Entacapone teva

Overdose

The post-marketing data include isolated cases of overdose in which the reported highest daily dose of entacapone has been 16,000 mg. The acute symptoms and signs in these cases of overdose included confusion, decreased activity, somnolence, hypotonia, skin discolouration and urticaria. Management of acute overdose is symptomatic.

The postmarketing data include several cases of overdose. The highest reported dose of entacapone was at least 40,000 mg. The acute symptoms and signs commonly seen in these cases included somnolence and decreased activity, states related to depressed level of consciousness (e.g., coma, confusion and disorientation) and discolorations of skin, tongue, and urine, as well as restlessness, agitation, and aggression.

COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of Comtan (entacapone) may theoretically produce a 100% inhibition of the COMT enzyme in humans, thereby preventing the metabolism of endogenous and exogenous catechols.

The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with levodopa and carbidopa for 14 days in 15 Parkinson’s disease patients, and in another study as 800 mg three times daily for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 mcg per mL (at 45 minutes, compared to 1.0 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 minutes). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg Comtan have been administered as 200 mg 10 times daily with levodopa and carbidopa or levodopa and benserazide for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1,600 mg is limited.

The range of lethal plasma concentrations of entacapone based on animal data was 80 mcg per mL to 130 mcg per mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses.

Management of Comtan overdose is symptomatic; there is no known antidote to Comtan. Hospitalization is advised, and general supportive care is indicated. There is no experience with hemodialysis or hemoperfusion, but these procedures are unlikely to be of benefit, because Comtan is highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of Comtan by decreasing its absorption and reabsorption from the gastrointestinal (GI) tract. The adequacy of the respiratory and circulatory systems should be carefully monitored and appropriate supportive measures employed. The possibility of drug interactions, especially with catechol-structured drugs, should be borne in mind.

Contraindications

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- Hepatic impairment.

- Phaeochromocytoma.

- Concomitant use of entacapone and non-selective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine).

- Concomitant use of a selective MAO-A inhibitor plus a selective MAO-B inhibitor and entacapone.

- A previous history of neuroleptic malignant syndrome (NMS) and/or non-traumatic rhabdomyolysis.

Comtan is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Incompatibilities

Not applicable.

Pharmaceutical form

Undesirable effects

Summary of the safety profile

The most frequent adverse reactions caused by entacapone relate to the increased dopaminergic activity and occur most commonly at the beginning of treatment. Reduction of levodopa dosage decreases the severity and frequency of these reactions. The other major class of adverse reactions are gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipation and diarrhoea. Urine may be discoloured reddish-brown by entacapone, but this is a harmless phenomenon.

Usually the adverse reactions caused by entacapone are mild to moderate. In clinical studies the most common adverse reactions leading to discontinuation of entacapone treatment have been gastrointestinal symptoms (e.g. diarrhoea, 2.5%) and increased dopaminergic adverse reactions of levodopa (e.g. dyskinesias, 1.7%).

Dyskinesias (27%), nausea (11%), diarrhoea (8%), abdominal pain (7%) and dry mouth (4.2%) were reported significantly more often with entacapone than with placebo in pooled data from clinical studies involving 406 patients taking the medicinal product and 296 patients taking placebo.

Some of the adverse reactions, such as dyskinesia, nausea, and abdominal pain, may be more common with the higher doses (1,400 to 2,000 mg per day) than with the lower doses of entacapone.

Tabulated list of adverse reactions

The following adverse reactions, listed below in Table 1, have been accumulated both from clinical studies with entacapone and since the introduction of entacapone into the market.

Table 1. Adverse drug reactions*

* Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data, since no valid estimate can be derived from clinical trials or epidemiological studies).

** The incidence rates of myocardial infarction and other ischaemic heart disease events (0.43% and 1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2,082 patients with end-of-dose motor fluctuations receiving entacapone.

Description of selected adverse reactions

Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.

Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments such as Entacapone Teva in association with levodopa.

Isolated cases of NMS have been reported following abrupt reduction or discontinuation of entacapone and other dopaminergic treatments.

Isolated cases of rhabdomyolysis have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie e-mail: [email protected]

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

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 Comtan 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 Comtan 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%).

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 Comtan group, compared to placebo. In these studies, either Comtan 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 Comtan Group and Greater Than Placebo

No differences were noted in the rate of adverse events attributable to entacapone by age or gender.

The following spontaneous reports of adverse events temporally associated with Comtan 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 Comtan exposure.

Hepatitis with mainly cholestatic features has been reported.

Entacapone Teva price

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies, anaemia most likely due to iron chelating properties of entacapone was observed. Regarding reproduction toxicity, decreased foetal weight and a slightly delayed bone development were noticed in rabbits at systemic exposure levels in the therapeutic range.

Therapeutic indications

Entacapone is indicated as an adjunct to standard preparations of levodopa/benserazide or levodopa/carbidopa for use in adult patients with Parkinson's disease and end-of-dose motor fluctuations, who cannot be stabilised on those combinations.

Comtan is 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).

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

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: other dopaminergic agents, ATC code: N04BX02.

Entacapone belongs to a new therapeutic class, catechol-O-methyl transferase (COMT) inhibitors. It is a reversible, specific, and mainly peripherally acting COMT inhibitor designed for concomitant administration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to 3-O-methyldopa (3-OMD) by inhibiting the COMT enzyme. This leads to a higher levodopa AUC. The amount of levodopa available to the brain is increased. Entacapone thus prolongs the clinical response to levodopa.

Entacapone inhibits the COMT enzyme mainly in peripheral tissues. COMT inhibition in red blood cells closely follows the plasma concentrations of entacapone, thus clearly indicating the reversible nature of COMT inhibition.

Clinical studies

In two phase III double-blind studies in a total of 376 patients with Parkinson's disease and end-of-dose motor fluctuations, entacapone or placebo was given with each levodopa/dopa decarboxylase inhibitor dose. The results are given in Table 2. In study I, daily ON time (hours) was measured from home diaries and in study II, the proportion of daily ON time.

Table 2. Daily ON time (Mean ±SD)

There were corresponding decreases in OFF time.

The % change from baseline in OFF time was -24% in the entacapone group and 0% in the placebo group in study I. The corresponding figures in study II were -18% and -5%.

Pharmacokinetic properties

General characteristics of the active substance

Absorption

There are large intra- and interindividual variations in the absorption of entacapone.

The peak concentration (Cmax) in plasma is usually reached about one hour after ingestion of a 200 mg entacapone tablet. The substance is subject to extensive first-pass metabolism. The bioavailability of entacapone is about 35% after an oral dose. Food does not affect the absorption of entacapone to any significant extent.

Distribution

After absorption from the gastrointestinal tract, entacapone is rapidly distributed to the peripheral tissues with a distribution volume of 20 litres at steady state (Vdss). Approximately 92 % of the dose is eliminated during ß-phase with a short elimination half-life of 30 minutes. The total clearance of entacapone is about 800 ml/min.

Entacapone is extensively bound to plasma proteins, mainly to albumin. In human plasma the unbound fraction is about 2.0% in the therapeutic concentration range. At therapeutic concentrations, entacapone does not displace other extensively bound substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations.

Biotransformation

A small amount of entacapone, the (E)-isomer, is converted to its (Z)-isomer. The (E)-isomer accounts for 95% of the AUC of entacapone. The (Z)-isomer and traces of other metabolites account for the remaining 5%.

Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC50 4 µM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19).

Elimination

The elimination of entacapone occurs mainly by non-renal metabolic routes. It is estimated that 80-90% of the dose is excreted in faeces, although this has not been confirmed in man. Approximately 10-20% is excreted in urine. Only traces of entacapone are found unchanged in urine. The major part (95%) of the product excreted in urine is conjugated with glucuronic acid. Of the metabolites found in urine only about 1% have been formed through oxidation.

Characteristics in patients

The pharmacokinetic properties of entacapone are similar in both young people and elderly. The metabolism of the medicinal product is slowed in patients with mild to moderate liver insufficiency (Child-Pugh Class A and B), which leads to an increased plasma concentration of entacapone in both the absorption and elimination phases. Renal impairment does not affect the pharmacokinetics of entacapone. However, a longer dosing interval may be considered for patients who are receiving dialysis therapy.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease.

NMS, including rhabdomyolysis and hyperthermia, is characterised by motor symptoms (rigidity, myoclonus, tremor), mental status changes (e.g. agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase. In individual cases, only some of these symptoms and/or findings may be evident.

Neither NMS nor rhabdomyolysis have been reported in association with entacapone treatment from controlled trials in which entacapone was discontinued abruptly. Since the introduction into the market, isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic medicinal products. When considered necessary, withdrawal of entacapone and other dopaminergic treatment should proceed slowly, and if signs and/or symptoms occur despite a slow withdrawal of entacapone, an increase in levodopa dosage may be necessary.

Entacapone therapy should be administered cautiously to patients with ischaemic heart disease.

Because of its mechanism of action, entacapone may interfere with the metabolism of medicinal products containing a catechol group and potentiate their action.).

Entacapone is always given as an adjunct to levodopa treatment.). To reduce levodopa-related dopaminergic adverse reactions, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating entacapone treatment, according to the clinical condition of the patient.

Entacapone may aggravate levodopa-induced orthostatic hypotension. Entacapone should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension.

In clinical studies, undesirable dopaminergic effects, e.g. dyskinesia, were more common in patients who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine compared to those who received placebo with this combination. The doses of other antiparkinsonian medicinal products may need to be adjusted when entacapone treatment is initiated.

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For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, the medicinal product should be discontinued and appropriate medical therapy and investigations considered.

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments such as Entacapone Teva in association with levodopa. Review of treatment is recommended if such symptoms develop.

For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered.

Entacapone Teva contains soya lecithin. Patients who are hypersensitive to peanut or soya, should not use this medicinal product.

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 Comtan (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 Comtan and a non-selective MAO inhibitor.

Entacapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline).

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.

Patients with Parkinson's disease treated with Comtan, 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 Comtan, 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 (Comtan 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 Comtan. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with Comtan.

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

Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. In controlled studies, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in both treatment groups who had an episode of documented hypotension.

Dopaminergic therapy in patients with Parkinson's disease has been associated with hallucinations. In clinical studies, hallucinations led to drug discontinuation and premature withdrawal in 0.8% and 0% of patients treated with 200 mg 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. Agitation occurred in 1% of patients treated with COMTAN and 0% treated with placebo.

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during Comtan treatment or after starting or increasing the dose of Comtan. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. Abnormal thinking and behavior can cause paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Psychotic-like behaviors were also observed during the clinical development of Comtan.

Patients with a major psychotic disorder should ordinarily not be treated with Comtan because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Comtan.

Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are used for the treatment of Parkinson's disease and that increase central dopaminergic tone, including Comtan taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with entacapone. Physicians should consider dose reduction or stopping Comtan if a patient develops such urges while taking Comtan.

In clinical studies, diarrhea developed in 60 of 603 (10%) and 16 of 400 (4%) 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 regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of Comtan. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 weeks to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia.

Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases diarrhea has usually been moderate to severe, watery, and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when Comtan treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of Comtan but recurred after retreatment with Comtan.

If prolonged diarrhea is suspected to be related to Comtan, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered.

Comtan may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled studies continued to experience frequent dyskinesia despite a reduction in their dose of levodopa. The incidence of dyskinesia was 25% for treatment with Comtan and 15% for placebo. The incidence of study withdrawal for dyskinesia was 1.5% for 200 mg Comtan and 0.8% for placebo.

The events listed below are events associated with the use of drugs that increase dopaminergic activity.

Cases of severe rhabdomyolysis have been reported following the approval of Comtan. Although the reactions typically occurred while patients were treated with Comtan, the complicated nature of these cases makes it difficult to determine what role, if any, Comtan played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Signs and symptoms include fever, alteration of consciousness, myalgia, increased values of creatine phosphokinase (CPK) and myoglobin (see PRECAUTIONS, Other Events Reported With Dopaminergic Therapy).

Cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) characterized by elevated temperature, muscular rigidity, altered consciousness, and elevated CPK have been reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs. In most of these cases, symptoms began after abrupt discontinuation of treatment with entacapone or reduction of its dose, or after the initiation of treatment with entacapone. The complicated nature of these cases makes it difficult to determine what role, if any, Comtan may have played in their pathogenesis. No cases have been reported following the 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 the decision is made to discontinue treatment with Comtan, recommendations include monitoring the patient closely and adjusting other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering Comtan has not been systematically evaluated.

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, whether other, nonergot derived drugs (e.g., entacapone) that increase dopaminergic activity can cause them is unknown. 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 months to 17 months.

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Comtan for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

In a 1-year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1,600 mg) caused an increased incidence of nephrotoxicity in male rats 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.

Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease compared to controls (see CLINICAL PHARMACOLOGY, Pharmacokinetics of Entacapone and DOSAGE AND ADMINISTRATION).

Comtan is a chelator of iron. The impact of entacapone on the body's iron stores is unknown; however, a tendency towards decreasing serum iron concentrations was noted in clinical studies. 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 rates of anemia or decreased hemoglobin levels.

Patients with hepatic impairment should be treated with caution (see INDICATIONS, DOSAGE AND ADMINISTRATION).

Two-year carcinogenicity studies of entacapone were conducted in mice and rats. Rats were treated once-daily by oral gavage with entacapone doses of 20, 90, or 400 mg/kg. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose of entacapone. Plasma exposures (AUC) associated with this dose were approximately 20 times higher than estimated plasma exposures of humans receiving the maximum recommended daily dose (MRDD) of entacapone (1,600 mg). Mice were treated once daily by oral gavage with doses of 20, 100, or 600 mg/kg of entacapone (0.05, 0.3, and 2 times the MRDD for humans on a mg/m² basis). Because of a high incidence of premature mortality in mice receiving the highest dose of entacapone, the mouse study is not an adequate assessment of carcinogenicity. Although no treatment related tumors were observed in animals receiving the lower doses, the carcinogenic potential of entacapone has not been fully evaluated. The carcinogenic potential of entacapone administered in combination with levodopa and carbidopa has not been evaluated.

Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk 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 levodopa and carbidopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test).

Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg/kg/day (plasma AUCs 28 times those in humans receiving the MRDD of 1,600 mg). Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg/kg/day of entacapone.

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 Comtan in pregnant women. Therefore, Comtan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In animal studies, entacapone was excreted into maternal rat milk.

It is not known whether entacapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when entacapone is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established.

Effects on ability to drive and use machines

Entacapone Teva in association with levodopa may have a major influence on the ability to drive and use machines. Entacapone may, together with levodopa, cause dizziness and symptomatic orthostatism. Therefore, caution should be exercised when driving or using machines.

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 (see also section 4.4).

Dosage (Posology) and method of administration

Entacapone should only be used in combination with levodopa/benserazide or levodopa/carbidopa. The prescribing information for these levodopa preparations is applicable to their concomitant use with entacapone.

Posology

One 200 mg tablet is taken with each levodopa/dopa decarboxylase inhibitor dose. The maximum recommended dose is 200 mg ten times daily, i.e. 2,000 mg of entacapone.

Entacapone enhances the effects of levodopa. Hence, to reduce levodopa-related dopaminergic adverse reactions, e.g. dyskinesias, nausea, vomiting and hallucinations, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating entacapone treatment. The daily dose of levodopa should be reduced by about 10-30% by extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the patient.

If entacapone treatment is discontinued, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.

Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations slightly (5-10%) more than from standard levodopa/carbidopa preparations. Hence, patients who are taking standard levodopa/benserazide preparations may need a larger reduction of levodopa dose when entacapone is initiated.

Renal impairment

Renal insufficiency does not affect the pharmacokinetics of entacapone and there is no need for dose adjustment. However, for patients who are receiving dialysis therapy, a longer dosing interval may be considered.

Hepatic impairment

Elderly

No dosage adjustment of entacapone is required for elderly.

Paediatric population

The safety and efficacy of Entacapone Teva in children below age 18 have not been established. No data are available.

Method of administration

Entacapone is administered orally and simultaneously with each levodopa/carbidopa or levodopa/benserazide dose.

Entacapone can be taken with or without food.

The recommended dose of Comtan (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.

Comtan 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.)

Comtan can be combined with both the immediate and sustained-release formulations of levodopa and carbidopa.

Comtan may be taken with or without food (see CLINICAL PHARMACOLOGY).

Patients with hepatic impairment should be treated with caution. The AUC and Cmax 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).

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 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 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.

Special precautions for disposal and other handling

No special requirements for disposal.