Rythmol SR

Mechanism of Action

Class IC antiarrhythmic; slows conduction in cardiac tissue by altering transport of ion across membranes; causes slight prolongation of AV nodal refractory periods; decreases rate of rise of action potential without affecting its duration

Absorption

Bioavailability: 3.4% (150 mg IR); 10.6% (300 mg IR)

Peak serum time: 2-3.5 hr (IR); 3-8 hr (ER)

Distribution

Protein bound: 95%

Vd: 252 L (adults)

Metabolism

Metabolism: Via CYP2D6 to 5-hydroxypropafenone; via CYP1A2 and CYP3A4 to N-depropylpropafenone

Metabolites: 5-hydroxypropafenone (active), N-depropylpropafenone (active), at least 9 other metabolites

Enzymes inhibited: CYP2D6

Elimination

Half-life: 2-10 hr (extensive metabolizers); 10-32 hr (poor metabolizers)

Dialyzable: No (HD)

Total body clearance: 1-1.3 L/kg/hr

Excretion: Urine; feces

Pharmacogenomics

Approximately 7-10% of whites and 3-8% of African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs)

Increased exposure may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity

Because of propafenone’s metabolism by CYP2D6, deficiency of this isoenzyme is potentially hazardous

Genetic testing laboratories

• The Roche Cytochrome AmpliChip P450 2D6/2C19 Genotyping and Phenotyping Assay can be used to identify 26 different alleles of CYP2D6
• LabCorp (http://www.labcorp.com/); testing for CYP2D6 variants

Take the missed dose as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

• Rythmol^®
• Rythmol^® SR

Rythmol SR is a prescription medication used to treat life-threatening, ventricular arrhythmias (irregular heartbeats). Rythmol SR is also used to correct abnormal heart rate in patients with:

• paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease.
• paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take Rythmol SR.
• Myasthenia gravis that has gotten worse has happened during care with this medicine. Talk with the doctor.
• If you have a pacemaker, talk with your doctor.
• This medicine has caused new or worsened abnormal heartbeats. These can be life-threatening or can cause sudden death. Talk with the doctor.
• You will need an ECG before starting Rythmol SR and during treatment. Talk with your doctor.
• Avoid grapefruit and grapefruit juice.
• Tell your doctor if you have too much sweat, fluid loss, throwing up, loose stools (diarrhea), not hungry, or more thirst.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this medicine with your other drugs.
• This medicine may lower sperm counts in men. This may affect being able to father a child. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Rythmol SR while you are pregnant.

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.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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)].

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 Rythmol SR Atrial Fibrillation Trial (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.

5.2 Unmasking Brugada Syndrome

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)].

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.

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 SR 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 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 less than 0.2% of patients with ventricular arrhythmia and in 1.9% of patients with paroxysmal AF or PSVT.

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 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 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)].

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)].

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.

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.

Teratogenic Effects: Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg per kg per day (about 3 times the maximum recommended human dose [MRHD] on a mg per m2 basis) and 600 mg per kg per day (about 6 times the MRHD on a mg per m2 basis), respectively. Although maternally tolerated doses (up to 270 mg per kg per day, about 3 times the MRHD on a mg per 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 per kg per day, about 1/3 the MRHD on a mg per m2 basis).

Non-teratogenic Effects: 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 per kg per day (equivalent to the MRHD on a mg per m2 basis) produced increases in maternal deaths. Doses of 360 or more mg per kg per day (4 or more times the MRHD on a mg per m2 basis) resulted in reductions in neonatal survival, body weight gain, and physiological development.

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.

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.

Pediatric Use

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

Geriatric Use

Of the total number of subjects in Phase 3 clinical trials of Rythmol SR (propafenone hydrochloride) 46% were 65 and older, while 16% were 75 and older. 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.