Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/805
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Propafenone HCl (Tablet, Film Coated)
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The dose of Propafenone HCl must be individually titrated on the basis of response and tolerance. It is recommended that therapy be initiated with 150 mg propafenone hydrochloride 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) and, if necessary, 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 those patients in whom significant widening of the QRS complex or second or third degree AV block occurs, dose reduction should be considered. As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of Propafenone HCl should be increased more gradually during the initial phase of treatment.
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Mechanism of Action: Propafenone HCl 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. Propafenone has local anesthetic activity approximately equal to procaine.<br/>Electrophysiology: Electrophysiology studies in patients with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular (AV) nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolf Parkinson's White (WPW), propafenone reduces conduction and increases the effective refractory period of the accessory pathway in both directions. Propafenone slows conduction and consequently produces dose-related changes in the PR interval and QRS duration. QTc interval does not change. Mean Changes in ECG Intervals* Total Daily Dose (mg) In any individual patient, the above ECG changes cannot be readily used to predict either efficacy or plasma concentration. Propafenone causes a dose-related and concentration-related decrease in the rate of single and multiple PVCs and can suppress recurrence of ventricular tachycardia. Based on the percent of patients attaining substantial (80-90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 mcg/mL can provide good suppression, with higher concentrations giving a greater rate of good response. When 600 mg/day propafenone was administered to patients with paroxysmal atrial tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beats/min and 37 beats/min for paroxysmal atrial fibrillation/flutter (PAF) patients and paroxysmal supraventricular tachycardia (PSVT) patients, respectively.<br/>Hemodynamics: Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by the beta blockade produced by propafenone may in itself aggravate congestive heart failure. Additionally, like other Class 1C antiarrhythmic drugs, studies in humans have shown that propafenone exerts a negative inotropic effect on the myocardium. Cardiac catheterization studies in patients with moderately impaired ventricular function (mean C.I.=2.61 L/min/m) utilizing intravenous propafenone infusions (2 mg/kg over 10 min+2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 mcg/mL (well above the therapeutic range of 0.2-1.5 mcg/mL) showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index.<br/>Pharmacokinetics and Metabolism: Propafenone is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration in most individuals. Propafenone exhibits extensive saturable presystemic biotransformation (first pass effect) resulting in a dose dependent and dosage form dependent absolute bioavailability; e.g., a 150 mg tablet had absolute bioavailability of 3.4%, while a 300 mg tablet had absolute bioavailability of 10.6%. A 300 mg solution which was rapidly absorbed, had absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability increases still further. Decreased liver function also increases bioavailability; bioavailability is inversely related to indocyanine green clearance reaching 60-70% at clearances of 7 mL/min and below. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction . Propafenone follows a nonlinear pharmacokinetic disposition presumably due to saturation of first pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of interindividual variability. For example, for a three-fold increase in daily dose from 300 to 900 mg/day there is a tenfold increase in steady-state plasma concentration. The top 25% of patients given 375 mg/day,however, had a mean concentration of propafenone larger than the bottom 25%, and about equal to the second 25%, of patients given a dose of 900 mg. Although food increased peak blood level and bioavailability in a single dose study, during multiple dose administration of propafenone to healthy volunteers food did not change bioavailability significantly. There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2-10 hours. These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone which is formed by both CYP3A4 and CYP1A2. In vitro preparations have shown these two metabolites to have antiarrhythmic activity comparable to propafenone but in man they both are usually present in concentrations less than 20% of propafenone. Nine additional metabolites have been identified, most only in trace amounts. It is the saturable hydroxylation pathway that is responsible for nonlinear pharmacokinetic disposition. In less than 10% of patients (and in any patient also receiving quinidine, see PRECAUTIONS), metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. The estimated propafenone elimination half-life ranges from 10-32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolize debrisoquine and a variety of other drugs (encainide, metoprolol, dextromethorphan). In these patients, the N-depropylpropafenone occurs in quantities comparable to the levels occurring in extensive metabolizers. In slow metabolizers propafenone pharmacokinetics are linear. There are significant differences in plasma concentrations of propafenone in slow and extensive metabolizers, the former achieving concentrations 1.5 to 2.0 times those of the extensive metabolizers at daily doses of 675 to 900 mg/day. At low doses the differences are greater, with slow metabolizers attaining concentrations more than five times that of extensive metabolizers. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxy metabolite in the slow metabolizers, and because steady-state conditions are achieved after 4-5 days of dosing in all patients, the recommended dosing regimen is the same for all patients. The greater variability in blood levels require that the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity . In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone during steady state.<br/>Clinical Trials: In two randomized, crossover, placebo-controlled, double-blind trials of 60-90 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 the following table: 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 the 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.
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Propafenone HCl tablets are supplied as the following: 150 mg: White, scored, round film-coated tablets containing 150 mg of propafenone hydrochloride and debossed with���ETH���on one side and���331���with a bisect on the other side. 100 Count Bottles������������. . . . . . . NDC 58177-331-04 Unit Dose Blister Packs���..���.... . . . . NDC 58177-331-11 225 mg: White, scored, round film-coated tablets containing 225 mg of propafenone hydrochloride and debossed with���ETH���on one side and���332���with a bisect on the other side. 100 Count Bottles������������. . . . . . . NDC 58177-332-04 300 mg: White, scored, round film-coated tablets containing 300 mg of propafenone hydrochloride and debossed with���ETH���on one side and���333���with a bisect on the other side. 100 Count Bottles���������������. . . . NDC 58177-333-04<br/>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, light-resistant container as defined in the USP. Manufactured by: KV Pharmaceutical Co. forETHEX CorporationSt. Louis, MO 63044
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Mortality: In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, 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.
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dailymed-ingredient:carnauba_wax,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:opadry_white,
dailymed-ingredient:povidone,
dailymed-ingredient:pregelatinized_starch,
dailymed-ingredient:sodium_starch_glycolate
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Propafenone Hydrochloride
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Propafenone HCl (Tablet, Film Coated)
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Adverse reactions associated with propafenone occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems. About 20% of patients treated with propafenone have discontinued treatment because of adverse reactions. Adverse reactions reported for>1.5% of 474 SVT patients who received propafenone in U.S. clinical trials are presented in the following table by incidence and percent discontinuation, reported to the nearest percent. Results of controlled trials in ventricular arrhythmia patients comparing adverse reaction rates on propafenone and placebo, and on propafenone and quinidine are shown in the following table. Adverse reactions reported for���1% of the patients receiving propafenone are shown, unless they were more frequent on placebo than propafenone. The most common events were unusual taste, dizziness, first degree AV block, intraventricular conduction delay, nausea and/or vomiting, and constipation. Headache was relatively common also, but was not increased compared to placebo. Adverse reactions reported for���1% of 2,127 ventricular arrhythmia patients who received propafenone in U.S. clinical trials are presented in the following table by propafenone daily dose. The most common adverse reactions in controlled clinical trials appeared dose-related (but note that most patients spent more time at the larger doses), especially dizziness, nausea and/orvomiting, unusual taste, constipation, and blurred vision. Some less common reactions may also have been dose-related such as first degree AV block, congestive heart failure, dyspepsia, and weakness. The principal causes of discontinuation were the most common events and are shown in the table. In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience (adverse events for marketing experience are given in italics). Causality and relationship to propafenone therapy cannot necessarily be judged from these events.<br/>Cardiovascular System: Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia.<br/>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.<br/>Gastrointestinal: A number of patients with liver abnormalities associated with propafenone therapy have been reported in 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 including fulminant hepatitis and death. One case was rechallenged with a positive outcome. Cholestasis (0.1%), elevated liver enzymes (alkaline phophatase, serum transaminases) (0.2%), gastroenteritis, hepatitis (0.03%).<br/>Hematologic: Agranulocytosis, anemia, bruising, granulocytopenia, increased bleeding time, leukopenia, purpura, thrombocytopenia.<br/>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.
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In patients without structural heart disease, propafenone HCl is indicated to prolong the time to recurrence of - paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms. - paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms. As with other agents, 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 AV refractory period is recommended. The use of propafenone in patients with chronic atrial fibrillation has not been evaluated. Propafenone should not be used to control ventricular rate during atrial fibrillation. Propafenone is also indicated for the treatment of Initiation of propafenone treatment, as with other antiarrhythmics used to treat life-threatening ventricular arrhythmias, should be carried out in the hospital. Propafenone, like other antiarrhythmic drugs, has not been shown to enhance survival in patients with ventricular or atrial arrhythmias.
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Propafenone HCl
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