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Drug Profile

Do NOT stop taking this or any drug without the advice of your physician. Some drugs can cause severe adverse effects when they are stopped suddenly.

Do Not Use [what does this mean?]
Generic drug name: tolcapone (TOLE ka pone)
Brand name(s): TASMAR
GENERIC: not available FAMILY: Drugs for Parkinson’s Disease
Find the drug label by searching at DailyMed.

Alternative Treatment [top]

See entacapone.

Safety Warnings For This Drug [top]

FDA BLACK BOX WARNING

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.

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the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.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.

Patients who develop evidence of hepatocellular injury [liver toxicity] while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced.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 retreatment.

Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing 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 face of the 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 (eg, clay colored stools, jaundice) and the nonspecific ones (eg, 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 for 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 [3 times a day] liver enzyme monitoring should take place before increasing the dose and then be reinitiated 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).

Facts About This Drug [top]

Tolcapone (TASMAR) was approved by the Food and Drug Adminstration (FDA) in January 1998 for the treatment of Parkinson’s disease in conjunction with other drugs such as levodopa and carbidopa (SINEMET).

Drug pulled from market in Europe due to safety concerns

Tolcapone was first marketed in Europe in June 1997, six months before the FDA cleared it for use in the U.S. The liver toxicity warning was strengthened in Europe on October 1998, one month before the same change was made in the...

Tolcapone (TASMAR) was approved by the Food and Drug Adminstration (FDA) in January 1998 for the treatment of Parkinson’s disease in conjunction with other drugs such as levodopa and carbidopa (SINEMET).

Drug pulled from market in Europe due to safety concerns

Tolcapone was first marketed in Europe in June 1997, six months before the FDA cleared it for use in the U.S. The liver toxicity warning was strengthened in Europe on October 1998, one month before the same change was made in the U.S.

In November 1998, less than one year after the drug came on the market in the U.S., the FDA required new warnings in the drug’s professional product labeling (package insert) about cases of liver failure, some resulting in death, associated with the use of tolcapone.[1]

One day after the FDA’s November 1998 announcement, the European Medicines Evaluation Agency (EMEA) announced that the sale of tolcapone would be suspended in European markets.[2]

After its withdrawal from the European markets, the EMEA agreed to re-approve tolcapone if there was evidence of a therapeutic benefit in patients who switched to tolcapone from another COMT inhibitor. After re-examining the evidence, the EMEA granted a new, more restrictive license for tolcapone. It is reserved only for treatment in patients when another COMT inhibitor fails or is poorly tolerated.

The evidence presented by the manufacturer was a double-blind trial conducted between 2000 and 2002 in which 178 patients with Parkinson’s disease were randomized to receive either entacapone or tolcapone for three weeks. The primary outcome was the number of people for whom the treatment was effective. The response rate was 53 percent with tolcapone and 43 percent with entacapone, a difference that is not statistically significant.

There is no evidence showing that tolcapone is effective in most patients in whom entacapone fails, or that its adverse effect profile is better. The only trial that touches on these issues is flawed and fails to answer these questions.[3]

Tolcapone’s labeling now cautions that the drug should be reserved for use in patients who do not respond to or who are not appropriate candidates for other available treatments. A boxed warning also advises that in light of the severe liver toxicity, if a patient fails to show a substantial clinical benefit within the first three weeks of use, treatment should be withdrawn. The complete text of tolcapone’s boxed warning precedes this profile.

The actual number of people killed or injured by tolcapone is unknown because the FDA’s postmarketing safety surveillance system relies largely on health professionals’ voluntary reports of adverse drug reactions. There is no law or regulatory requirement for the reporting of adverse reactions. Consequently, the FDA estimates that only about 10 percent of actual incidents get reported.

Using the FDA’s adverse drug reaction database, we estimate that through the third quarter of 2001 there had been 21 cases of severe liver toxicity reported with tolcapone. Eight of these cases resulted in death.

The new labeling also includes an informed consent document that doctors are advised to use when prescribing tolcapone. Patients are asked to initial the following five statements:[4]

  1. The patient understands that tolcapone is used to treat certain types of patients with Parkinson’s disease and the doctor has told the patient that he/she is this type of patient.
  2. The patient understands there is a serious risk of severe liver failure, which may be potentially fatal, in using tolcapone.
  3. The patient understands that there are no laboratory tests that will predict an increased risk of fatal liver failure.
  4. The patient understands that he/she should have recommended blood tests before treatment with tolcapone is begun or continued, on a schedule of every two weeks for the first year, then every four weeks for the next six months, and then every eight weeks thereafter while taking tolcapone. The patient understands that although the blood tests may help detect liver failure if it develops, it may do so only after significant, irreversible, and potentially fatal damage has already occurred.
  5. The patient understands the need to report any unusual symptoms to the doctor and be especially aware of persistent nausea, fatigue, lethargy, decreased appetite, jaundice (yellowing of the skin or whites of the eyes), dark urine, itchiness, or right-side abdominal pain (the location of the liver), all typical symptoms of liver toxicity.

Very troubling is the fact that tolcapone’s original professional product labeling raised a red flag about the risk of liver toxicity, indicating that this possibility was well known before the drug was approved.[5] In clinical trials conducted before approval, approximately 1% of patients taking 100 milligrams three times a day and 3% taking twice that dose had liver-enzyme elevations three times the upper limit of normal. Such blood-level elevations are an early indicator of potential liver toxicity.

In reading the labeling for tolcapone, it appears that there is no way that this drug can be used safely. Liver toxicity testing is now required every two weeks for the first year that the drug is used. We have never seen another drug that requires such intensive testing to detect the development of an adverse drug reaction. Even this exhaustive level of testing may not detect liver damage soon enough to prevent significant, irreversible, and potentially fatal liver damage.

Regulatory actions surrounding tolcapone

2009: The patient package insert for tolcapone has been updated to include information on reports of an intense urge to gamble, increased sexual urges and other intense urges (and the inability to control these urges) in patients using this drug. In some cases the urges were stopped when the drug was decreased or stopped. However it has not been proven that the drug caused these events.[6]

last reviewed June 30, 2021