TASMAR, SO FAR                     5 December 98    Page 1 of 3

I. Introduction and Summary

In the past few weeks I've read (and written) a lot about Tasmar
but I want now to draw it all into a concise and coherent story.
Since completion of trials and approval about a year ago, Tasmar
(tolcapone) has enjoyed great success among PD patients, because
it conserves levodopa, thereby reducing the needed frequency and
amount of levodopa dosage by about half. But two recent deaths,
and one earlier, from fulminant hepatitis (acute liver failure)
have prompted new warnings and restrictions, and great concern
among doctors and thousands of patients about whether to
continue with Tasmar, since the causal relation remains obscure.

II. Tolcapone: General

The symptoms of PD result mainly from a deficiency of dopamine,
a neurotransmitter that is produced in the brain. The aim of
drug treatment for PD is to compensate for that deficiency. For
nearly 40 years the most important PD drug has been levodopa
(as part of Sinemet), which is converted in the brain to
dopamine. But only 1% or so of levodopa taken orally gets into
the brain(1). Much of it is destroyed by a natural enzyme called
Catechol-O-Methyl Transferase (COMT). Tolcapone is one of only
two drugs known so far to conserve levodopa by blocking the
action of COMT. The other drug, entacapone (Comtan), isn't yet
approved. There is some concern that blocking COMT may be
harmful because, along with one other enzyme called MonoAmine
Oxidase (MAO-A), it helps to eliminate certain neurotoxins.
Therefore the combination of tolcapone with a MAO-A inhibitor
should be avoided. However, the selective MAO-B inhibitor
selegiline (Eldepryl) is safe to combine with tolcapone(2).

III. Fulminant Hepatitis

The liver is vulnerable to many threats, including several
viruses and a number of medical drugs. The response usually
is gradual deterioration, indicated by external symptoms such
as diarrhea, loss of weight and/or appetite, and jaundice
(yellowing of the skin and eyes). Two very sensitive internal
signs of liver distress are the enzymes Serum Glutamic-Pyruvic
Transaminase (SGPT) now called Alanine Transaminase (ALT), and
Serum Glutamic-Oxaloacetic Transaminase (SGOT) now called
Aspartate Transaminase (AST). Elevated AST indicates several
possible conditions besides liver disease, while ALT is more
specific to the liver. There are two confusing units of
measurement, but the smaller Systeme International, or
International Unit, seems to be the present standard. The
normal (healthy) range for AST is 117-450 IU, and that for
ALT is 17-350 IU. Higher than Upper Limit of Normal (ULN) is
cause for concern(3).

Unlike most liver disease which is chronic, fulminant hepatitis
has very fast onset, with diarrhea, confusion, and unconscious
spells followed within hours, if untreated, by coma and death.
The most successful treatment is surgical transplant to replace
the affected portion, which is found usually to be atrophied
and/or necrotic. Remarkably, survivors usually recover without
permanent liver damage(4). Tolcapone is implicated in the
three fulminant hepatitis deaths (known to me so far) that have
TASMAR SO FAR                                        Page 2 of 3

prompted the warning letter from Roche to U.S. doctors(5), and
suspension in Europe. The letter states that the "package
labeling" product description has been extensively revised.
Fulminant hepatitis is thought most often to be caused by one or
more viruses. One review(6) mentions a report of 16 cases, of
whom 14 died, from the Epstein-Barr virus. Various other
viruses are suspected but drugs, notably anticonvulsants for
epilepsy such as valproate (23 deaths), topiramate, and
felbamate, also have caused fulminant hepatitis(7).

IV. Safety and Efficacy Trials of Tolcapone

Nearly 600 subjects, plus controls, took part in the Phase 3
trials; half took 100mg of tolcapone 3 times a day, the others
took 200mg 3 times a day. Diarrhea was the 9th most common
adverse complaint, by 16% and 18% respectively, of each group.
The total who quit for any reason was 16%, of whom 1/3, 6%
of the total, quit because of diarrhea. Nausea was reported
by 30% and 35% of each group, and constipation by 6% and 8%(8).
Of the two groups, 1% and 3% had AST or ALT levels greater
than 3 times the upper limit of normal range (ULN) after 6
weeks to 3 months into the trial. A smaller number had levels
higher than 8 times normal, and quit the trial for that reason.
Of those having elevated transaminase levels who remained in
the trial, about half returned to baseline level within 1 to 3
months even though they continued taking tolcapone. Most of
those who quit because of the high level returned to baseline
within 2 to 3 weeks, although some took 1 or 2 months(9).

V. Value of Laboratory Testing

As a result of the elevated AST or ALT levels found in a few
of the trial subjects, the original product description leaflet
recommended checking those levels monthly for the first 3
months of taking tolcapone, every 6 weeks for the second 3
months, and more frequently if the level exceeds the ULN(9).
The more recent letter to doctors(5) advises checking both
enzymes every 2 weeks for the first year, every 4 weeks for the
next 6 months, and every 8 weeks thereafter, and to restart the
sequence if the dose is raised from 100mg 3 times a day to 200mg
3 times a day. The letter comments:
"Although frequent ...monitoring ...is deemed essential, it is
not clear that [it] 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..."
It also advises doctors prescribing tolcapone to obtain written
"informed consent" from patients who elect to start or continue
taking the drug, and that such patients should monitor
themselves for signs such as jaundice, clay-colored stools,
fatigue, loss of appetite, or lethargy.





TASMAR SO FAR                                     Page 3 of 3

VI. Case Reports of Fulminant Hepatitis

- A 55-yr-old female, after 53 days taking tolcapone 200mg tid
  developed diarrhea. Day 57, yellowing of skin and eyes. On day
  60, she died. No liver function tests were done after onset(9).

- A 74-yr-old female had PD for 20 yr, on levodopa (Madopar),
  amantadine, and other unrelated drugs. Hepatic aminotransfer-
  ases had been checked repeatedly and were normal. Stopped
  amantadine and began tolcapone 100mg bid. On day 63, admitted
  to hospital for confusion, falls, and jaundice. She was
  jaundiced, disoriented, sleepy, and had a mild asymmetric
  akinetic-rigid syndrome with resting tremor. AST 2541 IU/L,
  ALT 2904 IU/L (5 and 8 times ULN). Liver biopsy showed severe
  necrosis. Despite stopping tolcapone, she deteriorated quickly
  and died in coma on day 77. Permission for necropsy denied.
  Authors believe tolcapone was involved because of:
    Short preceding period of tolcapone treatment
    Histological evidence of drug-related toxicity
    Exclusion of other possible causes
    Occasional elevation by tolcapone of ALT or AST(10).

- A 39-yr-old female in treatment for siezures with drugs
  including topiramate. At start of topiramate, all blood tests
  for liver function were normal. Dosage increased stepwise
  from 50mg day to 300 mg/day in about 4 months. Felt tired and
  seemed drowsy; after a week, admitted because of lapses of
  consciousness. ALT was 1350 IU/L (4xULN). Next day, ALT was
  10,000 IU/L and during the next 2 days she developed severe
  encephalopathy. Four days after admission, she received a
  liver allograft and had an uncomplicated recovery. The tissue
  removed had massive necrosis and signs of fulminant hepatitis.
  (7)


1.  Duvoisin and Sage, Parkinson's Disease: 65,135
2.  Tasmar (tolcapone) product description leaflet: Warnings
3.  Merck Manual, 16th Ed.:2576,2582
4.  ibid:904
5.  Letter, Roche Laboratories Inc., 16 November 1988
6.  Feranchak A et al; Liver Transplant Surg 1998;4:469-476
7.  Bjoro K et al; Lancet, 7 October 1998:1119
8.  Tasmar product description leaflet: Adverse Reactions
9.  ibid: Precautions
10. Assai F et al; Lancet, 19 September 1998:958

--
J. R. Bruman   (818) 789-3694
3527 Cody Road
Sherman Oaks, CA 91403-5013