Propafenone Hydrochloride 150 MG Oral Tablet

DRUG INTERACTIONS

7 Inhibitors of CYP2D6, 1A2, and 3A4 increase propafenone exposure.

( 7.1 ) Propafenone may increase digoxin or warfarin levels.

( 7.2 , 7.3 ) Orlistat may reduce propafenone exposure.

Taper orlistat withdrawal.

( 7.4 ) Lidocaine may increase central nervous system side effects.

( 7.6 ) 7.1 CYP2D6 and CYP3A4 Inhibitors Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, or sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, or grapefruit juice) can be expected to cause increased plasma levels of propafenone.

The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia.

Therefore, simultaneous use of propafenone hydrochloride with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions (5.4) and Dosage and Administration (2) ].

A m iodarone: Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.

Cimetidine: Concomitant administration of propafenone immediate release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone.

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

Quinidine: Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers [see Clinical Pharmacology (12) ] .

Concomitant administration of quinidine (50 mg three times daily) with 150 mg immediate release propafenone three times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them slow metabolizers.

Steady-state plasma concentrations more than doubled for propafenone, and decreased 50% for 5-OH-propafenone.

A 100 mg dose of quinidine tripled steady state concentrations of propafenone.

Avoid concomitant use of propafenone and quinidine.

Rifampin: Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%.

The concentrations of norpropafenone increased by 30%.

In slow metabolizers, there was a 50% decrease in propafenone plasma concentrations and increased the AUC and C max of norpropafenone by 74% and 20%, respectively.

Urinary excretion of propafenone and its metabolites decreased significantly.

Similar results were noted in elderly patients: Both the AUC and C max propafenone decreased by 84%, with a corresponding decrease in AUC and C max of 5-OH-propafenone by 69% and 57%.

7.2 Digoxin Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270%, and decreased the clearance of digoxin by 31% to 67%.

Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed.

7.3 Warfarin The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin.

Adjust the warfarin dose as needed by monitoring INR (international normalized ratio).

7.4 Orlistat Orlistat may limit the fraction of propafenone available for absorption.

In post marketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block and acute circulatory failure.

7.5 Beta-Antagonists Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%.

In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%.

The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol.

In clinical trials using propafenone immediate release tablets, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects.

7.6 Lidocaine No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients.

However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine.

OVERDOSAGE

10 The symptoms of overdosage may include hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and rarely convulsions and high grade ventricular arrhythmias.

Defibrillation as well as infusion of dopamine and isoproterenol have been effective in controlling abnormal rhythm and blood pressure.

Convulsions have been alleviated with intravenous diazepam.

General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.

The hemodialysis of propafenone in patients with an overdose is expected to be of limited value in the removal of propafenone as a result of both its high protein binding (>95%) and large volume of distribution.

DESCRIPTION

11 Propafenone hydrochloride tablets, USP are an antiarrhythmic drug supplied in scored, film-coated tablets of 150, 225 and 300 mg for oral administration.

Propafenone has some structural similarities to beta-blocking agents.

Chemically, propafenone hydrochloride (HCl) is 2’-[2-Hydroxy-3-(propylamino)- propoxy]-3-phenylpropiophenone hydrochloride, with a molecular weight of 377.92.

The molecular formula is C 21 H 27 NO 3 •HCl.

The structural formula of propafenone HCl is given below: Propafenone HCl occurs as colorless crystals or white crystalline powder with a very bitter taste.

It is slightly soluble in water (20°C), chloroform and ethanol.

The following inactive ingredients are contained in the tablet: carnauba wax, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, sodium starch glycolate, stearic acid, titanium dioxide and triacetin.

This is the structural formula for Propafenone HCl.

CLINICAL STUDIES

14 In two randomized, crossover, placebo-controlled, double-blind trials of 60 to 90 days duration in patients with paroxysmal supraventricular arrhythmias [paroxysmal atrial fibrillation/flutter (PAF), or paroxysmal supraventricular tachycardia (PSVT)], propafenone reduced the rate of both arrhythmias, as shown in Table 3.

Table 3: Reduction of Arrythmias in Patients with PAF or PSVT Study 1 Study 2 Propafenone Placebo Propafenone Placebo PAF n = 30 n = 30 n = 9 n = 9 Percent attack free 53% 13% 67% 22% Median time to first recurrence > 98 days 8 days 62 days 5 days PSVT n = 45 n = 45 n = 15 N = 15 Percent attack free 47% 16% 38% 7% Median time to first recurrence > 98 days 12 days 31 days 8 days The patient population in the above trials was 50% male with a mean age of 57.3 years.

Fifty percent of the patients had a diagnosis of PAF and 50% had PSVT.

Eighty percent of the patients received 600 mg/day propafenone.

No patient died in the above 2 studies.

In U.S.

long-term safety trials, 474 patients (mean age: 57.4 ± 14.5 years) with supraventricular arrhythmias [195 with PAF, 274 with PSVT and 5 with both PAF and PSVT] were treated up to 5 years (mean: 14.4 months) with propafenone.

Fourteen of the patients died.

When this mortality rate was compared to the rate in a similar patient population (n = 194 patients; mean age: 43.0 ± 16.8 years) studied in an arrhythmia clinic, there was no age-adjusted difference in mortality.

This comparison was not, however, a randomized trial and the 95% confidence interval around the comparison was large, such that neither a significant adverse or favorable effect could be ruled out.

HOW SUPPLIED

16 /STORAGE AND HANDLING Product: 63629-3869 NDC: 63629-3869-1 30 TABLET, FILM COATED in a BOTTLE

RECENT MAJOR CHANGES

Contraindications ( 4 ) 3/2013 Warnings and Precautions, Unmasking Brugada Syndrome ( 5.2 ) 3/2013

GERIATRIC USE

8.5 Geriatric Use Clinical studies of propafenone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 150 mg, 225 mg and 300 mg scored, round, film-coated tablets.

Tablets: 150 mg, 225 mg, 300 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes.

The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential.

In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions.

Diastolic excitability threshold is increased and effective refractory period prolonged.

Propafenone reduces spontaneous automaticity and depresses triggered activity.

Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1/50 the potency of propranolol.

Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta- adrenergic blocking potency (per mg) about 1/40 that of propranolol in man.

In clinical trials, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range.

At very high concentrations in vitro , propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy.

Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e.

the transient outward, the delayed rectifier, and the inward rectifier current).

Propafenone has local anesthetic activity approximately equal to procaine.

Compared to propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors).

INDICATIONS AND USAGE

1 Propafenone hydrochloride tablets are indicated to: prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease.

prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease.

treat documented ventricular arrhythmias, such as sustained ventricular tachycardia that, in the judgment of the physician, are life-threatening.

Initiate treatment in the hospital.

Usage Considerations: The use of propafenone hydrochloride tablets in patients with permanent atrial fibrillation (AF) or in patients exclusively with atrial flutter or PSVT has not been evaluated.

Do not use propafenone hydrochloride tablets to control ventricular rate during AF.

Some patients with atrial flutter treated with propafenone have developed 1:1 conduction, producing an increase in ventricular rate.

Concomitant treatment with drugs that increase the functional atrioventricular (AV) nodal refractory period is recommended.

The use of propafenone hydrochloride tablets in patients with chronic atrial fibrillation has not been evaluated.

Because of the proarrhythmic effects of propafenone hydrochloride tablets, its use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic, and any use of the drug should be reserved for patients in whom, in the opinion of the physician, the potential benefits outweigh the risks.

The effect of propafenone on mortality has not been determined [see Boxed Warning ] .

Propafenone hydrochloride tablets are an antiarrhythmic indicated to: prolong the time to recurrence of symptomatic atrial fibrillation (AF) in patients with episodic (most likely paroxysmal or persistent) AF who do not have structural heart disease.

( 1 ) prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients who do not have structural heart disease.

( 1 ) treat documented life-threatening ventricular arrhythmias.

( 1 ) U sage Considerations: Use in patients with permanent atrial fibrillation or with atrial flutter or PSVT has not been evaluated.

Do not use to control ventricular rate during atrial fibrillation.

( 1 ) In patients with atrial fibrillation and atrial flutter, use propafenone hydrochloride tablets with drugs that increase the atrioventricular nodal refractory period.

( 1 ) Because of proarrhythmic effects, use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic.

( 1 ) The effect of propafenone on mortality has not been determined.

( 1 )

PEDIATRIC USE

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

PREGNANCY

8.1 Pregnancy Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women.

Propafenone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

An imal Data: T e r a togenic Effects: Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg day (about 3 times the maximum recommended human dose [MRHD] on a mg/m 2 basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m 2 basis), respectively.

Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m 2 basis) produced no evidence of embryotoxicity in rats, post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m 2 basis).

Non-teratogenic Effects: In a study in which female rats received daily oral doses of propafenone from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis) produced increases in maternal deaths.

Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m 2 basis) resulted in reductions in neonatal survival, body weight gain and physiological development.

NUSRING MOTHERS

8.3 Nursing Mothers Propafenone is excreted in human milk.

Because of the potential for serious adverse reactions in nursing infants from propafenone, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNING: MORTALITY In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than 6 days but less than 2 years previously, an increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725).

The average duration of treatment with encainide or flecainide in this study was 10 months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any IC antiarrhythmic to have a significant proarrhythmic risk in patients with structural heart disease.

Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unp leasant, but not life-threatening, symptoms or signs.

W A RN I N G: M ORTALITY S e e full prescribing information for complete boxed warning.

A n increased rate of death or reversed cardiac arrest rate was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in patients assigned to placebo.

At present it is prudent to consider any IC antiarrhythmic to have a significant risk of provoking proarrhythmic events in patients with structural heart disease.

Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non- life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS May cause new or worsened arrhythmias.

Evaluate patients via ECG prior to and during therapy.

( 5.1 ) Propafenone hydrochloride may unmask Brugada or Brugada-like Syndrome.

( 4 , 5.2 ) Avoid use with other drugs that prolong the QT interval.

( 5.3 ) Avoid simultaneous use of propafenone with both a cytochrome P450 2D6 inhibitor and a 3A4 inhibitor.

( 5.4 ) May provoke overt heart failure.

( 5.5 ) May cause dose-related first degree AV block or other conduction disturbances.

Only use in patients with conduction disorders who have pacemakers.

( 5.6 ) May affect artificial pacemakers.

Monitor pacemaker function.

( 5.7 ) Agranulocytosis: Patients should report signs of infection.

( 5.8 ) May exacerbate myasthenia gravis.

( 5.11 ) 5.1 Proarrhythmic Effects Propafenone has caused new or worsened arrhythmias.

Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole and torsade de pointes.

It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval.

It is therefore essential that each patient given propafenone hydrochloride be evaluated electrocardiographically prior to and during therapy to determine whether the response to propafenone hydrochloride supports continued treatment.

Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret [see Clinical Pharmacology (12.2) ].

In a U.S.

uncontrolled, open label, multicenter trial in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study.

However, in 4 of the 9 patients, the ventricular tachycardia was of atrial origin.

Six of the nine patients that developed ventricular arrhythmias did so within 14 days of onset of therapy.

About 2.3% (11/474) of all patients had a recurrence of SVT during the study which could have been a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event.

Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death.

Overall in clinical trials with propafenone hydrochloride (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance, of VT or VF).

Of the patients who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction.

The incidence of proarrhythmia in patients with less serious or benign arrhythmias, which include patients with an increase in frequency of PVCs, was 1.6%.

Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST study [see Boxed Warning: Mortality ] suggests that an increased risk of proarrythmia is present throughout treatment.

In a study of sustained-release propafenone, there were too few deaths to assess the long term risk to patients.

There were 5 deaths, 3 in the pooled sustained-release propafenone group (0.8%) and 2 in the placebo group (1.6%).

In the overall sustained-release propafenone and propafenone hydrochloride immediate-release database of 8 studies, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo.

Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

5.2 Unmasking Brugada Syndrome Brugada Syndrome may be unmasked after exposure to propafenone hydrochloride.

Perform an ECG after initiation of propafenone hydrochloride, and discontinue the drug if changes are suggestive of Brugada Syndrome [see Contraindications (4) ] .

5.3 Use with Drugs that Prolong the QT Interval and Antiarrhythmic Agents The use of propafenone hydrochloride in conjunction with other drugs that prolong the QT interval has not been extensively studied.

Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides.

Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with propafenone hydrochloride.

Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone).

There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.

5.4 Drug Interactions: Simultaneous Use with Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4 Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes.

Approximately 6% of Caucasians in the U.S.

population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups.

Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.

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

Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous.

Therefore, avoid simultaneous use of propafenone hydrochloride with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

5.5 Use in Patients with a History of Heart Failure Propafenone exerts a negative inotropic activity on the myocardium as well as beta blockade effects and may provoke overt heart failure.

In clinical trial experience with propafenone hydrochloride, new or worsened congestive heart failure (CHF) has been reported in 3.7% of patients with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone HCl.

Of the patients with CHF probably related to propafenone, 80% had preexisting heart failure and 85% had coronary artery disease.

CHF attributable to propafenone HCl developed rarely (< 0.2%) in ventricular arrhythmia patients who had no previous history of CHF.

CHF occurred in 1.9% of patients studied with PAF or PSVT.

In a U.S.

trial of sustained-release propafenone in patients with symptomatic AF, heart failure was reported in 4 (1.0%) patients receiving sustained-release propafenone (all doses), compared to 1 (0.8%) patient receiving placebo.

5.6 Conduction Disturbances Propafenone slows atrioventricular conduction and may also cause dose-related first degree AV block.

Average PR interval prolongation and increases in QRS duration are also dose-related.

Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker [see Contraindications (4) and Clinical Pharmacology (12.2) ].

The incidence of first degree, second degree, and third degree AV block observed in 2,127 ventricular arrhythmia patients was 2.5%, 0.6%, and 0.2%, respectively.

Development of second or third degree AV block requires a reduction in dosage or discontinuation of propafenone HCl.

Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in patients receiving propafenone.

Bradycardia has also been reported (1.5%).

Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.

In a U.S.

trial in 523 patients with a history of symptomatic AF treated with sustained-release propafenone, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with sustained-release propafenone and placebo.

5.7 Effects on Pacemaker Threshold Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators.

During and after therapy, monitor and re-program these devices accordingly.

5.8 Agranulocytosis Agranulocytosis has been reported in patients receiving propafenone.

Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days.

Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia.

Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.

5.9 Use in Patients with Hepatic Dysfunction Propafenone is highly metabolized by the liver.

Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3 to 40% in patients with normal liver function.

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

Increased bioavailability of propafenone in these patients may result in excessive accumulation.

Carefully monitor patients with impaired hepatic function for excessive pharmacological effects [see Overdosage (10) ] .

5.10 Use in Patients with Renal Dysfunction Approximately 50% of propafenone metabolites are excreted in the urine following administration of propafenone hydrochloride.

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

5.11 Use in Patients with Myasthenia Gravis Exacerbation of myasthenia gravis has been reported during propafenone therapy.

5.12 Elevated ANA Titers Positive ANA titers have been reported in patients receiving propafenone.

They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy.

These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy.

Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.

5.13 Impaired Spermatogenesis Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone.

Evaluation of the effects of short-term propafenone hydrochloride administration on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

17.1 Information for Patients Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription and supplement use.

The health care provider should assess the patients’ medication history including all over-the-counter, prescription and herbal/natural preparations for those that may affect the pharmacodynamics or kinetics of propafenone hydrochloride [see Warnings and Precautions (5.4) ] .

Patients should also check with their health care providers prior to taking a new over-the-counter medicine.

If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their health care provider.

Patients should be instructed NOT to double the next dose if a dose is missed.

The next dose should be taken at the usual time.

DOSAGE AND ADMINISTRATION

2 The dose of propafenone hydrochloride tablets must be individually titrated on the basis of response and tolerance.

Initiate therapy with propafenone hydrochloride tablets 150 mg given every eight hours (450 mg/day).

Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg/day).

If additional therapeutic effect is needed, the dose of propafenone hydrochloride tablets may be increased to 300 mg every 8 hours (900 mg/day).

The usefulness and safety of dosages exceeding 900 mg per day have not been established.

In patients with hepatic impairment or those with significant widening of the QRS complex or second or third degree AV block, consider reducing the dose.

As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of propafenone hydrochloride tablets should be increased more gradually during the initial phase of treatment.

The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proarrhythmia and other adverse events.

Therefore, avoid simultaneous use of propafenone hydrochloride tablets with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions (5.4) and Drug Interactions (7.1) ] .

Initiate therapy with 150 mg given every 8 hours.

( 2 ) As needed, uptitrate in 3 to 4 days to 225 to 300 mg every 8 hours.

( 2 ) Consider reducing the dose in patients with hepatic impairment, significant widening of the QRS complex, or second or third degree AV block.

( 2 )