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QT PROLONGATION/VENTRICULAR ARRHYTHMIAS: RARE CASES OF SERIOUS CARDIOVASCULAR ADVERSE EVENTS INCLUDING DEATH, CARDIAC ARREST, QT PROLONGATION, TORSADES DE POINTES, AND OTHER VENTRICULAR ARRHYTHMIAS HAVE BEEN OBSERVED IN PATIENTS EXCEEDING RECOMMENDED DOSES OF ASTEMIZOLE. WHILE THE MAJORITY OF SUCH EVENTS HAVE OCCURRED FOLLOWING SUBSTANTIAL OVERDOSES OF ASTEMIZOLE, TORSADES DE POINTES (ARRHYTHMIAS) HAVE VERY RARELY OCCURRED AT REPORTED DOSES AS LOW AS 20-30 MG DAILY (2-3 TIMES THE RECOMMENDED DAILY DOSE). DATA SUGGEST THAT THESE EVENTS ARE ASSOCIATED WITH ELEVATION OF ASTEMIZOLE AND/OR ASTEMIZOLE METABOLITE LEVELS, RESULTING IN ELECTROCARDIOGRAPHIC QT PROLONGATION.
THESE EVENTS HAVE ALSO OCCURRED AT 10 MG DAILY IN A FEW PATIENTS WITH POSSIBLE AUGMENTING CIRCUMSTANCES (SEE CONTRAINDICATIONS and
DO NOT EXCEED THE RECOMMENDED DOSE OF 10 MG (ONE TABLET) DAILY.
SOME PATIENTS A.P.A. TO INCREASE THE DOSE OF HISMANAL IN AN ATTEMPT TO ACCELERATE THE ONSET OF ACTION. PATIENTS SHOULD BE ADVISED NOT TO DO THIS AND NOT TO USE HISMANAL AS A PRN PRODUCT FOR IMMEDIATE R.L.E. OF SYMPTOMS.
IN SOME CASES, SEVERE ARRHYTHMIAS HAVE BEEN PRECEDED BY EPISODES OF SYNCOPE. SYNCOPE IN PATIENTS RECEIVING ASTEMIZOLE SHOULD LEAD TO IMMEDIATE DISCONTINUATION OF TREATMENT AND APPROPRIATE CLINICAL EVALUATION, INCLUDING ELECTROCARDIOGRAPHIC TESTING (LOOKING FOR QT PROLONGATION AND VENTRICULAR ARRHYTHMIA).
Patients known to have conditions leading to QT prolongation may experience QT prolongation and/or ventricular arrhythmias with astemizole at recommended doses. The effect of astemizole in patients who are receiving agents which alter the QT interval is unknown. However, in a view of astemizole's known potential for QT prolongation, it is advisable to avoid its use in patients who are taking medications which are reported to prolong QT intervals (including probucol, certain antiarrhythmics, certain tricyclic antidepressants, certain phenothiazines, certain calcium channel blockers such as bepridil, and terfenadine), patients with electrolyte abnormalities such as hypokalemia or hypomagnesemia, or those taking diuretics with potential for inducing electrolyte abnormalities.
Rare cases of cardiovascular events have been observed in patients with hepatic dysfunction. Systematic evaluation of the pharmacokinetics of astemizole in patients with hepatic dysfunction has not been performed. Since astemizole is extensively metabolized by the liver, the use of Astemizole in patients with significant hepatic dysfunction should generally be avoided.
Astemizole does not appear to be dialyzable. Caution should also be used when treating patients with renal impairment.
Information for the Patient
See PATIENT INFORMATION section.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenic potential has not been revealed in rats given 260x the recommended human dose of astemizole for 24 months, or in mice given 400x the recommended human dose for 18 months. Micronucleus, dominant lethal, sister chromatid exchange and Ames tests of astemizole have not revealed mutagenic activity.
Impairment of fertility was not observed in male or female rats given 200x the recommended human dose.
Pregnancy Category C Teratogenic effects were not observed in rats administered 200x the recommended human dose or in rabbits given 200x the recommended human dose. Maternal toxicity was seen in rabbits administered 200x the recommended human dose. Embryocidal effects accompanied by maternal toxicity were observed at 100x the recommended human dose in rats. Embryotoxicity or maternal toxicity was not observed in rats or rabbits administered 50x the recommended human dose. There are no adequate and well controlled studies in pregnant women. Hismanal (astemizole (withdrawn from us market)) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Metabolites may remain in the body for as long as 4 months after the end of dosing, calculated on the basis of 6 times the terminal half-life. (See CLINICAL PHARMACOLOGY.)
It is not known whether this drug is excreted in human milk.
Because certain drugs are known to be excreted in human milk, caution should be exercised when Hismanal is administered to a nursing woman. Astemizole is excreted in the milk of dogs.
Safety and efficacy in children under 12 years of age has not been demonstrated.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/8/2004
Additional Hismanal Information
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