Tasmar Information
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 CHNO 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
Tolcapone is a selective and reversible inhibitor of catechol--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.
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 (C) and the time of its occurrence (T) 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.
Tasmar () 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 ).
Tasmar () 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 ).
Tasmar () Warnings
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.
Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline).
Tasmar () Precautions
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 have had at least one episode of orthostatic hypotension) eventually withdrew from treatment due to adverse events presumably related to hypotension.
In controlled Phase 3 trials, approximately 5%, 4% and 3% of tolcapone 200 mg tid, 100 mg tid and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in all three treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement) compared to patients who did not have any episodes of documented hypotension.
In clinical trials, diarrhea developed in approximately 8%, 16% and 18% of patients treated with placebo, 100 mg and 200 mg Tasmar () tid, respectively. While diarrhea was generally regarded as mild to moderate in severity, approximately 3% to 4% of patients on tolcapone had diarrhea which was regarded as severe. Diarrhea was the adverse event which most commonly led to discontinuation, with approximately 1%, 5% and 6% of patients treated with placebo, 100 mg and 200 mg Tasmar () tid, respectively, withdrawing from the trials prematurely. Discontinuing Tasmar () for diarrhea was related to the severity of the symptom. Diarrhea resulted in withdrawal in approximately 8%, 40% and 70% of patients with mild, moderate and severe diarrhea, respectively. Although diarrhea generally resolved after discontinuation of Tasmar () , it led to hospitalization in 0.3%, 0.7% and 1.7% of patients in the placebo, 100 mg and 200 mg Tasmar () tid groups.
Typically, diarrhea presents 6 to 12 weeks after tolcapone is started, but it may appear as early as 2 weeks and as late as many months after the initiation of treatment. Clinical trial data suggested that diarrhea associated with tolcapone use may sometimes be associated with anorexia (decreased appetite).
No consistent description of tolcapone-induced diarrhea has been derived from clinical trial data, and the mechanism of action is currently unknown.
It is recommended that all cases of persistent diarrhea should be followed up with an appropriate work-up (including occult blood samples).
In clinical trials, hallucinations developed in approximately 5%, 8% and 10% of patients treated with placebo, 100 mg and 200 mg Tasmar () tid, respectively. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.3%, 1.4% and 1.0% of patients treated with placebo, 100 mg and 200 mg Tasmar () tid, respectively. Hallucinations led to hospitalization in 0.0%, 1.7% and 0.0% of patients in the placebo, 100 mg and 200 mg Tasmar () tid groups, respectively.
In general, hallucinations present shortly after the initiation of therapy with tolcapone (typically within the first 2 weeks). Clinical trial data suggest that hallucinations associated with tolcapone use may be responsive to levodopa dose reduction. Patients whose hallucinations resolved had a mean levodopa dose reduction of 175 mg to 200 mg (20% to 25%) after the onset of the hallucinations. Hallucinations were commonly accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming.
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (eg, tolcapone) that increase dopaminergic activity can cause them is unknown.
Three cases of pleural effusion, one with pulmonary fibrosis, occurred during clinical trials. These patients were also on concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion).
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Tasmar () for indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
Patients should be instructed to take Tasmar () only as prescribed.
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).
Patients should be informed of the clinical signs and symptoms that suggest the onset of hepatic injury (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness) (see ). If symptoms of hepatic failure occur, patients should be advised to contact their physician immediately.
Patients should be informed that hallucinations can occur.
Patients should be informed of the need to have regular blood tests to monitor liver enzymes.
Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with Tasmar () .
Patients should be advised that they should neither drive a car nor operate other complex machinery until they have gained sufficient experience on Tasmar () to gauge whether or not it affects their mental and/or motor performance adversely. Because of the possible additive sedative effects, caution should be used when patients are taking other CNS depressants in combination with Tasmar () .
Patients should be informed that nausea may occur, especially at the initiation of treatment with Tasmar () .
Patients should be advised of the possibility of an increase in dyskinesia and/or dystonia.
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease, including Tasmar () . Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Tasmar () . Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Tasmar () . Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Tasmar () .
Although Tasmar () has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see ).
Tolcapone is excreted into maternal milk in rats. Because of the possibility that tolcapone may be excreted into human maternal milk, patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
Although a program of frequent laboratory monitoring for evidence of hepatocellular injury is deemed essential, 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 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).
In animal studies, tolcapone was excreted into maternal rat milk.
It is not known whether tolcapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tolcapone is administered to a nursing woman.
Tasmar () Adverse Reactions
The imprecision of the estimated increase is due to uncertainties about the base rate and the actual number of cases occurring in association with Tasmar () . The incidence of idiopathic potentially fatal fulminant hepatic failure (ie, not due to viral hepatitis or alcohol) is low. One estimate, based upon transplant registry data, is approximately 3/1,000,000 patients per year in the United States. Whether this estimate is an appropriate basis for estimating the increased risk of liver failure among Tasmar () users is uncertain. Tasmar () users, for example, differ in age and general health status from candidates for liver transplantation. Similarly, underreporting of cases may lead to significant underestimation of the increased risk associated with the use of Tasmar () .
During the premarketing development of tolcapone, two distinct patient populations were studied, patients with end-of-dose wearing-off phenomena and patients with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects. Adverse events are, therefore, shown for these two populations combined.
The most commonly observed adverse events (>5%) in the double-blind, placebo-controlled trials (N=892) associated with the use of Tasmar () not seen at an equivalent frequency among the placebo-treated patients were dyskinesia, nausea, sleep disorder, dystonia, dreaming excessive, anorexia, cramps muscle, orthostatic complaints, somnolence, diarrhea, confusion, dizziness, headache, hallucination, vomiting, constipation, fatigue, upper respiratory tract infection, falling, sweating increased, urinary tract infection, xerostomia, abdominal pain, urine discoloration.
Approximately 16% of the 592 patients who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared to 10% of the 298 patients who received placebo. Diarrhea was by far the most frequent cause of discontinuation (approximately 6% in tolcapone patients vs 1% on placebo).
Tasmar () Drug Abuse And Dependence
Tolcapone is not a controlled substance.
Studies conducted in rats and monkeys did not reveal any potential for physical or psychological dependence. Although clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence, systematic studies in humans designed to evaluate these effects have not been performed.
Tasmar () Overdosage
The highest dose of tolcapone administered to humans was 800 mg tid, with and without levodopa/carbidopa coadministration. This was in a 1-week study in elderly, healthy volunteers. The peak plasma concentrations of tolcapone at this dose were on average 30 µg/mL (compared to 3 µg/mL and 6 µg/mL with 100 mg and 200 mg tolcapone, respectively). Nausea, vomiting and dizziness were observed, particularly in combination with levodopa/carbidopa.
The threshold for the lethal plasma concentration for tolcapone based on animal data is >100 µg/mL. Respiratory difficulties were observed in rats at high oral (gavage) and intravenous doses and in dogs with rapidly injected intravenous doses.
Tasmar () Dosage And Administration
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.
Treatment with Tasmar () should always be initiated at a dose of 100 mg tid, always as an adjunct to levodopa/carbidopa therapy. 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 , , ). 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 ).
Tasmar () How Supplied
Tasmar () is supplied as film-coated tablets containing 100 mg or 200 mg tolcapone. The 100 mg beige tablet and the 200 mg reddish-brown tablet are hexagonal and biconvex. Debossed on one side of the 100 mg tablet is Tasmar () and the tablet strength (100), on the other side is a V. Imprinted with black ink on one side of the 200 mg tablet is Tasmar () and the tablet strength (200), on the other side is a V.
Tasmar () 100 mg Tablets: bottles of 90 (NDC 0187-0938-01).
Tasmar () 200 mg Tablets: bottles of 90 (NDC 0187-0939-01).
Tasmar ()
Tasmar ()
Tasmar () Principal Display Panel - Mg Tablet Bottle Label
Tasmar () Principal Display Panel - Mg Tablet Bottle Label
