ly. therefore, drugs known to be metabolized by comt, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetharine, 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, possibly 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 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 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.

00 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.

use of entacapone tablets 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 tablets group and greater than placebo system organ class preferred term entacapone tablets (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 tablets 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 tablets exposure. hepatitis with mainly cholestatic features has been reported.

he 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. pharmacokinetics of entacapone entacapone pharmacokinetics are linear over the dose range of 5 mg to 800 mg, and are independent of levodopa and carbidopa coadministration. the elimination of entacapone is biphasic, with an elimination half-life of 0.4 hour to 0.7 hour based on the β-phase and 2.4 hours based on the γ-phase. the γ-phase accounts for approximately 10% of the total auc. the total body clearance after intravenous administration is 850 ml per min. after a single 200 mg dose of entacapone tablets , the c max is approximately 1.2 mcg per ml. absorption : entacapone is rapidly absorbed, with a t max of approximately 1 hour. the absolute bioavailability following oral administration is 35%. food does not affect the pharmacokinetics of entacapone. distribution : the volume of distribution of entacapone at steady state after intravenous injection is small (20 l). entacapone does not distribute widely into tissues due to its high plasma protein binding. based on in vitro studies, the plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per ml to 50 mcg per ml. entacapone binds mainly to serum albumin. metabolism and elimination : entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. the main metabolic pathway is isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive. after oral administration of a 14c-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces. special populations : entacapone pharmacokinetics are independent of age. no formal gender studies have been conducted. racial representation in clinical studies was largely limited to caucasians; therefore, no conclusions can be reached about the effect of entacapone tablets on groups other than caucasian. hepatic impairment : a single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately 2-fold higher auc and cmax values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). all patients had biopsy-proven liver cirrhosis caused by alcohol. according to child-pugh grading seven patients with liver disease had mild hepatic impairment and three patients had moderate hepatic impairment. 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. consequently, entacapone should be administered with care to patients with biliary obstruction. renal impairment : the pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose, without levodopa and dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. there were three groups: normal subjects (n=7; creatinine clearance greater than 1.12 ml per sec per 1.73 m2), moderate impairment (n=10; creatinine clearance ranging from 0.60 ml per sec per 1.73 m2 to 0.89 ml per sec per 1.73 m2), and severe impairment (n=7; creatinine clearance ranging from 0.20 ml per sec per 1.73 m2 to 0.44 ml per sec per 1.73 m2). no important effects of renal function on the pharmacokinetics of entacapone were found. drug interactions : see precautions , drug interactions . clinical studies the effectiveness of entacapone tablets as an adjunct to levodopa in the treatment of parkinson’s disease was established in three 24-week multicenter, randomized, double-blind, placebo-controlled studies in patients with parkinson’s disease. in two of these studies, patients had motor “fluctuations”, characterized by documented periods of “on” (periods of relatively good functioning) and “off” (periods of relatively poor functioning), despite optimum levodopa therapy. there was also a withdrawal period following 6 months of treatment. in the third study, patients were not required to have motor fluctuations. prior to the controlled part of the studies, patients were stabilized on levodopa for 2 weeks to 4 weeks. entacapone tablets have not been systematically evaluated in patients who have parkinson’s disease without motor fluctuations. in the first two studies to be described, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of levodopa and carbidopa (up to 10 times daily, but averaging 4 doses to 6 doses per day). the formal double-blind portion of both studies was 6 months long. patients recorded the time spent in the “on” and “off” states in home diaries periodically throughout the duration of the study. in one study, conducted in the nordic countries, the primary outcome measure was the total mean time spent in the “on” state during an 18-hour diary recorded day (6 am to midnight). in the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the “on” state. in addition to the primary outcome measure: the amount of time spent in the “off” state, subparts of the unified parkinson’s disease rating scale (updrs) including mentation (part i), activities of daily living (adl) (part ii), motor function (part iii), complications of therapy (part iv), and disease staging (part v and vi) were assessed. additional secondary endpoints included the investigator’s and patient’s global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in parkinson’s disease; and the change in daily levodopa and carbidopa dose. in one of the studies, 171 patients were randomized in 16 centers in finland, norway, sweden, and denmark (nordic study), all of whom received concomitant levodopa plus dopa-decarboxylase inhibitor (either levodopa and carbidopa or levodopa and benserazide). in the second study, 205 patients were randomized in 17 centers in north america (us and canada); all patients received concomitant levodopa and carbidopa. the following tables display the results of these two studies: table 1: nordic study * mean; the month 6 values represent the average of weeks 8, 16, and 24, by protocol-defined outcome measure, except for investigator’s and patient’s global improvement. ** at least one category change at endpoint. *** not an endpoint for this study but primary endpoint in the north american study. ‡ not significant. ‡‡ p values for secondary measures and other secondary measures are nominal p values without any adjustment for multiplicity. primary measure from home diary (from an 18-hour diary day) baseline change from baseline at month 6 * p-value vs. placebo hours of awake time “on” placebo 9.2 +0.1 - entacapone tablets 9.3 +1.5 less than 0.001 duration of “on” time after first am dose (hrs) placebo 2.2 0.0 - entacapone tablets 2.1 +0.2 less than 0.05 secondary measures from home diary (from an 18-hour diary day) ‡‡ hours of awake time “off” placebo 5.3 0.0 - entacapone tablets 5.5 - 1.3 less than 0.001 proportion of awake time “on” *** (%) placebo 63.8 +0.6 - entacapone tablets 62.7 +9.3 less than 0.001 levodopa total daily dose (mg) placebo 705 +14 - entacapone tablets 701 -87 less than 0.001 frequency of levodopa daily intakes placebo 6.1 +0.1 - entacapone tablets 6.2 -0.4 less than 0.001 other secondary measures ‡‡ baseline change from baseline at month 6 * p-value vs. placebo investigator’s global (overall) % improved ** placebo - 28 - entacapone tablets - 56 less than 0.01 patient’s global (overall) % improved ** placebo - 22 - entacapone tablets - 39 n.s.‡ updrs total placebo 37.4 -1.1 - entacapone tablets 38.5 -4.8 less than 0.01 updrs motor placebo 24.6 -0.7 - entacapone tablets 25.5 -3.3 less than 0.05 updrs adl placebo 11.0 -0.4 - entacapone tablets 11.2 -1.8 less than 0.05 table 2: north american study * mean; the month 6 values represent the average of weeks 8, 16, and 24, by protocol-defined outcome measure, except for investigator’s and patient’s global improvement. ** at least one category change at endpoint. *** score change at endpoint similarly to the nordic study. ‡ not significant. ‡‡ p values for secondary measures and other secondary measures are nominal p values without any adjustment for multiplicity. effects on “on” time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline primary measure from home diary (for a 24-hour diary day) baseline change from baseline at month 6 * p-value vs. placebo percent of awake time “on” placebo 60.8 +2.0 - entacapone tablets 60.0 +6.7 less than 0.05 secondary measures from home diary (from an 24-hour diary day) ‡‡ hours of awake time “off” placebo 6.6 -0.3 - entacapone tablets 6.8 -1.2 less than 0.01 hours of awake time “on” placebo 10.3 +0.4 - entacapone tablets 10.2 +1.0 n.s.‡ levodopa total daily dose (mg) placebo 758 +19 - entacapone tablets 804 -93 less than 0.001 frequency of levodopa daily intakes placebo 6.0 +0.2 - entacapone tablets 6.2 0.0 n.s.‡ other secondary measures ‡‡ baseline change from baseline at month 6 * p-value vs. placebo investigator’s global (overall) % improved ** placebo - 21 - entacapone tablets - 34 less than 0.05 patient’s global (overall) % improved ** placebo - 20 - entacapone tablets - 31 less than 0.05 updrs total *** placebo 35.6 +2.8 - entacapone tablets 35.1 -0.6 less than 0.05 updrs motor *** placebo 22.6 +1.2 - entacapone tablets 22.0 -0.9 less than 0.05 updrs adl *** placebo 11.7 +1.1 - entacapone tablets 11.9 0.0 less than 0.05 withdrawal of entacapone : in the north american study, abrupt withdrawal of entacapone, without alteration of the dose of levodopa and carbidopa, resulted in a significant worsening of fluctuations, compared to placebo. in some cases, symptoms were slightly worse than at baseline, but returned to approximately baseline severity within two weeks following levodopa dose increase on average by 80 mg. in the nordic study, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed two weeks after drug withdrawal. at this phase, the symptoms were approximately at baseline severity following levodopa dose increase by about 50 mg. in the third placebo-controlled study, a total of 301 patients were randomized in 32 centers in germany and austria. in this study, as in the other two studies, entacapone 200 mg was administered with each dose of levodopa and dopa decarboxylase inhibitor (up to 10 times daily) and updrs parts ii and iii and total daily “on” time were the primary measures of effectiveness. the following results were observed for the primary measures, as well as for some secondary measures: table 3: german-austrian study * total population; score change at endpoint. ** fluctuating population, with 5 doses to 10 doses; score change at endpoint. *** total population; at least one category change at endpoint. ‡ not significant. ‡‡ p values for secondary measures are nominal p values without any adjustment for multiplicity. primary measures baseline change from baseline at month 6 p-value vs. placebo (locf) updrs adl * placebo 12.0 +0.5 - entacapone tablets 12.4 -0.4 less than 0.05 updrs motor * placebo 24.1 +0.1 - entacapone tablets 24.9 -2.5 less than 0.05 hours of awake time “on” (home diary) ** placebo 10.1 +0.5 - entacapone tablets 10.2 +1.1 n.s.‡ secondary measures ‡‡ baseline change from baseline at month 6 p-value vs. placebo updrs total * placebo 37.7 +0.6 - entacapone tablets 39.0 -3.4 less than 0.05 percent of awake time “on” (home diary)** placebo 59.8 +3.5 - entacapone tablets 62.0 +6.5 n.s.‡ hours of awake time “off” (home diary)** placebo 6.8 -0.6 - entacapone tablets 6.3 -1.2 0.07 levodopa total daily dose (mg)* placebo 572 +4 - entacapone tablets 566 -35 n.s.‡ frequency of levodopa daily intake* placebo 5.6 +0.2 - entacapone tablets 5.4 0.0 less than 0.01 global (overall) % improved*** placebo - 34 - entacapone tablets - 38 n.s.‡