Entacapone is available as tablets containing 200 mg entacapone USP.

Entacapone is an inhibitor of catechol- O-methyltransferase (COMT), used in the treatment of Parkinson’s disease as an adjunct to levodopa and 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. Its molecular formula is C 14H 15N 3O 5 and its structural formula is:

The inactive ingredients of the entacapone tablets, USP are croscarmellose sodium, glycerin, hydrogenated vegetable oil, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polysorbate, sodium starch glycolate, sucrose, and titanium dioxide.

Mechanism of Action

Entacapone is a selective and reversible inhibitor of 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. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.

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 central nervous system (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.

Pharmacodynamics

COMT Activity in Erythrocytes

Studies in healthy volunteers have shown that entacapone reversibly inhibits human erythrocyte COMT activity after oral administration. There was a linear correlation between entacapone dose and erythrocyte COMT inhibition, the maximum inhibition being 82% following an 800 mg single dose. With a 200 mg single dose of entacapone, maximum inhibition of erythrocyte COMT activity is on average 65% with a return to baseline level within 8 hours.

Effect on the Pharmacokinetics of Levodopa and its Metabolites

When 200 mg entacapone is administered together with levodopa and carbidopa, it increases the area under the curve (AUC) of levodopa by approximately 35% and the elimination half-life of levodopa is prolonged from 1.3 hours to 2.4 hours. In general, the average peak levodopa plasma concentration and the time of its occurrence (T max of 1 hour) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in Parkinson’s disease patients suggest that the maximal effect occurs with 200 mg entacapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by entacapone when given with levodopa and carbidopa.

Entacapone tablets, USP are indicated as an adjunct to levodopa and carbidopa to treat end-of-dose “wearing-off” in patients with Parkinson’s disease (see CLINICAL PHARMACOLOGY, Clinical Studies).

Entacapone tablets, USP effectiveness has not been systematically evaluated in patients with Parkinson’s disease who do not experience end-of-dose “wearing-off”.

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

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).

Drugs Metabolized By 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 pre-existing 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.

Hypotension, Orthostatic Hypotension, and Syncope

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 controlled studies, 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.

Hallucinations and Psychotic-Like Behavior

Dopaminergic therapy in patients with Parkinson’s disease has been associated with hallucinations. In clinical studies, hallucinations led to drug discontinuation and premature withdrawal in 0.8% and 0% of patients treated with 200 mg entacapone and placebo, respectively. Hallucinations led to hospitalization in 1% and 0.3% of patients in the 200 mg entacapone and placebo groups, respectively. Agitation occurred in 1% of patients treated with entacapone and 0% treated with placebo.

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during entacapone treatment or after starting or increasing the dose of entacapone. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. Abnormal thinking and behavior can cause paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Psychotic-like behaviors were also observed during the clinical development of entacapone.

Patients with a major psychotic disorder should ordinarily not be treated with entacapone because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of entacapone (see PRECAUTIONS).

Impulse Control and Compulsive Behaviors

Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are used for the treatment of Parkinson’s disease and that increase central dopaminergic tone, including entacapone taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with entacapone. Physicians should consider dose reduction or stopping entacapone if a patient develops such urges while taking entacapone.

Diarrhea and Colitis

In clinical studies, diarrhea developed in 60 of 603 (10%) and 16 of 400 (4%) of patients treated with 200 mg entacapone and placebo, respectively. In patients treated with entacapone, 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 entacapone. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 weeks to 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. Diarrhea may be associated with weight loss, dehydration, and hypokalemia.

Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases diarrhea has usually been moderate to severe, watery, and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when entacapone treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of entacapone but recurred after retreatment with entacapone.

If prolonged diarrhea is suspected to be related to entacapone, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered.

Dyskinesia

Entacapone may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled studies continued to experience frequent dyskinesia despite a reduction in their dose of levodopa. The incidence of dyskinesia was 25% for treatment with entacapone and 15% for placebo. The incidence of study withdrawal for dyskinesia was 1.5% for 200 mg entacapone and 0.8% for placebo.

Because clinical studies are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment per total number of patients treated) observed in the clinical studies of a drug cannot be directly compared to the incidence of adverse reactions in the clinical studies of another drug and may not reflect the incidence of adverse reactions observed in practice.

A total of 1,450 patients with Parkinson’s disease were treated with entacapone in premarketing clinical studies. Included were patients with fluctuating symptoms, as well as those with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects.

The most commonly observed adverse reactions (incidence at least 3% greater than placebo) in double-blind, placebo-controlled studies (N=1,003) associated with the use of entacapone were: dyskinesia, urine discoloration, diarrhea, nausea, hyperkinesia, abdominal pain, vomiting, and dry mouth. Approximately 14% of the 603 patients given entacapone in the double-blind, placebo-controlled studies discontinued treatment due to adverse reactions, compared to 9% of the 400 patients who received placebo. The most frequent causes of discontinuation in decreasing order were: psychiatric disorders (2% vs. 1%), diarrhea (2% vs. 0%), dyskinesia and hyperkinesia (2% vs. 1%), nausea (2% vs. 1%), and abdominal pain (1% vs. 0%).

Adverse Event Incidence in Controlled Clinical Studies

Table 4 lists treatment-emergent adverse events that occurred in at least 1% of patients treated with entacapone participating in the double-blind, placebo-controlled studies and that were numerically more common in the entacapone group, compared to placebo. In these studies, either entacapone or placebo was added to levodopa and carbidopa (or levodopa and benserazide).

Effects of Gender and Age on Adverse Reactions

No differences were noted in the rate of adverse events attributable to entacapone by age or gender.

Postmarketing Reports

The following spontaneous reports of adverse events temporally associated with entacapone have been identified since market introduction and are not listed in Table 4. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to entacapone exposure.

Hepatitis with mainly cholestatic features has been reported.

Entacapone is not a controlled substance. Animal studies to evaluate the drug abuse and potential dependence have not been conducted. Although clinical studies have not revealed any evidence of the potential for abuse, tolerance or physical dependence, systematic studies in humans designed to evaluate these effects have not been performed.

The postmarketing data include several cases of overdose. The highest reported dose of entacapone was at least 40,000 mg. The acute symptoms and signs commonly seen in these cases included somnolence and decreased activity, states related to depressed level of consciousness (e.g., coma, confusion and disorientation) and discolorations of skin, tongue, and urine, as well as restlessness, agitation, and aggression.

COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of entacapone may theoretically produce a 100% inhibition of the COMT enzyme in humans, thereby preventing the metabolism of endogenous and exogenous catechols.

The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with levodopa and carbidopa for 14 days in 15 Parkinson’s disease patients, and in another study as 800 mg three times daily for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2 mcg per mL (at 45 minutes, compared to 1 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 minutes). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg entacapone have been administered as 200 mg 10 times daily with levodopa and carbidopa or levodopa and benserazide for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1,600 mg is limited.

The range of lethal plasma concentrations of entacapone based on animal data was 80 mcg per mL to 130 mcg per mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses.

Management of Overdose

Management of entacapone overdose is symptomatic; there is no known antidote to entacapone. Hospitalization is advised, and general supportive care is indicated. There is no experience with hemodialysis or hemoperfusion, but these procedures are unlikely to be of benefit, because entacapone is highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of entacapone by decreasing its absorption and reabsorption from the gastrointestinal (GI) tract. The adequacy of the respiratory and circulatory systems should be carefully monitored and appropriate supportive measures employed. The possibility of drug interactions, especially with catechol-structured drugs, should be borne in mind.

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 x 8 = 1,600 mg per day). Clinical experience with daily doses above 1,600 mg is limited.

Entacapone tablets 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 tablets can be combined with both the immediate and sustained-release formulations of levodopa and carbidopa.

Entacapone tablets may be taken with or without food (see CLINICAL PHARMACOLOGY).

Patients With Impaired Hepatic Function

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 (see CLINICAL PHARMACOLOGY, Pharmacokinetics of Entacapone).

Withdrawing Patients from Entacapone Tablets

Rapid withdrawal or abrupt reduction in the entacapone tablets dose could lead to emergence of signs and symptoms of Parkinson’s disease (see CLINICAL PHARMACOLOGY, Clinical Studies), and may lead to hyperpyrexia and confusion, a symptom complex resembling NMS (see PRECAUTIONS, Other Events Reported With Dopaminergic Therapy). 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 tablets, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed. Although tapering entacapone tablets has not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made.

Entacapone Tablets USP, 200 mg are light brownish-orange colored, film-coated, oval shaped tablets debossed “Y 16” on one side and plain on other side.

Unit dose packages of 30 (3 x 10) NDC 60687-188-21

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Aurobindo Pharma USA, Inc. as follows:

(200 mg / 30 UD) NDC 60687-188-21 packaged from NDC 65862-654

Distributed by:

American Health Packaging

Columbus, OH 43217

8418821/0821

NDC 60687- 188-21

Entacapone

Tablets, USP

200 mg

30 Tablets (3 x 10)                 Rx Only

Each Film-Coated Tablet Contains:

Entacapone USP............................................................... 200 mg

Usual Adult Dosage: See package insert for full prescribing

information.

Store at 20° to 25°C (68° to 77°F); excursions permitted

between 15° to 30°C (59° to 86°F) [see USP Controlled Room

Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or

broken.

The drug product contained in this package is from

NDC # 65862-654, Aurobindo Pharma USA, Inc.

Packaged and Distributed by:

American Health Packaging

Columbus, Ohio 43217

718821

418821/0619

Entacapone

Tablet, USP

200 mg