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TASMAR - IMPORTANT DRUG WARNING Source: November 16, 1998 MedWatch News MedWatch Program Food and Drug Administration This is the retyped text of a letter from Hoffmann-LaRoche Laboratories. Contact the company for a copy of any referenced enclosures. Dear Healthcare Professional: Hoffmann-La Roche Inc. would like to advise you of new warnings in the labeling for TASMAR (tolcapone) Tablets, a COMT inhibitor that is indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of Parkinson's disease. These new warnings pertain to reports of severe, potentially life threatening cases of severe hepatocellular injury, including three deaths from acute fulminant liver failure, that have been reported in association with the use of TASMAR. The revised labeling now includes a boxed warning which emphasizes that TASMAR should be used as an adjunct only in patients with Parkinson's disease on levodopa/carbidopa who are experiencing symptom fluctuations, and who are not responding satisfactorily to, or who are not appropriate candidates for other adjunctive therapies. The revisions to the labeling, made in consultation with the US Food and Drug Administration, reflect additional information obtained through postmarketing experience in an estimated 60,000 patients providing approximately 40,000 patient-years of worldwide use. The incidence of hepatocellular injury may be 10- to 100-fold higher than the background incidence in the general population. Before prescribing TASMAR, the physician should be thoroughly familiar with the details of the TASMAR prescribing information. TASMAR should not be used by patients until there has been a complete discussion of the risks. A "Patient Consent" section has been added to the revised labeling which should be thoroughly reviewed with any patient currently taking TASMAR or any new patient for whom it is intended to prescribe TASMAR. A boxed WARNING has been added to the approved product labeling as follows: Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections). Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR. TASMAR therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS: Rhabdomyolysis). Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. Accordingly, such patients should not ordinarily be considered for re-treatment. Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in post-marketing use. As of October 1998, 3 cases of fatal fulminant hepatic failure have been reported from approximately 60,000 patients providing about 40,000 patient years of worldwide use. This incidence may be 10- to 100-fold higher than the background incidence in the general population. Underreporting of cases may lead to significant underestimation of the increased risk associated with the use of TASMAR. A prescriber who elects to use TASMAR in the face of increased risk of liver injury is strongly advised to monitor patients for evidence of emergent liver injury. Patients should be advised of the need for self-monitoring for both the classical signs of liver disease (e.g., clay colored stools, jaundice) and the nonspecific ones (e.g., fatigue, loss of appetite, lethargy). Although a program of frequent laboratory monitoring for evidence of hepatocellular injury is deemed essential, it is not clear that baseline and periodic monitoring of liver enzymes will prevent the occurrence of fulminant liver failure. However, it is generally believed that early detection of drug-induced hepatic injury, along with immediate withdrawal of the suspect drug enhances the likelihood of recovery. It is also widely held, without a robust body of evidence, that patients with preexisting hepatic disease are more vulnerable to hepatotoxins. Accordingly, the following liver monitoring program is recommended. Before starting treatment with TASMAR, the physician should conduct appropriate tests to exclude the presence of liver disease. In patients determined to be appropriate candidates for treatment with TASMAR, serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) levels should be determined at baseline and then every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months, and then every 8 weeks thereafter. If the dose is increased to 200 mg tid (see DOSAGE and ADMINISTRATION section), liver enzyme monitoring should take place before increasing the dose and then be re-initiated at the frequency above. TASMAR should be discontinued if SGPT/ALT or SGOT/AST exceeds the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic failure (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness). Other related changes have been made to the INDICATIONS, WARNINGS, CONTRAINDICATIONS, PRECAUTIONS, ADVERSE EVENTS and DOSAGE AND ADMINISTRATION sections of the labeling. A highlighted list of the changes is attached. A full copy of the revised package insert is enclosed. WITHDRAWING PATIENTS FROM TASMAR: As with any dopaminergic drug, withdrawal or abrupt reduction in the TASMAR dose may lead to emergence of signs and symptoms of Parkinson's disease or Hyperpyrexia and Confusion, a syndrome complex resembling the Neuroleptic Malignant Syndrome. (See full package insert DOSAGE and ADMINISTRATION section.) FDA requests that all cases of serious liver injury occurring in Parkinson's patients whether on TASMAR or any other drug, be reported to the Agency via MEDWATCH by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, by mail at MEDWATCH HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857 or on the MEDWATCH web site at www.fda.gov/medwatch. Hoffmann-La Roche Inc. is committed to helping you treat your Parkinson's disease patients, and encourages you to follow these new recommendations carefully. The medical community can further our understanding of Tasmar by reporting adverse events to Roche Laboratories at 1-800-526-6367. Thank you for your continued support for Tasmar. If you have any questions about the new information in the package insert for Tasmar Tablets, please contact Roche Laboratories at 1-800-526-6367. Cordially, Russell H. Ellison, M.D. Vice President Medical Affairs Roche Laboratories Inc. 340 Kingsland Street Nutley, New Jersey 07110-1199 PharmInfoNet <http://pharminfo.com/medwatch/mwrpt61.html> Food and Drug Administration: MedWatch <http://www.fda.gov/medwatch/safety/1998/tasmar.htm> janet paterson 52 now / 41 dx / 37 onset snail-mail: PO Box 171 Almonte Ontario K0A 1A0 Canada website: a new voice <http://www.geocities.com/SoHo/Village/6263/> e-mail: <[log in to unmask]>