Betaloc Zok

Metoprolol succinate.

1 prolonged release tablet contains: 23.75 mg, 47.5 mg metoprolol succinate corresponding to 25 mg, 50 mg metoprolol tartrate respectively.
The score mark is not intended to divide the tablet into two equal doses. It is only intended to facilitate swallowing.
Excipients/Inactive Ingredients: Ethylcellulose, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, paraffin, macrogol, anhydrous non-colloidal silicon dioxide, sodium stearyl fumarate, titanium dioxide (E 171).

Pharmacotherapeutic group: Beta-receptor blocker, selective. ATC code: C07A B02.
Pharmacology: Pharmacodynamics: Metoprolol is a beta₁-selective receptor blocker, i.e. metoprolol affects the beta₁-receptors of the heart in lower doses than needed to affect beta2-receptors in peripheral vessels and bronchi. The selectivity for Betaloc ZOK is dose dependent, but, as the peak plasma concentration for this dosage form is significantly lower compared to the same dose given as ordinary tablets, a higher degree of beta₁-selectivity is obtained with the ZOC-dosage form.
Metoprolol has no beta-stimulating effect and has little membrane- stimulating effect. Beta-receptor blockers have negative inotropic and chronotropic effect.
Metoprolol therapy reduces the effect of catecholamines in association with physical and psychic strain and gives lower heart rate, cardiac output and blood pressure. In stress situations with an increased release of adrenaline from the adrenal glands, metoprolol does not prevent the normal physiological vascular dilation. In therapeutic doses, metoprolol has less contractile effect on the bronchial muscles than non- selective beta-blockers. This property enables treatment of patients with bronchial asthma or other pronounced obstructive lung diseases with metoprolol in combination with beta₂-receptor stimulants. Metoprolol influences insulin release and carbohydrate metabolism to less extent than non-selective beta-blockers and therefore it can also be given to patients with diabetes mellitus. The cardiovascular reaction in hypoglycaemia, e.g. tachycardia, is less influenced by metoprolol and the return of blood sugar level to normal is faster than for non-selective beta-receptor blockers.
In hypertension, Betaloc ZOK lowers the blood pressure significantly for more than 24 hours both in lying and standing position as well as during exercise. In treatment with metoprolol an increase in the peripheral vascular resistance is observed initially. In long-term treatment, however, the obtained lowering in blood pressure may be due to reduced peripheral vascular resistance and unchanged cardiac output.
Paediatric population: In a four-week study with 144 patients between 6 and 16 years old with essential hypertension, doses of 1.0 and 2.0 mg/kg of Betaloc ZOK decreased placebo-corrected systolic blood pressure by 4-6 mmHg. Diastolic blood pressure showed a placebo-corrected decrease for the higher dose with 5 mmHg and a dose-dependent decrease for 0.2, 1.0 and 2.0 mg/kg. No noticeable differences between ages, Tanner scale (adolescent physical development) or race.
Metoprolol reduces the risk of cardiovascular-related deaths in men with moderate/serious hypertension. There is no disturbance in the electrolyte balance.
Effect in chronic heart failure: In MERIT-HF, a survival study comprising 3,991 patients with heart failure (NYHA II-IV) and decreased ejection fraction (≤ 0.40), Betaloc ZOK has been shown to increase survival and to reduce the number of hospitalisations. In long-term treatment the patients experience a general improvement of symptoms (New York Heart Association class and Overall Treatment Evaluation score).
In addition, it has been shown that Betaloc ZOK therapy increases the ejection fraction and reduces the left ventricular end systolic and end diastolic volumes.
In tachyarrhythmias the effect of increased sympatholytic activity is blocked and this gives a lower heart rate primarily by reduced automatisation in the pacemaker cells, but also through a prolonged supraventricular conduction time. Metoprolol reduces the risk of reinfarction and cardiac death, especially sudden death after myocardial infarction.
Pharmacokinetics: The Betaloc ZOK prolonged release tablet consists of micro-encapsulated beads of metoprolol succinate, and each bead is a separate depot unit. Each bead is coated with a polymeric membrane, which controls the rate of drug release. The tablet disintegrates rapidly in contact with fluid whereby the beads are dispersed over a large surface in the gastrointestinal tract. The release is independent of the pH of the surrounding fluid and goes on with an almost constant rate for about 20 hours. The dosage form gives an even plasma concentration and effect duration over 24 hours.
The absorption is complete after oral administration and the substance is absorbed along the whole gastrointestinal tract, also in colon. The bioavailability of Betaloc ZOK is 30-40%. Metoprolol is metabolised in the liver mainly by CYP2D6. Three main metabolites have been identified, though none has a beta-blocking effect of clinical importance. Metoprolol is excreted to approximately 5% in unchanged form via the kidneys, the remaining dose as metabolites.
The pharmacokinetics of metoprolol in children and young adults, 6 - 17 years, resembles that of adults. Clearance of orally given metoprolol (CL/F) increased with linear relation to the bodyweight.
Toxicology: Preclinical safety data: Metoprolol has been tested clinically to a very large extent.

Hypertension, angina pectoris and maintenance treatment after myocardial infarction.

Betaloc ZOK prolonged release tablets are given once daily, preferably in the morning. The prolonged release tablets can be divided. They must not be chewed or crushed. The tablets should be swallowed together with at least half a glass of liquid. Concomitant intake of food does not influence the bioavailability.
Dosage should be adjusted individually to avoid bradycardia. The following is valid as guidelines: Hypertension: 50-100 mg once daily. In patients not responding to 100 mg, the dose could be combined with other antihypertensive agents, preferably diuretics and calcium antagonists of the dihydropyridine type, or increased.
Angina pectoris: 100-200 mg once daily. If needed, the dose can be combined with nitrates or increased.
Maintenance treatment after myocardial infarction: Long-term treatment with metoprolol in doses of 200 mg given once daily has been shown to reduce the risk of death (including sudden death), and to reduce the risk of reinfarction (also in patients with diabetes mellitus).
Impaired renal function: The elimination rate is insignificantly affected by renal function, and dose adjustment is therefore not needed in impaired renal function.
Impaired hepatic function: Usually Betaloc ZOK is given in the same dose to patients suffering from liver cirrhosis as to patients with normal liver function. Only when there are signs of very severe impairment of liver function (e.g. shunt-operated patients), a dose reduction should be considered.
Elderly: Dose adjustment is not needed.

Toxicity: 7.5 g to an adult caused lethal intoxication. 100 mg to a 5-year old gave no symptoms after gastric lavage. 450 mg to a 12-year old and 1.4 g to an adult gave moderate intoxication, 2.5 g to an adult caused serious intoxication, and 7.5 g to an adult gave very serious intoxication.
Symptom: Cardiovascular symptoms are most important, but in some cases, especially in children and young individuals, CNS symptoms and respiratory depression may dominate. Bradycardia, AV-block I-III, QT-prolongation (exceptional cases), asystole, fall in blood pressure, poor peripheral perfusion, cardiac insufficiency, cardiogenic shock. Respiratory depression, apnoea. Others: Fatigue, confusion, unconsciousness, fine tremor, cramps, perspiration, paraesthesiae, bronchospasm, nausea, vomiting, possibly oesophageal spasm, hypoglycaemia (especially in children) or hyperglycaemia, hyperkalaemia. Effect on the kidneys. Transient myasthenic syndrome. Concomitant ingestion of alcohol antihypertensives, quinidine or barbiturates may aggravate the patient's condition. The first signs of overdosing may be seen 20 minutes to 2 hours after ingestion.
Management: Care should be provided at a unit that can offer suitable support measures, monitoring and supervision.
If justified, gastric lavage and/or activated charcoal can be used.
Atropine, adrenoceptor stimulant or pacemaker for treatment of bradycardia and conduction disorders.
Intubation and mechanical ventilation should be done with very broad indication. Pacemaker is option. With circulatory arrest in connection with overdose, resuscitation measures for several hours may be warranted.
Hypotension, acute myocardial infarction and shock should be treated with appropriate volume expansion, administration of glucagon (followed by intravenous infusion of glucagon if necessary), intravenous administration of an adrenoceptor stimulant, such as dobutamine, with the addition of α1 receptor agonists upon vasodilation. Intravenous use of Ca²⁺ may also be considered.
Bronchospasm can usually be reversed through bronchodilators.

Cardiogenic shock.
Sick-sinus syndrome (provided there is no permanent pacemaker).
AV-block of second and third degree.
Patients with unstable, not compensated heart failure (pulmonary oedema, hypoperfusion or hypotension), and patients with continuous or intermittent inotropic therapy acting through beta-receptor agonism.
Symptomatic bradycardia or hypotension. Metoprolol should not be given to patients with suspected acute myocardial infarction as long as the heart rate is < 45 beats/min, the P-Q interval is > 0.24 sec or the systolic blood pressure is < 100 mm Hg.
In the indication heart failure, patients with repeated supine blood pressure below 100 mmHg should be re-evaluated before treatment is initiated.
Serious peripheral vascular disease with gangrene threat.
Hypersensitivity to the active substance, to other beta-blockers or to any of the excipients specified in Description.

ISCHEMIC HEART DISEASE: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered BETALOC ZOK, 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. If angina markedly worsens or acute coronary insufficiency develops, BETALOC ZOK administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue BETALOC ZOK therapy abruptly even in patients treated only for hypertension.

Intravenous administration of calcium antagonists of the verapamil-type should not be given to patients treated with β-blockers.
Generally when treating patients with asthma, concomitant therapy with a β2-agonist (tablet and/or inhalation) should be administered. The dosage of β2-agonists may require adjustment (increase) when treatment with metoprolol CR/ZOK is started. The risk of metoprolol CR/ZOK interfering with β2-receptors is however less than with conventional tablet formulations of β1-selective blockers.
During treatment with metoprolol CR/ZOK, the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is likely to be less than during treatment with conventional tablet formulations of β1-selective blockers and much less than with non-selective β-blockers.
Very rarely, a pre-existing A-V conduction disorder of moderate degree may become aggravated (possibly leading to A-V block).
If the patients develop increasing bradycardia, metoprolol CR/ZOK should be given in lower doses or gradually withdrawn.
Metoprolol CR/ZOK may aggravate the symptoms of peripheral arterial circulatory disorders.
Where metoprolol CR/ZOK is prescribed for a patient known to be suffering from a phaeochromocytoma, an alpha-blocker should be given concomitantly.
Abrupt withdrawal of β-blockade is hazardous especially in high risk patients, and should therefore not be done.
If there is a need to discontinue treatment with metoprolol CR/ZOK, this should preferably be done gradually over at least two weeks when the dose is reduced by half in each step down to the final step when a whole 25 mg tablet is reduced to a half tablet.
The final dose should be taken for at least four days before discontinuation. If symptoms occur, a slower withdrawal rate is recommended. Sudden withdrawal of β-blockade may aggravate chronic heart failure and also increase the risk of myocardial infarction and sudden death.
Prior to surgery the anaesthetist should be informed that the patient is receiving metoprolol CR/ZOK. It is not recommended to stop β-blocker treatment in patients undergoing surgery. Acute initiation of high-dose metoprolol to patients undergoing non-cardiac surgery should be avoided, since it has been associated with bradycardia, hypotension and stroke including fatal outcome in patients with cardiovascular risk factors.
In patients taking β-blockers anaphylactic shock assumes a more severe form and may be resistant to usual doses of adrenaline. Whenever possible, β-blockers should be avoided in patients who are at increased risk of anaphylaxis.
Effect on ability to drive and use machines: As dizziness and fatigue may occur in Betaloc ZOK treatment, this should be considered when strict attention is required, e.g. when driving or operating machines.

Pregnancy: Betaloc ZOK should only be given during pregnancy and lactation when use is considered essential. In general, β-blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion and early labour. It is therefore suggested that appropriate maternofetal monitoring be performed in pregnant women treated with metoprolol. Beta-receptor blockers may cause bradycardia in the foetus and in the new-born infant. This should be considered if these drugs are prescribed in the last trimester and in association with delivery. Betaloc ZOK should gradually be withdrawn 48-72 hours before planned childbirth. If this is not possible the newborn infant should be supervised during 48-72 hours postpartum for signs and symptoms of beta-blockade (e.g. heart- and lung complications).
Lactation: Metoprolol is concentrated in human breast milk in a quantity that corresponds to approximately three times the quantity found in the plasma of the mother. The risk for harmful reactions with respect to the breastfeeding child seems to be low at therapeutic doses of the medicine. The breast-feeding child should however be observed regarding signs of betablockade.

Adverse reactions occur in approximately 10% of the patients and they are usually dose-related. Adverse reactions, related to metoprolol are presented as follows according to organ class and frequency. The frequencies are defined as following: very common (≥1/10), common (≥1/100, <1/10), less common (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000) and frequency unknown (cannot be calculated from available data).
Blood and lymphatic system: Rare: Thrombocytopenia.
Psychiatric disorders: Less common: Depression, nightmares, sleeping disturbance.
Rare: Memory impairment, confusion, hallucinations, nervousness, anxiety.
Frequency unknown: Impaired concentration ability.
Central and peripheral nervous system: Very common: Fatigue.
Common: Dizziness, headache.
Less common: Paraesthesiae.
Rare: Taste disturbances.
Frequency unknown: Muscular cramps.
Eyes: Rare: Visual disturbances, dry and/or irritated eyes.
Unknown frequency: Conjunctivitis-like symptoms.
Ears and balance organ: Rare: Tinnitus.
Heart: Common: Peripheral coldness in extremities, bradycardia, palpitations.
Less common: Transient aggravation of heart failure, cardiogenic shock in patients with acute myocardial infarction.
Rare: Prolonged AV-conduction time, cardiac arrhythmias.
Frequency unknown: Gangrene in patients with severe peripheral vascular disorders.
Respiratory: Common: Shortness of breath when physically active.
Less common: Bronchospasm in patients with bronchial asthma or asthmatic problems.
Frequency unknown: Rhinitis.
Gastrointestinal: Common: Abdominal pain, nausea, vomiting, diarrhoea, constipation.
Frequency unknown: Dry mouth.
Liver and biliary tracts: Rare: Elevated transaminases.
Frequency unknown: Hepatitis.
Skin and subcutaneous tissue: Less common: Hypersensitivity reactions in the skin.
Rare: Aggravated psoriasis, photosensitivity reactions, hyperhidrosis, hair loss.
Musculoskeletal system and connective tissue: Frequency unknown: Arthralgia.
Reproductive organs and mammary glands: Rare: Reversible libido dysfunction.
General: Less common: Chest pain, oedema, weight gain.

Metoprolol is a CYP2D6-substrate. Drugs that inhibit CYP2D6 can have an effect on the plasma concentration of metoprolol. Examples of drugs that inhibit CYP2D6 are quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine. When treatment with these drugs is initiated the dose of Betaloc ZOK might have to be reduced for patients treated with Betaloc ZOK.
The following combinations with Betaloc ZOK should be avoided: Barbituric acid derivatives: Barbiturates (investigated for pentobarbital) induce the metabolism of metoprolol by enzyme induction.
Propafenone: Upon administration of propafenone to four patients on metoprolol therapy, the plasma concentrations of metoprolol increased 2-5 fold and two patients experienced side-effects typical of metoprolol. The interaction was confirmed in eight healthy volunteers. The interaction is probably explained by the fact that propafenone, similarly to quinidine, inhibits the metabolism of metoprolol via cytochrome P450 2D6. The combination is probably difficult to handle since propafenone also has beta-receptor blocking properties.
Verapamil: In combination with beta-receptor blocking drugs (described for atenolol, propranolol and pindolol) verapamil may cause bradycardia and fall in blood pressure. Verapamil and beta-blockers have additive inhibitory effects on AV-conduction and sinusnode function.
The following combinations with Betaloc ZOK may require modified drug dosage: Amiodarone: A case report suggests that patients treated with amiodarone may develop pronounced sinus bradycardia when treated simultaneously with metoprolol. Amiodarone has extremely long half-life (around 50 days), which implies that interactions can occur for a long time after withdrawal of the drug.
Antiarrythmics, class I: Class I-antiarrythmics and beta-receptor blocking drugs have additive negative inotropic effects which may result in serious haemodynamic side effects in patients with impaired left ventricular function. The combination should also be avoided in "sick sinus syndrome" and pathological AV-conduction. The interaction is best documented for disopyramide.
Non-steroidal anti-inflammatory/antirheumatic drugs: NSAID-antiphlogistics have been shown to counteract the antihypertensive effect of beta-receptor blocking drugs. Primarily, indomethacin has been studied. This interaction probably does not occur with sulindac. A negative interaction study on diclofenac has been performed.
Digitalis glycosides: digitalis glycosides in association with β-blockers, may increase atrioventricular conduction time and may induce bradycardia.
Diphenhydramine: Diphenhydramine decreases (2.5 times) clearance of metoprolol to alpha- hydroximetoprolol via CYP 2D6 in fast hydroxylating persons. The effects of metoprolol are enhanced.
Diltiazem: Diltiazem and beta-receptor blockers have additive inhibitory effects on the AV-conduction and sinusnode function. Pronounced bradycardia has been observed (case reports) during combination treatment with diltiazem.
Epinephrine: There are about ten reports on patients treated with nonselective beta-receptor blockers (including pindolol and propranolol) that developed pronounced hypertension and bradycardia after administration of epinephrine (adrenaline). These clinical observations have been confirmed in studies in healthy volunteers. It has also been suggested that epinephrine in local anestethics may provoke these reactions upon intravasal administration. The risk is probably less with cardioselective beta-receptor blockers.
Phenylpropanolamine: Phenylpropanolamine (norephedrine) in single doses of 50 mg may increase the diastolic blood pressure to pathological values in healthy volunteers. Propranolol generally counteracts the rise in blood pressure induced by phenylpropanolamine. However, beta-receptor blockers may provoke paradoxical hypertensive reactions in patients who take high doses of phenylpropanolamine. Hypertensive crises during treatment with only phenylpropanolamine have been described in a couple of cases.
Quinidine: Quinidine inhibits the metabolism of metoprolol in so-called rapid hydroxylators (more than 90% in Sweden) with markedly elevated plasma levels and enhanced beta-blockade as a result. A corresponding interaction might occur with other beta-blockers metabolised by the same enzyme (cytochrome P450 2D6).
Clonidine: The hypertensive reaction when clonidine is suddenly withdrawn may be potentiated by beta-blockers. If concomitant treatment with clonidine is to be discontinued, the beta-blocker medication should be withdrawn several days before clonidine.
Rifampicin: Rifampicin may induce the metabolism of metoprolol resulting in decreased plasma levels.
Patients receiving concomitant treatment with other beta-blockers (i.e. eye drops) or MAO-inhibitors should be kept under close surveillance. In patients receiving beta-receptor blocker therapy, inhalation anaesthetics enhance the cardio-depressant effect. The dosages of oral antidiabetics may have to be readjusted in patients receiving beta-blockers. The plasma concentration of metoprolol can increase when cimetidine or hydralazine are administered simultaneously.

Incompatibilities: Not applicable.
Special precautions for disposal: Not applicable.

Do not store above 30°C.
Shelf life: 3 years.

Beta-Blockers

C07AB02 - metoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.

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