SUMMARY OF PRODUCT CHARACTERISTICS. for. / /, prolonged-release tablets mg metoprolol succinate equivalent to 25 mg metoprolol tartrate.

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS for / /, prolonged-release tablets 1. NAME OF THE MEDICINAL PRODUCT / / 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each prolonged-release tablet contains mg metoprolol succinate equivalent to 25 mg metoprolol tartrate mg metoprolol succinate equivalent to 50 mg metoprolol tartrate. 95 mg metoprolol succinate equivalent to 100 mg metoprolol tartrate. 190 mg metoprolol succinate equivalent to 200 mg metoprolol tartrate. For the full list of excipients, see section PHARMACEUTICAL FORM Prolonged-release tablets mg: White, oval biconvex approx. 9 x 5 mm film-coated tablets scored on both sides 47.5 mg: White, oval biconvex approx. 11 x 6 mm film-coated tablets scored on both sides 95 mg: White, oval biconvex approx. 16 x 8 mm film-coated tablets scored on both sides 190 mg: White, oval biconvex approx. 19 x 10 mm film-coated tablets scored on both sides. The tablet can be divided into equal doses. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Hypertension. Angina pectoris. Heart arrhythmia, particularly supraventricular tachycardia. Prophylaxis to prevent cardiac death and reinfarction after the acute phase

2 of myocardial infarction. Palpitations in the absence of organic heart diseases. Prophylaxis against migraine. Stabile, symptom-producing heart failure (NYHA II-IV, left ventricular ejection fraction < 40 %), combined with other heart failure therapies (see section 5.1). 4.2 Posology and method of administration Metoprolol succinate tablets should be taken once daily, it is recommended to take the tablet in the morning. The tablets must be swallowed whole or divided. They must not be chewed or crushed. The tablets should be taken with water (at least half a glass). The dose may be adjusted in accordance with the following guidelines: Hypertension: 47.5 mg metoprolol succinate (equivalent to 50 mg metoprolol tartrate) once daily for patients with mild to moderate hypertension. If necessary, the dose may be increased to mg metoprolol succinate (equivalent to mg metoprolol tartrate) daily, or another antihypertensive agent may be added to the treatment regimen. Angina pectoris: mg metoprolol succinate (equivalent to mg metoprolol tartrate) once daily. If necessary, other medicinal products may be added to the treatment regimen for treatment of arteriosclerosis. Heart arrhythmia: mg metoprolol succinate (equivalent to mg metoprolol tartrate) once daily. Prophylaxis after myocardial infarction: 190 mg metoprolol succinate (equivalent to 200 mg metoprolol tartrate) once daily. Palpitations due to functional heart diseases: 95 mg metoprolol succinate (equivalent to 100 mg metoprolol tartrate) once daily. If necessary, the dose may be increased to 190 mg metoprolol succinate (equivalent to 200 mg metoprolol tartrate). Prophylaxis against migraine: mg metoprolol succinate (equivalent to mg metoprolol tartrate) once daily. Stable, symptom-producing heart failure: The metoprolol succinate dose is determined individually for patients with stable, symptom-producing heart failure regulated by other treatment against heart failure. The recommended initial dose for NYHA III-IV patients is mg metoprolol succinate (equivalent to 12.5 mg metoprolol tartrate) once daily for the first week. The dose may possibly be increased to mg metoprolol

3 succinate (equivalent to 25 mg metoprolol tartrate) daily for the second week. The recommended initial dose for NYHA II patients is mg metoprolol succinate (equivalent to 25 mg metoprolol tartrate) once daily for the first two weeks. It is recommended to double the dose after the first two weeks. The dose should be increased every second week up to 190 mg metoprolol succinate (equivalent to 200 mg metoprolol tartrate) daily or until the maximum tolerated dose is reached. For long-term treatment, the target dose should be fixed at 190 mg metoprolol succinate (equivalent to 200 mg metoprolol tartrate) daily or until the maximum tolerated dose is reached. It is recommended that the treating doctor is familiar with treating stable, symptom-producing heart failure. After each dose increase, the patient s condition should be carefully checked. If the blood pressure drops, it may be necessary to reduce the dose of other concomitant medication. A blood pressure drop is not necessarily an impediment for long-term use of metroprolol, but the dose should be reduced until the patient s condition is stable. Impaired renal function: Dose adjustment is not required. Impaired hepatic function: In patients with severe hepatic insufficiency, e.g. when treating patients with portocaval shunt, a dose reduction should be considered (see section 5.2). Elderly: There are no adequate data from the use in patients above the age of 80. Take special precautions when increasing the dose. Children and adolescents: There is limited data on the use of metoprolol in children and adolescents. 4.3 Contraindications Metoprolol is contraindicated in case of: Hypersensitivity to metoprolol succinate, other beta blockers or to any of the excipients listed in section 6.1. Grade II or III atrioventricular block. Untreated heart failure (pulmonary oedema, reduced blood flow or hypotension) and continuous or periodic treatment increasing the heart contractility (beta receptor agonism). Manifest and clinically significant sinus bradycardia (heart frequency < 50/min.). Sick sinus syndrome. Cardiogenic shock. Severe disease of the peripheral arterial circuit. Hypotension (systolic < 90 mmhg). Metabolic acidosis. Severe bronchial asthma or chronic obstructive pulmonary disease. Concomitant use of MAO inhibitors (except from MAO-B inhibitors).

4 Metoprolol may not be administered to patients with suspected acute myocardial infarction and a heart rate of < 45 beats/min., PQ interval > 0.24 seconds or systolic blood pressure < 100 mmhg. In addition, metoprolol is contraindicated in patients with heart failure and with a systolic blood pressure which repeatedly falls below 100 mmhg (examination required before initiating treatment). Concomitant intravenous administration of calcium blockers of the type verapamil or diltiazem or other antiarrhythmics (such as disopyramide) is contraindicated (exception: intensive care unit). Untreated phaeochromocytoma. 4.4 Special warnings and precautions for use Beta blockers must be administered with caution to asthmatics. If an asthmatic uses a beta2 agonist (as tablets or by inhalation) when initiating metoprolol treatment, the dose of the beta2 agonist must be controlled and increased if necessary. Metoprolol prolonged-release tablets affect beta2 receptors to a lesser degree than regular tablet forms for beta1 selective beta blockers. Metoprolol may reduce the effect of diabetes treatment and mask the symptoms of hypoglycaemia. The risk of a carbohydrate metabolism disorder or masking of the symptoms of hypoglycaemia is lower when using metoprolol prolongedrelease tablets than when using regular tablet forms for beta1 selective beta blockers and significantly lower than when using non-selective beta blockers. AV conduction may be aggravated in rare cases in connection with metoprolol treatment (possible atrioventricular block). Metoprolol may exacerbate the symptoms of peripheral vascular due to its antihypertensive effect. When prescribing metoprolol to patients with a pheochromocytoma, an alpha blocker must be used before initiating treatment and during the metoprolol treatment. In patients with Prinzmetal s angina β1 selctive agents should be used with care. Metoprolol treatment may possibly mask the symptoms of thyrotoxicosis. Before surgery, the anaesthesiologist must be informed that the patient takes beta blockers. It is not recommended to discontinue beta blocker treatment during a surgical procedure. Beta blocker treatment must not be suddenly discontinued. If the treatment is to be discontinued, it must, where possibly, be gradually reduced over a period of at least two weeks during which the dose is gradual halved until reaching the lowest dose, which is one half prolonged-release tablet in the lowest strength,

5 i.e mg metoprolol succinate (corresponding to 12.5 mg metoprolol tartrate). The final dose should be used for at least four days before the treatment is fully discontinued. If the patient presents with any symptoms, the dose should be reduced at a lower rate. Sudden discontinuation of beta blockers may possibly exacerbate heart failure and increase the risk of myocardial infarction and sudden death. Like other beta blockers, metoprolol may also increase both the sensitivity to allergens and the severity of anaphylactic reactions. Adrenalin treatment does not always give the desired therapeutic effect in individuals receiving beta blockers (see also section 4.5). Beta blockers may trigger or exacerbate psoriasis. Up to the present, there is insufficient data from the use of metoprolol in patients with heart failure and the following accompanying factors: Unstable heart failure (NYHA IV). Acute myocardial infarction or unstable angina pectoris in the preceding 28 days. Impaired renal function. Impaired hepatic function. Patients above the age of 80. Patients under the age of 40. Haemodynamically significant valve diseases. Hypertrophic obstructive cardiomyopathy. During or after cardiac surgery within the last four months before treatment with metoprolol succinate. 4.5 Interaction with other medicinal products and other forms of interaction Pharmacodynamic interactions If sympathetic ganglion blocking substances are administered concomitantly with other beta blockers (e.g. eye drops) or MAO inhibitors, the patient s condition should be monitored carefully. If concomitant treatment with clonidine will be discontinued, the beta blocker treatment must be discontinued several days before. The patient must be monitored for every form of negative inotropic and chronotropic effects if metoprolol is administered concomitantly with calcium blockers of the type verapamil or diltiazem or with antiarrhythmics. Calcium blockers of the verapamil type should not be administered intravenously to patients receiving beta blockers. Class I antiarrhythmics: Class I antiarrhythmics and beta receptor blockers have further negative inotropic effects which may cause serious haemodynamic adverse effects in patients with reduced left ventricular function. The combination should also be avoided in case of sick sinus syndrome and pathological AV conduction. The interaction is best documented for disopyramide.

6 In patients receiving beta blockers, inhalation of anaesthetics may increase the bradycardiac effect of the beta blockers. Metoprolol can potentiate the effect of concomitantly administrated blood pressure lowering medicines. If metoprolol and noradrenalin, adrenalin or other sympathomimetics are administered concomitantly, the blood pressure can increase significantly. There may be a pronounced drop in the heart rate and the heart s conductivity in case of concomitant treatment with metoprolol and reserpine, alphamethyldopa, clonidine, guanfacine and cardiac glycosides. Patients in concomitant treatment with other beta adrenergic antagonists (e.g. timolol eye drops) must be under close medical supervision. Metoprolol succinate may mitigate the symptoms of hypoglycaemia, particularly tachycardia. Beta receptor blockers may inhibit insulin release in type II diabetics. Blood sugar should be measured regularly and the antidiabetic treatment (insulin and oral antidiabetics) should be adjusted accordingly. Concomitant use of indometacin or another inhibitor of the prostaglandin synthesis may reduce the antihypertensive effect of beta blockers. When, under certain circumstances, adrenalin is administered to a patient in treatment with beta blockers, cardio-selective beta blockers affect the blood pressure regulation significantly less than non-selective beta blockers. The effect of adrenalin in the treatment of anaphylactic reactions may be weakened in patients receiving beta blockers (see also section 4.4). Pharmacokinetic interactions Enzyme inducing or inhibiting drugs may affect the plasma concentration of metoprolol. Rifampicin lowers the plasma concentration of metoprolol, while cimetidine, alcohol and hydralazine may possibly increase the metoprolol plasma concentration. Metoprolol is metabolised primarily, but not solely, by the hepatic enzyme cytochrome (CYP) 2D6 (see also section 5.2). Substances with an inhibiting effect on CYP 2D6, e.g. selective serotonin reuptake inhibitors (SSRIs) as paroxetine, fluoxetine and sertraline, diphenhydramine, hydroxychloroquine, celecoxib, terbinafine, neuroleptics (e.g. chlorpromazine, triflupromazine, chlorprothixene) and possibly also propafenone may increase the plasma concentration of metoprolol. An inhibiting effect on CYP 2D6 for amiodarone and chinidine (antiarrhythmics) has also been reported. Clearance of other medicinal products may possibly be reduced due to metoprolol (e.g. lidocaine).

7 4.6 Fertility, pregnancy and lactation Pregnancy Since there are no well-controlled studies of the use of metoprolol in pregnant women, metoprolol may only be used during pregnancy if the benefits to the mother outweigh the risk to the embryo/foetus. Beta blockers reduce placental perfusion and may cause foetal death and premature birth. Intrauterine growth retardation has been observed after longtime treatment of pregnant women with mild to moderate hypertension. Beta blockers have been reported to cause prolonged delivery and bradycardia in the foetus and the newborn child. There are also reports of hypoglycaemia, hypotension, increased bilirubinaemia and inhibited response to anoxia in newborn children. Treatment with metoprolol should be discontinued hours before the calculated birth date. If this is not possible, the newborn child should be monitored for hours post partum for signs and symptoms of beta blocking (e.g. cardiac and pulmonary complications). Beta blockers have not indicated potential teratogenic activity in animals, but reduced blood flow in the umbilical cord, growth retardation, reduced ossification and increased numbers of foetal and post-natal deaths. Breastfeeding The concentration of metoprolol in breast milk is approximately three times higher than the one in the mother s plasma. Even though the risk of adverse effects in the breastfeeding baby would appear to be low after administration of therapeutic doses of the medicinal product (except in individuals with poor metabolic capacity), breastfeeding babies should be monitored for signs of beta blocking. 4.7 Effects on ability to drive and use machines Metoprolol succinate Actavis has negligible influence on the ability to drive and use machines. The patient should pay attention to how metoprolol affects him/her before driving a vehicle or operating machinery, as dizziness and fatigue may possibly occur during metoprolol treatment. These effects may possibly be enhanced in case of concomitant ingestion of alcohol or after changing to another medicinal product. 4.8 Undesirable effects The undesirable effects have generally been mild and transient. The undesirable effects stated below occurred in connection with clinical trials or clinical use, particularly when using metoprolol tartrate tablets. In many cases, the causal relation to metoprolol could not be confirmed. Blood and Very common ( 1/10) Common ( 1/100 and < 1/10) Uncommon ( 1/1,000 and < 1/100) Rare ( 1/10,000 and < 1/1,000) Very rare (< 1/10,000), not known (cannot be estimated from the available data) Thrombocytope

8 lymphatic system Endocrine Metabolism and nutrition Weight gain. Deterioration of latent diabetes mellitus. nia, leukopenia Psychiatric Nervous system Eye Ear and labyrinth Cardiac Vascular Pronounced blood pressure drop and orthostatic hypotension, very rarely with syncope. Dizziness, headache. Bradycardia, balance disturbances (very rarely with associated syncope), palpitations. Cold hand and feet. Depression, concentration problems, drowsiness or insomnia, nightmares. Paresthesia. Temporary exacerbation of symptoms of heart failure, first-degree atrioventricular block, precordial pain. Nervousness, anxiety. Visual disturbances, dry or irritated eyes, conjunctivitis. Functional heart symptoms, heart arrhythmia, conductivity disturbances. Forgetfulness or memory impairment, confusion, hallucinations, personality changes (e.g. mood changes). Tinnitus, hearing problems. Necrosis in patients with severe peripheral vascular prior to treatment, exacerbation of claudicatio intermittens or Raynaud s syndrome. Respiratory, thoracic and mediastinal Gastrointestinal Functional dyspnea. Nausea, abdominal pain, diarrhoea, obstipation. Bronchospasms. Vomiting. Rhinitis. Dryness of mouth. Taste disturbances. Hepatobiliary Abnormal LFT Hepatitis. values. Skin and Rash (psoriasis- Hair loss. Light

9 subcutaneous tissue Musculoskeletal and connective tissue Reproductive system and breast General and administration site conditions Fatigue. like urticaria and dystrophic cutaneous lesions), increased perspiration. Muscle spasms. Oedema. Impotence and other sexual dysfunctions, induratio penis plastica (Peyronie s syndrome). hypersensitivity reactions, exacerbation of psoriasis, new psoriasis manifestation, psoriasis-like dermatological changes. Arthralgia, muscle weakness. 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 Symptoms: An overdose of metoprolol may cause severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasms, loss of consciousness (even coma), nausea, vomiting or cyanosis. The symptoms may be exacerbated by concomitant ingestion of alcohol, antihypertensive agents, chinidine or barbiturates. The first signs of an overdose present within 20 minutes to 2 hours after taking the medicinal product. Management: Active charcoal, gastric emptying if necessary. In case of severe hypotension, bradycardia or in risk of heart failure, the patient should be given a beta1 agonist (e.g. prenalterol) intravenously at intervals of 2-5 minutes or as continuous infusion until achieving the desired effect. If a selective beta1 agonist is unavailable, dopamine may be used. Atropine sulphate may also be administered ( mg intravenously) for blocking nervus vagus. If the desired effect is not achieved, another sympathomimetic agent may be used, e.g. dobutamine or noradrenaline.

10 The patient may also be given 1-10 mg glucagon. It may be necessary to use a pacemaker. A beta2 agonist may be administered intravenously to prevent bronchospasms in the patient. Note! The doses required for managing overdoses are much higher than the therapeutic doses usually applied as the beta blocker has blocked the beta receptors. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Beta blockers, selective. ATC code: C 07 AB 02. Metoprolol is a beta1 selective beta blocker, i.e. blocking beta1 receptors in the heart at significantly lower doses than those required for blocking beta2 receptors. Metoprolol only exhibits insignificant membrane stabilising effect and has no agonist effect. Metoprolol reduces or blocks the stimulating effect of catecholamines (particularly released in case of physical or mental stress) on the heart. Metoprolol reduces tachycardia, decreases the cardiac output and the contractility, and lowers the blood pressure. The plasma concentrations and effect (beta1 blocking) of prolonged-release tablets with metoprolol succinate are more evenly distributed over a given period in a day than those obtained with traditional tablet forms with beta1 selective beta blockers. As the plasma concentrations are stable, the clinical beta1 selectivity is better than the one obtained with traditional tablet forms with beta1 selective beta blockers. The risk of undesirable effects associated with maximum concentrations is also minimal (e.g. bradycardia or limb weakness). If required, metoprolol may be administered concomitantly with a beta2 agonist to patients with symptoms of obstructive pulmonary disease. Effect on heart failure: The MERIT-HF study (3,991 NYHA II-IV patients, ejection fraction 40 %), which combined metoprolol with standard heart failure therapy, showed e.g. a reduction in overall mortality. Mortality (notwithstanding cause) in the metoprolol group was 145 (7.2 % per patient year at follow -up) against 217 (11.0 %) in the placebo group, with a relative risk of 0.66 [95 % CI ]. 5.2 Pharmacokinetic properties

11 Absorption Metoprolol is completely absorbed after an oral dose. Due to a pronounced first passage metabolism for metoprolol, the bioavailability of a single oral dose is approx. 50 %. The bioavailability of prolonged-release tablets is approx % lower than for regular tablets. Only a small fraction of metoprolol (approx %) binds to plasma proteins. Distribution Each prolonged-release tablet with metoprolol succinate contains a large number of pellets containing metoprolol succinate with controlled release. Each pellet is coated with a polymer coating which controls the metoprolol release speed. A prolonged-release tablet is quickly disintegrated, and the controlled release granulate spreads to the gastrointestinal tract where it releases metoprolol continuously over a period of 20 hours. After one daily dose, the maximum plasma concentrations of metoprolol reach approximately twice the trough levels. Biotransformation Metoprolol is metabolised by hepatic oxidation. The three known main metabolites have been shown not to have a clinically significant beta blocking effect. Metoprolol is metabolised primarily, but not solely, by the hepatic enzyme cytochrome (CYP) 2D6. Due to the polymorphy of the CYP 2D6 gene, the turnover rates vary with the individual. Individuals with poor metabolic capacity (approx. 7-8 %) exhibit higher plasma concentrations and slower elimination than individuals with good metabolic capacity. The plasma concentrations are stable and repeatable in the individuals, however. Elimination More than 95 % of an oral dose is excreted in urine. Approximately 5 % of the dose is excreted in unchanged form; in single cases up to an entire 30 %. The elimination half-life of metoprolol in plasma is 3.5 hours on average (interval 1-9 hours). Total clearance is approx. 1 L/min. The pharmacokinetics of metoprolol in the elderly is not significantly different from that in younger populations. The systemic bioavailability and elimination of metoprolol is normal in renal failure patients. The elimination of metabolites is slower than normal, however. Significant accumulation of metabolites has been observed in patients with a glomerular filtration rate of less than 5 ml/min. The metabolite accumulation does not potentiate the beta blocking action of metoprolol. Patients with hepatic cirrhosis may experience an increase in the bioavailability of metoprolol and a decline in total clearance. However, the exposure increase only has clinical relevance in patients with severely impaired hepatic function or portocaval shunt. In patients with portocaval shunt, the total clearance is approx. 0.3 L/min, and the AUC values are approx. six times larger than in healthy individuals.

12 5.3 Preclinical safety data There are no other relevant preclinical data than those already mentioned in other sections of this summary of product characteristics. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Cellulose, microcrystalline Methylcellulose Maize starch Glycerol Ethylcellulose Magnesium stearate Tablet coating: Hypromellose Cellulose, microcrystalline Stearic acid Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 36 months. 6.4 Special precautions for storage No special precautions for storage. 6.5 Nature and contents of container Blister pack (PVC-PE-PVDC/Al) Pack sizes: 10, 14, 20, 28, 30, 50, 50x1, 56, 60, 98 and 100 prolonged-release tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements for disposal. 7. MARKETING AUTHORISATION HOLDER <to be completed nationally> 8. MARKETING AUTHORISATION NUMBERS mg: 47.5 mg: 95 mg: 190 mg:

13 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: {DD month YYYY} <Date of latest renewal: {DD month YYYY}> 10. DATE OF REVISION OF THE TEXT 04/2013