"Jan. 29, 2013 -- Older women with heart problems may be at greater risk for mental changes that are thought to signal the beginnings of a type of dementia, a new study shows.
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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 HCl, like other antiarrhythmic agents, may cause new or worsened arrhythmias. Such proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, ventricular fibrillation or torsade de pointes; i.e., tachycardia that is more sustained or more rapid which may lead to fatal consequences. It is therefore essential that each patient given propafenone HCl be evaluated electrocardiographically and clinically prior to, and during therapy to determine whether the response to propafenone HCl supports continued treatment.
Overall in clinical trials with propafenone, 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing a pro-arrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance, of VT or ventricular fibrillation [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 an increased risk is present throughout treatment.
In the 474 patient U.S. 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 HCl for atrial fibrillation/flutter have included increased PVCs, VT, VF, and death.
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.
Congestive Heart Failure
During treatment with oral propafenone in patients with depressed baseline function (mean ejection fraction [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 with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone HCl. 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 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.
As propafenone HCl exerts both beta blockade and a (dose-related) negative inotropic effect on cardiac muscle, patients with congestive heart failure should be fully compensated before receiving propafenone HCl. If congestive heart failure worsens, propafenone HCl 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.
Propafenone HCl slows atrioventricular conduction and also causes first degree AV block. Average PR interval prolongation and increases in QRS duration are closely correlated with dosage increases and concomitant increases in propafenone plasma concentrations. 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.
Effects on Pacemaker Threshold
Propafenone HCl may alter both pacing and sensing thresholds of artificial pacemakers. Pacemakers should be monitored and programmed accordingly during therapy.
Agranulocytosis (fever, chills, weakness, and neutropenia) has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first two months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days. Unexplained fever and/or decrease in white cell count, particularly during the initial three months of therapy, warrant consideration of possible agranulocytosis/granulocytopenia. Patients should be instructed to promptly report the development of any signs of infection such as fever, sore throat, or chills.
Propafenone is highly metabolized by the liver and should, therefore, be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3-40% for patients with normal liver function. In eight patients with moderate to severe liver disease, the mean half-life was approximately 9 hours. As a result, the dose of propafenone given to patients with impaired hepatic function should be approximately 20-30% of the dose given to patients with normal hepatic function (see DOSAGE AND ADMINISTRATION). Careful monitoring for excessive pharmacological effects (see OVERDOSAGE) should be carried out.
A considerable percentage of propafenone metabolites (18.5%-38% of the dose/48 hours) are excreted in the urine.
Until further data are available, propafenone HCl should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for signs of overdosage (see OVERDOSAGE).
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. 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.
Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone HCl. Evaluation of the effects of short-term RYTHMOL (propafenone) administration on spermatogenesis in 11 normal subjects had suggested that propafenone HCl produced a reversible, short-term drop (within normal range) in sperm count. Subsequent evaluations in 11 patients receiving RYTHMOL chronically have suggested no effect of propafenone HCl on sperm count.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 3 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 the mouse dominant lethal test, and tested negative for clastogenicity in the Chinese hamster micronucleus test, and other in vivo 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 PRECAUTIONS, Impaired Spermatogenesis). 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 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 3 times the maximum recommended human dose [MRHD] on a mg/m² basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m² basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 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. RYTHMOL (propafenone) 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 (4 or more times the MRHD on a mg/m² basis) resulted in reductions in neonatal survival, body weight gain and physiological development.
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.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serous adverse reactions in nursing infants from propafenone HCl, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of propafenone HCl in pediatric patients have not been established.
Clinical studies of RYTHMOL (propafenone) 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.
Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.
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