Published: December 1998

Tasmar (tolcapone) and Adverse Hepatic Events

December 1998

Medsafe Editorial Team

Also see 'Information for Consumers' and Consumer Medicine Information for Tasmar

On 17 December 1998 the terms of consent to the distribution of Tasmar in New Zealand changed as a result of reports of hepatoxicity and fulminant liver failure in patients treated with Tasmar.

New marketing and prescribing requirements

The new conditions of the consent to distribute Tasmar are:

  1. Only medical practitioners vocationally registered under the Medical Practitioners Act 1995 in the branch of internal medicine (i.e. specialist neurologists, geriatricians and general physicians) may prescribe Tasmar. The conditions of consent do not permit the prescribing of Tasmar by a general practitioner, not even after initiation of therapy by a specialist.
  2. Patients must be informed of the risk of adverse effects associated with Tasmar, and of the monitoring protocol, and give informed consent to the treatment. For patients already taking Tasmar, the information should be conveyed and informed consent given before the next prescription.
  3. Liver function tests must be performed:
    • before starting Tasmar;
    • every 2 weeks for the first 3 months; and
    • then every 4 weeks thereafter.

Patients with liver function enzyme test results above the normal should not be started on Tasmar. Patients whose liver function test results rise above normal levels should have a repeat test to confirm this result. If the result is confirmed, Tasmar should be discontinued by tapering the dose over a period of 5 days and increasing the dose of levodopa. The tapering is because the risk of neuroleptic malignant syndrome increases with a change in dose of Tasmar or other medication used in the treatment of Parkinson’s disease. If liver function is seriously impaired, it may be necessary to discontinue Tasmar more rapidly.

All cases of transaminase levels above the normal range, and of hepatic failure, should be reported to the Centre for Adverse Reactions Monitoring. This is a way both of continuing to monitor the safety of Tasmar and of determining the effectiveness of the monitoring programme.

Patients who are currently taking Tasmar under the supervision of a general practitioner should be referred to an appropriate specialist before their prescription runs out.

Pharmacists may dispense new and repeat prescriptions of Tasmar written by a general practitioner prior to 17 December 1998. Pharmac has advised Medsafe that Health Benefits Ltd will reimburse such presciptions.

On 14 December 1998 the general manager of Roche Products (New Zealand) Ltd, the sponsor of Tasmar, wrote to general practitioners and pharmacists about these new conditions for consent to distribute Tasmar in New Zealand.

Roche Products (New Zealand) Ltd intends to update Tasmar’s data sheet as soon as possible.

Tasmar and liver toxicity

Around 100,000 patients worldwide have used Tasmar. There have been 3 reports of fulminant liver failure resulting in death, associated with Tasmar. Two of these cases were confounded by the use of other medication or other diseases. In one additional case in which the patient recovered, no possible causes other than Tasmar were identified. The fulminant liver failure with Tasmar appears to be idiosyncratic. In both cases of unconfounded hepatic failure, the first signs developed within a month of commencing Tasmar.

In addition, around 19 cases of elevated transaminase levels above the upper level of normal have been reported. In some of these patients treatment was continued for two or more weeks after this result was obtained without serious clinical consequences. It appears that this group of cases is distinct from those resulting in liver failure.

In response to these data about liver toxicity some overseas regulatory agencies have withdrawn or suspended registration of Tasmar. Canada, Australia and the European Agency for the Evaluation of Medicinal Products have or will soon take this action. The US Food and Drug Administration has not suspended marketing authorisation but has introduced a strict monitoring protocol similar to that which Medsafe has introduced in New Zealand (see above).

In some patients Tasmar produces significant quality of life gains, which have not been achieved with other medication.

Medsafe considered that since there is a group of patients who clearly benefit significantly from Tasmar, and the demonstrated risk of hepatic failure is of a similar frequency to that seen with other medication (in particular halothane and isoniazid), it was best to manage the risk of hepatic failure by monitoring liver enzymes. It is not clear whether monitoring liver function fortnightly in the first 3 months, and 4-weekly thereafter, will prevent all cases of impairment of liver function leading to liver failure. Nor is it apparent whether there is a time after which it is no longer necessary to monitor liver function. All reported cases of transaminase levels above the normal range have occurred within the first 6 months of therapy, and most have occurred within 3 months.

Roche Products (New Zealand) Ltd and Medsafe will continue to monitor new data concerning liver toxicity with Tasmar and advise medical practitioners of new information and update the monitoring protocol as necessary.

Contact Roche Products (New Zealand) Ltd if you have any queries: PO Box 12-492, Penrose, Auckland phone 09 633 0700, fax 09 633 0722.