4.1. 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.

4.2. 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 anti-Parkinsonian 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 (see section 5.2).

Hepatic impairment

See section 4.3.

Elderly

No dosage adjustment of entacapone is required for elderly patients.

Paediatric population

The safety and efficacy of entacapone in children below 18 years of age 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 (see section 5.2).

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in 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 and entacapone (see section 4.5).

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

4.4. 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 ischemic 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. Thus, entacapone should be administered 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 for levodopa treatment should also be taken into account for entacapone treatment. Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations 5–10% more than from standard levodopa/carbidopa preparations. Consequently, adverse dopaminergic reactions may be 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 levodopa dosage within the first days to first weeks after initiating entacapone treatment, according to the clinical condition of the patient (see sections 4.2 and 4.8).

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, adverse dopaminergic reactions, 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 anti-Parkinsonian medicinal products may need to be adjusted when entacapone treatment is initiated.

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

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 drug should be discontinued and appropriate medical therapy and investigations considered.

Impulse control disorders

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 Mylan 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 Mylan 200 mg film-coated tablets contain sucrose: patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

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

In single-dose studies in healthy volunteers, no interactions were observed between entacapone and imipramine or between entacapone and moclobemide. Similarly, no interactions between entacapone and selegiline were observed in repeated-dose studies in Parkinsonian patients. However, the experience of the clinical use of entacapone with several medicinal products, including MAO-A inhibitors, tricyclic antidepressants, noradrenaline reuptake inhibitors such as desipramine, maprotiline and venlafaxine, and medicinal products that are metabolised by COMT (e.g. catechol-structured compounds: rimiterol, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-methyldopa, apomorphine, and paroxetine) is still limited. Caution should be exercised when these 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 of selegiline should not exceed 10 mg.

Entacapone may form chelates with iron in the gastrointestinal tract. Entacapone and iron preparations 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 medicinal products, including diazepam and ibuprofen. Clinical interaction studies with diazepam and non-steroidal anti-inflammatory medicinal products have not been carried out. According to in vitro studies, significant displacement is not anticipated at therapeutic concentrations of the medicinal products.

Due to its affinity to cytochrome P450 2C9 in vitro (see section 5.2), entacapone may potentially interfere with medicinal products with metabolism 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

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.

4.7. Effects on ability to drive and use machines

Entacapone Mylan in association with levodopa may have 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).

4.8. Undesirable effects

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.

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).

The following adverse drug reactions have been accumulated both from clinical studies with entacapone and since the introduction of entacapone into the market.

Psychiatric disorders

Common

Insomnia, hallucinations, confusion, paroniria

Very rare

Agitation

Nervous system disorders

Very common

Dyskinesia

Common

Parkinsonism aggravated, dizziness, dystonia, hyperkinesia

Cardiac disorders*

Common

Ischemic heart disease events other than myocardial infarction (e.g. angina pectoris)

Uncommon

Myocardial infarction

Gastrointestinal disorders

Very common

Nausea

Common

Diarrhoea, abdominal pain, dry mouth, constipation, vomiting

Very rare

Anorexia

Not known

Colitis

Hepatobiliary disorders

Rare

Hepatic function tests abnormal

Not known

Hepatitis with mainly cholestatic features (see section 4.4)

Skin and subcutaneous tissue disorders

Rare

Erythematous or maculopapular rash

Very rare

Urticaria

Not known

Skin, hair, beard and nail discolorations

Renal and urinary disorders

Very common

Urine discoloration

General disorders and administration site conditions

Common

Fatigue, sweating increased, fall

Very rare

Weight decrease

* The incidence rates of myocardial infarction and other ischemic heart disease events (0.43% and 1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2082 patients with end-of-dose motor fluctuations receiving entacapone.

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 Mylan in association with levodopa (see Section 4.4).

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 the Yellow Card Scheme website www.mhra.gov.uk/yellowcard.

4.9. 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.