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Entacapone: Drug information

Entacapone: Drug information
(For additional information see "Entacapone: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Comtan
Brand Names: Canada
  • Comtan;
  • SANDOZ Entacapone;
  • TEVA-Entacapone
Pharmacologic Category
  • Anti-Parkinson Agent, COMT Inhibitor
Dosing: Adult
Parkinson disease

Parkinson disease: Oral: 200 mg with each dose of levodopa/carbidopa, up to a maximum of 8 times daily (maximum daily dose: 1600 mg daily).

Note: To optimize therapy, the dosage of levodopa may need to be reduced or the dosing interval may need to be extended. Patients taking levodopa ≥800 mg daily or who had moderate-to-severe dyskinesias prior to therapy required an average decrease of 25% in the daily levodopa dose.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, renal function was not found to significantly affect the pharmacokinetics of entacapone.

Dosing: Hepatic Impairment: Adult

U.S. labeling: There are no dosage adjustments provided in the manufacturer's labeling. Treat with caution and monitor carefully; AUC and Cmax may possibly be doubled.

Canadian labeling: Use is contraindicated.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Comtan: 200 mg [DSC]

Comtan: 200 mg [contains polysorbate 80]

Generic: 200 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Comtan: 200 mg [contains polysorbate 80]

Generic: 200 mg

Administration: Adult

Always administer in association with levodopa/carbidopa; can be combined with both the immediate and sustained release formulations of levodopa/carbidopa. May be administered without regard to meals. Should not be abruptly withdrawn from patient's therapy due to significant worsening of symptoms.

Use: Labeled Indications

Parkinson disease: Adjunct to levodopa/carbidopa therapy in patients with idiopathic Parkinson disease who experience “wearing-off” symptoms at the end of a dosing interval

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Gastrointestinal: Nausea (14%)

Neuromuscular & skeletal: Dyskinesia (25%)

1% to 10%:

Cardiovascular: Syncope (1%)

Central nervous system: Dizziness (8%), fatigue (6%), anxiety (2%), drowsiness (2%), agitation (1%), hallucination (≤1%)

Dermatologic: Diaphoresis (increased; 2%)

Gastrointestinal: Diarrhea (10%), abdominal pain (8%), constipation (6%), vomiting (4%), xerostomia (3%), dyspepsia (2%), flatulence (2%), dysgeusia (1%), gastritis (1%), gastrointestinal disease (1%)

Genitourinary: Urine discoloration (brown-orange; 10%)

Hematologic & oncologic: Purpura (2%)

Infection: Bacterial infection (1%)

Neuromuscular & skeletal: Hyperkinesia (10%), hypokinesia (9%), back pain (2% to 4%), weakness (2%)

Respiratory: Dyspnea (3%)

<1%, postmarketing, and/or case reports: Behavioral changes (including psychotic-like behavior), hepatitis (mainly cholestatic features), impulse control disorder (eg, pathological gambling, hypersexuality, spending money), mental status changes, neurological signs and symptoms (hyperpyrexia and confusion [resembling neuroleptic malignant syndrome]), orthostatic hypotension, pulmonary fibrosis, retroperitoneal fibrosis, rhabdomyolysis, sudden onset of sleep

Contraindications

Hypersensitivity to entacapone or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hematologic, pulmonary (including bronchial asthma), or renal disease; history of neuroleptic malignant syndrome (NMS) and/or nontraumatic rhabdomyolysis; hepatic impairment; narrow-angle glaucoma; pheochromocytoma; in the presence of a suspicious, undiagnosed skin lesion or history of melanoma; concomitant use with a nonselective monoamine oxidase (MAO) inhibitor (eg, tranylcypromine, phenelzine) or concomitant use with both a selective MAO-A and selective MAO-B inhibitor; when administration of a sympathomimetic amine is contraindicated

Warnings/Precautions

Concerns related to adverse effects:

• Abnormal thinking/behavioral changes: Abnormal thinking and behavior changes have been reported and may include aggressive behavior, agitation, confusion, delirium, delusions, disorientation, paranoid ideation, and psychotic-like behavior.

• Diarrhea: Has been associated with delayed development of diarrhea (usual onset after 4 to 12 weeks); use with caution in patients with lower gastrointestinal disease or an increased risk of dehydration. Diarrhea may be a sign of drug-induced colitis (primarily lymphocytic). Monitor for weight loss. Discontinue use with prolonged diarrhea.

• Dyskinesia: New-onset or exacerbation of preexisting dyskinesia may occur when used as an adjunct to levodopa. Decreasing the dose of levodopa may ameliorate these side effects in some cases.

• Hallucinations: May cause hallucinations.

• Impulse control disorders: Compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), intense urges to spend money uncontrollably, and other intense urges have been reported. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed. The Canadian labeling contraindicates use in patients with suspicious, undiagnosed skin lesions or history of melanoma.

• Neuroleptic malignant syndrome: Entacapone, in conjunction with other drug therapy that alters brain biogenic amine concentrations (eg, MAO inhibitors, SSRIs), has been associated with a syndrome resembling neuroleptic malignant syndrome (hyperpyrexia and confusion - some fatal) on abrupt withdrawal or dosage reduction. Concomitant use of entacapone and nonselective MAO inhibitors should be avoided.

• Orthostatic hypotension: May cause orthostatic hypotension and syncope.

• Pleural/retroperitoneal fibrosis: Dopaminergic agents from the ergot class have been associated with fibrotic complications, such as retroperitoneal fibrosis, pulmonary infiltrates or pleural effusion and thickening. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. It is unknown whether nonergot, pro-dopaminergic agents like entacapone confer this risk.

• Rhabdomyolysis: Severe rhabdomyolysis has been reported with use.

• Somnolence: Patients have reported falling asleep while engaging in activities of daily living; this has been reported to occur without significant warning signs and may occur as late as up to 1 year after initiation of treatment. Monitor for daytime somnolence or preexisting sleep disorder. Use caution in the presence of sleep disorders, with other CNS depressants, sedating agents, psychoactive drugs or ethanol. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Cardiovascular disease: The Canadian product labeling notes to use with caution in patients with cardiovascular disease, including a history of myocardial infarction (MI) and arrhythmias; MI and other ischemic adverse events have been observed in clinical trials.

• Hepatic impairment: Use with caution in patients with hepatic impairment or biliary obstruction. The Canadian labeling contraindicates use in hepatic impairment.

• Psychotic disorders: Avoid use in patients with major psychotic disorder due to the risk of exacerbating psychosis. Many treatments for psychosis may exacerbate the symptoms of Parkinson disease and may also decrease the effectiveness of entacapone.

Concurrent drug therapy issues:

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Other warnings/precautions:

• Discontinuation of therapy: Do not withdraw therapy abruptly.

• Urine discoloration: Urine may appear dark in color (brownish orange) during therapy.

Metabolism/Transport Effects

Inhibits COMT

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

COMT Substrates: COMT Inhibitors may increase the serum concentration of COMT Substrates. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Iron Preparations: May decrease the serum concentration of Entacapone. Management: Consider separating doses of the agents by 2 or more hours to minimize the effects of this interaction. Monitor for decreased therapeutic effects of levodopa during concomitant therapy, particularly if doses cannot be separated. Risk D: Consider therapy modification

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofepramine: Entacapone may enhance the adverse/toxic effect of Lofepramine. Risk X: Avoid combination

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: COMT Inhibitors may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Management: Avoid coadministration of COMT inhibitors and nonselective monoamine oxidase inhibitors (MAOIs) (eg, isocarboxazid, phenelzine, tranylcypromine, linezolid, methylene blue) whenever possible. Risk D: Consider therapy modification

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Pipamperone [INT]: COMT Inhibitors may diminish the therapeutic effect of Pipamperone [INT]. Pipamperone [INT] may diminish the therapeutic effect of COMT Inhibitors. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

Entacapone has been reported to chelate iron and decreasing serum iron levels were noted in clinical trials; however, clinically significant anemia has not been observed.

Pregnancy Considerations

The incidence of Parkinson disease in pregnancy is relatively rare and information related to the use of entacapone in pregnant women is very limited (Kranick 2010; Tüfekçioğlu 2018).

Breastfeeding Considerations

It is not known if entacapone is present in breast milk.

The manufacturer recommends that caution be exercised when administering entacapone to breast-feeding women.

Monitoring Parameters

Signs and symptoms of Parkinson's disease; liver function tests, blood pressure, patient's mental status and impulse control disorders; daytime sleepiness; serum iron (if signs of anemia); weight loss (patients experiencing diarrhea); signs and symptoms of neuroleptic malignant syndrome if abrupt discontinuation required; dermatologic examination (regularly while on therapy).

Canadian labeling (additional monitoring recommendations): Cardiac function with initial dosage adjustments and periodically during prolonged therapy (patients with history of MI or arrhythmia)

Mechanism of Action

Entacapone is a reversible and selective inhibitor of catechol-O-methyltransferase (COMT). When entacapone is taken with levodopa, the pharmacokinetics are altered, resulting in more sustained levodopa serum levels compared to levodopa taken alone. The resulting levels of levodopa provide for increased concentrations available for absorption across the blood-brain barrier, thereby providing for increased CNS levels of dopamine, the active metabolite of levodopa.

Pharmacokinetics

Onset of action: Rapid

Absorption: Rapid

Distribution: IV: Vdss: 20 L

Protein binding: 98%, primarily to albumin

Metabolism: Isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer

Bioavailability: 35%

Half-life elimination: Beta phase: 0.4 to 0.7 hours; gamma phase: 2.4 hours

Time to peak, serum: 1 hour

Excretion: Feces (90%); urine (10%)

Pharmacokinetics: Additional Considerations

Hepatic function impairment: AUC and Cmax are approximately 2-fold higher in those with a history of alcoholism and hepatic impairment.

Pricing: US

Tablets (Comtan Oral)

200 mg (per each): $9.25

Tablets (Entacapone Oral)

200 mg (per each): $3.95 - $4.54

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Adcapone (BD, IN);
  • Anxopone (TW);
  • Comtade (CO);
  • Comtan (AE, AR, AT, AU, BB, BE, BG, BR, CH, CL, CN, CY, CZ, DE, DK, EC, EE, ES, FI, FR, GB, GR, HK, HN, HR, HU, ID, IE, IL, IT, JO, JP, KR, KW, LT, LU, MT, MX, MY, NL, NZ, PE, PH, PL, PT, RO, RU, SA, SG, SK, TH, TR, TW, UY, VE, ZA);
  • Comtapone (EG);
  • Comtess (AT, BE, BG, CZ, DE, DK, EE, FR, GB, GR, HN, HR, IE, IS, IT, LT, MT, NL, NO, PL, PT, RU, SE, SK);
  • Encapia (NL);
  • Entapon (TW);
  • Entapone (NZ);
  • Parkicapone (EG)


For country code abbreviations (show table)
  1. Comtan (entacapone) [prescribing information]. Morristown, NJ: Almatica Pharma LLC; May 2020.
  2. Comtan [product monograph]. Boucherville, Quebec, Canada: Sandoz Canada Inc; July 2020.
  3. Kranick SM, Mowry EM, Colcher A, et al, "Movement Disorders and Pregnancy: A Review of the Literature," Mov Disord, 2010, 25(6):665-71. [PubMed 20437535]
  4. Pahwa R, Factor SA, Lyons KE, et al, “Practice Parameter: Treatment of Parkinson Disease With Motor Fluctuations and Dyskinesia (An Evidence-Based Review): Report of the Quality Standards Subcommittee of the American Academy of Neurology," Neurology, 2006, 66(7):983-95. [PubMed 16606909]
  5. Tüfekçioğlu Z, Hanağası H, Yalçın Çakmaklı G, et al. Use of anti-Parkinson medication during pregnancy: a case series. J Neurol. 2018;265(8):1922-1929. [PubMed 29926223]
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