Tasmar (tolcapone)

For the management of idiopathic parkinson disease, tolcapone is given in conjunction with levodopa/carbidopa. To optimize patient response, reductions in the daily levodopa/carbidopa dosage may be necessary. 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 dosage; the average reduction in daily levodopa dosage was about 30%.

The usual initial dosage of tolcapone is 100 mg 3 times daily. 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. 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. 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.

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. Following initiation of tolcapone therapy, symptomatic improvement generally is evident within 3 weeks. 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. 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. Tolcapone therapy generally should not be reintroduced in a patient who previously experienced tolcapone-associated hepatic injury. Tolcapone should be used with caution in patients with severe dystonia or dyskinesia.

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

Tolcapone is administered orally in 3 equally divided doses daily. 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. 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. Tolcapone can be administered with conventional or extended-release preparations of levodopa/carbidopa.

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.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Comt Inhibitors/Selected Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Since MAOI's and COMT are the two major enzymes responsible for the metabolism of catecholamines, the combination of entacapone, tolcapone, or opicapone and a non-selective MAOI may inhibit the majority of catecholamine metabolism pathways.(1-3)

CLINICAL EFFECTS: Concurrent administration of entacapone, tolcapone, or opicapone with a non-selective MAOI may result in elevated levels of catecholamines, which may result in elevated heart rate and blood pressure.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian(4) and UK(1) manufacturers of entacapone state that concomitant use of either a non-selective MAOI or a selective MAO-A inhibitor with a selective MAO-B inhibitor with entacapone is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating entacapone therapy.(4) The UK manufacturer of tolcapone states that tolcapone should not be coadministered with either a non-selective MAOI or a selective MAO-A inhibitor with a selective MAO-B inhibitor. (5) The US manufacturer of tolcapone states that patients should not ordinarily be treated concomitantly with tolcapone and a non-selective MAOI. Tolcapone may be concurrently administered with a selective MAO-B inhibitor.(2) The Middle East and US manufacturers of opicapone state that concomitant use of opicapone with MAO inhibitors other than those for the treatment of Parkinson's disease is contraindicated.(10,11)

DISCUSSION: Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes systems involved in the metabolism of catecholamines. Therefore, theoretically, the combination of either entacapone, tolcapone, or opicapone with a non-selective MAO inhibitor will result in inhibition of the majority of catecholamine metabolism pathways.(1,2) At daily oral doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A.(6) At dosages administered transdermally for the treatment of depression, selegiline is not selective for MAO-B.(7) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(8,9) Metaxalone is a weak inhibitor of MAO.(12,13)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Comt Inhibitors/Rasagiline; Oral Selegiline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Since MAOIs and COMT are the two major enzymes responsible for the metabolism of catecholamines, the combination of entacapone, tolcapone, or opicapone and a non-selective MAOI may inhibit the majority of catecholamine metabolism pathways.(1-3)

CLINICAL EFFECTS: Concurrent administration of entacapone, tolcapone, or opicapone with a non-selective MAOI may result in elevated levels of catecholamines, which may result in elevated heart rate and blood pressure.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Entacapone(1,4), tolcapone(5), and opicapone(9,10) should not be used with either a non-selective MAOI or the combination of a selective MAO-A inhibitor and a selective MAO-B inhibitor. Nonselective MAOIs should be discontinued at least 2 weeks prior to initiating COMT inhibitor therapy. Entacapone, tolcapone, or opicapone may be used with oral selegiline, provided that the daily dose of selegiline does not exceed 10 mg, and with rasagiline, provided that the daily dose of rasagiline does not exceed 1 mg, and that patients are not also receiving a selective MAO-A inhibitor.

DISCUSSION: Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes systems involved in the metabolism of catecholamines. Therefore, theoretically, the combination of either entacapone or tolcapone with a non-selective MAO inhibitor will result in inhibition of the majority of catecholamine metabolism pathways.(1,2) Rasagiline is selective for MAO-B in humans at recommended dosages of 1 mg per day or less.(6) Rasagiline has been used with entacapone in clinical trials with no reports of adverse effects.(6) Concurrent administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.(7) At daily doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A.(8)

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• Acute hepatic failure

• Disease of liver
• Hypotension
• Psychotic disorder

• Hallucinations
• Malignant melanoma
• Severe diarrhea

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More Frequent

• Anorexia
• Diarrhea
• Dizziness
• Drowsy
• Dyskinesia
• Hallucinations
• Headache disorder
• Insomnia
• Nausea
• Orthostatic hypotension
• Syncope
• Tremor
• Vomiting

Less Frequent

• Accidental fall
• Acquired dystonia
• Acute cognitive impairment
• Chest pain
• Dyspnea
• Fatigue
• Flu-like symptoms
• Hematuria

Rare or Very Rare

• Abnormal hepatic function tests
• Acute hepatic failure
• Agitation
• Arthritis
• Chest tightness
• Concentration difficulty
• Cramps
• Drug-induced psychosis
• Hepatocellular damage
• Hypotension
• Irritability
• Joint stiffness
• Neck pain
• Paresthesia
• Rhabdomyolysis
• Sinusitis
• Sudden onset of sleep
• Urinary tract infection

More Frequent

• Constipation
• Hyperhidrosis
• Upper respiratory infection
• Urine discoloration
• Xerostomia

Less Frequent

• Acute abdominal pain
• Dream disorder
• Dysesthesia
• Dyspepsia
• Flatulence
• Hyperkinesis
• Sleep disorder

Rare or Very Rare

• Impulse control disorder

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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. 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. 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.

Tolcapone is administered in conjunction with levodopa/carbidopa; levodopa/carbidopa cause visceral and skeletal malformations in rabbits. 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. 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). While tolcapone does not appear to be teratogenic in animals, there are no adequate and controlled studies to date in humans. Tolcapone should only be used during pregnancy when the potential benefits justify the possible risks to the fetus. 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.

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

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