Entacapone

Entacapone
Clinical data
Pronunciation /ˌɛntəkəˈpoʊn/ or /ɛnˈtækəpoʊn/
Trade names Comtan (single ingredient), Stalevo (multi-ingredient)
AHFS/Drugs.com Monograph
MedlinePlus a601236
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
ATC code N04BX02 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 35%
Protein binding 98% (binds to serum albumin)
Metabolism Hepatic
Biological half-life 0.4-0.7 hours
Excretion Feces (90%), Urine (10%)
Identifiers
CAS Number 130929-57-6 YesY
PubChem (CID) 5281081
IUPHAR/BPS 6647
DrugBank DB00494 YesY
ChemSpider 4444537 YesY
UNII 4975G9NM6T YesY
KEGG D00781 YesY
ChEBI CHEBI:4798 YesY
ChEMBL CHEMBL953 YesY
ECHA InfoCard 100.128.566
Chemical and physical data
Formula C14H15N3O5
Molar mass 305.286 g/mol
3D model (Jmol) Interactive image
  (verify)

Entacapone (INN) is a medication commonly used in combination with other medications for the treatment of Parkinson's disease.[1] 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.[1]

Entacapone is known as a selective and reversible inhibitor of the enzyme catechol-O-methyltransferase (COMT).[1] When taken together with levodopa (L-DOPA) and carbidopa, entacapone stops catechol-O-methyltransferase from breaking down and metabolizing levodopa, resulting in an overall increase of levodopa remaining in the brain and body.[1]

Entacapone is developed by Orion Pharma and marketed by Novartis under the trade name Comtan.[1] Stalevo, another medication developed by Orion Pharma and marketed by Novartis, is a single tablet formulation that contains levodopa, carbidopa, and entacapone.[2]

Medical use

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."[3] "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.[4] In clinical trials, entacapone has not been shown to slow progression or reverse Parkinson’s disease.[1][4][5]

Entacapone is an orally active drug that can be taken with or without food.[3][5]

Pregnancy and breastfeeding

Pregnancy Category C: risk is not ruled out.[1]

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.[1]

Children

Entacapone safety and efficacy have not been assessed in infants or children.[1]

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.[1]

Kidney problems

There are no significant considerations for people with poor kidney function taking entacapone.[1]

Side effects

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

Movement problems

The most common side-effect of entacapone is movement problems, which occur in 25% of people taking entacapone.[1] This drug may cause or worsen dyskinesia for people with Parkinson's disease treated together with levodopa and carbidopa.[1] In particular, "peak-dose dyskinesias" may occur when levodopa levels are at its peak concentration in the serum plasma.[6][7]

Diarrhea

10% of patients taking entacapone have been shown to experience diarrhea.[1] 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.[1] In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone.[8]

Urine color

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.[8]

Sudden sleep onset

People have reported sudden sleep onset while engaging in daily activities without prior warning of drowsiness. In controlled studies, patients on entacapone had a 2.0% increased risk of somnolence compared to placebo.[1]

Low 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.[1]

Behavior problems

Post-marketing data shows that entacapone may change or worsen mental status, leading to behaviors such as delusions, agitation, confusion, and delirium.[1]

People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors.[1]

Contraindications

There is a high risk for allergic reactions for people who are hypersensitive to entacapone.[1]

Potential limiting conditions to consider before starting entacapone include:[5]

Mechanism of action

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).[1] 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.[1]

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 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.[1]

Pharmacokinetics

Absorption

The Tmax is approximately 1 hour. Absolute oral bioavailability (F) is 35.0%.[1]

Distribution

The volume of distribution (VD) after intravenous injection approximately 20.0 liters. Entacapone has high binding activity to serum albumin that limits its distribution into tissues.[1]

Metabolism and elimination

Entacapone has a half-life of approximately 0.3-0.7 hours.[1] It is primarily metabolized by the liver with 0.2% of the medication unchanged in urine.[1]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 "Comtan Full Prescribing Information-Novartis" (PDF). Pharma.us.novartis.com. July 2014. Retrieved 4 November 2015.
  2. ↑ "Stalevo Prescribing Information" (PDF). Novartis. Novartis Pharmaceuticals. Retrieved 4 November 2015.
  3. 1 2 "PubMedHealth". PubMedHealth. 1 October 2015. Retrieved 4 November 2015.
  4. 1 2 Pahwa, R (April 2009). "Levodopa-related wearing-off in Parkinson's disease: Identification and Management". Current Medical Research and Opinion. 25: 841–9. doi:10.1185/03007990902779319. PMID 19228103.
  5. 1 2 3 "Entacapone". Medlineplus - NIH. American Society of Health-System Pharmacist. September 2010. Retrieved 4 November 2015.
  6. ↑ "Late (complicated) Parkinson's Disease". National Guideline Clearing House. November 2006. Retrieved 3 November 2015.
  7. ↑ Salat, David (1 January 2013). "Levodopa in the Treatment of Parkinson's Disease: Current Status and New Developments". Journal of Parkinson's Disease. 3: 255–69. doi:10.3233/JPD-130186. PMID 23948989.
  8. 1 2 Koda-Kimble, Mary Anne (2013). Koda-Kimble & Young's Applied Therapeutics: The Clinical Use of Drugs. Philadelphia: Lippincott Williams & Wilkins. pp. 1373–1374. ISBN 978-1609137137.
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