PROPAFENONE HYDROCHLORIDE 150 mg Tablet, Film Coated

5 WARNINGS AND PRECAUTIONS May cause new or worsened arrhythmias. Evaluate patients via ECG prior to and during therapy. (5.1) Propafenone hydrochloride may unmask Brugada or Brugada-like Syndrome.

(4 , 5.2) Avoid use with other drugs that prolong the QT interval. (5.3) Avoid simultaneous use of propafenone with both a cytochrome P450 2D6 (CYP2D6) inhibitor and a 3A4 (CYP3A4) inhibitor. (5.4) May provoke overt heart failure.

(5.5) May cause dose-related first-degree AV block or other conduction disturbances. Only use in patients with conduction disorders who have pacemakers. (5.6) May affect artificial pacemakers.

Monitor pacemaker function. (5.7) Agranulocytosis: Patients should report signs of infection. (5.8) May exacerbate myasthenia gravis.

(5.11)

5.1Proarrhythmic Effects Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole and torsade de pointes. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval.

It is therefore essential that each patient given propafenone hydrochloride be evaluated electrocardiographically prior to and during therapy to determine whether the response to propafenone hydrochloride supports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret [see Clinical Pharmacology (12.2) ]. In a U.S. uncontrolled, open label, multicenter trial in subjects with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these subjects experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial.

However, in 4 of the 9 subjects, the ventricular tachycardia was of atrial origin. Six of the nine subjects that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all subjects had a recurrence of SVT during the trial which could have been a change in the subjects' arrhythmia behavior or could represent a proarrhythmic event.

Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death. Overall in clinical trials with propafenone hydrochloride (which included subjects treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all subjects had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance of VT or VF).

Of the subjects who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in subjects with less serious or benign arrhythmias, which include subjects with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial [see Boxed Warning : Mortality] suggests that an increased risk of proarrhythmia is present throughout treatment.

In a trial of sustained-release propafenone, there were too few deaths to assess the long-term risk to patients. There were 5 deaths; 3 in the pooled group for sustained-release propafenone (0.8%) and 2 in the placebo group (1.6%). In the overall database of 8 trials of sustained-release propafenone and immediate-release propafenone hydrochloride, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo.

Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

5.2Unmasking Brugada Syndrome Brugada Syndrome may be unmasked after exposure to propafenone hydrochloride. Perform an ECG after initiation of propafenone hydrochloride, and discontinue the drug if changes are…

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 Strides Pharma Inc 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems. About 20% of subjects treated with propafenone hydrochloride have discontinued treatment because of adverse reactions.

Adverse reactions reported for greater than 1.5% of 474 subjects with SVT who received propafenone hydrochloride 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 Reactions 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 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 The f…

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)

7.1CYP2D6 and CYP3A4 Inhibitors Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, or 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 with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions (5.4) and 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 three times daily) with 150 mg immediate release propafenone three 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 propafenone decreased by 84%, with a corresponding decrease in AUC and C max of 5-OH-propafenone by 69% and 57%, respectively.

7.2Digoxin 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.

7.3Warfarin 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).

7.4Orlistat Orlistat may limit the fraction of propafenone available for absorption. In post marketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block, and acute circulatory failure .

7.5Beta-Antagonists Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In 4 patients, administration of metoprolol…