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September 22, 2000

Dear Doctor or Pharmacist:

This communication is to advise you of important labeling changes for all dosage forms of Serentil (mesoridazine besylate). Based on discussion with the Food and Drug Administration (FDA), Novartis has made the following major modifications to the labeling for these products:

• A boxed WARNING has been added to prominently advise clinicians that Serentil has been shown to prolong the QTc interval in a dose related manner, and drugs with this potential, including Serentil, have been associated with torsade de pointes-type arrhythmias and sudden death.

• Serentil is now indicated only for schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects. Serentil has not been systematically evaluated in controlled trials in treatment refractory schizophrenic patients and its efficacy in such patients is unknown.

• Serentil is contraindicated with other drugs known to prolong the QTc interval.

• Patients being considered for treatment with Serentil should have a baseline ECG performed and serum potassium levels measured. Serum potassium should be normalized before starting treatment and patients with a QTc interval greater than 450 msec should not receive Serentil. Periodic ECG's and serum potassium levels during Serentil treatment may be useful and Serentil should be discontinued in patients who are found to have a QTc interval over 500 msec.

• Treatment of Serentil overdosage should entail immediate cardiovascular monitoring to include continuous electrocardiographic monitoring to detect arrhythmias. Drugs that may produce additive QT-prolonging effects, such as disopyramide, procainamide, and quinidine, should be avoided in the treatment of Serentil overdosage.

These changes to the product labeling are based primarily on the FDA's review of a published study involving nine schizophrenic patients who had normal ECG tracings at baseline, a washout of prior psychotropic medication, and no significant cardiovascular, renal, or liver disease¹. These patients were treated with mesoridazine 75 mg/day for the first week, 200 mg/day during week 2, and 300 mg/day during weeks 3 and 4. ECG tracings were obtained at baseline, during weeks 2,3 and 4, and two weeks after drug discontinuation. At the lowest dose (75 mg), 4 of 9 patients displayed mild to moderate prolongation of the QT interval. At the highest dose (300 mg), all 9 patients had moderate prolongation of the QT interval. Two weeks after discontinuation, ECG's for 8 of the 9 patients had normalized. There were no reports of syncope or other serious adverse experiences in this study. Five of the patients did experience mild orthostatic hypotension.

Prolongation of the QTc interval has been associated with torsade de pointes-type arrhythmias and sudden death. There have been three published case reports of ventricular tachycardia, one with lethal outcome, in association with mesoridazine overdosage^2,3,4. A causal relationship between these events and mesoridazine therapy has not been established but, given the ability of mesoridazine to prolong the QTc interval, such a relationship is possible.

It is reasonable to assume that the co-administration of medications that prolong the QTc interval with Serentil would produce additive prolongation of the QTc interval. Therefore, the co-administration of Serentil with such drugs (e.g., quinidine) is now contraindicated.

Furthermore, patients with congenital long QT syndrome or a history of cardiac arrhythmias may be at increased risk for cardiac arrhythmias in the context of mesoridazine-associated QTc interval prolongation. Thus, Serentil is contraindicated in such patients as well.

Patients currently being treated with Serentil should be fully informed of the above information. Switching to a different antipsychotic agent should be considered and a decision regarding continuation of Serentil treatment should be based on a careful assessment of the potential benefits and risks of Serentil for each patient. Please note that thioridazine, a metabolic precursor of inesoridazine, also appears to have the capacity to prolong the QTc interval.

Please see the enclosed revised package insert for complete prescribing information.

Sincerely,

Alan Bess, MD
Vice President
Clinical Safety Epidemiology

Steven Cunningham, M.D.
Vice President
Medical Affairs

___________________________________________________________________

REFERENCES:
¹Dillenkoffer RL, et al. Electrocardiographic Evaluation of Mesoridazine (Serentil). Current Therapeutic Research 1972;14(2):71-72.
²Marrs-Simon PA, et al. Cardiotoxic manifestations of mesoridazine overdose. Ann Emerg Med 1988;17(10):1984-90.
³Niemann JT, et al. Cardiac conduction and rhythm disturbances following suicidal ingestion of mesoridazine, Ann Emerg Med 198 1;10(11):585-8.
⁴Vertrees JE and Siebel G. Rapid death resulting from mesoridazine overdose. Vet Hum Toxicol 1987;29(1):65-7.

Please note that Novartis Pharmaceuticals Corporation manufactures Serentil for distribution by Boehringer Ingelheim.

Boehringer Ingelheim is committed to providing you with the most current product information available for the management of patients receiving Serentil. For additional medical information about Serentil, call the Drug Information Unit at Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 during regular business hours. You can also further our understanding of adverse events by reporting all cases to Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., P.O. Box 368, Ridgefield, Connecticut 06877-0368 by phone (800) 542-6257 or to the FDA Program by phone at 1-800-FDA-1088, by fax 1-800-FDA-0178, by mail (using a postage-paid form) MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787; or the internet at www.FDA.gov/medwatch.

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