PART IB : SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT GUTRON QUALITATIVE AND QUANTITATIVE COMPOSITION

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1 1 PART IB : SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT GUTRON QUALITATIVE AND QUANTITATIVE COMPOSITION For each tablet 2,5 mg midodrine hydrochloride. For excipients see PHARMACEUTICAL FORM Tablets White round biplanar scored tablets with bevelled edge 4. CLINICAL PARTICULARS 4.1. Therapeutic indications The treatment of severe orthostatic hypotension due to autonomic dysfunction when corrective factors have been ruled out and other forms of treatment are inadequate Posology and method of administration Initial dose: 2.5 mg three times a day. Depending on results of supine and standing blood pressure recordings, this dosage can be increased weekly up to a dose of 10 mg three times a day. This is the normal maintenance dosage. Higher dosages have not been studied. It is essential to individually adjust the dosage to achieve a correct balance between the therapeutic effects and the possible risks. No data is available regarding the use in children, elderly and in patients with impaired hepatic or renal function (See section 4.3 Contra-indications). The last daily dose should be taken at least 4 hours before bedtime in order to prevent supine hypertension (See also section 4.4 Special warnings and special precautions for use). Midodrine may be taken with food (See section 5.2 Pharmacokinetic properties) Contra-indications Hypersensitivity to the active substance or to any of the excipients. Midodrine must not be administered to patients with: hypertension, bradycardia, urinary retention, ischaemic heart disease, congestive heart failure, cardiac conduction disturbances, narrow angle glaucoma, serious obliterative blood vessel disease, cerebrovascular occlusions and vessel spasms, aortic aneurism, proliferative diabetic retinopathy, thyrotoxicosis, pheochromocytoma, severe renal insufficiency (creatinine clearance of less than 30 ml/min.) and serious prostate disorder Special warnings and special precautions for use Serious orthostatic hypotension: Regular monitoring of orthostatic blood pressure is necessary due to the risk of hypertension in the supine position, e.g. at night. If hypertension occurs in the supine position and does not respond to a reduction of the dosage, treatment with midodrine must be stopped. The time of administration of the drug is important in this context: Avoid administration in the evenings. The risk of hypertension during the night is reduced by elevating the head. In patients suffering from serious disturbances of the autonomous nervous system, administration of midodrine may lead to a further reduction of blood pressure in the standing position. If this is the case, further treatment with midodrine should be stopped. Caution must be observed in patients with atherosclerotic disease especially with symptoms of intestinal angina or claudication of the legs.

2 Caution is recommended in the case of patients with prostrate disorders. Use of the drug may cause urinary retention. It is advised to measure renal function before start of treatment. The medicinal product should not be used in the paediatric age group until further data are available Interactions with other medicinal products and other forms of interaction 2 - Concomitant treatment with sympathomimetics and other vasoconstrictive substances such as reserpine, guanethidine, tricyclic antidepressants, antihistamines, thyroid hormones and MAOinhibitors should be avoided as a pronounced increase in blood pressure may occur. - As with other specific α-adrenergic agonists, the effect of midodrine is blocked by α-adrenergic blockers such as prazosine and doxazosine and vice versa. - Simultaneous use of digitalis preparations is not recommended, since the bradycardia which occurs as a result of the use of midodrine is then potentiated and heart block may occur. - Midodrine may potentiate the hypertensive effects of fludrocortisone acetate. - Monitoring is recommended if midodrine is combined with other drugs that directly or indirectly reduce the heart rate Pregnancy and lactation Data on the use of Midodrine in pregnant women are inadequately available. Also the experimental research on the effects of the medication on pregnancies, foetal development, delivery and post-natal developments is inadequate. Based on the pharmacological effects of α-mimetics, which can lead to uterine contractions, use during pregnancy is not recommended. No human data is available on use during lactation. Excretion into the breast milk was confirmed in animal experiments. The therapeutic effect on the mother needs to be weighed against the risk to the infant Effects on ability to drive and use machines - No data is available with regard to this. - Based on its pharmaco-dynamic profile, the drug appears to be safe and disadvantageous effects are unlikely Undesirable effects Very common (>10%): Chills and pilo-erection (goosebumps); paresthesia and pruritus, mainly of the scalp Common (1-10%): Supine hypertension (dose-dependent effect), urinary retention, headache Uncommon (0.1-1%): Nausea/dyspepsia, urinary urgency Rare ( %): Palpitations, tachycardia, bradycardia, restlessness, excitability and irritability Very rare (<0.01%): Ventricular arrhythmia 4.9. Overdose In the event of an overdose hypertension and bradycardia (reflex-bradycardia) might be induced. Urine retention has been reported. Measures to prevent any further absorption of the drug from the gastrointestinal tract should be considered. In the event of severe hypertension an alpha-sympatholytic agent like phentolamine can counteract the alpha-1-adrenoreceptor agonist actions of the drug. The degradation product desglymidodrine is dialyzable.

3 3 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties ATC-code: C01C A17 Midodrine is the rapidly absorbed pro-drug of the pharmacologically active constituent desglymidodrine. Desglymidodrine is a sympathicomimetic with a direct and selective effect on the peripheral α1- adrenergic receptors. This α1-stimulative effect induces vasoconstriction of the venous system (reduction in the venous pool). The α-adrenergic effects of desglymidodrine are almost wholly attributable to the (-) enantiomer of desglymidodrine. After taking midodrine (as a racemic mixture present in the tablets) (+) desglymidodrine is also formed, though this contributes almost nothing to the desired effect. Desglymidodrine increases the peripheral arterial resistance, resulting in an increase of the arterial blood pressure. Only limited data is available on the longterm effects of administering midodrine. Stimulation of the α-adrenergic receptors of the bladder and the ureter increases the sphincter muscle tone. Desglymidodrine has no β-adrenergic effects Pharmacokinetic properties Absorption After oral administration, Midodrine is rapidly absorbed. The peak plasma concentrations are reached after approximately 30 minutes, and the plasma concentration of the active metabolite, desglymidodrine, peaks after approximately 1 hour. AUC and C max increase proportionally to the doses in a dosage range of mg. Administration with food increases the AUC by approximately 25%, and the C max decreases by approximately 30%. The pharmacokinetics of desglymidodrine is not affected. Distribution Midodrine and desglymidodrine bind for less than 30% to plasma proteins. Studies on animals show that desglymidodrine is distributed in the target organs. Records are made of diffusion across the bloodbrain barrier, the placenta and the human milk. Metabolism Midodrine is partially hydrolised before absorption (in the intestines), and partially after absorption (in plasma) by the separation of glycine, herewith generating the active metablolite, desglymidodrine. The elemination of desglymidodrine is primarily caused by an oxidating metabolism, followed by (paratial) conjugation. Excretion Midodrine (8%), desglymidodrine (40%), and their degradation products (55%) are excreted in the urine within 24 hours in conjugated or non-conjugated form. The plasma elimination half-life for midodrine is approximately 30 minutes, and is approximately 3 hours for desglymidodrine. Elimination of the active (- )enantiomere of desglymidodrine is slower than the elimination of the inactive (+) enantiomere Preclinical safety data Pharmacology safety studies and toxicity studies with animals did not show any indications of a safety risk for humans after repeated administration. Studies on animals are inadequate to determine the effects on the reproduction system. In carcinogenic trials in rats a heightened tumour incidence in the testicular interstitial cells was observed; the relevance of this for humans is however unclear. The results of the micro-nucleic tests in rats also show that the genotoxicity of midodrine cannot be ruled out.

4 4 6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients The Gutron 2.5, tablets 2.5 mg contain the following excipients : Magnesium stearate Talc Colloidal anhydrous silica Microcrystalline cellulose Maize starch 6.2. Incompatibilities not applicable 6.3. Shelf-life 3 years 6.4. Special precautions for storage Do not store above 25 C. Store in the original package. Keep container in the outer carton Nature and content of container Gutron 2.5, tablets 2.5 mg are packed in PVC/PVDC/aluminium strips or alternatively in brown, hydrolytic glass type III bottles with cap to cap closure. Pack sizes: Glass bottle with 100 tablets Blister with 20, 30, 50, 90 or 100 tablets Not all pack sizes may be marketed Instructions for use or handling No special requirements 7. NAME AND ADRESS OF THE MARKETING AUTHORISATION HOLDER CHRISTIAENS B.V. Nikkelstraat AE BREDA THE NETHERLANDS 8. MARKETING AUTHORISATION NUMBERS Gutron 2.5, tablets 2.5 mg is registered with number RVG DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION 30 JAN DATE OF REVISION OF THE TEXT

5 PART IB : SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT GUTRON 5 2. QUALITATIVE AND QUANTITATIVE COMPOSITION For each tablet 5 mg midodrine hydrochloride. For excipients see PHARMACEUTICAL FORM Tablets Orange round biplanar scored tablets with bevelled edge 4. CLINICAL PARTICULARS 4.1. Therapeutic indications The treatment of severe orthostatic hypotension due to autonomic dysfunction when corrective factors have been ruled out and other forms of treatment are inadequate Posology and method of administration Initial dose: 2.5 mg three times a day (Gutron 2.5, tablets 2.5 mg are also available). Depending on results of supine and standing blood pressure recordings, this dosage can be increased weekly up to a dose of 10 mg three times a day. This is the normal maintenance dosage. Higher dosages have not been studied. It is essential to individually adjust the dosage to achieve a correct balance between the therapeutic effects and the possible risks. No data is available regarding the use in children, elderly and in patients with impaired hepatic or renal function (See section 4.3 Contra-indications). The last daily dose should be taken at least 4 hours before bedtime in order to prevent supine hypertension (See also section 4.4 Special warnings and special precautions for use). Midodrine may be taken with food (See section 5.2 Pharmacokinetic properties) Contra-indications Hypersensitivity to the active substance or to any of the excipients. Midodrine must not be administered to patients with: hypertension, bradycardia, urinary retention, ischaemic heart disease, congestive heart failure, cardiac conduction disturbances, narrow angle glaucoma, serious obliterative blood vessel disease, cerebrovascular occlusions and vessel spasms, aortic aneurism, proliferative diabetic retinopathy, thyrotoxicosis, pheochromocytoma, severe renal insufficiency (creatinine clearance of less than 30 ml/min.) and serious prostate disorder Special warnings and special precautions for use Serious orthostatic hypotension: Regular monitoring of orthostatic blood pressure is necessary due to the risk of hypertension in the supine position, e.g. at night. If hypertension occurs in the supine position and does not respond to a reduction of the dosage, treatment with midodrine must be stopped. The time of administration of the drug is important in this context: Avoid administration in the evenings. The risk of hypertension during the night is reduced by elevating the head. In patients suffering from serious disturbances of the autonomous nervous system, administration of midodrine may lead to a further reduction of blood pressure in the standing position. If this is the case, further treatment with midodrine should be stopped. Caution must be observed in patients with atherosclerotic disease especially with symptoms of intestinal angina or claudication of the legs.

6 Caution is recommended in the case of patients with prostrate disorders. Use of the drug may cause urinary retention. It is advised to measure renal function before start of treatment. The medicinal product should not be used in the paediatric age group until further data are available. 4.5 Interactions with other medicinal products and other forms of interaction 6 - Concomitant treatment with sympathomimetics and other vasoconstrictive substances such as reserpine, guanethidine, tricyclic antidepressants, antihistamines, thyroid hormones and MAOinhibitors should be avoided as a pronounced increase in blood pressure may occur. - As with other specific α-adrenergic agonists, the effect of midodrine is blocked by α-adrenergic blockers such as prazosine and doxazosine and vice versa. - Simultaneous use of digitalis preparations is not recommended, since the bradycardia which occurs as a result of the use of midodrine is then potentiated and heart block may occur. - Midodrine may potentiate the hypertensive effects of fludrocortisone acetate. - Monitoring is recommended if midodrine is combined with other drugs that directly or indirectly reduce the heart rate. 4.6 Pregnancy and lactation Data on the use of Midodrine in pregnant women are inadequately available. Also the experimental research on the effects of the medication on pregnancies, foetal development, delivery and post-natal developments is inadequate. Based on the pharmacological effects of α-mimetics, which can lead to uterine contractions, use during pregnancy is not recommended. No human data is available on use during lactation. Excretion into the breast milk was confirmed in animal experiments. The therapeutic effect on the mother needs to be weighed against the risk to the infant Effects on ability to drive and use machines - No data is available with regard to this. - Based on its pharmaco-dynamic profile, the drug appears to be safe and disadvantageous effects are unlikely. 4.8 Undesirable effects Very common (>10%): Chills and pilo-erection (goosebumps); paresthesia and pruritus, mainly of the scalp Common (1-10%): Supine hypertension (dose-dependent effect), urinary retention, headache Uncommon (0.1-1%): Nausea/dyspepsia, urinary urgency Rare ( %): Palpitations, tachycardia, bradycardia, restlessness, excitability and irritability Very rare (<0.01%): Ventricular arrhythmia 4.9 Overdose In the event of an overdose hypertension and bradycardia (reflex-bradycardia) might be induced. Urine retention has been reported. Measures to prevent any further absorption of the drug from the gastrointestinal tract should be considered. In the event of severe hypertension an alpha-sympatholytic agent like phentolamine can counteract the alpha-1-adrenoreceptor agonist actions of the drug. The degradation product desglymidodrine is dialyzable.

7 7 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties ATC-code: C01C A17 Midodrine is the rapidly absorbed pro-drug of the pharmacologically active constituent desglymidodrine. Desglymidodrine is a sympathicomimetic with a direct and selective effect on the peripheral α1- adrenergic receptors. This α1-stimulative effect induces vasoconstriction of the venous system (reduction in the venous pool). The α-adrenergic effects of desglymidodrine are almost wholly attributable to the (-) enantiomer of desglymidodrine. After taking midodrine (as a racemic mixture present in the tablets) (+) desglymidodrine is also formed, though this contributes almost nothing to the desired effect. Desglymidodrine increases the peripheral arterial resistance, resulting in an increase of the arterial blood pressure. Only limited data is available on the longterm effects of administering midodrine. Stimulation of the α-adrenergic receptors of the bladder and the ureter increases the sphincter muscle tone. Desglymidodrine has no β-adrenergic effects Pharmacokinetic properties Absorption After oral administration, Midodrine is rapidly absorbed. The peak plasma concentrations are reached after approximately 30 minutes, and the plasma concentration of the active metabolite, desglymidodrine, peaks after approximately 1 hour. AUC and C max increase proportionally to the doses in a dosage range of mg. Administration with food increases the AUC by approximately 25%, and the C max decreases by approximately 30%. The pharmacokinetics of desglymidodrine is not affected. Distribution Midodrine and desglymidodrine bind for less than 30% to plasma proteins. Studies on animals show that desglymidodrine is distributed in the target organs. Records are made of diffusion across the bloodbrain barrier, the placenta and the human milk. Metabolism Midodrine is partially hydrolised before absorption (in the intestines), and partially after absorption (in plasma) by the separation of glycine, herewith generating the active metablolite, desglymidodrine. The elemination of desglymidodrine is primarily caused by an oxidating metabolism, followed by (paratial) conjugation. Excretion Midodrine (8%), desglymidodrine (40%), and their degradation products (55%) are excreted in the urine within 24 hours in conjugated or non-conjugated form. The plasma elimination half-life for midodrine is approximately 30 minutes, and is approximately 3 hours for desglymidodrine. Elimination of the active (- )enantiomere of desglymidodrine is slower than the elimination of the inactive (+) enantiomere Preclinical safety data Pharmacology safety studies and toxicity studies with animals did not show any indications of a safety risk for humans after repeated administration. Studies on animals are inadequate to determine the effects on the reproduction system. In carcinogenic trials in rats a heightened tumour incidence in the testicular interstitial cells was observed; the relevance of this for humans is however unclear. The results of the micro-nucleic tests in rats also show that genotoxicity of midodrine cannot be ruled out.

8 8 6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients The Gutron 5, tablets 5 mg contain the following excipients : Magnesium stearate Talc Colloidal anhydrous silica Microcrystalline cellulose Maize starch Orange-yellow S colouring agent (E110) 6.2. Incompatibilities not applicable 6.3. Shelf-life 3 years 6.4. Special precautions for storage Do not store above 25 C. Store in the original package. Keep container in the outer carton. 6.5 Nature and content of container Gutron 5 mg tablets are packed in PVC/PVDC/aluminium strips or alternatively in brown, hydrolytic glass type III bottles with cap to cap closure. Pack sizes: Glass bottle with 100 tablets Blister with 20, 30 or 50 tablets Not all pack sizes may be marketed. 6.6 Instructions for use or handling No special requirements 7 NAME AND ADRESS OF THE MARKETING AUTHORISATION HOLDER CHRISTIAENS B.V. Nikkelstraat AE BREDA THE NETHERLANDS 8 MARKETING AUTHORISATION NUMBERS Gutron 5, tablets 5 mg is registered with number RVG DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION 30 JAN DATE OF REVISION OF THE TEXT