Entacapone (Page 2 of 5)

INDICATIONS

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

CONTRAINDICATIONS

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

WARNINGS

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

Before initiating treatment with Entacapone Tablets, 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 Tablets should ordinarily be discontinued (see DOSAGE AND ADMINISTRATION for guidance on discontinuing Entacapone Tablets). If the decision is made to continue Entacapone Tablets, 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.

PRECAUTIONS

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 Tablets and placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200 mg Entacapone Tablets and placebo groups, respectively. Agitation occurred in 1% of patients treated with Entacapone Tablets 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 Tablets treatment or after starting or increasing the dose of Entacapone Tablets. 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 Tablets.

Patients with a major psychotic disorder should ordinarily not be treated with Entacapone Tablets 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 Tablets (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 Tablets 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 Tablets if a patient develops such urges while taking Entacapone Tablets.

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 Tablets and placebo, respectively. In patients treated with Entacapone Tablets, 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 Tablets. 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 Tablets treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of Entacapone Tablets but recurred after retreatment with Entacapone Tablets.

If prolonged diarrhea is suspected to be related to Entacapone Tablets, 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.

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