Entacapone
Entacapone Uses, Dosage, Side Effects, Food Interaction and all others data.
Carbidopa presents a chemical denomination of N-amino-alpha-methyl-3-hydroxy-L-tyrosine monohydrate. It potently inhibits aromatic amino acid decarboxylase (DDC) and due to its chemical properties, it does not cross the blood-brain barrier. Due to its activity, carbidopa is always administered concomitantly with levodopa. An individual formulation containing solely carbidopa was generated to treat nausea in patients where the combination therapy levodopa/carbidopa is not efficient reducing nausea.
The first approved product by the FDA containing only carbidopa was developed by Amerigens Pharmaceuticals Ltd and approved on 2014. On the other hand, the combination treatment of carbidopa/levodopa was originally developed by Watson Labs but the historical information by the FDA brings back to the approval of this combination therapy developed by Mayne Pharma in 1992.
When mixed with levodopa, carbidopa inhibits the peripheral conversion of levodopa to dopamine and the decarboxylation of oxitriptan to serotonin by aromatic L-amino acid decarboxylase. This results in an increased amount of levodopa and oxitriptan available for transport to the central nervous system. Carbidopa also inhibits the metabolism of levodopa in the GI tract, thus, increasing the bioavailability of levodopa.
Entacapone decreases the metabolic loss of levodopa to 3-O-methyldopa (3-OMD) through inhibition of COMT enzyme leading to an increased levodopa concentration, thus, extending the duration and effect in the brain.
Entacapone is structurally and pharmacologically related to tolcapone, but unlike tolcapone, is not associated with hepatotoxicity. Entacapone is used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa therapy. Entacapone selectively and reversiblly inhibits catechol-O-methyltransferase (COMT). In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
Levodopa is a prodrug of dopamine that is administered to patients with Parkinson's due to its ability to cross the blood-brain barrier. Levodopa can be metabolised to dopamine on either side of the blood-brain barrier and so it is generally administered with a dopa decarboxylase inhibitor like carbidopa to prevent metabolism until after it has crossed the blood-brain barrier. Once past the blood-brain barrier, levodopa is metabolized to dopamine and supplements the low endogenous levels of dopamine to treat symptoms of Parkinson's. The first developed drug product that was approved by the FDA was a levodopa and carbidopa combined product called Sinemet that was approved on May 2, 1975.
Levodopa is able to cross the blood-brain barrier while dopamine is not. The addition of a peripheral dopa decarboxylase inhibitor prevents the conversion of levodopa to dopamine in the periphery so that more levodopa can reach the blood-brain barrier. Once past the blood-brain barrier, levodopa is converted to dopamine by aromatic-L-amino-acid decarboxylase.
| Trade Name | Entacapone |
| Generic | Carbidopa + Entacapone + Levodopa |
| Weight | 200mg |
| Type | Oral Tablet |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Carbidopa is a dopa decarboxylase inhibitor used in combination with levodopa for the symptomatic treatment of idiopathic Parkinson disease and other conditions associated with parkinsonian symptoms.
Carbidopa is indicated with levodopa for the treatment of symptoms of idiopathic Parkinson disease, postencephalitic parkinsonism and symptomatic parkinsonism followed by carbon monoxide or manganese intoxication.
The combination therapy is administered for the reduction of levodopa-driven nausea and vomiting.
The product of carbidopa should be used in patients where the combination therapy of carbidopa/levodopa provide less than the adequate daily dosage.
As well carbidopa can be used in patients where the dosages of carbidopa and levodopa require individual titration.
Adjunct to levodopa treatment in Parkinson's disease
Levodopa is a dopamine precursor used in the management of Parkinson's disease, often in combination with carbidopa, as well as other conditions associated with parkinsonism.
Levodopa on its own is formulated as an oral inhalation powder indicated for intermittent treatment of off episodes in Parkinson's patients who are already being treated with carbidopa and levodopa. Levodopa is most commonly formulated as an oral tablet with a peripheral dopa decarboxylase inhibitor indicated for treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism following carbon monoxide intoxication or manganese intoxication.
Entacapone is also used to associated treatment for these conditions: Parkinson's Disease (PD), Postencephalitic parkinsonism, Symptomatic Parkinson Disease, Levodopa-driven nausea and vomitingParkinson's Disease (PD)Paralysis agitans, Parkinson's Disease (PD), Parkinsonism, Postencephalitic parkinsonism, Restless Legs Syndrome (RLS), Advanced Motor fluctuations
How Entacapone works
Carbidopa is an inhibitor of the DDC which in order, inhibits the peripheral metabolism of levodopa. DDC is very important in the biosynthesis of L-tryptophan to serotonin and the modification of L-DOPA to dopamine.
DDC can be found in the body periphery and in the blood-brain barrier. The action of carbidopa is focused on peripheral DDC as this drug cannot cross the blood-brain barrier. Hence, it will prevent the metabolism of levodopa in the periphery but it will not have any activity on the generation of dopamine in the brain.
The mechanism of action of entacapone is believed to be through its ability to inhibit COMT in peripheral tissues, altering the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to a greater reduction in the manifestations of parkinsonian syndrome.
Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors.
Dosage
Entacapone dosage
200 mg with each levodopa/dopa decarboxylase inhibitor dose. Max: 200 mg 10 times daily (2,000 mg daily). Gradually reduce levodopa dose by approx 10-30% or increase dosing interval w/in the 1st few wk of starting treatment.
May be taken with or without food.
Side Effects
Abdominal pain, nausea, vomiting, diarrhoea, constipation, colitis, dry mouth, dyskinesia, dizziness, nightmares, insomnia, hallucinations, confusion, fatigue, increased sweating, behavioural disturbances; urine, skin, hair, beard and nail discolourations; cholestatic hepatitis, rhabdomyolysis. Rarely, agitation, urticaria, erythematous or maculopapular rash, anorexia, wt decrease, increased liver enzymes.
Toxicity
The LD50 of carbidopa is reported to be in the rat of 4810 mg/kg. In animal studies, carbidopa showed no incidences on neoplasia and showed no effect on the fertility status and development.
No reports of overdosage have been registered with the carbidopa-only product. In the event of overdosage, immediate gastric lavage is recommended as well as intravenous fluid administration. Continuous electrocardiographic monitoring is required.
Side effect include increase the occurrence of orthostatic hypotension, severe rhabdomyolysis, dyskinesia, hallucinations, hyperkinesia, hypokinesia, dizziness, fatigu,e gastrointestinal effects including abdominal pain constipation diarrhea nausea
There is no readily available data for the use of levodopa in pregnancy. Rabbits treated with levodopa and carbidopa produced smaller litters and their offspring developed visceral and skeletal deformities. Levodopa may lower prolactin and interfere with lactation but there is limited human data to demonstrate this effect. Levodopa is present in human breast milk and so the potential effects of nursing while taking levodopa should be considered before prescribing levodopa to nursing mothers. There is currently a lack of data on the safety and effectiveness of using levodopa in pediatric patients. Patients over 65 years of age are more likely to experience adverse effects associated with taking levodopa, however this generally is not sufficient to exclude this patient group from treatment.
Precaution
Patient with biliary obstruction, ischaemic heart disease. Avoid abrupt withdrawal. Pregnancy and lactation.
Interaction
May interfere with metabolism of other drugs metabolised by COMT (e.g. rimiterole). May aggravate levodopa-induced orthostatic hypotension. Risk of dopaminergic effects with dopamine agonists (e.g. bromocriptine), selegiline, amantadine. May form chelates with Fe in the GI tract. Additive sedative effects with other CNS depressants.
Volume of Distribution
The volume of distribution reported for the combination therapy of carbidopa/levodopa is of 3.6 L/kg. However, carbidopa is widely distributed in the tissues, except in the brain. After one hour, carbidopa is found mainly in the kidney, lungs, small intestine and liver.
- 20 L
168L for orally inhaled levodopa.
Elimination Route
When levodopa/carbidopa is administered orally, 40-70% of the administered dose is absorbed. Once absorbed, carbidopa shows bioavailability of 58%. A maximum concentration of 0.085 mcg/ml was achieved after 143 min with an AUC of 19.28 mcg.min/ml.
Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.
Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide.
Half Life
The reported half-life of carbidopa is of approximately 107 minutes.
0.4-0.7 hour
2.3 hours for orally inhaled levodopa. Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours.
Clearance
The reported clearance rate for the combination therapy of levodopa/carbidopa is 51.7 L/h.
- 850 mL/min
Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients.
Elimination Route
In animal studies, 66% of the administered dose of carbidopa was eliminated via the urine while 11% was found in feces. These studies were performed in humans and it was observed a urine excretion covering 50% of the administered dose.
Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug.
After 48 hours, 0.17% of an orally administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine
Pregnancy & Breastfeeding use
Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.
Contraindication
Phaeochromocytoma, history of neuroleptic malignant syndrome and/or non-traumatic rhabdomyolysis. Hepatic impairment. Concomitant use w/ non-selective MAOIs.
Acute Overdose
Symptoms: Decreased activity, confusion, somnolence, hypotonia, urticaria, skin discolouration.
Management: Symptomatic treatment.
Storage Condition
Store at 25°C.
Innovators Monograph
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