Drug Profile

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]

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]