Rythmol (Propafenone HCl)

RYTHMOL®

Knoll

Propafenone HCl

Antiarrhythmic Agent

Action And Clinical Pharmacology: Propafenone is an antiarrhythmic agent which possesses class 1c properties in the modified electrophysiological classification of Vaughan-Williams. It has a direct stabilizing action on myocardial cell membranes. The electrophysiological effect of propafenone manifests itself as a reduction of the upstroke velocity (Phase 0) of the monophasic action potential, while phase 4 spontaneous automaticity is depressed. Diastolic excitability threshold is increased and effective refractory period prolonged. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward sodium current.

In addition to a local anesthetic effect, approximately equal to procaine, propafenone has weak beta-blocking activity. Clinical trials employing isoproterenol challenge and exercise testing suggest that the affinity of propafenone for beta-adrenergic receptors, as calculated from dose ratios and drug concentrations, is about 1/40 that of propranolol. Propafenone also inhibits the slow calcium influx at high concentrations, however, this action is weak (approximately 1/100 of verapamil) and does not contribute to its antiarrhythmic effect.

Electrophysiology studies have shown that propafenone prolongs atrioventricular conduction and in some instances significantly lengthens sinus nodal recovery times with a non-significant effect on sinus cycle length. AV nodal conduction time (AH interval) as well as His-Purkinje conduction time (HV interval) are prolonged. Propafenone increases atrial, AV nodal and ventricular effective refractory periods. Propafenone causes a dose-dependent increase in the PR interval and QRS complex duration. Non-significant increases in the QTc interval and occasional slowing of the heart rate have also been observed.

Propafenone can exert a negative inotropic effect on the myocardium. Increases in pulmonary capillary wedge pressure and systemic and pulmonary vascular resistance, with a concurrent mild depression of cardiac output and cardiac index, have occurred following propafenone administration. Decreases in left ventricular function have been recorded in patients with depressed baseline function.

Pharmacokinetics: Following oral administration, propafenone is nearly completely absorbed but undergoes extensive first-pass hepatic metabolism resulting in a dose-dependent absolute bioavailability ranging from 3 to 40%. Bioavailability is enhanced by administration of the drug with food. Peak plasma concentrations occur within 3 hours. There is a non-linear increase in both plasma concentration and bioavailability with increase in dosage, presumably due to saturation of first pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone. This departure from dose linearity occurs when single doses above 150 mg are given. A 300 mg dose gives plasma levels 6 times that of a 150 mg dose. Similarly, for a 3-fold increase in daily dose from 300 to 900 mg/day there is a 10-fold increase in steady state plasma concentration.

Patients may be categorized into fast (90%) or slow (10%) metabolizers of propafenone, resulting in low or high plasma concentrations respectively. This variability in metabolism is thought to be due to a genetically determined deficiency in one pathway. Propafenone undergoes extensive hepatic metabolism with
Therapeutic plasma levels of propafenone appear to be in the range of 0.5 to 2.0 g/mL. Propafenone is 97% bound to plasma proteins.

Indications And Clinical Uses:

No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.

For the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. May also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Because of the proarrhythmic effects of propafenone, its use should be reserved for patients in whom, in the opinion of the physician, the benefit of treatment clearly outweighs the risks.

For patients with sustained ventricular tachycardia, propafenone therapy should be initiated in the hospital. Initiation in hospital may also be required for certain other patients depending on their cardiac status and underlying cardiac disease.

The effects of propafenone in patients with recent myocardial infarction have not been adequately studied and, therefore, its use in this condition cannot be recommended.

There is no evidence from controlled clinical trials that the use of propafenone favorably affects survival or the incidence of sudden death.

Contra-Indications: In the presence of the following: severe or uncontrolled congestive heart failure (see Warnings); cardiogenic shock; sinoatrial, atrioventricular and intraventricular disorders of impulse conduction and sinus node dysfunction (e.g. sick sinus syndrome) in the absence of an artificial pacemaker; severe bradycardia (less than 50 beats/min); marked hypotension; bronchospastic disorders; severe disorders of electrolyte balance; severe hepatic failure (see Precautions); known hypersensitivity to the drug.

Manufacturers’ Warnings In Clinical States: Mortality: The results of the Cardiac Arrhythmia Suppression Trials (CAST) in post-myocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in the non-fatal cardiac arrest rate in patients treated with flecainide or encainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group.

The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent.

Proarrhythmic Effects: Propafenone may cause new or worsen existing arrhythmias. Such proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, ventricular fibrillation or torsades de pointes. It is therefore essential that each patient administered propafenone be evaluated clinically and electrocardiographically prior to, and during therapy to determine whether the response to propafenone supports continued treatment.

Overall in clinical trials with propafenone, 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 above) suggests that a risk is present throughout treatment.

Congestive Heart Failure: During treatment with oral propafenone in patients with depressed baseline function (mean EF=33.5%), no significant decreases in ejection fraction were seen. In clinical trial experience, new or worsened CHF has been reported in 3.7% of patients; of those 0.9% were considered probably or definitely related to propafenone. Of the patients with congestive heart failure probably related to propafenone, 80% had preexisting heart failure and 85% had coronary artery disease. CHF attributable to propafenone developed rarely.
Propafenone exerts both beta blockade and a dose related direct negative inotropic effect on myocardium. Therefore, patients with congestive heart failure should be compensated before receiving propafenone, and then closely monitored with careful attention being given to the maintenance of cardiac function. If congestive heart failure worsens, propafenone should be discontinued (unless congestive heart failure is due to the cardiac arrhythmia) and, if indicated, restarted at a lower dosage only after adequate cardiac compensation has been established.

Caution should be exercised when using propafenone in patients with minimal cardiac reserve or in those who are receiving other drugs with negative inotropic potential.

Effects on Cardiac Conduction: Propafenone slows cardiac conduction which may result in a dose-related prolongation of PR interval and QRS complex, development of first or higher degree AV block, bundle branch block and intraventricular conduction delay (see Adverse Effects). Therefore, development of signs of increasing depression of cardiac conductivity during drug therapy requires a reduction in dosage or a discontinuation of propafenone unless the ventricular rate is adequately controlled by a pacemaker.

Hematologic Disturbances: Agranulocytosis has been reported infrequently in patients taking propafenone. The onset is generally within 4 to 6 weeks and presenting symptoms have included fever, fatigue, and malaise. Agranulocytosis occurs in less than 0.1% of patients taking propafenone. Patients should be instructed to immediately report fever, fatigue, malaise or any signs of infection, especially in the first 3 months of therapy. Prompt discontinuation of propafenone therapy is recommended when a decreased white blood cell count or other signs and symptoms warrant consideration of agranulocytosis/granulocytopenia. Cessation of propafenone therapy is usually followed by recovery of blood counts within 2 weeks.

Nonallergic Bronchospasm (e.g. chronic bronchitis, emphysema): Patients with bronchospastic disease should, in general, not receive propafenone or other agents with beta-adrenergic blocking activity (see Contraindications).

Precautions: Effects on Pacemaker Threshold: Patients with permanent pacemakers should have their existing thresholds re-evaluated after initiation of or change in propafenone therapy because of a possible increase in endocardial stimulation threshold.

Patients with Impaired Hepatic Function: Since propafenone is highly metabolized by the liver it should be administered cautiously to patients with impaired hepatic function (see Contraindications). Administration of propafenone to these patients results in an increase in bioavailability to approximately 70% compared to 3 to 40% for patients with normal liver function, prolongation of the half-life, a decrease in the systemic clearance, and a reduction in the serum protein binding of the drug. As a result, the dose given to patients with impaired hepatic function should be reduced (see Dosage). It is important to monitor ECG intervals for signs of excessive pharmacological effects (see Overdose) and/or adverse effects, until an individualized dosage regimen has been determined.

Patients with Impaired Renal Function: To date there is no experience with use of oral propafenone in patients with impaired renal function. Since a considerable percentage of propafenone metabolites are excreted in the urine (18.5 to 38% of the dose/48 hours), propafenone should be used cautiously in patients with renal impairment and only after consideration of the benefit/risk ratio. These patients should be carefully monitored for signs of toxicity (see Overdose). The dose in these patients has not been determined.

Neuromuscular Dysfunction: Exacerbation of myasthenia gravis has been reported during propafenone therapy.

Elevated ANA Titres: In long-term studies positive antinuclear antibody (ANA) titres have been reported in 21% of patients receiving propafenone. However, it is impossible to determine what exact percentage of patients had a new positive ANA titre as a result of propafenone therapy. This laboratory finding has not been associated with clinical symptoms. One case of Lupus-like syndrome has been reported which resolved upon discontinuation of therapy. Laboratory evaluation for antinuclear antibodies should be performed initially and at regular intervals. It is recommended that patients in whom an abnormal ANA test has occurred be evaluated regularly. If worsening elevation of ANA titres or clinical symptoms are detected, the drug should be discontinued.

Impaired Spermatogenesis: Clinical evaluation of spermatogenesis was undertaken in 11 normal subjects, given oral propafenone 300 mg twice daily for 4 days which was then increased to 300 mg three times daily for an additional 4 days. Patients were followed for 128 days post-treatment and demonstrated a 28% reduction in semen sample volume following the last dose (day 8) and a 27% reduction in sperm count, on day 72. FSH and testosterone levels were also slightly decreased. Neither the decrease in sperm count nor the decrease in sample volume were sustained beyond the single visit in which they occurred, and both values remained within the laboratories normal reference range. Reduced spermatogenesis was also observed in animal experiments. The significance of these findings is uncertain.

Geriatrics: A slight increase in the incidence of dizziness was observed in elderly patients. Because of the possible increased risk of impaired hepatic or renal function in this age group, propafenone should be used with caution. The effective dose may be lower in these patients.

Children: The use of propafenone in children is not recommended, since safety and efficacy has not been established.

Pregnancy: Propafenone has been shown to be embryotoxic in the rat when given in doses of 600 mg/kg and in the rabbit when given in doses of 150 mg/kg. In a perinatal and postnatal study in rats, propafenone produced dose dependent increases in maternal and neonatal mortality, decreased maternal and pup body weight gain and reduced neonatal physiological development.

There are no studies in pregnant women. Propafenone should be used during pregnancy only when the potential benefit outweighs the risk to the fetus.

Labor and Delivery: It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.

Lactation: Propafenone and 5-hydroxypropafenone are excreted in human milk. Because of possible serious adverse reactions in nursing infants, an alternative method of infant feeding should be considered when the use of propafenone is considered essential.

Drug Interactions: Quinidine: Small doses of quinidine completely inhibit the hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers (see Pharmacology). There is, as yet, too little information to recommend concomitant use of propafenone and quinidine.

Digitalis: Propafenone produces dose-related increases in serum digoxin levels ranging from approximately 35% at 450 mg/day to 85% at 900 mg/day of propafenone without affecting digoxin renal clearance. These elevations of digoxin levels were maintained for up to 16 months during concomitant administration. Plasma digoxin levels of patients on concomitant therapy should be measured, and digoxin dosage should ordinarily be reduced when propafenone is started, especially if a relatively large digoxin dose is used or if plasma concentrations are relatively high.

Beta-Antagonists: In a study involving healthy subjects, concomitant administration of propafenone and propranolol has resulted in substantial increases in propanolol plasma concentration and elimination half-life with no change in propafenone plasma levels from control values. Similar observations have been reported with metoprolol. Propafenone appears to inhibit the hydroxylation pathway for the two beta-antagonists (just as quinidine inhibits propafenone metabolism). Increased plasma concentrations of metoprolol could overcome its relative cardioselectivity. In propafenone clinical trials, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects. While the therapeutic range for beta-blockers is wide, a reduction in dosage may be necessary during concomitant administration with propafenone.

Warfarin: Concurrent administration of propafenone and warfarin leads to a 39% increase in warfarin plasma levels with a corresponding prolongation in prothrombin times of approximately 25%. It is therefore recommended that in patients treated with propafenone and warfarin concomitantly, prothrombin time should be carefully monitored and the dose of warfarin adjusted as necessary.

Cimetidine: Concomitant administration of propafenone and cimetidine resulted in a 20% increase in plasma concentrations of propafenone. Therefore, patients should be carefully monitored and the dose adjusted when appropriate.

Local Anesthetics: Concomitant use of local anesthetics and propafenone may increase the risk of CNS side effects.

Desipramine: Concomitant administration of propafenone and desipramine may result in elevated serum desipramine levels. Both desipramine, a tricyclic antidepressant, and propafenone are cleared by oxidative pathways of demethylation and hydroxylation carried out by the hepatic P-450 cytochrome.

Cyclosporine: Propafenone therapy may increase levels of cyclosporine.

Theophylline: Propafenone may increase theophylline concentration during concomitant therapy with the development of theophylline toxicity.

Rifampin: Rifampin may accelerate the metabolism and decrease the plasma levels and antiarrhythmic efficacy of propafenone.

Adverse Reactions: In 2 127 patients treated with propafenone in North American controlled and open clinical trials, the most common adverse reactions reported were dizziness (12.5%) nausea and/or vomiting (10.7%), unusual taste (8.8%) and constipation (7.2%). The adverse effects judged to be most severe were aggravation or induction of arrhythmia (4.7%), congestive heart failure (3.7%) and ventricular tachycardia (3.4%). The incidences for these 3 adverse reactions in patients with a previous history of MI were 6.9%, 5.3% and 5.5%, while in patients without a history of MI the incidences were 3.0%, 2.4% and 1.8%, respectively. Approximately 20% of patients had propafenone discontinued due to adverse reactions.

Adverse reactions were dose related and occurred most frequently during the first month of therapy.

In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience (adverse events from marketing experience are given in italics ). Causality and relationship to propafenone therapy cannot necessarily be judged from these events.

Cardiovascular: artrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia, Torsades de Pointes.

Nervous System: abnormal dreams, abnormal speech, abnormal vision, apnea, coma, confusion, depression, memory loss, numbness, paresthesias, psychosis/mania, seizures (0.3%), tinnitus, unusual smell sensation, vertigo.

Gastrointestinal: A number of patients with liver abnormalities associated with propafenone therapy have been reported in foreign post-marketing experience. Some appeared due to hepatocellular injury, some were cholestatic and some showed a mixed picture. Some of these reports were simply discovered through clinical chemistries, others because of clinical symptoms. One case was rechallenged with a positive outcome.

Cholestasis (0.1%), elevated liver enzymes (alkaline phosphatase, serum transaminases) (0.2%), gastroenteritis, hepatitis (0.03%).

Hematologic: agranulocytosis (see Warnings), anemia, bruising, granulocytopenia, increased bleeding time, leukopenia, purpura, thrombocytopenia.

Other: alopecia, eye irritation, hyponatremia/inappropriate ADH secretion, impotence, increased glucose, kidney failure, positive ANA (0.7%), lupus erythematosis, muscle cramps, muscle weakness, nephrotic syndrome, pain, pruritus.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The symptoms of overdose include hypotension, somnolence, convulsions, bradycardia, conduction disturbances, ventricular tachycardia and/or ventricular fibrillation.

If ingestion is recent, perform gastric lavage or induce emesis. Supportive measures such as mechanical respiratory assistance and cardiac massage may be necessary.

Defibrillation and the use of a temporary pacemaker, as well as infusion of isoproterenol and dopamine have been effective in controlling cardiac rhythm and blood pressure. Convulsions have been alleviated with i.v. diazepam.

Detoxification measures such as forced diuresis, hemoperfusion and hemodialysis have not proven useful.

Dosage And Administration: The dose of propafenone must be individually determined on the basis of patient’s response and tolerance. The usefulness of monitoring plasma levels for optimization of therapy has not been established. The recommended dose titration regimen can be used for both fast and slow metabolizers (see Pharmacology).

The initial dose is 150 mg given every 8 hours (450 mg/day). Dosage may be increased at 3 to 4 day intervals to 300 mg every 12 hours (600 mg/day). Should a further increase in dosage be necessary a maximum dose of 300 mg every 8 hours (900 mg/day) may be given.

In those patients in whom widening of the QRS complex (>0.12 sec) or prolongation or PR interval (>0.24 sec) occurs, the dosage should be reduced.

Administration of propafenone with food is recommended.

In patients with mild to moderate hepatic insufficiency (see Precautions), therapy should be initiated with 150 mg given once daily. The dosage may be increased at a minimum of 4 day intervals to 150 mg twice (300 mg/day) daily then to 150 mg every 8 hours (450 mg/day) and, if necessary, to 300 mg every 12 hours (600 mg/day).

There is no information on dosing with propafenone in patients with renal impairment. It should be used cautiously in these patients and only after consideration of the benefit/risk ratio. These patients should be carefully monitored for signs of toxicity. Lower doses may be required (see Precautions).

In elderly patients the effective dose of propafenone may be lower (see Precautions).

There is no information on the appropriate regimen for the transfer from lidocaine to propafenone.

Availability And Storage: 150 mg: Each white, film-coated, round, unscored tablet contains: propafenone HCl 150 mg. Nonmedicinal ingredients: hydroxypropylmethylcellulose, magnesium stearate, maize starch, polyethylene glycol, sodium dodecyl sulfate, talc, titanium dioxide and vinyl pyrrolidone-vinyl acetate copolymer. Bottles of 100.

300 mg: Each white, film-coated, round, scored tablet contains: propafenone HCl 300 mg. Nonmedicinal ingredients: hydroxypropylmethylcellulose, magnesium stearate, maize starch, polyethylene glycol, sodium lauryl sulfate, talc, titanium dioxide and vinyl pyrrolidone-vinyl acetate copolymer. Bottles of 100.

Do not use beyond the expiry date indicated on the label. (Shown in Product Recognition Section)

RYTHMOL® Knoll Propafenone HCl Antiarrhythmic Agent

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