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MUTUAL PHARM CO
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53489055101

propafenone hcl 150 mg tablet

Generic
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Uses

Supraventricular Tachyarrhythmias

When given as immediate-release tablets, propafenone hydrochloride is used to prolong the time to recurrence of symptomatic, disabling paroxysmal supraventricular tachycardia (PSVT) (e.g., atrioventricular [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. While comparative studies are limited, propafenone appears to be comparable to other antiarrhythmic agents (e.g., quinidine, disopyramide, flecainide, procainamide, sotalol) in preventing recurrences of PAF and maintaining sinus rhythm following successful cardioversion of atrial fibrillation.

When given as extended-release capsules, propafenone is used to prolong the time to recurrence of symptomatic paroxysmal atrial fibrillation in patients without structural heart disease. The safety and efficacy of propafenone as extended-release capsules have not been established in patients with exclusively PSVT or atrial flutter.

Propafenone also has been used for termination of supraventricular tachycardias; analysis of combined data from controlled and uncontrolled clinical studies in patients receiving oral (immediate-release tablets) or IV (IV dosage form not commercially available in the US) propafenone therapy has demonstrated termination of PAF, PSVT, or tachycardia associated with WPW syndrome in 73, 57, or 45%, respectively, of patients. However, vagal maneuvers, IV adenosine, AV nodal blocking agents (e.g., calcium-channel blocking agents, β-adrenergic blocking agents) and/or synchronized cardioversion are the treatments of choice for acute conversion of PSVT.

The safety and efficacy of propafenone hydrochloride as immediate-release tablets or extended-release capsules have not been established in patients with chronic atrial fibrillation, and the manufacturer states that the drug should not be used to control ventricular rate in patients with atrial fibrillation.

Because of the risk of proarrhythmia, propafenone should not be used in patients with structural heart disease or ischemic heart disease.

Paroxysmal Atrial Fibrillation/Flutter and Paroxysmal Supraventricular Tachyarrhythmias

Immediate-release Propafenone Hydrochloride

Controlled and uncontrolled clinical studies have shown that propafenone (immediate-release tablets) may prevent or delay recurrence of PAF or increase the interval between recurrences of PAF in 39-64% of patients monitored for 6-18 months. Preliminary analysis of combined data from clinical studies indicates that propafenone prevented or delayed recurrence of PAF in 51 or 33% of patients monitored for 1 or 2 years, respectively, and prevented or delayed recurrence of PSVT or AV reentrant tachycardia (WPW syndrome) syndrome in 63 or 83%, respectively, of patients treated during a 10-month period. Long-term therapy with oral propafenone also has been effective in some patients for suppression and prevention of atrial fibrillation refractory to other antiarrhythmic agents. It has been suggested that propafenone may be more effective than flecainide in patients with adrenergically mediated atrial fibrillation or flutter, possibly because of its β-adrenergic blocking activity.

Control of ventricular rate should be the first therapeutic step in most patients with hemodynamically stable, acute atrial fibrillation. The goal of therapy should be a reduction of ventricular rate to less than 80-90 beats/minute and prevention of inappropriately high ventricular rates during activity. The use of propafenone in patients with chronic atrial fibrillation has not been adequately evaluated to date, and the manufacturer states that the drug should not be used to control ventricular rate in patients with atrial fibrillation. However, some experts and clinicians suggest that propafenone may be useful in controlling ventricular response rate in patients with stable but rapid atrial fibrillation/flutter and ventricular preexcitation via an accessory pathway (e.g., WPW syndrome).

In a randomized, crossover clinical trial of approximately 2-3 months' duration, the median time to arrhythmia recurrence was greater than 98 days in patients with PAF or PSVT receiving propafenone and 8 or 12 days in patients with PAF or PSVT, respectively, receiving placebo. Recurrences of PAF or PSVT were completely prevented in 53 or 47%, respectively, of patients receiving propafenone and in 13 or 16%, respectively, of those receiving placebo. In another randomized, crossover clinical trial of 2-3 months' duration, the median time to arrhythmia recurrence in patients with PAF or PSVT was 62 or 31 days, respectively, with propafenone therapy and 5 or 8 days, respectively, with placebo. Recurrences of PAF or PSVT were completely prevented in 67 or 38%, respectively, of patients receiving propafenone and in 22 or 7%, respectively, of those receiving placebo. Patients enrolled in these 2 trials had a mean age of 57.3 years; 50% of patients were male, and 80% received a daily propafenone hydrochloride dosage of 600 mg. Patients with PSVT or PAF were equally represented in the 2 studies.

Propafenone has been used orally for the long-term management of AV nodal reentrant tachycardia; however, the drug is generally reserved for patients in whom other therapies (e.g., catheter ablation, β-adrenergic blocking agents, diltiazem, verapamil) are ineffective or contraindicated.

In a randomized crossover study, the rate of recurrence of tachycardia with propafenone therapy was approximately one-fifth that with placebo. Propafenone may be particularly effective and may be considered first-line therapy in patients with atrial fibrillation/flutter associated with ventricular preexcitation and WPW syndrome; in these patients, the drug may slow the ventricular rate and possibly restore and maintain normal sinus rhythm. However, in patients with WPW syndrome whose condition is unstable (e.g., those with hypotension or heart failure), immediate cardioversion may be required. In studies in patients with recurrent episodes of supraventricular tachyarrhythmia associated with WPW syndrome, administration of oral propafenone hydrochloride (300-1200 mg daily prevented arrhythmia recurrence in 38-100% of patients during 7-36 months of follow-up. Propafenone therapy also has been effective for arrhythmias associated with WPW syndrome and a short anterograde refractory period of the accessory pathway, although radiofrequency catheter ablation of the accessory pathway may be preferred for the long-term management of this condition.

Based on findings from the Cardiac Arrhythmia Suppression (CAST) study of substantial risk associated with flecainide or encainide therapy in certain patients with ventricular arrhythmias, some experts currently caution that use of class Ic antiarrhythmic agents in supraventricular arrhythmias be limited to the management of symptomatic, disabling supraventricular arrhythmias (paroxysmal atrial fibrillation, AV junctional tachycardias) in patients without structural heart disease. However, some clinicians state that even these patients may be at risk of developing drug-induced arrhythmogenic effects (e.g., during exercise testing). The risks versus benefits of propafenone for the management of such arrhythmias in patients with structural heart disease remain to be elucidated, and assessment of the possible risks and potential benefits in such patients must be individualized. Current evidence indicates that initiation of antiarrhythmic therapy in patients with atrial fibrillation is associated with a notable risk for adverse cardiac events, particularly in geriatric patients or those with structural heart disease (e.g., heart failure); initiation of antiarrhythmic therapy in such patients should be performed in a hospital setting with ECG monitoring for the initial 24-48 hours. Some clinicians do not recommend the use of antiarrhythmic agents in patients with atrial fibrillation or flutter because increased mortality has been reported in patients receiving antiarrhythmic therapy after conversion of atrial fibrillation to normal sinus rhythm.

Extended-release Propafenone Hydrochloride

The FDA-labeled indication for extended-release propafenone hydrochloride in prolonging the time to first recurrence of symptomatic paroxysmal atrial fibrillation is based principally on the results of 2 multicenter, randomized, double-blind, placebo-controlled trials in patients with a history of ECG-documented recurrent episodes of this arrhythmia. Patients had a median duration of paroxysmal atrial fibrillation of 13 months and ECG-documented symptomatic atrial fibrillation within 12 months in one trial, and a median duration of paroxysmal atrial fibrillation of 39.6 months and ECG-documented symptomatic atrial fibrillation within 28 days in the second trial. In the first trial, the median time to first recurrence of atrial fibrillation from day 1 of randomization (primary efficacy variable) was 112, 291, or 41 days in patients receiving extended-release propafenone hydrochloride 225 or 325 mg twice daily or placebo, respectively, for up to 39 weeks. Additional analysis indicated that extended-release propafenone hydrochloride 425 mg twice daily also increased the interval to first recurrence of symptomatic atrial fibrillation. A dose-response relationship was observed with respect to time to first recurrence of ECG-documented symptomatic atrial fibrillation. The time to first recurrence of atrial fibrillation from day 5 of randomization (primary efficacy variable) also was increased in patients receiving extended-release propafenone hydrochloride (325 or 425 mg twice daily) for 91 days in the second trial.

IV† Propafenone Hydrochloride

Propafenone has been administered IV with some success in the acute treatment of supraventricular reentrant tachycardias. In a randomized, crossover, placebo-controlled study in patients with AV nodal reentrant tachycardia, intraatrial orthodromic reentrant tachycardia, or tachycardia associated with WPW syndrome, conversion to normal sinus rhythm occurred in 75% of patients receiving 1 or 2 rapid IV injections of propafenone hydrochloride (2 mg/kg) and in no patients receiving placebo. However, an IV dosage form is not commercially available in the US and other therapies (e.g., vagal maneuvers, IV adenosine, calcium-channel blocking agents, β-adrenergic blocking agents, synchronized cardioversion) are recommended for acute conversion of PSVT.

Conversion of Atrial Fibrillation or Flutter to Normal Sinus Rhythm

Propafenone has been used for pharmacologic cardioversion of atrial fibrillation or flutter. Both oral (immediate-release tablets) and IV propafenone (IV dosage form currently not commercially available in the US) have been effective for conversion of recent-onset atrial fibrillation, including atrial fibrillation occurring after open-heart surgery, to normal sinus rhythm, and some clinicians suggest that propafenone may be considered first-line therapy for this use. Conversion rates are inversely related to both duration of atrial fibrillation, number of previous drug treatment failures, and degree of atrial enlargement. Some patients with atrial flutter receiving propafenone (immediate-release tablets) may develop 1:1 AV conduction and a rapid ventricular response; therefore, concomitant therapy with drugs that prolong the functional AV refractory period (e.g., cardiac glycoside, β-adrenergic blocking agent) is recommended in such patients.

In acute, hemodynamically stable atrial fibrillation of less than 48 hours' duration, antiarrhythmic drug therapy may result in conversion to sinus rhythm in about 60-90% of patients; however, such therapy is effective in only 15-30% or less of patients with atrial fibrillation of longer duration. Conversion of atrial fibrillation or flutter to normal sinus rhythm may be associated with embolism, particularly when the arrhythmia has been present for more than 48 hours, unless the patient is adequately anticoagulated.

Propafenone hydrochloride also has been administered orally (150-600 mg as immediate-release tablets) or IV (2 mg/kg over 10 minutes) as a single dose for restoration of sinus rhythm in patients with infrequent episodes of paroxysmal atrial fibrillation when it is desirable to avoid potential adverse effects of long-term antiarrhythmic drug therapy. Limited data suggest that oral propafenone therapy (immediate-release tablets) initiated 48 hours prior to electrical cardioversion of patients with chronic atrial fibrillation may decrease the recurrence rate of this arrhythmia without an untoward effect on defibrillation threshold or electrical cardioversion rates.

Self-administration for Conversion of Paroxysmal Atrial Fibrillation

Limited evidence suggests that out-of-hospital self-administration (''pill-in-the-pocket'' approach) of a single oral loading dose of propafenone hydrochloride (immediate-release tablets) or flecainide is safe and effective for terminating recent-onset paroxysmal atrial fibrillation and can reduce hospitalizations and emergency room visits in carefully selected patients who have mild or no heart disease.In-hospital administration of propafenone hydrochloride (immediate-release tablets) or flecainide as a single oral dose for terminating acute atrial fibrillation has been shown to be effective with a low incidence of adverse effects in several randomized, controlled studies; however, the safety of such treatment without initial evaluation in a hospital setting or in patients with substantial structural heart disease has not been established. In addition, additional study and experience are required to assess the possible need for concomitant antithrombotic (e.g., warfarin) therapy and potential for adverse drug interactions (e.g., with warfarin or digoxin) in patients self-administering antiarrhythmic agents for recent-onset paroxysmal atrial fibrillation on an out-of-hospital basis.

In a prospective, uncontrolled study, 268 patients (18-75 years of age) with mild or no heart disease who had hemodynamically well-tolerated atrial fibrillation of recent (less than 48 hours) onset were treated in-hospital (i.e., in the emergency room or cardiology ward) with a single oral dose of propafenone hydrochloride (immediate-release tablets) or flecainide (according to clinician preference) to restore normal sinus rhythm. Patients weighing 70 kg or more received 600 mg of propafenone hydrochloride (immediate-release tablets) or 300 mg of flecainide acetate and those weighing less than 70 kg received 450 mg of propafenone hydrochloride (immediate-release tablets) or 200 mg of flecainide acetate. In-hospital treatment was considered effective if conversion of atrial fibrillation to sinus rhythm occurred within 6 hours of administration of the antiarrhythmic agent without clinically important adverse effects (i.e., symptomatic hypotension, symptomatic bradycardia after restoration of sinus rhythm, dyspnea, presyncope, syncope, conversion to atrial flutter or atrial tachycardia, or episodes of sustained or unsustained ventricular tachycardia). The time to conversion to sinus rhythm following in-hospital treatment with propafenone hydrochloride (immediate-release tablets) or flecainide in these patients averaged 135 minutes (median: 120 minutes). Patients in whom inpatient administration of these antiarrhythmics was effective and who were not excluded during subsequent examination were discharged and given propafenone hydrochloride (immediate-release tablets) or flecainide for treatment of subsequent episodes of palpitations (presumed recurrent atrial fibrillation) on an outpatient basis. These patients were instructed to take a single oral dose of the assigned antiarrhythmic drug 5 minutes after noting the onset of palpitations (self-assessed) and then to assume a resting state (e.g., a supine or sitting position) until resolution of the palpitations or for a period of at least four hours.

Analysis of data from 2 of the study sites indicated that 12% of patients presenting to the emergency room for recent-onset atrial fibrillation were candidates for out-of-hospital treatment with propafenone hydrochloride or flecainide. During a mean follow-up period of 15 months (range: 7-19 months), 79% of patients included in the out-of-hospital phase of the study experienced episodes of palpitations (presumed atrial fibrillation); patients self-administered propafenone hydrochloride (immediate-release tablets) (mean dose: 555 mg) or flecainide acetate (mean dose: 263 mg) within a mean of 36 minutes (median: 10 minutes) after the onset of symptoms in 92% of such episodes. Each antiarrhythmic agent was effective in interrupting 94% of episodes of palpitations (a primary end point); time to resolution of symptoms after drug administration averaged 113 minutes (median: 98 minutes). In patients who had multiple recurrences of palpitations during the follow-up period, self-administration of propafenone or flecainide hydrochloride terminated all such episodes in 84% of patients. Self-administration of oral propafenone (immediate-release tablets) or flecainide also was associated with reductions in emergency room visits and hospital admissions (secondary end points); calls for emergency room intervention during the study averaged 4.9 per month compared with 45.6 per month during the year prior to the study, while the number of hospitalizations averaged 1.6 per month during the study compared with 15 per month during the prior year.

Other Atrial Tachycardias

Propafenone is one of several drugs that may be used for the ongoing management of focal atrial tachycardia or junctional tachycardia in patients without structural or ischemic heart disease.

Supraventricular Tachyarrhythmias in Children

Although controlled studies generally are lacking, oral (immediate-release tablets) or IV propafenone (IV dosage form currently not commercially available in the US) has been used successfully for the management of supraventricular tachyarrhythmias (e.g., PSVT, postoperative or congenital junctional ectopic tachycardia, atrial ectopic tachycardia, chaotic atrial tachycardia, atrial fibrillation or flutter) in children. Oral propafenone (immediate-release tablets) reportedly has been effective in treating refractory atrial flutter in children; however, experience is limited and the drug cannot currently be recommended as first-line therapy for this use.

Ventricular Arrhythmias

Propafenone hydrochloride (immediate-release tablets) is used orally to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation). Based on the results of the Cardiac Arrhythmia Suppression Trial (CAST) (), FDA, the manufacturer, and many clinicians recommend that therapy with antiarrhythmic agents, including propafenone, be reserved for the suppression and prevention of documented ventricular tachyarrhythmias that, in the clinician's judgment, are considered life-threatening.

Because of propafenone's arrhythmogenic potential and the associated risk of death identified with other class Ic antiarrhythmic drugs (encainide, flecainide) in CAST, use of propafenone for less severe ventricular arrhythmias (e.g., asymptomatic ventricular premature complexes [VPCs]), is not recommended. The findings of CAST involved a select patient population with recent myocardial infarction, mild to moderate left ventricular dysfunction (e.g., mean baseline ejection fraction of 40%), and asymptomatic or mildly symptomatic ventricular arrhythmias (mean baseline VPCs of 127/hour as evidenced by ambulatory ECG [Holter] monitoring during at least 18 hours of analyzable time, with about 20% of patients exhibiting at least one run of nonsustained ventricular tachycardia during such monitoring); such patients also had demonstrated drug-induced suppressibility of VPCs during the initial phase of the open trial.

It currently is not known whether the findings of CAST can be extrapolated to other patient populations with non-life-threatening ventricular arrhythmias (e.g., patients with arrhythmias in the absence of ventricular dysfunction, myocardial ischemia, or recent myocardial infarction) or to other antiarrhythmic drugs (e.g., propafenone). CAST principally involved suppression and prevention of VPCs, with only about 10% of patients exhibiting more than a single run of tachycardia at baseline. Some clinicians also question whether the results of CAST even can be extrapolated to patients with recurrent nonsustained ventricular tachycardia and ventricular dysfunction, since these patients are known to be at high risk of sudden death if untreated, and since CAST did not include sufficient numbers of such patients to clearly determine the benefit-to-risk ratio. However, despite the limitations of the CAST findings, the manufacturer, FDA, and other experts consider the potential risks of antiarrhythmic therapy substantial and currently do not recommend use of propafenone in any patient with non-life-threatening ventricular arrhythmias in the absence of substantial evidence of safety and efficacy. They state that it is prudent to consider the risks of class Ic antiarrhythmic agents and current lack of evidence of improved survival unacceptable in patients without life-threatening ventricular arrhythmias, even in patients experiencing unpleasant but non-life-threatening manifestations. However, some clinicians, while recognizing the strong evidence of risk in the patient population studied in CAST and the substantial limitations of current evidence on safety and efficacy in other patient populations, question such an extreme limitation of usage.

Life-threatening Ventricular Arrhythmias

Monotherapy

The optimum role of propafenone (immediate-release tablets) in the suppression and prevention of ventricular arrhythmias remains to be clearly determined. In addition, it remains to be determined whether antiarrhythmic agents, including propafenone, have a beneficial effect on mortality or sudden death. Although propafenone (immediate-release tablets) has been used for chronic suppression and prevention of ventricular arrhythmias in carefully selected patients, further study is needed to evaluate the long-term efficacy and safety and the relative role of the drug in such patients. Therefore, it is recommended that propafenone (immediate-release tablets) generally be reserved for patients who have an insufficient therapeutic response to, or who do not tolerate, conventional orally administered antiarrhythmic agents (e.g., class IA agents). In addition, because of propafenone's negative inotropic potential, some clinicians would avoid use of the drug as a first-line agent in patients with life-threatening ventricular arrhythmias who also have congestive heart failure and/or substantial ventricular dysfunction (e.g., left ventricular ejection fraction less than 30%). While it currently is not known whether the findings of the CAST study apply to class Ic antiarrhythmic agents other than flecainide and encainide, some experts state that, in the absence of specific evidence of safety and efficacy, other class Ic drugs should be considered to share the risks of flecainide and encainide.

Available data suggest that the efficacy of propafenone (immediate-release tablets) for suppression and prevention of recurrent, life-threatening ventricular arrhythmias is comparable to that of other antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), with propafenone considered effective in approximately 22-50% of patients. The decision to use propafenone therapy (immediate-release tablets) should be based on an analysis of each patient's risk profile, including consideration of the type and prognosis of the specific arrhythmia, presence of underlying heart disease, degree of ventricular dysfunction, and any other serious comorbidities (e.g., hepatic or renal impairment, conduction abnormalities). Additional studies, including comparative studies with other antiarrhythmic agents, are needed to evaluate the use of propafenone (immediate-release tablets) in the management of life-threatening ventricular arrhythmias.

In a cohort study, oral propafenone hydrochloride (750-900 mg daily) (immediate-release tablets) was effective in rendering arrhythmias noninducible in 26% of patients with documented sustained ventricular arrhythmias and/or ventricular fibrillation as determined by programmed ventricular stimulation. An analysis of 27 studies in a combined total of 684 patients with malignant ventricular arrhythmias receiving propafenone yielded overall efficacy rates of 61 and 71% as determined by invasive and noninvasive testing methods, respectively. In the invasive method efficacy studies, propafenone therapy (immediate-release tablets) was considered effective in 25% of patients whose arrhythmias became noninducible, 32% of patients whose arrhythmias remained inducible but who developed improved hemodynamic tolerance and prolongation of ventricular tachycardia cycle length (100 msec or greater), and 4% of patients whose inducible sustained ventricular tachycardia was improved to inducible nonsustained ventricular tachycardia. In the noninvasive method efficacy studies, short-term propafenone therapy (1-5 days) (immediate-release tablets) was considered effective in 53-92% (mean: 71%) of patients as determined by the complete elimination of ventricular tachycardia, greater than 90% reduction in frequency of ventricular coupled beats, or greater than 50% reduction in the total number of VPCs compared with baseline arrhythmia frequency. Overall long-term efficacy, defined as the absence of symptomatic recurrence of the baseline arrhythmia, was determined by evaluation of the 90% of patients who had a positive initial response to therapy (measured by invasive or noninvasive efficacy criteria) and who continued propafenone therapy (immediate-release tablets) after hospital discharge. Long-term propafenone therapy (immediate-release tablets) (mean duration of follow-up: 14 months; range: 1-57 months) was considered effective in 67% of patients discharged on the drug and in 36% of the combined total of patients enrolled in the studies.

Combination Therapy

Limited information is available on the use of propafenone (immediate-release tablets) in conjunction with other antiarrhythmic agents for the management of severe, refractory ventricular arrhythmias. In a limited number of patients, propafenone (immediate-release tablets) has been combined with procainamide, quinidine, or mexiletine with good results in selected patients.(See Drug Interactions: Antiarrhythmic Agents.)

Concomitant use of 2 or more antiarrhythmic drugs requires extreme caution and generally is reserved for patients with life-threatening ventricular arrhythmias inadequately controlled by single-agent therapy with propafenone (immediate-release tablets) or another antiarrhythmic agent. Combination antiarrhythmic therapy for severe refractory ventricular arrhythmias generally is empiric and must be individualized.

Other Ventricular Arrhythmias

Controlled and uncontrolled clinical studies in patients with chronic stable ventricular arrhythmias have shown that propafenone (immediate-release tablets) is highly effective in suppressing and preventing nonsustained ventricular tachycardia and frequent VPCs, including complex VPCs. In short-term clinical studies, propafenone therapy (immediate-release tablets) produced approximately 66-98% suppression of VPCs in about 90% of patients; in approximately 75% of patients, ventricular tachycardia was abolished and ventricular couplets suppressed. However, despite such documented evidence of efficacy in suppressing and preventing these arrhythmias, there currently is no evidence of a beneficial effect on mortality, and in at least one patient population (those with mild-to-moderate ventricular dysfunction and recent myocardial infarction) with such arrhythmias treated with other class Ic antiarrhythmic drugs (i.e., flecainide, encainide), there was evidence of substantial risk (including mortality and nonfatal cardiac arrest) associated with therapy. (.) Therefore, use of propafenone in non-life-threatening ventricular arrhythmias currently is not recommended by the manufacturer, FDA, and other experts.

Although controlled studies generally are lacking, both oral (immediate-release tablets) and IV propafenone (IV dosage form currently not commercially available in the US) have been used successfully in the management of ventricular arrhythmias (e.g., VPCs, coupled VPCs, nonsustained ventricular tachycardia) in children.

Dosage and Administration

Administration

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, .

Dosage

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.)

Supraventricular Arrhythmias

For the prevention of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms and for disabling paroxysmal atrial fibrillation/flutter (PAF), the recommended initial adult dosage of propafenone hydrochloride (immediate-release tablets) is 150 mg every 8 hours. Dosage (immediate-release tablets) may be increased after 3-4 days to 225 mg 3 times daily if necessary. If the desired therapeutic response is not attained after an additional 3-4 days, dosage (immediate-release tablets) may be increased again to 300 mg 3 times daily. The safety and efficacy of propafenone hydrochloride dosages (immediate-release tablets) exceeding 900 mg daily have not been established.

Some clinicians suggest a maximum daily propafenone hydrochloride dosage (immediate-release tablets) of 600 mg/m in children.

When propafenone hydrochloride is given as extended-release capsules for the prevention of symptomatic atrial fibrillation, the recommended initial adult dosage is 225 mg every 12 hours. Dosage may be increased after at least 5 days to 325 mg every 12 hours if necessary. If the desired therapeutic response is not attained after an additional 5 days, dosage may be increased again to 425 mg every 12 hours. If a dose of propafenone hydrochloride as extended-release capsules is missed, the patient should take only the next scheduled dose (i.e., the next dose should not be doubled to make up for the missed dose).

During relative bioavailability studies, a higher daily dosage of propafenone hydrochloride as extended-release capsules was required to obtain similar exposure to propafenone compared with that following immediate-release tablets. Because of decreased saturation of hepatic metabolic pathways and increased first-pass hepatic metabolism associated with the extended-release formulation compared with the immediate-release formulation, the bioavailability of propafenone hydrochloride 325 mg given every 12 hours as extended-release capsules is similar to that following 150 mg of the drug given every 8 hours as immediate-release tablets. Therefore, when switching therapy in a patient who currently is receiving the immediate-release dosage form to the extended-release dosage form, the dosage conversion ratio is not a 1:1 substitution (e.g., a patient who currently is receiving 150 mg every 8 hours of propafenone hydrochloride immediate-release tablets may be switched to 325 mg of extended-release capsules every 12 hours).

Self-administration for Conversion of Paroxysmal Atrial Fibrillation

For self-administration on an outpatient basis for termination of atrial fibrillation of recent onset in carefully selected patients with mild or no heart disease, propafenone hydrochloride (immediate-release tablets) has been given as a single oral loading dose of 600 mg in patients weighing 70 kg or more and 450 mg in patients weighing less than 70 kg. Some clinicians suggest that propafenone hydrochloride (immediate-release tablets) be taken 5 minutes after noting the onset of palpitations and that patients remain in a supine or sitting position until resolution of palpitations or for a period of at least four hours following the dose. Patients should seek medical advice if palpitations do not resolve within 6-8 hours, if previously unexperienced symptoms (e.g., dyspnea, presyncope, syncope) occur, or if a marked increase in heart rate occurs after taking the antiarrhythmic drug. Patients should not take more than a single oral dose of propafenone hydrochloride (immediate-release tablets) during a 24-hour period.

Life-threatening Ventricular Arrhythmias

For the suppression and prevention of life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia), the recommended initial adult dosage of propafenone hydrochloride (immediate-release tablets) is 150 mg every 8 hours. Dosage (immediate-release tablets) may be increased after 3-4 days to 225 mg 3 times daily if necessary. If the desired therapeutic response is not attained after an additional 3-4 days, dosage (immediate-release tablets) may be increased again to 300 mg 3 times daily. The safety and efficacy of propafenone hydrochloride dosages (immediate-release tablets) exceeding 900 mg daily have not been established.

Some clinicians suggest a maximum daily propafenone hydrochloride dosage (immediate-release tablets) of 600 mg/m in children.

Dosage in Renal and Hepatic Impairment

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.

Cautions

The most common adverse effects of propafenone involve the GI, cardiovascular, and central nervous systems and generally are dose related. Discontinuance of propafenone therapy was required in about 20% of patients receiving the drug in clinical trials. Drug discontinuance in patients treated for ventricular arrhythmias was required most frequently (i.e., in greater than 1% of patients) for proarrhythmia (4.7%), nausea and/or vomiting (3.4%), dizziness (2.4%), dyspnea (1.6%), congestive heart failure (1.4%), and ventricular tachycardia (1.2%). In patients treated for supraventricular arrhythmias in clinical trials, discontinuance of therapy was required most frequently (i.e., in greater than 1% of patients) for nausea and/or vomiting (2.9%), wide-complex tachycardia (1.9%), dizziness (1.7%), fatigue (1.5%), unusual taste (1.3%), and weakness (1.3%).

Propafenone-induced adverse effects tend to decrease with time and may be attenuated by dosage reduction and/or adjustment of dosage interval. Patients with the poor-metabolizer phenotype(see Pharmacokinetics: Elimination) and geriatric patients may be at increased risk of adverse effects because of increased plasma propafenone concentrations. In a multicenter, randomized study in patients with paroxysmal atrial fibrillation or paroxysmal supraventricular tachycardia (PSVT) who had no evidence of ischemic heart disease, the safety and tolerability (i.e., the incidence of adverse effects, including proarrhythmic events) of propafenone hydrochloride (450-900 mg daily, mean daily dosage: 569 mg) was comparable to that of flecainide acetate (100-300 mg daily, mean daily dosage: 167 mg) during a 12-month period of follow-up. In another multicenter, randomized study in patients with paroxysmal atrial fibrillation (more than 90% who were New York Heart Association [NYHA] functional class I) receiving extended-release capsules of propafenone hydrochloride (225 mg, 325 mg, or 425 mg twice daily) for up to 39 weeks, the most common adverse events included dizziness, chest pain, palpitations, taste disturbance, dyspnea, nausea, constipation, anxiety, fatigue, upper respiratory tract infection, influenza, first-degree heart block, and vomiting. The incidence of adverse effects in patients treated with extended-release propafenone hydrochloride capsules in this study was similar regardless of age or gender.

Nervous System Effects

Adverse nervous system effects reported in US clinical trials in patients receiving propafenone for the treatment of ventricular arrhythmias included dizziness and/or lightheadedness in 13% of patients, fatigue/lethargy in 6%, and headache in 5%. Weakness, ataxia, insomnia, or anxiety was reported in 2%, and tremor or drowsiness in 1% of patients receiving propafenone for ventricular arrhythmias. Pain or loss of balance also has been reported with propafenone therapy in patients with ventricular arrhythmias.

In US clinical trials in patients with supraventricular arrhythmias, adverse nervous system effects reported with propafenone therapy included dizziness in 9% of patients, headache or fatigue in 6%, weakness in 3%, and tremor or ataxia in 2%. Abnormal dreams, abnormal speech, agitation, delusions, disorientation, coma, confusion, decreased libido, depression, memory loss, paranoia, paresthesia/numbness, psychosis/mania, seizures, unusual smell sensation, or vertigo has been reported in less than 1% of patients receiving propafenone in clinical trials or during postmarketing experience.

Transient global amnesia, which resolved within hours after drug discontinuance, has been reported in at least one patient receiving propafenone. Peripheral neuropathy, which was characterized by episodic jabbing and crushing pain in the hands and feet and hyperesthesia of the extremities and resolved following discontinuance of the drug, has been reported rarely with propafenone therapy.

GI Effects

The most common adverse GI effect of propafenone therapy is nausea and/or vomiting, which was reported in 11% of patients receiving the drug for ventricular arrhythmias in US clinical trials. Propafenone is secreted by the salivary glands, and unusual (e.g., metallic or salty) taste (dysgeusia) was reported in 9% of patients treated for ventricular arrhythmias. Constipation occurred in 7%; dyspepsia and/or diarrhea in 3%; dry mouth, anorexia, and/or abdominal pain/cramps in 2%; and flatulence in 1% of patients receiving the drug for ventricular arrhythmias. Esophagitis and gastroenteritis also have been reported in clinical trials or during postmarketing experience in patients treated with propafenone for ventricular arrhythmias.

Unusual taste or nausea and/or vomiting was reported in 14 or 11%, respectively, of patients receiving propafenone for supraventricular arrhythmias in US clinical trials. Constipation occurred in 8% and anorexia or diarrhea in 2% of patients with supraventricular arrhythmias.

Arrhythmogenic Effects

Like other antiarrhythmic agents, propafenone can worsen existing arrhythmias or cause new arrhythmias; the arrhythmogenic potential is the most serious risk associated with the drug. Arrhythmogenic effects associated with propafenone range from an increased frequency of ventricular premature complexes (VPCs) to the development of new and/or more severe and potentially fatal ventricular tachyarrhythmias. Because of difficulties in distinguishing between spontaneous and drug-related variations in an underlying arrhythmia disorder in patients with complex arrhythmias, reported occurrence rates must be considered approximations.

Arrhythmogenic events associated with propafenone therapy in clinical trials reportedly have occurred with an overall frequency of about 5%. In patients with malignant ventricular arrhythmias monitored by invasive and noninvasive methods, the incidence of arrhythmogenic effects during propafenone therapy was 8-19%. About 82-85% of the arrhythmogenic effects associated with the drug have been new or worsened ventricular tachyarrhythmias (e.g., new occurrence of sustained or nonsustained ventricular tachycardia, including spontaneous wide-QRS complex tachycardia, torsades de pointes, progression of ventricular tachycardia to ventricular fibrillation), with the remainder consisting of increased frequency of VPCs. VPCs were reported in 2% of patients receiving propafenone for treatment of ventricular arrhythmias in US clinical trials.

An increased incidence of arrhythmogenic events also has been reported during propafenone therapy in patients with supraventricular tachyarrhythmias. Wide-QRS complex tachycardia was reported in 2% of patients receiving propafenone for supraventricular arrhythmias in overall US clinical trials. In a long-term multicenter trial in patients with symptomatic supraventricular tachycardia, ventricular tachycardia or ventricular fibrillation developed in 9 of 474 patients (1.9 %) receiving propafenone therapy. Ventricular tachycardia or ventricular fibrillation developed within the first 14 days of therapy in 6 of 9 patients; ventricular tachycardia appeared to be of atrial origin in 4 of these 9 patients. Approximately 2.3% of patients in this trial may have experienced an arrhythmogenic event manifested as a recurrence of supraventricular tachycardia. Increased VPCs, ventricular tachycardia, ventricular fibrillation, and death have been reported in patients with atrial fibrillation/flutter receiving propafenone therapy. The overall annual mortality rate based on data from 8 clinical studies was 2.5 or 4% per year in patients receiving propafenone (extended-release or immediate-release formulation) or placebo, respectively.

Although the occurrence of propafenone-induced arrhythmias generally is unpredictable, the risk of arrhythmogenic effects generally appears to be related to dosage and underlying cardiac disease, including severity of the preexisting ventricular arrhythmia and myocardial dysfunction (e.g., low left ventricular ejection fraction, congestive heart failure (New York Heart Association [NYHA] functional class III or IV), myocardial ischemia). Of patients in clinical trials who had worsening of ventricular tachycardia while receiving propafenone, 92% had a history of ventricular tachycardia and/or ventricular fibrillation, 71% had coronary artery disease, and 68% had a history of myocardial infarction. During long-term (mean: 14.4 months) therapy in patients with symptomatic atrial fibrillation, atrial flutter, or supraventricular tachycardia, propafenone therapy was associated with a 20% incidence of adverse cardiovascular effects (e.g., arrhythmogenicity, congestive heart failure, conduction disturbance) in patients with structural heart disease compared with a 13% incidence in those without structural heart disease. While the overall incidence of adverse reactions was similar for patients with or without structural heart disease, the incidence was directly related to dosage and age. The incidence of proarrhythmia in patients receiving propafenone for less serious or benign arrhythmias, including an increased frequency of VPCs, was 1.6%.

Although most proarrhythmic events occurred during the first week of therapy in clinical trials with propafenone, such events also occurred later in therapy, and results of the CAST study suggest that an increased risk of proarrhythmic events is present throughout treatment with antiarrhythmic agents. When propafenone is administered according to currently recommended dosage regimens and precautions, the risk of arrhythmogenic effects appears to be comparable to or less than that associated with other antiarrhythmic agents (e.g., encainide, flecainide).

Effects on Cardiac Conduction

Clinically important conduction disturbances may occur during propafenone therapy in patients without preexisting conduction abnormalities; however, the risk of adverse cardiac effects probably increases progressively as plasma propafenone concentrations increase. There is a correlation between propafenone dosage, plasma concentration, and the degree of lengthening of PR and QRS intervals.

First-, second-, or third-degree AV block occurred in about 2.5, 0.6, or 0.2%, respectively, of patients with ventricular arrhythmias receiving propafenone (immediate-release tablets) in clinical trials. First-degree AV block occurred in approximately 2-3% of patients with symptomatic paroxysmal atrial fibrillation receiving the extended-release formulation of propafenone hydrochloride in a clinical trial. There were no cases of sinus rhythm with Mobitz type I (Wenckenbach) second-degree AV block, sinus rhythm with Mobitz Type II second-degree AV block, third-degree AV block, or increased sinus bradycardia in a clinical trial of patients with symptomatic paroxysmal atrial fibrillation receiving the extended-release formulation of the drug. Dosage reduction or discontinuance of the drug may be necessary in patients who develop second- or third-degree AV block.(See Cautions: Precautions and Contraindications.) Bundle branch block, intraventricular conduction delay/increased QRS duration, or bradycardia occurred in about 1-2% of patients with ventricular arrhythmias in clinical trials. Bradycardia was reported in 2% of patients receiving propafenone therapy for supraventricular arrhythmias in clinical trials. A paradoxical increase in ventricular rate also has occurred with propafenone therapy in patients with atrial flutter or fibrillation because of a reduction in the degree of AV nodal block or enhanced conduction through an accessory bypass tract (e.g., in patients with Wolff-Parkinson-White [WPW] syndrome).(See Cautions: Precautions and Contraindications.)

Cardiovascular Effects

The manufacturer states that clinically important decreases in left ventricular ejection fraction with oral propafenone therapy did not occur in clinical trials in patients with depressed baseline ejection fraction (mean ejection fraction: 33.5%). However, because of propafenone's dose-related β-adrenergic blocking and negative inotropic effects, the drug may cause or worsen congestive heart failure, particularly in patients with preexisting heart failure or decreased left ventricular ejection fraction (less than 30%). New or worsened congestive heart failure occurred in about 1-4% of patients treated for ventricular arrhythmias in clinical trials. In patients in whom these adverse effects were considered probably or definitely related to propafenone therapy (about 1%), 80% had preexisting heart failure and 85% had coronary artery disease. Patients with no prior history of congestive heart failure receiving propafenone rarely (less than 0.2%) developed congestive heart failure. Congestive heart failure or palpitations occurred in about 2% of patients receiving propafenone therapy for supraventricular arrhythmias (PAF or PSVT) in clinical trials.

Chest pain or angina, palpitations, or syncope/near syncope occurred in about 2-5% of patients receiving propafenone in clinical trials for treatment of ventricular arrhythmias. Atrial fibrillation or edema has occurred in about 1% of patients receiving propafenone therapy for ventricular arrhythmias. Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause, sinus arrest, or supraventricular tachycardia has been reported in less than 1% of patients receiving propafenone.

Hepatic Effects

Propafenone is extensively metabolized in the liver and should be administered with caution to patients with impaired hepatic function.(See Cautions: Precautions and Contraindications.) There have been postmarketing reports of hepatic dysfunction, including hepatocellular, cholestatic, and mixed hepatotoxicity in patients receiving the drug. In at least one case, hepatotoxicity recurred upon rechallenge with propafenone. Cholestasis, hepatitis, and increases in serum aminotransferase (AST [SGOT], ALT [SGPT]) and alkaline phosphatase concentrations have been reported in patients receiving the drug. In toxicology studies, fatty degenerative liver changes were observed in rats following long-term (6 months) administration of oral propafenone hydrochloride at a dosage of 270 mg/kg daily (about 3 times the maximum recommended human daily dosage based on body surface area) but not at 90 mg/kg daily (equivalent to the maximum recommended human daily dosage based on body surface area).

Dermatologic and Sensitivity Reactions

Rash has been reported in 3% of patients with ventricular arrhythmias receiving propafenone in clinical trials, and diaphoresis has been reported in 1% of such patients. Pruritus also have been reported in patients receiving the drug. Possible propafenone-associated drug fever has been reported in at least one patient receiving oral propafenone therapy for sustained ventricular tachycardia. Fever and an erythematous, papular rash developed 10 days after initiation of propafenone therapy and resolved following drug discontinuance; fever recurred upon rechallenge with the drug but resolved completely upon termination of therapy.

Alopecia also has been reported with propafenone therapy.

Hematologic Effects

Granulocytopenia, leukopenia, lymphopenia, leukocytosis, thrombocytosis, thrombocytopenia, purpura, anemia, bruising, and increased bleeding time have been reported in less than 1% of patients receiving propafenone. Agranulocytosis (fever, chills, weakness, and neutropenia) also has been reported with propafenone therapy, generally within 8 weeks after initiation of therapy. The leukocyte count generally returned to normal within 14 days after discontinuance of therapy. The possibility of agranulocytosis should be considered in any patient receiving propafenone who develops unexplained fever and/or decreases in leukocyte count, particularly during the 3 months following initiation of therapy.(See Cautions: Precautions and Contraindications.)

Musculoskeletal Effects

Joint pain occurred in about 1% of patients receiving propafenone for ventricular arrhythmias in clinical trials. Arthritis, arthralgia, gout, muscle pain, muscle weakness, or muscle cramps were reported in less than 1% of such patients. Lupus erythematosus has been reported in less than 1% of patients receiving propafenone therapy in clinical trials or during postmarketing experience; in at least one patient, propafenone-induced lupus erythematosus recurred following rechallenge with the drug but resolved completely upon discontinuance of therapy. Positive antinuclear antibody (ANA) titers have been reported with propafenone therapy; these abnormalities generally were not associated with clinical manifestations and resolved upon discontinuance of the drug or even with continued therapy. In a randomized, controlled trial, positive ANA titers were found in about 24% of patients who had negative ANA titers before initiation of propafenone therapy.

Exacerbation of myasthenia gravis, which was evident within a few hours after initiation of propafenone hydrochloride (450 mg daily) in a patient with ocular myasthenia gravis and resolved upon drug discontinuance, has been reported with propafenone therapy.

Other Adverse Effects

Blurred vision occurred in 4% of patients receiving propafenone therapy for ventricular arrhythmias in clinical trials; abnormal vision also has been reported. Asthma, increased serum glucose concentration, diabetes mellitus, hypochloremia, hyponatremia, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, nephrotic syndrome, renal failure, nasal congestion, ocular irritation, tinnitus,pneumonia, respiratory failure, pain, increased urinary frequency or urgency, impotence, or prostatitis occurred in less than 1% of patients receiving propafenone for treatment of ventricular arrhythmias in clinical trials.

Blurred vision was reported in 3% and dyspnea in 2% of patients receiving propafenone therapy for supraventricular arrhythmias in clinical trials.

Both inflammatory and noninflammatory lesions in the renal tubules, with accompanying interstitial nephritis, have been observed in rats following administration of oral propafenone hydrochloride for 6 months at dosages of 180 and 360 mg/kg daily (2 or 4 times the maximum recommended human daily dosage based on body surface area) but not at 90 mg/kg daily (equivalent to the maximum recommended human daily dosage based on body surface area). However, these lesions appeared reversible as they were not found 6 weeks after discontinuance of the drug.

Precautions and Contraindications

Findings from the postmarketing Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind study in patients with asymptomatic, non-life-threatening ventricular arrhythmias who had had a myocardial infarction more than 6 days but less than 2 years previously, indicate that the rate of total mortality and nonfatal cardiac arrest in patients treated with encainide or flecainide (7.7%) was increased compared with that seen in patients who received placebo (3%). The applicability of these results to other populations (e.g., those without recent myocardial infarction) or to other antiarrhythmic drugs is uncertain; however, the manufacturer of propafenone states that use of any class Ic antiarrhythmic drug in patients with structural heart disease may be associated with substantial risk. In addition, the manufacturer, FDA, and some experts currently recommend that use of propafenone or other class I agents in patients with ventricular arrhythmias be limited to those with life-threatening arrhythmias.(See Uses.) Use in less severe ventricular arrhythmias, including even those with unpleasant manifestations, currently is not recommended, and treatment of asymptomatic VPCs should be avoided. In addition, current evidence indicates that initiation of antiarrhythmic therapy in patients with atrial fibrillation is associated with a notable risk for adverse cardiac events, particularly in geriatric patients or those with structural heart disease.

Since propafenone, like other antiarrhythmic agents, can worsen existing arrhythmias or cause new arrhythmias in some patients, clinical and ECG evaluations are essential prior to and during propafenone therapy to monitor for the appearance of arrhythmias and to determine the need for continued therapy. Use of propafenone in patients with atrial flutter has resulted in an increase in AV conduction (1:1 ratio) and the development of very rapid ventricular rates.(See Cautions: Effects on Cardiac Conduction.) Risk of this tachycardia may be reduced by concomitant administration of a cardiac glycoside or a β-adrenergic blocking agent. Patients with permanent artificial pacemakers should be monitored and, if necessary, have their pacemakers reprogrammed since propafenone may affect endocardial pacing and sensing thresholds (e.g., increased stimulation threshold) of these devices.

The patient's medication history should be carefully screened prior to and during propafenone therapy, including obtaining information on all OTC, prescription, and herbal/natural preparations with emphasis on those that may affect the pharmacodynamics or pharmacokinetics of propafenone.(See Drug Interactions.) Patients should be advised to inform their health-care providers of any change in the use of medications (OTC, prescription) and supplements. Patients should be advised to inform their health-care providers that they are receiving propafenone when hospitalized or prescribed a new medication for any condition. Patients should be advised to immediately inform their health care providers if they experience symptoms associated with electrolyte imbalance (e.g., excessive or prolonged diarrhea, sweating, vomiting, loss of appetite or thirst).

Because of propafenone's mild to moderate negative inotropic and β-adrenergic blocking effects, as well as an increased risk of arrhythmogenic effects, the immediate-release formulation of the drug should be used with caution in patients with a history of congestive heart failure or myocardial dysfunction; the manufacturer of the extended-release formulation of propafenone states that the drug should not be used in patients with congestive heart failure. Congestive heart failure should be fully compensated before propafenone therapy with the immediate-release formulation is initiated. If cardiovascular manifestations increase, therapy should be discontinued (unless congestive heart failure is caused by the cardiac arrhythmia) and adequate cardiac compensation reestablished before resuming propafenone therapy, if indicated, at a lower dosage of the immediate-release formulation.

Propafenone slows AV conduction and may cause AV block. A correlation exists between dosage and plasma concentrations of propafenone hydrochloride and the degree of lengthening of PR and QRS intervals. Some clinicians have suggested limiting QRS interval increases to 25% or less in patients receiving propafenone. If second- or third-degree AV block occurs during propafenone therapy, the dosage should be reduced or the drug discontinued.

Because reversible granulocytopenia and agranulocytosis have occurred rarely with propafenone therapy, patients receiving the drug should be advised to promptly report fever, sore throat, chills, or any other manifestations of infection.

Positive antinuclear antibody (ANA) titers have been reported in patients receiving propafenone therapy.(See Cautions: Musculoskeletal Effects.) Patients who develop an abnormal ANA test following initiation of propafenone therapy should be monitored carefully and, if titers remain elevated or increase further, drug discontinuance should be considered.

Propafenone is extensively metabolized in the liver, and dosage should be reduced substantially in patients with impaired hepatic function. The drug also should be used with caution in patients with renal dysfunction since a considerable portion of the dose is excreted in urine as active metabolites.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Reversible disorders of spermatogenesis have been demonstrated in animals following high-dose IV administration of propafenone. Transient, reversible decreases (within the normal range) in sperm count have been reported in healthy men receiving short-term propafenone therapy but subsequent evaluations in patients receiving long-term therapy have suggested no effect of the drug on sperm count.(See Cautions: Pregnancy, Fertility, and Lactation.)

Pending further accumulation of data, patients should be discouraged from ingesting grapefruit juice concomitantly with propafenone because of the potential for increased propafenone bioavailability and possible adverse effects associated with such concomitant administration.(See Dosage and Administration: Administration.)

Propafenone, like other agents with nonselective β-adrenergic blocking activity, generally should not be used in patients with asthma/bronchospastic disease or nonallergic bronchospastic disease (e.g., chronic bronchitis, emphysema) since the drugs may inhibit bronchodilation produced by endogenous catecholamines.

Propafenone has been reported to exacerbate myasthenia gravis, and it has been suggested that use of the drug be avoided in patients with this condition.

Propafenone (immediate-release formulation) is contraindicated in patients with uncontrolled congestive heart failure; the extended-release formulation of the drug is contraindicated in patients with congestive heart failure. Propafenone is contraindicated in patients with cardiogenic shock, atrioventricular or intraventricular disorders of impulse generation and/or conduction (e.g., sick sinus node syndrome, atrioventricular block) unless an artificial pacemaker is present, bradycardia, severe hypotension, marked electrolyte imbalance, or known hypersensitivity to the drug.

The manufacturer of ritonavir states that concomitant use of ritonavir with propafenone is contraindicated because such use is likely to produce substantially increased plasma concentrations of propafenone and associated serious toxicity.(See Drug Interactions: Ritonavir.)

Pediatric Precautions

Safety and efficacy of propafenone in patients younger than 18 years of age have not been established. However, the drug has been used successfully and without unusual adverse effects in a limited number of infants and children for the management of various refractory supraventricular (e.g., PSVT, junctional ectopic tachycardia, atrial fibrillation or flutter) and ventricular (e.g., VPCs, ventricular tachycardia) arrhythmias.(See Uses.)

Geriatric Precautions

Data from clinical studies with propafenone (immediate-release tablets) in patients 65 years of age or older is insufficient to determine whether geriatric patients respond differently than younger adults. Dosage of propafenone (immediate-release tablets) should be selected with caution and generally initiated at the lower end of the recommended range since geriatric patients are more likely to have impaired renal, hepatic, and/or cardiac function and concomitant disease and drug therapy. Data from clinical studies indicate that safety and efficacy of propafenone as extended-release capsules are similar in geriatric patients and younger adults. Nevertheless, the manufacturer states that the possibility that some older patients may exhibit increased sensitivity to the drug as extended-release capsules cannot be ruled out.

Mutagenicity and Carcinogenicity

No evidence of propafenone-induced mutagenicity was seen with in vitro microbial (Ames test), dominant lethal tests in mice, mammalian mutagenicity assays using Chinese hamster spermatogonoia and bone marrow cells, rat bone marrow, and Chinese hamster micronucleus test.

No evidence of carcinogenesis was seen in mice and rats receiving oral propafenone hydrochloride dosages up to 360 mg/kg (about 2 times the maximum recommended human daily dosage based on body surface area) and 270 mg/kg daily (about 3 times the maximum recommended human daily dosage based on body surface area), respectively.

Pregnancy, Fertility, and Lactation

Pregnancy

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.

Fertility

The effect of propafenone on fertility in humans is not known. Temporary decreases in sperm count have been observed in healthy men receiving short-term, oral propafenone therapy; this effect was reversible following discontinuance of the drug and did not persist during long-term propafenone therapy. Administration of large IV doses of propafenone in monkeys, dogs, and rabbits has caused transient, reversible decreases in spermatogenesis; this effect was observed only at lethal or sublethal dosages and was not seen in rats receiving oral or IV propafenone. Reproduction studies in male rabbits using an oral propafenone hydrochloride dosage of 120 mg/kg daily (about 2.4 times the maximum recommended human daily dosage based on body surface area) or an IV dosage of 3.5 mg/kg daily (a dosage associated with impairment of spermatogenesis) have not revealed evidence of impaired fertility. In addition, reproduction studies in male and female rats using oral propafenone hydrochloride dosages up to 270 mg/kg daily (about 3 times the maximum recommended human daily dosage based on body surface area) have not revealed evidence of impaired fertility.

Lactation

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.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolism of propafenone is mediated by the cytochrome P-450 (CYP) isoenzyme system, including CYP2D6 (major metabolic pathway), CYP1A2 and CYP3A4; patients should be monitored and dosage of propafenone hydrochloride should be reduced accordingly when the drug is used concurrently with inhibitors of CYP2D6 (e.g., desipramine, paroxetine, quinidine, ritonavir, sertraline), CYP1A2 (e.g., amiodarone), or CYP3A4 (e.g., erythromycin, ketoconazole, ritonavir, saquinavir), because plasma propafenone concentrations may increase. In addition, propafenone inhibits CYP2D6 and caution is advised if the drug is used concurrently with substrates of CYP2D6 (e.g., desipramine, haloperidol, imipramine, metoprolol, propranolol, venlafaxine) since increased plasma concentrations of these drugs may occur, and consideration should be given to reduction of dosage for drugs that are substrates of CYP2D6 when such drugs are used concurrently with propafenone.

Drugs Metabolized by P-glycoprotein Transporter

The effect, if any, of propafenone on the p-glycoprotein transport system has not been systematically evaluated.

Digoxin

Concomitant administration of propafenone and oral or IV digoxin has resulted in increased serum or plasma digoxin concentrations, associated in some cases with enhanced effects of digoxin (e.g., decreased heart rate, shortened QT interval) and at least one case of digoxin toxicity.In some studies, increases in serum digoxin concentrations with propafenone hydrochloride dosages of 450 or 900 mg daily averaged about 35 or 85%, respectively; such increases in digoxin concentrations have been maintained over a period of up to 16 months of concomitant therapy with the drugs. Changes in digoxin concentrations in patients receiving concomitant propafenone therapy have exhibited wide interindividual and intraindividual variation, with a relationship to propafenone and/or digoxin dosage or plasma propafenone concentration being reported in some studies.

Although the exact mechanism of this interaction has not been established, some evidence suggests that propafenone may reduce the renal clearance of digoxin by inhibiting renal tubular transport of the drug. Other data suggest no alterations in digoxin renal clearance, but decreases in total body and/or nonrenal clearance or volume of distribution of digoxin have been reported.

Digoxin dosage generally should be reduced in patients in whom propafenone therapy is initiated, especially in those who have relatively high digoxin dosages or serum concentrations. Careful monitoring of serum digoxin concentrations and appropriate adjustments in digoxin dosage should be performed in patients receiving concomitant propafenone and digoxin therapy.

β-Adrenergic Blocking Agents

In healthy individuals, concomitant administration of propafenone and propranolol or metoprolol has resulted in substantial increases in plasma concentrations and terminal elimination half-lives of the β-adrenergic blocking agents; plasma propafenone concentrations were unchanged. These increases in plasma concentration and half-life apparently are the result of propafenone's inhibition of the hydroxylation pathway responsible for metabolism of the β-adrenergic blocking agents. Increases in plasma metoprolol concentrations may result in loss of the drug's relative cardioselectivity and an increase in adverse effects. Although pharmacokinetics of propafenone were not affected and concomitant use of β-adrenergic blocking agents was not associated with an increased incidence of adverse effects in clinical trials of propafenone, an increase in the manifestations of acute metoprolol-induced brain syndrome (e.g., delirium, fatigue, lassitude) has been reported in a patient receiving concomitant metoprolol and propafenone. Patients receiving propafenone and β-adrenergic blocking agents concomitantly may require a reduction in the dosage of the β-adrenergic blocking agent.

Antiarrhythmic Agents

There is limited information on the use of propafenone in conjunction with other antiarrhythmic agents for the management of severe, refractory ventricular or supraventricular arrhythmias.(See Combination Therapy under Ventricular Arrhythmias: Life-threatening Ventricular Arrhythmias, in Uses.) Combination antiarrhythmic therapy for severe refractory arrhythmias generally is empiric and must be individualized. Since the cardiac effects of multiple antiarrhythmic agents may be additive, synergistic, or antagonistic and adverse effects may be additive, combination therapy must be used only when the increased risk is justified and with careful monitoring.

The manufacturer of propafenone states that the extended-release formulation of the drug should not be used concomitantly with class Ia or III antiarrhythmic agents (including quinidine or amiodarone) and that class Ia or III antiarrhythmic agents should be withheld for at least 5 half-lives prior to administration of extended-release propafenone. Experience is limited with the concomitant use of propafenone and class Ib or other class Ic antiarrhythmic agents.

Quinidine

Quinidine, even at small doses, completely inhibits the CYP2D6 hydroxylation pathway responsible for propafenone's metabolism; therefore, patients receiving concomitant quinidine and propafenone effectively are rendered poor metabolizers. Propafenone clearance decreased by 60%, plasma steady-state propafenone concentrations increased twofold, and 5-hydroxypropafenone (5-OHP) concentrations were reduced by approximately 50%, in patients with the extensive-metabolizer phenotype who received concomitant quinidine (50 mg 3 times daily) and propafenone as the immediate-release formulation (150 mg every 8 hours); steady-state plasma propafenone concentrations increased threefold in such patients who received concomitant quinidine at a dosage of 100 mg every 8 hours. Poor metabolizers receiving the 2 drugs concomitantly did not exhibit changes in plasma concentrations of propafenone or 5-OHP.

In a limited number of patients with ventricular arrhythmias refractory to procainamide or quinidine monotherapy, combined therapy with propafenone and quinidine or procainamide resulted in a substantial reduction in the frequency of ventricular premature complexes (VPCs) compared with drug-free baseline VPC frequencies. VPC frequency was reduced from a baseline geometric mean of 406/hour before treatment to 33/hour in patients receiving concomitant propafenone/quinidine therapy and from a baseline geometric mean of 211/hour to 27/hour in patients receiving concomitant propafenone/procainamide.

The manufacturer states that the concomitant use of propafenone and quinidine is not recommended; however, some clinicians have suggested that such combined therapy may be useful in selected patients.

Mexiletine

Combined therapy with propafenone and mexiletine was effective in preventing the induction of ventricular tachycardia by programmed electrical stimulation in 3 of 16 patients with refractory sustained ventricular tachycardia; however, ventricular tachycardia with hemodynamic deterioration requiring defibrillation occurred in 5 patients (31%) receiving propafenone alone and 2 patients (13%) receiving propafenone and mexiletine. Additional data are needed to determine whether the observed benefit from combined therapy is attributable to potential synergism of the electrophysiologic effects of the 2 drugs or to alterations in hepatic metabolism of the drug(s), resulting in increased plasma concentrations of one or both drugs and decreased plasma concentrations of drug metabolites.

Lidocaine

In patients with ventricular arrhythmias who received propafenone and lidocaine concomitantly by IV infusion, the negative inotropic effect of propafenone was increased and the effect of propafenone in prolonging atrial and ventricular refractoriness was attenuated. Although propafenone and lidocaine have been used concomitantly without notable effect on the pharmacokinetics of either drug, an increased risk of lidocaine-related adverse effects involving the central nervous system has been reported in patients receiving such concomitant therapy.

Other Antiarrhythmic Agents

Sotalol or amiodarone reportedly may enhance the antiarrhythmic effect of propafenone. However, prolongation of the QT interval and atypical ventricular tachycardia (torsades de pointes) have been reported rarely in patients receiving concomitant propafenone and amiodarone therapy. Concomitant use of propafenone and amiodarone may affect cardiac conduction and repolarization. The manufacturer of propafenone states that concomitant use of propafenone and amiodarone is not recommended.

Other Drugs That Prolong QT Interval

Although specific pharmacokinetic drug interaction studies are not available, the manufacturer of propafenone states that the drug should not be used concomitantly with other drugs that prolong the QT interval, including certain phenothiazines, cisapride, bepridil (not currently commercially available in the US), tricyclic antidepressant agents, or macrolides.

Ritonavir

Although specific pharmacokinetic drug interaction studies are not available, the manufacturer of ritonavir states that ritonavir should not be used concomitantly with certain cardiovascular agents, including propafenone, because of the potential for substantially increased plasma concentrations of these cardiovascular drugs and potentially serious and/or life-threatening adverse effects. This pharmacokinetic interaction may occur because ritonavir has high affinity for several cytochrome P-450 (CYP) isoenzymes (e.g., CYP3A, CYP2D6, CYP1A2) involved in propafenone metabolism.

Local Anesthetic Agents

The manufacturer states that concomitant use of propafenone and local anesthetic agents (i.e., during pacemaker implantation, surgery, or dental procedures) may increase the risk of adverse nervous system effects.

Warfarin

Concomitant administration of propafenone and warfarin results in increased plasma warfarin concentrations and corresponding increases in prothrombin times (PTs), possibly because of competition for a common metabolic pathway. Steady-state plasma warfarin concentrations and PTs increased an average of 39 and 25%, respectively, in a limited number of healthy individuals receiving concomitant propafenone and warfarin therapy. PTs or international normalized ratios (INRs) should be monitored closely and, if required, adjustments in warfarin dosage should be made in patients receiving concurrent propafenone and warfarin therapy.

Cimetidine

In a limited number of healthy individuals receiving concomitant propafenone and cimetidine therapy, steady-state plasma propafenone concentrations averaged 20% higher than those with propafenone therapy alone.

Theophylline

Increased serum theophylline concentrations have been reported in patients receiving theophylline concomitantly with propafenone and some clinicians suggest that serum theophylline concentrations and ECGs be monitored closely in patients receiving such combined therapy.

Rifampin

Rifampin may increase the metabolism of concomitant propafenone; reductions in plasma propafenone concentrations and decreased antiarrhythmic efficacy have been reported in patients receiving these drugs concomitantly. Plasma propafenone concentrations decreased 67%, 5-OHP concentrations were reduced by 65%, and N-depropylpropafenone (NDPP) concentrations were increased by 35% in patients with the extensive-metabolizer phenotype who received concomitant propafenone and rifampin. Plasma propafenone concentrations decreased 50%, NDPP exposure and peak plasma concentration increased by 74 and 20%, respectively, and urinary excretion of propafenone, 5-OHP, and NDPP was reduced in patients with the poor-metabolizer phenotype who received such concomitant therapy. Propafenone exposure and peak plasma concentration both decreased by 84% and 5-OHP exposure and peak plasma concentration decreased by 69 and 57% in elderly patients with the poor-metabolizer phenotype who received concomitant propafenone and rifampin.

Phenobarbital

Concomitant therapy with phenobarbital and propafenone reportedly may increase the clearance of propafenone, resulting in decreased plasma propafenone concentrations.

Fluoxetine

Concomitant therapy with fluoxetine and propafenone in patients with the extensive-metabolizer phenotype increased the peak plasma concentrations and area under the plasma concentration-time curve (AUC) of the S-enantiomer by 39 and 59%, respectively, and the peak plasma concentrations and AUC of the R-enantiomer by 71 and 50%, respectively.

Orlistat

Orlistat may limit absorption of propafenone during concomitant therapy with the drugs. There have been postmarketing reports of severe adverse effects, including seizures, atrioventricular block, and acute circulatory failure that occurred following abrupt discontinuance of orlistat in patients receiving chronic propafenone therapy.

Other Drugs

Increases in blood cyclosporine or serum desipramine concentrations have been reported during concomitant administration of propafenone.

The manufacturer states that clinical experience in patients receiving propafenone concomitantly with calcium-channel blocking agents or diuretics has not revealed evidence of clinically important adverse interactions.

Pharmacokinetics

Absorption

Propafenone hydrochloride (immediate-release tablets) is rapidly and almost completely absorbed from the GI tract following oral administration. The absolute bioavailability averages approximately 5-50% for propafenone immediate-release tablets and has not been determined for extended-release capsules. The absolute bioavailability of propafenone depends principally on a patient's genetically determined ability to metabolize the drug.(See Pharmacokinetics: Elimination.) In most patients (those with the extensive-metabolizer phenotype), propafenone is metabolized extensively and undergoes first-pass metabolism in the liver, producing the 2 major, active metabolites 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP). In these patients, the absolute bioavailability of propafenone is dependent on dosage and dosage form; 150- and 300-mg immediate-release tablets of propafenone hydrochloride had absolute bioavailabilities of 3.4 and 10.6%, respectively, while a more rapidly absorbed solution of propafenone hydrochloride 3.5 mg/mL had an absolute bioavailability of 21.4%. In patients with the extensive-metabolizer phenotype, the drug exhibits nonlinear pharmacokinetics: a threefold increase in propafenone hydrochloride dosage (300 versus 900 mg as immediate-release tablets) results in a 10-fold increase in steady-state plasma concentration, while in a small fraction of patients (those with the poor-metabolizer phenotype or those receiving concurrent quinidine) (see Antiarrhythmic Agents: Quinidine, in Drug Interactions) propafenone exhibits linear pharmacokinetics, and 5-OHP is not formed or only minimally formed because the drug undergoes little or no first-pass metabolism. The nonlinear pharmacokinetics observed in patients with the extensive-metabolizer phenotype has been attributed to the saturation of the hydroxylation pathway.

Although the rate and extent of propafenone absorption were increased (bioavailability was increased by an average of 147%) when the drug was administered with food in a single-dose study in healthy individuals, the manufacturer states that bioavailability of the drug is not appreciably affected by food during multiple-dose administration of immediate-release tablets. Propafenone exposure was increased 4-fold when a single 425-mg extended-release capsule was administered with food in healthy individuals; however, the bioavailability of the drug is not appreciably affected by food during multiple-dose administration (425-mg extended-release capsules twice daily).

Bioavailability of propafenone is increased in patients with hepatic impairment (e.g., cirrhosis) and is inversely proportional to indocyanine green clearance. Bioavailability of immediate-release propafenone averages approximately 60-70% in patients with marked hepatic impairment (indocyanine green clearance of 7 mL/minute or less) and 3-40% in patients with normal hepatic function; the relative bioavailability of the extended-release formulation has not been determined.

Peak plasma propafenone concentrations generally occur approximately 2-3.5 hours after oral administration of immediate-release tablets in most individuals. Peak plasma concentration of propafenone after a single 300-mg oral dose of propafenone hydrochloride immediate-release tablets in patients with ventricular arrhythmias averaged 416 ng/mL; peak drug concentrations were 1198 and 1213 ng/mL with a dosage of 900 mg (immediate-release tablets) daily for 1 and 3 months, respectively. Increases in area under the plasma concentration-time curve (AUC) in these patients were similar following single- or multiple-dose drug administration of immediate-release tablets. Following single-dose administration of propafenone immediate-release tablets, the ratio of the AUCs of parent drug to 5-OHP was 0.43; with multiple dosing for 1 or 3 months, the ratio was 0.24 or 0.25, respectively. Peak plasma propafenone concentrations generally occur approximately 3-8 hours after oral administration of extended-release capsules in most individuals.

In healthy individuals, administration of propafenone hydrochloride as a single oral (300- or 450-mg immediate-release tablet) or IV (35-50 mg) dose produced similar peak plasma concentrations of the parent drug (278 versus 295 ng/mL, respectively). However, neither 5-OHP nor NDPP was detectable in plasma after IV administration in these individuals. Since 5-OHP and NDPP has clinically important antiarrhythmic activity, propafenone's effect may differ with oral versus IV administration. Considerable interindividual variation exists in plasma concentrations of propafenone and its metabolites with a given dosage. Peak plasma concentrations of 5-OHP and NDPP average 101-288 and 8-40 ng/mL, respectively, in healthy individuals after administration of a single oral dose (300-450 mg) of propafenone hydrochloride immediate-release tablets. Propafenone, 5-OHP, and NDPP exhibit nonlinear pharmacokinetics in patients with the extensive-metabolizer phenotype, although the pharmacokinetics of 5-OHP and NDPP deviate from linearity only to a small extent. The pharmacokinetic profiles of propafenone, 5-OHP, and NDPP apparently are not affected substantially by age or gender.

The considerable degree of interindividual variability observed in the pharmacokinetics of propafenone in individuals with the extensive-metabolizer phenotype is principally attributable to first-pass hepatic metabolism and non-linear pharmacokinetics. The degree of interindividual variability in propafenone pharmacokinetic parameters is increased following single and multiple dose administration of propafenone hydrochloride extended-release capsules. The fact that interindividual variability in the pharmacokinetics of propafenone appears to be substantially less in individuals with the poor-metabolizer phenotype than in those with the extensive-metabolizer phenotype suggests that such variability may be due to CYP2D6 polymorphism rather than to the formulation.

The pattern of plasma concentrations of propafenone and its metabolites observed in an individual patient with long-term oral propafenone therapy depends principally on the genetically determined metabolizer phenotype and, to a lesser extent, on hepatic blood flow and enzyme function.(See Pharmacokinetics: Elimination.) Following oral administration of propafenone (immediate-release tablets), steady-state plasma concentrations of the parent drug and its metabolites are attained within 4-5 days in individuals with normal hepatic and renal function. Plasma concentrations of 5-OHP and NDPP generally average less than 20% those of propafenone. Poor metabolizers achieve plasma propafenone concentrations 1.5-2 times higher than those of extensive metabolizers at propafenone hydrochloride dosages of 675-900 mg (immediate-release tablets) daily; at lower dosages, poor metabolizers may attain plasma propafenone concentrations more than fivefold higher than those of extensive metabolizers.

In patients with ventricular arrhythmias and the extensive-metabolizer phenotype receiving 337.5, 450, 675, or 900 mg of propafenone hydrochloride daily (immediate-release tablets), the proportions of 5-OHP to propafenone in plasma were 45, 40, 24, or 19%, respectively, while a subset of patients with the poor-metabolizer phenotype had higher relative plasma concentrations of the parent drug at each dosage and no detectable 5-OHP. Ratios of NDPP to propafenone are similar in extensive and poor metabolizers (approximately 10 and 6%, respectively). In poor metabolizers, NDPP is the principal metabolite and 5-OHP may not be detectable. Following oral administration of propafenone hydrochloride 300 mg (immediate-release tablets) every 8 hours for 14 days, plasma propafenone, 5-OHP, and NDPP concentrations averaged 1010, 174, and 179 ng/mL, respectively, in healthy individuals with the extensive-metabolizer phenotype. In an individual presumed to have the poor-metabolizer phenotype, plasma concentrations of propafenone, 5-OHP, and NDPP concentrations were 1048, undetectable, and 219 ng/mL, respectively, following oral administration of immediate-release tablets. Following administration of extended-release capsules of propafenone hydrochloride, plasma concentrations of 5-OHP and NDPP are generally less than 40 and 10% of plasma propafenone concentrations, respectively.

In extensive metabolizers, propafenone bioavailability following administration of extended-release capsules is less than that following administration of the immediate-release tablets; the more gradual release of propafenone from the extended-release formulation results in an increase in the extent of first-pass hepatic metabolism. During relative bioavailability studies, higher daily dosages of propafenone administered as extended-release capsules compared with immediate-release tablets were required to obtain similar exposure to propafenone. The bioavailability of propafenone following 325-mg extended-release capsules given twice daily is similar to 150-mg immediate-release tablets given 3 times daily. Following administration of extended-release capsules, the mean exposure to 5-OHP was approximately 20-25% higher compared with such exposure following immediate-release tablets.

Because propafenone, 5-OHP, and NDPP are pharmacologically active and plasma concentrations of the parent drug and these metabolites vary considerably depending on the patient's metabolizer phenotype, duration of drug administration, and dosage formulation relationships between plasma concentrations of propafenone and/or its metabolites and antiarrhythmic and electrophysiologic effects are complex.(See Pharmacology: Antiarrhythmic and Electrophysiologic Effects.) Limited data suggest that in patients with the extensive-metabolizer phenotype, the antiarrhythmic and electrophysiologic effects are correlated principally with plasma concentrations of unchanged propafenone and 5-OHP. In patients with the poor-metabolizer phenotype, the antiarrhythmic and electrophysiologic effects appear to be correlated with plasma concentrations of unchanged propafenone. In a study in patients with chronic ventricular arrhythmias, plasma propafenone concentrations of 250-490 ng/mL were associated with at least 90% suppression of ventricular premature complexes (VPCs), ventricular coupled beats, and nonsustained ventricular tachycardia in 47, 70, and 78% of patients, respectively; propafenone concentrations of 1500 ng/mL or higher produced at least 90% suppression of VPCs, ventricular coupled beats, and nonsustained ventricular tachycardia in 67, 83, and 100% of patients, respectively.

Following long-term administration of 850 mg of propafenone hydrochloride daily as extended-release capsules, plasma concentrations of propafenone in individuals with the poor-metabolizer phenotype was approximately twice that observed in individuals with the extensive-metabolizer phenotype. Following lower daily dosages of propafenone hydrochloride as extended-release capsules, the difference in plasma concentrations of propafenone is larger between the metabolizer phenotypes; plasma concentrations of propafenone in individuals with the poor-metabolizer phenotype are approximately 3-4 times higher than those observed in individuals with the extensive-metabolizer phenotype. Following saturation of the hydroxylation pathway (CYP2D6) in individuals with the extensive-metabolizer phenotypes, plasma propafenone concentrations increase at a greater-than-linear rate after administration of extended-release capsules of propafenone hydrochloride. In individuals with the poor-metabolizer phenotype, propafenone exhibits linear pharmacokinetics.

Despite the complex nature of the contribution of propafenone and its metabolites to clinical response in individual patients, clinical response generally is related to dosage and the usually effective dosages in patients with the poor- or extensive-metabolizer phenotype are comparable.(See Dosage and Administration: Dosage.) This recommendation is based on consideration of propafenone pharmacokinetics including the fact that differences in pharmacokinetics between metabolizer phenotypes decrease as dosage is increased, mitigation by the lack of the active 5-OHP metabolite in individuals with the poor-metabolizer phenotype, and the fact that steady-state occurs following 4-5 days of therapy in all patients. However, plasma concentrations of the drug may increase disproportionately during dosage titration in patients with the poor-metabolizer phenotype, resulting in an increased occurrence of adverse effects, especially CNS effects (e.g., dizziness, blurred vision, taste disturbances).

Limited data suggest that a partial tolerance to the antiarrhythmic effects of propafenone may develop during long-term therapy so that higher plasma concentrations are required to produce equivalent effects.

A relationship between plasma concentrations of propafenone or its metabolites and arrhythmogenic effects has not been established.(See Cautions: Arrhythmogenic Effects.)

Distribution

Distribution of propafenone and its metabolites into human body tissues and fluids has not been fully characterized. Propafenone is highly lipophilic and rapidly distributed into lung, liver, and heart tissue. The apparent volume of distribution of propafenone averages 3 L/kg (range: 2.5-4 L/kg). In patients receiving propafenone who underwent heart surgery, 5-OHP was detected in higher concentrations in right atrial tissue than in plasma, and ratios of parent drug to metabolites were lower in plasma than in atrial tissue (1.7 versus 3.9, respectively).

The degree of protein binding of propafenone is concentration dependent. In healthy individuals, 81-97% of propafenone is bound in vitro to plasma proteins at plasma propafenone concentrations of 0.25-100 mcg/mL, while protein binding averages 96% at plasma propafenone concentrations of 0.5-2 mcg/mL. Most propafenone in plasma is bound to α1-acid glycoprotein and a lesser extent to albumin.

In patients with severe hepatic dysfunction, approximately 88% of propafenone is bound in vitro to plasma proteins.

Propafenone and 5-OHP cross the placenta and are distributed into milk.(See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

There are two principal patterns of propafenone metabolism. These patterns are genetically determined by an individual's ability to metabolize the drug via a hepatic oxidation pathway. The ability to oxidatively metabolize propafenone is dependent on an individual's ability to metabolize debrisoquin (debrisoquin phenotype). The debrisoquin phenotype or the observed pattern of propafenone metabolites may be used to determine an individual's metabolic phenotype for propafenone. Individuals who extensively metabolize propafenone via the oxidation pathway exhibit the extensive-metabolizer phenotype, while those who have an impaired ability to metabolize the drug by this pathway exhibit the poor-metabolizer phenotype. Approximately 90-95% of Caucasians exhibit the extensive-metabolizer phenotype, with the remainder being poor metabolizers. Propafenone metabolism in patients with the poor-metabolizer phenotype is characterized by a linear dose-concentration relationship and a relatively long terminal elimination half-life; these individuals have increased plasma propafenone concentrations relative to individuals with the extensive-metabolizer phenotype and are more likely to experience β-adrenergic blocking and adverse effects of the drug.

Following single or multiple oral doses of immediate-release tablets in adults with the extensive-metabolizer phenotype and normal renal and hepatic function, the elimination half-life of propafenone averages about 1-3 hours (range: 2-10 hours). The half-life of propafenone averages approximately 8-13 hours (range: 6-36 hours) in adults with the poor-metabolizer phenotype. Following a single oral dose of 300 mg of propafenone hydrochloride as immediate-release tablets, a half-life of 3.5 hours was reported; after administration of 300 mg of propafenone hydrochloride daily for 1 and 3 months, the reported half-lives were 6.7 and 5.8 hours, respectively. Steady-state plasma elimination half-life of propafenone is prolonged in poor metabolizers, averaging 17.2 hours (range: 10-32 hours) compared with 5.5 hours (range: 2-10 hours) in extensive metabolizers.

In individuals with the extensive-metabolizer phenotype, propafenone is metabolized in the liver to 2 active metabolites and at least 9 additional metabolites. The 2 active metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), are formed through hydroxylation and dealkylation of the parent drug. Propafenone hydroxylation via cytochrome CYP2D6, a cytochrome P-450 isoenzyme under genetic control, produces 5-OHP. Formation of NDPP is catalyzed by different isoenzymes, cytochrome CYP1A2 and CYP3A4. Differences in metabolism between R- and S-propafenone related to stereoselective interaction with the CYP2D6 isoenzyme have been observed in animals and humans receiving single enantiomers of the drug. Following a 250-mg oral dose of R- or S-propafenone hydrochloride administered to adults with the extensive-metabolizer phenotype, the mean values for elimination half-life, clearance, and volume of distribution for R-propafenone were smaller than those for S-propafenone, while AUC was larger; however, these stereospecific effects were not observed in an adult with the poor-metabolizer phenotype who received the separate drug enantiomers. In vitro and in vivo studies indicate that the R-enantiomer is cleared faster than the S-enantiomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of the S-enantiomer to R-enantiomer at steady state. Although the enantiomers have equivalent sodium-channel blocking potency, the S-enantiomer is a more potent β-adrenergic antagonist than the R-enantiomer. Following administration of propafenone hydrochloride (immediate-release tablets or extended-release capsules), the observed ratio of S-enantiomer to R-enantiomer (S/R ratio) for AUC was approximately 1.7. The S/R ratios after administration of 225-, 325-, or 425-mg extended-release capsules were independent of dose. In addition, similar S/R ratios were observed among metabolizer genotypes and following long-term administration.

When racemic propafenone is administered, some data indicate that metabolic inhibition between the enantiomers appears to result in reversal of these enantiomer-dependent pharmacokinetic differences. In patients with extensive or poor metabolizer phenotypes receiving propafenone hydrochloride 450 mg daily (immediate-release tablets), the clearance of R-propafenone was approximately 1.7 times that of the S-enantiomer, and the AUC was smaller for R-propafenone regardless of metabolizer phenotype. In adults with the poor-metabolizer phenotype, the clearance of both enantiomers is reduced; however, the clearance of the R-enantiomer still exceeds that of the S-enantiomer.

Although conflicting data exist, clearance of propafenone appears to be reduced during long-term administration, presumably as a result of reduced hepatic metabolism. Increases in steady-state bioavailability, elimination half-life, and peak plasma concentration have been reported following oral administration of propafenone hydrochloride (150-300 mg as immediate-release tablets 3 times daily) for 5-30 days compared with these values after single-dose administration, suggesting a reduction in propafenone clearance during chronic dosing. However, the minimum plasma propafenone concentration required for antiarrhythmic efficacy also has been reported to increase with long-term therapy, suggesting the development of partial tolerance to the drug.(See Pharmacokinetics: Absorption.)

Propafenone clearance directly correlates with hepatic function as indicated by indocyanine green clearance, prothrombin time, and serum concentrations of albumin, total bilirubin, and AST (SGOT). The drug's terminal elimination half-life is increased to approximately 9 hours in patients with moderate to severe hepatic impairment (e.g., cirrhosis).

The volume of distribution, clearance, and elimination half-life of propafenone were similar in healthy individuals, patients undergoing hemodialysis, and those with moderate renal impairment (mean creatinine clearance: about 40 mL/minute per 1.73 m) receiving a single IV dose of the drug. Propafenone is not removed by hemodialysis.

Limited data indicate that mean interdose plasma propafenone concentrations in patients with the extensive-metabolizer phenotype and renal impairment receiving maintenance therapy with oral propafenone hydrochloride 450 mg daily (immediate-release tablets) may be decreased slightly compared with those in healthy individuals with normal renal function. However, steady-state concentrations of 5-OHP were decreased, and those of NDDP were increased, in patients with the extensive-metabolizer phenotype and renal impairment compared with those concentrations in healthy individuals with normal renal function. In another study, impaired renal function did not alter plasma concentrations of propafenone or 5-OHP at steady state in patients receiving 600 mg of propafenone hydrochloride (immediate-release tablets) daily for 4 days. The disposition of propafenone hydrochloride after administration of a single IV dose (70 mg) was similar in a limited number of patients with renal impairment (mean creatinine clearance: 0.66 mL/minute per 1.73 m) or renal failure compared with those with normal renal function (mean creatinine clearance: 1.43 mL/minute per 1.73 m). More data from long-term studies are needed to determine the effect of decreased renal function on the pharmacokinetics of propafenone.

Less than 1% of a dose of propafenone is excreted unchanged in urine or feces following oral administration of the drug; metabolites are mainly excreted in feces via biliary elimination. Urinary excretion of propafenone and its metabolites in patients with the extensive-metabolizer phenotype and cirrhosis generally is similar to that in healthy individuals with the same metabolizer phenotype, although the fraction of the dose excreted as unchanged drug is increased substantially and some NDDP also is excreted.

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