Tolcapone

Pronunciation: TOLE-kah-pone
Class: Antiparkinson agent

Trade Names

Tasmar
- Tablets 100 mg
- Tablets 200 mg

Pharmacology

The exact mechanism of action is unknown. Inhibits catechol-O-methyl transferase (COMT) thus blocking the degradation of catechols including dopamine and levodopa. This may lead to more sustained levels of dopamine and consequently a more prolonged antiparkinson's effect.

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Pharmacokinetics

Absorption

Tolcapone T max is about 2 h. Bioavailability is 65%. Food given within 1 h before and 2 h after dosing decreases the bioavailability 10% to 20%.

Distribution

Tolcapone Vd is 9 L and it does not distribute widely into tissues. Protein binding is about 99%.

Metabolism

Tolcapone's main metabolic pathway is glucuronidation. The drug is almost completely metabolized prior to excretion, with only a very small amount (0.5% of a dose) found unchanged in urine.

Elimination

Tolcapone's t ½ is 2 to 3 h. Systemic clearance is about 7 L/h.

Special Populations

Hepatic Function Impairment

In patients with moderate cirrhotic liver disease, clearance and Vd is reduced about 50%. Do not initiate therapy if the patient exhibits clinical evidence of active liver disease or 2 ALT or AST values greater than the ULN.

Indications and Usage

As an adjunct to levodopa/carbidopa for the management of signs and symptoms of Parkinsons disease.

Contraindications

Hypersensitivity to the drug or its ingredients; patients with liver disease; patients who were withdrawn from tolcapone because of evidence of tolcapone-induced hepatocellular injury; patients with a history of non-traumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication.

Dosage and Administration

Adults

PO 100 or 200 mg 3 times daily. The max recommended dose is 600 mg/day.

Storage/Stability

Store at room temperature.

Drug Interactions

None well documented.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Orthostatic complaints; syncope; chest pain; hypotension; chest discomfort.

CNS

Sleep disorder; excessive dreaming; somnolence; confusion; dizziness; headache; hallucination; dyskinesia; dystonia; fatigue; balance loss; hyperkinesia; paresthesia; hypokinesia; agitation; irritability; mental deficiency; hyperactivity; panic reaction; euphoria; hypertonia.

Dermatologic

Dermal bleeding; skin tumor; alopecia.

EENT

Xerostomia; cataract; eye inflammation.

Hepatic

Severe hepatocellular injury, including fulminant liver failure resulting in death.

GI

Nausea; diarrhea; vomiting; constipation; abdominal pain; dyspepsia; flatulence.

Genitourinary

Urinary tract infection; urine discoloration; micturition disorder; uterine tumor.

Respiratory

Upper respiratory tract infection; dyspnea; sinus congestion.

Miscellaneous

Muscle cramps; anorexia; falling; increased sweating; rhabdomyolysis; stiffness; arthritis; neck pain; influenza; burning; malaise; fever.

Precautions

Warnings

Hepatotoxicity may be fatal, thus reserve for use in Parkinson patients on levodopa/carbidopa with symptom fluctuations and not satisfactorily responding. If no benefit observed after 3 wk of therapy, discontinue drug. Do not initiate therapy if patient exhibits clinical evidence of liver disease or 2 AST or ALT values greater than upper limit of normal. Monitor baseline AST and ALT and every 2 wk for first yr, every 4 wk for next 6 mo, and every 8 wk thereafter. Withdraw therapy if patient exhibits clinical evidence of liver disease. Use with caution in patients with severe dystonia/dyskinesias.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Diarrhea

Diarrhea is the most common reason for stopping therapy. Follow up all cases with appropriate work-up, including occult blood.

Dosage reduction

Decrease levodopa dosage appropriately when used concurrently.

Dyskinesia

Tolcapone may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.

Fibrotic complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot-derived dopaminergic agents.

Hallucinations

Patients treated with placebo, 100, and 200 mg tolcapone 3 times daily developed hallucinations at an incidence of approximately 5%, 8%, and 10%, respectively. Hallucinations present shortly after the initiation of therapy with tolcapone (typically within the first 2 wk).

Hepatic enzyme abnormalities

Elevations usually occurred within 6 wk to 6 mo of starting treatment. In about half the cases, enzyme levels returned to baseline within 1 to 3 mo and when treatment was discontinued, enzymes generally declined within 2 to 3 wk, but in some cases it took as long as 1 to 2 mo to return to normal.

Hypertension/Syncope

Dopaminergic therapy in Parkinson disease patients has been associated with orthostatic hypotension.

Monoamine oxidase (MAO) inhibitors

Avoid concurrent use of MAO inhibitors. Administration of MAO inhibitors may result in inhibition of the majority of pathways for catecholamine metabolism.

Rhabdomyolysis

Cases of severe rhabdomyolysis, with 1 case of multiorgan failure rapidly progressing to death, have been reported.

Withdrawal-emergent hyperpyrexia and confusion

Cases resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported.

Overdosage

Symptoms

Nausea, vomiting, dizziness.

Patient Information

  • Provide patient information leaflet.
  • Instruct patient to take drug only as prescribed.
  • Inform patient that postural hypotension with or without symptoms (eg, dizziness, syncope) may occur and caution patients against rising rapidly after sitting or lying down.
  • Inform patient that nausea may occur.
  • Advise patient of the possibility of an increase in dyskinesia and dystonia.
  • Instruct patient to notify their health care provider if they become pregnant or intend to become pregnant during therapy.
  • Advise patient to notify their health care provider if they intend to breast-feed an infant.
  • Advise patients about the need for self-monitoring for classical signs of liver disease (eg, clay-colored stools, jaundice) and nonspecific ones (eg, fatigue, appetite loss, lethargy).
  • Inform patient of the clinical signs and symptoms that suggest the onset of hepatic injury (eg, persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, right upper quadrant tenderness).

Copyright © 2009 Wolters Kluwer Health.

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