TASMAR - IMPORTANT DRUG WARNING
Source: November 16, 1998
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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
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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/>
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