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. 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