ENTACAPONE
Clinical safety rating: safe
Animal studies have demonstrated safety
Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), which inhibits the metabolism of levodopa to 3-O-methyldopa, thereby increasing the plasma half-life and bioavailability of levodopa in the brain.
| Metabolism | Entacapone is extensively metabolized, primarily by glucuronidation via UGT1A9 and UGT2B7, with minor metabolism via COMT and CYP450 enzymes. |
| Excretion | Primarily hepatic metabolism with biliary excretion: about 90% of dose excreted in feces, 10% in urine (as metabolites). |
| Half-life | Terminal elimination half-life is approximately 0.4–0.7 hours in the initial phase, with a terminal half-life of 2–2.5 hours, reflecting rapid elimination; clinically, entacapone is administered with each levodopa/carbidopa dose to inhibit COMT. |
| Protein binding | Approximately 98% bound, primarily to albumin. |
| Volume of Distribution | Vd is approximately 0.4 L/kg (20–25 L for a 70 kg person), suggesting distribution into extracellular fluid. |
| Bioavailability | Oral bioavailability is approximately 35% (extensive first-pass metabolism). |
| Onset of Action | Oral: Onset of COMT inhibition occurs within 30 minutes, with peak effect at approximately 1 hour. |
| Duration of Action | Oral: Duration of COMT inhibition is about 4–6 hours, corresponding to the dosing interval (given with each levodopa dose). |
200 mg orally administered concomitantly with each dose of carbidopa/levodopa, up to a maximum of 8 times daily (1600 mg/day).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended for use in patients with severe renal impairment (CrCl <20 mL/min) or those undergoing dialysis. |
| Liver impairment | Contraindicated in patients with hepatic impairment (Child-Pugh class B or C). Use with caution in mild hepatic impairment, with no specific dose adjustment available. |
| Pediatric use | Safety and efficacy not established in pediatric patients (<18 years). |
| Geriatric use | No specific dose adjustment required for elderly patients, but consider age-related renal function decline; monitor for adverse effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Nonselective MAOIs are contraindicated Can cause diarrhea and urine discoloration.
| Breastfeeding | Entacapone is excreted in rat milk. It is not known whether entacapone is excreted in human milk. The M/P ratio is unknown. Because many drugs are excreted in human milk, caution should be exercised when entacapone is administered to a nursing woman. Due to the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
| Teratogenic Risk | Entacapone is categorized as FDA Pregnancy Category C. No adequate and well-controlled studies in pregnant women. In animal studies, entacapone was not teratogenic in rats or rabbits at doses up to 20 times the maximum recommended human dose. However, embryotoxicity (increased resorptions, reduced fetal weight) occurred at maternally toxic doses. Use during pregnancy only if potential benefit justifies potential risk to the fetus. |
■ FDA Black Box Warning
None
| Common Effects | Diarrhea |
| Serious Effects |
["Hypersensitivity to entacapone or any component of the formulation","Concurrent use of non-selective MAO inhibitors (e.g., phenelzine, tranylcypromine)","History of pheochromocytoma","History of neuroleptic malignant syndrome (NMS) or non-traumatic rhabdomyolysis"]
| Precautions | ["May cause hepatotoxicity, including fulminant hepatitis; monitor liver function tests.","May cause or exacerbate dyskinesia, hypotension, syncope, and hallucinations.","May cause diarrhea, often developing 4-12 weeks after initiation.","May cause urine discoloration (brownish-orange).","May cause impulse control disorders or compulsive behaviors."] |
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| Fetal Monitoring | No specific maternal or fetal monitoring is routinely recommended. As with all medications during pregnancy, standard prenatal care should continue. Monitor for maternal adverse effects such as dyskinesia, nausea, and diarrhea. Fetal monitoring should be considered if there are maternal complications or signs of fetal distress. Ultrasound for fetal growth and well-being may be indicated in the setting of prolonged exposure or maternal comorbidities. |
| Fertility Effects | In animal studies, entacapone had no effects on fertility in rats at doses up to 20 times the maximum recommended human dose. There are no human data on the effect of entacapone on fertility. It is not known whether entacapone affects fertility in humans. |