Propafenone Information
Propafenone () Description
Propafenone () hydrochloride is an antiarrhythmic drug supplied in extended-release capsules of 225 mg, 325 mg and 425 mg for oral administration.
The structural formula of Propafenone () HCl is given below:
Propafenone () HCl has some structural similarities to beta-blocking agents. Propafenone () HCl occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20ºC), chloroform and ethanol. Propafenone () extended release are capsules filled with granules containing the following inactive ingredients: ethylcellulose, lactose anhydrous, magnesium stearate and povidone. The capsules consist of D&C Red #28, FD&C Blue #1, FD&C Red #40, FD&C Yellow #5, FD&C Yellow #6, gelatin and titanium dioxide. In addition the ink consists of D&C Yellow #10 aluminum lake, iron oxide black, n-butyl alcohol, propylene glycol, FD&C Blue #2 aluminum lake, FD&C Red #40 aluminum lake, FD&C Blue #1 aluminum lake and shellac glaze~45% (20% esterfied) in ethanol.
Propafenone () Clinical Pharmacology
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 with the immediate release formulation, 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).
Propafenone () Indications And Usage
Propafenone () Extended Release Capsules are indicated to prolong the time to recurrence of symptomatic atrial fibrillation in patients without structural heart disease.
The use of Propafenone () ER capsules in patients with permanent atrial fibrillation or in patients exclusively with atrial flutter or PSVT has not been evaluated. Propafenone () ER capsules should not be used to control ventricular rate during atrial fibrillation.
The effect of Propafenone () ER capsules on mortality has not been determined (see black box ).
Propafenone () Contraindications
Propafenone () ER capsules are contraindicated in the presence of congestive heart failure, cardiogenic shock, sinoatrial, atrioventricular and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, atrioventricular block) in the absence of an artificial pacemaker, bradycardia, marked hypotension, bronchospastic disorders, electrolyte imbalance, or hypersensitivity to the drug.
Propafenone () Warnings
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 six days but less than two 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 1C 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 ten 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 1C antiarrhythmic to have a significant 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 unpleasant, but not life-threatening, symptoms or signs.
Propafenone () Precautions
Approximately 50% of Propafenone () metabolites are excreted in the urine following administration of Propafenone () HCl immediate release tablets. No studies have been performed to assess the percentage of metabolites eliminated in the urine following the administration of Propafenone () ER capsules.
Until further data are available, Propafenone () ER capsules should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for signs of overdosage (see ).
Medications and Supplements:
Assessment of patients’ medication history should include all over-the-counter, prescription and herbal/natural preparations with emphasis on preparations that may affect the pharmacodynamics or kinetics of Propafenone () ER capsules (see ). Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription and supplement use. If a patient is hospitalized or is prescribed new medication for any condition, the patient must inform the health care provider of ongoing Propafenone () ER capsules therapy. Patients should also check with their health care providers prior to taking a new over-the-counter medicine.
Electrolyte Imbalance:
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.
Dosing Schedule:
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.
Elevated ANA Titers:
Positive ANA titers have been reported in patients receiving Propafenone () . They have been reversible upon cessations 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 erythematosus (positive rechallenge); it resolved completely upon discontinuation of therapy. Patients who develop an abnormal ANA test should be carefully evaluated and, if persistent or worsening elevation of ANA titers is detected, consideration should be given to discontinuing therapy.
The 225 mg capsules contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Propafenone () is metabolized by CYP2D6 (major pathway) and CYP1A2 and CYP3A4. Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline), CYP1A2 (such as amiodarone), and CYP3A4 (such as ketaconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) can be expected to cause increased plasma levels of Propafenone () . Appropriate monitoring is recommended when Propafenone () ER capsules are used together with such drugs. In addition, Propafenone () is an inhibitor of CYP2D6. Coadministration of Propafenone () with drugs metabolized by CYP2D6 (such as desipramine, imipramine, haloperidol, venlafaxine) might lead to increased plasma concentrations of these drugs. The effect of Propafenone () on the P-Glycoprotein transporter has not been studied.
Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on a mg/m² basis) and rats (up to 270 mg/kg/day, about three times the MRHD on a mg/m² basis) provided no evidence of a carcinogenic potential for Propafenone () HCl.
Propafenone () HCl tested negative for mutagenicity in the Ames (salmonella) test and in the mouse dominant lethal test. It tested negative for clastogenicity in the human lymphocyte chromosome aberration assay and in rat and Chinese hamster micronucleus tests, and other tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.
Propafenone () HCl, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of Propafenone () HCl, were seen at lethal or near lethal dose levels and were not seen in rats treated either orally or intravenously (see ). Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m² basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when Propafenone () HCl was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m² basis).
Teratogenic Effects: Pregnancy Category C. Propafenone () HCl 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 three times the maximum recommended human dose [MRHD] on a mg/m² basis) and 600 mg/kg/day (about six times the MRHD on a mg/m² basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about three times the MRHD on a mg/m² basis) produced no evidence of embryotoxicity in rats, post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m² basis). There are no adequate and well-controlled studies in pregnant women. Propafenone () ER capsules (Propafenone () hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Non-Teratogenic Effects: In a study in which female rats received daily oral doses of Propafenone () HCl from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m² basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (four or more times the MRHD on a mg/m² basis) resulted in reductions in neonatal survival, body weight gain and physiological development.
Propafenone () Adverse Reactions
The data described below reflect exposure to Propafenone () ER capsules 225 mg BID in 126 patients, to Propafenone () ER capsules 325 mg BID in 135 patients, to Propafenone () ER capsules 425 mg BID in 136 patients, and to placebo in 126 patients for up to 39 weeks in a placebo-controlled trial (RAFT) conducted in the U.S. The most commonly reported adverse events in the trial included dizziness, chest pain, palpitations, taste disturbance, dyspnea, nausea, constipation, anxiety, fatigue, upper respiratory tract infection, influenza, first degree heart block and vomiting. The frequency of discontinuation due to adverse events was highest during the first 14 days of treatment. The majority of the patients with serious adverse events who withdrew or were discontinued recovered without sequelae.
Adverse events occurring in 2% or more of the patients in any of the RAFT Propafenone () ER capsules treatment groups and more common with Propafenone () than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, are listed in Table 2.
No clinically important differences in incidence of adverse reactions were noted by age, or gender. Too few non-White patients were enrolled to assess adverse events according to race. Adverse events occurring in 2% or more of the patients in any of the ERAFT Propafenone () ER treatment groups and not listed in Table 2 include the following: bundle branch block left, bundle branch block right, conduction disorders, sinus bradycardia and hypotension.
Other adverse events reported with Propafenone () clinical trials not already listed in Table 2 include the following adverse events by body and preferred term.
Propafenone () Overdosage
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 ventricular 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.
Propafenone () Dosage And Administration
The dose of Propafenone () ER capsules must be individually titrated on the basis of response and tolerance. Therapy should be initiated with Propafenone () ER capsules 225 mg given every twelve hours. Dosage may be increased at a minimum of five day interval to 325 mg given every twelve hours. If additional therapeutic effect is needed, the dose of Propafenone () ER capsules may be increased to 425 mg given every twelve hours.
In patients with hepatic impairment or having significant widening of the QRS complex or second or third degree AV block, dose reduction should be considered.
Propafenone () ER capsules can be taken with or without food. Do not crush or further divide the contents of the capsule.
Propafenone () How Supplied
Propafenone () Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of Propafenone () HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.
NDC 49884-210-02 Bottles of 60 capsules
NDC 49884-210-01 Bottles of 100 capsules
NDC 49884-210-05 Bottles of 500 capsules
NDC 49884-210-10 Bottles of 1000 capsules
Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.
Manufactured by:
Spring Valley, NY 10977
I03/10
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
Propafenone () Principal Display Panel – Mg
