RYTHMOL

GlaxoSmithKline LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use RYTHMOL SR safely and effectively. See full prescribing information for RYTHMOL SR. RYTHMOL SR (propafenone hydrochloride) Extended-Release Capsules for oral use Initial U.S. Approval: 1989BOXED WARNINGWARNING: MORTALITY See full prescribing information for complete boxed warning • An increased rate of death or reversed cardiac arrest rate was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in patients assigned to placebo. At present it is prudent to consider any IC antiarrhythmic to have a significant risk of provoking proarrhythmic events in patients with structural heart disease. • Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs. INDICATIONS AND USAGERYTHMOL SR is 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) Usage Considerations: •Use in patients with permanent atrial fibrillation or with atrial flutter or paroxysmal supraventricular tachycardia (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 RYTHMOL SR with drugs that increase the atrioventricular nodal refractory period. (1) •The effect of propafenone on mortality has not been determined. (1) DOSAGE AND ADMINISTRATION •Initiate therapy with 225 mg given every 12 hours. (2) •Dosage may be increased at a minimum of 5-day intervals to 325 mg every 12 hours and, if necessary, to 425 mg every 12 hours. (2) •Dose reduction should be considered in patients with hepatic impairment, significant widening of the QRS complex, or second-or third-degree AV block. (2) DOSAGE FORMS AND STRENGTHSCapsules: 225 mg, 325 mg, 425 mg. (3)CONTRAINDICATIONS •Heart failure (4) •Cardiogenic shock (4) •Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation and/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) WARNINGS AND PRECAUTIONS •May cause new or worsened arrhythmias. Evaluate patients via ECG prior to and during therapy. (5.1) •RYTHMOL SR may unmask Brugada or Brugada-like Syndrome. Evaluate patients via ECG after initiation of therapy. (4, 5.2) •Avoid use with other antiarrhythmic agents or drugs that prolong the QT interval. (5.3) •Avoid simultaneous use of propafenone with both a cytochrome P450 2D6 inhibitor and a 3A4 inhibitor. (5.4) •May provoke overt heart failure. (5.5) •May cause dose-related first-degree AV block or other conduction disturbances. Should not be given to patients with conduction defects in absence of a pacemaker. (5.6) •May affect artificial pacemakers. Pacemakers should be monitored during therapy. (5.7) •Agranulocytosis: Patients should report signs of infection. (5.8) •Administer cautiously to patients with impaired hepatic and renal function. (5.9, 5.10) •Exacerbation of myasthenia gravis has been reported. (5.11) Side EffectsThe most commonly reported adverse events with propafenone (>5% and greater than placebo) excluding those not reasonably associated with the use of the drug included the following: dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •Inhibitors of CYP2D6, 1A2, and 3A4 may increase propafenone levels which may lead to cardiac arrhythmias. Simultaneous use with both a CYP3A4 and CYP2D6 inhibitor (or in patients with CYP2D6 deficiency) should be avoided. (7.1) •Propafenone may increase digoxin or warfarin levels. (7.2, 7.3) •Orlistat may reduce propafenone concentrations. Abrupt cessation of orlistat in patients stable on RYTHMOL SR has resulted in convulsions, atrioventricular block, and circulatory failure. (7.4) •Concomitant use of lidocaine may increase central nervous system side effects. (7.6)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: MORTALITY
• 1 RYTHMOL INDICATIONS AND USAGE
• 2 RYTHMOL DOSAGE AND ADMINISTRATION
• 3 DOSAGE FORMS AND STRENGTHS
• 4 RYTHMOL CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Proarrhythmic Effects
  • 5.3 Use With Drugs That Prolong the QT Interval and Antiarrhythmic Agents
  • 5.4 Drug Interactions: Simultaneous Use With Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4
  • 5.5 Use in Patients With a History of Heart Failure
  • 5.6 Conduction Disturbances
  • 5.7 Effects on Pacemaker Threshold
  • 5.8 Agranulocytosis
  • 5.9 Use in Patients With Hepatic Dysfunction
  • 5.10 Use in Patients With Renal Dysfunction
  • 5.11 Use in Patients With Myasthenia Gravis
  • 5.12 Elevated ANA Titers
  • 5.13 Impaired Spermatogenesis
• 6 RYTHMOL ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
• 7 DRUG INTERACTIONS
  • 7.1 CYP2D6 and CYP3A4 Inhibitors
  • 7.2 Digoxin
  • 7.3 Warfarin
  • 7.4 Orlistat
  • 7.5 Beta-Antagonists
  • 7.6 Lidocaine
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 RYTHMOL DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Information for Patients

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

RYTHMOL SR^® is 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.

Usage Considerations:

• •The use of RYTHMOL SR in patients with permanent AF or in patients exclusively with atrial flutter or paroxysmal supraventricular tachycardia (PSVT) has not been evaluated. Do not use RYTHMOL SR 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 effect of propafenone on mortality has not been determined [see Boxed Warning].

2 DOSAGE AND ADMINISTRATION

RYTHMOL SR can be taken with or without food. Do not crush or further divide the contents of the capsule.

The dose of RYTHMOL SR must be individually titrated on the basis of response and tolerance. Initiate therapy with RYTHMOL SR 225 mg given every 12 hours. Dosage may be increased at a minimum of 5-day intervals to 325 mg given every 12 hours. If additional therapeutic effect is needed, the dose of RYTHMOL SR may be increased to 425 mg given every 12 hours.

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.

The combination of CYP3A4 inhibition and either 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 RYTHMOL SR with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions (5.4), Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS

RYTHMOL SR (propafenone HCl) Capsules are supplied as white, opaque, hard gelatin capsules containing either 225 mg, 325 mg, or 425 mg of propafenone HCl. The 225 mg strength is imprinted in red with GS EUG followed by 225. The 325-mg strength is imprinted in red with GS F1Y followed by 325, and also has a single red band around ¾ of the circumference of the body. The 425-mg strength is imprinted in red with GS UY2 followed by 425, and also has 3 red bands around ¾ of the circumference of the body.

4 CONTRAINDICATIONS

RYTHMOL SR is 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

5 WARNINGS AND PRECAUTIONS

5.1 Proarrhythmic 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 RYTHMOL SR be evaluated electrocardiographically prior to and during therapy to determine whether the response to RYTHMOL SR 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 the RAFT trial [see Clinical Studies (14)], there were too few deaths to assess the long-term risk to patients. There were 5 deaths, 3 in the pooled group for RYTHMOL SR (0.8%) and 2 in the placebo group (1.6%). In the overall database of 8 trials of RYTHMOL SR and immediate-release RYTHMOL, 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.

In a US uncontrolled, open-label, multicenter trial using the immediate-release formulation in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. However, in 4 of the 9 patients, the ventricular tachycardia was of atrial origin. Six of the 9 patients that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all patients had recurrence of SVT during the trial which could have been a change in the patients’ 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, torsades de pointes, asystole, and death.

Overall in clinical trials with RYTHMOL immediate-release (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all patients 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 patients 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 patients with less serious or benign arrhythmias, which include patients 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 proarrythmia is present throughout treatment.

Brugada Syndrome may be unmasked after exposure to RYTHMOL SR. Perform an ECG after initiation of RYTHMOL SR and discontinue the drug if changes are suggestive of Brugada Syndrome [see Contraindications (4)].

5.3 Use With Drugs That Prolong the QT Interval and Antiarrhythmic Agents

The use of RYTHMOL SR in conjunction with other drugs that prolong the QT interval has not been extensively studied. Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides. Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with RYTHMOL SR. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.

5.4 Drug Interactions: Simultaneous Use With Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4

Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the US population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.

Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of RYTHMOL SR with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

5.5 Use in Patients With a History of Heart Failure

Propafenone exerts a negative inotropic activity on the myocardium as well as beta blockade effects and may provoke overt heart failure. In the US trial (RAFT) in patients with symptomatic AF, heart failure was reported in 4 (1.0%) patients receiving RYTHMOL SR (all doses), compared with 1 (0.8%) patient receiving placebo. Proarrhythmic effects more likely occur when propafenone is administered to patients with heart failure (NYHA III and IV) or severe myocardial ischemia [see Contraindications (4)].

In clinical trial experience with RYTHMOL immediate-release, new or worsened heart failure has been reported in 3.7% of patients with ventricular arrhythmia. These events were more likely in subjects with pre-existing heart failure and coronary artery disease. New onset of heart failure attributable to propafenone developed in <0.2% of patients with ventricular arrhythmia and in 1.9% of patients with paroxysmal AF or PSVT.

5.6 Conduction Disturbances

Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related. Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker [see Contraindications (4), Clinical Pharmacology (12.2)].

In a US trial (RAFT) in 523 patients with a history of symptomatic AF treated with RYTHMOL SR, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with RYTHMOL SR and placebo.

5.7 Effects on Pacemaker Threshold

Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.

5.8 Agranulocytosis

Agranulocytosis has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy and upon discontinuation of therapy; the white count usually normalized by 14 days. Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.

5.9 Use in Patients With Hepatic Dysfunction

Propafenone is highly metabolized by the liver. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared with 3% to 40% in patients with normal liver function when given RYTHMOL immediate-release tablets. In 8 patients with moderate to severe liver disease administered RYTHMOL immediate-release tablets, the mean half-life was approximately 9 hours. No trials have compared bioavailability of propafenone from RYTHMOL SR in patients with normal and impaired hepatic function. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects [see Overdosage (10)].

5.10 Use in Patients With Renal Dysfunction

Approximately 50% of propafenone metabolites are excreted in the urine following administration of RYTHMOL immediate-release tablets. No trials have been performed to assess the percentage of metabolites eliminated in the urine following the administration of RYTHMOL SR Capsules.

In patients with impaired renal function monitor for signs of overdosage [see Overdosage (10)].

5.11 Use in Patients With Myasthenia Gravis

Exacerbation of myasthenia gravis has been reported during propafenone therapy.

5.12 Elevated ANA Titers

Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy. Carefully evaluate patients who develop an abnormal ANA test and if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.

5.13 Impaired Spermatogenesis

Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after high-dose intravenous administration of propafenone. Evaluation of the effects of short-term administration of RYTHMOL on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count.

6 ADVERSE REACTIONS

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.

The data described below reflect exposure to RYTHMOL SR 225 mg twice daily in 126 patients, to RYTHMOL SR 325 mg twice daily in 135 patients, to RYTHMOL SR 425 mg twice daily in 136 patients, and to placebo in 126 patients for up to 39 weeks (mean 20 weeks) in a placebo-controlled trial (RAFT) conducted in the US. The most commonly reported adverse events with propafenone (>5% and greater than placebo) excluding those not reasonably associated with the use of the drug or because they were associated with the condition being treated, were dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza. The frequency of discontinuation due to adverse events was 17%, and the rate was highest during the first 14 days of treatment.

Cardiac-related adverse events occurring in ≥ 2% of the patients in any of the RAFT propafenone SR treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: angina pectoris, atrial flutter, AV block first-degree, bradycardia, congestive cardiac failure, cardiac murmur, edema, dyspnea, rales, wheezing, and cardioactive drug level above therapeutic.

Propafenone prolongs the PR and QRS intervals in patients with atrial and ventricular arrhythmias. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval [see Clinical Pharmacology (12.2)].

Non-cardiac related adverse events occurring in ≥2% of the patients in any of the RAFT propafenone SR treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: blurred vision, constipation, diarrhea, dry mouth, flatulence, nausea, vomiting, fatigue, weakness, upper respiratory tract infection, blood alkaline phosphatase increased, hematuria, muscle weakness, dizziness (excluding vertigo), headache, taste disturbance, tremor, somnolence, anxiety, depression, ecchymosis.

No clinically important differences in incidence of adverse reactions were noted by age or gender. Too few non-Caucasian patients were enrolled to assess adverse events according to race.

Adverse events occurring in 2% or more of the patients in any of the ERAFT [see Clinical Studies (14)] propafenone SR treatment groups and not listed above include the following: bundle branch block left, bundle branch block right, conduction disorders, sinus bradycardia, and hypotension.

Other adverse events reported with propafenone clinical trials not already listed elsewhere in the prescribing information include the following adverse events by body system and preferred term.

Anemia, lymphadenopathy, spleen disorder, thrombocytopenia.

Unstable angina, atrial hypertrophy, cardiac arrest, coronary artery disease, extrasystoles, myocardial infarction, nodal arrhythmia, palpitations, pericarditis, sinoatrial block, sinus arrest, sinus arrhythmia, supraventricular extrasystoles, ventricular extrasystoles, ventricular hypertrophy.

Hearing impaired, tinnitus, vertigo.

Eye hemorrhage, eye inflammation, eyelid ptosis, miosis, retinal disorder, visual acuity reduced.

Abdominal distension, abdominal pain, duodenitis, dyspepsia, dysphagia, eructation, gastritis, gastroesophageal reflux disease, gingival bleeding, glossitis, glossodynia, gum pain, halitosis, intestinal obstruction, melena, mouth ulceration, pancreatitis, peptic ulcer, rectal bleeding, sore throat.

Chest pain, feeling hot, hemorrhage, malaise, pain, pyrexia.

Hepatomegaly.

Abnormal heart sounds, abnormal pulse, carotid bruit, decreased blood chloride, decreased blood pressure, decreased blood sodium, decreased hemoglobin, decreased neutrophil count, decreased platelet count, decreased prothrombin level, decreased red blood cell count, decreased weight, glycosuria present, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, increased blood cholesterol, increased blood creatinine, increased blood glucose, increased blood lactate dehydrogenase, increased blood pressure, increased blood prolactin, increased blood triglycerides, increased blood urea, increased blood uric acid, increased eosinophil count, increased gamma-glutamyltransferase, increased monocyte count, increased prostatic specific antigen, increased prothrombin level, increased weight, increased white blood cell count, ketonuria present, proteinuria present.

Anorexia, dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia.

Arthritis, bursitis, collagen-vascular disease, costochondritis, joint disorder, muscle cramps, muscle spasms, myalgia, neck pain, pain in jaw, sciatica, tendonitis.

Amnesia, ataxia, balance impaired, brain damage, cerebrovascular accident, dementia, gait abnormal, hypertonia, hypothesia, insomnia, paralysis, paresthesia, peripheral neuropathy, speech disorder, syncope, tongue hypoesthesia.

Decreased libido, emotional disturbance, mental disorder, neurosis, nightmare, sleep disorder.

Dysuria, nocturia, oliguria, pyuria, renal failure, urinary casts, urinary frequency, urinary incontinence, urinary retention, urine abnormal.

Breast pain, impotence, prostatism.

Atelectasis, breath sounds decreased, chronic obstructive airways disease, cough, epistaxis, hemoptysis, lung disorder, pleural effusion, pulmonary congestion, rales, respiratory failure, rhinitis, throat tightness.

Alopecia, dermatitis, dry skin, erythema, nail abnormality, petechiae, pruritus, sweating increased, urticaria.

Arterial embolism limb, deep limb venous thrombosis, flushing, hematoma, hypertension, hypertensive crisis, hypotension, labile blood pressure, pallor, peripheral coldness, peripheral vascular disease, thrombosis.

7 DRUG INTERACTIONS

7.1 CYP2D6 and CYP3A4 Inhibitors

Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, and 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 RYTHMOL SR with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions (5.4), Dosage and Administration (2)].

Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.

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.

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.

Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers [see Clinical Pharmacology (12)]. 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 poor metabolizers. Steady-state plasma concentrations increased by more than 2 fold for propafenone, and decreased 50% for 5-OH-propafenone. A 100-mg dose of quinidine increased steady state concentrations of propafenone 3 fold. Avoid concomitant use of propafenone and quinidine.

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 poor 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.

7.2 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 metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In clinical trials using propafenone immediate-release tablets, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects.

7.6 Lidocaine

No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. RYTHMOL SR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg/day (about 3 times the maximum recommended human dose [MRHD] on a mg/m² basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m² basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m² basis) produced no evidence of embryotoxicity in rats, post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m² basis).

In a study in which female rats received daily oral doses of propafenone from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m² basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m² basis) resulted in reductions in neonatal survival, body weight gain, and physiological development.

8.2 Labor and Delivery

It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.

8.3 Nursing Mothers

Propafenone is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from propafenone, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of propafenone in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in Phase 3 clinical trials of RYTHMOL SR (propafenone hydrochloride) 46% were 65 and over, while 16% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals at higher doses cannot be ruled out. The effect of age on the pharmacokinetics and pharmacodynamics of propafenone has not been studied.

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 have 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 (>95%) and large volume of distribution.

11 DESCRIPTION

RYTHMOL SR (propafenone hydrochloride) is an antiarrhythmic drug supplied in extended-release capsules of 225, 325 and 425 mg for oral administration.

Chemically, propafenone hydrochloride is 2’-[2-Hydroxy-3-(propylamino)-propoxy]-3-phenylpropiophenone hydrochloride, with a molecular weight of 377.92. The molecular formula is C₂₁H₂₇NO₃•HCl.

Propafenone HCl has some structural similarities to beta-blocking agents. The structural formula of propafenone HCl is given below: