tolcapone 100 MG Oral Tablet

INDICATIONS: TASMAR is indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson's disease. 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the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR. The effectiveness of TASMAR was demonstrated in randomized controlled trials in patients receiving concomitant levodopa therapy with carbidopa or another aromatic amino acid decarboxylase inhibitor who experienced end of dose wearing-off phenomena as well as in patients who did not experience such phenomena (see CLINICAL PHARMACOLOGY: Clinical Studies ).

DOSAGE AND ADMINISTRATION: 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 (see INDICATIONS and DOSAGE AND ADMINISTRATION sections). 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THE PATIENT WHO FAILS TO SHOW SUBSTANTIAL CLINICAL BENEFIT WITHIN 3 WEEKS OF INITIATION OF TREATMENT, SHOULD BE WITHDRAWN FROM TASMAR.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 (see PRECAUTIONS: Rhabdomyolysis ). Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. These patients should not ordinarily be considered for retreatment with TASMAR. Only prescribe TASMAR for patients taking concomitant carbidopa levodopa therapy. The initial dose of TASMAR is always 100 mg three times per day. The recommended daily dose of TASMAR is also 100 mg tid. In clinical trials, elevations in ALT occurred more frequently at the dose of 200 mg tid. While it is unknown whether the risk of acute fulminant liver failure is increased at the 200-mg dose, it would be prudent to use 200 mg only if the anticipated incremental clinical benefit is justified (see BOXED WARNING , WARNINGS , and PRECAUTIONS: Laboratory Tests ). If a patient fails to show the expected incremental benefit on the 200-mg dose after a total of 3 weeks of treatment (regardless of dose), TASMAR should be discontinued. In clinical trials, the first dose of the day of TASMAR was always taken together with the first dose of the day of levodopa/carbidopa, and the subsequent doses of TASMAR were given approximately 6 and 12 hours later. In clinical trials, the majority of patients required a decrease in their daily levodopa dose if their daily dose of levodopa was >600 mg or if patients had moderate or severe dyskinesias before beginning treatment. To optimize an individual patient's response, reductions in daily levodopa dose may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 30% in those patients requiring a levodopa dose reduction. (Greater than 70% of patients with levodopa doses above 600 mg daily required such a reduction.) TASMAR can be combined with both the immediate and sustained release formulations of levodopa/carbidopa. TASMAR may be taken with or without food (see CLINICAL PHARMACOLOGY ). Patients With Impaired Hepatic Function: TASMAR therapy should not be initiated in any patient with liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. (see BOXED WARNING , WARNINGS , and CLINICAL PHARMACOLOGY .) Patients With Impaired Renal Function: No dose adjustment of TASMAR is recommended for patients with mild to moderate renal impairment. However, patients with severe renal impairment should be treated with caution. The safety of tolcapone has not been examined in subjects who had creatinine clearance less than 25 mL/min (see CLINICAL PHARMACOLOGY ). Withdrawing Patients From TASMAR: As with any dopaminergic drug, withdrawal or abrupt reduction in the TASMAR dose may lead to emergence of signs and symptoms of Parkinson's disease or Hyperpyrexia and Confusion, a syndrome complex resembling the neuroleptic malignant syndrome (see PRECAUTIONS: Events Reported With Dopaminergic Therapy ). If a decision is made to discontinue treatment with TASMAR, then it is recommended to closely monitor the patient and adjust other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering TASMAR has not been systematically evaluated. As the duration of COMT inhibition with TASMAR is generally 5 to 6 hours on average, decreasing the frequency of dosage to twice or once a day may not in itself prevent withdrawal effects.

WARNINGS: (see BOXED 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 (see INDICATIONS and DOSAGE AND ADMINISTRATION sections). 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 (see PRECAUTIONS: Rhabdomyolysis ). Patients who develop evidence of hepatocellular injury 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. In controlled Phase 3 trials, increases to more than 3 times the upper limit of normal in ALT or AST occurred in approximately 1% of patients at 100 mg tid and 3% of patients at 200 mg tid. Females were more likely than males to have an increase in liver enzymes (approximately 5% vs 2%). Approximately one third of patients with elevated enzymes had diarrhea. Increases to more than 8 times the upper limit of normal in liver enzymes occurred in 0.3% at 100 mg tid and 0.7% at 200 mg tid. Elevated enzymes led to discontinuation in 0.3% and 1.7% of patients treated with 100 mg tid and 200 mg tid, respectively. Elevations usually occurred within 6 weeks to 6 months of starting treatment. In about half the cases with elevated liver enzymes, enzyme levels returned to baseline values within 1 to 3 months while patients continued TASMAR treatment. When treatment was discontinued, enzymes generally declined within 2 to 3 weeks but in some cases took as long as 1 to 2 months to return to normal. Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of TASMAR and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with TASMAR and a non-selective MAO inhibitor. Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline). Falling Asleep During Activities of Daily Living and Somnolence Tolcapone (TASMAR) increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products (see DOSAGE AND ADMINISTRATION ). Patients taking carbidopa levodopa products alone or with other dopaminergic medications have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes the operation of motor vehicles). Some of these episodes resulted in automobile accidents. Although many of these patients reported somnolence while on TASMAR, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events one year after the initiation of treatment. The risk for somnolence was increased with TASMAR treatment (TASMAR 100 mg-18%, 200 mg-14%, vs placebo-13%) compared to placebo treatment. In clinical trials, discontinuation due to somnolence occurred in 1% of patients treated with 200 mg TASMAR and 0% of patients treated with 100 mg TASMAR or placebo. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with TASMAR. Before initiating treatment with TASMAR, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with TASMAR such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing TASMAR in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with TASMAR continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

CONTRAINDICATIONS: TASMAR tablets are contraindicated in patients with liver disease, in patients who were withdrawn from TASMAR because of evidence of TASMAR-induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or its ingredients. TASMAR is also contraindicated in patients with a history of nontraumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication (see PRECAUTIONS: Events Reported With Dopaminergic Therapy ).

Mechanism of Action: Tolcapone is a selective and reversible inhibitor of catechol- O -methyltransferase (COMT). In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone enters the CNS to a minimal extent, but has been shown to inhibit central COMT activity in animals.