Rythmol

Propafenone comes as a tablet or extended-release capsule to take by mouth.

The tablet is usually taken three times a day (once every eight hours).

The extended-release capsule is usually taken twice daily (once every 12 hours).

Follow the instructions on your prescription label carefully when taking this medicine. Don't take more or less propafenone than is recommended.

Be sure to swallow the extended-release capsule whole. Don't crush, chew, or split the capsule.

Your doctor may start on you a low dose of propafenone and gradually increase it.

Your first dose may be given in a hospital setting so that your healthcare provider can monitor your condition carefully.

Continue to take this medicine even if you feel well. Don't stop using propafenone without first talking with your doctor.

Propafenone Overdose

Symptoms of a propafenone overdose may include:

• Slow or irregular heartbeat
• Seizures
• Tiredness or extreme drowsiness

If you suspect an overdose, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Propafenone

If you miss a dose of propafenone, take it as soon as you remember.

But if it's almost time for your next scheduled dose, skip the missed dose and continue with your regular medication schedule.

Don't double up on doses to make up for a missed one.

Dosage Forms And Strengths

150 mg and 225 mg scored, round, film-coated tablets.

Storage And Handling

RYTHMOL tablets are supplied as white, biconvex, scored, round, film-coated tablets containing either 150 mg or 225 mg of propafenone hydrochloride and embossed (on the same side) with GS and TF5 for the 150 mg tablet, and GS and F1X for the 225 mg tablet, in the following package sizes:

150 mg bottles of 100: NDC 0173-0792-20
225 mg bottles of 100: NDC 0173-0794-20

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Dispense in a tight, light-resistant container.

Manufactured for GlaxoSmithKline by: Halo Pharmaceutical, Inc., Whippany, NJ 07981. Distributed by: GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: March 2013

You should not use this medication if you are allergic to propafenone, or if you have:

• untreated or uncontrolled congestive heart failure;
• a heart condition called "sick sinus syndrome" or "AV block" (unless you have a pacemaker);
• slow heartbeats or severely low blood pressure;
• a severe or uncontrolled electrolyte imbalance (such as low levels of potassium in your blood); or
• a breathing disorder such as severe COPD (chronic obstructive pulmonary disorder).

To make sure you can safely take propafenone, tell your doctor if you have any of these other conditions:

• congestive heart failure;
• a breathing disorder;
• liver disease;
• kidney disease;
• lupus;
• arthritis;
• myasthenia gravis; or
• if you have had a heart attack within the past 2 years.

FDA pregnancy category C. It is not known whether propafenone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether propafenone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using propafenone.

• Abnormal Heart Rhythms (Heart Rhythm Disorders)
• Atrial Fibrillation (AF, AFib)
• Palpitations

• Glaxo SmithKline Pharmaceuticals

Supraventricular Tachyarrhythmias

Used (as conventional [immediate-release] tablets) to prolong the time to recurrence of symptomatic, disabling paroxysmal supraventricular tachycardia (PSVT) (e.g., AV nodal reentrant tachycardia or AV reentrant tachycardia [Wolff-Parkinson-White, WPW, syndrome]) and symptomatic, disabling paroxysmal atrial fibrillation/flutter (PAF) in patients without structural heart disease.1 3 67 68 90 91 92 93 94 99 101 102 105 107 108 109 110 132 133 173 187 206 211

Used (as extended-release capsules) to prolong the time to recurrence of symptomatic PAF in patients without structural heart disease.289 Safety and efficacy of extended-release capsules not established in patients with exclusively PSVT or atrial flutter.289

One of several drugs that may be used for ongoing management of patients with PSVT who do not have structural or ischemic heart disease; generally reserved for patients in whom other therapies (e.g., catheter ablation, β-adrenergic blocking agents, diltiazem, verapamil) are ineffective or contraindicated.700

Comparably effective to quinidine, disopyramide, flecainide, procainamide, sotalol in preventing recurrences of PAF and maintaining sinus rhythm following successful cardioversion of atrial fibrillation.3 68 89 129 133 183 200 201 202 204 205

Safety and efficacy not established in patients with chronic atrial fibrillation.1 289

Has been used for pharmacologic cardioversion of atrial fibrillation or flutter†.15 68 88 89 90 101 103 104 109 110 111 195 196 197 198 199 207 208 211 272 701

May be used for ongoing management of other supraventricular tachycardias (SVTs) (e.g., focal atrial tachycardia†, junctional tachycardia†).700

Because of risk of proarrhythmia, do not use in patients with structural heart disease or ischemic heart disease.700

Ventricular Arrhythmias

As conventional (immediate-release) tablets, suppresses and prevents recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained VT, VF).1 3 (See Mortality under Cautions.)

• If you have an allergy to propafenone or any other part of Rythmol (propafenone tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Breathing or lung problems, Brugada syndrome, electrolyte problems in your blood, low blood pressure, recent heart attack, sick sinus syndrome or heart block without a working pacemaker, slow heartbeat, or heart failure.
• If you have been taking any drugs to treat a heartbeat that is not normal.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Rythmol with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Upset stomach or throwing up.
• Feeling tired or weak.
• Hard stools (constipation).
• Change in taste.
• Headache.
• Anxiety.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

The dose of Rythmol must be individually titrated on the basis of response and tolerance. Initiate therapy with Rythmol 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 Rythmol 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 Rythmol should be increased more gradually during the initial phase of treatment.

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 with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions (5.4), Drug Interactions (7.1)].

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 be evaluated electrocardiographically prior to and during therapy to determine whether the response to Rythmol 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 US 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 9 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 Rythmol (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 proarrythmia is present throughout treatment.

In a trial of sustained-release propafenone (Rythmol SR®), 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.

Unmasking Brugada Syndrome

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

Use with Drugs that Prolong the QT Interval and Antiarrhythmic Agents

The use of Rythmol 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. 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.

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 other demographic groups are deficient to a somewhat lesser extent. 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 with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

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 clinical trial experience with Rythmol, new or worsened congestive heart failure (CHF) has been reported in 3.7% of subjects with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone HCl. Of the subjects with CHF probably related to propafenone, 80% had pre-existing heart failure and 85% had coronary artery disease. CHF attributable to propafenone HCl developed rarely (less than 0.2%) in subjects with ventricular arrhythmia who had no previous history of CHF. CHF occurred in 1.9% of subjects studied with PAF or PSVT.

In a US trial of Rythmol SR in subjects with symptomatic AF, heart failure was reported in 4 (1.0%) subjects receiving Rythmol SR (all doses) compared with 1 (0.8%) subject receiving placebo.

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)].

The incidence of first-degree, second-degree, and third-degree AV block observed in 2,127 subjects with ventricular arrhythmia was 2.5%, 0.6%, and 0.2%, respectively. Development of second- or third-degree AV block requires a reduction in dosage or discontinuation of propafenone HCl. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.

In a US trial in 523 subjects with a history of symptomatic AF treated with Rythmol SR, sinus bradycardia (rate less than 50 beats per min) was reported with the same frequency with Rythmol SR and placebo.

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.

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.

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. In 8 subjects with moderate to severe liver disease, the mean half-life was approximately 9 hours. 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)].

Use in Patients with Renal Dysfunction

Approximately 50% of propafenone metabolites are excreted in the urine following administration of Rythmol.

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

Use in Patients with Myasthenia Gravis

Exacerbation of myasthenia gravis has been reported during propafenone therapy.

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.

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.

More frequent side effects include: ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, first degree atrioventricular block, and unpleasant taste. See below for a comprehensive list of adverse effects.