Tolcapone (Monograph)

Brand name: Tasmar
Drug class: Catechol-O-Methyltransferase (COMT) Inhibitors
- Antiparkinsonian Agents
VA class: CN500
Chemical name: (3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)-methanone
Molecular formula: C₁₄H₁₁NO₅
CAS number: 134308-13-7

Medically reviewed by Drugs.com on May 14, 2024. Written by ASHP.

Introduction

Reversible catechol-O-methyltransferase (COMT) inhibitor.^{1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 18 19 28}

Uses for Tolcapone

Parkinsonian Syndrome

Adjunct to levodopa/carbidopa therapy for the symptomatic treatment of idiopathic parkinson disease; 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 23 26 28}

Generally reserve therapy for patients with parkinson disease receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies (e.g., dopamine receptor agonists, selective MAO-B inhibitors).^{1 31 32} (See Boxed Warning.)

Tolcapone Dosage and Administration

General

• Symptomatic improvement generally is evident within 3 weeks following initiation of tolcapone.^{1 7} Discontinue tolcapone if the patient fails to show symptomatic improvement within 3 weeks of initiating therapy.¹ (See Boxed Warning.)

Concomitant Levodopa/Carbidopa Therapy

• Administer in conjunction with levodopa/carbidopa (conventional or extended-release preparations).^{1 9}

• To optimize patient response, reductions in the daily levodopa/carbidopa dosage may be necessary.^{1 6 7 9 16 28} In clinical trials, most patients receiving levodopa dosages >600 mg daily or with moderate to severe dyskinesia prior to initiation of tolcapone required reduction of levodopa dosage (average reduction: about 30%).^{1 6 7 9 16 23}

Discontinuance of Tolcapone

• Discontinuance or abrupt dosage reduction may lead to reemergence of signs and symptoms of parkinson disease or a symptom complex resembling neuroleptic malignant syndrome (e.g., hyperpyrexia, confusion).¹

• If tolcapone is discontinued, monitor the patient closely and adjust the dosage of dopaminergic therapy, if needed.¹

• If hyperpyrexia or severe rigidity occurs following drug discontinuance, the differential diagnosis should include the possibility of a symptom complex resembling neuroleptic malignant syndrome.¹

• Tapering the dosage of tolcapone has not been systematically evaluated;¹ however, reducing the frequency to twice or once daily prior to discontinuance 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}

Administration

Oral Administration

Administer orally in 3 equally divided doses daily^{1 6 7 9 16 23 28} without regard to meals.¹

In clinical studies, the first dose of the day 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}

Dosage

Adults

Parkinsonian Syndrome

Oral

Usual dosage: 100 mg 3 times daily.^{1 28}

Reserve higher dosage (200 mg 3 times daily) for situations when the anticipated incremental benefit is justified.¹ If the patient fails to show the expected clinical benefit while receiving 200 mg 3 times daily for 3 weeks, discontinue the drug.¹ (See Hepatic Effects under Cautions.)

Special Populations

Renal Impairment

Dosage adjustment not required in patients with mild to moderate renal impairment (Cl_cr >30 mL/minute).¹ Safety not evaluated in patients with Cl_cr <25 mL/minute.¹

Cautions for Tolcapone

Contraindications

• Liver disease.¹

• Patients in whom tolcapone was discontinued because of evidence of tolcapone-induced hepatocellular injury.¹

• History of nontraumatic rhabdomyolysis.¹

• History of drug-related hyperpyrexia and confusion.¹

• Known hypersensitivity to tolcapone or any ingredient in the formulation.¹

Warnings/Precautions

Warnings

Hepatic Effects

Risk of potentially fatal, acute fulminant hepatic failure.^{1 30 31 32} (See Boxed Warning.)

Increases in ALT reported more frequently in patients receiving tolcapone 200 mg 3 times daily than in those receiving 100 mg 3 times daily; not known whether the risk of fulminant hepatic failure is increased in patients receiving the higher dosage.¹

Frequency of aminotransferase elevations greater in women than men.¹

In clinical studies, aminotransferase elevations generally occurred 6 weeks to 6 months following initiation of therapy; concentrations generally returned to baseline within 1–3 months in about 50% of patients who continued tolcapone therapy and within 2–3 weeks up to 1–2 months in patients who discontinued the drug.^{1 7 16} However, rapid deterioration³⁰ and death^{1 30 31 32} can occur despite drug discontinuance.³⁰

MAO Inhibitors

Concomitant administration with a nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine) could result in inhibition of the 2 principal pathways of catecholamine metabolism (i.e., metabolism by COMT and MAO^{1 2 3 4 5 6 7 8 9 10 13} ).¹ Avoid concomitant administration with a nonselective MAO inhibitor;^{1 28} may administer tolcapone concomitantly with a selective inhibitor of MAO-B (e.g., selegiline).^{1 19} (See Interactions.)

Falling Asleep During Activities of Daily Living

Episodes of falling asleep while engaged in activities of daily living (e.g., driving) have occurred with levodopa, and tolcapone increases plasma concentrations of levodopa; these episodes have sometimes resulted in accidents.¹ Some patients perceived no warning signs (e.g., excessive drowsiness) and believed they were alert immediately prior to the event.¹

Falling asleep while engaged in such activities usually occurs in the setting of preexisting somnolence, although patients may not give such a history.¹

Continually reassess patients for drowsiness or sleepiness during therapy.¹ Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.¹ Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs, presence of sleep disorders).¹

Consider discontinuing therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).¹ If the drug is continued, advise patient not to drive and to avoid other potentially dangerous activities.¹ (See Advice to Patients.) Insufficient information to establish whether dosage reduction will eliminate this adverse event.¹

General Precautions

Orthostatic Hypotension and Syncope

Increased occurrence of orthostatic instability^{1 2 3 6 10 13 15 16} in patients receiving tolcapone in combination with levodopa and a decarboxylase inhibitor relative to patients receiving levodopa and a decarboxylase inhibitor (17 versus 14%).^{1 16} Mechanism not fully established, but an increase would be expected because dopaminergic therapy in patients with parkinsonian syndrome is associated with orthostatic hypotension and tolcapone increases systemic exposure to levodopa.¹

Orthostatic hypotension usually is asymptomatic;¹ however, patients with orthostatic instability at baseline are more likely than patients without symptoms to experience orthostatic hypotension.¹ No apparent increase in the incidence of orthostatic hypotension in patients receiving a dopamine agonist or selegiline at baseline.^{1 19}

Possible syncope;¹ reported more frequently in patients who had an episode of documented hypotension than in those who did not have an episode of documented hypotension.¹

Diarrhea

Possible diarrhea,^{1 2 4 5 7 9 15 16} generally mild to moderate^{1 7} but can be severe and result in hospitalization.¹

Generally occurs during the first 6–12 weeks of therapy but may occur as early as 2 weeks or as late as several months following initiation of therapy.^{1 7 16}

Frequently is associated with anorexia, is dose related, and resolves with continued therapy or following drug discontinuance.^{1 7 15 16}

Patients experiencing persistent diarrhea should be evaluated by appropriate clinical and laboratory studies, including fecal occult blood studies.¹

Hallucinations and Psychotic-like Behavior

Hallucinations^{1 6 9 10 13 15 16} reported in 8–10% of patients receiving tolcapone in clinical studies, required hospitalization in up to 1.7% of patients, and resulted in drug discontinuance in 1–1.4% of patients.^{1 9 15}

Hallucinations generally occur within first 2 weeks of therapy; are commonly accompanied by confusion and, less commonly, insomnia and excessive dreaming; and occur more frequently in patients ≥75 years of age.¹

During postmarketing experience, other new or worsening mental status and behavioral changes (e.g., paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, delirium) reported during therapy or after initiating or increasing dosage.¹ Other antiparkinsonian agents can produce similar effects.¹

Dyskinesia

Addition of tolcapone may exacerbate levodopa-associated dyskinesias.^{1 2 6 7 9 15 16 26} Usually occurs within 24 hours after initiating tolcapone and is controlled by reducing the levodopa dosage by 20–30%.^{1 2 6 7 9 16 26} However, some patients continue to experience frequent dyskinesias after reduction of levodopa dosage.¹

Impulse Control/Compulsive Behaviors

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 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, consider reducing dosage or discontinuing therapy.¹ (See Advice to Patients.)

Rhabdomyolysis

Severe rhabdomyolysis,¹ including multiorgan system failure progressing to death, reported rarely.¹ Causal relationship not established.¹

Severe, prolonged motor activity (e.g., dyskinesia) may account for rhabdomyolysis; however, some cases included fever, altered consciousness, and muscular rigidity and resembled neuroleptic malignant syndrome.¹

Use with caution in patients with severe dystonia or dyskinesia.¹

Renal Effects

High incidence of proximal tubule cell damage (degeneration, single cell necrosis, hyperplasia, karyocytomegaly, atypical nuclei) in rats receiving tolcapone for 1 or 2 years at dosages ≥6 times the recommended human dosage; not associated with changes in clinical chemistry values.¹ No established method for monitoring for occurrence of such lesions in humans.¹ Species-specific mechanism postulated, but studies to confirm this theory not conducted.¹

Possible hematuria.^{1 28}

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome has occurred in patients receiving psychotherapeutic agents and in patients with parkinson disease during withdrawal of dopaminergic agents.²⁰

Symptom complex resembling neuroleptic malignant syndrome (elevated temperature, muscular rigidity, altered consciousness) reported rarely in association with abrupt withdrawal or dosage reduction of tolcapone.^{1 28} Creatine kinase concentrations may be increased.¹ (See Discontinuance of Tolcapone under Dosage and Administration.)

Fibrosis

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and thickening of pleura reported in patients receiving ergot-derivative dopamine receptor agonists (e.g., bromocriptine, pergolide);¹ presumably related to the ergoline structure of these agents.¹ However, consider the possibility that non-ergot-derived drugs that increase dopaminergic activity (e.g., tolcapone) may induce similar changes.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use with caution in nursing women.¹

Pediatric Use

Safety and efficacy not established.¹ No identified potential use in children.¹

Geriatric Use

Safety and efficacy 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 >50 years of age.^{1 6 7 8 9} Patients ≥75 years of age may be more likely to develop hallucinations but less likely to develop dystonia than younger patients.¹

No evidence of age-related differences in tolcapone pharmacokinetics.^{1 4 5}

Hepatic Impairment

Do not initiate therapy in patients with clinical evidence of active liver disease, ALT or AST concentrations exceeding the ULN, or any other evidence of hepatocellular dysfunction.¹

Renal Impairment

Use with caution in patients with severe renal impairment.¹

Common Adverse Effects

Many CNS and psychiatric disturbances in patients receiving tolcapone in conjunction with levodopa are likely to result from increased levodopa concentrations and CNS bioavailability induced by tolcapone.^{1 7 9 16 24 33}

Dyskinesia, dystonia, nausea, anorexia, sleep disturbances/insomnia, orthostatic instability, muscle cramping, excessive dreaming, somnolence; these are dopaminergic effects associated with levodopa therapy.^{7 9 15 16 28} Most frequent nondopaminergic adverse effect: diarrhea.^{7 9 15 16 28 29}

Drug Interactions

Metabolized in part by COMT^{1 2 27 28} and by CYP3A4 and CYP2A6.^{1 28}

Inhibits COMT; has affinity for CYP2C9 in vitro.^{1 20}

Drugs Metabolized by Hepatic Microsomal Enzymes

Clinically important interactions with drugs metabolized by CYP2C9 and CYP2D6 are not expected to occur.¹ In vitro studies did not reveal important interactions with substrates for CYP isoenzymes 2A6, 1A2, 3A4, 2C19, or 2D6.¹

Drugs Metabolized by COMT

Tolcapone may alter the metabolism of drugs metabolized by COMT.¹

Drugs Affecting CNS Monoaminergic or Cholinergic System

Symptom complex resembling neuroleptic malignant syndrome reported in patients receiving tolcapone in combination with other drugs that affect brain monoaminergic or anticholinergic systems; caution is advised if such combinations are used.¹

Specific Drugs

Tolcapone Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability following oral administration is about 65–68%.^{1 27}

Rapidly absorbed following oral administration, with peak plasma concentrations generally attained within 2 hours.^{1 2 3 4 5 8 14 27 28}

Onset

Maximum inhibition of erythrocyte COMT activity is achieved within 1 hour and exceeds 80% following a single oral 200-mg dose in healthy individuals;^{1 2 4 5 8} maximum inhibition is about 80% following administration of 200 mg 3 times daily for 7 days.^{1 8}

Duration

COMT inhibitory activity persists for 16–24 hours following a single oral 200-mg dose in healthy individuals;^{1 2 4 5 8} inhibition at trough tolcapone concentrations is 30–45% following administration of 200 mg 3 times daily for 7 days.^{1 8}

Food

Administration within 1 hour before or 2 hours after a meal reduces bioavailability by 10–20% compared with administration in the fasting state.¹

Distribution

Extent

Distribution into body tissues and fluids is not fully characterized;^{1 33} however, the drug is not widely distributed.^{1 2 13}

Distributes into brain tissue.^{1 2 13}

Distributes into milk in rats; not known whether tolcapone distributes into human milk.¹

Plasma Protein Binding

>99.9% (principally albumin).^{1 27}

Special Populations

In patients with moderate cirrhotic liver disease (Child-Pugh class B), volume of distribution of unbound tolcapone is reduced almost 50%.^{1 27}

Elimination

Metabolism

Extensively metabolized by a variety of mechanisms:^{1 27 28} glucuronidation (principal metabolic pathway),^{1 27 28} metabolism by COMT to catechol-3-O-methyltolcapone,^{1 2 27 28} hydroxylation followed by oxidation to a carboxylic acid derivative,^{1 28} and reduction followed by N-acetylation.¹ In vitro data indicate that CYP3A4 and CYP2A6 catalyze the oxidation reaction.^{1 28}

Elimination Route

Excreted in urine (60%) and feces (40%);¹ minimally excreted in urine as unchanged drug (<0.5%).^{1 27}

Half-life

Terminal elimination half-life of tolcapone: 2–3 hours.^{2 3 4 5 8 27 28}

Terminal elimination half-life of catechol-3-O-methyltolcapone: 30–60 hours (but does not appear to accumulate with multiple dosing because tolcapone inhibits COMT).^{2 3 4 5 8 27}

Special Populations

In patients with moderate cirrhotic liver disease (Child-Pugh class B), clearance of unbound tolcapone reduced almost 50%.^{1 27}

In patients with Cl_cr of 30–130 mL/minute, pharmacokinetics not altered.¹

No evidence of gender-, age-, or weight-related pharmacokinetic differences.^{1 4 5}

Stability

Storage

Oral

Tablets

Tight containers at 20–25°C.¹

Actions

• Selective, potent, peripheral and to a lesser extent central, reversible inhibitor of COMT.^{1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 18 19 23 26 28}

• Lacks antiparkinsonian effects when administered as monotherapy.

• Is believed to act principally by inhibiting COMT in peripheral tissues and altering the plasma pharmacokinetics of levodopa, resulting in more sustained plasma levodopa concentrations (see Specific Drugs under Interactions).^{1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 18 19 23 26 28} 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}

• 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 (3-OMD) for transport mechanisms.²⁶

Advice to Patients

• Risk of hepatic toxicity.¹ Necessity of laboratory monitoring of liver enzymes.¹ Importance of contacting clinician immediately if signs or symptoms suggestive of hepatic failure (e.g., clay-colored stools, jaundice, fatigue, loss of appetite, lethargy) occur.¹

• Potential for tolcapone to exacerbate levodopa-associated adverse effects (e.g., dyskinesias, dystonia).^{1 7 9 16}

• Risk of orthostatic hypotension with or without symptoms (e.g., dizziness, nausea, syncope, sweating).¹ Avoid rising rapidly after prolonged sitting or lying down, especially during the first few weeks of therapy.¹

• Possible occurrence of hallucinations.¹

• Importance of advising patients of the potential for sedating effects, including somnolence and the possibility of falling asleep while engaged in activities of daily living.¹ Patients should avoid driving, operating machinery, or engaging in other potentially dangerous activities until effects on the individual are known.¹ Importance of advising patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving) occur at any time during therapy, they should not drive or participate in potentially dangerous activities until they have contacted their clinician.¹

• Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving tolcapone and of advising them of the importance of reporting such urges.¹

• Risk of nausea, especially during the first 3 months of therapy.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., liver disease).¹

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Medical Disclaimer