Entacapone

Pronunciation

Pronunciation: en-TAK-a-pone
Class: Antiparkinson agent

Trade Names

Comtan
- Tablets, oral 200 mg

Pharmacology

Inhibits catechol-O-methyltransferase (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 effect.

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Pharmacokinetics

Absorption

Rapidly absorbed. T max is approximately 1 h. C max is approximately 1.2 mcg/mL (single 200 mg dose). Absolute bioavailability is 35%.

Distribution

Vd is 20 L (IV). 98% is protein bound, mainly to albumin.

Metabolism

Almost completely metabolized; inactive metabolites formed by isomerization and glucuronidation.

Elimination

Approximately 10% is excreted in the urine (0.2% as unchanged drug) and 90% in feces. The elimination of entacapone is biphasic, with an elimination half-life of 0.4 to 0.7 hours based on the beta-phase and 2.4 hours based on the gamma-phase. The total body Cl after IV administration is 850 mL/min.

Special Populations

Renal Function Impairment

No important effects of renal function on the pharmacokinetics of entacapone have been demonstrated.

Hepatic Function Impairment

AUC and C max are approximately 2-fold higher in those with a history of alcoholism and hepatic impairment.

Elderly

Pharmacokinetics of entacapone are independent of age.

Gender

No studies have been conducted.

Race

Racial representation in clinical trials was largely limited to white patients; therefore, no conclusions can be reached about the effect of entacapone on other racial groups.

Indications and Usage

As an adjunct to levodopa/carbidopa for the treatment of idiopathic Parkinson disease in patients who experience signs and symptoms of end-of-dose “wearing-off.”

Contraindications

Hypersensitivity to the drug or its ingredients.

Dosage and Administration

Adults

PO 200 mg concomitantly with each levodopa/carbidopa dose; max, 1,600 mg/day.

General Advice

  • May be taken with or without food.
  • To optimize an individual patient's response, reducing the daily levodopa dose or extending the interval between doses may be necessary.
  • The majority of patients required a decrease in daily levodopa dose by approximately 25% if their daily dose of levodopa had been at least 800 mg, or if patients had moderate or severe dyskinesias before beginning treatment.
  • Entacapone can be combined with the immediate- or sustained-release formulation of levodopa/carbidopa.
  • Withdraw patients slowly if a decision is made to discontinue treatment. Patients should be monitored closely, and other dopaminergic treatments should be adjusted as needed.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Ampicillin, chloramphenicol, cholestyramine, erythromycin, probenecid, rifampin

May interfere with biliary excretion or metabolism of entacapone. Use with caution.

Apomorphine, dobutamine, dopamine, epinephrine, isoproterenol, methyldopa, norepinephrine

Excessive changes in BP and increased heart rate, possibly arrhythmias, may occur. Use with caution. Closely monitor the clinical response of the patient.

MAOIs

Because MAO and COMT are the 2 major enzyme systems involved in catecholamine metabolism, it is theoretically possible that the combination of entacapone and a nonselective MAOI (eg, phenelzine, tranylcypromine) could result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. Therefore, usually do not treat patients concomitantly with entacapone and a nonselective MAOI. However, entacapone may be coadministered with a selective MAO-B inhibitor (eg, selegiline).

Adverse Reactions

Adverse reactions listed are a result of entacapone coadministered with levodopa/carbidopa:

Cardiovascular

Orthostatic hypotension (4%); syncope (1%).

CNS

Dyskinesia (25%); hyperkinesia (10%); hypokinesia (9%); dizziness (8%); fatigue (6%); hallucinations (4%); anxiety, asthenia, somnolence (2%); agitation (1%).

GI

Nausea (14%); diarrhea (10%); abdominal pain (8%); constipation (6%); vomiting (4%); dry mouth (3%); dyspepsia, flatulence (2%); gastritis, GI disorders, taste perversion (1%); microscopic colitis, primarily lymphocytic colitis (postmarketing).

Miscellaneous

Urine discoloration (10%); back pain (4%); dyspnea (3%); sweating increased, purpura (2%); bacterial infection (1%); rhabdomyolysis.

Precautions

Monitor

Monitor patients closely if entacapone is discontinued. Monitor patients for melanoma frequently and on a regular basis. Monitor for postural hypotension, increased dyskinesia, and CNS changes (eg, hallucinations).


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

Use with caution.

Cardiovascular effects

May increase the incidence of orthostatic hypotension and syncope associated with dopaminergic therapy.

Discontinuation

Exercise caution when discontinuing treatment. Withdrawal of entacapone should proceed slowly.

Dyskinesia

May cause and/or exacerbate preexisting dyskinesia.

Fibrotic complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported.

GI effects

Diarrhea may occur as early as the first week or as late as many months after initiating entacapone. Diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis.

Hallucinations

May occur.

Melanoma

Risk of melanoma is higher in patients with Parkinson disease compared with the general population; however, it has not been determined if this is caused by the disease or the treatment.

Neuroleptic malignant syndrome symptoms

Rhabdomyolysis and a symptom complex resembling NMS (eg, elevated temperature, muscular rigidity, altered consciousness, elevated CPK) have been reported in association with therapy. Exercise caution.

Overdosage

Symptoms

Abdominal pain, loose stools.

Patient Information

  • Inform patient that entacapone is not a cure for Parkinson disease, but should help reduce the symptoms and decrease the need for higher doses of their other medications.
  • Instruct patient to take entacapone only as prescribed.
  • Advise patient that hallucinations can occur.
  • Advise patient that postural (orthostatic) hypotension with or without symptoms, such as dizziness, nausea, sweating, and syncope, may develop. Hypotension may occur more frequently during initial therapy.
  • Caution patient against rising rapidly, especially after prolonged periods of sitting or lying down.
  • Caution patient about possible additive sedative effects when taking other CNS depressants in combination with entacapone.
  • Caution patient not to drive a car, operate other complex machinery, or engage in any hazardous activity until tolerance is determined.
  • Inform patient that nausea or hypotension may occur, especially at the initiation of treatment.
  • Advise patients of the possibility of an increase in dyskinesia.
  • Advise patients of the possibility of experiencing intense urges while taking 1 or more of the medications generally used to treat Parkinson disease. Instruct patients to inform their health care provider if they experience new or increased gambling urges, sexual urges, or other intense urges while taking entacapone.
  • Inform patients that diarrhea may occur and may have a delayed onset. Advise patients with diarrhea to drink fluids to maintain adequate hydration and monitor for weight loss.
  • Inform patient that treatment with entacapone may cause a change in urine color to a brownish orange in approximately 10% of people, but that it will not cause harm should it occur.
  • Advise female patients to notify their health care provider if they become pregnant, plan to become pregnant, or are breast-feeding.

Copyright © 2009 Wolters Kluwer Health.

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