Rythmol Sr (propafenone HCl)

Dosage of propafenone hydrochloride must be adjusted carefully according to individual requirements and response, patient tolerance, and the general condition and cardiovascular status of the patient. The manufacturer recommends that propafenone therapy (immediate-release tablets) for life-threatening ventricular arrhythmias be initiated in a hospital setting. Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring), is recommended during therapy with the drug. However, ECG determination of propafenone's effect on the QT interval may be confounded by drug-induced prolongation of the QRS interval. (See Effects on Cardiac Conduction under Cautions.) Because of considerable interindividual variation in plasma concentrations of propafenone and its metabolites with a given dosage and their variable contribution to clinical response, the value of monitoring plasma concentrations of the drug and its metabolites has not been established.

At a given dosage, the relative proportion of propafenone in plasma is substantially higher in poor metabolizers than in extensive metabolizers. (See Pharmacokinetics: Absorption.) However, these differences in plasma propafenone concentrations are smaller at higher dosages of the drug and the pharmacologic effects of the drug in poor metabolizers are attenuated by the lack of the active 5-OHP metabolite; in addition, steady state is achieved after 4-5 days of dosing in all patients. Therefore, based on pharmacokinetic considerations and clinical experience, the recommended oral dosage regimens for propafenone are appropriate for initial dosing regardless of the patient's genetically determined ability to metabolize the drug. Reduction of the initial dosage of immediate-release tablets should be considered in patients weighing less than 70 kg.

The manufacturer and some clinicians state that oral loading doses of propafenone hydrochloride (immediate-release tablets) may lead to acute toxicity and are not recommended; however, oral loading doses (e.g., 450-750 mg as immediate-release tablets have been used with apparent safety for conversion of recent-onset atrial fibrillation to normal sinus rhythm+ in individuals without heart failure. (See Conversion of Atrial Fibrillation or Flutter to Normal Sinus Rhythm, under Uses: Supraventricular Tachyarrhythmias.)

Since steady-state plasma concentrations of propafenone and the optimum therapeutic effect may not be attained for 1-3 days at a given dosage (immediate-release tablets) in patients with normal renal and hepatic function, increases in propafenone hydrochloride (immediate-release tablets) dosage should be made at intervals of not less than 3-4 days. More gradual dosage escalation should be performed in geriatric patients and patients with marked previous myocardial damage during initiation of propafenone therapy (immediate-release tablets). Increases in propafenone hydrochloride dosage as (extended-release capsules) should be made at intervals of not less than 5 days. Dosage reduction also should be considered in patients who develop excessive prolongation of the PR interval, excessive QRS widening, or second- or third-degree AV block during propafenone therapy. While it has been suggested that a reduction in propafenone hydrochloride dosage (immediate-release tablets) from initial levels may be needed because of a decrease in propafenone metabolism with long-term therapy, other limited data suggest that a partial tolerance to the antiarrhythmic effects of the drug may develop with continued therapy. (See Pharmacokinetics: Absorption.)

Propafenone should be used with caution in patients with renal impairment since a considerable proportion of the dose (approximately 20-40%) administered as the immediate-release formulation is excreted in urine as active metabolites over a 48-hour period. The amount of the extended-release formulation excreted in urine has not been determined. The manufacturer states that data currently are insufficient to recommend a propafenone hydrochloride dosage for patients with renal impairment; however, such patients should be monitored closely for manifestations of toxicity, including hypotension, somnolence, bradycardia, conduction disturbances (intra-atrial and intraventricular), seizures, and serious ventricular arrhythmias.

Elimination of propafenone may be decreased in patients with hepatic impairment, including cirrhosis and alcoholic liver disease; the terminal elimination half-life of propafenone (immediate-release tablets) of the drug is increased to approximately 9 hours in such patients. (See Pharmacokinetics: Elimination.) In addition, the bioavailability of propafenone (immediate-release tablets) is increased to approximately 70% in patients with substantial hepatic impairment compared with a range of 3-40% in patients with normal hepatic function; absolute bioavailability of propafenone as the extended-release formulation has not been determined. When propafenone (immediate-release tablets) is used in patients with hepatic impairment, the initial dosage of the drug should be approximately 20-30% of the dosage given to patients with normal hepatic function (i.e., a 70-80% reduction in dosage), and these patients should be monitored for signs of toxicity, including hypotension, somnolence, bradycardia, conduction disturbances (intra-atrial and intraventricular), seizures, and/or ventricular arrhythmias.

Propafenone hydrochloride is administered orally. Propafenone hydrochloride is commercially available as conventional (immediate-release) tablets and extended-release capsules. The drug also has been administered IV+, but a parenteral dosage form of propafenone hydrochloride currently is not commercially available in the US.

Propafenone hydrochloride (immediate-release tablets) usually is administered orally in 3 equally divided doses daily at 8-hour intervals. Administration of single doses of propafenone hydrochloride (immediate-release tablets) with food has increased the rate and extent of drug absorption in healthy individuals with the extensive-metabolizer phenotype, and limited data indicate that this effect also may occur in those with the poor-metabolizer phenotype. Therefore, while appreciable alterations in propafenone bioavailability have not been documented during multiple-dose administrations of immediate-release tablets with food, patients should be advised of the importance of taking propafenone hydrochloride (immediate-release tablets) in a consistent manner relative to food intake to ensure consistent bioavailability and clinical effect.

Extended-release capsules of propafenone hydrochloride usually are administered orally in equally divided doses every 12 hours. The extended-release capsules should be swallowed intact and should not be crushed; extended-release capsules of the drug may be taken without regard to food.

Concomitant oral administration of grapefruit juice with drugs that undergo hepatic oxidation by cytochrome P-450 isoenzymes (e.g., cyclosporine, midazolam, felodipine, nifedipine) has been reported to increase bioavailability of these drugs, resulting in increased plasma concentrations of the unchanged drugs and potential adverse effects. The possibility that a similar interaction could occur between grapefruit juice and propafenone should be considered since the reported increase in bioavailability appears to result from inhibition, probably prehepatic, of the cytochrome P-450 enzyme system. Therefore, pending further accumulation of data, clinicians should be aware of this potential interaction and should discourage patients from ingesting grapefruit juice concomitantly with propafenone. For additional information on drug interactions with grapefruit juice, see Grapefruit Juice, under Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes, in the Antihistamines General Statement 4:00.

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There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Propafenone has been shown to be embryotoxic, but not teratogenic, in rabbits and rats when given at a dosage 3 (150 mg/kg daily) and 6 times (600 mg/kg daily), respectively, the maximum recommended human daily dose based on body surface area. Embryotoxic effects were not observed in rats given propafenone hydrochloride dosages up to 270 mg/kg daily (about 3 times the maximum recommended human daily dose based on body surface area); however, dose-dependent increases in post-implantation loss were observed in rabbits given propafenone hydrochloride dosages as low as 15 mg/kg daily (about 33% of the maximum recommended human daily dose based on body surface area). Increased maternal death was observed in rats receiving oral propafenone hydrochloride dosages as low as 90 mg/kg daily (equivalent to the maximum recommended human daily dosage) from mid-gestation through weaning. Decreases in neonatal survival, weight gain, and physiologic development were observed in rats receiving oral propafenone hydrochloride dosages of 360 mg/kg or more daily (4 or more times the maximum recommended human daily dosage) from mid-gestation through weaning. Unchanged propafenone and its metabolite, 5-hydroxypropafenone (5-OHP), have been reported to cross the placenta in humans. However, there are no adequate and controlled studies to date using propafenone in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. It is not known whether use of the drug during labor or delivery could have any immediate or delayed adverse effects on the mother or fetus, affect the duration of labor, or increase the likelihood of forceps delivery or other obstetrical intervention.

Since propafenone is distributed in milk, caution is advised if the drug is administered in nursing women. (See Pharmacokinetics: Distribution.) Because of the potential for serious adverse reactions to propafenone in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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