Cardiovascular Adverse Events

Rare reports of severe cardiovascular adverse effects have been received which include ventricular tachyarrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation, and cardiac arrest), hypotension, palpitations, syncope, and dizziness. Rare reports of deaths resulting from ventricular tachyarrhythmias have been received (see CONTRAINDICATIONS, WARNINGS, and DRUG INTERACTIONS). Hypotension, palpitations, syncope, and dizziness could reflect undetected ventricular arrhythmia. IN SOME PATIENTS, DEATH, CARDIAC ARREST, OR TORSADES DE POINTES HAVE BEEN PRECEDED BY EPISODES OF SYNCOPE. (See BOXED WARNING). Rare reports of serious cardiovascular adverse events have been received, some involving QT prolongation and torsades de pointes, in apparently normal individuals without identifiable risk factors. There is not conclusive evidence of causal relationship of these events with terfenadine. Although in rare cases there was measurable plasma terfenadine, the implications of this finding with respect to the variability of terfenadine metabolism in the normal population cannot be assessed without further study. In controlled clinical trials in otherwise normal patients with rhinitis, small increases in QTc interval were observed at doses of 60 mg b.i.d. In studies of 300 mg b.i.d. a mean increase in QTc of 10% (range -4% to +30%)(mean increase of 46 msec) was observed.

General Adverse Events

Experience from clinical studies, including both controlled and uncontrolled studies involving more than 2,400 patients who received terfenadine, provides information on adverse experience incidence for periods of a few days up to six months. The usual dose in these studies was 60 mg twice daily, but in a small number of patients, the dose was as low as 20 mg twice a day, or as high as 600 mg daily.

In controlled clinical studies using the recommended dose of 60 mg b.i.d., the incidence of reported adverse effects in patients receiving terfenadine was similar to that reported in patients receiving placebo. (See TABLE 1).

TABLE 1 - ADVERSE EVENTS REPORTED IN CLINICAL STUDIES

In addition to the more frequent side effects reported in clinical trials, adverse effects have been reported at a lower incidence in clinical trials and/or spontaneously during marketing of terfenadine that warrant listing as possibly associated with drug administration. These include: alopecia (hair loss or thinning), anaphylaxis, angioedema, bronchospasm, confusion, depression, galactorrhea, insomnia, menstrual disorder (including dysmenorrhea), musculoskeletal symptoms, nightmares, paresthesia, photosensitivity, rapid flare of psoriasis, seizures, sinus tachycardia, sweating, thrombocytopenia, tremor, urinary frequency and visual disturbances.

In clinical trials, severe instances of mild, or in one case, moderate transaminase elevations were seen in patients receiving terfenadine. Mild elevations were also seen in placebo treated patients. Marketing experiences include isolated reports of jaundice, cholestatic hepatitis, and hepatitis. In most cases available information is incomplete.

Ketoconazole

Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals.Concomitant administration of ketoconazole and terfenadine is contraindicated (see CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS).

Itraconazole

Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated (see CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS).

Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions.

Macrolides

Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin.

Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: (See CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS.) Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress.

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