Entacapone | apollo | +9191 46 950 950

Entacapone | apollo | +9191 46 950 950

Entacapone

CAS Number : 130929-57-6

Bioavailability : 35%

Protein binding : 98%

Molecular Weight : 305.29 g/mol Molecular Formula : C14H15N3O5

Systematic (IUPAC) : (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide

DRUG DESCRIPTION

Entacaponeis a prescription medication used to treat Parkinson's disease. It is always used in combination with carbidopa-levodopa products as it does not have any activity for treating Parkinson's disease when used without levodopa. Entacapone is useful for people who experience "wearing off" of their carbidopa-levodopa

before each dose. Entacapone is a member of the class of drugs known as

nitrocatechols. Entacapone is an inhibitor of catechol-O-

methyltransferase (COMT), used in the treatment of Parkinson's Disease as an adjunct to

levodopa/carbidopa therapy. It is a nitrocatechol-structured compound with a relative molecular mass of 305.29. The chemical name of entacapone is (E)-2-

cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide.

DOSAGE

This medicine is taken by mouth, with or without food Entacapone generally is taken at the same time as your levodopa/carbidopa medicine, or as directed. Follow all instructions carefully; you may need to decrease the dosage of your levodopa/carbidopa, depending on the

amount of levodopa you currently take. Your levodopa/carbidopa dosing schedule may change as well. Do not suddenly stop using this drug: the dosage should be reduced gradually to minimize possible side effects. Consult your doctor or pharmacist for more

information. The manufacturer advises a maximum of 8 doses per day.

Entacapone is always used in combination with carbidopa and levodopa; it has no activity against

Parkinson's disease when used alone. The drug works by

increasing blood levels of levodopa and helping levodopa to last longer in the body. Entacapone works by inhibiting an enzyme known as catechol-O-

methyltransferase (COMT) that breaks down levodopa before it has a chance to reach the brain.

SIDE EFFECTS

Diarrhea, drowsiness, upset stomach or dizziness may occur. If these effects persist or worsen, notify your doctor promptly. Tell your doctor immediately if you have any of these unlikely but serious side effects:

mental/mood changes, fainting, muscle coordination problems. Tell your doctor immediately if you have any of these highly unlikely but very serious side effects: muscle pain, change in the amount of urine. This drug may cause a harmless discoloration (brownish-orange color) of your urine. If you notice other effects not listed

above, contact your doctor or pharmacist. In clinical studies, entacapone plus carbidopa-levodopa has been shown to be more effective than just carbidopa-levodopa for Parkinson's treatment. In these studies, people who were experiencing wearing-off fluctuations of their carbidopa-levodopa therapy were given either entacapone or a placebo (a "sugar pill" with no active ingredient) to take with each dose of their carbidopa-

levodopa. These studies showed that entacapone helped carbidopa-levodopa work longer, with shorter "off"

periods

PRECAUTIONS

Tell your doctor your medical history, including: liver disease, any allergies. To minimize dizziness and

lightheadedness, get up slowly when rising from a seated or lying position. This drug may make you dizzy or

drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit

alcoholic beverages. Entacapone is not indicated for use in children. This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor. It is not known whether this drug passes into breast milk. Consult your doctor before

breast-feeding. Dopaminergic therapy in Parkinson's Disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and,

therefore, might be expected to increase the occurrence of orthostatic hypotension. In Comtan (entacapone)

clinical trials, however, no differences from placebo were seen for measured orthostasis or symptoms of

orthostasis. Orthostatic hypotension was documented at least once in 2.7% and 3.0% of the patients treated with 200 mg Comtan and placebo, respectively. A total of 4.3% and 4.0% of the patients treated with 200 mg

Comtan and placebo, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was not accompanied by vital sign measurements). Neither baseline treatment with

dopamine agonists or selegiline, nor the presence of orthostasis at baseline, increased the risk of orthostatic hypotension in patients treated with Comtan compared

to patients on placebo. In the large controlled trials, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients,

respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in

patients in both treatment groups who had an episode of

documented hypotension (although the episodes of syncope, obtained by history, were themselves not

documented with vital sign measurement). Diarrhea

In clinical trials, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg Comtan and placebo, respectively. In patients treated with Comtan, diarrhea was generally mild to

moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate

diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of Comtan. Two

patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 - 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment.

Hallucinations

Dopaminergic therapy in Parkinson's Disease patients has been associated with hallucinations. In clinical trials,

hallucinations developed in approximately 4.0% of patients treated with 200 mg Comtan or placebo. Hallucinations led to drug discontinuation and

premature withdrawal from clinical trials in 0.8% and 0% of patients treated with 200 mg Comtan and

placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200

mg Comtan and placebo groups, respectively. Dyskinesia

Comtan may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent

dyskinesias despite a reduction in their dose of levodopa. The rates of withdrawal for dyskinesia were

1.5% and 0.8% for 200 mg Comtan and placebo, respectively.

INTERACTION

his drug should not be used with the following medications because very serious interactions may occur: certain MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine,

procarbazine, tranylcypromine). Certain MAO inhibitors (selegiline, rasagiline) may be used cautiously with close monitoring by your doctor.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting

entacapone. If you are taking rasagiline or selegiline for Parkinson's disease, ask your doctor if you should

continue taking it. Before using this medication, tell your doctor or

pharmacist of all prescription and nonprescription/herbal products you may use, especially

of: isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, methyldopa, apomorphine, isoetharine, bitolterol, probenecid, cholestyramine,

erythromycin, rifampicin, ampicillin, chloramphenicol. Tell your doctor or pharmacist if you also take drugs that may cause drowsiness or lower your blood pressure such

as: antihistamines that cause drowsiness (e.g., diphenhydramine), anti-anxiety drugs (e.g., diazepam), anti-seizure drugs (e.g., carbamazepine), medicine for

sleep (e.g., sedatives, hypnotics), muscle relaxants, other narcotic pain relievers (e.g., codeine), psychiatric

medicines (e.g., phenothiazines such as chlorpromazine, tricyclics such as amitriptyline), tranquilizers.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share

the list with your doctor and pharmacist.

PHARMALOGY

The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter 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 greater effects on the signs and symptoms of Parkinson's Disease. The higher levodopa levels also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of

levodopa. In animals, while entacapone enters the CNS to a minimal extent, it has been shown to inhibit central COMT activity. In humans, entacapone inhibits the COMT enzyme in peripheral tissues. The effects of

entacapone on central COMT activity in humans have not been studied.

CONSUMER INFORMATION

USES

This medication is used with other medications (levodopa/carbidopa) to treat Parkinson's disease.

Entacapone belongs to a class of drugs known as COMT inhibitors. Many people taking levodopa for Parkinson's have problems with the effects of the levodopa wearing off between scheduled doses, causing symptoms to

return or worsen. Entacapone blocks a certain natural substance (COMT enzyme) that breaks down the

levodopa in the body. This effect allows the levodopa to last longer in the system so that it doesn't wear off

before the next dose.

HOW TO USE

Dosage is based on your medical condition, liver function, and response to therapy.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. Do not suddenly stop taking this medication unless instructed to do so by your doctor. Doing so may cause your Parkinson's symptoms to become much

worse.

SIDE EFFECTS

Nausea/vomiting, increased abnormal/uncontrolled/fast movements, dizziness upon

standing, fainting, abnormal sweating, drowsiness, tiredness, dry mouth, constipation, gas, and abdominal pain may occur. Diarrhea may occur 4-12 weeks after

you start the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do

not double the dose to catch up. STORAGE: Store at room temperature between 59-86

degrees F (15-30 degrees C) away from light and

moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Type

small molecule

Description

Entacapone is a selective, reversible catechol-O-methyl transferase (COMT) inhibitor for the treatment of Parkinson’s disease. It is a member of the class of

nitrocatechols. When administered concomittantly with levodopa and a decarboxylase inhibitor (e.g., carbidopa),

increased and more sustained plasma levodopa concentrations are reached as compared to the administration of levodopa and a decarboxylase

inhibitor.

Categories

Central Nervous System Agents

Antiparkinson Agents

Antidyskinetics

Enzyme Inhibitors

Taxonomy

Kingdom

Organic

Classes

Phenols and Derivatives

Nitrobenzenes

Phenylpropenes

Nitrophenols and Derivatives

Aminophenols and Derivatives

Cinnamaldehydes

Substructures

Hydroxy Compounds

Phenols and Derivatives

Alkanes and Alkenes

Nitrobenzenes

Oxoazaniums

Amino Ketones

Phenylpropenes

Nitriles and Derivatives

Nitrophenols and Derivatives

Benzene and Derivatives

Aliphatic and Aryl Amines

Aminophenols and Derivatives

Nitro compounds

Cyanides

Catechols

Aromatic compounds

Cinnamaldehydes

Carboxamides and Derivatives

Styrene Derivatives

Phenyl Esters

Anilines

Pharmacology

Indication

Used as an adjunct to levodopa / carbidopa in the symptomatic treatment of patients with idiopathic Parkinson's Disease who experience the signs and

symptoms of end-of-dose "wearing-off".

Pharmacodynamics

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 is a selective and reversible inhibitor of 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.

Mechanism of Action

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.

Absorption

Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral

administration is 35%.

Metabolism

Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-

isomer.

Route of Elimination

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.

Toxicity

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

Affected Organisms

Humans and other mammals

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