Rilmenidine, FR/H/0460/001, 19.07.2016 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT <Invented name> 1 mg tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 1 mg rilmenidine in the form of rilmenidine dihydrogen phosphate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet. Round, biconvex white tablets. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Arterial Hypertension 4.2 Posology and method of administration Posology Adults The recommended dosage is 1 tablet daily, taken as a single dose in the morning. If the result is insufficient after 1 month of treatment, the dosage can be increased to 2 tablets per day, in 2 divided doses (1 tablet morning and evening) at the beginning of meals. Special patients group Due to its good clinical and biological acceptability, rilmenidine can be administered to both elderly and diabetic hypertensive patients. In patients with renal impairment, with creatinine clearance greater than 15 ml/min, no dose adjustment is necessary. The treatment may be continued indefinitely. Paediatric population This medicine is not recommended for use in children due to a lack of data on safety and efficacy (see section 4.4). Method of administration Oral use. 1 Rilmenidine, FR/H/0460/001, 19.07.2016 4.3 Contraindications This medicinal product must never be used in the following cases: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 Severe depression Severe renal impairment (creatinine clearance < 15 ml/min), as a precaution due to a lack of available research. 4.4 Special warnings and precautions for use Special warnings Never stop treatment suddenly, but gradually decrease the dosage. Precautions for use As with all antihypertensive drugs, in patients with a recent history of vascular problems (stroke, heart attack), rilmenidine must be administered under regular medical supervision. Due to the risk of rilmenidine to decrease heart rate and trigger bradycardia, initiation of treatment should be carefully considered in patients with existing bradycardia or risk factors for bradycardia (e.g. in the elderly, patients with sick sinus syndrome, AV-block, pre-existing heart failure, or any condition when heart rate is maintained by an excessive sympathetic tone). Monitoring of heart rate, particularly in the first 4 weeks of therapy is warranted in such patients. The consumption of alcohol is not recommended during treatment. This medicinal product must not generally be used if you suffer from heart failure treated by beta- blockers (see section 4.5). In patients with renal impairment, with creatinine clearance greater than 15 ml/min, no dose adjustment is necessary. Paediatric population Due to a lack of documented experience, do not prescribe to children. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use not recommended Alcohol: the sedative effect of these substances is increased by alcohol. Impaired alertness can make driving and the use of machines dangerous. Avoid alcoholic beverages and medicinal products containing alcohol. Beta-blockers used in treating heart failure: A central reduction in sympathetic tone and the vasodilator effect of central antihypertensive drugs can be harmful in cases of cardiac insufficiency treated with beta-blockers and vasodilators. Combinations that should be used with caution Baclofen: Increased risk of hypotension, particularly orthostatic. Blood pressure should be monitored and the dose of the hypertensive drug should be adapted if necessary. Beta-blockers (except Esmolol): Significant increase in blood pressure if treatment by a centrally-acting antihypertensive drug is stopped abruptly. Avoid abruptly stopping treatment by a centrally-acting antihypertensive drug. Clinical monitoring is required. Combinations to be taken into account 2 Rilmenidine, FR/H/0460/001, 19.07.2016 Alpha-blocker antihypertensive drugs: Increased antihypertensive effect, especially orthostatic hypotension. Alpha-blockers for urological purposes (except Doxazosin): Increased antihypertensive effect, especially orthostatic hypotension. Doxazosin: Increased antihypertensive effect, especially severe orthostatic hypotension. Amifostine: Increased risk of hypotension, particularly orthostatic. Impramine antidepressants: Increased risk of hypotension, particularly orthostatic. Glucocorticoids (except hydrocortisone as a replacement therapy): Reduction in the antihypertensive effect (fluid retention induced by corticosteroids) Mineralocorticoids: Reduction in the antihypertensive effect (fluid retention induced by corticosteroids) Neuroleptics: Increased risk of hypotension, especially orthostatic hypotension. Nitro and related compounds: Increased risk of hypotension, especially orthostatic hypotension. Other sedative medicines: Increase in central depression. The effect on concentration could make it dangerous to drive vehicles and operate machinery. 4.6 Fertility, pregnancy and lactation Pregnancy As with all new molecules, administration of this medicinal product should be avoided in pregnant women, although no teratogenic or embryotoxic effects were observed during experiments on animals. Breast-feeding As rilmenidine is excreted in breast milk, administration of this medicinal product is not recommended while breast-feeding. 4.7 Effects on ability to drive and use machines Double-blind placebo-controlled studies have not demonstrated any effect of rilmenidine on alertness at therapeutic doses (1 or 2 daily doses of 1 mg). In the case of higher doses or in combination with other medications likely to impair alertness, drivers and machine operators should be warned about the risk of drowsiness. 4.8 Undesirable effects Summary of the safety profile 3 Rilmenidine, FR/H/0460/001, 19.07.2016 At a 1 mg dose taken once a day, in controlled studies, the incidence of undesirable effects is comparable to that observed under placebo. At a 2 mg dose of rilmenidine a day, comparative controlled studies versus clonidine at a dose of 0.15 to 0.30 mg/day or alpha-methyldopa at a dose of 500 to 1000 mg/day, showed that the incidence of undesirable effects was significantly lower than that observed under clonidine or alpha-methyldopa. Tabulated list of adverse reactions Undesirable effects are ranked in order of decreasing frequency 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). System Organ Class Frequency Undesirable effect Psychiatric disorders Common anxiety, depression, insomnia Nervous system disorders Common somnolence Cardiac disorders Common palpitation Not known bradycardia Vascular disorders Common cold extremities Uncommon flushing, orthostatic hypotension Gastrointestinal disorders Common stomach ache, dry mouth, diarrhea, constipation Uncommon nausea Skin and subcutaneous tissue Common pruritus, rash disorders Musculoskeletal and connective Common muscle cramps tissue disorders Reproductive system and breast Common sexual dysfunction disorders General disorders and Common asthenia, fatigue on exertion, administration site conditions oedema 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 national reporting system listed in Appendix V. 4.9 Overdose No case of overdose has been reported. Predictable symptoms of overdose would be marked hypotension and impaired alertness. The recommended treatment, in addition to gastric lavage, is the use of sympathomimetics. Rilmenidine is poorly dialysable. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Imidazoline receptor agonists, ATC code: C02AC06 Mechanism of action Rilmenidine, an oxazoline compound with antihypertensive properties, acts on both medullary and peripheral vasomotor structures. Rilmenidine shows greater selectivity for imidazoline receptors than for cerebral alpha2-adrenergic receptors, distinguishing it from reference alpha2-agonists. 4 Rilmenidine, FR/H/0460/001, 19.07.2016 Rilmenidine exerts a dose-dependent antihypertensive effect in genetically hypertensive rats. Rilmenidine is not accompanied by the central neuropharmacological effects usually observed with alpha-2 agonists except at doses higher than the antihypertensive dose in animals. In particular, the central sedative effect appears to be less marked. Pharmacodynamic effects This dissociation between antihypertensive activity and neuropharmacological effects has been confirmed in man. Rilmenidine exerts a dose-dependent antihypertensive activity on systolic and diastolic blood pressures in the supine and upright positions. At therapeutic doses, 1 mg once daily or 2 mg in two divided doses, double-blind controlled studies versus placebo and comparator have demonstrated the antihypertensive efficacy of rilmenidine in mild-to-moderate hypertension. This efficacy is maintained for 24 hours and on effort. These results have been confirmed in the long term with no therapeutic escape phenomenon. At the dose of 1 mg once daily, double-blind placebo-controlled studies showed that rilmenidine did not modify alertness tests; the incidence of adverse effects