Entacapone
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| Pronunciation | /ˌɛntəkəˈpoʊn/ or /ɛnˈtækəpoʊn/ |
| Trade names | Comtan (single ingredient), Stalevo (multi-ingredient) |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a601236 |
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| Routes of administration | By mouth |
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| Bioavailability | 35% |
| Protein binding | 98% (binds to serum albumin) |
| Metabolism | Hepatic |
| Elimination half-life | 0.4–0.7 hours |
| Excretion | Feces (90%), urine (10%) |
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| ECHA InfoCard | 100.128.566 |
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| Formula | C14H15N3O5 |
| Molar mass | 305.290 g·mol−1 |
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Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease.[2] Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson's disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.[2]
Entacapone is a selective and reversible inhibitor of the enzyme catechol-O-methyltransferase (COMT).[2] When taken together with levodopa (L-DOPA) and carbidopa, entacapone stops COMT from breaking down levodopa, resulting in an overall increase of levodopa remaining in the brain and body.[2] Entacapone does not cross into the brain and hence does not inhibit COMT there.[3]
Carbidopa/levodopa/entacapone (Stalevo), a medication developed by Orion Pharma and marketed by Novartis, is a single tablet formulation that contains levodopa, carbidopa, and entacapone.[4]
Medical uses
[edit]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] In clinical trials, entacapone has not been shown to slow progression or reverse Parkinson's disease.[2][6][7]
Entacapone is an orally active drug that can be taken with or without food.[5][7]
Pregnancy and breastfeeding
[edit]Pregnancy category C: risk is not ruled out.[2]
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.[2]
Children
[edit]Entacapone safety and efficacy have not been assessed in infants or children.[2]
Liver problems
[edit]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.[2]
Kidney problems
[edit]There are no significant considerations for people with poor kidney function taking entacapone.[2]
Contraindications
[edit]There is a high risk for allergic reactions for people who are hypersensitive to entacapone.[2]
Potential limiting conditions to consider before starting entacapone include:[7]
- History of allergic reaction to entacapone
- History of liver disease, liver dysfunction, or alcoholism
- Current or planned pregnancy
- Current or planned surgeries
Side effects
[edit]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
[edit]The most common side effect of entacapone is movement problems, which occur in 25% of people taking entacapone.[2] This drug may cause or worsen dyskinesia for people with Parkinson's disease treated together with levodopa and carbidopa.[2] In particular, "peak-dose dyskinesias" may occur when levodopa levels are at its peak concentration in the serum plasma.[8][9]
Diarrhea
[edit]10% of patients taking entacapone have been shown to experience diarrhea.[2] 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.[2] In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone.[10]
Urine color
[edit]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.[10]
Sudden sleep onset
[edit]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.[2]
Low blood pressure
[edit]Episodes of orthostatic hypotension have been shown to be more common at the start of entacapone use due to increased levels of levodopa.[2]
Behavior problems
[edit]Post-marketing data shows that entacapone may change or worsen mental status, leading to behaviors such as delusions, agitation, confusion, and delirium.[2]
People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors.[2]
Interactions
[edit]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.[11]
Pharmacology
[edit]Mechanism of action
[edit]Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).[2] 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.[2]
For the treatment of Parkinson's disease, entacapone is given as an adjunct to levodopa and an aromatic amino acid decarboxylase inhibitor, carbidopa. Entacapone is peripherally selective and inhibits COMT in the body but not in the brain.[3][12] As a result, entacapone inhibits the peripheral metabolism of levodopa, thus increasing plasma levels of levodopa.[3][2] This causes more constant dopaminergic stimulation in order to reduce the signs and symptoms presented in the disease.[2]
Pharmacokinetics
[edit]Absorption
[edit]The time to highest blood plasma concentrations is approximately one hour. The substance undergoes extensive first-pass metabolism. Absolute oral bioavailability (F) is 35%.[2][11]
Distribution
[edit]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.[2][11] Entacapone has low lipophilicity and does not significantly cross the blood–brain barrier.[3] As a result, it is a peripherally selective drug and does not act in the brain.[3]
Metabolism and elimination
[edit]Entacapone is primarily metabolized to its glucuronide in the liver, and 5% are converted into the Z-isomer.[11] It has a half-life of approximately 0.3–0.7 hours, with only 0.2% being excreted unchanged in the urine.[2]
Research
[edit]Restless legs syndrome
[edit]Entacapone, in conjunction with levodopa and carbidopa, was under development for use in the treatment of restless legs syndrome (RLS), but development was discontinued.[13][14]
References
[edit]- ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z "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.
- ^ a b c d e Habet S (August 2022). "Clinical Pharmacology of Entacapone (Comtan) From the FDA Reviewer". Int J Neuropsychopharmacol. 25 (7): 567–575. doi:10.1093/ijnp/pyac021. PMC 9352175. PMID 35302623.
Entacapone is a potent and specific peripheral catechol-O-methyltransferase inhibitor. [...] Entacapone has no antiparkinsonian activity as a sole agent. Therefore, it must be given as an adjunct to LD and a peripherally acting DDC inhibitor, such as carbidopa. Entacapone acts peripherally and does not penetrate the blood-brain barrier (BBB). [...] It is poorly lipophilic and does not penetrate the BBB to any significant extent. Its clinical effects are thus due to peripheral COMT inhibition only (Nutt, 1998; Fahn et al, 2004). [...] Entacapone is poorly lipophilic. Therefore, its clinical effects are due to peripheral COMT inhibition alone. [...] Entacapone is a potent, specific, and reversible COMT inhibitor. The drug has been shown to act peripherally, but not centrally, when given at clinically effective doses.
- ^ "Stalevo- carbidopa, levodopa, and entacapone tablet, film coated". DailyMed. 7 January 2020. Retrieved 14 March 2020.
- ^ a b "PubMedHealth". PubMedHealth. 1 October 2015. Retrieved 4 November 2015.
- ^ a b 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.
- ^ a b c "Entacapone". Medlineplus - NIH. American Society of Health-System Pharmacist. September 2010. Retrieved 4 November 2015.
- ^ "Late (complicated) Parkinson's Disease". National Guideline Clearing House. November 2006. Archived from the original on 24 October 2015. Retrieved 3 November 2015.
- ^ 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.
- ^ a b 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.
- ^ a b c d "Comtan: EPAR – Product Information" (PDF). European Medicines Agency. 10 March 2015. Archived from the original (PDF) on 16 March 2018. Retrieved 17 April 2017.
- ^ Dinnendahl V, Fricke U, eds. (2000). Arzneistoff-Profile (in German). Vol. 4 (16 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
- ^ "Entacapone - Novartis/Orion - Novartis/Orion". AdisInsight. 5 November 2023. Retrieved 10 July 2024.
- ^ Fulda S, Wetter TC (August 2005). "Emerging drugs for restless legs syndrome". Expert Opin Emerg Drugs. 10 (3): 537–552. doi:10.1517/14728214.10.3.537. PMID 16083328.
