tolcapone
Dosage Form: tablet, film coated
Tasmar®
(tolcapone)
TABLETS
Before prescribing Tasmar, the physician should be thoroughly familiar with the details of this prescribing information.
Tasmar SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A COMPLETE DISCUSSION OF THE RISKS AND THE PATIENT HAS PROVIDED WRITTEN ACKNOWLEDGEMENT THAT THE RISKS HAVE BEEN EXPLAINED (SEE PATIENT ACKNOWLEDGEMENT OF RISKS SECTION).
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the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from Tasmar.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Patients who develop evidence of hepatocellular injury while on Tasmar and are withdrawn from the drug for any reason may be at increased risk for liver injury if Tasmar is reintroduced.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.
Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use. As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from more than 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. All 3 cases were reported within the first six months of initiation of treatment with Tasmar. Analysis of the laboratory monitoring data in over 3,400 Tasmar-treated patients participating in clinical trials indicated that increases in SGPT/ALT or SGOT/AST, when present, generally occurred within the first 6 months of treatment with 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 periodic laboratory monitoring for evidence of hepatocellular injury is recommended, it is not clear that 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. 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 periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy. After the first six months, periodic monitoring is recommended at intervals deemed clinically relevant. Although more frequent monitoring increases the chances of early detection, the precise schedule for monitoring is a matter of clinical judgement. If the dose is increased to 200 mg tid (see DOSAGE AND ADMINISTRATION section), liver enzyme monitoring should take place before increasing the dose and then be conducted every 2 to 4 weeks for the following 6 months of therapy. After six months, periodic monitoring is recommended at intervals deemed clinically relevant.
Tasmar should be discontinued if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness).
Tasmar Description
Tasmar® is available as tablets containing 100 mg or 200 mg tolcapone.
Tolcapone, an inhibitor of catechol-O-methyltransferase (COMT), is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy. It is a yellow, odorless, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25. The chemical name of tolcapone is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. Its empirical formula is C14H11NO5 and its structural formula is:
Inactive ingredients: Core: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone K-30, sodium starch glycolate, talc and magnesium stearate. Film coating: hydroxypropyl methylcellulose, titanium dioxide, talc, ethylcellulose, triacetin and sodium lauryl sulfate, with the following dye systems: 100 mg — yellow and red iron oxide; 200 mg — red iron oxide.
Tasmar - Clinical Pharmacology
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.
Pharmacodynamics
COMT Activity in Erythrocytes
Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte catechol-O-methyltransferase (COMT) activity after oral administration. The inhibition is closely related to plasma tolcapone concentrations. With a 200-mg single dose of tolcapone, maximum inhibition of erythrocyte COMT activity is on average greater than 80%. During multiple dosing with tolcapone (200 mg tid), erythrocyte COMT inhibition at trough tolcapone blood concentrations is 30% to 45%.
Effect on the Pharmacokinetics of Levodopa and its Metabolites
When tolcapone is administered together with levodopa/carbidopa, it increases the relative bioavailability (AUC) of levodopa by approximately twofold. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). In general, the average peak levodopa plasma concentration (Cmax) and the time of its occurrence (Tmax) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in healthy volunteers and Parkinson's disease patients have confirmed that the maximal effect occurs with 100 mg to 200 mg tolcapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by tolcapone when given with levodopa/carbidopa.
Population pharmacokinetic analyses in patients with Parkinson's disease have shown the same effects of tolcapone on levodopa plasma concentrations that occur in healthy volunteers.
Pharmacokinetics of Tolcapone
Tolcapone pharmacokinetics are linear over the dose range of 50 mg to 400 mg, independent of levodopa/carbidopa coadministration. The elimination half-life of tolcapone is 2 to 3 hours and there is no significant accumulation. With tid dosing of 100 mg or 200 mg, Cmax is approximately 3 µg/mL and 6 µg/mL, respectively.
Absorption
Tolcapone is rapidly absorbed, with a Tmax of approximately 2 hours. The absolute bioavailability following oral administration is about 65%. Food given within 1 hour before and 2 hours after dosing of tolcapone decreases the relative bioavailability by 10% to 20% (see DOSAGE AND ADMINISTRATION).
Distribution
The steady-state volume of distribution of tolcapone is small (9 L). Tolcapone does not distribute widely into tissues due to its high plasma protein binding. The plasma protein binding of tolcapone is >99.9% over the concentration range of 0.32 to 210 µg/mL. In vitro experiments have shown that tolcapone binds mainly to serum albumin.
Metabolism and Elimination
Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The main metabolic pathway of tolcapone is glucuronidation; the glucuronide conjugate is inactive. In addition, the compound is methylated by COMT to 3-O-methyl-tolcapone. Tolcapone is metabolized to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidized to the carboxylic acid. In vitro experiments suggest that the oxidation may be catalyzed by cytochrome P450 3A4 and P450 2A6. The reduction to an amine and subsequent N-acetylation occur to a minor extent. After oral administration of a 14C-labeled dose of tolcapone, 60% of labeled material is excreted in urine and 40% in feces. Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15) with a moderate systemic clearance of about 7 L/h.
Special Populations
Tolcapone pharmacokinetics are independent of sex, age, body weight, and race (Japanese, Black and Caucasian). Polymorphic metabolism is unlikely based on the metabolic pathways involved.
Hepatic Impairment
A study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. In patients with moderate cirrhotic liver disease (Child-Pugh Class B), however, clearance and volume of distribution of unbound tolcapone was reduced by almost 50%. This reduction may increase the average concentration of unbound drug by twofold (see DOSAGE AND ADMINISTRATION). Tasmar therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING).
Renal Impairment
The pharmacokinetics of tolcapone have not been investigated in a specific renal impairment study. However, the relationship of renal function and tolcapone pharmacokinetics has been investigated using population pharmacokinetics during clinical trials. The data of more than 400 patients have confirmed that over a wide range of creatinine clearance values (30 mL/min to 130 mL/min) the pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact that only a negligible amount of unchanged tolcapone (0.5%) is excreted in the urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. Accumulation of this stable and inactive metabolite should not present a risk in renally impaired patients with creatinine clearance above 25 mL/min (see DOSAGE AND ADMINISTRATION). Given the very high protein binding of tolcapone, no significant removal of the drug by hemodialysis would be expected.
Drug Interactions
See PRECAUTIONS: Drug Interactions.
Clinical Studies
The effectiveness of Tasmar as an adjunct to levodopa in the treatment of Parkinson's disease was established in three multicenter randomized controlled trials of 13 to 26 weeks' duration, supported by four 6-week trials whose results were consistent with those of the longer trials. In two of the longer trials, tolcapone was evaluated in patients whose Parkinson's disease was characterized by deterioration in their response to levodopa at the end of a dosing interval (so-called fluctuating patients with wearing-off phenomena). In the remaining trial, tolcapone was evaluated in patients whose response to levodopa was relatively stable (so-called non-fluctuators).
Fluctuating Patients
In two 3-month trials, patients with documented episodes of wearing-off phenomena, despite optimum levodopa therapy, were randomized to receive placebo, tolcapone 100 mg tid or 200 mg tid. The formal double-blind portion of the trial was 3 months long, and the primary outcome was a comparison between treatments in the change from baseline in the amount of time spent "On" (a period of relatively good functioning) and "Off" (a period of relatively poor functioning). Patients recorded periodically, throughout the duration of the trial, the time spent in each of these states.
In addition to the primary outcome, patients were also assessed using sub-parts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Parts V and VI); an Investigator's Global Assessment of Change (IGA), a subjective scale designed to assess global functioning in 5 areas of Parkinson's disease; the Sickness Impact Profile (SIP), a multi-item scale in 12 domains designed to assess the patient's functioning in multiple areas; and the change in daily levodopa/carbidopa dose.
In one of the studies, 202 patients were randomized in 11 centers in the United States and Canada. In this trial, all patients were receiving concomitant levodopa and carbidopa. In the second trial, 177 patients were randomized in 24 centers in Europe. In this trial, all patients were receiving concomitant levodopa and benserazide.
The following tables display the results of these 2 trials:
| |||
| Primary Measure | |||
| Baseline (hrs) | Change from Baseline at Month 3 (hrs) | p-value* | |
| Hours of Wake Time "Off " † | |||
| Placebo | 6.2 | -1.2 | — |
| 100 mg tid | 6.4 | -2.0 | 0.169 |
| 200 mg tid | 5.9 | -3.0 | <0.001 |
| Hours of Wake Time "On" † | |||
| Placebo | 8.7 | 1.4 | — |
| 100 mg tid | 8.1 | 2.0 | 0.267 |
| 200 mg tid | 9.1 | 2.9 | 0.008 |
| Secondary Measures | |||
| Baseline | Change from Baseline | ||
| at Month 3 | p-value* | ||
| Levodopa Total Daily Dose (mg) | |||
| Placebo | 948 | 16 | — |
| 100 mg tid | 788 | -166 | <0.001 |
| 200 mg tid | 865 | -207 | <0.001 |
| Global (overall) % Improved | |||
| Placebo | — | 42 | — |
| 100 mg tid | — | 71 | <0.001 |
| 200 mg tid | — | 91 | <0.001 |
| UPDRS Motor | |||
| Placebo | 19.5 | -0.4 | — |
| 100 mg tid | 17.6 | -1.9 | 0.217 |
| 200 mg tid | 20.6 | -2.0 | 0.210 |
| UPDRS ADL | |||
| Placebo | 7.5 | -0.3 | — |
| 100 mg tid | 7.7 | -0.8 | 0.487 |
| 200 mg tid | 8.3 | 0.2 | 0.412 |
| SIP (total) | |||
| Placebo | 14.7 | -2.2 | — |
| 100 mg tid | 14.9 | -0.4 | 0.210 |
| 200 mg tid | 17.6 | -0.3 | 0.216 |
| Effects on "Off" time and levodopa dose did not differ by age or sex. | |||
| |||
| Primary Measure | |||
| Baseline (hrs) | Change from Baseline at Month 3 (hrs) | p-value* | |
| Hours of Wake Time "Off " † | |||
| Placebo | 6.1 | -0.7 | — |
| 100 mg tid | 6.5 | -2.0 | 0.008 |
| 200 mg tid | 6.0 | -1.6 | 0.081 |
| Hours of Wake Time "On" † | |||
| Placebo | 8.5 | -0.1 | — |
| 100 mg tid | 8.1 | 1.7 | 0.003 |
| 200 mg tid | 8.4 | 1.7 | 0.003 |
| Secondary Measures | |||
| Baseline | Change from Baseline | ||
| at Month 3 | p-value* | ||
| Levodopa Total Daily Dose (mg) | |||
| Placebo | 660 | -29 | — |
| 100 mg tid | 667 | -109 | 0.025 |
| 200 mg tid | 675 | -122 | 0.010 |
| Global (overall) % Improved | |||
| Placebo | — | 37 | — |
| 100 mg tid | — | 70 | 0.003 |
| 200 mg tid | — | 78 | <0.001 |
| UPDRS Motor | |||
| Placebo | 24.0 | -2.1 | — |
| 100 mg tid | 22.4 | -4.2 | 0.163 |
| 200 mg tid | 22.4 | -6.5 | 0.004 |
| UPDRS ADL | |||
| Placebo | 7.9 | -0.5 | — |
| 100 mg tid | 7.5 | -0.9 | 0.408 |
| 200 mg tid | 7.7 | -1.3 | 0.097 |
| SIP (total) | |||
| Placebo | 21.6 | -0.9 | — |
| 100 mg tid | 16.6 | -1.9 | 0.419 |
| 200 mg tid | 18.4 | -4.2 | 0.011 |
In this study, 298 patients with idiopathic Parkinson's disease on stable doses of levodopa/carbidopa who were not experiencing wearing-off phenomena were randomized to placebo, tolcapone 100 mg tid, or tolcapone 200 mg tid for 6 months at 20 centers in the United States and Canada. The primary measure of effectiveness was the Activities of Daily Living portion (Subscale II) of the UPDRS. In addition, the change in daily levodopa dose, other subscales of the UPDRS, and the SIP were assessed as secondary measures. The results are displayed in the following table:
| Effects on Activities of Daily Living did not differ by age or sex. | |||
| |||
| Primary Measure | |||
| Baseline | Change from Baseline | ||
| at Month 6 | p-value* | ||
| UPDRS ADL | |||
| Placebo | 8.5 | 0.1 | — |
| 100 mg tid | 7.5 | -1.4 | <0.001 |
| 200 mg tid | 7.9 | -1.6 | <0.001 |
| Secondary Measures | |||
| Baseline | Change from Baseline | ||
| at Month 6 | p-value* | ||
| Levodopa Total Daily Dose (mg) | |||
| Placebo | 364 | 47 | — |
| 100 mg tid | 370 | -21 | <0.001 |
| 200 mg tid | 381 | -32 | <0.001 |
| UPDRS Motor | |||
| Placebo | 19.7 | 0.1 | — |
| 100 mg tid | 17.3 | -2.0 | 0.018 |
| 200 mg tid | 16.0 | -2.3 | 0.008 |
| SIP (total) | |||
| Placebo | 6.9 | 0.4 | — |
| 100 mg tid | 7.3 | -0.9 | 0.044 |
| 200 mg tid | 7.3 | -0.7 | 0.078 |
| Percent of Patients who | |||
| Developed Fluctuations | |||
| Placebo | — | 26 | — |
| 100 mg tid | — | 19 | 0.297 |
| 200 mg tid | — | 14 | 0.047 |
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).
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).
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 (eg, 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 (eg, selegiline).
Precautions
Hypotension/Syncope
Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Tolcapone enhances levodopa bioavailability and, therefore, may increase the occurrence of orthostatic hypotension. In Tasmar clinical trials, orthostatic hypotension was documented at least once in 8%, 14% and 13% of the patients treated with placebo, 100 mg and 200 mg Tasmar tid, respectively. A total of 2%, 5% and 4% of the patients treated with placebo, 100 mg and 200 mg Tasmar tid, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was invariably not accompanied by vital sign measurements). Patients with orthostasis at baseline were more likely than patients without symptoms to have orthostatic hypotension during the study, irrespective of treatment group. In addition, the effect was greater in tolcapone-treated patients than in placebo-treated patients. Baseline treatment with dopamine agonists or selegiline did not appear to increase the likelihood of experiencing orthostatic hypotension when treated with Tasmar. Approximately 0.7% of the patients treated with Tasmar (5% of patients who were documented to ha
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