PRODUCT MONOGRAPH

PrCOMTAN * (entacapone) tablets, 200 mg Adjunct to levodopa and DDC inhibitor / COMT-Inhibitor

S u b m i s s i o n C o n t r o l # 1 0 8 5 7 1

Novartis Pharmaceuticals Canada Inc. DATE OF PREPARATION: 385 Bouchard Blvd. April 23, 2001 Dorval, Quebec H9S 1A9 *Registered Trademark DATE OF REVISION: December 01, 2006

PRODUCT MONOGRAPH

NAME OF DRUG

PrCOMTAN *

(entacapone)

tablets, 200 mg

PHARMACODYNAMICS

Effect of Entacapone on erythrocyte COMT activity

Studies in healthy volunteers and patients with Parkinson's disease have shown that entacapone dose-dependently and reversibly inhibits human erythrocyte COMT activity after oral administration. Following single doses of 200 and 800 mg of entacapone, maximal inhibition of erythrocyte COMT activity was 64% and 82%, respectively.

Effect of entacapone on the pharmacokinetics of levodopa and its metabolites

When 200 mg entacapone is administered together with levodopa/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 h to 2.4 h. In general, the average peak levodopa plasma concentration and the time of its occurrence (Tmax of 1 hour) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. In a dose-response study in patients with Parkinson's disease, the maximal effect was obtained with a single dose of 200 mg entacapone. Doses of entacapone greater than 200 mg did not further improve the bioavailability of levodopa. Studies in healthy volunteers and in patients with Parkinson's disease show that entacapone dose-dependently decreases the formation of 3-OMD from levodopa. The chronic use of entacapone (200 mg, 3 to 10 times daily) in patients with Parkinson's disease, decreases the AUC of 3-OMD by 42 to 61%.

PHARMACOKINETICS AND METABOLISM OF ENTACAPONE

Entacapone pharmacokinetics are linear over a dose range of 5 to 200 mg. A slight non linearity in AUC was seen at doses greater than or equal to 400 mg in a single dose, dose- response, study in patients with Parkinson's disease. The pharmacokinetics of entacapone are independent of levodopa/DDC coadministration.

Absorption

There are large intra- and interindividual variations in the absorption of entacapone. Entacapone is rapidly absorbed from the GI tract, reaching peak concentrations (Cmax) in the plasma in approximately one hour. The drug has an extensive first-pass metabolism with bioavailability of about 35% following oral administration of a 200 mg dose. Cmax, after a single 200 mg dose of entacapone, is approximately 1.2 ug/mL. Food does not affect the absorption of entacapone to any significant extent.

Distribution and protein binding

The volume of distribution of entacapone at steady state after i.v. injection is small (20L). 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 to 50 ug/mL. Entacapone binds mainly to serum albumin.

Metabolism/Elimination

Entacapone undergoes extensive metabolism, mainly in the liver. The main metabolic pathway of entacapone in humans is the isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive. The elimination of entacapone occurs mainly by non-renal metabolic pathways. It is estimated that 80-90% of the dose is excreted in feces, although this has not been confirmed in man. Approximately 10-20% is excreted in urine. Only traces of entacapone are found as unchanged drug in urine. The major part (95 %) of the drug excreted in urine is conjugated with glucuronic acid. Of the metabolites found in urine only about 1 % have been formed through oxidation. The total body clearance of entacapone, after i.v. administration, is about 800 mL/min. It is eliminated with a short elimination half-life; the half-life for ss-phase being about 0.5 hours and for the g-phase about 2.5 hours. The ss-phase is predominant, and the g-phase accounts for approximately 8 % of the plasma-time-concentration curve (AUC) following i.v. administration.

Hepatic Impairment

The metabolism of the drug is slowed in patients with mild to moderate (Child-Pugh grading Class A and B) hepatic insufficiency caused by cirrhotic disease. In these patients, the AUC and Cmax values were approximately two-fold greater than those in demographically-matched healthy volunteers. As there are no clinical trial data to establish a safe and effective dosing regimen for hepatically impaired patients, entacapone should be not be administered to patients with hepatic impairment (see CONTRAINDICATIONS).

Renal Impairment

The pharmacokinetics of entacapone were evaluated in healthy volunteers and in patients with moderately (Clcr 0.60 - 0.89 mL/sec/1.73 m2) and severely (Clcr 0.20 - 0.44 mL/sec/1.73 m2) impaired renal function. After a single oral dose of 200 mg, the pharmacokinetics of entacapone were not significantly changed in patients with moderate to severe renal insufficiency.

Age, gender and race

Entacapone pharmacokinetics are independent of age. No formal gender studies have been conducted. Racial representation in clinical trials was largely limited to Caucasians (there were only 4 blacks in one US trial and no Asians in any of the clinical trials); no conclusions can therefore be reached about the effect of entacapone on groups other than Caucasian.

Studies Assessing Potential Drug Interactions

Effect of entacapone on the metabolism of other drugs

Protein binding: Entacapone is highly protein bound (98%). In vitro studies have shown that entacapone, at therapeutic concentrations, does not displace drugs of which a large proportion is bound to plasma proteins (e.g. warfarin, salicylic acid, phenylbutazone, and diazepam). On the other hand, entacapone is not markedly displaced by any of these drugs at therapeutic concentrations.

CLINICAL TRIALS

The effectiveness of COMTAN * as an adjunct to levodopa/ DDC therapy in the treatment of Parkinson's disease was demonstrated in three separate 24-week randomized, placebo- controlled, double-blind, multicenter studies in 676 patients with mild to moderate Parkinson's disease (average Hoen and Yahr score: 1.5-3) . In two of these studies (Nordic Study and North American "SEESAW" Study), the patients' disease was "fluctuating", i.e. was characterized by documented periods of "On" (periods with relatively good functioning) and "Off" (periods of relatively poor functioning), despite optimum levodopa therapy. In the third trial (German-Austrian "CELOMEN" Study) patients were not required to have been experiencing fluctuations. On average the patients evaluated had been treated with levodopa/ DDC inhibitor therapy for 8.3 years and 86 % were treated with other antiparkinsonian medication (dopamine agonists, selegiline, amantadine, anticholinergics) in addition to a levodopa/DDC inhibitor. In the two studies in patients with Parkinson's disease with documented episodes of end-of- dose motor fluctuations despite optimal levodopa therapy, patients were randomized to receive placebo (n=188) or 200 mg entacapone (n=188) with each daily dose of levodopa/dopa decarboxylase inhibitor (carbidopa or benserazide; average 4 -to- 6 doses per day). The formal double-blind portion of both trials was 6 months. Patients recorded the time spent in the "On" and "Off" states in home diaries periodically throughout the duration of the trial. In the Nordic Study the primary outcome measure was the total mean time spent in the "On" state during an 18-hour diary recorded day, in the North American "SEESAW" 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, as secondary measures, the amount of time spent in the "Off" state was evaluated and patients were also evaluated in subparts of the Unified Parkinson's Disease Rating Scale (UPDRS), an investigator's and patients's global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson's Disease and for change in daily levodopa/DDC dose. Results for the primary efficacy measure for these two studies are shown in Table 1.

TABLE 1: Primary Outcome Measures: Hours of awake time "On" (Nordic Study) ; Percent of Awake time "On" (North American "SEESAW" study)

* daily ON time (h); + Values represent the average of weeks 8, 16 and 24, by protocol-defined outcome

measure.

* * Proportion ON time %; ++Values represent the average of weeks 8, 16 and 24, by protocol defined outcome measure. Effects on "On" time did not differ by age, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline. Corresponding significant decreases in OFF time were also noted. Change from baseline in hours of awake time AOff A in the Nordic Study were: -1.3 hours for the entacapone group; 0 hours for the placebo group and in the North American "SEESAW" Study were: -1.2 hours for the entacapone group; -0.3 for the placebo group.

Withdrawal of entacapone

: In the North American "SEESAW" Study, abrupt withdrawal of entacapone, without alteration of the dose of levodopa/carbidopa, resulted in significant worsening of fluctuations, compared to placebo. In some cases, symptoms were slightly worse 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 were observed after entacapone withdrawal, as assessed two weeks after drug withdrawal. At this phase the symptoms were approximately baseline severity following levodopa dose increase by about 50 mg.

In the third placebo controlled trial (Austrian-German "CELOMEN" Study), as in the other two trials, patients were randomized to receive 200 mg entacapone or placebo with each dose of levodopa / dopa decarboxylase inhibitor (up to 10 times daily). The CELOMEN study was primarily designed as a safety trial. Measures of effectiveness in this study were the UPDRS Parts II and III and total daily "On" time (see Table 2).

TABLE 2: Outcome Measures: UPDRS and Hours of awake time "On" (Austrian- German "CELOMEN" Study)

*Total population; score change at endpoint

* *Fluctuating population, with 5-10 doses

INDICATIONS AND CLINICAL USE

COMTAN * (entacapone) is indicated as an adjunct to levodopa/carbidopa or levodopa/ benserazide preparations to treat patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose "wearing-off" (see CLINICAL PHARMACOLOGY: Clinical Trials). COMTAN *'s effectiveness has not been systematically evaluated in patient's with idiopathic Parkinson's Disease who do not experience end-of-dose "wearing-off". Since COMTAN * is to be used in combination with a levodopa/dopa-decarboxylase inhibitor, the prescribing information for levodopa/carbidopa and levodopa/benserazide are also applicable when COMTAN * is added to the treatment regimen.

CONTRAINDICATIONS

COMTAN * (entacapone) is contraindicated in patients with known hypersensitivity to entacapone or to the excipients of the drug product. COMTAN * should not be given concomitantly with non-selective monoamine oxidase (MAO) inhibitors (e.g. phenelzine and tranylcypromine). The combination of selective MAO-A and selective MAO-B inhibitors is equivalent to non-selective MAO-inhibition, therefore, they should not both be given concomitantly with COMTAN * and levodopa preparations. Non-selective MAO inhibitors must be discontinued at least two weeks prior to initiating therapy with entacapone. Selective MAO-B inhibitors should not be used at higher than recommended doses (e.g. selegiline 10 mg/day) when co-administered with COMTAN * (see PRECAUTIONS, Drug Interactions, Selegiline). COMTAN * is contraindicated in patients with a previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis. COMTAN * is contraindicated in patients with liver impairment. COMTAN * is contraindicated in patients with pheochromocytoma due to the increased risk of hypertensive crisis.

WARNINGS

Drugs metabolized by Catechol-O-methyltransferase (COMT):

When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa/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, possibly arrhythmias, and excessive changes in blood pressure. Ventricular tachycardia was noted in a 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.

Sudden Onset of Sleep

Patients receiving treatment with COMTAN * in combination with levodopa/decarboxylase inhibitor and/or other dopaminergic agents have reported suddenly falling asleep while engaged in activities of daily living, including the driving of a car, which sometimes resulted in accidents. Although some of the patients reported somnolence while treated with levodopa/dopa decarboxylase inhibitor and COMTAN *, others perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Physicians should alert patients of the reported cases of sudden onset of sleep, bearing in mind that these events are NOT limited to initiation of therapy. Patients should also be advised that sudden onset of sleep has occurred without warning signs and should be specifically asked about factors that may increase the risk with COMTAN used in combination with levodopa/decarboxylase inhibitor, such as concomitant medications or the presence of sleep disorders. Given the reported cases of somnolence and sudden onset of sleep (not necessarily preceded by somnolence), physicians should caution patients about the risk of operating hazardous machinery, including driving motor vehicles, while taking COMTAN in combination with levodopa/decarboxylase inhibitor. If drowsiness or sudden onset of sleep should occur, patients should be informed to immediately contact their physician. Episodes of falling asleep while engaged in activities of daily living have also been reported in patients taking other dopaminergic agents, therefore, symptoms may not be alleviated by substituting these products. While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. Currently, the precise cause of this event is unknown. It is known that many Parkinson's disease patients experience alterations in sleep architecture, which results in excessive daytime sleepiness or spontaneous dozing, and that dopaminergic agents can also induce sleepiness.

PRECAUTIONS

General

COMTAN * enhances the effects of levodopa. Therefore, to reduce levodopa-related dopaminergic adverse effects, e.g. dyskinesias, nausea, vomiting and hallucinations, it may be necessary to adjust the levodopa dosage within the first days to first weeks following the initiation of COMTAN * treatment. COMTAN * has no antiparkinsonian effect of its own and therefore should only be used as an adjunct to levodopa/carbidopa or levodopa/benserazide treatment. The warnings and precautions given for levodopa/carbidopa and levodopa/benserazide treatment should therefore be taken into account when COMTAN * is used. If COMTAN * treatment is discontinued, it is necessary to adjust the dosing of other parkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms (see DOSAGE AND ADMINISTRATION).

Neuroleptic Malignant Syndrome

A symptom complex resembling the neuroleptic malignant syndrome (NMS), characterized by elevated temperature, muscular rigidity, altered consciousness (e.g., agitation, confusion, coma), autonomic instability (tachycardia, labile blood pressure) and elevated CPK has been reported in association with the rapid dose reduction, or withdrawal of, or changes in antiparkinsonian therapy. In individual cases, only some of these symptoms and/or findings may be evident. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Cases with similar signs and symptoms have been reported in association with COMTAN * (entacapone) therapy, especially following abrupt reduction or discontinuation of entacapone and other dopaminergic medications. The complicated nature of these cases makes it difficult to determine what role, if any, entacapone may have played in their pathogenesis. No cases have been reported following abrupt withdrawal or dose reduction of entacapone treatment during clinical studies. Prescribers should exercise caution when discontinuing entacapone treatment. When considered necessary, withdrawal should proceed slowly. If a decision is made to discontinue treatment with COMTAN *, recommendations include monitoring the patient closely and adjusting other dopaminergic treatments as needed. If signs and/or symptoms occur despite a slow withdrawal of entacapone, an increase in levodopa dosage may be necessary. Tapering COMTAN * has not been systematically evaluated.

Rhabdomyolysis

Rhabdomyolysis secondary to severe dyskinesias or Neuroleptic Malignant Syndrome (NMS) has been observed rarely in patients with Parkinson's disease Very rare cases of rhabdomyolysis have been reported with entacapone treatment. Symptoms associated with rhabdomyolysis can include muscle pain, muscle tenderness and weakness, bruising, elevated temperature, urinary retention, confusion, and elevated CPK. Acute renal failure is serious complication associated rhabdomyolysis and has been reported in some cases of rhabdomyolysis that have occurred during entacapone treatment.

Orthostatic Hypotension/Syncope

COMTAN * may aggravate levodopa-induced orthostatic hypotension. COMTAN * should be given with caution to patients who are treated with drugs which may cause orthostatic hypotension. In controlled clinical trials approximately 1.2% of patients who received 200 mg COMTAN * and 0.8% of patients treated with placebo 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.

Diarrhea

In clinical trials, diarrhea was reported as an adverse event in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg COMTAN * and placebo, respectively. In patients treated with COMTAN * diarrhea was generally mild to moderate in severity (8.6%) but was reported as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients (1.2% with mild to moderate diarrhea and 0.3% with severe diarrhea). Diarrhea generally resolved after discontinuation of COMTAN *. Two patients with diarrhea required hospitalization. Typically, diarrhea presents within 4 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. For patients experiencing diarrhea, close monitoring of weight is recommended in order to assess the need for treatment discontinuation to avoid excessive weight loss. Some patients who experienced diarrhea and weight loss during COMTAN treatment were subsequently diagnosed with colitis, following colonoscopy and biopsy (See ADVERSE REACTIONS- Post Introduction Reports).

Skin

Some epidemiological studies have shown that patients with Parkinson's disease have a higher risk (perhaps 2- to 4-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, was unclear. COMTAN is one of the drugs used to treat Parkinson's disease. Although COMTAN has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systematically studied. Patients treated with COMTAN should be made aware of these results and should undergo periodic dermatologic screening.

Patients with Fructose Intolerance

COMTAN * tablets contain sucrose. Therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Dyskinesia

COMTAN * may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The rates of withdrawal for dyskinesia were 1.5% and 0.8% for 200 mg COMTAN * and placebo, respectively.

Hallucinations

Dopaminergic therapy in Parkinson's disease patients has been associated with hallucinations. In clinical trials, hallucinations developed in approximately 4% of patients treated with 200 mg COMTAN * or placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with 200 mg COMTAN * and placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200 mg COMTAN * and placebo groups, respectively.

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, it is unknown whether other, non-ergot derived drugs (e.g., entacapone) that increase dopaminergic activity can cause them. It should be noted that the expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to entacapone. Four cases of pulmonary fibrosis were reported during clinical development of entacapone; three of these patients were also treated with pergolide and one with bromocriptine. The duration of treatment with entacapone ranged from 7 to 17 months.

Urine Discolouration

COMTAN * may cause a harmless intensification in the color of the patient's urine to brownish-orange.

Occupational Hazards: Psychomotor Performance

COMTAN * together with levodopa may cause dizziness and symptomatic orthostatism. Therefore, patients should be cautioned about operating machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

Patients being treated with entacapone in association with levodopa and presenting with somnolence and/or sudden sleep onset episodes must be instructed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes have resolved.

Special Populations

Hepatic Impairment

The metabolism of entracapone is slowed in patients with mild to moderate (Child-Pugh grading Class A and B) hepatic insufficiency caused by cirrhotic disease. In these patients, the AUC and Cmax values were approximately two-fold greater than those in demographically-matched healthy volunteers. As there are no clinical trial data to establish a safe and effective dosing regimen for hepatically impaired patients, entacapone should be not be administered to patients with hepatic impairment (see CONTRAINDICATIONS).

Renal Impairment

The pharmacokinetics of entacapone were not significantly changed in patients with moderate to severe renal insufficiency and there is no need for dose adjustment (see PHARMACOKINETICS AND METABOLISM OF COMTAN *). There is no experience with entacapone in patients receiving dialysis.

Pregnant Women

There are no studies or clinical experience of the use of COMTAN * in pregnant women. Use of COMTAN * in women of child-bearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to mother and child (see TOXICOLOGY, Reproductive Studies).

Nursing Mothers

Studies in rats have shown that entacapone is excreted in milk. It is not known whether entacapone is excreted in human milk. Since the safety of COMTAN * in infants is unknown, women should not breast-feed during treatment with COMTAN *.

Pediatrics

The safety and efficacy of COMTAN * in pediatric patients has not been established and use in patients below the age of 18 is not recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies have been conducted in the mouse at dosages up to 600 mg/kg/day and in the rat at dosages up to 400 mg/kg/day. In the rat, the only drug-related finding was an increased incidence of renal tubular adenomas and carcinomas noted in males at doses of 400 mg/kg/day. Plasma exposures (AUC) associated with this dose were approximately 20 times higher than estimated plasma exposures of humans receiving the maximum recommended daily dose of entacapone (8 x 200 mg = 1600 mg). In the mouse study, there was a high incidence of premature mortality in animals receiving the highest dose of entacapone (600 mg/kg/day, corresponding to 2 times the maximum recommended human dose on a mg/m2 basis). Thus, the mouse study does not allow adequate assessment of carcinogenicity. Although no treatment related tumors were observed in animals receiving lower doses, the carcinogenic potential of entacapone has not been fully evaluated. The carcinogenic potential of COMTAN * in combination with levodopa/DDC has not been studied.

Mutagenesis

Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma/ thymidine kinase assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with Sinemet, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test).

Teratogenicity

Reproduction studies have been performed in rats and rabbits at doses up to 1000 mg/kg/day and 300 mg/kg/day, respectively, of entacapone. Increased incidence of fetal variations were evident in litters from rats treated at the highest dose in the absence of overt maternal toxicity. The maternal plasma drug exposure (AUC) associated with this dose was approximately 34 times the estimated plasma exposure in humans receiving the maximal recommended dose of 8 x 200 mg (1600 mg/day). Increased frequencies of abortion and late/total resorptions and decreased fetal weights were observed in litters of rabbits treated with maternotoxic doses of 100 mg/kg/day (plasma AUC 0.4 times those in humans receiving the maximal recommended daily dose) 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 litters of dams treated with doses of 160 mg/kg/day (plasma AUCs 7 times those in humans receiving the maximal recommended daily dose) 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 maximal recommended daily dose) to female rats during the later part of gestation and throughout lactation produced no evidence of developmental impairments in the offspring. Entacapone is always given concomitantly with levodopa/dopa-decarboxylase inhibitor, which is known to cause visceral and skeletal malformations in rabbits. Although the teratogenicity of entacapone was assessed in animals, the teratogenic potential of entacapone in combination with levodopa/carbidopa was not assessed.

Impairment of fertility

No effect on fertility was observed in male and female rats treated with up to 700 mg/kg/day of COMTAN * (exposure achieved approximately 28 times higher than that in man after the maximum recommended daily dose of 8 x 200 mg/day).

Drug Interactions

Protein binding

Entacapone is highly protein bound (98%). In vitro studies have shown that entacapone, at therapeutic concentrations, does not displace drugs of which a large proportion is bound to plasma proteins (e.g. warfarin, salicylic acid, phenylbutazone and diazepam). Entacapone is not markedly displaced by any of these drugs at therapeutic concentrations (see ACTIONS AND CLINICAL PHARMACOLOGY).

Drugs metabolized by Cytochrome P450

Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC50 ~ 4 uM). Other P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19) were inhibited only by very high concentrations of entacapone (IC50 from 200 to greater than 1000 uM). The highest concentration of entacapone achieved with an oral 200 mg dose is approximately 5 uM and is not expected to inhibit these enzymes.

Drugs metabolized by Cytochrome P450 (CYP2C9)

Entacapone has been shown to inhibit the activity of cytochrome P450 2C9 in vitro and may potentially interfere with drugs whose metabolism is dependent on this isoenzyme, such as S-warfarin . However, in an interaction study in healthy volunteers, entacapone did not change the plasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11-26%]. The INR values increased on average by 13% [CI90 6-19%]. Thus, control of INR is recommended when entacapone treatment is initiated for patients receiving warfarin.

Drugs metabolized by the Catechol-O-methyltransferase (COMT):

The experience of the clinical use of entacapone with medicinal products that are metabolized by COMT (e.g. catechol-structured compounds: rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-methyldopa, apomorphine, and paroxetine) is still limited (see WARNINGS). Regardless of their route of administration, including inhalation, drugs known to be metabolized by COMT should be used with caution in patients treated concomitantly with entacapone, as their interaction may result in increased heart rates, possible arrhythmias and excessive changes in blood pressure (see WARNINGS).

Non-selective MAO inhibitors: CONTRAINDICATIONS).

COMTAN * should not be given concomitantly with non- selective monoamine oxidase (MAO) inhibitors (e.g. phenelzine and tranylcypromine). The combination of selective MAO-A and selective MAO-B inhibitors is equivalent to non- selective MAO-inhibition, therefore, they should not both be given concomitantly with COMTAN * and levodopa preparations. Non-selective MAO inhibitors must be discontinued at least two weeks prior to initiating therapy with entacapone (See

Selegiline

In two multiple-dose interaction studies in patients with Parkinson's disease, no interactions between COMTAN * and selegiline (10 mg) were observed in the presence of coadministered levodopa/dopa decarboxylase inhibitor. More than 400 parkinsonian patients in phase 2 and 3 studies used selegiline in combination with entacapone and levodopa/DDC inhibitor without any apparent interactions (also see CONTRAINDICATIONS).

Tricyclic antidepressants and noradrenaline re-uptake inhibitors

In a single-dose study in healthy volunteers, no interactions between COMTAN * and imipramine were observed in the absence of coadministration of levodopa/dopa decarboxylase inhibitor. The potential for interactions between COMTAN * and tricyclic antidepressants or noradrenaline re-uptake inhibitors has not been systematically evaluated in patients with Parkinson's disease. The experience on the clinical use of COMTAN * with tricyclic antidepressants and noradrenaline reuptake inhibitors (desipramine, maprotiline and venlafaxine) is limited. Therefore, patients should be carefully monitored when COMTAN * is administered in combination with these drugs.

Dopa Decarboxylase Inhibitors

Carbidopa

No interaction of COMTAN * with carbidopa were observed with the recommended dosage regimen; however, high single doses (in excess of 400 mg of COMTAN *) may decrease the bioavailability of carbidopa.

Benserazide

Pharmacokinetic interaction studies with benserazide have not been conducted. COMTAN * increases the bioavailability of levodopa from standard levodopa/benserazide preparations 5-10% more than from standard levodopa/carbidopa preparations. Consequently, undesirable dopaminergic effects may be more frequent when entacapone is added to levodopa/benserazide treatment. A larger reduction of the levodopa dose may be required when COMTAN * treatment is initiated in patients receiving levodopa/benserazide (see DOSAGE and ADMINISTRATION)

Drugs interfering with biliary excretion

As most COMTAN * 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 COMTAN *. These include probenicid, cholestyramine, and some antibiotics (e.g. erythromycin, rifampicin, ampicillin and chloramphenicol).

Iron

Similar to levodopa, COMTAN may impair the absorption of iron from the gastrointestinal tract. Therefore, COMTAN and iron-containing supplements or multivitamins should be ingested at least 2 to 3 hours apart.

Hormone levels

Levodopa is known to depress prolactin secretion and increase growth hormone levels. Treatment with COMTAN * coadministered with levodopa/dopa decarboxylase inhibitor does not change these effects.

Laboratory Tests

COMTAN * is a chelator of iron. The impact of entacapone on the body's iron stores is unknown; however, a tendency towards decreased serum iron concentrations was noted in a clinical trial. In a controlled clinical study serum ferritin levels (as marker of iron deficiency and subclinical anemia) were not changed with entacapone compared to placebo after one year of treatment and there was no difference in the rates of anemia or decreased hemoglobin levels. The laboratory tests required during extended levodopa therapy should be normally conducted also during COMTAN * treatment.

ADVERSE REACTIONS

A total of 1450 patients with Parkinson's Disease received COMTAN * (entacapone) during the pre-marketing clinical trials. Approximately 14% of the 603 patients given entacapone in the double-blind placebo-controlled trials discontinued treatment due to adverse events compared to 9% of the 400 patients who received placebo. The most frequent causes of discontinuation in decreasing order for COMTAN * vs placebo are: psychiatric reasons (2% vs 1%), diarrhea (2 % vs 0%), dyskinesia/hyperkinesia (2% vs 1%), nausea (2% vs 1%), abdominal pain (1% vs 0%), and aggravation of Parkinson's Disease symptoms (1% vs 1%).

Incidence of Adverse Events in Placebo Controlled Trials

Dosage

The recommended dose of COMTAN * is one 200 mg tablet administered concomitantly with each levodopa/carbidopa or levodopa/benserazide dose up to 8 times daily (1600 mg/day). Because entacapone enhances the bioavailability and therefore the central effects of levodopa, it may be necessary to adjust the dosage of levodopa during the initial days to weeks of entacapone therapy in order to reduce levodopa-related dopaminergic side effects, e.g., dyskinesias, nausea, vomiting and hallucinations. In some cases, it may be necessary to reduce the daily dosages of levodopa by about 10-30%. This can be achieved through either reducing the dose of the levodopa preparation itself, or by extending the interval between doses, according to the clinical condition of the patient. In clinical trials, 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 dyskinesias before beginning treatment. The average reduction in daily levodopa dose for patients in clinical trials requiring levodopa dose reduction was about 25% (more than 58% of patients with levodopa doses above 800 mg daily required such a reduction). COMTAN * increases the bioavailability of levodopa from standard levodopa/benserazide preparations slightly (5-10%) more than from standard levodopa/carbidopa preparations. Therefore, patients who are taking standard levodopa/benserazide preparations may need a larger reduction of levodopa dose when entacapone is initiated.

Patients with Impaired Hepatic Function

As there is no clinical trial data to establish a safe and effective dosing regimen for hepatically impaired patients, entacapone should be not be administered to patients with hepatic impairment (see CONTRAINDICATIONS)

Patients with Impaired Renal Function

No dose adjustment of COMTAN * is necessary in patients with moderate to severe renal insufficiency. There is no experience with COMTAN * in patients receiving dialysis therapy.

Elderly

No dose adjustment is required in elderly patients.

Discontinuation of COMTAN *

Rapid withdrawal or abrupt reduction in the COMTAN * dose could lead to emergence of signs and symptoms of Parkinson's disease (see Clinical Pharmacology, Clinical Trials) and may lead to a symptom complex resembling neuroleptic malignant syndrome (see PRECAUTIONS, Neuroleptic Malignant Syndrome). This syndrome should be considered in the differential diagnosis for any patient who develops high fever or severe rigidity. If a decision is made to discontinue treatment with COMTAN *, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed. Although tapering COMTAN * has not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made.

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name:

entacapone

Chemical Name: (E)-%-Cyano-N,N-diethyl-3,4-dihydroxy-5-nitrocinnamamide Empirical Formula: C14H15N3O5 Molecular Weight: 305.28 Structural Formula:

HO HO

O

N CH3 CN

CH3

Description:

Entacapone is a yellow or greenish yellow, non-hygroscopic powder. It is practically insoluble in water and in acidic aqueous medium, but slightly soluble in organic solvents. The pKa value is approximately 4.5. The partition coefficient in 1-octanol/phosphate buffer pH 7.4 is -0.25. Its melting point is approximately 163degC.

Composition:

COMTAN * 200 mg film coated tablets contain 200 mg of the active ingredient entacapone. The non-medicinal ingredients are: Core: croscarmellose sodium, hydrogenated vegetable oil, magnesium stearate, mannitol, microcrystalline cellulose. Coating: glycerol 85%, hydroxypropylmethyl cellulose, magnesium stearate, polysorbate 80, red iron oxide, sucrose, titanium dioxide, yellow iron oxide.

Storage

Store at room temperature (15deg and 30degC).

AVAILABILITY OF DOSAGE FORMS

COMTAN * (entacapone) 200 mg is a brownish-orange, unscored, oval-shaped film-coated tablet embossed with "COMTAN" on one side. COMTAN * tablets are availabe in bottles of 30, 60, 100 and 500 tablets.

INFORMATION FOR THE PATIENT/CAREGIVER

The information presented in this leaflet is not complete. Complete information is available from your doctor or pharmacist. This leaflet is meant to supplement what your doctor or pharmacist have told you about PrCOMTAN * (entacapone). Be sure to follow your doctor's and pharmacist's instructions and read the materials given to you. If you have any questions after reading this information leaflet, be sure to ask your doctor or pharmacist.

What is COMTAN * used for?

COMTAN *,

also known as entacapone, is used together with levodopa/carbidopa or levodopa/benserazide to treat people with Parkinson's disease in whom the effect of each levodopa dose becomes shorter and who subsequently experience fluctuations in the symptoms of Parkinson's Disease (end-of-dose "wearing-off").

In Parkinson's disease the amount of dopamine is decreased in certain areas of the brain and oral levodopa is given to compensate for this decrease. Levodopa is converted to dopamine in the brain, but part of the dose of levodopa is broken down by enzyme to an inactive compound before it reaches the brain. COMTAN * inhibits this enzymatic degradation of levodopa, and therefore increases the amount of levodopa reaching the brain. When taken together with levodopa, COMTAN * prolongs the efficacy of levodopa therapy in alleviating the symptoms of Parkinson's disease. COMTAN * is used in patients in whom the effect of each levodopa dose becomes shorter ("wearing-off") and who subsequently experience fluctuations in the symptoms of Parkinson's Disease. COMTAN * has no antiparkinsonian activity without levodopa.

What should I know before taking COMTAN *?

Some people feel sleepy, drowsy, or, rarely, may suddenly fall asleep without warning (i.e. without feeling sleepy or drowsy) when taking COMTAN in combination with levodopa and other drugs used to treat Parkinson's disease. Take special care when you drive or operate a machine. If you experience excessive drowsiness or a sudden sleep onset episode, refrain from driving and operating machines, and contact your physician. Studies of people with Parkinson's disease show that they may be at an increased risk of developing melanoma, a form of skin cancer, when compared to people without Parkinson's disease. It is not known if this problem is associated with Parkinson's disease or the drugs used to treat Parkinson's disease. Therefore, your doctor should perform periodic skin examinations.

Using COMTAN * safely

You should NOT take COMTAN * if you :

• Have a history of allergic reactions to entacapone or any other components of the COMTAN * tablet (see AWhat does COMTAN * contain @)

• Are taking certain antidepressants (both MAO-A and MAO-B inhibitors simultaneously, or non-selective MAO-inhibitors). If you are taking antidepressants and need further information, please ask your doctor or your pharmacist whether your antidepressive medication can be taken together with COMTAN *

• Have a history of Neuroleptic Malignant Syndrome (NMS) (rare reaction to antipsychotic medicines) and/or non-traumatic rhabdomyolysis (rare form of muscle disorder)

• Have pheochromocytoma (a tumor of the adrenal gland), because it may increase the risk of severe hypertensive reactions.

• Have liver disease

• Are pregnant (see below)

• Are breast-feeding (see below)

• Are under 18 years of age

If any of these apply to you, tell your doctor before taking COMTAN *.

What does your doctor need to know about you?

To be sure that you can use COMTAN * safely, your doctor must know if you: have any other illnesses have ever had abnormal liver function tests have any allergies to medicines, food, dyes, or preservatives are taking or have recently taken any medications, including herbal and non prescription medicines. It may be necessary to change the dose, take other precautions, or perhaps stop one of the medicines. This applies to both prescription and non-prescription medicines, especially rimiterol, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-methyldopa, apomorphine, and paroxetine. are taking any iron supplements. Similarly to levodopa, COMTAN * may impair the absorption of iron from the gastrointestinal tract. Therefore, COMTAN * and iron-containing medicinal products should be taken at least 2 -to 3 hours apart. COMTAN * tablets contain a sugar called sucrose. Therefore, if you have been told by your doctor that you have an inherited intolerance to sucrose or fructose, you should not take COMTAN *.

Are you pregnant or breast-feeding?

COMTAN * is not recommended if you are pregnant

. There is no experience in using COMTAN * in pregnant women. It is therefore important to tell your doctor immediately if you think you may have become pregnant, or are planning to become pregnant.

COMTAN * is not recommended if you are breast-feeding

, because it is not known whether COMTAN * is excreted into breast milk. Tell your doctor if you are breast-feeding, so that other treatment options can be tried.

How to take COMTAN *?

COMTAN * should always be used in combination with levodopa preparations, either levodopa/carbidopa or levodopa/benserazide. You may also use other antiparkinsonian drugs simultaneously as advised by your doctor. The usual dose of COMTAN * is one 200 mg tablet with each levodopa dose. The maximum recommended dose is 200 mg eight times a day, i.e. 1600 mg of entacapone. It is important to follow your doctor's instructions. If you have any concerns about the schedule for taking your medication, talk to your doctor or pharmacist to help you sort it out. COMTAN * can be taken with or without food. Do not break or crush the tablets.

What to expect when you start taking COMTAN *?

Soon after beginning and during treatment with COMTAN *, you may experience an increase in uncontrolled movements (dyskinesia), nausea and abdominal pain. These effects may also be more common with higher doses (1400 to 1600 mg per day) than with lower doses. This is because COMTAN * increases the availability of levodopa and enhances both its effectiveness and side effects. Therefore, if, for example, you notice a disturbing increase in involuntary movements (dyskinesias) after starting treatment with COMTAN *, you should contact your doctor for possible adjustment of your levodopa dosage to decrease the severity and frequency of these effects.

Driving and using machines

COMTAN * taken together with levodopa may lower your blood pressure, which may make you feel light-headed or dizzy. You should not drive a car or operate machinery until you are reasonably certain that COMTAN * does not affect your ability to carry out these activities. See also What should I know before taking COMTAN?

What happens if a dose is missed?

To obtain the maximum benefit from your antiparkinsonian therapy always take all medicines, including COMTAN *, exactly as prescribed by your doctor. However, if you have forgotten to take the COMTAN * tablet with your levodopa dose, you should continue the treatment by taking the next COMTAN * tablet with your next levodopa dose. If you have missed several doses, please inform your doctor immediately and follow the advice given to you. Do not change the dose of COMTAN * unless instructed by your doctor.

What to do in case of overdose?

In the event of accidental overdosage, contact your doctor immediately so that medical attention may be given promptly.

Effects when treatment with COMTAN * is stopped

Do not stop taking COMTAN * unless your doctor tells you to. In such case, your doctor may need to re-adjust the dosage of your other antiparkinsonian medication. Abrupt discontinuation of both COMTAN * and other antiparkinsonian medication may result in unwanted side effects, such as severe muscular stiffness, high fever and altered consciousness.

ANIMAL PHARMACOLOGY

In Vitro

Entacapone is a potent inhibitor of COMT in vitro suppressing COMT activity in crude tissue preparations (brain, duodenum, rat and human red blood cells, liver) with IC50-values ranging from uM for rat brain S-COMT to 0.16 uM for rat liver S-COMT. The IC50-values for (Z)-OR-611, the (Z)-isomer of entacapone, were of approximately the same magnitude as those measured for entacapone. The IC50-values for human and rat RBC were similar. The Ki-value, which indicates the affinity of the inhibitor to the enzyme, was 14 nM for rat liver sol-COMT. The enzyme kinetic studies revealed that entacapone is a reversible and selective inhibitor of the COMT-enzyme.

Ex Vivo

In ex vivo tests, following oral or i.v. administration of entacapone 10 mg/kg, S-COMT was inhibited generally in good correlation with in vitro IC50-values of the same tissue, excepting the brain which reflects poor penetration of entacapone into the CNS . In most tissues, inhibition of COMT was transient indicating that entacapone is a reversible COMT- inhibitor. In rats, the inhibition of duodenal COMT activity was more complete and sustained as compared to other tissues.

In Vivo

Levodopa Pharmacokinetics

Entacapone administered orally at doses of 0.3 - 30 mg/kg, caused a dose-dependent and sustained inhibition of 3-OMD formation from levodopa in rat serum. The inhibition of 3-OMD formation was reflected by elevated levodopa concentrations in serum. Accordingly, addition of entacapone (30 mg/kg) to levodopa/ carbidopa treatment prolonged the elimination half-life of levodopa about 5-fold after i.v. levodopa and about 2-fold after oral levodopa.

Peripheral COMT Inhibition and Central Levodopa Metabolism

Entacapone added to the levodopa/carbidopa treatment reduced rat striatal 3-OMD levels and increased both dopamine and levodopa concentrations. Striatal HVA levels were not reduced, supporting the inhibition of peripheral COMT activity by entacapone. Following addition of entacapone to levodopa/carbidopa treatment, the dose of levodopa could be decreased by 70 % and reach the same striatal dopamine concentration as with levodopa/carbidopa alone. A significant reduction in 3-OMD concentration and a significant increase in levodopa concentration was observed with entacapone treatment, indicating that entacapone improved the availability of levodopa in the brain.

Efficacy of entacapone in animal models of Parkinson's disease

Entacapone significantly improves and sustains the dopaminergic effect of levodopa therapy, when given in combination with carbidopa, in various animal models of Parkinson's disease. The locomotor activity of hypokinetic reserpine treated mice was potentiated by the oral administration of entacapone at doses of 3, 10 and 30 mg/kg to the levodopa/carbidopa treatment. In rats with unilateral 6-hydroxy-dopamine (6-OHDA) induced lesions of the substantia nigra, entacapone administered orally at doses of 1, 3 and 10 mg/kg potentiated levodopa/carbidopa induced contralateral circling behaviour up to approximately 3 hours post-dosing. In another study, the addition of entacapone, administered orally at dose of 10 mg/kg, to the levodopa/carbidopa treatment allowed a 50% reduction in the levodopa dose without reducing the contralateral turning. Entacapone, at oral doses of 12.5 mg/kg, significantly increased and potentiated the antiparkinsonian effect of low dose levodopa/carbidopa in MPTP treated marmosets.

Special studies

TOXICOLOGY

Acute Toxicity

The acute toxicity of the (Z)-isomer is similar to that of (E)-isomer of entacapone and are considered to be low.

Subchronic/Chronic Toxicity with Entacapone

* No Toxic Effects Level (NTEL). MC = 0.05 or 1.2 % methylcellulose

Combination toxicity with L-DOPA + Carbidopa

No distinct organ toxicity was observed in chronic toxicity studies. Entacapone did not increase the toxic effects of L-DOPA + Carbidopa in combination toxicity studies.

Renal Toxicity

In a 1 year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1600 mg) caused an increased incidence in male rats of nephrotoxicity that was characterized by regenerative tubules, thickening of basement membranes, infiltration of mononuclear cells and tubular protein casts. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although this toxicity could represent a species-specific effect, there is not yet evidence that this is so.

Teratological and Reproductive Studies

In the Segment I study, entacapone did not have any effect on male or female fertility up to doses of 350 mg/kg twice daily. The exposure achieved in this study was approximately 50 times higher than the average exposure in man (AUCman with 6 x 200 mg). In the Segment II studies, entacapone was not teratogenic up to doses of 500 mg/kg twice daily (1000 mg/kg/day), which approximates 100 times higher than the average exposure in man. The rabbit did not tolerate entacapone as well as the rat, the dose increment being limited by maternal toxicity and only 5 times higher exposure was achieved than the average exposure in man. Increased frequencies of abortions and late/total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternotoxic doses of 100 mg/kg/day (plasma AUCs 0.4 times those in humans receiving the maximum recommended therapeutic dose of 1600 mg/day) or greater. In the Segment III studies, maternal treatment with entacapone did not affect the pre- and post- natal development or the subsequent growth development or the fertility of the F1 generation. The exposure achieved in these studies was up to 50 times higher than the average exposure in man.

Mutagenicity Studies with Entacapone

Entacapone was not mutagenic in the Ames bacterial mutagenicity tested in four strains of Salmonella typhimurium and two strains of Escherichia coli in the presence and absence of metabolic activation (S-9 mix). Entacapone induced a significant increase in TK mutant frequency in L5178Y mouse lymphoma cells at a concentration range of 25 - 150 Fg/mL with or without S-9 mix. The scoring of the number of wells containing small and large colonies showed that the majority of entacapone induced mutants were of the small colony type which indicates a chromosome-type damage of entacapone. In vitro, no substantial amount of entacapone seems to bind to DNA when thymus DNA was exposed to 25 - 50 Fg/mL of entacapone. Bacteria, which do not possess chromosomes, were not affected by entacapone. Hence, the negative DNA-binding data is in good correlation with the results of Ames test strengthening the hypothesis that the damage induced by entacapone is at the chromosomal level. In in vitro chromosomal aberration test with human lymphocytes, entacapone induced increases in chromosomal aberrations only in the presence of S-9 mix . The significant increases in the frequency of aberrant metaphases were observed at 400 Fg/mL (1.3 mM) of entacapone. When mitotic indices were scored, entacapone was more toxic to the cells in the absence of S-9 mix than in its presence, the concentration difference being approximately 5-fold. Observed differences in mitotic indices could be due to differences in the treatment period, i.e. continuous and pulse treatment without and with S-9-mix, respectively. Entacapone did not induce chromosomal or any other damage which leads to micronucleus formation in polychromatic erythrocytes of treated mice 24, 48 or 72 h after oral administration of a single MTD dose of 1000 mg/kg, or 24 h after a single i.v. dose of 35 mg/kg.

Mutagenicity Studies of Entacapone in combination with L-DOPA + Carbidopa

*The ratio of 4:4:1 of entacapone: L-DOPA: carbidopa at each dose-level was employed in the bacterial mutagenicity tests. In the mice micronucleus test L-DOPA 40 mg/kg + carbidopa 10 mg/kg were administered orally, concomitantly with various doses of entacapone. Combination treatment with L-DOPA + carbidopa + entacapone was not mutagenic in the Ames bacterial mutagenicity test, tested in four strains of Salmonella typhimurium and two strains of Escherichia coli in the presence and absence of metabolic activation (S-9 mix). The highest dose-level of entacapone was shown to be toxic to the test bacteria. In mice, entacapone (up to 1000 mg/kg p.o.) did not induce micronuclei in polychromatic erythrocytes when administered concomitantly with L-dopa + carbidopa (40 + 10 mg/kg p.o.)

Carcinogenicity Studies

* Exposure factor was calculated by dividing the AUCanimal by AUCman. The AUC in man was derived by multiplying the AUC of entacapone after a single (200 mg) dose (1.5 hCFg/ml) with the number of the average dosing frequency, i.e. 6 times a day.

* * Rest of the female mice were sacrificed on week 95. # MC = 0.5% methyl cellulose

The mouse study did not allow for adequate assessment of the carcinogenic potential of entacapone due to the high incidence of premature mortality occurring at high doses. In the rat two year carcinogenicity study, high doses (400 mg/kg) of entacapone caused renal adenomas and increased the number of carcinomas in male rats. The carcinogenic potential of enatcapone administered in combination with levodopa/carbidopa has not been evaluated.

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