Entacapone

Entacapone
Skeletal formula
Space-filling model of entacapone
Names
Pronunciation/ˌɛntəkəˈpoʊn/ or /ɛnˈtækəpoʊn/
Trade namesComtan, Comtess, others
IUPAC name
  • (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide
Clinical data
Drug classCOMT inhibitors[1]
Main usesParkinson's disease[1]
Side effectsUncontrollable movements, nausea, change in urine color[2]
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    External links
    AHFS/Drugs.comMonograph
    US NLMEntacapone
    MedlinePlusa601236
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability35%
    Protein binding98% (binds to serum albumin)
    MetabolismLiver
    Elimination half-life0.4–0.7 hours
    ExcretionFeces (90%), urine (10%)
    Chemical and physical data
    FormulaC14H15N3O5
    Molar mass305.290 g·mol−1
    3D model (JSmol)
    SMILES
    • [O-][N+](=O)c1cc(\C=C(/C#N)C(=O)N(CC)CC)cc(O)c1O
    InChI
    • InChI=1S/C14H15N3O5/c1-3-16(4-2)14(20)10(8-15)5-9-6-11(17(21)22)13(19)12(18)7-9/h5-7,18-19H,3-4H2,1-2H3/b10-5+ checkY
    • Key:JRURYQJSLYLRLN-BJMVGYQFSA-N checkY

    Entacapone, sold under the brand name Comtan among others, is a medication used to treat Parkinson's disease.[1] It is used to prevent the wearing off of levodopa/carbidopa before the next dose is due.[1] It is taken by mouth.[3]

    Common side effects include uncontrollable movements, nausea, and change in urine color.[2] Other side effects may include abdominal pain, urge to gamble, falling asleep, prostate cancer, low blood pressure with standing, and hallucinations.[1] It works by blocking the enzyme that breaks down levodopa, catechol-O-methyltransferase (COMT).[2]

    Entacapone was approved for medical use in Europe in 1998 and the United States in 1999.[1][2] It is available as a generic medication.[3] In the United Kingdom 100 tablets of 200 mg costs the NHS about £16 as of 2021.[3] This amount in the United States costs about 40 USD.[4]

    Medical uses

    Entacapone is used in addition to levodopa and carbidopa for people with Parkinson's disease to treat the signs and symptoms of end-of-dose "wearing-off."[5] "Wearing-off" is characterized by the re-appearance of both motor and non-motor symptoms of Parkinson's disease occurring towards the end of a previous levodopa and carbidopa dose.[6] Entacapone has not been shown to slow progression or reverse Parkinson's disease.[7][6][8]

    Dosage

    It is taken at a dose of 200 mg at the same time as levodopa/carbidopa.[3] Up to 10 tablets may be taken per day.[2] Use is only recommended with normal release levodopa.[2]

    Entacapone is an orally active drug that can be taken with or without food.[5][8] It is also available as the combination pill carbidopa/levodopa/entacapone (Stalevo).[9]

    Contraindications

    There is a high risk for allergic reactions for people who are hypersensitive to entacapone.[7]

    Potential limiting conditions to consider before starting entacapone include:[8]

    Side effects

    The following side effects have been reported by people with Parkinson's disease treated with entacapone:

    • Abdominal pain
    • Nausea
    • Vomiting
    • Fatigue
    • Dry mouth
    • Back ache

    Movement problems

    The most common side effect of entacapone is movement problems, which occur in 25% of people taking entacapone.[7] This drug may cause or worsen dyskinesia for people with Parkinson's disease treated together with levodopa and carbidopa.[7] In particular, "peak-dose dyskinesias" may occur when levodopa levels are at its peak concentration in the serum plasma.[10][11]

    Diarrhea

    10% of patients taking entacapone have been shown to experience diarrhea.[7] Diarrhea may occur within 4–12 weeks of initial entacapone use but resolves after discontinuation of the drug. Use of entacapone in the presence of diarrhea can also be associated with weight loss, low potassium levels, and dehydration.[7] In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone.[12]

    Urine

    10% of people taking entacapone experience a change in urine color to orange, red, brown, or black. This side effect is due to entacapone metabolism and excretion in the urine and shown to not be harmful.[12]

    Sleep

    People have reported sudden sleep onset while engaging in daily activities without prior warning of drowsiness. In controlled studies, patients on entacapone had a 2% increased risk of somnolence compared to placebo.[7]

    Blood pressure

    Episodes of orthostatic hypotension have been shown to be more common at the start of entacapone use due to increased levels of levodopa.[7]

    Behavior

    Post-marketing data shows that entacapone may change or worsen mental status, leading to behaviors such as delusions, agitation, confusion, and delirium.[7]

    People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors.[7]

    Liver problems

    Biliary excretion is the major route of excretion for entacapone. People with liver dysfunction may require additional caution and more frequent liver function monitoring while taking entacapone.[7]

    Kidney problems

    There are no significant considerations for people with poor kidney function taking entacapone.[7]

    Pregnancy and breastfeeding

    Pregnancy category C: risk is not ruled out.[7]

    Although there have been animal studies that showed that entacapone was excreted into maternal rat milk, there have been no studies with human breast milk. Caution is advised for mothers taking entacapone while breastfeeding or during pregnancy.[7]

    Children

    Entacapone safety and efficacy have not been assessed in infants or children.[7]

    Interactions

    In studies, entacapone has shown a low potential for interaction with other drugs. In theory, it could interact with MAO inhibitors, tricyclic antidepressants and noradrenaline reuptake inhibitors because they also increase catecholamine levels in the body, with drugs being metabolized by COMT (for example methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline), with iron because it could form chelates, with substances binding to the same albumin site in the blood plasma (for example diazepam and ibuprofen), and with drugs being metabolized by the liver enzyme CYP2C9 (for example warfarin). None of the medications tested in studies have shown clinically relevant interactions, except perhaps warfarin for which a 13% (CI90: 6–19%) increase in INR was seen when combined with entacapone.[13]

    Pharmacology

    Mechanism of action

    Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).[7] COMT eliminates biologically active catechols present in catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. When administered with a decarboxylase inhibitor, COMT acts as the major metabolizing enzyme for levodopa and metabolizes it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and in the periphery.[7]

    For the treatment of Parkinson's disease, entacapone is given as an adjunct to levodopa and an aromatic amino acid decarboxylase inhibitor, carbidopa. Entacapone inhibits COMT in the periphery (but not, or at most marginally, in the brain[14]) and the metabolism of levodopa, thus increasing plasma levels of levodopa and causing more constant dopaminergic stimulation in order to reduce the signs and symptoms presented in the disease.[7]

    Pharmacokinetics

    Absorption

    The time to highest blood plasma concentrations is approximately one hour. The substance undergoes extensive first-pass metabolism. Absolute oral bioavailability (F) is 35%.[7][13]

    Distribution

    The volume of distribution (Vd) after intravenous injection is approximately 20 liters. 98% of the circulating entacapone is bound to serum albumin, which limits its distribution into tissues.[7][13]

    Metabolism and elimination

    Entacapone is primarily metabolized to its glucuronide in the liver, and 5% are converted into the Z-isomer.[13] It has a half-life of approximately 0.3–0.7 hours, with only 0.2% being excreted unchanged in the urine.[7]

    References

    1. 1 2 3 4 5 6 "Entacapone Monograph for Professionals". Drugs.com. Archived from the original on 8 May 2021. Retrieved 15 December 2021.
    2. 1 2 3 4 5 6 "Comtess". Archived from the original on 12 November 2020. Retrieved 15 December 2021.
    3. 1 2 3 4 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 433. ISBN 978-0857114105.
    4. ↑ "Entacapone Prices and Entacapone Coupons - GoodRx". GoodRx. Retrieved 15 December 2021.
    5. 1 2 "PubMedHealth". PubMedHealth. 1 October 2015. Retrieved 4 November 2015.
    6. 1 2 Pahwa R, Lyons KE (April 2009). "Levodopa-related wearing-off in Parkinson's disease: identification and management". Current Medical Research and Opinion. 25 (4): 841–9. doi:10.1185/03007990902779319. PMID 19228103. S2CID 71616140.
    7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 "Comtan Full Prescribing Information-Novartis" (PDF). Pharma.us.novartis.com. July 2014. Archived from the original (PDF) on 15 March 2016. Retrieved 4 November 2015.
    8. 1 2 3 "Entacapone". Medlineplus - NIH. American Society of Health-System Pharmacist. September 2010. Archived from the original on 6 October 2015. Retrieved 4 November 2015.
    9. ↑ "Stalevo- carbidopa, levodopa, and entacapone tablet, film coated". DailyMed. 7 January 2020. Archived from the original on 21 January 2021. Retrieved 14 March 2020.
    10. ↑ "Late (complicated) Parkinson's Disease". National Guideline Clearing House. November 2006. Archived from the original on 24 October 2015. Retrieved 3 November 2015.
    11. ↑ Salat D, Tolosa E (January 2013). "Levodopa in the treatment of Parkinson's disease: current status and new developments". Journal of Parkinson's Disease. 3 (3): 255–69. doi:10.3233/JPD-130186. PMID 23948989.
    12. 1 2 Koda-Kimble MA (2013). Koda-Kimble & Young's Applied Therapeutics: The Clinical Use of Drugs. Philadelphia: Lippincott Williams & Wilkins. pp. 1373–1374. ISBN 978-1609137137.
    13. 1 2 3 4 "Comtan: EPAR – Product Information" (PDF). European Medicines Agency. 10 March 2015. Archived (PDF) from the original on 16 March 2018. Retrieved 13 December 2020.
    14. ↑ Dinnendahl V, Fricke U, eds. (2000). Arzneistoff-Profile (in Deutsch). Vol. 4 (16 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
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