FR/H/462/001/MR - Rilmenidine Winthrop - Day 90 texts
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
RILMENIDINE WINTHROP 1 mg, comprimé
2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains: Rilmenidine 1 mg as rilmenidine dihydrogen phosphate
Excipient(s): For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM Tablet. Round, biconvex and white tablet.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications Arterial hypertension.
4.2 Posology and method of administration
Adults The recommended dosage is 1 tablet once daily 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 laboratory acceptability, rilmenidine can be administered to elderly hypertensive patients and hypertensive diabetic patients.
In patients with renal insufficiency, with creatinine clearance greater than 15 ml/min, no dose adjustment is necessary.
The treatment must be continued indefinitely. Children This medicine is not recommended for use in children due to a lack of data on safety and efficacy (see section 4.4).
4.3 Contraindications This medicinal product must never be used in the following cases:
Hypersensitivity to the active substance rilmenidine or to any of the excipient. Severe depression Severe renal insufficiency (creatinine clearance< 15 ml/min), as a precaution due to a lack of available research
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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 antihypertensives, rilmenidine must be administered under regular medical surveillance in patients with a recent cardiovascular history (stroke, myocardial infarction). The consumption of alcohol is not recommended during treatment. This medicine should generally not be used if you suffer from heart failure treated by beta-blockers (see section 4.5). In patients with renal insufficiency, with creatinine clearance greater than 15 ml/min, no dose adjustment is necessary. Due to a lack of documented experience do not prescribe in children.
4.5. Interaction with other medicinal products and other forms of interactions 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 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.
Concomitant medications requiring certain precautions + Baclofen Increased risk of hypotension, especially orthostatic hypotension. Monitoring of blood pressure and adjustment of the dose of antihypertensive, 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.
Concomitant medications to be taken into account + Alpha-blockers (except doxazosine) Increased risk of hypotension, especially orthostatic hypotension.
+ Doxazosine Increased risk of hypotension, especially severe orthostatic hypotension.
+ Amifostine Increased risk of the antihypertensive effect.
+ Glucocorticoids (except hydrocortisone used as replacement therapy) Reduction of the antihypertensive effect (fluid retention induced by corticosteroids).
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+ Mineralocorticoid Reduction of the antihypertensive effect (fluid retention induced by corticosteroids).
+ Tricyclic antidepressants Increased risk of hypotension, especially orthostatic hypotension.
+ Neuroleptics Increased risk of hypotension, especially orthostatic hypotension.
+ Nitrate derivates Increased risk of hypotension, especially orthostatic hypotension.
+ Other sedatives Increased in central depression. The effect on concentration could make it dangerous to drive vehicles and operate machinery.
4.6 Pregnancy and lactation Pregnancy Like all new molecules, administration of this medicinal product should be avoided in pregnant women, although no teratogenic or embryotoxic effect has been observed during animal experimentations.
Lactation 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 able to impair alertness, drivers and machine operators should be warned about the risk of drowsiness.
4.8 Undesirable effects 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):
At the dose of 1 mg once daily, in controlled trials, the incidence of adverse effects was comparable to that observed with placebo. At the dose of 2 mg per day of rilmenidine, comparative controlled studies versus clonidine at the dose of 0.15 to 0.30 mg/day or alphamethyldopa at the dose of 500 to 1000 mg/day, showed that the incidence of adverse effects with rilmenidine was significantly lower than that observed with clonidine or alphamethyldopa.
Cardiac disorders Common: palpitation
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Nervous system disorders Common: somnolence Skin and subcutaneous tissue disorders Common: pruritus, rash Reproductive system and breast disorders Common: sexual dysfunction Gastrointestinal disorders Common: stomach ache, dry mouth, diarrhea, constipation Uncommon: nausea Musculoskeletal and connective tissue disorders Common: muscle cramps Psychiatric disorders Common: anxiety, depression, insomnia Vascular disorders Common: cold extremities, edema Uncommon: flushing, orthostatic hypotension General disorders and administration site conditions Common: asthenia, fatigue on exertion
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: CO2AC06.
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.
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.
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.
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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 (drowsiness, dry mouth, constipation) did not differ from that observed with placebo.
At the dose of 2 mg per day, double-blind studies versus a comparator alpha 2 agonist administered at equihypotensive doses showed that the incidence and severity of these adverse effects were significantly lower with rilmenidine.
At therapeutic doses, rilmenidine does not alter cardiac function, does not induce fluid retention and does not alter the metabolic equilibrium: Rilmenidine maintains a significant antihypertensive activity 24 hours after the dose, with reduction of total peripheral resistance without any variation of cardiac output. Contractility indices and cardiac electrophysiology are not modified. Rilmenidine preserves the adaptation to standing, particularly in the elderly, and physiological adaptation of heart rate to effort. Rilmenidine does not induce any variation of renal blood flow rate, glomerular filtration or filtration fraction and does not modify renal function. Rilmenidine does not interfere with glucose regulation including in insulin-dependent or non-insulin-dependent diabetics, and does not modify parameters of lipid metabolism.
5.2 Pharmacokinetic properties Absorption Absorption is: rapid: the peak plasma concentration, 3.5 ng/ml, is reached 1.5 to 2 hours after absorption of a single dose of 1 mg of rilmenidine. total: absolute bioavailability is 100%, with no first-pass effect; regular: interindividual variations are low and concomitant ingestion of food does not modify the bioavailable quantity; the absorption rate does not vary at recommended therapeutic doses.
Distribution Plasma protein binding is less than 10%. The volume of distribution is 5 l/kg.
Metabolism Rilmenidine is very slightly biotransformed. Metabolites are found in the urine as traces and are derived from hydrolysis or oxidation of the oxazoline ring. These metabolites have no alpha 2 agonist activity.
Elimination Rilmenidine is essentially eliminated by the kidneys: 65% of the dose administered are excreted in the unchanged form in urine. Renal clearance represents two-thirds of total clearance. The elimination half-life is 8 hours: it is not modified by the dose administered or by repeated dosing. The duration of pharmacological action is longer, as antihypertensive
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activity is significantly maintained 24 hours after the last dose in hypertensive patients treated at the dose of 1 mg once daily.
With repeated dosing, steady-state is reached by the 3rd day; plasma levels remained stable when studied over 10 days.
Long-term surveillance of plasma levels in hypertensive patients (treatment for 2 years) showed that plasma rilmenidine concentrations remained stable.
Elderly: pharmacokinetic studies in patients over the age of 70 showed an elimination half- life of 12 hours.
Hepatic insufficiency: the elimination half-life is 11 hours.
Renal insufficiency: due to its essentially renal elimination, delayed elimination is observed, proportional to the degree of renal insufficiency. In patients with severe renal insufficiency (creatinine clearance less than 15 ml/min), the elimination half-life is about 35 hours.
5.3. Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity to reproduction.
Due to low affinity of Rilmenidine to 2-adrenergic receptors, Rilmenidine is different from Clonidine and apparented substances. Therefore, there is a dissociation between sedative and antihypertensive effects of Rilmenidine.
There is no genotoxic or long-term carcinogenic studies performed in animals to assess the mutagenic and carcinogenic toxicity of Rilmenidine.
6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose, crospovidone, stearic acid, talc, colloidal anhydrous silica.
6.2 Incompatibilities Not applicable.
6.3 Shelf life 3 years.
6.4 Special precautions for storage Store below 30°C.
6.5 Nature and content of container 28, 30, 60, 90 or 100 tablets in blister packs (Aluminium/Aluminium).
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Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling No special requirements.
7. MARKETING AUTHORISATION HOLDER [to be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S) [to be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [to be completed nationally]
10. DATE OF REVISION OF THE TEXT
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LABELLING
PARTICULARS TO APPEAR ON THE OUTER AND IMMEDIATE PACKAGING
1. NAME OF THE MEDICINAL PRODUCT
RILMENIDINE WINTHROP 1 mg, tablet rilmenidine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains Rilmenidine 1mg as rilmenidine dihydrogen phosphate.
3. LIST OF EXCIPIENTS
-
4. PHARMACEUTICAL FORM AND CONTENTS tablet
28 tablets 30 tablets 60 tablets 90 tablets 100 tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP:
9. SPECIAL STORAGE CONDITIONS
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Store below 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Not applicable.
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Marketing authorization holder SANOFI-AVENTIS FRANCE 1-13, boulevard Romain Rolland 75014 Paris
Manufacturer DELPHARM BRETIGNY Usine du Petit Paris 91220 BRETIGNY SUR ORGE
12. MARKETING AUTHORISATION NUMBER(S)
Reg.No.:
13. BATCH NUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
Liste I.
15. INSTRUCTIONS ON USE
Not applicable
16. INFORMATION IN BRAILLE
RILMENIDINE WINTHROP 1 mg, tablet
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MINIMUM PARTICULARS TO APPEAR ON BLISTERS
1. NAME OF THE MEDICINAL PRODUCT
RILMENIDINE WINTHROP 1 mg, tablet rilmenidine
2. NAME OF THE MARKETING AUTHORISATION HOLDER
SANOFI-AVENTIS FRANCE
3. EXPIRY DATE
Expiry date
4. BATCH NUMBER
Batch number
5. OTHER
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PACKAGE LEAFLET: INFORMATION FOR THE USER
RILMENIDINE WINTHROP 1 mg, tablet rilmenidine
Read all of this leaflet carefully, before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
In this leaflet: 1. What RILMENIDINE WINTHROP 1 mg is and what it is used for 2. Before you take RILMENIDINE WINTHROP 1 mg 3. How to take RILMENIDINE WINTHROP 1 mg 4. Possible side effects 5. How to store RILMENIDINE WINTHROP 1 mg 6. Further information
1. WHAT RILMENIDINE WINTHROP 1 mg IS AND WHAT IT IS USED FOR
This medecine is an antihypertensive agent which acts centrally. RILMENIDINE WINTHROP 1 mg is used to treat essential hypertension (high blood pressure).
2. BEFORE YOU TAKE RILMENIDINE WINTHROP 1 mg
Do not take RILMENIDINE WINTHROP 1 mg - if you are allergic (hypersensitive) to rilmenidine or any of the other ingredients of RILMENIDINE WINTHROP 1 mg - if you suffer from severe depression - if you suffer from severe renal insufficiency
YOU SHOULD CHECK WITH YOUR DOCTOR OR PHARMACIST IF YOU ARE NOT SURE.
Take special care with RILMENIDINE WINTHROP 1 mg - Your treatment must not be interrupted suddenly, you should reduce your dose gradually. - While taking this medication you should be monitored regularly by your doctor. - Tell your doctor if you have severe kidney failure. - Avoid drinking alcohol while taking this medicine. This medicinal product must not generally be used in case of heart failure treated by beta blockers YOU SHOULD CHECK WITH YOUR DOCTOR OR PHARMACIST IF YOU ARE NOT SURE.
Taking other medicines
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Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without prescription, especially medicines containing alcohol or beta-blocker in heart.
Taking RILMENIDINE WINTHROP 1 mg with food and drink Drinking alcohol is not recommended during treatment.
Pregnancy and breast-feeding If you are pregnant or breast-feeding you should avoid taking RILMENIDINE WINTHROP. Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines There is a potential risk of drowsiness when using this medicine. Be very careful. Do not drive without the advice from your doctor or pharmacist.
3. HOW TO TAKE RILMENIDINE WINTHROP 1 mg
Dosage Always take RILMENIDINE WINTHROP 1 mg exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. The recommended dosage is 1 tablet once daily 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. In patients with renal insufficiency, with creatinine clearance greater than 15 ml/min, the dosage generally does not need to be modified. This medecine is not intended for the treatment of children due to the lack efficacy and safety data. If you feel that the effect of RILMENIDINE WINTHROP 1 mg, tablet is too strong or too weak, ask your doctor or pharmacist for advice.
ALWAYS TAKE RILMENIDINE WINTHROP 1 MG, TABLET EXACTLY AS YOUR DOCTOR HAS TOLD YOU
Method of administration Oral route. -Your tablets should be swallowed whole with a glass of water.
Duration of treatment Treatment should be long-term.
If you take more RILMENIDINE WINTHROP 1 mg, tablet that you should: Ask your doctor or pharmacist for advice.
If you forget to take RILMENIDINE WINTHROP 1 mg, tablet: Do not take a double dose to make up for a forgotten dose.
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4. POSSIBLE SIDE EFFECTS
Like all medicines, RILMENIDINE WINTHROP 1 mg can cause side effects, although not everybody gets them.
The following adverse effects have been observed
Frequent (affecting 1 out of 10 patients): palpitations, insomnia, drowsiness, anxiety, depressive syndrome, sexual problems, stomach pains, dry mouth, diarrhoea, constipation, rash, itching sensations, cramps, cold extremities (hands and/or feet), oedema, tiredness, fatigue on exertion.
Infrequently (affecting 1 to 10 out of every 1000 patients): hot flushes, nausea, drop in blood pressure when standing up, sometimes accompanied by dizziness.
If any of the side effects persists, tell your doctor.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
5. HOW TO STORE RILMENIDINE WINTHROP 1 mg
Keep out of the reach and sight of children. Do not use RILMENIDINE WINTHROP 1 mg after the expiry date which is stated on the package. The expiry date refers to the last day of that month. Store below 30°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What RILMENIDINE WINTHROP 1 mg contains
The active substance is: Rilmenidine ...... 1 mg As rilmenidine dihydrogen phosphate For one tablet.
The other ingredients are microcrystalline cellulose, crospovidone, stearic acid, talc, colloidal anhydrous silica.
What RILMENIDINE WINTHROP 1 mg looks like and contents of the pack
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28, 30, 60, 90 or 100 tablets in blister packs. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer To be completed nationally.
This leaflet was last approved in {MM/YYYY}.
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