"The U.S. Food and Drug Administration is alerting hospitals, health care professionals, and patients of a voluntary recall of all non-expired drug products produced and distributed for sterile use by Abrams Royal Compounding Pharmacy in Dallas, T"...
(Generic versions may still be available.)
Induction of New Serious Arrhythmias
VASCOR (bepridil hydrochloride) has Class 1 anti-arrhythmic properties and, like other such drugs, can induce new arrhythmias, including VT/VF. In addition, because of its ability to prolong the QT interval, VASCOR (bepridil) can cause torsades de pointes type ventricular tachycardia. Because of these properties VASCOR (bepridil) should be reserved for patients in whom other anti-anginal agents do not offer a satisfactory effect.
In US clinical trials, the QT and QTc intervals were commonly prolonged by VASCOR (bepridil) in a dose-related fashion. While the mean prolongation of QTc was 8% and of QT was 10%. Increases of 25% or more were not uncommon, occurring in 5% of the studied population for QTc and 8.7% of the studied population for QT. Increased QT and QTc may be associated with torsades de pointes type VT, which was seen at least briefly, in about 1.0% of patients in US trials; in many cases, however, patients with marked prolongation of QTc were taken off VASCOR (bepridil) therapy. All of the US patients with torsades de pointes had a prolonged QT interval and relatively low serum potassium. French marketing experience has reported over one hundred verified cases of torsades de pointes. While this number, based on total use, represents a rate of only 0.01%, the true rate is undoubtedly much higher, as spontaneous reporting systems all suffer from substantial under reporting.
Torsades de pointes is a polymorphic ventricular tachycardia often but not always associated with a prolonged QT interval, and often drug induced. The relation between the degree of QT prolongation and the development of torsades de pointes is not linear and the likelihood of torsades appears to be increased by hypokalemia, use of potassium wasting diuretics, and the presence of antecedent bradycardia. While the safe upper limit of QT is not defined, it is suggested that the interval not be permitted to exceed 0.52 seconds during treatment. If dose reduction does not eliminate the excessive prolongation, VASCOR (bepridil) should be stopped.
Because most domestic and foreign cases of torsades have developed in patients with hypokalemia, usually related to diuretic use or significant liver disease, if concomitant diuretics are needed, low doses and addition or primary use of a potassium sparing diuretic should be considered and serum potassium should be monitored.
VASCOR (bepridil) has been associated with the usual range of pro-arrhythmic effects characteristic of Class 1 anti-arrhythmics (increased premature ventricular contraction rates, new sustained VT, and VT/VF that is more resistant to sinus rhythm conversion). Use in patients with severe arrhythmias (who are most susceptible to certain pro-arrhythmic effects) has been limited, so that risk in these patients is not defined.
In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had myocardial infarctions more than six days but less than two years previously, an excess mortality/non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The applicability of these results to other populations (e.g., those without recent myocardial infarction) or to other anti-arrhythmic drugs is uncertain, but at present it is prudent to consider any drug documented to provoke new serious arrhythmias or worsening of pre-existing arrhythmias as having a similar risk and to avoid their use in the post-infarction period.
Agranulocytosis: In US clinical trials of over 800 patients treated with VASCOR (bepridil) for up to five years, two cases of marked leukopenia and neutropenia were reported. Both patients were diabetic and elderly. One died with overwhelming gram-negative sepsis, itself a possible cause of marked leukopenia. The other patient recovered rapidly when VASCOR (bepridil) was stopped.
Congestive Heart Failure: Congestive heart failure has been observed infrequently (about 1%) during US controlled clinical trials, but experience with the use of VASCOR (bepridil) in patients with significantly impaired ventricular function is limited. There is little information on the effect of concomitant administration of VASCOR (bepridil) and digoxin; therefore, caution should be exercised in treating patients with congestive heart failure.
Hepatic Enzyme Elevation: In US clinical studies with VASCOR (bepridil) in about 1000 patients and subjects, clinically significant (at least 2 times the upper limit of normal) transaminase elevations were observed in approximately 1% of the patients. None of these patients became clinically symptomatic or jaundiced and values returned to normal when the drug was stopped.
Hypokalemia: In clinical trials VASCOR (bepridil) has not been reported to reduce serum potassium levels. Because hypokalemia has been associated with ventricular arrhythmias, potassium insufficiency should be corrected before VASCOR (bepridil) therapy is initiated and normal potassium concentrations should be maintained during VASCOR (bepridil) therapy. Serum potassium should be monitored periodically.
Caution should be exercised when using VASCOR (bepridil hydrochloride) in patients with left bundle branch block or sinus bradycardia (less than 50 b.p.m.). Care should also be exercised in patients with serious hepatic or renal disorders because such patients have not been studied and bepridil is highly metabolized, with metabolites excreted primarily in the urine.
Recent Myocardial Infarction
In US clinical trials with VASCOR (bepridil) , patients with myocardial infarctions within three months prior to initiation of drug treatment were excluded. The initiation of VASCOR (bepridil) therapy in such patients, therefore, cannot be recommended.
There have been cases of noninfective, noncardiogenic pulmonary interstitial infiltrates (with or without the presence of eosinophilia), including cases of pulmonary fibrosis in patients taking VASCOR (bepridil) . These cases may present as dyspnea or cough within a few weeks of commencing VASCOR (bepridil) ; infiltrates may be seen on chest x-ray.
Although the relationship of pulmonary infiltration to VASCOR (bepridil) is unclear, any patient who develops dyspnea or cough of unspecified etiology should be adequately evaluated. If other causes cannot be identified, discontinuation of VASCOR (bepridil) therapy should be considered.
Information for Patients
Since QT prolongation is not associated with defined symptomatology, patients should be instructed on the importance of maintaining any potassium supplementation or potassium sparing diuretic, and the need for routine electrocardiograms and periodic monitoring of serum potassium.
The following Patient Information is printed on the carton label of each unit of use bottle of 30 tablets:
|As with any medication that you take, you should notify your physician of any changes in your overall condition. Be sure to follow your physician's instructions regarding follow-up visits. Please notify any physician who treats you for a medical condition that you are taking VASCOR® (bepridil hydrochloride), as well as any other medications.|
Nitrates: The concomitant use of VASCOR (bepridil) with long- and short-acting nitrates has been safely tolerated in patients with stable angina pectoris. Sublingual nitroglycerin may be taken if necessary for the control of acute angina attacks during VASCOR (bepridil) therapy.
Beta-blocking Agents: The concomitant use of VASCOR (bepridil) and beta-blocking agents has been well tolerated in patients with stable angina. Available data are not sufficient, however, to predict the effects of concomitant medication on patients with impaired ventricular function or cardiac conduction abnormalities (see CLINICAL PHARMACOLOGYand DOSAGE AND ADMINISTRATION ).
Digoxin: In controlled studies in healthy volunteers, bepridil hydrochloride either had no effect (one study) or was associated with modest increases, about 30% (two studies) in steady-state serum digoxin concentrations. Limited clinical data in angina patients receiving concomitant bepridil hydrochloride and digoxin therapy indicate no discernible changes in serum digoxin levels. Available data are neither sufficient to rule out possible increases in serum digoxin with concomitant treatment in some patients, nor other possible interactions, particularly in patients with cardiac conduction abnormalities (Also see WARNINGS Congestive Heart Failure).
Oral Hypoglycemics: VASCOR (bepridil) has been safely used in diabetic patients without significantly lowering their blood glucose levels or altering their need for insulin or oral hypoglycemic agents.
General Interactions: Certain drugs could increase the likelihood of potentially serious adverse effects with bepridil hydrochloride. In general, these are drugs that have one or more pharmacologic activities similar to bepridil hydrochloride, including anti-arrhythmic agents such as quinidine and procainamide, cardiac glycosides and tricyclic anti-depressants. Anti-arrhythmics and tricyclic anti-depressants could exaggerate the prolongation of the QT interval observed with bepridil hydrochloride. Cardiac glycosides could exaggerate the depression of AV nodal conduction observed with bepridil hydrochloride.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was revealed in one lifetime study in mice at dosages up to 60 times (for a 60 kg subject) the maximum recommended dosage in man. Unilateral follicular adenomas of the thyroid were observed in a study in rats following lifetime administration of high doses of bepridil hydrochloride, i.e., ≥ 100 mg/kg/day (20 times the usual recommended dose in man). No mutagenic or other genotoxic potential of bepridil hydrochloride was found in the following standard laboratory tests: the Micronucleus Test for Chromosomal Effects, the Liver Microsome Activated Bacterial Assay for Mutagenicity, the Chinese Hamster Ovary Cell Assay for Mutagenicity, and the Sister Chromatid Exchange Assay. No intrinsic effect on fertility by bepridil hydrochloride was demonstrated in rats.
In monkeys, at 200 mg/kg/day, there was a decrease in testicular weight and spermatogenesis. There were no systematic studies in man related to this point. In rats, at doses up to 300 mg/kg/day, there was no observed alteration of mating behavior nor of reproductive performance.
Usage in Pregnancy
Pregnancy Category C. Reproductive studies (fertility and peri-postnatal) have been conducted in rats. Reduced litter size at birth and decreased pup survival during lactation was observed at maternal dosages 37 times (on a mg/kg basis) the maximum daily recommended therapeutic dosage.
In teratology studies, no effects were observed in rats or rabbits at these same dosages.
Bepridil is excreted in human milk. Bepridil concentration in human milk is estimated to reach about one third the concentration in serum. Because of the potential for serious adverse reactions in nursing infants from VASCOR (bepridil) 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 VASCOR (bepridil) in children have not been established.
Clinical studies of bepridil 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.
Bepridil is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug is greater in patients with impaired renal function (see CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism ).
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
Additional Vascor Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.