COMTESS 200mg tablets medication leaflet

Comtess 200 mg film-coated tablets

Each film-coated tablet contains 200 mg entacapone.

Each film-coated tablet contains 0.53 mg soya lecithin, and 7.9 mg sodium as a constituent of theexcipients.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Brownish-orange, oval, biconvex film-coated tablet with 'COMT' engraved on one side.

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

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 usewith entacapone.

One 200 mg tablet is taken with each levodopa/dopa decarboxylase inhibitor dose. The maximumrecommended 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 dopaminergicadverse reactions, e.g. dyskinesias, nausea, vomiting and hallucinations, it is often necessary toadjust levodopa dosage within the first days to first weeks after initiating entacapone treatment. Thedaily dose of levodopa should be reduced by about 10-30% by extending the dosing intervals and/orby 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 antiparkinsoniantreatments, especially levodopa, to achieve a sufficient level of control of the parkinsoniansymptoms.

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

Renal insufficiency does not affect the pharmacokinetics of entacapone and there is no need for doseadjustment. However, for patients who are receiving dialysis therapy, a longer dosing interval maybe considered (see section 5.2).

See section 4.3.

No dosage adjustment of entacapone is required for elderly.

The safety and efficacy of Comtess in children below age 18 have not been established. No data areavailable.

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

Entacapone can be taken with or without food (see section 5.2).

- Hypersensitivity to the active substance or to peanut or soya or to any of the excipients listedin section 6.1.

- 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 andentacapone (see section 4.5).

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

Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has beenobserved 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, autonomicdysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase. Inindividual cases, only some of these symptoms and/or findings may be evident.

Neither NMS nor rhabdomyolysis have been reported in association with entacapone treatment fromcontrolled trials in which entacapone was discontinued abruptly. Since the introduction into themarket, isolated cases of NMS have been reported, especially following abrupt reduction ordiscontinuation of entacapone and other concomitant dopaminergic medicinal products. Whenconsidered necessary, withdrawal of entacapone and other dopaminergic treatment should proceedslowly, and if signs and/or symptoms occur despite a slow withdrawal of entacapone, an increase inlevodopa 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 medicinalproducts containing a catechol group and potentiate their action. Thus, entacapone should beadministered cautiously to patients being treated with medicinal products metabolised by catechol-O-methyl transferase (COMT), e.g. rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine,dobutamine, alpha-methyldopa, and apomorphine (see also section 4.5).

Entacapone is always given as an adjunct to levodopa treatment. Hence, the precautions valid forlevodopa treatment should also be taken into account for entacapone treatment. Entacapone increasesthe bioavailability of levodopa from standard levodopa/benserazide preparations 5-10% more thanfrom standard levodopa/carbidopa preparations. Consequently, adverse dopaminergic reactions maybe more frequent when entacapone is added to levodopa/benserazide treatment (see also section 4.8).

To reduce levodopa-related dopaminergic adverse reactions, it is often necessary to adjust levodopadosage within the first days to first weeks after initiating entacapone treatment, according to theclinical condition of the patient (see sections 4.2 and 4.8).

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

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

Entacapone in association with levodopa has been associated with somnolence and episodes ofsudden sleep onset in patients with Parkinson’s disease and caution should therefore be exercisedwhen driving or operating machines (see also section 4.7).

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

Patients should be regularly monitored for the development of impulse control disorders. Patientsand carers should be made aware that behavioural symptoms of impulse control disorders includingpathological gambling, increased libido, hypersexuality, compulsive spending or buying, bingeeating and compulsive eating can occur in patients treated with dopamine agonists and/or otherdopaminergic treatments such as Comtess in association with levodopa. Review of treatment isrecommended if such symptoms develop.

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

Comtess contains soya lecithin. Patients who are hypersensitive to peanut or soya, should not usethis medicinal product.

This medicinal product contains 7.9 mg sodium per tablet. The maximum recommended daily dose(10 tablets) contains 79 mg sodium, equivalent to 4% of the WHO recommended maximum dailyintake of 2 g sodium for an adult.

No interaction of entacapone with carbidopa has been observed with the recommended treatmentschedule. Pharmacokinetic interaction with benserazide has not been studied.

In single-dose studies in healthy volunteers, no interactions were observed between entacapone andimipramine or between entacapone and moclobemide. Similarly, no interactions between entacaponeand selegiline were observed in repeated-dose studies in parkinsonian patients. However, theexperience of the clinical use of entacapone with several medicinal products, including MAO-Ainhibitors, tricyclic antidepressants, noradrenaline reuptake inhibitors such as desipramine,maprotiline and venlafaxine, and medicinal products that are metabolised by COMT (e.g. catechol-structured compounds: rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine,alpha-methyldopa, apomorphine, and paroxetine) is still limited. Caution should be exercised whenthese medicinal products are used concomitantly with entacapone (see also sections 4.3 and 4.4).

Entacapone may be used with selegiline (a selective MAO-B inhibitor), but the daily dose ofselegiline should not exceed 10 mg.

Entacapone may form chelates with iron in the gastrointestinal tract. Entacapone and ironpreparations should be taken at least 2-3 hours apart (see section 4.8).

Entacapone binds to human albumin binding site II which also binds several other medicinalproducts, including diazepam and ibuprofen. Clinical interaction studies with diazepam and non-steroidal anti-inflammatory medicinal products have not been carried out. According to in vitrostudies, significant displacement is not anticipated at therapeutic concentrations of the medicinalproducts.

Due to its affinity to cytochrome P450 2C9 in vitro (see section 5.2), entacapone may potentiallyinterfere with medicinal products with metabolism dependent on this isoenzyme, such as S-warfarin.

However, in an interaction study with healthy volunteers, entacapone did not change the plasma levelsof S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11-26%]. The INRvalues increased on average by 13% [CI90 6-19%]. Thus, control of INR is recommended whenentacapone treatment is initiated for patients receiving warfarin.

No overt teratogenic or primary foetotoxic effects were observed in animal studies in which theexposure levels of entacapone were markedly higher than the therapeutic exposure levels. As there isno experience in pregnant women, entacapone should not be used during pregnancy.

In animal studies entacapone was excreted in milk. The safety of entacapone in infants is unknown.

Women should not breast-feed during treatment with entacapone.

Comtess in association with levodopa may have a major influence on the ability to drive and usemachines. 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 somnolenceand/or sudden sleep onset episodes must be instructed to refrain from driving or engaging inactivities 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).

The most frequent adverse reactions caused by entacapone relate to the increased dopaminergicactivity and occur most commonly at the beginning of treatment. Reduction of levodopa dosagedecreases the severity and frequency of these reactions. The other major class of adverse reactionsare gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipation anddiarrhoea. Urine may be discoloured reddish-brown by entacapone, but this is a harmlessphenomenon.

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

Dyskinesias (27%), nausea (11%), diarrhoea (8%), abdominal pain (7%) and dry mouth (4.2%) werereported significantly more often with entacapone than with placebo in pooled data from clinicalstudies 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 morecommon with the higher doses (1,400 to 2,000 mg per day) than with the lower doses of entacapone.

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

Table 1. Adverse drug reactions*

Common: Insomnia, hallucinations, confusion, paroniria

Very rare: Agitation

Very common: Dyskinesia

Common: Parkinsonism aggravated, dizziness, dystonia, hyperkinesia

Cardiac disorders**

Common: Ischaemic heart disease events other than myocardialinfarction (e.g. angina pectoris)

Uncommon: Myocardial infarction

Very common: Nausea

Common: Diarrhoea, abdominal pain, dry mouth, constipation, vomiting

Very rare: Anorexia

Not known: Colitis

Rare: Hepatic function tests abnormal

Not known: Hepatitis with mainly cholestatic features (see section 4.4.)

Rare: Erythematous or maculopapular rash

Very rare: Urticaria

Not known: Skin, hair, beard and nail discolourations

Very common: Urine discoloration

Common: Fatigue, sweating increased, fall

Very rare: Weight decrease

* Adverse reactions are ranked under headings of frequency, the most frequent first, using thefollowing 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 (cannotbe estimated from the available data, since no valid estimate can be derived from clinical trialsor 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 involving2,082 patients with end-of-dose motor fluctuations receiving entacapone.

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

Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsivespending or buying, binge eating and compulsive eating can occur in patients treated with dopamineagonists and/or other dopaminergic treatments such as Comtess in association with levodopa (seesection 4.4).

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

Isolated cases of rhabdomyolysis have been reported.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Entacapone belongs to a new therapeutic class, catechol-O-methyl transferase (COMT) inhibitors. Itis a reversible, specific, and mainly peripherally acting COMT inhibitor designed for concomitantadministration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to3-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 clinicalresponse to levodopa.

Entacapone inhibits the COMT enzyme mainly in peripheral tissues. COMT inhibition in red bloodcells closely follows the plasma concentrations of entacapone, thus clearly indicating the reversiblenature 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 decarboxylaseinhibitor dose. The results are given in Table 2. In study I, daily ON time (hours) was measured fromhome diaries and in study II, the proportion of daily ON time.

Table 2. Daily ON time (Mean ±SD)

Study I: Daily On time (h)

Entacapone (n=85) Placebo (n=86) Difference

Baseline 9.3±2.2 9.2±2.5

Week 8-24 10.7±2.2 9.4±2.6 1 h 20 min(8.3%)

CI95% 45 min, 1 h 56 min

Study II: Proportion of daily On time (%)

Entacapone (n=103) Placebo (n=102) Difference

Baseline 60.0±15.2 60.8±14.0

Week 8-24 66.8±14.5 62.8±16.80 4.5% (0 h 35 min)

CI95% 0.93%, 7.97%

There were corresponding decreases in OFF time.

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

General characteristics of the active substance

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 a200 mg entacapone tablet. The substance is subject to extensive first-pass metabolism. Thebioavailability of entacapone is about 35% after an oral dose. Food does not affect the absorption ofentacapone to any significant extent.

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

Entacapone is extensively bound to plasma proteins, mainly to albumin. In human plasma theunbound 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 substancesat therapeutic or higher concentrations.

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

Data from in vitro studies using human liver microsomal preparations indicate that entacaponeinhibits cytochrome P450 2C9 (IC50 4 µM). Entacapone showed little or no inhibition of other typesof P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19) (see section4.5).

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. Approximately10-20% 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 foundin urine only about 1% have been formed through oxidation.

The pharmacokinetic properties of entacapone are similar in both young people and elderly. Themetabolism 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 boththe absorption and elimination phases (see section 4.3). Renal impairment does not affect thepharmacokinetics of entacapone. However, a longer dosing interval may be considered for patientswho are receiving dialysis therapy.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In repeated dosetoxicity studies, anaemia most likely due to iron chelating properties of entacapone was observed.

Regarding reproduction toxicity, decreased foetal weight and a slightly delayed bone developmentwere noticed in rabbits at systemic exposure levels in the therapeutic range.

Microcrystalline cellulose

Croscarmellose sodium

Povidone

Magnesium stearate

Polyvinyl alcohol, partly hydrolysed

Talc

Macrogol

Soya lecithin

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Titanium dioxide (E 171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

White high-density polyethylene (HDPE) bottles with white tamper proof polypropylene (PP)closures containing 30, 60, 100 or 175 tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

EU/1/98/082/001-003

EU/1/98/082/005

Date of first authorisation: 16 September 1998

Date of latest renewal: 3 September 2008

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.