Tasmar (tolcapone) for Parkinson’s disease

 

What is Tasmar for Parkinson’s disease?

Tasmar (tolcapone) is an oral therapy that’s approved for use in combination with carbidopa and levodopa to ease the symptoms of Parkinson’s disease.

The therapy is usually prescribed to people who either are taking carbidopa and levodopa but experience off episodes, or periods when a medication wears off and motor symptoms return, or who have failed to respond to, or are not appropriate candidates for, other conventional adjunctive or additional treatments.

Tasmar initially was approved in the U.S. in 1998, but soon was withdrawn after several cases of acute liver failure were linked to its use. Later it was reintroduced, but with the additional requirement that patients must be informed about the potential risk of liver injury, and that liver enzyme levels should be strictly monitored during treatment.

Roche originally developed the therapy, but it was later acquired in the U.S and other regions, in 2004, by Bausch Health (formerly Valeant Pharmaceuticals). Generic equivalents of Tasmar also have been available since 2015.

Therapy Snapshot

Brand Name:	Tasmar
Chemical Name:	Tolcapone
Usage:	Used as an add-on therapy to ease Parkinson’s symptoms; can reduce off episodes
Administration:	Oral tablets

 

How does Tasmar work?

Parkinson’s disease is characterized by the progressive degeneration and death of nerve cells in the brain that produce the neurotransmitter dopamine. That chemical messenger sends signals between nerve cells and is essential for muscle movement.

Levodopa is the first-line treatment in Parkinson’s disease. It relieves motor symptoms as it is converted into dopamine in the brain, a process that serves to counterbalance the decline of nerve cells responsible for dopamine production.

However, as the disease progresses, patients’ responses to levodopa typically decrease. This often leads to so-called off episodes, in which patients experience flares of symptoms between doses of levodopa.

Therefore, the treatment is typically paired with substances that inhibit the actions of DOPA decarboxylase (DDC) and catechol-o-methyl transferase (COMT), two enzymes that convert levodopa into dopamine in the body prior to its delivery to the brain.

These combinations boost the amount of levodopa that reaches the brain, which lowers the required levodopa doses and eases its related side effects. Carbidopa is the most common DDC inhibitor used alongside levodopa.

Tasmar is a COMT inhibitor. By blocking the COMT enzyme, it increases the amount of levodopa that reaches the brain, which helps ensure a continuous stimulation of brain cells.

Who can take Tasmar?

Tasmar was approved by the U.S. Food and Drug Administration in 1998 as an add-on treatment to levodopa and carbidopa to help ease disease symptoms in Parkinson’s patients.

Due to an increased risk of liver failure among patients taking the therapy, it’s only recommended for use in individuals who experience symptom fluctuations despite treatment with levodopa and carbidopa and who are not responding adequately to, or are not candidates for, other adjunctive therapies.

In Europe, Tasmar was approved in 1997 as an add-on to levodopa and a DOPA decarboxylase inhibitor — either carbidopa or benserazide — among patients experiencing motor fluctuations who are intolerant or have failed to respond to other COMT inhibitors.

As in the U.S., Tasmar’s marketing authorization was suspended in Europe in 1998 after several patients experienced severe liver complications, some of which were fatal. That suspension was then lifted in 2004.

Who should not take Tasmar?

Tasmar is not recommended for certain patients, including:

• those with liver disease
• individuals who have previously discontinued Tasmar due to treatment-induced liver injury
• those with a known allergy to the medication or any of its ingredients
• people with a history of muscle damage or fever and confusion caused by using any medication.

The prescribing label for Tasmar has a boxed warning for serious, potentially life-threatening acute liver failure. Thus, if a patient fails to show substantial benefits from Tasmar within three weeks of treatment initiation, the medication should be discontinued.

Regular monitoring of liver enzyme levels is recommended for anyone taking Tasmar. If levels rise above two times the upper limit of normal, or if patients develop symptoms suggestive of liver problems, treatment should be stopped and not restarted.

In addition to these contraindications, patients typically should not receive Tasmar and a nonselective MAO inhibitor, used to treat depression. The medications together may result in an inhibition of normal metabolism. Also, patients with a major psychotic disorder should not be given Tasmar due to the risk of exacerbating psychosis.

Finally, caution is recommended when using the medication for those with severe dyskinesia — involuntary, uncontrolled movements common in Parkinson’s — or dystonia, characterized by repetitive muscle contractions. Patients with severe kidney impairment also should be extra careful when taking Tasmar.

How is Tasmar administered in Parkinson’s?

Tasmar is available as film-coated hexagonal tablets, each containing 100 mg of tolcapone. These tablets are beige to yellowish in color and imprinted with “Tasmar 100” on one side and a “V” on the other.

The recommended dose of the medication is 100 mg, or one tablet, given three times a day. The first daily dose is taken with the first dose of carbidopa and levodopa, while the second and third tablets are taken about six and 12 hours later.

If patients fail to experience benefits on a 100 mg dose, they can increase their dosage with caution to 200 mg three times a day. But due to the risk of liver injury, Tasmar should be discontinued if the expected benefits are not observed with that dose within three weeks.

While on treatment with Tasmar, patients may require adjustments in their daily levodopa dose to achieve optimal results. In clinical trials, most participants needed a reduction in their levodopa dose if they were taking more than 600 mg per day or had moderate to severe dyskinesias before starting treatment.

Tasmar can be used alongside both immediate and sustained-release forms of levodopa and carbidopa. It also can be taken with or without food.

Tasmar in clinical trials

The effectiveness of Tasmar as an addition to levodopa treatment for Parkinson’s disease was established in three large clinical trials, lasting from 13 to 26 weeks. These findings were then confirmed in four six-week trials.

Among the larger clinical studies, two included patients who were experiencing off periods, or motor fluctuations, at the end of the interval between levodopa doses. The third trial included participants whose response to levodopa was stable, without any motor fluctuations.

Trials in fluctuating patients

In the first two studies, patients with off periods despite optimal levodopa therapy were randomly assigned to receive a placebo, 100 mg Tasmar, or 200 mg Tasmar, three times daily for three months.

The main goal was to assess changes from the beginning of the study in daily on time, a period where motor symptoms are well controlled, and off time, where motor symptoms return and patients have poor functioning. During the trial, patients regularly recorded the time spent in each state.

One study involved 202 patients from the United States and Canada who received treatment as an add-on to carbidopa and levodopa for three months. Results showed the 200 mg dose significantly reduced daily off periods by three hours, and significantly increased on time by roughly the same amount of time.

While improvements also were seen with a 100 mg treatment, these were not considered statistically significant.

Significant reductions in the total daily doses of levodopa, as well as improvements in global functioning, were seen with both Tasmar doses, however.

The second study enrolled 177 patients in Europe, all of whom received Tasmar along with levodopa and benserazide. After three months, treatment with 100 mg Tasmar significantly reduced daily off periods by two hours, and increased the amount of time in an on state by 1.7 hours.

The 200 mg dose also significantly increased on time by the same amount, but reductions in off time were not statistically significant with this dose. As in the previous trial, both doses of Tasmar resulted in considerable reductions in the total daily doses of levodopa, and improvements in global functioning.

Additionally, significant gains were observed in motor function, as measured with the third part of the the Unified Parkinson’s Disease Rating Scale (UPDRS), in patients given the higher, 200 mg dose.

Trial in nonfluctuating patients

A total of 298 people with Parkinson’s disease were involved in the third study, conducted at sites in the U.S. and Canada. All of the participants were on stable doses of levodopa and carbidopa and not experiencing off periods.

Each was randomly assigned to a placebo, Tasmar 100 mg, or Tasmar 200 mg, given three times daily for six months. The main goal was to assess changes in the patients’ ability to perform activities of daily living, as measured by the UPDRS Part II.

At six months, both doses of Tasmar resulted in significant improvements in daily living activities. They also both led to significant reductions in the total daily dose of levodopa needed and improved motor function.

Common side effects of Tasmar

The most common side effects of Tasmar observed in clinical trials include:

• uncontrolled, involuntary movements, known as dyskinesia
• nausea
• diarrhea and vomiting
• anorexia
• a sleep disorder
• urine discoloration
• somnolence
• hallucinations
• abnormal muscle tone, known as dystonia
• sweating.

Liver injury

There have been reports of patients experiencing severe liver injury while on treatment with Tasmar, including some cases that were fatal. The incidence of deadly liver failure is about 10 to 100 times higher in people receiving the medication than in the general population. In all cases, these effects occurred in the first six months after the start of treatment.

Due to the potential for liver injury, treatment with Tasmar should not be started in patients with liver disease. Among individuals considered appropriate candidates for treatment, regular liver function checks are necessary. If patients exhibit any signs of liver injury — such as elevated liver enzymes or symptoms such as unusual fatigue, loss of appetite, dark urine, clay-colored stools, or jaundice, characterized by yellowing of the skin or eyes — a healthcare provider should be contacted immediately and treatment should be discontinued.

Patients taken off the medication due to signs of liver injury may face a higher risk of liver failure if Tasmar is reintroduced. Therefore, such patients should generally not be considered for retreatment.

Falling asleep during daily activities

There are reports of people falling asleep during daily activities while on levodopa and carbidopa or other dopaminergic treatments. As Tasmar increases the levels of levodopa in the blood in those receiving carbidopa and levodopa therapy, patients given this medication also have experienced increased sleepiness in some cases.

Before prescribing the therapy, healthcare providers should discuss any risk factors for increased sleepiness, such as sleep disorders and other coprescribed medications, with their patients.

People who experience any of these problems should notify their healthcare provider, and the possibility of discontinuing the treatment should be taken into consideration. Should these patients decide to continue on the therapy, they are advised to avoid activities like driving that could be dangerous if unexpected sleep episodes occur.

Low blood pressure and fainting

A number of levodopa-based therapies have been shown to increase the risk of orthostatic hypotension, a phenomenon in which blood pressure suddenly drops when rising from sitting or lying down. These episodes may lead to fainting.

Because Tasmar increases the amount of levodopa that’s available in the body, it may increase the risk of orthostatic hypotension and fainting episodes.

Diarrhea

Patients treated with Tasmar have reported experiencing diarrhea, which can be severe in some cases and lead to treatment discontinuation. Diarrhea usually occurs six to 12 weeks after starting treatment, but can appear as early as two weeks. Tasmar-related diarrhea might be linked to reduced appetite.

While discontinuing treatment generally resolves this symptom, all cases of persistent diarrhea should be followed up with an appropriate evaluation.

Hallucinations, psychosis, and impulse control

Tasmar has the potential to induce symptoms such as hallucinations (hearing or seeing things that are not real) and psychotic behavior. Impulse control issues like gambling or increased sexual urges also have been reported.

Patients with a major psychotic disorder should not be treated with Tasmar due to the risk of exacerbating psychosis. Those who develop impulse control disorders should consider reducing or discontinuing the treatment.

Dyskinesia

Because Tasmar increases levodopa availability, it may cause or exacerbate side effects such as dyskinesia that commonly occur with levodopa-based therapies. This symptom may require a reduction in levodopa daily dosage, but most patients in trials continued to experience frequent dyskinesia despite dose adjustments.

Blood in the urine

Some cases of blood in the urine, also known as hematuria, have been observed in clinical trials of Tasmar. The reasons for this occurrence were not fully known in some of these cases.

High fever and confusion associated with dose reductions

High fever, stiff muscles, and confusion have been reported following rapid dose reductions or discontinuation of Tasmar. Thus, any patients or healthcare providers who decide to lower the dose of the medication or discontinue it entirely should complete that process slowly and with the patient under supervision.

Muscle injury

Severe cases of muscle breakdown, called rhabdomyolysis, have been reported during treatment with Tasmar, but it’s not known if the medication plays a role in this symptom. Some cases may be due to prolonged and intense muscle movements, such as dyskinesias, while others may be related to the high fever often experienced by patients during rapid treatment discontinuation.

Tissue scarring complications

Complications associated with tissue scarring — including fluid accumulation between the membranes that cover the lungs, a thickening of those membranes, and scar tissue in the back of the abdominal cavity — have been observed in patients taking dopaminergic therapies, including some cases with Tasmar treatment. Although discontinuing the therapy may help resolve these issues, complete resolution is not always certain.

Melanoma

Individuals with Parkinson’s disease are more likely to develop melanoma, a form of skin cancer. The exact cause of this heightened risk remains uncertain, however, and could be associated with the disease or other factors like medications. Therefore, patients receiving Tasmar treatment are advised to undergo regular skin examinations to keep a close watch for any signs of melanoma.

Use in pregnancy and breastfeeding

Tasmar has limited research data regarding its use in pregnant patients. Animal studies suggest it may cause harm to a developing fetus, so its use during pregnancy should be carefully considered, with the potential benefits weighed against possible risks to both the mother and child.

Although data on tolcapone in human milk is lacking, the medication has been found in rat milk. Therefore, caution is advised when giving Tasmar to nursing patients.

Patients who are or plan to become pregnant, and those who are nursing or plan to breastfeed, should discuss this issue with their healthcare provider.

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