Entacapone

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

INDICATIONS AND USAGE 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's effectiveness has not been systematically evaluated in patients with Parkinson's disease who do not experience end-of-dose "wearing-off".

DOSAGE AND ADMINISTRATION 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 (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 Rapid withdrawal or abrupt reduction in the entacapone 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, 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.

ADVERSE REACTIONS 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). Table 4: Summary of Patients with Adverse Events after Start of Trial Drug Administration At least 1% in Entacapone Group and Greater Than Placebo SYSTEM ORGAN CLASS Entacapone Placebo Preferred term (n = 603) % of patients (n = 400)) % of patients SKIN AND APPENDAGES DISORDERS Sweating increased 2 1 MUSCULOSKELETAL SYSTEM DISORDERS Back pain 2 1 CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS Dyskinesia 25 15 Hyperkinesia 10 5 Hypokinesia 9 8 Dizziness 8 6 SPECIAL SENSES, OTHER DISORDERS Taste perversion 1 0 PSYCHIATRIC DISORDERS Anxiety 2 1 Somnolence 2 0 Agitation 1 0 GASTROINTESTINAL SYSTEM DISORDERS Nausea 14 8 Diarrhea 10 4 Abdominal pain 8 4 Constipation 6 4 Vomiting 4 1 Mouth dry 3 0 Dyspepsia 2 1 Flatulence 2 0 Gastritis 1 0 Gastrointestinal disorders 1 0 RESPIRATORY SYSTEM DISORDERS Dyspnea 3 1 PLATELET, BLEEDING AND CLOTTING DISORDERS Purpura 2 1 URINARY SYSTEM DISORDERS Urine discoloration 10 0 BODY AS A WHOLE - GENERAL DISORDERS Back pain 4 2 Fatigue 6 4 Asthenia 2 1 RESISTANCE MECHANISM DISORDERS Infection bacterial 1 0 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.

Drug Interactions See PRECAUTIONS, Drug Interactions .