VA Class:CN500

AHFS Class:

• Catechol-O-Methyltransferase (COMT) Inhibitors 28:36.12

Generic Name(s):

• Tolcapone

Chemical Name:

• (3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)-methanone

Molecular Formula:

• C₁₄H₁₁NO₅

Tolcapone is a reversible catechol- O -methyltransferase (COMT) inhibitor; concomitant administration of tolcapone with levodopa and a decarboxylase inhibitor (e.g., carbidopa) results in more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,28

Parkinsonian Syndrome

Tolcapone is used as an adjunct to levodopa/carbidopa therapy for the symptomatic treatment of idiopathic parkinson disease.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,23,26,28 Because of the risk of potentially fatal, acute fulminant liver failure,1,30,31,32 tolcapone generally should be reserved for patients with parkinson disease receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to other adjunctive therapies (e.g., dopamine receptor agonists, monoamine oxidase [MAO] inhibitors) or are not candidates for these adjunctive therapies.1,31,32 Tolcapone therapy should not be initiated until the risks of therapy have been discussed with the patient and the patient has provided written acknowledgment that the risks have been explained.1 (See Cautions: Precautions and Contraindications.) Following initiation of tolcapone therapy, symptomatic improvement generally is evident within 3 weeks.1,7 Because of the risk of liver injury, the drug should be discontinued in patients who fail to show substantial clinical benefit (symptomatic improvement) within 3 weeks of initiating tolcapone therapy.1 (See Cautions: Hepatic Effects.)

Levodopa currently is the most effective drug for relieving the manifestations of parkinson disease.2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,23,26,29 However, the effectiveness of levodopa decreases substantially after the third year of treatment, and about 50% of patients develop motor response fluctuations after 5 years of treatment.2,9,26,29 Several types of motor fluctuations including a return of parkinsonian manifestations toward the end of an interdose period (“off” effect) may occur in some patients during long-term levodopa therapy.2,6,7,9,15,16,23,26,29 While the mechanisms underlying the changes in response to levodopa have not been fully elucidated, the “off” effect may be related to the pharmacokinetics of levodopa and its short plasma elimination half-life.2,9,16,23,26,29 The short half-life of levodopa is a result of rapid absorption and rapid metabolism by enzymatic decarboxylation and O -methylation.1,2,3,4,5,6,7,8,9,10,23

Several strategies have been evaluated and/or used to optimize the pharmacokinetics of levodopa.1,2,3,4,5,6,7,8,9,10,23,29 One widely employed strategy is administration of levodopa in combination with a decarboxylase inhibitor.1,2,3,4,5,6,7,8,9,10,23,26 Concomitant administration of a decarboxylase inhibitor (e.g., carbidopa) with levodopa increases the bioavailability of levodopa, but does not increase plasma half-life.23 COMT inhibitors (e.g., tolcapone) provide another strategy to optimize the pharmacokinetics of levodopa.1,2,3,4,5,6,7,8,9,10,23,26,29

Tolcapone enhances the clinical efficacy of levodopa by increasing the AUC and half-life of levodopa without increasing the peak plasma concentration.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,23,26 Pharmacokinetic alterations associated with tolcapone may be preferred to increasing the levodopa dosage, since increasing the levodopa dosage results in increased peak plasma levodopa concentrations and increased incidence of dyskinesia and other potential toxicities as well as in potentially greater peak-trough fluctuations.23,26 While extended-release preparations of levodopa/carbidopa slow absorption and may result in decreased peak-trough fluctuations when dosed appropriately, these preparations also result in less predictable time to peak plasma levodopa concentrations and reduced bioavailability of levodopa, and have not resulted in substantially different incidences of motor complications compared with conventional preparations in some studies;23,26,29 it has been suggested that more frequent dosing of extended-release preparations, particularly when combined with a COMT inhibitor, may improve therapeutic benefit.26

Efficacy of tolcapone as an adjunct to levodopa for the management of parkinson disease has been established in several randomized, placebo controlled studies of up to 12 months' duration in patients receiving levodopa in combination with a decarboxylase inhibitor (e.g., carbidopa).1,6,7,9,15,16,26,28 Tolcapone has been evaluated in patients who exhibited predictable end-of-dose motor fluctuations in response to levodopa (i.e., fluctuating response with “off” phenomena) and in patients with early parkinson disease whose response to levodopa was stable (nonfluctuating).1,2,6,7,9,15,16,26,28 In studies in patients with “off” phenomena, the primary efficacy index was change between baseline and month 3 in the amount of time in a 16-hour day spent “on” (period of good functioning) and “off” (period of poor functioning) as measured using self rating charts.1,6,9,16 In addition, improvement in manifestations of parkinson disease was assessed using parts of the Unified Parkinson's Disease Rating Scale (UPDRS), a Global Assessment of Change (IGA), the Sickness Impact Profile (SIP), and changes in levodopa dosage.1,6,7,9,15,16 In patients with early parkinson disease whose response to levodopa was stable, the primary efficacy index was the UPDRS subset II (activities of daily living).1,9 Improvement in manifestations of parkinson disease was also assessed using UPDRS subset III (motor functioning), SIP scores, and changes in levodopa dosage.1,9

Results of clinical studies indicate that tolcapone enhances the efficacy of levodopa.1,2,6,9,16,28 In placebo-controlled studies in patients who were experiencing a deteriorating response to levodopa, tolcapone reduced the severity of “off” motor fluctuations, allowed a reduction in levodopa dosage, and improved overall clinical status.1,6,9,16 In placebo-controlled studies in North American and European patients whose levodopa therapy was complicated by “off” phenomena, therapy with tolcapone 200 mg 3 times daily was associated with a decrease in “off” time of 1.6-3 hours and an increase in “on” time of 1.7-2.9 hours.1,9,16 Clinically important changes in “on/off” time in North American patients receiving tolcapone 100 mg 3 times daily were not observed; however, a decrease in “off” time of 2 hours and an increase in “on” time of 1.7 hours occurred in European patients receiving tolcapone 100 mg 3 times daily.1,9,16 Response to tolcapone in terms of changes in “off” time in patients receiving levodopa as levodopa/carbidopa conventional tablets could not be distinguished from that in patients receiving levodopa/carbidopa extended-release tablets; however, the study was not specifically designed to assess potential differences between the levodopa/carbidopa formulations.9 While further study is needed to establish safety and efficacy of tolcapone during long-term therapy, improvement in “off” phenomena observed at 3 months was maintained throughout the study (i.e., at 9-12 months).9,16

In these studies, maintenance dosage of levodopa was reduced in patients receiving tolcapone.1,9,16,23 The mean total daily levodopa dosage decreased 166 mg from the baseline dose of 788 mg in North American patients receiving tolcapone 100 mg 3 times daily for 3 months, and 207 mg from a baseline of 865 mg in North American patients receiving tolcapone 200 mg 3 times daily.1,9 The mean total daily levodopa dosage decreased 109 mg from the baseline dose of 667 mg in European patients receiving tolcapone 100 mg 3 times daily for 3 months, and 122 mg from a baseline of 675 mg in European patients receiving tolcapone 200 mg 3 times daily.1,16 In addition, 3 months of therapy with tolcapone 100 or 200 mg 3 times daily resulted in an overall improvement as measured by IGA in 70-71 or 78-91% of patients, respectively.1,9,16 Improvement in the UPDRS subscale III (motor functioning) and total SIP scores was seen in European patients receiving tolcapone 200 mg 3 times daily; however, substantial improvement in UPDRS subscale II (activities in daily living), UPDRS subscale III, and total SIP scores was not observed in North American patients receiving either tolcapone dosage or in European patients receiving tolcapone 100 mg 3 times daily.1,9,16 While both dosages of tolcapone were equally effective in terms of changes in “on-off” time in European patients, changes in “on-off” time in North American patients and UPDRS and SIP scores in European patients suggest that tolcapone 200 mg 3 times daily is more effective than 100 mg 3 times daily.1,9,16 Because the 200-mg dose is not as well tolerated as the 100-mg dose, the higher dosage should be reserved for patients who do not respond adequately to the lower dosage.1,16,28

In placebo-controlled studies in levodopa-treated patients with early parkinson disease, addition of tolcapone 100 or 200 mg 3 times daily for 6 months was associated with a substantial reduction in UPDRS activity of daily living and motor scores, and a reduction in mean daily levodopa dosage of 21-32 mg from a baseline of 370-381 mg.1,7,28 The effect of tolcapone on activities of daily living was evident after 1-2 weeks of therapy; continued improvement occurred during the first 6 weeks, and was greatest in those with the most severe impairment at baseline.7 Improvement in quality of life was maintained throughout the study (i.e., 12 months).7 While both dosages appear to be equally effective in improving clinical status in stable patients with early parkinson disease, fewer patients receiving the 200-mg dose of tolcapone developed levodopa-associated motor fluctuation than those receiving placebo.1,7,33

Initially, it had been hoped that the long-term benefits of tolcapone therapy might be greatest if therapy were initiated early in the course of parkinson disease before motor complications of levodopa had developed or become established;26 however, reports of severe hepatotoxicity have resulted in a far more cautious and conservative approach to tolcapone therapy.1,30,31,32 The benefits (more consistent levodopa concentrations, reduced risk of motor complications) associated with use of tolcapone in patients with parkinson disease26 must be weighed against the risk of liver injury associated with the drug.33

For additional information on the management of parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa 28:92.

Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone generally should be reserved for patients with parkinson disease receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to other adjunctive therapies or are not candidates for these adjunctive therapies.1 Following initiation of tolcapone therapy, symptomatic improvement generally is evident within 3 weeks.1,7 Because of the risk of liver injury in patients receiving tolcapone, the drug should be discontinued in patients who do not experience symptomatic improvement within 3 weeks of initiating tolcapone therapy.1 Tolcapone therapy should not be initiated in patients with clinical evidence of active liver disease, or ALT (SGPT) or AST (SGOT) concentrations exceeding the upper limit of normal, or any other evidence of hepatocellular dysfunction.1 Tolcapone therapy generally should not be reintroduced in a patient who previously experienced tolcapone-associated hepatic injury.1 Tolcapone should be used with caution in patients with severe dystonia or dyskinesia.1

Administration

Tolcapone is administered orally in 3 equally divided doses daily.1,6,7,9,16,23,28 Although food may reduce the bioavailability of tolcapone (e.g., by 10-20%), the manufacturer states that the drug can be taken without regard to meals.1 In clinical studies, the first dose of the day of tolcapone was administered together with the first dose of the day of levodopa/carbidopa; subsequent doses of tolcapone are administered 6 and 12 hours later.1,6,7,9,28 Tolcapone can be administered with conventional or extended-release preparations of levodopa/carbidopa.1,9

Tolcapone therapy should not be initiated until the risks of therapy have been discussed with the patient and the patient has provided written informed consent.1

Dosage

For the management of idiopathic parkinson disease, tolcapone is given in conjunction with levodopa/carbidopa.1 To optimize patient response, reductions in the daily levodopa/carbidopa dosage may be necessary.1,6,7,9,16,28 In clinical studies, most patients (70%) who were receiving more than 600 mg of levodopa daily or who had moderate to severe dyskinesias before initiating tolcapone therapy required a reduction in levodopa dosa the average reduction in daily levodopa dosage was about 30%.1,6,7,9,16,23

The usual initial dosage of tolcapone is 100 mg 3 times daily.1,28 In clinical studies, increases in liver function test results (i.e., ALT) occurred more frequently in patients receiving tolcapone 200 mg 3 times daily than in those receiving 100 mg 3 times daily.1 Whether the risk of fulminant hepatic failure is increased in patients receiving the higher dosage is not known; however, the manufacturer states that it is prudent to reserve the higher dosage of 200 mg 3 times daily for situations when the anticipated incremental benefit is justified.1 If a patient fails to show the expected clinical benefit while receiving tolcapone 200 mg 3 times daily for 3 weeks, the drug should be discontinued.1

Dosage in Renal Impairment

The manufacturer states that dosage adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance exceeding 30 mL/minute).1 The safety of tolcapone in patients with creatinine clearance less than 25 mL/minute has not been evaluated.1

Discontinuance of Tolcapone Therapy

Like dopaminergic drugs, discontinuance of tolcapone or abrupt reduction in dosage may lead to reemergence of the signs and symptoms of parkinson disease or a symptom complex resembling neuroleptic malignant syndrome (e.g., hyperpyrexia and confusion).1 If tolcapone therapy is discontinued, the patient should be closely monitored and adjustments made, if needed, in the dosage of dopaminergic therapy.1 If a patient experiences hyperpyrexia or severe rigidity following discontinuance of tolcapone, the possibility that the patient is experiencing a symptom complex resembling neuroleptic malignant syndrome should be considered in the differential diagnosis.1 Tapering the dosage of tolcapone has not been systematically evaluated.1 Reducing the frequency of administration to twice or once daily prior to discontinuing may not prevent these events, since the duration of COMT inhibition associated with tolcapone therapy is 5-6 hours or longer.1,2,4,5,8

Information on the safety of tolcapone has been obtained principally from clinical studies in patients experiencing a deteriorating response to levodopa and in patients with early parkinson disease whose response to levodopa was stable.1,7,9,16 While tolcapone generally is well tolerated,1,7,9,16 cases of serious and potentially fatal adverse effects (e.g., severe hepatocellular injury) have been reported during postmarketing surveillance.1,30,31,32 (See Cautions: Precautions and Contraindications.)

The most frequent adverse effects reported in patients receiving tolcapone in clinical studies included dyskinesia, dystonia, nausea, anorexia, sleep disturbances/insomnia, orthostatic instability, muscle cramping, excessive dreaming, and somnolence; these effects are dopaminergic effects associated with levodopa therapy.7,9,15,16,28 The most frequent adverse nondopaminergic effect reported in patients receiving tolcapone was diarrhea.7,9,15,16,28,29 Discontinuance of tolcapone therapy was required in about 16% of patients in clinical studies, principally because of diarrhea.1,7,9,16

Hepatic Effects

Severe hepatocellular injury, including fulminant liver failure resulting in death, has been reported during postmarketing surveillance.1,30,31,32 As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from more than 40,000 patient-years of worldwide use.1,30,31,32 The 3 cases of fatal fulminant hepatic failure occurred during the first 6 months of tolcapone therapy.1 This incidence may be 10- to 100-fold higher than the background incidence in the general population.1,32 While these figures provide an estimate of the increased risk of severe hepatocellular injury associated with tolcapone therapy, a more precise determination of risk cannot be made because of possible underreporting of the number of tolcapone-treated patients who experienced adverse hepatic effects and uncertainty in the base rate of hepatic failure in individuals in the same age group and with the same health profile as the patients who received tolcapone.1

Elevations in the results of one or more liver function test results have occurred in patients receiving tolcapone in phase III clinical studies, and required discontinuance of therapy in 0.3% of those receiving tolcapone 100 mg 3 times daily and in 1.7% of those receiving tolcapone 200 mg 3 times daily.1,7,9,16 Increases in liver function test results have been reported more frequently in women than men (5 versus 2%), and were accompanied by diarrhea in about one-third of patients.1 Increases in serum concentrations in ALT (SGPT) or AST (SGOT) (more than 3 times the upper limit of normal) occurred in 1 or 3% of patients receiving tolcapone 100 or 200 mg 3 times daily in clinical studies.1,7,9,16,28 Substantial increases in serum concentrations of ALT or AST (more than 8 times the upper limit of normal) occurred in 0.3 or 0.7% of patients receiving tolcapone 100 or 200 mg 3 times daily.1

Most cases of elevated liver function test results occurred 6 weeks to 6 months following initiation of tolcapone therapy; enzyme concentrations generally returned to baseline within 1-3 months in about 50% of patients in clinical studies who continued tolcapone therapy and within 2-3 weeks up to 1-2 months in patients who discontinued tolcapone.1,7,16 However, the patient's condition also can deteriorate rapidly30 and result in death1,30,31,32 despite discontinuance of the drug.30 (See Cautions: Precautions and Contraindications.) Liver biopsy findings in fulminant cases of hepatitis with tolcapone have included severe centrolobular necrosis and lobular inflammatory infiltrate consisting mainly of plasma cells and eosinophilia;30 hepatic changes may not be visible on ultrasound.30

GI Effects

Diarrhea has been reported in 16-18% of patients receiving tolcapone in clinical studies, and 6% of patients required discontinuance of the drug because of diarrhea.1,2,4,5,7,9,15,16 Discontinuance of tolcapone was related to the severity of diarrhea, with 8, 40, or 70% of those with mild, moderate, or severe diarrhea discontinuing the drug.1 While diarrhea generally was of mild to moderate intensity,1,7 severe diarrhea occurred in 3-4% of patients and resulted in hospitalization in 0.7 or 1.7% of patients receiving tolcapone 100 or 200 mg 3 times daily.1 Diarrhea generally occurs during the first 6-12 weeks of tolcapone therapy, but may occur as early as 2 weeks or as late as several months following initiation of tolcapone therapy.1,7,16 Diarrhea frequently is associated with anorexia, is dose-related, and resolves with continuing therapy or following discontinuance of tolcapone.1,7,15,16

Nausea, which likely is a dopaminergic effect (secondary to tolcapone-induced increases in levodopa concentrations) and generally occurs during the first 3 months of therapy, was reported in 30-35% of patients receiving tolcapone in clinical studies.1,2,5,6,7,8,9,10,14,15,16 Anorexia,1,7,9 vomiting,1,5,6,7,8,14,15,16 constipation,1,8,9,15 abdominal pain,1,2,5,6,16 xerostomia,1,7,9,10 dyspepsia,1,2 or flatulence1 was reported in 19-23, 8-10, 6-8, 5-6, 5-6, 3-4, or 2-4%, respectively, of patients receiving tolcapone in clinical studies.1 While a causal relationship to the drug has not been established, taste alteration,1 tooth disorder,1 or weight loss1 occurred in at least 1% of patients receiving tolcapone, and dysphagia,1 GI hemorrhage,1 gastroenteritis,1 mouth ulceration,1 increased salivation,1 abnormal stools,1 esophagitis,1 cholelithiasis,1 colitis,1 tongue disorder,1 or rectal disorder occurred in 0.1-1% of patients.1 Cholecystitis,1 duodenal ulcer,1 GI carcinoma,1 or stomach atony1 occurred in less than 0.1% of patients.1

Nervous System and Muscular Effects

Addition of tolcapone may exacerbate levodopa-associated dyskinesias, especially in patients already experiencing dyskinesias.1,2,6,7,9,15,16,26 This effect, which was reported in 42 or 51% of patients receiving tolcapone 100 or 200 mg 3 times daily in clinical studies, usually occurs within 24 hours after initiating tolcapone therapy and is controlled by reducing the levodopa dosage 20-30%.1,2,6,7,9,16,26 However, some patients continue to experience frequent dyskinesias after reduction in the levodopa dosage.1 Discontinuance of tolcapone because of dyskinesia was required in 0.3 or 1% of patients receiving tolcapone 100 or 200 mg 3 times daily.1

Dystonia,1,10,15 muscle cramping,1,10,15,16 hyperkinesia,1 hypokinesia,1 or hypertonia1 was reported in 19-22, 17-18, 2-3, 1-3, or 1%, respectively, of patients receiving tolcapone in clinical studies.1 Dystonia has been reported more frequently in patients younger than 75 years of age than in older patients.1

Numerous CNS and psychiatric disturbances may occur in patients receiving tolcapone in conjunction with levodopa, and many are likely to be the result of increased levodopa concentrations and CNS bioavailability induced by tolcapone.1,7,9,16,24,33 Hallucinations1,6,9,10,13,15,16 have been reported in 8-10% of patients receiving tolcapone in clinical studies, required hospitalization in up to 1.7% of patients, and resulted in discontinuance of the drug in 1-1.4% of patients.1,9,15 Hallucinations generally present within the first 2 weeks of tolcapone therapy, are commonly accompanied by confusion and to a lesser extent insomnia and excessive dreaming, and occur more frequently in patients 75 years of age or older than in younger patients.1 Experience from clinical studies indicates that tolcapone-associated hallucinations may be responsive to levodopa dosage reduction; patients whose hallucinations resolved had a mean levodopa dosage reduction from baseline (i.e., onset of hallucinations) of 175-200 mg daily (20-25%).1

New or worsening mental status and behavioral changes, which can be severe and include psychotic-like behavior, have been reported during tolcapone therapy or after initiating or increasing dosage of the drug in the postmarketing setting.1 Such abnormal thinking and behavior may consist of one or more of the following manifestations: paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.1 Other drugs used in the treatment of parkinson disease can produce similar effects on thinking and behavior.1

Sleep disturbances/insomnia,1,6,7,9,16 excessive dreaming,1,15,16 somnolence,1,2,4,5,9,14,16 confusion,1,6,15,24 dizziness,1,5,7,8,14,15 or headache1,2,4,5,7,8,14,16 has been reported in 24-25, 16-21, 14-18, 10-11, 6-13, or 10-11%, respectively, of patients receiving tolcapone in clinical studies.1 Somnolence was reported more frequently in women than men.1 Most of these effects presumably result from increased dopaminergic effects.7,9,16

Adverse nervous system effects occurring in 1-3% of patients include paresthesia,1,2,4 stiffness,1 arthritis,1 agitation,1,15 irritability,1 mental deficiency,1 hyperactivity,1 panic reaction,1 or euphoria.1 While a causal relationship has not been established, mental depression,1 hypoesthesia,1 tremor,1,15 speech disorder,1 vertigo,1 emotional disorder,1 myalgia,1 arthralgia,1 limb pain,1 anxiety,1 paresis,1 lethargy,1 asthenia,1 or abnormal gait1 has been reported in at least 1% of tolcapone-treated patients, and migraine headache,1 neuralgia,1 amnesia,1 extrapyramidal syndrome,1 hostility,1 increased or decreased libido,1 manic reactions,1 nervousness,1 paranoid reaction,1 cerebral ischemia,1 cerebrovascular accident,1 delusions,1 neuropathy,1 apathy,1 choreoathetosis,1 myoclonus,1 psychosis,1 abnormal thinking,1 twitching,1 tenosynovitis,1 arthrosis,1 or joint disorder has occurred in 0.1-1% of patients.1 Antisocial reaction,1 delirium,1 encephalopathy,1 hemiplegia,1 or meningitis1 has occurred in less than 0.1% of patients.1

Falling asleep while engaged in activities of daily living, including operating a motor vehicle, has been reported in patients receiving levodopa/carbidopa, and tolcapone can increase plasma concentrations of levodopa.1 Some of the cases resulted in accidents and were reported as late as 1 year after initiation of treatment.1 Although many patients reported somnolence, some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to sudden sleep onset.1 Falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history.1

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and the inability to control these urges have been reported in patients receiving tolcapone in conjunction with levodopa/carbidopa and other dopaminergic agents.1 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1 If a patient develops any such behaviors while receiving tolcapone, consideration should be given to reducing the dosage or discontinuing therapy.1

Neuroleptic malignant syndrome has occurred in patients receiving psychotherapeutic agents and in patients with parkinson disease during withdrawal of dopaminergic agents.20 In clinical studies, a symptom complex resembling neuroleptic malignant syndrome (elevated temperature, muscular rigidity, altered consciousness) in association with abrupt withdraw or lowering of the dosage of tolcapone occurred in 4 patients.1,28 Creatine kinase (CK, creatine phosphokinase, CPK) values were increased in 3 patients; one patient died, and the other patients recovered over 2-6 weeks.1 There also have been rare postmarketing reports of this symptom complex; however, the role of tolcapone in these events remains to be determined since they were of a complicated nature and involved concomitant administration of other drugs that affect brain monoaminergic (i.e., nonselective MAO inhibitors, tricyclic antidepressants, selective serotonin-reuptake inhibitors) and anticholinergic systems.1

Severe rhabdomyolysis,1 including multiorgan system failure progressing to death in one patient, has been reported in a few patients receiving tolcapone.1 Because of the complex nature of these adverse events, the role of tolcapone, if any, in severe rhabdomyolysis has not been determined.1 While severe prolonged motor activity including dyskinesia may be associated with the development of rhabdomyolysis, some cases have included fever, alteration of consciousness, and muscular rigidity and resembled neuroleptic malignant syndrome.1

Cardiovascular Effects

Orthostatic instability1,2,3,6,10,13,15,16 occurs frequently in parkinsonian patients receiving dopaminergic agents, including levodopa.1 In clinical studies, orthostatic instability occurred more frequently in patients receiving tolcapone in combination with levodopa and a decarboxylase inhibitor than in patients receiving levodopa and a decarboxylase inhibitor (17 versus 14%).1,16 While the mechanism of this increased incidence has not been fully elucidated, such an increase would be expected because tolcapone increases the bioavailability of levodopa.1 Orthostatic hypotension was documented in 13-14% of patients receiving tolcapone in clinical studies; however, it was usually asymptomatic and only 4-5% of tolcapone-treated patients reported orthostatic symptoms.1 While patients (including those randomized to placebo therapy) with orthostatic instability at baseline were more likely than patients without symptoms to experience orthostatic hypotension,1 therapy with a dopamine agonist or selegiline hydrochloride at baseline did not appear to increase the incidence of orthostatic hypotension in patients receiving tolcapone.1,19 About 0.7% of patients receiving tolcapone in clinical studies discontinued the drug because of adverse effects related to hypotension.1

Syncope1 has occurred in 4-5% of patients receiving tolcapone in clinical studies.1 Syncope was reported more frequently in patients (including those randomized to placebo) who had an episode of documented hypotension than in those who did not have an episode of documented hypotension.1 Falls1 or loss of balance1 occurred in 4-6 or 2-3% of patients receiving tolcapone in clinical studies.1

Adverse cardiovascular effects reported in 1-3% of patients receiving tolcapone in clinical studies included chest pain,1 hypotension,1 or chest discomfort.1 While a causal relationship has not been established, peripheral edema1 or palpitations1 have occurred in at least 1% of patients receiving tolcapone, and hypertension,1 vasodilation,1 angina pectoris,1 heart failure,1 atrial fibrillation,1 tachycardia,1 aortic stenosis,1 arrhythmia,1 arteriospasm,1 bradycardia,1 cerebral hemorrhage,1 coronary artery disorder,1 heart arrest,1 myocardial infarction,1 myocardial ischemia,1 or pulmonary embolus1 has occurred in 0.1-1% of patients.1 Arteriosclerosis,1 cardiovascular disorder,1 pericardial effusion,1 or thrombosis1 has occurred in less than 0.1% of patients.1

Respiratory Effects

Upper respiratory tract infection,1,7,9 dyspnea,1,16 or sinus congestion1 has been reported in 5-7, 3, or 1-2%, respectively, of patients receiving tolcapone in clinical studies.1 Pneumonia,1 sinusitis,1 bronchitis,1 or pharyngitis1 has occurred in at least 1% of patients receiving tolcapone, and increased cough,1 rhinitis,1 asthma,1 epistaxis,1 hyperventilation,1 laryngitis,1 or hiccup1 has occurred in 0.1-1% of patients.1 Apnea,1 hypoxia,1 or lung edema1 has occurred in less than 0.1% of patients; however, these adverse effects have not been directly attributed to the drug.1

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and thickening of the pleura have been reported in a few patients receiving ergot-derivative dopamine receptor agonists (e.g., bromocriptine, pergolide).1 In most reported cases, these pulmonary changes slowly reverted to normal following discontinuance of the ergot-derivative dopamine receptor agonist; however, complete resolution did not always occur.1 While these pulmonary changes presumably are related to the ergoline structure of bromocriptine or pergolide, the possibility exists that non-ergot derived drugs that increase dopaminergic activity such as tolcapone may induce similar pulmonary changes.1 Pleural effusion1 occurred in 3 patients and pulmonary fibrosis1 occurred in 1 patient in clinical studies evaluating tolcapone; these patients also were receiving an ergot-derivative dopamine-receptor agonist (i.e., bromocriptine, pergolide) and had a history of cardiac disease or pulmonary pathology (i.e., nonmalignant lung lesion).1

Genitourinary Effects

Urinary tract infection,1 urine discoloration (i.e., increased yellow color attributed to tolcapone metabolites),1,2,6,7,9,14,28 micturition disorder,1,5 or uterine tumor1 has occurred in 5, 2-7, 1-2, or 1% of patients receiving tolcapone.1 Although not directly attributable to tolcapone, micturition frequency,1 urinary incontinence,1 or impotence1 has been reported in at least 1% of tolcapone-treated patients, and prostatic disorder,1 dysuria,1 nocturia,1 polyuria,1 urinary retention,1 urinary tract disorder,1 renal calculus,1 prostatic carcinoma,1 oliguria,1 uterine atony,1 uterine disorder,1 or vaginitis1 has been reported in 0.1-1% of patients.1 Bladder calculus,1 ovarian carcinoma,1 or uterine hemorrhage1 has been reported in less than 0.1% of patients.1

Hematuria1,28 occurred in 4-5% of patients receiving tolcapone in placebo- controlled studies, and microscopically confirmed hematuria was reported in 2% of patients receiving the drug in US placebo-controlled studies.1 While the etiology of the increased incidence of hematuria in tolcapone-treated patients remains to be determined, the increased incidence was not attributed to urinary tract infection or oral anticoagulant therapy.1

Rats given tolcapone in a dosage equivalent to 6 times or more of the recommended human dosage for 1 or 2 years developed a high incidence of proximal tubule cell damage consisting of degeneration, single cell necrosis, hyperplasia, karyocytomegaly and atypical nuclei.1 These effects were not accompanied by changes in clinical chemistry parameters, and currently there is no established method for monitoring the possible occurrence of these types of lesions in humans.1 While it has been suggested that these toxic renal effects may result from a species-specific mechanism, experiments to confirm such a theory have not been conducted.1

Dermatologic and Sensitivity Reactions

Increased sweating1 has occurred in 4-7% of patients receiving tolcapone in clinical studies; dermal bleeding,1 skin tumor,1 or alopecia1 has been reported in 1% of patients.1 Rash has occurred in at least 1% of tolcapone-treated patients, and allergic reaction,1 herpes zoster,1 pruritus,1 seborrhea,1 skin discoloration,1 eczema,1 erythema multiforme,1 skin disorder,1 cellulitis,1 furunculosis,1 herpes simplex,1 facial edema,1 or urticaria1 has occurred in 0.1-1% of patients; however, these adverse effects have not been directly attributed to the drug.1

Otic and Ocular Effects

While not directly attributed to tolcapone, otic or ocular effects reported in at least 1% of tolcapone-treated patients include cataract,1 inflamed eye,1 blurred vision,1 or tinnitus;1 those occurring in 0.1-1% of patients include diplopia,1 ear pain,1 ocular hemorrhage,1 ocular pain,1 lacrimation disorder,1 otitis media,1 or parosmia.1 Glaucoma has occurred in less than 0.1% of tolcapone-treated patients.1

Other Adverse Effects

Fatigue1,14 or influenza1 has occurred in 3-7 or 3-4% of tolcapone-treated patients and neck pain,1 burning,1 malaise,1 or fever1 has occurred in 1-2% of patients.1 Fractures,1 flank pain,1 accidental injury,1 or infection1 has occurred in at least 1% of patients receiving tolcapone, and hernia,1 pain,1 bacterial infection,1 fungal infection,1 viral infection,1 chills,1 breast carcinoma,1 carcinoma,1 neoplasm,1 abscess,1 edema,1 hypercholesterolemia,1 thirst,1 dehydration,1 anemia,1 or diabetes mellitus1 has occurred in 0.1-1% of patients; these adverse effects have not been directly attributed to tolcapone.1 Other events not directly attributable to the drug include surgical procedure.1 Death has been reported in less than 0.1% of tolcapone-treated patients in clinical studies.1

Studies in rats and monkeys given tolcapone have not revealed any potential for physical or psychologic dependence.1 While clinical studies have not revealed any evidence of potential for abuse, systematic studies in humans designed to evaluate abuse potential have not been performed.1

Precautions and Contraindications

Therapy with tolcapone should not be initiated until the clinician has fully explained the risks of such therapy and the patient (or his representative) has provided written informed consent.1

Hepatotoxic Risk

Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone generally should be reserved for patients with parkinson disease receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to other adjunctive therapies (e.g., ergot- and nonergot-derivative dopamine receptor agonists, selegiline hydrochloride) or are not candidates for these adjunctive therapies.1,30,31,32 Following initiation of tolcapone therapy, symptomatic improvement generally is evident within 3 weeks.1,7 Because of the risk of hepatic injury in patients receiving tolcapone and the normal time course of tolcapone response, the drug should be discontinued in patients who do not experience symptomatic improvement within 3 weeks of initiating tolcapone therapy.1 Tolcapone therapy should not be initiated in patients with clinical evidence of active liver disease, ALT (SGPT) or AST (SGOT) concentrations exceeding the upper limit of normal, or any other evidence of hepatocellular dysfunction.1 In addition, tolcapone therapy should be discontinued if ALT or AST concentrations increase to more than 2 times the upper limit of normal or if clinical manifestations suggest the onset of hepatic failure (e.g., persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, upper right quadrant tenderness).1

Patients who develop evidence of hepatocellular injury while receiving tolcapone and in whom such therapy is discontinued for any reason may be at increased risk for hepatic injury if tolcapone is reintroduced.1 Accordingly, such patients ordinarily should not be considered for retreatment with the drug.1

Patients receiving tolcapone should be monitored for evidence of emergent liver injury.1 In addition, patients should be advised of the clinical manifestations that suggest the onset of hepatic injury such as clay-colored stools, jaundice, fatigue, loss of appetite, and lethargy.1 If signs or symptoms suggestive of hepatic failure occur, patients should be advised to contact their clinician immediately.1

Because tolcapone therapy has been associated with alterations in some liver function laboratory test results, liver enzymes (i.e., serum AST, ALT) should be evaluated at baseline, every 2-4 weeks during the first 6 months of therapy, and then as often as is clinically indicated.1 If the dose of tolcapone is increased to 200 mg 3 times daily, serum AST and ALT should be determined prior to increasing the dosage and then at the same frequency as that recommended when therapy is initiated.1

While a program of frequent laboratory monitoring for evidence of hepatocellular injury is considered essential, whether periodic monitoring of liver enzymes will prevent the occurrence of fulminant tolcapone-induced liver failure is not known.1 Frequent monitoring is considered important since early detection of drug-induced hepatic injury along with immediate discontinuance of the suspect drug is believed to enhance the likelihood for recovery.1

Other Precautions and Contraindications

COMT and MAO are the 2 principal enzymes involved in the metabolism of catecholamines.1,2,3,4,5,6,7,8,9,10,13 Because the possibility exists that concomitant administration of tolcapone and a nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine) would result in inhibition of the principal pathways involved in the metabolism of catecholamines, administration of tolcapone with a nonselective MAO inhibitor should be avoided.1,28 However, tolcapone can be administered concomitantly with a selective inhibitor of MAO-B (e.g., selegiline hydrochloride).1,19 (See Drug Interactions: Monoamine Oxidase Inhibitors.)

Tolcapone may exacerbate levodopa-associated adverse effects in some patients, presumably by increasing dopaminergic activity; many of these adverse effects can be mitigated by reducing the levodopa dosage.1,7,9,16 Patients should be advised that they may develop orthostatic hypotension with or without symptoms such as dizziness, nausea, syncope, and sweating.1 The manufacturer states that patients should be cautioned against rising rapidly after prolonged sitting or lying down, especially during the first few weeks of tolcapone therapy.1 Patients should be informed that hallucinations can occur with tolcapone therapy.1 Patients also should be advised that tolcapone may cause somnolence and that they should not drive a car or operate other complex machinery until they have gained sufficient experience with the drug to determine whether it has adverse effects on their mental and/or motor performance.1 In addition, the possibility of additive sedative effects should be considered in patients receiving other CNS depressants concomitantly with tolcapone.1

Tolcapone can increase plasma concentrations of levodopa, and levodopa/carbidopa has been associated with sudden sleep onset during activities of daily living.1 (See Cautions: Nervous System and Muscular Effects.) Before initiating tolcapone therapy, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs, presence of sleep disorders).1 Patients should be continually reassessed for drowsiness or sleepiness during therapy, especially since some of these episodes occur well after starting treatment.1 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), tolcapone generally should be discontinued.1 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.1 There is insufficient information to establish whether dosage reduction will eliminate this adverse event.1

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and the inability to control these urges have been reported in patients receiving tolcapone in conjunction with levodopa/carbidopa and other dopaminergic agents.1 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1 If a patient develops any such behaviors while receiving tolcapone, consideration should be given to reducing the dosage or discontinuing therapy.1

Patients experiencing persistent diarrhea should be evaluated by appropriate clinical and laboratory studies, including fecal occult blood studies.1 Patients receiving tolcapone should be advised that they may experience nausea, especially during the first 3 months of therapy.1

Tolcapone should be used with caution in patients with dystonia or dyskinesia.1 Tolcapone also should be used with caution in patients with severe renal failure.1

Tolcapone is contraindicated in patients with liver disease, those in whom tolcapone was discontinued because of evidence of tolcapone-induced hepatocellular injury, and those with known hypersensitivity to the drug or any ingredient in the formulation.1 Tolcapone also is contraindicated in patients with a history of nontraumatic rhabdomyolysis, or drug-related hyperpyrexia and confusion.1

Pediatric Precautions

The manufacturer states that there is no identified potential use of tolcapone in pediatric patients.1 Therefore, safety and efficacy of the drug in children have not been determined.1

Geriatric Precautions

Safety and efficacy of tolcapone in geriatric patients have not been studied specifically to date; however, parkinson disease, for which safety and efficacy have been established, occurs principally in patients older than 50 years of age.1,6,7,8,9 Experience in clinical studies suggests that patients 75 years of age or older are more likely to develop hallucinations but less likely to develop dystonia than younger patients.1 Pharmacokinetic studies have not revealed age-related differences in the pharmacokinetics of tolcapone.1,4,5

Mutagenicity and Carcinogenicity

Tolcapone was not mutagenic in the Ames test, the in vitro V79/HPRT gene mutation assay, or the unscheduled DNA synthesis assay.1 Tolcapone was clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence of metabolic activation; however, tolcapone was not clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes or in an in vivo micronucleus assay in mice.1

There was no evidence of carcinogenicity in male or female mice given oral tolcapone dosages of 100, 300, or 800 mg/kg daily (equivalent to 0.8, 1.6, or 4 times the human exposure based on area under the plasma concentration-time curve [AUC] at a dosage of 600 mg daily) for 80-95 weeks.1

The carcinogenic potential of tolcapone has been evaluated in rats given oral dosages of 50, 250, or 450 mg/kg daily (equivalent in male rats to 1, 6.3, or 13 times the human exposure based on AUC at a dosage of 600 mg daily and in female rats to 1.7, 11.8, or 26.4 times human exposure) for 104 weeks.1 An increased incidence of uterine adenocarcinomas was observed in female rats at exposure levels equivalent to 26.4 times human exposure.1

While exposure equivalent to one times the human exposure in male rats or 1.7 in female rats were not associated with renal tumors, renal tubular cell adenomas occurred at middle and high doses in female rats and tubular cell carcinomas occurred in middle and high doses in male rats and high doses in female rats.1 Minimal to marked damage to the renal tubules, characterized by proximal tubule cell degeneration, single cell necrosis, hyperplasia, and karyocytomegaly, occurred at doses associated with renal tumors.1 Renal tubule damage, characterized by proximal tubule cell degeneration and presence of atypical nuclei, were observed in rats receiving oral tolcapone dosages of 150 or 450 mg/kg daily for 1 year; in addition, adenocarcinoma was reported in one male rat receiving tolcapone 450 mg/kg daily.1 These histopathologic changes suggest that the renal tumor formation might be secondary to chronic cell damage and sustained repair; however, further study is needed to define this relationship.1 The clinical importance of these findings in rats to humans remains to be determined.1 The carcinogenic potential of tolcapone in combination with levodopa/carbidopa has not been examined.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproductive studies in rats or rabbits given oral tolcapone dosages up to 300 or 400 mg/kg daily (5.7 or 15 times the 600-mg daily dose on a mg/m² basis) during organogenesis did not reveal teratogenic effects.1 However, an increased rate of abortion occurred in rabbits given tolcapone 100 mg/kg daily (3.7 times the 600-mg daily dose on a mg/m² basis), and maternal toxicity (i.e., decreased weight gain, death) occurred in rats given 300 mg/kg daily and in rabbits given 400 mg/kg daily.1 Decreased litter size and impaired growth and learning performance in female pups were observed in reproductive studies in female rats given tolcapone 250-150 mg/kg daily (4.8-2.9 times the 600-mg daily dose on a mg/m² basis; dose reduced from 250 mg/kg daily to 150 mg/kg daily during late gestation because of high rate of maternal toxicity) during the last part of gestation and during lactation.1

Tolcapone is administered in conjunction with levodopa/carbidopa; levodopa/carbidopa cause visceral and skeletal malformations in rabbits.1 An increased incidence of fetal malformations (i.e., principally external and skeletal digit defects) was observed in rabbits given tolcapone 100 mg/kg daily (plasma exposure 0.5 times the expected human exposure based on AUC) in combination with levodopa 80 mg/kg daily (plasma exposure 6 times the expected human exposure) and carbidopa 20 mg/kg daily throughout organogenesis compared with rabbits given levodopa/carbidopa.1 In embryo/fetal development studies, fetal body weights were reduced in offspring of rats given tolcapone 10, 30, or 50 mg/kg daily (at least 0.5 times the expected human exposure) in combination with levodopa 120 mg/kg daily (at least 21 times the expected human exposure) and carbidopa 30 mg/kg daily or levodopa/carbidopa alone, but not in offspring of rats given tolcapone 50 mg/kg daily (1.4 times the expected human exposure).1 While tolcapone does not appear to be teratogenic in animals, there are no adequate and controlled studies to date in humans.1 Tolcapone should only be used during pregnancy when the potential benefits justify the possible risks to the fetus.1 Because tolcapone is used in conjunction with levodopa/carbidopa (which cause skeletal malformations in animals), patients should notify their clinician if they are or intend to become pregnant while receiving tolcapone in combination with levodopa/carbidopa.1

Fertility

Reproductive studies in rats using tolcapone dosages up to 300 mg/kg daily (5.7 times the human dose on a mg/m² basis) have not revealed evidence of impaired fertility or changes in general reproductive performance.1

Lactation

Because it is not known whether tolcapone is distributed into human milk, the drug should be used with caution in nursing women.1 Patients should be advised to notify their physician if they are nursing an infant or intend to nurse an infant.1

Levodopa and Other Catecholamines

Tolcapone alters the pharmacokinetics of levodopa (i.e., increases the area under the plasma concentration-time curve and half-life) and enhances the clinical efficacy of levodopa.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,26 (See Pharmacology.) Thus, this interaction is used for therapeutic effect.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,26

While tolcapone may influence the pharmacokinetics of drugs metabolized by catechol- O -methyltransferase (COMT), tolcapone does not alter the pharmacokinetics of carbidopa.1 Although the effect of tolcapone on other drugs metabolized by COMT (i.e., methyldopa, dobutamine, apomorphine, isoproterenol) has not been evaluated, a dosage reduction in these drugs should be considered if they are administered in conjunction with tolcapone.1,28

Drugs Undergoing Microsomal Enzyme-mediated Metabolism

The manufacturer of tolcapone states that clinically important drug interactions involving tolcapone and drugs metabolized by microsomal cytochrome P-450 isoenzymes CYP2C9 and CYP2D6 are not expected to occur.1 Results from in vitro studies that assessed the potential for tolcapone to interact with cytochrome P-450 isoenzymes did not reveal important interactions with substrates for CYP2A6 (warfarin), CYP1A2 (caffeine), CYP3A4 (cyclosporine, midazolam, terfenadine), CYP2C19 ( S -mephenytoin), or CYP2D6 (desipramine).1

In in vivo studies, tolcapone did not alter the pharmacokinetics of desipramine or tolbutamide (a substrate for CYP2C9).1 The possibility that tolcapone may affect the metabolism of warfarin via CYP2C9 should be considered.1,28,33 (See Drug Interactions: Anticoagulants.)

Anticoagulants

Tolcapone has affinity for CYP2C9, the isoenzyme involved in the metabolism of S -warfarin.1,20 While not studied specifically, concomitant administration of tolcapone and warfarin may result in increased plasma concentration of the anticoagulant.1,28,33 Because warfarin has a narrow therapeutic index, prothrombin time, preferably using the international normalized ratio (INR), should be determined frequently and appropriate dosage adjustments made in patients receiving concomitant tolcapone.1,28,33

Protein-bound Drugs

In in vitro studies, tolcapone 50 mcg/mL did not displace therapeutic concentrations of warfarin (0.5-7.2 mcg/mL), phenytoin (4-38.7 mcg/mL), tolbutamide (24.5-96.1 mcg/mL), or digitoxin (9-27 mcg/mL) from binding sites.1

Antipsychotic Agents

Concomitant use of tolcapone with certain antipsychotic agents may exacerbate parkinsonian symptoms and result in decreased efficacy of tolcapone.1

Monoamine Oxidase Inhibitors

Because the possibility exists that concomitant administration of tolcapone and a nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine) could result in inhibition of the principal pathways involved in the metabolism of catecholamines, administration of tolcapone with a nonselective MAO inhibitor should be avoided.1 However, tolcapone can be administered concomitantly with a selective inhibitor of MAO-B (i.e., selegiline).1,19

The adverse effect profile associated with regimens that include tolcapone, levodopa/carbidopa, and selegiline is similar to that associated with regimens that do not include selegiline.1,19

CNS Depressants

The possibility of additive sedative effects should be considered in patients receiving CNS depressants concomitantly with tolcapone.1

Other Drugs Affecting the CNS or Cholinergic System

Caution is advised if tolcapone is administered with other drugs that affect brain monoaminergic (i.e., nonselective MAO inhibitors, tricyclic antidepressants, selective serotonin-reuptake inhibitors) or anticholinergic systems since a symptom complex resembling neuroleptic malignant syndrome has been reported in patients receiving such combinations.1

Tolcapone does not appear to alter the tolerability of ephedrine (i.e., hemodynamic parameters or plasma catecholamine concentrations at rest or during exercise), and these drugs can be administered concomitantly.1 Because regimens that include tolcapone, levodopa/carbidopa, and desipramine are not tolerated as well as regimens that do not include desipramine, caution is advised if desipramine is used in patients with parkinson disease receiving tolcapone and levodopa/carbidopa.1

Acute Toxicity

Manifestations

Based on animal data, the threshold for the lethal plasma concentration of tolcapone in humans is predicted to exceed 100 mcg/mL.1 The highest dosage of tolcapone, with or without levodopa/carbidopa, evaluated in healthy geriatric individuals has been 800 mg 3 times daily for 1 week; peak plasma tolcapone concentrations in elderly individuals receiving this dosage averaged 30 mcg/mL.1 Nausea, vomiting, and dizziness occurred in these patients and were more pronounced in patients receiving tolcapone in combination with levodopa/carbidopa than in those receiving tolcapone alone.1

Respiratory difficulties were observed in rats receiving high oral (i.e., gavage) or IV doses of the drug and in dogs receiving IV tolcapone.1

Treatment

The manufacturer recommends that, in the event of tolcapone overdosage, supportive and symptomatic treatment should be initiated and the patient hospitalized.1 Hemodialysis is unlikely to remove substantial amounts of tolcapone from the body, and this procedure should not be relied on to enhance elimination of the drug.1

Pharmacology

Tolcapone is a selective, potent, peripheral and to a lesser extent central, reversible inhibitor of catechol- O -methyltransferase (COMT).1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,23,26,28 Although tolcapone produces beneficial effects in levodopa-treated patients with parkinson disease, the drug lacks antiparkinsonian activity when administered alone.

COMT is an enzyme that catalyzes the transfer of a methyl group from S -adenosyl-l-methionine to a phenol group of a substrate containing a catechol structure.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,23 Physiologic substrates of COMT include dopa, catecholamines (dopamine, epinephrine, norepinephrine), their hydroxylated metabolites, catechol estrogens, and ascorbic acid.1,2,3,4,5,6,7,8,9,10,13 COMT, along with monoamine oxidase, plays a role in the metabolic transformation of dopamine, epinephrine, and norepinephrine.1,2,3,4,5,6,7,8,9,10,13 While COMT is found in many organs and tissues including neuronal tissues (especially glial cells), erythrocytes, the GI tract, heart, lung, adipose tissue, smooth and skeletal muscle, reproductive organs, and skin, the highest activity is present in the liver and kidney.1,2,3,4,5,6,7,8,9,10,13

Levodopa currently is the most effective drug for relieving manifestations of parkinson disease; however, duration of response is limited.2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,23,26,29 One approach for improving the effect of levodopa is to prevent its degradation by metabolizing enzymes.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,23 Following oral administration of levodopa, about 70% of a dose undergoes enzymatic decarboxylation and about 10% is O -methylated by COMT.1,2,3,4,5,6,7,8,9,10,23 When levodopa is administered concomitantly with a decarboxylase inhibitor (e.g., carbidopa), COMT is the major enzyme catalyzing the metabolism of levodopa to 3-methoxy-4-hydroxy-l-phenylalanine (3-OMD).1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19

While the precise mechanism of action of tolcapone remains to be determined, the drug is believed to act principally by inhibiting COMT and altering the plasma pharmacokinetics of levodopa.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,23,26,28 Concomitant administration of tolcapone with levodopa and a decarboxylase inhibitor results in more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,26 The principal effect of tolcapone is inhibition of COMT in peripheral tissues; secondarily, the reductions in circulating 3-OMD that result from decreased peripheral metabolism of levodopa may increase distribution of levodopa into the CNS by reducing the competitive substrate (i.e., 3-OMD) for transport mechanisms.26 Sustained levodopa concentrations presumably result in more consistent dopaminergic stimulation, resulting in greater reduction in the manifestations of parkinson disease.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,26 In addition, fluctuations in plasma levodopa concentrations cause dopamine receptors in the striatum to be exposed to alternating high and low concentrations of dopamine; under physiologic conditions, (e.g., in healthy individuals), stimulation of these receptors would be tonic (continuous).26 Pulsatile stimulation of dopamine receptors resulting from levodopa fluctuations is believed to induce postsynaptic changes that result in the development of motor fluctuations and dyskinesia in parkinson disease patients receiving long-term levodopa therapy.26 In addition, the decrease in striatal dopamine terminals that occurs with parkinsonian disease progression results in a diminished capacity of these terminals to buffer plasma levodopa fluctuations.26 Compared with administration of levodopa/carbidopa, administration of tolcapone in combination with levodopa/carbidopa increases levodopa AUC twofold, increases the terminal elimination half-life of levodopa from 2 hours (conventional tablets) to 3.5 hours, but does not increase the peak plasma levodopa concentration or change the time to peak plasma concentration, resulting in more stable plasma concentrations of levodopa.1,2,3,5,8,12,13,14,15,16,17,18,19,23,26 This stabilization in plasma levodopa concentrations combined with increased central bioavailability of levodopa (secondary to reductions in 3-OMD as a competitive substrate for central distribution) results in enhanced and smoother availability of levodopa to the CNS.26

The effect of tolcapone on the pharmacokinetics of levodopa is evident with the initial tolcapone dose and is maintained throughout long-term therapy.1,2,3,5,8,23 Dose response studies in healthy individuals and patients with parkinson disease indicate that optimum effect on the pharmacokinetics of levodopa (i.e., an increase in AUC and half-life without an increase in peak plasma concentration) occurs with a tolcapone dose of 100-200 mg.1,3,8,14 Studies to date indicate that the effects of tolcapone on the pharmacokinetics of levodopa in healthy individuals are similar to those in patients with parkinson disease.1,3,5,8,14

Complications such as motor fluctuations that occur with long-term levodopa therapy may be related to the peripheral conversion of levodopa to 3-OMD; this metabolite may compete with levodopa for transport across the GI membrane and blood-brain barrier.2,3,4,16,19,26 While the importance of competition between levodopa and 3-OMD remains to be determined, tolcapone's inhibition of COMT increases peripheral and central availability of levodopa and prevents biotransformation to 3-OMD.1,2,3,4,8,16,19,23,26 Peak plasma concentrations and AUC values for 3-OMD are substantially lower in individuals receiving tolcapone in conjunction with levodopa/carbidopa compared with individuals receiving levodopa/carbidopa.1,8,15,16 In one study in healthy individuals 55-75 years of age receiving tolcapone in conjunction with levodopa/carbidopa, the AUC for 3-OMD decreased about 80%.1,8,15,16

In addition to its effect on the pharmacokinetics of levodopa, tolcapone is expected to reduce utilization of S -adenosyl-l-methionine, a compound that reportedly has a therapeutic effect in mental depression.3,25 Tolcapone's potential to reduce metabolic degradation of dopamine in the striatum also may contribute to the drug's activity.2,3,4,6,23,25 However, the CNS effect of tolcapone appears to be minimal and clinically unimportant since the drug lacks antiparkinsonian effects when administered as monotherapy.23

Tolcapone reversibly inhibits human erythrocyte COMT.1,2,4,8,13 Measurement of erythrocyte COMT activity is a sensitive and precise method of estimating COMT activity in the liver, kidney, and lung.1,2,4 Inhibition of COMT activity is related to plasma tolcapone concentrations over a dosage range of 5-400 mg.2,3,4,5,8 Following oral administration of a single oral 200-mg dose of tolcapone in healthy individuals, maximum inhibition of erythrocyte COMT activity was achieved within 1 hour and exceeded 80%; inhibitory activity persisted for 16-24 hours.1,2,4,5,8 Following oral administration of tolcapone 200 mg 3 times daily for 7 days in healthy individuals, maximum erythrocyte COMT inhibition was about 80% and erythrocyte COMT inhibition at trough tolcapone concentrations was 30-45%.1,8 In vivo studies indicate that tolcapone inhibits brain COMT activity.13,23

Tolcapone does not affect monoamine oxidase, hydroxy-indole- O -methyltransferase, histamine- N -methyltransferase, or phenyl-ethanolamine- N - methyltransferase activities.13 Tolcapone does not interact with α- or β-adrenergic, serotonergic, or cholinergic receptors.13

Pharmacokinetics

Tolcapone exhibits linear pharmacokinetics, which are independent of levodopa/carbidopa coadministration, over the dosage range of 50-400 mg.1 Pharmacokinetic studies have not revealed gender-, age-, or weight-related differences in the pharmacokinetics of tolcapone.1,4,5 In addition, there has been no evidence of race-related differences in the pharmacokinetics of the drug in white, black, and Japanese individuals.1 Analysis of population pharmacokinetic data from clinical trials indicates that renal function does not alter the pharmacokinetics of tolcapone in individuals with creatinine clearance of 30-130 mL/minute.1 Although the pharmacokinetics of tolcapone have been studied in clinical studies in patients with moderate non-cirrhotic liver impairment (ALT [SGPT] concentrations at least 2 times the upper limit of normal, alkaline phosphatase concentrations at least 1.5 times the upper limit of normal, γ-glutamyltransferase [GGT, γ-glutamyltranspeptidase, GGTP] concentrations outside the normal range) and in patients with moderate cirrhotic liver disease (Child-Pugh class B), tolcapone therapy should not be initiated in patients with clinical evidence of active liver disease, or two ALT (SGPT) or AST (SGOT) values exceeding the upper limit of normal, or any other evidence of hepatocellular dysfunction.1 In addition, tolcapone therapy should be discontinued if ALT or AST concentrations exceed the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic failure.1

In healthy individuals, reversible inhibition of erythrocyte COMT activity following oral administration of tolcapone has been shown to be closely related to plasma concentrations of the drug.1 Maximum COMT inhibition following a single 200-mg oral dose averages greater than 80%, while inhibition with trough plasma tolcapone concentrations during multiple dosing (200 mg 3 times daily) is 30-45%.1

Absorption

Tolcapone is rapidly absorbed from the GI tract, with peak plasma concentrations generally occurring within 2 hours following single oral doses of 5-800 mg.1,2,3,4,5,8,14,27,28 The absolute bioavailability following oral administration is about 65-68%.1,27 When tolcapone is administered with food (within 1 hour before or 2 hours after a meal), bioavailability is reduced 10-20% compared with administration in the fasting state.1

In one study in healthy individuals 55-75 years of age, oral administration of a single dose of tolcapone 100 or 200 mg produced peak plasma concentrations of 2.8 or 5.9 mcg/mL, respectively.8 Following oral administration of tolcapone 100 or 200 mg 3 times daily for 7 days in healthy individuals 55-75 years of age, peak plasma tolcapone concentrations were 3.5 or 6.4 mcg/mL, respectively;1,8 in individuals receiving either tolcapone dosage, trough concentrations on day 8 were essentially the same as levels on day 2.8 Oral administration of tolcapone 100 or 200 mg 3 times daily is not associated with accumulation of tolcapone.5,8,27 The extent of absorption (i.e., AUC) is proportional to dose in individuals receiving single oral tolcapone doses of 5-800 mg.1,3,4

In clinical studies in a limited number of patients with moderate cirrhotic liver disease (Child-Pugh class B), plasma concentrations of unbound tolcapone were increased less than twofold compared with concentrations in individuals with normal hepatic function or non-cirrhotic liver disease.1,27

Distribution

Distribution of tolcapone into body tissues and fluids has not been fully characterized.1,33 The volume of distribution of tolcapone at steady-state is 9 L.1,4,27 The volume of distribution of unbound tolcapone reportedly was reduced almost 50% in clinical studies in patients with moderate cirrhotic liver disease (Child-Pugh class B).1,27 While tolcapone is not widely distributed, the drug is distributed into brain tissue.1,2,13

Tolcapone is more than 99.9% bound to plasma proteins, principally serum albumin, over a concentration range of 0.32-210 mcg/mL.1,27

It is not known whether tolcapone is distributed into human milk; however, the drug is distributed into milk in rats.1

Elimination

Tolcapone is extensively metabolized by a variety of mechanisms.1,27,28 The principal metabolic pathway identified involves glucuronidation.1,27,28 In addition, tolcapone is metabolized by catechol- O -methyltransferase (COMT) to 3- O -methyltolcapone.1,2,27,28 Tolcapone also undergoes hydroxylation of the methyl group resulting in a primary alcohol, which is then oxidized to the carboxylic acid.1,27 In vitro data indicate that cytochrome P-450 isoenyzmes CYP3A4 and CYP2A6 catalyze the oxidation to the carboxylic acid.1,28 Tolcapone also is reduced to an amine, which subsequently is N -acetylated.1

Tolcapone is a low-extraction ratio drug (0.15) with a systemic clearance of 7 L/hour.1,27 The terminal elimination half-life of tolcapone at recommended dosages is 2-3 hours.2,3,4,5,8,27,28 While the terminal elimination half-life of catechol-3- O -methyltolcapone is 30-60 hours, the metabolite does not appear to accumulate with multiple-dosing because tolcapone inhibits COMT.2,3,4,5,8,27 Clearance of unbound tolcapone was reduced almost 50% in clinical studies in patients with moderate cirrhotic liver disease (Child-Pugh class B).1,27

About 13% of an oral dose of tolcapone is excreted in the urine as the glucuronide metabolite, 2% as the carboxylic acid metabolite, and less than 0.5% as unchanged drug.1,27 While the glucuronide conjugate is excreted principally in urine, this metabolite also undergoes biliary excretion.1,27 Following oral administration of radiolabeled tolcapone, about 60% of a labeled dose is excreted in urine and 40% is excreted in feces.1

Chemistry and Stability

Chemistry

Tolcapone, a reversible catechol- O -methyltransferase (COMT) inhibitor, is a nitrocatechol.1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,28 Tolcapone differs chemically and pharmacologically from currently available antiparkinsonian agents (e.g., levodopa, carbidopa, ergot- and nonergot-derivative dopamine receptor agonists, the selective monoamine oxidase [MAO]-B inhibitor selegiline hydrochloride).1,2

Tolcapone occurs as a yellow, nonhygroscopic, crystalline compound.1

Stability

Commercially available tolcapone tablets should be stored in tight containers at a controlled room temperature of 20-25°C.1

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32. Ellison RH. Dear health professional letter regarding appropriate use of Tasmar^®. Nutley, NJ: Roche Laboratories; 1998 Nov. 16.

33. Reviewers' comments (personal observations).