Stalevo · 4.1 Therapeutic indications · 1

HOS-093658 · has-adverse-reaction-information · PDF-Seite 8

a. Summary of the safety profile The most frequently reported adverse reactions with Stalevo are dyskinesias occurring in approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurring in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective tissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration of urine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with Stalevo or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo although no cases have been identified from the clinical trial data. b. Tabulated list of adverse reactions The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of eleven double-blind clinical trials consisting of 3 230 patients (1 810 treated with Stalevo or entacapone combined with levodopa/DDC inhibitor, and 1 420 treated with placebo combined with levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post- marketing data since the introduction of entacapone into the market for the combination use of entacapone with levodopa/DDC inhibitor. 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). Table 1. Adverse reactions 8 Blood and lymphatic system disorders Common: Anaemia Uncommon: Thrombocytopenia Metabolism and nutrition disorders Common: Weight decreased*, decreased appetite* Psychiatric disorders Common: Depression, hallucination, confusional state*, abnormal dreams*, anxiety, insomnia Uncommon: Psychosis, agitation* Not known: Suicidal behaviour, Dopamine dysregulation syndrome Nervous system disorders Very common: Dyskinesia* Common: Parkinsonism aggravated (e.g. bradykinesia)*, tremor, on and off p

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HOS-093654 · has-contraindication-information · PDF-Seite 5

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. - Severe hepatic impairment. - Narrow-angle glaucoma. - Pheochromocytoma. - Coadministration of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine). - Coadministration with a selective MAO-A inhibitor and a selective MAO-B inhibitor (see section 4.5). - A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis.

HOS-093653 · has-indication-information · PDF-Seite 3

Stalevo is indicated for the treatment of adult patients with Parkinson’s disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.

HOS-093656 · has-interaction-information · PDF-Seite 7

Other antiparkinsonian medicinal products: To date there has been no indication of interactions that would preclude concurrent use of standard antiparkinsonian medicinal products with Stalevo therapy. Entacapone in high doses may affect the absorption of carbidopa. However, no interaction with carbidopa has been observed with the recommended treatment schedule (200 mg of entacapone up to 10 times daily). Interactions between entacapone and selegiline have been investigated in repeated dose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no interaction was observed. When used with Stalevo, the daily dose of selegiline should not exceed 10 mg. Caution should be exercised when the following active substances are administered concomitantly with levodopa therapy. Antihypertensives: Symptomatic postural hypotension may occur when levodopa is added to the treatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensive agent may be required. Antidepressants: Rarely, reactions including hypertension and dyskinesia have been reported with the concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone and imipramine and between entacapone and moclobemide have been investigated in single dose studies in healthy volunteers. No pharmacodynamic interactions were observed. A significant number of Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and entacapone with several active substances 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, paroxetine). No pharmacodynamic interactions have been observed. However, caution should be exercised when these medicinal products are used concomitantly with Stalevo (see sections 4.3 and 4.4). Other active substances: Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics), phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these medicinal products with Stalevo should be carefully observed for loss of therapeutic response. Due to entacapone's affinity to cytochrome P450 2C9 in vitro (see section 5.2), Stalevo may potentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as S-warfarin. However, in an interaction stu

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HOS-093657 · has-pregnancy-information · PDF-Seite 7

Pregnancy 7 There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see section 5.3). The potential risk for humans is unknown. Stalevo should not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the foetus. Breast-feeding Levodopa is excreted in human breast milk. There is evidence that breast-feeding is suppressed during treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in the infant is not known. Women should not breast-feed during treatment with Stalevo. Fertility No adverse reactions on fertility were observed in preclinical studies with entacapone, carbidopa or levodopa alone. Fertility studies in animals have not been conducted with the combination of entacapone, levodopa and carbidopa.

HOS-093655 · has-warning-information · PDF-Seite 5

- Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions. - Stalevo therapy should be administered cautiously to patients with ischemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease, history of peptic ulcer disease or history of convulsions. - In patients with a history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias; cardiac function should be monitored with particular care during the period of initial dose adjustments. - All patients treated with Stalevo should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients with past or current psychosis should be treated with caution. - Concomitant administration of antipsychotics with dopamine receptor-blocking properties, particularly D2 receptor antagonists should be carried out with caution, and the patient carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms. - Patients with chronic wide-angle glaucoma may be treated with Stalevo with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure. - Stalevo may induce orthostatic hypotension. Therefore Stalevo should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension. - 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 section 4.7). - In clinical studies, dopaminergic adverse reactions, e.g. dyskinesia, were more common in 5  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 Stalevo treatment is substituted for a patient currently not treated with entacapone. - Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson’s disease. The

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