Entacapone

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”.

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

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 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 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.

Drug Interactions In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations (IC50 from 200 microM to over 1,000 microM; an oral 200 mg dose achieves a highest level of approximately 5 microM in people); these enzymes would therefore not be expected to be inhibited in clinical use. In an interaction study in healthy volunteers, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% [Cl90 11% to 26%], and the INR values increased on average by 13% [Cl90 6% to 19%]. Nevertheless, cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postapproval use of entacapone. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Protein Binding Entacapone is highly protein bound (98%). In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone, and diazepam. Drugs Metabolized by Catechol- O -Methyltransferase (COMT) See WARNINGS. Hormone Levels Levodopa is known to depress prolactin secretion and increase growth hormone levels. Treatment with entacapone coadministered with levodopa and dopa decarboxylase inhibitor does not change these effects. Effect of Entacapone on the Metabolism of Other Drugs See WARNINGS regarding concomitant use of entacapone and non-selective MAO inhibitors. No interaction was noted with the MAO-B inhibitor selegiline in two multiple-dose interaction studies when entacapone was coadministered with a levodopa and dopa decarboxylase inhibitor (n=29). More than 600 patients with Parkinson’s disease in clinical studies have used selegiline in combination with entacapone and levodopa and dopa decarboxylase inhibitor. As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin, and chloramphenicol). No interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone without coadministered levodopa and dopa-decarboxylase inhibitor.

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 Preferred term Entacapone (n = 603) % of patients Placebo (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.

Pregnancy 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.