COMTAN

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.

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".

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.

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.

Entacapone is rapidly absorbed (approximately 1 hour).

The absolute bioavailability following oral administration is 35%.

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

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.

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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.

Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines.

It is theoretically possible, therefore, that the combination of entacapone and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism.

For this reason, patients should ordinarily not be treated concomitantly with entacapone and a non-selective MAO inhibitor.

Entacapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline).

Catechol-O-Methyltransferase (COMT) When a single 400 mg dose of entacapone was given with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively.

Therefore, drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possible arrhythmias, and excessive changes in blood pressure.

Ventricular tachycardia was noted in one 32-year-old healthy male volunteer in an interaction study after epinephrine infusion and oral entacapone administration.

Treatment with propranolol was required.

A causal relationship to entacapone administration appears probable but cannot be attributed with certainty.

Falling Asleep During Activities of Daily Living and Somnolence Patients with Parkinson's disease treated with entacapone, which increases plasma levodopa levels, or with levodopa have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (including the operation of motor vehicles).

Some of these episodes resulted in accidents.

Although many of these patients reported somnolence while on entacapone, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Some of these events have been reported as late as one year after initiation of treatment.

The risk of somnolence was increased (entacapone 2% and placebo 0%) in controlled studies.

It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history.

For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.

Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with entacapone.

Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with entacapone.

Before initiating treatment with entacapone, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase this risk such as concomitant use of sedating medications and the presence of sleep disorders.

If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc)., entacapone should ordinarily be discontinued See DOSAGE AND ADMINISTRATION for guidance on discontinuing entacapone.

If the decision is made to continue entacapone, patients should be advised not to drive and to avoid other potentially dangerous activities.

There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Entacapone is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

The recommended dose of entacapone is one 200 mg tablet administered concomitantly with each levodopa and carbidopa dose to a maximum of 8 times daily (200 mg × 8 = 1,600 mg per day).

Clinical experience with daily doses above 1,600 mg is limited.

Entacapone should always be administered in association with levodopa and carbidopa.

Entacapone has no antiparkinsonian effect of its own.

In clinical studies, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been greater than or equal to 800 mg or if patients had moderate or severe dyskinesia before beginning treatment.

To optimize an individual patient's response, reductions in daily levodopa dose or extending the interval between doses may be necessary.

In clinical studies, the average reduction in daily levodopa dose was about 25% in those patients requiring a levodopa dose reduction. (More than 58% of patients with levodopa doses above 800 mg daily required such a reduction). Entacapone can be combined with both the immediate and sustained-release formulations of levodopa and carbidopa.

Entacapone may be taken with or without food.

Patients with hepatic impairment should be treated with caution.

The AUC and

C max of entacapone approximately doubled in patients with documented liver disease, compared to controls.

However, these studies were conducted with single-dose entacapone without levodopa and dopa decarboxylase inhibitor coadministration, and therefore the effects of liver disease on the kinetics of chronically administered entacapone have not been evaluated.

Rapid withdrawal or abrupt reduction in the entacapone dose could lead to emergence of signs and symptoms of Parkinson's disease, and may lead to hyperpyrexia and confusion, a symptom complex resembling NMS.

This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity.

If a decision is made to discontinue treatment with entacapone, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed.

Although tapering entacapone has not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made.

Entacapone tablets

USP are supplied as 200 mg film-coated tablets for oral administration.

The capsular-shaped film-coated tablets are brownish orange, unscored, and debossed “S51” on one side and blank on the other side.

Tablets are provided in HDPE containers as follows: Bottles of 60 NDC 0527-1830-35 Bottles of 100 NDC 0527-1830-37 Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15°C to 30°C (59°F to 86°F).

Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15°C to 30°C (59°F to 86°F).

In embryofetal development studies, entacapone was administered to pregnant animals throughout organogenesis at doses of up to 1,000 mg/kg/day in rats and 300 mg/kg/day in rabbits.

Increased incidences of fetal variations were evident in litters from rats treated with the highest dose, in the absence of overt signs of maternal toxicity.

The maternal plasma drug exposure (AUC) associated with this dose was approximately 34 times the estimated plasma exposure in humans receiving the maximum recommended daily dose (MRDD) of 1,600 mg. Increased frequencies of abortions, late and total resorptions, and decreased fetal weights were observed in the litters of rabbits treated with maternally toxic doses of 100 mg/kg/day (plasma AUCs 0.4 times those in humans receiving the MRDD) or greater.

There was no evidence of teratogenicity in these studies.

However, when entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, anophthalmia) was observed in the litters of dams treated with doses of 160 mg/kg/day (plasma AUCs 7 times those in humans receiving the MRDD) or greater, in the absence of maternal toxicity.

Administration of up to 700 mg/kg/day (plasma AUCs 28 times those in humans receiving the MRDD) to female rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairment in the offspring.

Entacapone is always given concomitantly with levodopa and carbidopa, which is known to cause visceral and skeletal malformations in rabbits.

The teratogenic potential of entacapone in combination with levodopa and carbidopa was not assessed in animals.

There is no experience from clinical studies regarding the use of entacapone in pregnant women.

Therefore, entacapone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In animal studies, entacapone was excreted into maternal rat milk.

It is not known whether entacapone is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when entacapone is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established.