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This is the retyped text of a letter from Janssen Pharmaceutical Research Foundation. Contact the company for a copy of any referenced enclosures.

IMPORTANT PRESCRIBING INFORMATION

March 25, 1996

Dear Healthcare Professional:

Janssen Pharmaceutica would like to advise you of important new information concerning drug interactions with HISMANAL^® (astemizole).

The administration of quinine (doses of 430 mg or higher) is now contraindicated with HISMANAL. The agent will now be included in the WARNINGS Box. This is based on pharmacokinetic data and case reports which indicate that this agent may alter the pharmacokinetic parameters of astemizole, which may result in elevated plasma levels of astemizole and desmethylastemizole.

Tonic water beverages contain varying amounts of quinine. The FDA does not allow more than 2.45 mg/ounce of quinine to be contained in a carbonated beverage (CRF 21 part 172.575). Results of a pharmacokinetic study demonstrated that daily consumption of 80 mg of quinine per day (equivalent to approximately 32 ounces of a tonic water beverage) did not significantly alter the pharmacokinetics of astemizole, nor was it associated with any clinically or statistically significant effect on the QT interval.

The revised sections of the HISMANAL labeling are outlined below. The enclosed revised labeling is important and we request that you review it.

CONTRAINDICATIONS

Concomitant administration of astemizole with quinine is contraindicated because human data indicate that administration of quinine (single dose of 430 mg) with astemizole results in elevated plasma levels of astemizole and desmethylastemizole which is accompanied by electrocardiographic QT prolongation. These data also indicate that, although beverages containing quinine (up to 80 mg/day or about 32 ounces of tonic water) may elevate plasma levels of astemizole and desmethylastemizole, this effect is small and is not accompanied by significant prolongation of the QT interval.

WARNINGS

CONCOMITANT ADMINISTRATION OF ASTEMIZOLE WITH KETOCONAZOLE TABLETS, ITRACONAZOLE, ERYTHROMYCIN, OR QUININE IS CONTRAINDICATED (SEE CONTRAINDICATIONS AND PRECAUTIONS: DRUG INTERACTIONS.)

PRECAUTIONS: DRUG INTERACTIONS

Concomitant administration of astemizole with quinine is contraindicated. (See CONTRAINDICATIONS AND WARNINGS Box).

PRECAUTIONS: INFORMATION FOR PATIENTS

Patients should be questioned about use of any other prescription or over-the-counter medication, and should be cautioned regarding the potential for life-threatening arrhythmias with concurrent use of ketoconazole, itraconazole, erythromycin, or quinine. Human data indicate that although beverages containing quinine (up to 80 mg/day or about 32 ounces of tonic water) may elevate plasma levels of astemizole and desmethylastemizole, this effect is small and is not accompanied by significant prolongation of the QT interval.

The medical community can further our understanding of these events by reporting all cases to Janssen at 1-800-JANSSEN (526-7736) or the FDA MEDWATCH program by phone (1-800-FDA-1088); by FAX (1-800-FDA-1078); by modem (1-800-FDA-7737); or by mail (MEDWATCH, HF-2, FDA, 5600 Fishers Lane, Rockville, Maryland 20857).

Please refer to the enclosed revised package insert for full prescribing information. For additional medical information, please call 1-800-JANSSEN (526-7736) 9AM to 5PM Eastern Time, Monday through Friday.

Sincerely,

Mark A. Klausner, MD
Vice President, Medical Affairs

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