Section 03 · Monograph

Entacapone

Reviewed Nov 2026FDA label

ComtanCOMT inhibitor

Indications

Adjunct to levodopa and carbidopa to treat end-of-dose 'wearing-off' in Parkinson's diseaseFDA-labeled
Not systematically evaluated in patients without end-of-dose wearing-offFDA-labeled

Selective, reversible peripheral catechol-O-methyltransferase (COMT) inhibitor
Reduces peripheral metabolism of levodopa to 3-O-methyldopa, increasing levodopa's area-under-curve by approximately 35% when co-administered with carbidopa/levodopa
Prolongs the elimination half-life of levodopa from about 1.3 hours to 2.4 hours, producing more sustained dopaminergic stimulation and reducing 'off' time

200 mg administered orally with each levodopa/carbidopa dose, up to a maximum of 8 times daily (1600 mg/day)
Clinical experience with doses above 1600 mg/day is limited
Can be taken with or without food
When added, levodopa dosage may need reduction or interval extension: about 58% of patients on levodopa ≥800 mg/day required a dose reduction, averaging ~25%
Withdraw slowly rather than abruptly; rapid discontinuation risks worsening parkinsonism, hyperpyrexia, confusion, and a neuroleptic malignant syndrome (NMS)-like presentation

Use with caution in hepatic impairment — AUC and Cmax approximately double in patients with liver disease

Should not ordinarily be combined with non-selective MAO inhibitors (e.g., phenelzine, tranylcypromine) due to theoretical risk of blocking major catecholamine metabolic pathways; selective MAO-B inhibitors (e.g., selegiline) have been used concomitantly without reported interaction
Caution with drugs metabolized by COMT (isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetharine, bitolterol) — may cause increased heart rate, arrhythmias, and exaggerated blood pressure changes
Warfarin: R-warfarin AUC increased ~18% and INR increased ~13% on average in interaction studies; postmarketing reports of significantly increased INR — monitor INR when entacapone is initiated or dose-increased
Caution with drugs that interfere with biliary excretion, glucuronidation, or intestinal beta-glucuronidase (e.g., probenecid, cholestyramine, erythromycin, rifampicin, ampicillin, chloramphenicol), since entacapone is eliminated mainly via bile
No clinically significant CYP450 inhibition expected at therapeutic concentrations (in vitro IC50 values far exceed clinical exposure)
Entacapone is an iron chelator; clinical significance on iron stores is unknown

Dyskinesia — most common adverse reaction, 25% vs. 15% placebo; may potentiate dopaminergic side effects of levodopa
Diarrhea in 10% (vs. 4% placebo); onset typically 4–12 weeks but can occur within the first week or after many months; associated with weight loss, dehydration, hypokalemia; postmarketing reports of drug-induced (often lymphocytic) microscopic colitis
Nausea (14% vs. 8%), hyperkinesia (10% vs. 5%), abdominal pain (8% vs. 4%), vomiting (4% vs. 1%), dry mouth (3% vs. 0%)
Brownish-orange discoloration of urine in 10% vs. 0% placebo — considered not clinically relevant, but patients should be counseled to avoid alarm
Hallucinations and psychotic-like behavior — discontinuation in 0.8% vs. 0%, hospitalization in 1.0% vs. 0.3%
Somnolence and sudden sleep onset without warning, including during driving; reported as late as 1 year after starting therapy
Orthostatic hypotension/syncope (~1.2% vs. 0.8% placebo)
Rare postmarketing reports of severe rhabdomyolysis and hyperpyrexia/confusion (NMS-like) with abrupt dose reduction or withdrawal
Structurally related to tolcapone; unlike tolcapone, entacapone does not carry an FDA boxed warning for hepatotoxicity, but caution and hepatic-function awareness are still advised given the drug class and doubled exposure in hepatic impairment

INR at initiation or dose increase in patients on warfarin
Bowel habits — watch for diarrhea, dehydration, hypokalemia, and unexplained weight loss; consider colonoscopy/biopsy if diarrhea persists after discontinuation
Dyskinesia severity and need for levodopa dose reduction
Daytime somnolence and sudden sleep episodes; counsel on driving and hazardous activities
New or worsening hallucinations, confusion, agitation, or psychotic-like behavior
Impulse control/compulsive behaviors (gambling, hypersexuality, spending, binge eating) via direct questioning
Periodic skin examination given elevated melanoma risk described in Parkinson's disease populations
Signs of hyperpyrexia/rigidity (NMS-like syndrome) during dose reduction or discontinuation — taper slowly
Orthostatic blood pressure, particularly at treatment initiation

Older FDA labeling classifies entacapone as Pregnancy Category C; no adequate controlled human data exist
Animal studies: increased fetal variations in rats and increased abortion/resorption and decreased fetal weight in rabbits at maternally toxic doses; fetal eye anomalies (micro-/macro-/anophthalmia) seen in rats at higher doses without maternal toxicity
No evidence of teratogenicity from entacapone itself, but the teratogenic potential of the entacapone/levodopa/carbidopa combination has not been formally assessed in animals since levodopa/carbidopa alone is known to cause malformations in rabbits
Use during pregnancy only if potential benefit justifies potential fetal risk
Entacapone is excreted into milk in animal studies; human lactation data are unavailable — caution advised when administering to nursing women