles contain a desiccant canister.

STORAGE Store at 20° C to 25° C (68° to 77°F) [see USP Controlled Room Temperature] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured by: InvaGen Pharmaceuticals, Inc.

Hauppauge, NY 11788.

Manufactured for: Exelan Pharmaceuticals, Inc.

Lawrenceville, GA 30046.

Rev: 12/13

GERIATRIC USE

Geriatric Use Clinical studies of fosinopril sodium 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 response between the elderly and younger patients.

In general, dose selection for and 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.

INDICATIONS AND USAGE

Fosinopril sodium tablets, USP are indicated for the treatment of hypertension.

It may be used alone or in combination with thiazide diuretics.

Fosinopril sodium tablets, USP are indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics with or without digitalis (see DOSAGE AND ADMINISTRATION ).

In using fosinopril sodium, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease.

Available data are insufficient to show that fosinopril sodium does not have a similar risk (see WARNINGS ).

In considering use of fosinopril sodium, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non- blacks.

In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema ).

PEDIATRIC USE

Pediatric Use Neonates with a history of in utero exposure to fosinopril sodium tablets: 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.

Removal of fosinopril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means.

The antihypertensive effects of fosinopril have been evaluated in a double-blind study in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Hypertension ).

The pharmacokinetics of fosinopril have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism ).

Fosinopril was generally well tolerated and adverse effects were similar to those described in adults (see ADVERSE REACTIONS: Pediatric Patients ).

NUSRING MOTHERS

Nursing Mothers Ingestion of 20 mg daily for three days resulted in detectable levels of fosinoprilat in breast milk.

Fosinopril sodium should not be administered to nursing mothers.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue fosinopril sodium tablets as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

See Warnings: Fetal Toxicity

INFORMATION FOR PATIENTS

Information for Patients Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose.

Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema (e.g., swelling of face, eyes, lips, tongue, larynx, mucous membranes, and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy.

(See WARNINGS: Head and Neck Angioedema and ADVERSE REACTIONS .) Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to a physician.

Patients should be told that if syncope occurs, fosinopril sodium should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the physician.

Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

Pregnancy: Female patients of childbearing age should be told about the consequences of second-and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester.

These patients should be asked to report pregnancies to their physician as soon as possible.

DOSAGE AND ADMINISTRATION

Hypertension Adults The recommended initial dose of fosinopril sodium tablets is 10 mg once a day, both as monotherapy and when the drug is added to a diuretic.

Dosage should then be adjusted according to blood pressure response at peak (2-6 hours) and trough (about 24 hours after dosing) blood levels.

The usual dosage range needed to maintain a response at trough is 20-40 mg but some patients appear to have a further response to 80 mg.

In some patients treated with once daily dosing, the antihypertensive effect may diminish toward the end of the dosing interval.

If trough response is inadequate, dividing the daily dose should be considered.

If blood pressure is not adequately controlled fosinopril sodium alone, a diuretic may be added.

Concomitant administration of fosinopril sodium with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS ).

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of fosinopril sodium tablets.

To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with fosinopril sodium tablets (see WARNINGS).

Then, if blood pressure is not controlled with fosinopril sodium tablets alone diuretic therapy should be resumed.

If diuretic therapy cannot be discontinued, an initial dose of 10 mg of fosinopril sodium tablets should be used with careful medical supervision for several hours and until blood pressure has stabilized.

(See WARNINGS ; PRECAUTIONS: Information for Patients and Drug Interactions ).

Since concomitant administration of fosinopril sodium tablets with potassium supplements, or potassium containing salt substitutes or potassium-sparing diuretics may lead to increases in serum potassium, they should be used with caution (see PRECAUTIONS ).

Pediatrics Information related to the dosing of fosinopril sodium in the treatment of hypertension in pediatric patients weighing more than 50 kg is available in the approved labeling for Bristol-Myers Squibb Company’s fosinopril sodium drug product.

However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Heart Failure Digitalis is not required for fosinopril sodium tablets to manifest improvements in exercise tolerance and symptoms.

Most placebo-controlled clinical trial experience has been with both digitalis and diuretics presents as background therapy.

The usual starting dose of fosinopril sodium tablets should be 10 mg once daily.

Following the initial dose of fosinopril sodium tablets, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostasis and, if present, until blood pressure stabilizes.

An initial dose of 5 mg is preferred in heart failure patients with moderate to severe renal failure or those who have been vigorously diuresed.

Dosage should be increased, over a several week period, to a dose that is maximal and tolerated but not exceeding 40 mg once daily.

The usual effective dosage range is 20 to 40 mg once daily.

The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration.

Consideration should be given to reducing the dose of concomitant diuretic.

For Hypertensive or Heart Failure Patients with Renal Impairment: In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function.

Since hepatobiliary elimination partially compensates for diminished renal elimination, the totally body clearance for fosinoprilat does not differ appreciably with any degree of renal insufficiency (creatinine clearances <80 mL/min/1.73m 2 ), including end stage renal failure (creatinine clearance <10 mL/min/1.73m 2 ) This relative constancy of body clearance of active fosinoprilat, resulting from the dual route of elimination, permits use of the usual dose in patients with any degree of renal impairment.

(See WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis .)

Nicotine 2 MG Oral Lozenge

Generic Name: NICOTINE POLACRILEX

Brand Name: Topcare Nicotine Polacrilex

Substance Name(s):
NICOTINE

WARNINGS

Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider.

Smoking can seriously harm your child.

Try to stop smoking without using any nicotine replacement medicine.

This medicine is believed to be safer than smoking.

However, the risks to your child from this medicine are not fully known.

Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat.

Nicotine can increase your heart rate.

• high blood pressure not controlled with medication.

Nicotine can increase your blood pressure.

• stomach ulcer or diabetes • history of seizures Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking prescription medicine for depression or asthma.

Your prescription dose may need to be adjusted.

Stop use and ask a doctor if • mouth problems occur • persistent indigestion or severe sore throat occurs • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness or rapid heartbeat • you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets.

Nicotine lozenges may have enough nicotine to make children and pets sick.

If you need to remove the lozenge, wrap it in paper and throw away in the trash.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

INDICATIONS AND USAGE

Use • reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking

INACTIVE INGREDIENTS

Inactive ingredients aspartame, magnesium stearate, mannitol, natural peppermint flavor, potassium bicarbonate, sodium alginate, sodium carbonate, xanthan gum

PURPOSE

Purpose Stop smoking aid

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children and pets.

Nicotine lozenges may have enough nicotine to make children and pets sick.

If you need to remove the lozenge, wrap it in paper and throw away in the trash.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

ASK DOCTOR

Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat.

Nicotine can increase your heart rate.

• high blood pressure not controlled with medication.

Nicotine can increase your blood pressure.

• stomach ulcer or diabetes • history of seizures

DOSAGE AND ADMINISTRATION

Directions • if you are under 18 years of age, ask a doctor before use.

No studies have been done to show if this product will work for you.

• before using this product, read the enclosed User’s Guide for complete directions and other important information • begin using the lozenge on your quit day • if you smoke your first cigarette within 30 minutes of waking up, use 4 mg nicotine lozenge • if you smoke your first cigarette more than 30 minutes after waking up, use 2 mg nicotine lozenge according to the following 12 week schedule: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 lozenge every 1 to 2 hours 1 lozenge every 2 to 4 hours 1 lozenge every 4 to 8 hours • nicotine lozenge is a medicine and must be used a certain way to get the best results • place the lozenge in your mouth and allow the lozenge to slowly dissolve (about 20-30 minutes).

Minimize swallowing.

Do not chew or swallow lozenge.

• you may feel a warm or tingling sensation • occasionally move the lozenge from one side of your mouth to the other until completely dissolved (about 20-30 minutes) • do not eat or drink 15 minutes before using or while the lozenge is in your mouth • to improve your chances of quitting, use at least 9 lozenges per day for the first 6 weeks • do not use more than one lozenge at a time or continuously use one lozenge after another since this may cause you hiccups, heartburn, nausea or other side effects • do not use more than 5 lozenges in 6 hours.

Do not use more than 20 lozenges per day.

• it is important to complete treatment.

If you feel you need to use the lozenge for a longer period to keep from smoking, talk to your health care provider.

PREGNANCY AND BREAST FEEDING

If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider.

Smoking can seriously harm your child.

Try to stop smoking without using any nicotine replacement medicine.

This medicine is believed to be safer than smoking.

However, the risks to your child from this medicine are not fully known.

STOP USE

ACTIVE INGREDIENTS

Active ingredient (in each lozenge) Nicotine polacrilex, 2 mg (nicotine)

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking prescription medicine for depression or asthma.

Your prescription dose may need to be adjusted.

nabilone 1 MG Oral Capsule

WARNINGS

• The effects of Cesamet may persist for a variable and unpredictable period of time following its oral administration.

Adverse psychiatric reactions can persist for 48 to 72 hours following cessation of treatment.

• Cesamet has the potential to affect the CNS, which might manifest itself in dizziness, drowsiness, euphoria “high”, ataxia, anxiety, disorientation, depression, hallucinations and psychosis.

• Cesamet can cause tachycardia and orthostatic hypotension.

• Because of individual variation in response and tolerance to the effects of Cesamet, patients should remain under supervision of a responsible adult especially during initial use of Cesamet and during dose adjustments.

• Patients receiving treatment with Cesamet should be specifically warned not to drive, operate machinery, or engage in any hazardous activity while receiving Cesamet.

• Cesamet should not be taken with alcohol, sedatives, hypnotics, or other psychoactive substances because these substances can potentiate the central nervous system effects of nabilone.

DRUG INTERACTIONS

Drug Interactions Potential interactions between Cesamet 2 mg, and diazepam 5 mg; sodium secobarbital 100 mg; alcohol 45 mL (absolute laboratory alcohol); or codeine 65 mg, were evaluated in 15 subjects.

Only a single combination was utilized at any one time.

The subjects were evaluated according to physiologic (i.e., heart rate and blood pressure), psychometric, psychomotor, and subjective parameters.

In this study, as expected, the depressant effects of the combinations were additive.

Psychomotor function was particularly impaired with concurrent use of diazepam.

Caution must thus be used when administering nabilone in combination with any CNS depressant.

Nabilone is purportedly highly bound to plasma proteins, and therefore, might displace other protein-bound drugs.

Therefore, practitioners should monitor patients for a change in dosage requirements when administering nabilone to patients receiving other highly protein-bound drugs.

Published reports of drug-drug interactions involving cannabinoids are summarized in the following table.

CONCOMITANT DRUG CLINICAL EFFECT(S) Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco Opioids Cross-tolerance and mutual potentiation Naltrexone Oral THC effects were enhanced by opioid receptor blockade.

Alcohol Increase in the positive subjective mood effects of smoked marijuana

OVERDOSAGE

Signs and Symptoms Signs and symptoms of overdosage are an extension of the psychotomimetic and physiologic effects of Cesamet.

Treatment To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center.

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

In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Overdosage may be considered to have occurred, even at prescribed dosages, if disturbing psychiatric symptoms are present.

In these cases, the patient should be observed in a quiet environment and supportive measures, including reassurance, should be used.

Subsequent doses should be withheld until patients have returned to their baseline mental status; routine dosing may then be resumed if clinically indicated.

In such instances, a lower initiating dose is suggested.

In controlled clinical trials, alterations in mental status related to the use of Cesamet resolved within 72 hours without specific medical therapy.

In overdose settings, attention should be paid to vital signs, since both hypertension and hypotension have been known to occur; tachycardia and orthostatic hypotension were most commonly reported.

No cases of overdosage with more than 10 mg/day of nabilone were reported during clinical trials.

Signs and symptoms that would be expected to occur in large overdose situations are psychotic episodes, including hallucinations, anxiety reactions, respiratory depression, and coma.

If psychotic episodes occur, the patient should be managed conservatively, if possible.

For moderate psychotic episodes and anxiety reactions, verbal support and comforting may be sufficient.

In more severe cases, antipsychotic drugs may be useful; however, the utility of antipsychotic drugs in cannabinoid psychosis has not been systematically evaluated.

Support for their use is drawn from limited experience using antipsychotic agents to manage cannabis overdoses.

Because of the potential for drug-drug interactions (e.g., additive CNS depressant effects due to nabilone and chlorpromazine), such patients should be closely monitored.

Protect the patient’s airway and support ventilation and perfusion.

Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, as well as other laboratory values and physical assessments.

Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying.

Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed.

Safeguard the patient’s airway when employing gastric emptying or charcoal.

The use of forced diuresis, peritoneal dialysis, hemodialysis, charcoal hemoperfusion, or cholestyramine has not been reported.

In the presence of normal renal function, most of a dose of nabilone is eliminated through the biliary system.

Treatment for respiratory depression and comatose state consists in symptomatic and supportive therapy.

Particular attention should be paid to the occurrence of hypothermia.

If the patient becomes hypotensive, consider fluids, inotropes, and/or vasopressors.

The estimated oral median lethal dose in female mice is between 1,000 and 2,000 mg/kg; in the female rat, it is greater than 2,000 mg/kg, (See CLINICAL PHARMACOLOGY ).

DESCRIPTION

Cesamet ® (nabilone) is a synthetic cannabinoid for oral administration.

Nabilone as a raw material occurs as a white to off-white polymorphic crystalline powder.

In aqueous media, the solubility of nabilone is less than 0.5 mg/L, with pH values ranging from 1.2 to 7.0.

Chemically, nabilone is similar to the active ingredient found in naturally occurring Cannabis sativa L.

[Marijuana; delta-9-tetrahydrocannabinol (delta-9-THC)].

Nabilone is (±)- trans -3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one and has the empirical formula C 24 H 36 O 3 .

It has a molecular weight of 372.55.

The structural formula is as follows: Each 1 mg Cesamet capsule contains 1 mg of nabilone and the following inactive ingredients: povidone and corn starch.

The capsule shells contain the following inactive ingredients: FD&C Blue No.

2 (indigo carmine), red iron oxide, gelatin, and titanium dioxide.

Chemical Structure

CLINICAL STUDIES

Clinical Trials Cesamet was evaluated for its effectiveness and safety in the treatment of nausea and vomiting induced by cancer chemotherapy in patients receiving a wide variety of chemotherapy regimens, including low-dose cisplatin (20 mg/m 2 ) in both placebo-controlled and active controlled (prochlorperazine) trials.

During Cesamet treatment patients reported a higher incidence of adverse effects.

The most frequent were drowsiness, vertigo, dry mouth and euphoria.

However, most of the adverse effects occurring with Cesamet were of mild to moderate severity (See ADVERSE REACTIONS ).

HOW SUPPLIED

Cesamet ® capsules (blue and white): 1 mg (bottles of 50 capsules) NDC 0187-1221-03.

Capsules are imprinted with Valeant on the blue cap and a four-digit code (3101) on the white body.

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

GERIATRIC USE

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

Cesamet should be used with caution in elderly patients aged 65 and over because they are generally more sensitive to the psychoactive effects of drugs and Cesamet can elevate supine and standing heart rates and cause postural hypotension.

INDICATIONS AND USAGE

Cesamet capsules are indicated for the treatment of the nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

This restriction is required because a substantial proportion of any group of patients treated with Cesamet can be expected to experience disturbing psychotomimetic reactions not observed with other antiemetic agents.

Because of its potential to alter the mental state, Cesamet is intended for use under circumstances that permit close supervision of the patient by a responsible individual particularly during initial use of Cesamet and during dose adjustments.

Cesamet contains nabilone, which is controlled in Schedule II of the Controlled Substances Act.

Schedule II substances have a high potential for abuse.

Prescriptions for Cesamet should be limited to the amount necessary for a single cycle of chemotherapy (i.e., a few days).

Cesamet capsules are not intended to be used on as needed basis or as a first antiemetic product prescribed for a patient.

As with all controlled drugs, prescribers should monitor patients receiving nabilone for signs of excessive use, abuse and misuse.

Patients who may be at increased risk for substance abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness.

PEDIATRIC USE

Pediatric Use Safety and effectiveness have not been established in patients younger than 18 years of age.

Caution is recommended in prescribing Cesamet to children because of psychoactive effects.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Teratology studies conducted in pregnant rats at doses up to 12 mg/kg/day (about 16 times the human dose on a body surface area basis) and in pregnant rabbits at doses up to 3.3 mg/kg/day (about 9 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of nabilone.

However, there was dose related developmental toxicity in both species as evidenced by increases in embryo lethality, fetal resorptions, decreased fetal weights and pregnancy disruptions.

In rats, postnatal developmental toxicity was also observed.

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

Because animal studies cannot rule out the possibility of harm, Cesamet 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 this drug is excreted in breast milk.

Because many drugs including some cannabinoids are excreted in breast milk it is not recommended that Cesamet be given to nursing mothers.

INFORMATION FOR PATIENTS

Information for Patients Persons taking Cesamet should be alerted to the potential for additive central nervous system depression resulting from simultaneous use of Cesamet and alcohol or other central nervous system depressants such as benzodiazepines and barbiturates.

This combination should be avoided.

Patients receiving treatment with Cesamet should be specifically warned not to drive, operate machinery, or engage in any hazardous activity.

Patients using Cesamet should be made aware of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations.

Patients should remain under supervision of a responsible adult while using Cesamet.

DOSAGE AND ADMINISTRATION

The usual adult dosage is 1 or 2 mg 2 times a day.

On the day of chemotherapy, the initial dose should be given 1 to 3 hours before the chemotherapeutic agent is administered.

To minimize side effects, it is recommended that the lower starting dose be used and that the dose be increased as necessary.

Adose of 1 or 2 mg the night before may be useful.

The maximum recommended daily dose is 6 mg given in divided doses 3 times a day.

Cesamet may be administered 2 or 3 times a day during the entire course of each cycle of chemotherapy and, if needed, for 48 hours after the last dose of each cycle of chemotherapy.

Creon 24 (amylases 120,000 UNT / lipase 24,000 UNT / proteases 76,000 UNT) Delayed Release Oral Capsule

DRUG INTERACTIONS

7 No drug interactions have been identified.

No formal interaction studies have been conducted.

OVERDOSAGE

10 There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation of CREON.

Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures .

High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment .

[see Dosage and Administration ( ) and Warnings and Precautions ( )] 2.2 5.1 [see Warnings and Precautions ( )] 5.3

DESCRIPTION

11 CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands.

Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases.

Pancrelipase is a beige-white amorphous powder.

It is miscible in water and practically insoluble or insoluble in alcohol and ether.

Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in diameter).

The active ingredient evaluated in clinical trials is lipase.

CREON is dosed by lipase units.

Other active ingredients include protease and amylase.

CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate.

9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body.

The shells contain titanium dioxide and hypromellose.

3,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body.

The shells contain FD&C Blue No.

2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

6,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body.

The shells contain black iron oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

12,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body.

The shells contain gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

24,000 USP units of lipase;

CLINICAL STUDIES

14 The short-term efficacy of CREON was evaluated in three studies conducted in 103 patients with exocrine pancreatic insufficiency (EPI).

Two studies were conducted in 49 patients with EPI due to cystic fibrosis (CF); one study was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.

14.1 Cystic Fibrosis Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to 43 years, with exocrine pancreatic insufficiency due to cystic fibrosis.

Study 1 included patients aged 12 to 43 years (n = 32).

The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol deviations.

Study 2 included patients aged 7 to 11 years (n = 17).

The final analysis population was limited to 16 patients; 1 patient withdrew consent prior to stool collection during treatment with CREON.

In each study, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days.

All patients consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat) during the treatment periods.

The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured.

Each patient’s CFA during placebo treatment was used as their no-treatment CFA value.

In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment.

The mean difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.

In Study 2, mean CFA was 83% with CREON treatment compared to 47% with placebo treatment.

The mean difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p<0.001.

Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values.

There were no differences in response to CREON by age or gender, with similar responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older patients.

The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen).

Each patient’s CNA during placebo treatment was used as their no-treatment CNA value.

In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment.

The mean difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p<0.001.

In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment.

The mean difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p<0.001.

14.2 Chronic Pancreatitis or Pancreatectomy A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy.

The final analysis population was limited to 52 patients; 2 patients were excluded due to protocol violations.

Ten patients had a history of pancreatectomy (7 were treated with CREON).

In this study, patients received placebo for 5 days (run-in period), followed by pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by randomization to CREON or matching placebo for 7 days of treatment (double-blind period).

Only patients with CFA less than 80% in the run-in period were randomized to the double-blind period.

The dose of CREON during the double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks).

All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period.

The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods, when both fat excretion and fat ingestion were measured.

The mean change in CFA from the run-in period to the end of the double-blind period in the CREON and Placebo groups is shown in .

Table 3 Table 3: Change in CFA in the Chronic Pancreatitis and Pancreatectomy Trial (Run-in Period to End of Double-Blind Period) *p<0.0001 CREON n = 24 Placebo n = 28 CFA [%] Run-in Period (Mean, SD) 54 (19) 57 (21) End of Double-Blind Period (Mean, SD) 86 (6) 66 (20) Change in CFA * [%] Run-in Period to End of Double-Blind Period (Mean, SD) 32 (18) 9 (13) Treatment Difference (95% CI) 21 (14, 28) Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower run-in period CFA values than in patients with higher run-in period CFA values.

Only 1 of the patients with a history of total pancreatectomy was treated with CREON in the study.

That patient had a CFA of 26% during the run-in period and a CFA of 73% at the end of the double-blind period.

The remaining 6 patients with a history of partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a mean CFA of 84% at the end of the double-blind period.

RECENT MAJOR CHANGES

Dosage and Administration, ( ) 6/2011 Infants (up to 12 months) 2.1 Dosage and Administration ( ) 6/2011 2.2 Dosage and Administration, ( ) 6/2011 Infants (up to 12 months) 2.2

GERIATRIC USE

8.5 Geriatric Use Clinical studies of CREON 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.

DOSAGE FORMS AND STRENGTHS

3 The active ingredient in CREON evaluated in clinical trials is lipase.

CREON is dosed by lipase units.

Other active ingredients include protease and amylase.

Each CREON delayed-release capsule strength contains the specified amounts of lipase, protease, and amylase as follows: 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body.

6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1206” and a blue opaque body.

12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body.

24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1224” and a colorless transparent body.

Delayed-Release Capsules: 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase ( ) 3 Delayed-Release Capsules: 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase ( ) 3 Delayed-Release Capsules: 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase ( ) 3 Delayed-Release Capsules: 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase ( ) 3

MECHANISM OF ACTION

12.1 Mechanism of Action The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.

INDICATIONS AND USAGE

1 CREON (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.

® CREON is a combination of porcine-derived lipases, proteases, and amylases indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.

( ) 1

PEDIATRIC USE

8.4 Pediatric Use The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebo-controlled, crossover studies of 49 patients with EPI due to cystic fibrosis, 25 of whom were pediatric patients.

Study 1 included 8 adolescents between 12 and 17 years of age.

Study 2 included 17 children between 7 and 11 years of age.

The safety and efficacy in pediatric patients in these studies were similar to adult patients .

[see Adverse Reactions ( ) and Clinical Studies ( )] 6.1 14 An open-label, single-arm, short-term study of CREON was conducted in 18 infants and children, ages 4 months to six years of age, with EPI due to cystic fibrosis.

Patients received their usual pancreatic enzyme replacement therapy (mean dose of 7,000 lipase units/kg/day for a mean duration of 18.2 days) followed by CREON (mean dose of 7,500 lipase units/kg/day for a mean duration of 12.6 days).

The mean daily fat intake was 48 grams during treatment with usual pancreatic enzyme replacement therapy and 47 grams during treatment with CREON.

When patients were switched from their usual pancreatic enzyme replacement therapy to CREON, they demonstrated similar spot fecal fat testing results; the clinical relevance of spot fecal fat testing has not been demonstrated.

Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite .

[see Adverse Reactions ( )] 6.1 The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.

Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences .

Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age .

[see Dosage and Administration ( )] 2.1 [see Warnings and Precautions ( )] 5.1

PREGNANCY

8.1 Pregnancy Teratogenic effects Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase.

It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

CREON should be given to a pregnant woman only if clearly needed.

The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency.

Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth.

Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk.

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

The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement in the treatment of cystic fibrosis patients.

Exercise caution when doses of CREON exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day).

( ) 5.1 To avoid irritation of oral mucosa, do not chew CREON or retain in the mouth.

( ) 5.2 Exercise caution when prescribing CREON to patients with gout, renal impairment, or hyperuricemia.

( ) 5.3 There is theoretical risk of viral transmission with all pancreatic enzyme products including CREON.

( ) 5.4 Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin.

( ) 5.5 5.1 Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products.

Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis.

The underlying mechanism of fibrosing colonopathy remains unknown.

Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age.

Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation.

It is uncertain whether regression of fibrosing colonopathy occurs.

It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day 5, 6 1 1 [see Dosage and Administration ( )].

2.1 Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption.

Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

5.2 Potential for Irritation to Oral Mucosa Care should be taken to ensure that no drug is retained in the mouth.

CREON should not be crushed or chewed or mixed in foods having a pH greater than 4.5.

These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity .

For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature.

The CREON-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion.

[see Dosage and Administration ( ) and Patient Counseling Information ( )] 2.2 17.1 5.3 Potential for Risk of Hyperuricemia Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or hyperuricemia.

Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.

5.4 Potential Viral Exposure from the Product Source CREON is sourced from pancreatic tissue from swine used for food consumption.

Although the risk that CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses.

Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded.

However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.

5.5 Allergic Reactions Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin.

Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase).

The risks and benefits of continued CREON treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) 17.1 Dosing and Administration Instruct patients and caregivers that CREON should only be taken as directed by their healthcare professional.

Patients should be advised that the total daily dose should not exceed 10,000 lipase units/kg body weight/day unless clinically indicated.

This needs to be especially emphasized for patients eating multiple snacks and meals per day.

Patients should be informed that if a dose is missed, the next dose should be taken with the next meal or snack as directed.

Doses should not be doubled .

[see Dosage and Administration ( )] 2 Instruct patients and caregivers that CREON should always be taken with food.

Patients should be advised that CREON delayed-release capsules and the capsule contents must not be crushed or chewed as doing so could cause early release of enzymes and/or loss of enzymatic activity.

Patients should swallow the intact capsules with adequate amounts of liquid at mealtimes.

If necessary, the capsule contents can also be sprinkled on soft acidic foods .

[see Dosage and Administration ( )] 2 17.2 Fibrosing Colonopathy Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in children below the age of 12 years .

[see Dosage and Administration ( )] 2 17.3 Allergic Reactions Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to CREON develop .

[see Warnings and Precautions ( )] 5.5 17.4 Pregnancy and Breast Feeding Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming pregnant during treatment with CREON .

[see Use in Specific Populations ( )] 8.1 Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast feeding during treatment with CREON .

[see Use in Specific Populations ( )] 8.3 Manufactured by: Abbott Products GmbH Hannover, Germany Marketed By: Abbott Laboratories North Chicago, IL 60064, U.S.A.

DOSAGE AND ADMINISTRATION

2 CREON is not interchangeable with other pancrelipase products.

CREON is orally administered.

Therapy should be initiated at the lowest recommended dose and gradually increased.

The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below .

[see Dosage and Administration ( ) and Warnings and Precautions ( )] 2.2 5.1 CREON is not interchangeable with any other pancrelipase product.

( ) 2.1 Do not crush or chew capsules and capsule contents.

For infants or patients unable to swallow intact capsules, the contents may be sprinkled on soft acidic food, e.g., applesauce.

( ) Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.

( ) 2.1 2.2 Infants (up to 12 months) Prior to each feeding, infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding.

( ) 2.1 Do not mix CREON capsule contents directly into formula or breast milk prior to administration.

( ) 2.1 Children Older than 12 Months and Younger than 4 Years Begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

( ) 2.2 Children 4 Years and Older and Adults Begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

( ) 2.2 Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy Individualize dosage based on clinical symptoms, the degree of steatorrhea present and the fat content of the diet.

( ) 2.2 2.1 Administration Infants (up to 12 months) CREON should be administered to infants immediately prior to each feeding, using a dosage of lipase units per 120 mL of formula or prior to breast-feeding.

Contents of the capsule may be administered directly to the mouth or with a small amount of applesauce.

Administration should be followed by breast milk or formula.

Contents of the capsule be mixed directly into formula or breast milk as this may diminish efficacy.

Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.

3,000 should not Children and Adults CREON should be taken during meals or snacks, with sufficient fluid.

Capsules should be swallowed whole.

CREON capsules and capsule contents should not be crushed or chewed.

The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion.

Care should be taken to ensure that no drug is retained in the mouth.

2.2 Dosage Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.

CREON should be administered in a manner consistent with the recommendations of the Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.

1, 2, 3 Cystic Fibrosis Foundation Consensus Conferences (also known as Conferences) provided in the following paragraphs, except for infants.

Although the Conferences recommend doses of 2,000 to 4,000 lipase units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule.

Therefore, the recommended dose of CREON in infants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding.

Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.

Infants (up to 12 months) CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding.

Do not mix CREON capsule contents directly into formula or breast milk prior to administration .

[see Administration ( )] 2.1 Children Older than 12 Months and Younger than 4 Years Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Children 4 Years and Older and Adults Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.

The total daily dose should reflect approximately three meals plus two or three snacks per day.

Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.

Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.

In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at least 100 g of fat per day .

Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines.

Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.

[see Clinical Studies ( )] 14.2 1, 2, 3, 4 Limitations on Dosing Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.

If symptoms and signs of steatorrhea persist, the dosage may be increased by the healthcare professional.

Patients should be instructed not to increase the dosage on their own.

There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended.

Changes in dosage may require an adjustment period of several days.

If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted.

Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption.

Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age .

Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

1, 2, 3 [see Warnings and Precautions ( )] 5.1

Sudafed PE Children’s Cold & Cough 5 MG / 2.5 MG per 5 ML Oral Solution

Generic Name: DEXTROMETHORPHAN HYDROBROMIDE AND PHENYLEPHRINE HYDROCHLORIDE

Brand Name: Childrens SUDAFED PE Cold plus Cough

Substance Name(s):
DEXTROMETHORPHAN HYDROBROMIDE
PHENYLEPHRINE HYDROCHLORIDE

WARNINGS

Warnings Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

Ask a doctor before use if the child has heart disease high blood pressure thyroid disease diabetes persistent or chronic cough such as occurs with asthma cough that occurs with too much phlegm (mucus) a sodium-restricted diet When using this product do not exceed recommended dose Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever cough gets worse or lasts for more than 7 days cough tends to come back or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms due to the common cold, hay fever, or other upper respiratory allergies: cough nasal congestion sinus congestion and pressure

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, carboxymethylcellulose sodium, edetate disodium, FD&C blue no.

1, FD&C red no.

40, flavors, glycerin, purified water, sodium benzoate, sodium citrate, sorbitol solution, sucralose

PURPOSE

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg Nasal decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

ASK DOCTOR

DOSAGE AND ADMINISTRATION

Directions find right dose on chart below mL = milliliters repeat dose every 4 hours do not give more than 6 times in 24 hours Age (yr) Dose (mL) under 4 years do not use 4 to 5 years 5 mL 6 to 11 years 10 mL Attention: use only enclosed dosing cup specifically designed for use with this product.

Do not use any other dosing device.

DO NOT USE

Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

STOP USE

Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever cough gets worse or lasts for more than 7 days cough tends to come back or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

ACTIVE INGREDIENTS

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg Nasal decongestant

mercaptopurine 50 MG Oral Tablet

Generic Name: MERCAPTOPURINE

Brand Name: Mercaptopurine

Substance Name(s):
MERCAPTOPURINE

DRUG INTERACTIONS

7 • Allopurinol : Reduce the dose of mercaptopurine tablets when co-administered with allopurinol.

( 2.4 , 7.1 ) • Warfarin : Mercaptopurine tablets may decrease the anticoagulant effect.

( 7.2 ) 7.1 Allopurinol Allopurinol can inhibit the first-pass oxidative metabolism of mercaptopurine by xanthine oxidase, which can lead to an increased risk of mercaptopurine adverse reactions (i.e., myelosuppression, nausea, and vomiting) [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] .

Reduce the dose of mercaptopurine tablets when coadministered with allopurinol [see Dosage and Administration (2.4) ] .

7.2 Warfarin The concomitant administration of mercaptopurine tablets and warfarin may decrease the anticoagulant effectiveness of warfarin.

Monitor the international normalized ratio (INR) in patients receiving warfarin and adjust the warfarin dosage as appropriate.

7.3 Myelosuppressive Products Mercaptopurine tablets can cause myelosuppression.

Myelosuppression may be increased when mercaptopurine tablets are coadministered with other products that cause myelosuppression.

Enhanced myelosuppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole.

Monitor the CBC and adjust the dose of mercaptopurine tablets for excessive myelosuppression [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] .

7.4 Aminosalicylates Aminosalicylates (e.g., mesalamine, olsalazine or sulfasalazine) may inhibit the TPMT enzyme, which may increase the risk of myelosuppression when coadministered with mercaptopurine tablets.

When aminosalicylates and mercaptopurine tablets are coadministered, use the lowest possible doses for each drug and monitor more frequently for myelosuppression [see Warnings and Precautions (5.1) ] .

7.5 Hepatotoxic Products Mercaptopurine tablets can cause hepatotoxicity.

Hepatotoxicity may be increased when mercaptopurine tablets are coadministered with other products that cause hepatotoxicity.

Monitor liver tests more frequently in patients who are receiving mercaptopurine tablets with other hepatotoxic products [see Warnings and Precautions (5.2) ] .

OVERDOSAGE

10 Signs and symptoms of mercaptopurine overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed (myelosuppression, liver dysfunction, and gastroenteritis).

Dialysis cannot be expected to clear mercaptopurine.

Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of mercaptopurine into active metabolites with long persistence.

Withhold mercaptopurine tablets immediately for severe or life-threatening adverse reactions occur during treatment.

If a patient is seen immediately following an accidental overdosage, it may be useful to induce emesis.

DESCRIPTION

11 Mercaptopurine is a nucleoside metabolic inhibitor, the chemical name is Purine-6-thiol monohydrate.

The molecular formula is C 5 H 4 N 4 S•H 2 O and the molecular weight is 170.20.

Its structural formula is: Mercaptopurine, USP is a yellow, crystalline powder.

Mercaptopurine is practically insoluble in water and in ether.

It has a pKa of 7.8, an average tapped density of 1.0 g/mL and average bulk density of 0.85 g/mL.

It dissolves in solutions of alkali hydroxides.

Mercaptopurine tablets are available for oral use.

Each scored tablet contains 50 mg mercaptopurine and the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, pregelatinized starch (corn) and sodium lauryl sulfate.

Meets USP Dissolution Test 2.

Mercaptopurine Structural Formula

HOW SUPPLIED

16 /STORAGE AND HANDLING Mercaptopurine Tablets, USP are available containing 50 mg of mercaptopurine, USP.

The 50 mg tablets are off-white to light yellow, round, scored tablets debossed with M above the score and 547 below the score on one side of the tablet and blank on the other side.

They are available as follows: NDC 0378-3547-52 bottles of 25 tablets NDC 0378-3547-25 bottles of 250 tablets Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] Protect from moisture.

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

Mercaptopurine tablets are a cytotoxic drug.

Follow special handling and disposal procedures.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of mercaptopurine 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.

DOSAGE FORMS AND STRENGTHS

3 Mercaptopurine Tablets, USP are available containing 50 mg of mercaptopurine, USP.

• The 50 mg tablets are off-white to light yellow, round, scored tablets debossed with M above the score and 547 below the score on one side of the tablet and blank on the other side.

Tablets: 50 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Mercaptopurine is a purine analog that undergoes intracellular transport and activation to form metabolites including thioguanine nucleotides (TGNs).

Incorporation of TGNs into DNA or RNA results in cell-cycle arrest and cell death.

TGNs and other mercaptopurine metabolites are also inhibitors of de novo purine synthesis and purine nucleotide interconversions.

Mercaptopurine was cytotoxic to proliferating cancer cells in vitro and had antitumor activity in mouse tumor models.

It is not known which of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.

INDICATIONS AND USAGE

1 Mercaptopurine tablets are a nucleoside metabolic inhibitor indicated for treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.

( 1.1 ) 1.1 Acute Lymphoblastic Leukemia Mercaptopurine tablets are indicated for treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of mercaptopurine tablets have been established in pediatric patients.

Use of mercaptopurine tablets in pediatrics is supported by evidence from the published literature and clinical experience.

Symptomatic hypoglycemia has been reported in pediatric patients with ALL receiving mercaptopurine.

Reported cases were in pediatrics less than 6 years of age or with a low body mass index.

PREGNANCY

8.1 Pregnancy Risk Summary Mercaptopurine tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] .

Pregnant women who receive mercaptopurine have an increased incidence of miscarriage and stillbirth (see Data ) .

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) 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% to 4% and 15% to 20%, respectively.

Data Human Data Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of miscarriage; the risk of malformation in offspring surviving first trimester exposure is not known.

In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 mothers died prior to delivery, 1 delivered a stillborn child, and 1 aborted; there were no cases of macroscopically abnormal fetuses.

Animal Data Mercaptopurine was embryo-lethal and teratogenic in several animal species (rat, mouse, rabbit, and hamster) at doses less than the recommended human dose.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Myelosuppression : Monitor complete blood count (CBC) and adjust the dose of mercaptopurine tablets for excessive myelosuppression.

Consider testing in patients with severe myelosuppression or repeated episodes of myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency.

Patients with homozygous or homozygous TPMT or NUDT15 deficiency may require a dose reduction.

( 2.2 , 5.1 ) • Hepatotoxicity : Monitor transaminases, alkaline phosphatase and bilirubin.

Withhold mercaptopurine tablets at onset of hepatotoxicity.

( 5.2 ) • Immunosuppression : Response to all vaccines may be diminished and there is a risk of infection with live virus vaccines.

Consult immunization guidelines for immunocompromised patients.

( 5.3 ) • Treatment Related Malignancies : Aggressive and fatal cases of hepatosplenic T-cell lymphoma have occurred.

( 5.4 ) • Macrophage Activation Syndrome : Monitor for and treat promptly; discontinue mercaptopurine tablets.

( 5.5 ) • Embryo-Fetal Toxicity : Can cause fetal harm.

Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.

( 5.6 , 8.1 , 8.3 ) 5.1 Myelosuppression The most consistent, dose-related adverse reaction is myelosuppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these.

Monitor CBC and adjust the dosage of mercaptopurine tablets for excessive myelosuppression [see Dosage and Administration (2.1) ] .

Consider testing for TPMT or NUDT15 deficiency in patients with severe myelosuppression or repeated episodes of myelosuppression.

TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes.

Patients with heterozygous or homozygous TPMT or NUDT15 deficiency may require a dose reduction [see Dosage and Administration (2.2), Clinical Pharmacology (12.5) ] .

Myelosuppression can be exacerbated by coadministration with allopurinol, aminosalicylates or other products that cause myelosuppression [see Drug Interactions (7.1 , 7.3 , 7.4) ] .

Reduce the dose of mercaptopurine tablets when coadministered with allopurinol [see Dosage and Administration (2.4) ] .

5.2 Hepatoxicity Mercaptopurine is hepatotoxic.

There are reports of deaths attributed to hepatic necrosis associated with the administration of mercaptopurine.

Hepatic injury can occur with any dosage but seems to occur with greater frequency when the recommended dosage is exceeded.

In some patients, jaundice has cleared following withdrawal of mercaptopurine and reappeared with rechallenge.

Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months); however, jaundice has been reported as early as 1 week and as late as 8 years after the starting mercaptopurine.

The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites.

Hepatic encephalopathy has occurred.

Monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels at weekly intervals when first beginning therapy and at monthly intervals thereafter.

Monitor liver tests more frequently in patients who are receiving mercaptopurine tablets with other hepatotoxic products [see Drug Interactions (7.5) ] or with known pre-existing liver disease.

Withhold mercaptopurine tablets at onset of hepatotoxicity.

5.3 Immunosuppression Mercaptopurine is immunosuppressive and may impair the immune response to infectious agents or vaccines.

Due to the immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines.

Consult immunization guidelines for immunocompromised patients.

5.4 Treatment Related Malignancies Hepatosplenic T-cell lymphoma has been reported in patients treated with mercaptopurine for inflammatory bowel disease (IBD), an unapproved use.

Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the risk of secondary malignancies.

Patients receiving immunosuppressive therapy, including mercaptopurine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ.

The increased risk appears to be related to the degree and duration of immunosuppression.

It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.

A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities.

A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

5.5 Macrophage Activation Syndrome Macrophage activation syndrome (MAS) (hemophagocytic lymphohistiocytosis) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine (an unapproved use).

If MAS occurs, or is suspected, discontinue mercaptopurine tablets.

Monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

5.6 Embryo-Fetal Toxicity Mercaptopurine tablets can cause fetal harm when administered to a pregnant woman.

An increased incidence of miscarriage has been reported in women who received mercaptopurine in the first trimester of pregnancy.

Adverse embryo-fetal findings, including miscarriage and stillbirth, have been reported in women who received mercaptopurine after the first trimester of pregnancy.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 6 months after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Major Adverse Reactions: Advise patients and caregivers that mercaptopurine tablets can cause myelosuppression, hepatotoxicity, and gastrointestinal toxicity.

Advise patients to contact their healthcare provider if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] .

Embryo-Fetal Toxicity: • Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1) ] .

• Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 6 months after the last dose [see Use in Specific Populations (8.3) ] .

• Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 3 months after the last dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] .

Lactation: Advise women not to breastfeed during treatment with mercaptopurine tablets and for 1 week after the last dose [see Use in Specific Populations (8.2) ] .

Infertility: Advise males and females of reproductive potential that mercaptopurine tablets can impair fertility [see Use in Specific Populations (8.3) ] .

Other Adverse Reactions: Instruct patients to minimize sun exposure due to risk of photosensitivity [see Adverse Reactions (6.1) ] .

Manufactured for: Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Manufactured by: Auro PR Inc.

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Revised: 3/2022 MCPT:R8

DOSAGE AND ADMINISTRATION

2 • The recommended starting dose of mercaptopurine tablets is 1.5 mg/kg to 2.5 mg/kg orally once daily as part of a combination chemotherapy maintenance regimen.

Adjust dose to maintain desirable absolute neutrophil count and for excessive myelosuppression.

( 2.1 ) • Renal Impairment : Use the lowest recommended starting dose or increase the dosing interval.

( 2.3 , 8.6 ) • Hepatic Impairment : Use the lowest recommended starting dose.

( 2.3 , 8.7 ) 2.1 Recommended Dosage The recommended starting dosage of mercaptopurine tablets is 1.5 mg/kg to 2.5 mg/kg orally once daily as part of combination chemotherapy maintenance regimen.

A recommended dosage for patients less than 17 kg is not achievable, because the only available strength is 50 mg.

Take mercaptopurine tablets either consistently with or without food.

After initiating mercaptopurine tablets, monitor complete blood count (CBC) and adjust the dose to maintain absolute neutrophil count (ANC) at a desirable level and for excessive myelosuppression.

Evaluate the bone marrow in patients with prolonged myelosuppression or repeated episodes of myelosuppression to assess leukemia status and marrow cellularity.

Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status in patients with severe myelosuppression or repeated episodes or myelosuppression [see Dosage and Administration (2.2) ] .

Do not administer to patients who are unable to swallow tablets.

If a patient misses a dose, instruct the patient to continue with the next scheduled dose.

Mercaptopurine tablets are a cytotoxic drug.

Follow special handling and disposal procedures.

1 2.2 Dosage Modifications in Patients with TPMT and NUDT15 Deficiency Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression or repeated episodes of myelosuppression [see Warnings and Precautions (5.1) , Clinical Pharmacology (12.5) ] .

Homozygous Deficiency in either TPMT or NUDT15 Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage.

Reduce the recommended starting dosage of mercaptopurine tablets in patients who are known to have homozygous TPMT or NUDT15 deficiency.

Heterozygous Deficiency in TPMT and/or NUDT15 Reduce the mercaptopurine tablets dose based on tolerability.

Most patients with heterozygous TPMT or NUDT15 deficiency tolerate the recommended dosage, but some require a dose reduction based on adverse reactions.

Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

2.3 Dosage Modifications in Renal and Hepatic Impairment Renal Impairment Use the lowest recommended starting dosage for mercaptopurine tablets in patients with renal impairment (CLcr less than 50 mL/min).

Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.6) ] .

Hepatic Impairment Use the lowest recommended starting dosage for mercaptopurine tablets in patients with hepatic impairment.

Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.7) ] .

2.4 Dosage Modification with Concomitant Use of Allopurinol Reduce the dose of mercaptopurine tablets to one-third to one-quarter of the current dosage when coadministered with allopurinol [see Drug Interactions (7.1) ] .