Comtess · 4.4 Special warnings and precautions for use · 1

HOS-083582 · has-adverse-reaction-information · PDF-Seite 5

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 5 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* 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: Ischaemic 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

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HOS-083578 · has-contraindication-information · PDF-Seite 3

- Hypersensitivity to the active substance or to peanut or soya 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.

HOS-083577 · has-indication-information · PDF-Seite 2

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.

HOS-083580 · has-interaction-information · PDF-Seite 4

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 4 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: rimiterole, 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 with 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.

HOS-083581 · has-pregnancy-information · PDF-Seite 5

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.

HOS-083579 · has-warning-information · PDF-Seite 3

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 3 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 aggra

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