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(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 experiencing symptom fluctuations and are notdisease -dopa/carbidopa 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 (tolcapone) , 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the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR (tolcapone) .

TASMAR (tolcapone) 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Patients who develop evidence of hepatocellular injury while on TASMAR (tolcapone) and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR (tolcapone) is reintroduced.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 (tolcapone) 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 (tolcapone) 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).

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 (tolcapone) clinical trils,orthostatic hypotension was documented at least once in 8%, 14% and 13% of the patients treated with placebo, 100 mg and 200 mg TASMAR (tolcapone) tid, respectively. A total of 2%, 5% and 4% of the patients treated with placebo, 100 mg and 200 mg TASMAR (tolcapone) 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 (tolcapone) . Approximately 0.7% of the patients treated with TASMAR (tolcapone) (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.

Diarrhea

In clinical trials, diarrhea developed in approximately 8%, 16% and 18% of patients treated with placebo, 100 mg and 200 mg TASMAR (tolcapone) 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 (tolcapone) tid, respectively, withdrawing from the trials prematurely. Discontinuing TASMAR (tolcapone) 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 (tolcapone) , it led to hospitalization in 0.3%, 0.7% and 1.7% of patients in the placebo, 100 mg and 200 mg TASMAR (tolcapone) 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 workup (including occult blood samples).

Hallucinations

In clinical trials, hallucinations developed in approximately 5%, 8% and 10% of patients treated with placebo, 100 mg and 200 mg TASMAR (tolcapone) 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 (tolcapone) 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 (tolcapone) 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.

Dyskinesia

TASMAR (tolcapone) may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The rates of withdrawal for dyskinesia were 0.0%, 0.3% and 1.0% for placebo, 100 mg and 200 mg TASMAR (tolcapone) tid, respectively.

Rhabdomyolysis

Cases of severe rhabdomyolysis, with one case of multiorgan system failure rapidly progressing to death, have been reported. The complicated nature of these cases makes it impossible to determine what role, if any, TASMAR (tolcapone) played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Some cases, however, included fever, alteration of consciousness and muscular rigidity. It is possible, therefore, that the rhabdomyolysis may be a result of the syndrome described in Hyperpyrexia and Confusion (see PRECAUTIONS: Events Reported With Dopaminergic Therapy).

Renal Impairment

No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution (see CLINICAL PHARMACOLOGY: Pharmacokinetics of Tolcapone and DOSAGE AND ADMINISTRATION).

Renal Toxicity

When rats were dosed daily for 1 or 2 years (exposures 6 times the human exposure or greater) there was a high incidence of proximal tubule cell damage consisting of degeneration, single cell necrosis, hyperplasia, karyocytomegaly and atypical nuclei. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although it has been speculated that these toxicities may occur as the result of a species-specific mechanism, experiments which would confirm that theory have not been conducted.

Hepatic Impairment

Because of the risk of liver injury, TASMAR (tolcapone) therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING) or any other evidence of hepatocellular dysfunction.

Hematuria

The rates of hematuria in placebo-controlled trials were approximately 2%, 4% and 5% in placebo, 100 mg and 200 mg TASMAR (tolcapone) tid, respectively. The etiology of the increase with TASMAR (tolcapone) has not always been explained (for example, by urinary tract infection or coumadin therapy). In placebo-controlled trials in the United States (N=593) rates of microscopically confirmed hematuria were approximately 3%, 2% and 2% in placebo, 100 mg and 200 mg TASMAR (tolcapone) tid, respectively.

Events Reported With Dopaminergic Therapy

The events listed below are known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. While cases of Hyperpyrexia and Confusion have been reported in association with tolcapone withdrawal (see paragraph below), the expected incidence of fibrotic complications is so low that even if tolcapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that even a single example would have been detected in a cohort of the size exposed to tolcapone.

Hyperpyrexia and Confusion

In clinical trials, four cases of a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported during marketed use. These cases are of a complicated nature including the concomitant administration of several medications affecting brain monoaminergic (ie, MAO-I, tricyclic and selective serotonin reuptake inhibitors) and anticholinergic systems. It is difficult, therefore, to determine what role, if any, TASMAR (tolcapone) played in the pathogenesis. It may, therefore, be prudent to be particularly cautious if several concomitant medications of these types are used.

Fibrotic Complications

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).

Melanoma

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 Stalevo for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).

Laboratory Tests

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 (tolcapone) , the physician should conduct appropriate tests to exclude the presence of liver disease. In patients determined to be appropriate candidates for treatment with TASMAR (tolcapone) , 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 (tolcapone) 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).

Special Populations

TASMAR (tolcapone) 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. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS: Rhabdomyolysis). Patients with severe renal impairment should be treated with caution (see INDICATIONS, DOSAGE AND ADMINISTRATION, BOXED WARNING and WARNINGS).

Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis

Carcinogenicity studies in which tolcapone was administered in the diet were conducted in mice and rats. Mice were treated for 80 (female) or 95 (male) weeks with doses of 100, 300 and 800 mg/kg/day, equivalent to 0.8, 1.6 and 4 times human exposure (AUC = 80 ug·hr/mL) at the recommended daily clinical dose of 600 mg. Rats were treated for 104 weeks with doses of 50, 250 and 450 mg/kg/day. Tolcapone exposures were 1, 6.3 and 13 times the human exposure in male rats and 1.7, 11.8 and 26.4 times the human exposure in female rats. There was an increased incidence of uterine adenocarcinomas in female rats at exposure equivalent to 26.4 times the human exposure. There was evidence of renal tubular injury and renal tubular tumor formation in rats. A low incidence of renal tubular cell adenomas occurred in middle-and high-dose female rats; tubular cell carcinomas occurred in middle- and high-dose male and highdose female rats, with a statistically significant increase in high-dose males. Exposures were equivalent to 6.3 (males) or 11.8 (females) times the human exposure or greater; no renal tumors were observed at exposures of 1 (males) or 1.7 (females) times the human exposure. Minimal-to-marked damage to the renal tubules, consisting of proximal tubule cell degeneration, single cell necrosis, hyperplasia and karyocytomegaly, occurred at the doses associated with renal tumors. Renal tubule damage, characterized by proximal tubule cell degeneration and the presence of atypical nuclei, as well as one adenocarcinoma in a high-dose male, were observed in a 1-year study in rats receiving doses of tolcapone of 150 and 450 mg/kg/day. These histopathological changes suggest the possibility that renal tumor formation might be secondary to chronic cell damage and sustained repair, but this relationship has not been established, and the relevance of these findings to humans is not known. There was no evidence of carcinogenic effects in the long-term mouse study. The carcinogenic potential of tolcapone in combination with levodopa/carbidopa has not been examined.

Mutagenesis

Tolcapone was clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence of metabolic activation. Tolcapone was not mutagenic in the Ames test, the in vitro V79/HPRT gene mutation assay, or the unscheduled DNA synthesis assay. It was not clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes, or in an in vivo micronucleus assay in mice.

Impairment of Fertility

Tolcapone did not affect fertility and general reproductive performance in rats at doses up to 300 mg/kg/day (5.7 times the human dose on a mg/m2 basis).

Pregnancy

Pregnancy Category C

Tolcapone, when administered alone during organogenesis, was not teratogenic at doses of up to 300 mg/kg/day in rats or up to 400 mg/kg/day in rabbits (5.7 times and 15 times the recommended daily clinical dose of 600 mg, on a mg/m2 basis, respectively). In rabbits, however, an increased rate of abortion occurred at a dose of 100 mg/kg/day (3.7 times the daily clinical dose on a mg/m2 basis) or greater. Evidence of maternal toxicity (decreased weight gain, death) was observed at 300 mg/kg in rats and 400 mg/kg in rabbits. When tolcapone was administered to female rats during the last part of gestation and throughout lactation, decreased litter size and impaired growth and learning performance in female pups were observed at a dose of 250/150 mg/kg/day (dose reduced from 250 to 150 mg/kg/day during late gestation due to high rate of maternal mortality; equivalent to 4.8/2.9 times the clinical dose on a mg/m2 basis).

Tolcapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The combination of tolcapone (100 mg/kg/day) with levodopa/carbidopa (80/20 mg/kg/day) produced an increased incidence of fetal malformations (primarily external and skeletal digit defects) compared to levodopa/carbidopa alone when pregnant rabbits were treated throughout organogenesis. Plasma exposures to tolcapone (based on AUC) were 0.5 times the expected human exposure, and plasma exposures to levodopa were 6 times higher than those in humans under therapeutic conditions. In a combination embryo-fetal development study in rats, fetal body weights were reduced by the combination of tolcapone (10, 30 and 50 mg/kg/day) and levodopa/carbidopa (120/30 mg/kg/day) and by levodopa/carbidopa alone. Tolcapone exposures were 0.5 times expected human exposure or greater: levodopa exposures were 21 times the expected human exposure or greater. The high dose of 50 mg/kg/day of tolcapone given alone was not associated with reduced fetal body weight (plasma exposures of 1.4 times the expected human exposure).

There is no experience from clinical studies regarding the use of TASMAR (tolcapone) in pregnant women. Therefore, TASMAR (tolcapone) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women

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.

Pediatric Use

There is no identified potential use of tolcapone in pediatric patients.

Last reviewed on RxList: 3/12/2009
This monograph has been modified to include the generic and brand name in many instances.