KIMET XL 12.5 Tablets

S (-) Metoprolol Succinate Prolonged-Release Tablets

KIMET XL®-12.5

Each prolonged-release film-coated tablet contains:

S (-) Metoprolol Succinate 11.875 mg

equivalent to S (-) Metoprolol Tartrate 12.50 mg

Colour: Titanium Dioxide IP

KIMET XL®-25

Each prolonged-release film-coated tablet contains:

S (-) Metoprolol Succinate 23.75 mg

equivalent to S (-) Metoprolol Tartrate 25 mg

Colour: Titanium Dioxide IP

KIMET XL®-50

Each prolonged-release film-coated tablet contains

S (-) Metoprolol Succinate 47.50 mg

equivalent to S (-) Metoprolol Tartrate 50 mg

Colour: Titanium Dioxide IP

Tablets, 12.5 mg, 25 mg, 50 mg

4.1 Therapeutic indication

KIMET XL® tablets are indicated for the treatment of hypertension and angina pectoris.

KIMET XL® tablets are also used for the treatment of functional heart disorders, migraine prophylaxis, cardiac arrhythmias, prevention of cardiac death and re-infarction after the acute phase of myocardial infarction stable symptomatic CHF.

4.2 Posology and method of administration

One KIMET XL® tablet daily treatment is preferably taken in the morning. The dosage of KIMET XL® tablets should be individualized.

Hypertension: The usual initial dosage of KIMET XL® is 12.5 to 50 mg daily in a single dose alone or combined with other antihypertensive agents. A further reduction in blood pressure may be achieved if S (-) Metoprolol is used in conjunction with an antihypertensive diuretic or other hypotensive agent.

Angina Pectoris: KIMET XL® 25-50 mg twice or three times daily. In general, a significant improvement in exercise tolerance and reduction of anginal attacks may be expected with a dose of 25-50 mg twice daily.

Cardiac Arrhythmias: KIMET XL® dosage of 25 mg two or three times daily is usually sufficient. If necessary, the dose can be increased up to 150 mg per day and administered in divided doses.

Myocardial infarction: Early intervention: 25 mg every 6 hours for 48 hours, preferably within 12 hours of the onset of chest pain. Maintenance: The usual maintenance dose of KIMET XL® is 100 mg daily given in divided doses. The treatment should be continued for at least 3 months.

Prophylaxis of migraine: KIMET XL® dosage of 50-100 mg daily, given in divided doses (morning and evening).

Stable heart failure, function class II and III: A recommended initial dosage of KIMET XL® for the first two weeks is 12.5 mg once daily. In patients with more severe heart failure, the starting dose is 6.25mg once daily. After two weeks, the dosage can be doubled every second week upto the dosage tolerated by the patient. The target dose for long-term treatment is 100 mg once daily.

4.3 Contraindications

Hypersensitivity to the active substances, to related derivatives or to any of the excipients. KIMET XL® is contraindicated in

• Severe asthma or history of severe bronchospasm.
• Atrioventricular block of second or third degree.
• Uncontrolled heart failure.
• Clinically relevant sinus bradycardia.
• Sick-sinus syndrome.
• Severe peripheral arterial disease.
• Cardiogenic shock.
• Hypotension.
• Untreated phaeochromocytoma.
• Metabolic acidosis.

KIMET XL® is also contraindicated when myocardial infarction is complicated by significant bradycardia, first-degree heart block, systolic hypotension (less than 100 mmHg) and/or severe heart failure.

4.4 Special warnings and precautions for use

Special warnings

Cardiac Failure: In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, KIMET XL® should be administered cautiously as β blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure.

In Patients without a History of Cardiac Failure: Continued depression of the myocardium with β-blocking agents over a period of time can, in some cases, lead to cardiac failure.

Ischemic Heart Disease: Following abrupt cessation of therapy with certain β-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction has occurred. When discontinuing chronically administered KIMET XL®, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored.

Bronchospastic Diseases: Patients with bronchospastic diseases should, in general, not receive β blockers, including KIMET XL®. Because of its relative β1 selectivity, however, KIMET XL may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since β1 selectivity is not absolute, a β2-stimulating agent should be administered concomitantly, and the lowest possible dose of KIMET XL® should be used. In these circumstances it would be prudent initially to administer KIMET XL® in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval.

Major Surgery: Chronically administered β-blocking therapy should not be routinely withdrawn prior to major surgery.

Diabetes and Hypoglycemia: β blockers may mask tachycardia occurring with hypoglycemia.

Pheochromocytoma: If KIMET XL® is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of β blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of β-mediated vasodilatation in skeletal muscle.

Thyrotoxicosis: β-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of β blockade, which might precipitate a thyroid storm.

Bradycardia: KIMET XL® produces a decrease in sinus heart rate in most patients. Acute myocardial infarction (particularly inferior infarction) may in itself produce significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if associated with evidence of lowered cardiac output, atropine (0.25-0.5 mg) should be administered intravenously.

AV Block: KIMET XL® slows AV conduction and may produce significant first- (P-R interval≥0.26 sec), second-, or third-degree heart block. If heart block occurs, KIMET XL® should be discontinued and atropine (0.25-0.5 mg) should be administered intravenously.

Hypotension: If hypotension (systolic blood pressure ≤90 mmHg) occurs, KIMET XL® should be discontinued, and the hemodynamic status of the patient and the extent of myocardial damage carefully assessed.

Bronchospastic Diseases: Patients with bronchospastic diseases should, in general, not receive β blockers, including KIMET XL. Because of its relative β1 selectivity, KIMET XL® may be used with extreme caution in patients with bronchospastic disease.

Precautions

KIMET XL® should be used with caution in patients with impaired hepatic function.

KIMET XL® should be taken regularly and continuously as directed. It should not be discontinued without consulting the physician. Abrupt interruption of the medication is to be avoided. Sudden withdrawal of β blockade is hazardous, especially in high risk patients, and may aggravate chronic heart failure as well as increase the risk of myocardial infarction and sudden death. Any withdrawal of the product should therefore, if possible, be made gradually over at least two weeks where the dose is reduced by half in each step, down to the final dose when a 25 mg tablet is reduced to half a tablet. The final dose should be given for at least four days before discontinuation.

It is advisable (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with KIMET XL® has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking KIMET XL®.

Concomitant use of KIMET XL® with catecholamine-depleting drugs or digitalis glycosides can increase the risk of bradycardia and hypotension.

Risk of Anaphylactic Reaction: While taking β blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

General Anesthetics: Some inhalation anesthetics may enhance the cardio-depressant effect of β blockers.

CYP2D6 Inhibitors: Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of KIMET XL®. Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with KIMET XL®.

Clonidine: If a patient is treated with clonidine and KIMET XL® concurrently, and clonidine treatment is to be discontinued, KIMET XL® should be stopped several days before clonidine is withdrawn.

4.5 Drugs interactions

The effects of S (-) Metoprolol and other antihypertensive drugs on blood pressure are usually additive, and care should be taken to avoid hypotension. However, combinations of antihypertensive drugs may often be used with the benefit to improve the control of hypertension.

As beta-blockers may affect peripheral circulation, care should be exercised when drugs with similar activity, e.g. ergotamine are given concurrently.

Care should also be exercised when beta-blockers are given in combination with sympathetic ganglion-blocking agents, other beta-blockers (also in the form of eye drops), or MAO inhibitors.

Prazosin

The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker.

Clonidine

If combination treatment with clonidine is to be discontinued S (-) Metoprolol should be withdrawn several days before clonidine. This is because the hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.

Calcium channel blockers

Calcium channel blockers such as verapamil and diltiazem may potentiate the depressant effects of beta-blockers on blood pressure, heart rate, cardiac contractility and atrioventricular conduction. A calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving S (-) Metoprolol because there is a risk of cardiac arrest in this situation. Patients taking an oral calcium channel blocker of the verapamil type in combination with S (-) Metoprolol should be closely monitored.

CYP2D6 inhibitors

Potent inhibitors of this enzyme may increase the plasma concentration of S (-) Metoprolol (see section 5.2). Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.

Class I anti-arrhythmic drugs and amiodarone

Amiodarone, propafenone, and other class I anti-arrhythmic agents such as quinidine and disopyramide may potentiate the effects of beta-blockers on heart rate and atrioventricular conduction.

Nitroglycerin

Nitroglycerin may enhance the hypotensive effect of metoprolol.

Digitalis glycosides

Concurrent use of digitalis glycosides may result in excessive bradycardia and/or increase in atrioventricular conduction time.

Sympathomimetics

S (-) Metoprolol will antagonise the beta1 effects of sympathomimetic agents but should have little influence on the bronchodilator effects of beta2-agonists at normal therapeutic doses.

Insulin and oral hypoglycaemic drugs

In diabetic patients who use insulin, beta-blocker treatment may be associated with increased or prolonged hypoglycaemia. Beta-blockers may also antagonize the hypoglycaemic effects of sulfonylureas. The risk of either effect is less with a beta1-selective drug such as S (-) Metoprolol than with a non-selective beta-blocker. However, diabetic patients receiving S (-) Metoprolol should be monitored to ensure that diabetes control is maintained.

Non-steroidal anti-inflammatory drugs

Concurrent treatment with non-steroidal anti-inflammatory drugs such as indomethacin may decrease the antihypertensive effect of metoprolol.

Lignocaine

S (-) Metoprolol may impair the elimination of lignocaine.

General anaesthetics

Some inhalation anaesthetics may enhance the cardio-depressant effect of beta-blockers.

Hepatic enzyme inducers/inhibitors

Enzyme-inducing agents (e.g. rifampicin) may reduce plasma concentrations of metoprolol, whereas enzyme inhibitors (e.g. cimetidine) may increase plasma concentrations.

Alcohol

During concomitant ingestion of alcohol and metoprolol, the concentration of blood alcohol may reach higher levels and may decrease more slowly.

4.6 Use in special populations

S(-)Metoprolol should not be used in pregnancy or lactation unless it is considered that the benefit outweighs the possible risk to the fetus/infant.

If S(-)Metoprolol is used during pregnancy and lactation special attention should be paid to the fetus, neonate and breastfed infant for undesirable effects of the drug's beta-blocking action (e.g. bradycardia, hypoglycemia). The lowest possible dose should be used, and treatment should be discontinued at least 2 to 3 days before delivery to avoid increased uterine contractility and the effects of beta-blockade in the newborn baby.

Pregnancy

Beta-blockers reduce placental perfusion which may result in intrauterine fetal death, and immature and premature deliveries.

S(-)Metoprolol has, however, been used in pregnancy-associated hypertension under close supervision after 20 weeks gestation. Although the drug crosses the placental barrier and is present in cord blood no evidence of fetal abnormalities has been reported. Animal experiments have shown neither teratogenic potential nor other adverse events on the embryo and/or fetus relevant to the safety assessment of the product.

Breast-feeding

The amount of S(-)Metoprolol ingested via breast milk seems to be negligible with regard to its beta-blocking effects if the mother is treated in doses within the therapeutic range.

4.7 Effects on ability to drive and use machines

As with all beta-blockers, S(-)Metoprolol may affect patients' ability to drive and operate machinery. Patients should be warned accordingly.

4.8 Undesirable effects

Adverse reactions have been ranked under headings of 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.

Post-marketing experience

The following adverse reactions have been reported during post-approval use of S(-)Metoprolol: a confusional state, an increase in blood triglycerides and a decrease in high-density lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

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 email to: medico@zuventus.com

4.9 Overdose

Symptoms

In more severe cases an overdosage of S(-)Metoprolol may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, convulsions, nausea, vomiting, cyanosis, hypoglycaemia and occasionally hyperkalaemia.

Management

Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate. Even apparently well patients who have taken a small overdose should be closely observed for signs of poisoning for at least 4 hours. In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage (if within 4 hours after ingestion of metoprolol) and/or activated charcoal to remove the drug from the gastrointestinal tract. S (-) Metoprolol cannot be effectively removed by haemodialysis.

Atropine may be given intravenously to control significant bradycardia. Intravenous beta-agonists such as prenalterol or isoprenaline should be used to treat bradycardia and hypotension; very high doses may be needed to overcome the beta blockade. Dopamine, dobutamine or noradrenaline may be given to maintain blood pressure. Glucagon has positive inotropic and chronotropic effects on the heart that are independent of beta-adrenergic receptors and has proved effective in the treatment of resistant hypotension and heart failure associated with beta-blocker overdose.

5.1 Mechanism of Action

S(-)Metoprolol has a relatively greater blocking effect on beta1-receptors (i.e. those mediating adrenergic stimulation of heart rate and contractility and release of free fatty acids from fat stores) than on beta2-receptors which are chiefly involved in broncho and vasodilation. It has no membrane-stabilizing effect nor partial agonist (intrinsic sympathomimetic) activity.

The stimulant effect of catecholamines on the heart is reduced or inhibited by S(-)Metoprolol. This leads to a decrease in heart rate, cardiac contractility, and cardiac output.

5.2 Pharmacodynamic properties

S (-) Metoprolol is a selective β1 adrenergic receptor blocker. It has a preferential effect on β1 receptors, chiefly located in the cardiac muscle. This preferential effect is however not absolute, and at higher doses, S (-) Metoprolol also inhibits β2 receptors which are abundantly present in the bronchial and vascular musculature. S (-) Metoprolol has no intrinsic sympathomimetic activity and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for β-blockade.

The antihypertensive effects of β blocking agents may be attributed to

i) Competitive antagonism of catecholamines at peripheral (cardiac) adrenergic neuron sites, leading to decreased cardiac output; ii) A central effect leading to reduced sympathetic outflow to the periphery; and iii) Suppression of renin activity.

S (-) Metoprolol has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at doses of 100-400 mg daily.

In addition, S (-) Metoprolol reduces the oxygen requirements of the heart at any given level of effort by blocking catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and in blood pressure, thus making it useful in the long-term management of angina pectoris.

S (-) Metoprolol administered two or four times daily, has been shown to be an effective anti-anginal agent, reducing the number of angina attacks and increasing exercise tolerance.

5.3 Pharmacokinetic properties

Absorption

S (-) Metoprolol is well absorbed after oral administration, peak plasma concentrations occurring 1.5 - 2 hours after dosing. The bioavailability of a single dose is approximately 50%, increasing to approximately 70% during repeated administration. The bioavailability also increases if S (-) Metoprolol is given with food.

Distribution

Approximately 10% of S (-) Metoprolol in plasma is protein bound. S (-) Metoprolol crosses the placenta and is found in breast milk.

S (-) Metoprolol is extensively metabolized by enzymes of the cytochrome P450 system in the liver. The oxidative metabolism of S (-) Metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% of Orientals are PMs.

CYP2D6 poor metabolizers exhibit several-fold higher plasma concentrations of S (-) Metoprolol than extensive metabolizers with normal CYP2D6 activity. None of the metabolites of S (-) Metoprolol contribute significantly to its beta-blocking effect.

Elimination

Elimination is mainly by hepatic metabolism and the average elimination half-life is 3.5 hours (range 1 to 9 hours). Rates of metabolism vary between individuals, with poor metabolizers (approximately 10%) showing higher plasma concentrations and slower elimination than extensive metabolizers. Within individuals, however, plasma concentrations are stable and reproducible.

6.1 Animal Toxicology or Pharmacology

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60 kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug-related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21­month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor. All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative. No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient.

S(-)Metoprolol, is a beta 1-selective (cardioselective) adrenoceptor-blocking agent, for oral administration, available as prolonged-release tablets. Metoprolol succinate prolonged-release tablet has been formulated to provide a controlled and predictable release of S(-)Metoprolol for once-daily administration.

The tablets contain 11.875, 23.75, and 47.5 mg of S(-)Metoprolol succinate equivalent to 12.5, 25, and 50 mg of S(-)Metoprolol tartrate respectively. Its chemical name is (2S)-1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol. Its structural formula is: C15H25NO3

8.1 Incompatibilities

None

8.2 Shelf-life

24 Months

8.3 Packaging information

Strip of 10 tablets

8.4 Storage and handing instructions

The medical product does not require any special storage conditions

Heart failure patients should be advised if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.

Advise patients if a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue metoprolol succinate extended-release capsules without consulting the physician.

Advise patients

(1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with metoprolol succinate extended-release capsules has been determined;

(2) to contact the physician if any difficulty in breathing occurs;

(3) to inform the physician or dentist before any type of surgery that he or she is taking metoprolol succinate extended-release capsules.

Advise patients who are breastfeeding to monitor the infant for bradycardia, dry mouth, skin or eyes, and diarrhea or constipation.