RYTHMOL® SR (propafenone hydrochloride) extended release CAPSULES

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

The structural formula of propafenone HCl is given below:

2’-[2-Hydroxy-3-(propylamino)-propoxy]-3-phenylpropiophenone hydrochloride

Propafenone HCl has some structural similarities to beta-blocking agents. Propafenone HCl occurs as colorless crystals or white crystalline power with a very bitter taste. It is slightly soluble in water (20°C), chloroform and ethanol. Rythmol SR are capsules filled with cylindrical-shaped 2 x 2 mm microtablets containing propafenone and the following inactive ingredients: antifoam, gelatin, hypromellose, red iron oxide, magnesium stearate, shellac, sodium lauryl sulfate, sodium dodecyl sulfate, soy lecithin and titanium dioxide

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 with the immediate release formulation, 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 to 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).

Electrophysiology studies in patients with ventricular tachycardia (VT) have shown that propafenone prolongs atrioventricular (AV) conduction while having little or no effect on sinus node function. Both atrioventricular (AV) nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White (WPW) syndrome, RYTHMOL immediate release tablets reduce conduction and increase the effective refractory period of the accessory pathway in both directions (see ADVERSE REACTIONS/Electrocardiograms).

Studies in humans have shown that propafenone exerts a negative inotropic effect on the myocardium. Cardiac catherterization studies in patients with moderately impaired ventricular function (mean C.I.=2.61 L/min/m²), utilizing intravenous propafenone infusions (loading dose of 2 mg/kg over 10 min+ followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 µg/mL (a dose that produces plasma levels of propafenone greater than does recommended oral dosing), showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index.

With propafenone, there is a considerable degree of inter-subject variability in pharmacokinetics which is due in large part to the first pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. A higher degree of inter-subject variability in pharmacokinetic parameters of propafenone was observed following both single and multiple dose administration of RYTHMOL SR capsules. Inter-subject variability appears to be substantially less in the poor metabolizer group than in the extensive metabolizer group, suggesting that a large portion of the variability is intrinsic to CYP2D6 polymorphism rather than to the formulation.

The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction (see PRECAUTIONS). Decreased liver function also increases the bioavailability of propafenone. Absolute bioavailability assessments have not been determined for the RYTHMOL SR capsule formulation. Absolute bioavailability of RYTHMOL immediate release tablets has been demonstrated to be inversely related to indocyanine green clearance, reaching 60-70% at clearances of 7 mL/min and below.

RYTHMOL is a racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone to R-propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is a more potent β-antagonist than the R-enantiomer. Following administration of RYTHMOL immediate release tablets or RYTHMOL SR capsules, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. The S/R ratios of propafenone obtained after administration of 225, 325 and 425 mg RYTHMOL SR are independent of dose. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time.

RYTHMOL SR has been evaluated in patients with a history of electrocardiographically documented recurrent episodes of symptomatic atrial fibrillation in two randomized, double-blind, placebo controlled trials.

RYTHMOL SR is indicated to prolong the time to recurrence of symptomatic atrial fibrillation in patients without structural heart disease.

The use of RYTHMOL SR in patients with permanent atrial fibrillation or in patients exclusively with atrial flutter or PSVT has not been evaluated. RYTHMOL SR should not be used to control ventricular rate during atrial fibrillation.

The effect of RYTHMOL SR on mortality has not been determined (see black box WARNINGS).

RYTHMOL SR is contraindicated in the presence of congestive heart failure, cardiogenic shock, sinoatrial, atrioventricular and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, atrioventricular block) in the absence of an artificial pacemaker, bradycardia, marked hypotension, bronchospastic disorders, electrolyte imbalance, or hypersensitivity to the drug.

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.

In a 474 patient U.S. uncontrolled, open label multicenter trial using the immediate release formulation in patients with symptomatic SVT, 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. However, in four of the nine patients, the ventricular tachycardia was of atrial origin. Six of the nine 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 study which could have been a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with RYTHMOL for atrial fibrillation/flutter have included increased PVCs, VT, VF, Torsade de Pointes, asystole, and death.

In the RAFT study, there were five deaths, three in the pooled RYTHMOL SR group (0.8%) and two in the placebo group (1.6%). In the overall RYTHMOL SR and RYTHMOL immediate release database of eight studies, the mortality rate was 2.5% per year on RYTHMOL and 4.0% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

The use of RYTHMOL SR (propafenone hydrochloride) in conjunction with other drugs that prolong the QT interval has not been extensively studied and is not recommended. Such drugs may include many antiarrhythmics, some phenothiazines, cisapride, bepridil, tricyclic antidepressants and oral macrolides. Class Ia and III antiarrhythmic agents should be withheld for at least five half-lives prior to dosing with RYTHMOL SR. The use of propafenone with Class Ia and III antiarrhythmic agents (including quinidine and amiodarone) is not recommended. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics.

Patients with bronchospastic disease should not, in general, receive propafenone or other agents with beta-adrenergic-blocking activity.

Propafenone exerts a negative inotropic activity on the myocardium as well as beta blockade effects and may provoke overt congestive heart failure. In the U.S. trial (RAFT) in patients with symptomatic atrial fibrillation, congestive heart failure was reported in four (1.0%) patients receiving RYTHMOL SR (all doses), compared to one (0.8%) patient receiving placebo. Proarrhythmic effects are more likely to occur when propafenone is administered to patients with congestive heart failure (NYHA III and IV) or severe myocardial ischemia (see CONTRAINDICATIONS).

Propafenone causes dose-related first degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related.

Propafenone should not be given to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker (see CONTRAINDICATIONS).

In a U.S. trial (RAFT) in 523 patients with a history of symptomatic atrial fibrillation treated with RYTHMOL SR, electrocardiograms obtained in response to symptoms were associated with no patients having sinus rhythm with Mobitz Type I (Wenckenbach) second degree AV block, sinus rhythm with Mobitz Type II second degree AV block, or third degree AV block. Sinus bradycardia (rate <50 beats/min) was reported with the same frequency with RYTHMOL SR and placebo.

Propafenone may alter both pacing and sensing thresholds of artificial pacemakers. Pacemakers should be monitored and programmed accordingly during therapy.

Agranulocytosis (fever, chills, weakness, and neutropenia) has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first two months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days. Unexplained fever and/or decrease in white cell count, particularly during the initial three months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Patients should be instructed to report promptly the development of any signs of infection such as fever, sore throat, or chills.

Propafenone is highly metabolized by the liver and should, therefore, be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3-40% in patients with normal liver function when given RYTHMOL immediate release tablets. In eight patients with moderate to severe liver disease administered RYTHMOL immediate release tablets, the mean half-life was approximately nine hours. No studies are currently available comparing 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. Careful monitoring for excessive pharmacological effects (see OVERDOSAGE) should be performed for patients with impaired hepatic function.

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

Until further data are available, RYTHMOL SR should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for signs of overdosage (see OVERDOSAGE).

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 RYTHMOL administration on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count. Subsequent evaluations in 11 patients receiving RYTHMOL chronically have found no effect of propafenone on sperm count.

Exacerbation of myasthenia gravis has been reported during RYTHMOL immediate release tablet therapy.

Propafenone is metabolized by CYP2D6 (major pathway) and CYP1A2 and CYP3A4. Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline), CYP1A2 (such as amiodarone), and CYP3A4 (such as ketaconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) can be expected to cause increased plasma levels of propafenone. Appropriate monitoring is recommended when RYTHMOL SR is used together with such drugs. In addition, propafenone is an inhibitor of CYP2D6. Coadministration of propafenone with drugs metabolized by CYP2D6 (such as desipramine, imipramine, haloperidol, venlafaxine) might lead to increased plasma concentrations of these drugs. The effect of propafenone on the P-Glycoprotein transporter has not been studied.

Quinidine: Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers (see CLINICAL PHARMACOLOGY). Concomitant administration of quinidine (50 mg TID) with 150 mg immediate release propafenone TID decreased the clearance of propafenone by 60% in EM, making them PM. Steady-state plasma concentrations increased by more that 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. Concomitant use of propafenone and quinidine is not recommended.

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%. Plasma digoxin levels of patients receiving propafenone should be monitored and digoxin dosage adjusted as needed.

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 have been reported to increase the risks of central nervous system side effects of lidocaine.

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 100-400%. 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.

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 in patients taking warfarin. Adjustment of the warfarin dose should be guided by monitoring of the prothrombin time.

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.

Rifampin: Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5OH-propafenone by 65%. The concentrations of norpropafenone increased by 30%. In poor metabolizers, there was a 50% decrease in propafenone plasma concentrations and increased 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 5OH‑propafenone by 69 and 57%.

Fluoxetine: Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S propafenone C_max and AUC by 39 and 50% and the R propafenone C_max and AUC by 71 and 50%.

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

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

Renal changes have been observed in the rat following six months of oral administration of propafenone HCI at doses of 180 and 360 mg/kg/day (about two and four times, respectively, the maximum recommended human daily dose [MRHD] on a mg/m² basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for six weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCI at a dose of 270 mg/kg/day (about three times the MRHD on a mg/m² basis). There were no renal or hepatic changes at 90 mg/kg/day equivalent to the MRHD on a mg/m² basis).

Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on a mg/m² basis) and rats (up to 270 mg/kg/day, about three times the MRHD on a mg/m² basis) provided no evidence of a carcinogenic potential for propafenone HCI.

Propafenone HCI tested negative for mutagenicity in the Ames (salmonella) test and in the in vivo mouse dominant lethal test. It tested negative for clastogenicity in the human lymphocyte chromosome aberration assay in vitro and in rat and Chinese hamster micronucleus tests, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.

Propafenone HCI, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone HCI, were seen at lethal or near lethal dose levels and were not seen in rats treated either orally or intravenously (see PRECAUTIONS, Impaired Spermatogenesis). Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m² basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCI was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m² basis).

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.

Propafenone is excreted in human milk. Caution should be exercised when RYTHMOL SR is administered to a nursing mother.

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

Of the total number of subjects in Phase III clinical studies of RYTHMOL SR (propafenone hydrochloride) 45.7 percent were 65 and over, while 15.7 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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.

Of the total number of subjects in Phase III clinical studies of RYTHMOL SR (propafenone hydrochloride) 45.7 percent were 65 and over, while 15.7 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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.

No clinically important differences in incidence of adverse reactions were noted by age, or gender. Too few non-White 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 propafenone SR treatment groups and not uled in Table 2 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 uled in Table 3 include the following adverse events by body and preferred term.

BLOOD AND LYMPHATIC SYSTEM DISORDERS:  Anemia, lymphadenopathy, spleen disorder, thrombocytopenia.

CARDIAC DISORDERS: Angina unstable, arrhythmia, atrial hypertrophy, atrioventricular block, bundle branch block, bunch branch block left, bundle branch block right, cardiac arrest, cardiac disorder, conduction disorder, coronary artery disease, extrasystoles, myocardial infarction, nodal arrhythmia, palpitations, pericarditis, sinoatrial block, sinus arrest, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, supraventricular tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular hypertrophy.

EAR AND LABYRINTH DISORDERS: Hearing impaired, tinnitus, vertigo.

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

GASTROINTESTINAL DISORDERS: Abdominal distension, abdominal pain, dry throat, 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.

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Chest pain, feeling hot, hemorrhage, malaise, pain, pyrexia.

HEPATO-BILIARY DISORDERS: Hepatomegaly.

INVESTIGATIONS: Abnormal electrocardiogram, abnormal heart sounds, abnormal liver function tests, 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, electrocardiogram QT prolonged, glycosuria present, heart rate irregular, 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.

METABOLISM AND NUTRITION DISORDERS: Anorexia, dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia.

MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Arthritis, bursitis, collagen-vascular disease, costochondritis, joint disorder, muscle cramps, muscle spasms, myalgia, neck pain, pain in jaw, sciatica, tendonitis.

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

PSYCHIATRIC DISORDERS: Decreased libido, emotional disturbance, mental disorder, neurosis, nightmare, sleep disorder.

RENAL AND URINARY DISORDERS: Dysuria, nocturia, oliguria, pyuria, renal failure, urinary casts, urinary frequency, urinary incontinence, urinary retention, urine abnormal.

REPRODUCTIVE SYSTEM AND BREAST DISORDERS: Breast pain, impotence, prostatism.

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

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Alopecia, dermatitis, dry skin, erythema, nail abnormality, petechiae, pruritis, sweating increased, urticaria.

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

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 ventricular 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.

The dose of RYTHMOL SR must be individually titrated on the basis of response and tolerance. Therapy should be initiated with RYTHMOL SR 225 mg given every twelve hours. Dosage may be increased at a minimum of five day interval to 325 mg given every twelve hours. If additional therapeutic effect is needed, the dose of RYTHMOL SR may be increased to 425 mg given every twelve hours.

In patients with hepatic impairment or having significant widening of the QRS complex or second or third degree AV block, dose reduction should be considered.

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

RYTHMOL® SR (propafenone HCI) capsules are supplied as white, opaque, hard gelatin capsules containing either 225 mg, 325 mg, or 425 mg of propafenone HCI and imprinted in red with and strength. The 325 mg strength is also imprinted with a single red band around ¾ of the circumference of the body; the 425 mg strength is imprinted with three bands around ¾ of the circumference of the body.

Storage: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.

Rx Only

Revised: November, 2005

All Rights Reserved.

RYTHMOL is a registered trademark of G. Petrik used under license

by Abbott Laboratories.

Product of Switzerland

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Reliant Pharmaceuticals, Inc.

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