Propafenone Hydrochloride

1 INDICATIONS AND USAGE Propafenone Hydrochloride Tablets are indicated to: • prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. • prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease. • treat documented ventricular arrhythmias, such as sustained ventricular tachycardia that, in the judgment of the physician, are life-threatening. Initiate treatment in the hospital. Usage Considerations: • The use of Propafenone Hydrochloride Tablets in patients with permanent atrial fibrillation (AF) or in patients exclusively with atrial flutter or PSVT has not been evaluated. Do not use Propafenone Hydrochloride Tablets to control ventricular rate during AF. • Some patients with atrial flutter treated with propafenone have developed 1:1 conduction, producing an increase in ventricular rate. Concomitant treatment with drugs that increase the functional atrioventricular (AV) nodal refractory period is recommended. • The use of Propafenone Hydrochloride Tablets in patients with chronic atrial fibrillation has not been evaluated. • Because of the proarrhythmic effects of Propafenone Hydrochloride Tablets, its use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic, and any use of the drug should be reserved for patients in whom, in the opinion of the physician, the potential benefits outweigh the risks. • The effect of propafenone on mortality has not been determined [see Boxed Warning ] . Propafenone Hydrochloride Tablets are an antiarrhythmic indicated to: • prolong the time to recurrence of symptomatic atrial fibrillation (AF) in patients with episodic (most likely paroxysmal or persistent) AF who do not have structural heart disease. ( 1 ) • prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients who do not have structural heart disease. ( 1 ) • treat documented life-threatening ventricular arrhythmias. ( 1 ) Usage Considerations: • Use in patients with permanent atrial fibrillation or with atrial flutter or PSVT has not been evaluated. Do not use to control ventricular rate during atrial fibrillation. ( 1 ) • In patients with atrial fibrillation and atrial flutter, use Propafenone Hydrochloride Tablets with drugs that increase the atrioventricular nodal refractory period. ( 1 ) • Because of proarrhythmic effects, use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic. ( 1 ) • The effect of propafenone on mortality has not been determined. ( 1 )

2 DOSAGE AND ADMINISTRATION The dose of Propafenone Hydrochloride Tablets must be individually titrated on the basis of response and tolerance. Initiate therapy with Propafenone Hydrochloride Tablets 150 mg given every 8 hours (450 mg per day). Dosage may be increased at a minimum of 3- to 4- day intervals to 225 mg every 8 hours (675 mg per day). If additional therapeutic effect is needed, the dose of Propafenone Hydrochloride Tablets may be increased to 300 mg every 8 hours (900 mg per day). The usefulness and safety of dosages exceeding 900 mg per day have not been established. In patients with hepatic impairment or those with significant widening of the QRS complex or second- or third-degree AV block, consider reducing the dose. As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of Propafenone Hydrochloride Tablets should be increased more gradually during the initial phase of treatment. The combination of cytochrome P450 3A4 (CYP3A4) inhibition and either cytochrome P450 2D6 (CYP2D6) deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proarrhythmia and other adverse events. Therefore, avoid simultaneous use of Propafenone Hydrochloride Tablets with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.1 )] . • Initiate therapy with 150 mg given every 8 hours. ( 2 ) • As needed, uptitrate in 3 to 4 days to 225 to 300 mg every 8 hours. ( 2 ) • Consider reducing the dose in patients with hepatic impairment, significant widening of the QRS complex, or second- or third-degree AV block. ( 2 )

3 DOSAGE FORMS AND STRENGTHS 150 mg, 225 mg, and 300 mg scored, round, film-coated tablets. Tablets: 150 mg, 225 mg, 300 mg.

4 CONTRAINDICATIONS Propafenone hydrochloride tablets are contraindicated in the following circumstances: • Heart failure • Cardiogenic shock • Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, AV block) in the absence of an artificial pacemaker • Known Brugada Syndrome • Bradycardia • Marked hypotension • Bronchospastic disorders or severe obstructive pulmonary disease • Marked electrolyte imbalance • Heart failure ( 4 ) • Cardiogenic shock ( 4 ) • Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction in the absence of pacemaker ( 4 ) • Known Brugada Syndrome ( 4 ) • Bradycardia ( 4 ) • Marked hypotension ( 4 ) • Bronchospastic disorders and severe obstructive pulmonary disease ( 4 ) • Marked electrolyte imbalance ( 4 )

6 ADVERSE REACTIONS The most commonly reported adverse events with propafenone (greater than 5%) included: unusual taste, nausea and/or vomiting, dizziness, constipation, headache, fatigue, first-degree AV block, and intraventricular conduction delay. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions associated with propafenone hydrochloride tablets occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems. About 20% of subjects treated with propafenone hydrochloride tablets have discontinued treatment because of adverse reactions. Adverse reactions reported for greater than 1.5% of 474 subjects with SVT who received propafenone hydrochloride tablets in U.S. clinical trials are presented in Table 1 by incidence and percent discontinuation, reported to the nearest percent. Table 1. Adverse Reactions Reported for >1.5% of Subjects with Supraventricular Tachycardia Adverse Reaction Incidence (n = 480) % of Subjects Who Discontinued Unusual taste 14% 1.3% Nausea and/or vomiting 11% 2.9% Dizziness 9% 1.7% Constipation 8% 0.2% Headache 6% 0.8% Fatigue 6% 1.5% Blurred vision 3% 0.6% Weakness 3% 1.3% Dyspnea 2% 1.0% Wide complex tachycardia 2% 1.9% CHF 2% 0.6% Bradycardia 2% 0.2% Palpitations 2% 0.2% Tremor 2% 0.4% Anorexia 2% 0.2% Diarrhea 2% 0.4% Ataxia 2% 0.0% In controlled trials in subjects with ventricular arrhythmia, the most common reactions reported for propafenone hydrochloride tablets and more frequent than on placebo were unusual taste, dizziness, first-degree AV block, intraventricular conduction delay, nausea and/or vomiting, and constipation. Headache was relatively common also, but was not increased compared with placebo. Other reactions reported more frequently than on placebo or comparator and not already reported elsewhere included anxiety, angina, second-degree AV block, bundle branch block, loss of balance, congestive heart failure, and dyspepsia. Adverse reactions reported for greater than or equal to 1% of 2,127 subjects with ventricular arrhythmia who received propafenone in U.S. clinical trials were evaluated by daily dose. The most common adverse reactions appeared dose-related (but note that most subjects spent more time at the larger doses), especially dizziness, nausea and/or vomiting, unusual taste, constipation, and blurred vision. Some less common reactions may also have been dose-related such as first-degree AV block, congestive heart failure, dyspepsia, and weakness. Other adverse reactions included rash, syncope, chest pain, abdominal pain, ataxia, and hypotension. In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience. Causality and relationship to propafenone therapy cannot necessarily be judged from these events. Cardiovascular System Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia. Nervous System Abnormal dreams, abnormal speech, abnormal vision, confusion, depression, memory loss, numbness, paresthesias, psychosis/mania, seizures (0.3%), tinnitus, unusual smell sensation, vertigo. Gastrointestinal Cholestasis, elevated liver enzymes (alkaline phosphatase, serum transaminases), gastroenteritis, hepatitis. Hematologic Agranulocytosis, anemia, bruising, granulocytopenia, leukopenia, purpura, thrombocytopenia. Other Alopecia, eye irritation, impotence, increased glucose, positive ANA (0.7%), muscle cramps, muscle weakness, nephrotic syndrome, pain, pruritus. 6.2 Postmarketing Experience …

7 DRUG INTERACTIONS • Inhibitors of CYP2D6, 1A2, and 3A4 increase propafenone exposure. ( 7.1 ) • Propafenone may increase digoxin or warfarin levels. ( 7.2 , 7.3 ) • Orlistat may reduce propafenone exposure. Taper orlistat withdrawal. ( 7.4 ) • Lidocaine may increase central nervous system side effects. ( 7.6 ) 7.1 CYP2D6 and CYP3A4 Inhibitors Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, grapefruit juice) can be expected to cause increased plasma levels of propafenone. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Therefore, simultaneous use of propafenone hydrochloride tablets with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions ( 5.4 ), Dosage and Administration ( 2 )] . Amiodarone Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended. Cimetidine Concomitant administration of propafenone immediate-release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone. Fluoxetine Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone C max and AUC by 39% and 50%, respectively, and the R-propafenone C max and AUC by 71% and 50%, respectively. Quinidine Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers [see Clinical Pharmacology ( 12.3 )] . Concomitant administration of quinidine (50 mg 3 times daily) with 150 mg immediate-release propafenone 3 times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them slow metabolizers. Steady-state plasma concentrations more than doubled for propafenone and decreased 50% for 5-OH-propafenone. A 100-mg dose of quinidine tripled steady-state concentrations of propafenone. Avoid concomitant use of propafenone and quinidine. Rifampin Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%. The concentrations of norpropafenone increased by 30%. In slow metabolizers, there was a 50% decrease in propafenone plasma concentrations and an increase in the AUC and C max of norpropafenone by 74% and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients: Both the AUC and C max of propafenone decreased by 84%, with a corresponding decrease in AUC and C max of 5-OH-propafenone by 69% and 57%, respectively. 7.2 Digoxin Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270% and decreased the clearance of digoxin by 31% to 67%. Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed. 7.3 Warfarin The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin. Adjust the warfarin dose as needed by monitoring INR (international normalized ratio). 7.4 Orlistat Orlistat may limit the fraction of propafenone available for absorption. In postmarketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block, and acute circulatory failure. 7.5 Beta-Antagonists Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In 4 patients, administration of metopro …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no studies of propafenone hydrochloride tablets in pregnant women. Available data from published case reports and several decades of postmarketing experience with use of propafenone hydrochloride tablets in pregnancy have not identified any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. Untreated arrhythmias during pregnancy may pose a risk to the pregnant woman and fetus (see Clinical Considerations) . Propafenone and its metabolite, 5-OH-propafenone, cross the placenta in humans. In animal studies, propafenone was not teratogenic. At maternally toxic doses (ranging from 2 to 6 times the maximum recommended human dose [MRHD]), there was evidence of adverse developmental outcomes when administered to pregnant rabbits and rats during organogenesis or when administered to pregnant rats during mid-gestation through weaning of their offspring (see Data) . The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk: The incidence of VT is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state. Fetal/Neonatal Adverse Reactions: Propafenone and its metabolite have been shown to cross the placenta. Adverse reactions such as fetal/neonatal arrhythmias have been associated with the use of other antiarrhythmic agents by pregnant women. Fetal/neonatal monitoring for signs and symptoms of arrhythmia is recommended during and after treatment of pregnant women with propafenone. Labor or Delivery: Risk of arrhythmias may increase during labor and delivery. Patients treated with propafenone hydrochloride tablets should be monitored continuously for arrhythmias during labor and delivery [see Warnings and Precautions ( 5.1 )] . Data Propafenone has been shown to cause embryo-fetal mortality in rabbits and rats when given orally during organogenesis at maternally toxic doses of 150 mg/kg/day (rabbit: maternal mortality, decreased body weight gain and food consumption at approximately 3 times the MRHD on a mg/m 2 basis) and 600 mg/kg/day (rat: maternal decreased body weight gain and food consumption at approximately 6 times the MRHD on a mg/m 2 basis). In addition, a maternally toxic dose of 600 mg/kg/day (approximately 6 times the MRHD on a mg/m 2 basis) also caused decreased fetal weights in rats. Increased placental weights and delayed ossification occurred in rabbits at a dose of 30 mg/kg/day (less than the MRHD on a mg/m 2 basis) in the absence of maternal toxicity. No adverse developmental outcomes in the absence of maternal toxicity were seen following oral doses of 15 mg/kg/day to rabbits or up to 270 mg/kg/day to rats administered during organogenesis (equivalent to 0.3 times or approximately 3 times the MRHD on a mg/m 2 basis, respectively). In an oral study, female rats received propafenone up to 500 mg/kg/day from mid-gestation through weaning. At 90 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis), there were no adverse developmental outcomes in the absence of maternal toxicity. However, doses ≥180 mg/kg/day (2 or more times the MRHD on a mg/m 2 basis) produced increases in maternal deaths and resulted in reductions in neonatal survival, body we …

12.1 Mechanism of Action Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and, to a lesser extent, myocardial fibers, propafenone reduces the fast inward current carried by sodium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1/50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1/40 that of propranolol in man. In clinical trials, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro , propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e., the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared with propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity. (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors.)

11 DESCRIPTION Propafenone Hydrochloride Tablets USP are an antiarrhythmic drug supplied in scored, film-coated tablets of 150 mg, 225 mg and 300 mg for oral administration. Propafenone has some structural similarities to beta-blocking agents. Chemically, propafenone hydrochloride is 2’-[2-hydroxy-3-(propylamino)-propoxy]-3-phenylpropiophenone hydrochloride, with a molecular weight of 377.92. The molecular formula is C 21 H 27 NO 3 •HCl. The structural formula of propafenone hydrochloride is given below: Propafenone hydrochloride occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20°C), chloroform, and ethanol. The following inactive ingredients are contained in the tablet: corn starch, croscarmellose sodium, hypromellose, maltodextrin, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, silicon dioxide colloidal, titanium dioxide, and triacetin. structure

10 OVERDOSAGE The symptoms of overdosage may include hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and rarely, convulsions and high-grade ventricular arrhythmias. Defibrillation, as well as infusion of dopamine and isoproterenol, has been effective in controlling abnormal rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary. The hemodialysis of propafenone in patients with an overdose is expected to be of limited value in the removal of propafenone as a result of both its high protein binding (greater than 95%) and large volume of distribution.

16 HOW SUPPLIED/STORAGE AND HANDLING Propafenone Hydrochloride Tablets USP are supplied as: 150 mg – White, biconvex, round, film-coated tablets debossed with “ANI” over “230” and scored on one side and plain on the other side. This strength is supplied in bottles of 100 tablets under NDC 51407-015-01. 225 mg – White, biconvex, round, film-coated tablets debossed with “ANI” over “231” and scored on one side and plain on the other side. This strength is supplied in bottles of 100 tablets under NDC 51407-016-01. 300 mg – White, biconvex, round, film-coated tablets debossed with “ANI” over “232” and scored on one side and plain on the other side. This strength is supplied in bottles of 100 tablets under NDC 51407-017-01. Storage: Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container.