When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
4.1 Therapeutic Indications
1. Treatment of hypertension and angina pectoris.
2. As an adjunct in the treatment of thyrotoxicosis.
3. In the management of cardiac arrhythmias, particularly supraventricular tachyarrhythmia.
4. In the reduction of cardiac morbidity and mortality in patients after acute myocardial infarction.
5. Prophylaxis of migraine.
In the management of hypertension and angina pectoris.
Cardiac arrhythmias, especially supraventricular tachyarrhythmias.
Adjunct to the treatment of hyperthyroidism.
Early intervention with Metoprolol in acute myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics.
Metoprolol has been shown to reduce mortality when administered to patients with acute myocardial infarction.
Prophylaxis of migraine.
4.2 Posology and Method of Administration
For Oral administration only.
ADULTS
Hypertension:
Initially a dose of 100 mg daily should be given with weekly increments of 100 mg/day as appropriate. Doses of 100-200 mg twice daily may subsequently be prescribed depending upon the response. The total daily dose may be given as a single dose of 200-400 mg. If insufficient control is attained using dosage of 200-400 mg per day, combination treatment with a diuretic or other anti-hypertensive agent can be undertaken.
Angina Pectoris:
50-100 mg twice or three times daily
Thyrotoxicosis:
The usual dose is 50 mg four times daily
Cardiac Arrhythmias:
The usual daily dose is 50 mg twice or three times daily, but up to 100 mg thrice daily may be required. Following the treatment if an acute arrhythmias with Metoprolol injection, the control can be maintained using the tablets at a dose of 50 mg twice daily initiated 4-6 hours later.
Myocardial Infarction:
The usual dosage is 5 mg intravenously at 2 minute intervals to a total of 15 mg, 50 mg orally six hourly, for 48 hours, then 100 mg twice daily. Treatment should commence as soon as possible after infarction.
Prophylaxis of Migraine:
The usual dosage is 100-200 mg in 2 divided doses daily.
ELDERLY PERSONS
There are no special dosage requirements in otherwise healthy elderly patients. In patients with significant hepatic dysfunction a reduced dosage may be necessary.
CHILDREN, INFANTS AND NEONATES
The dosage has not been established in children.
The tablets should be taken on an empty stomach.
The dose must always be adjusted to the individual requirements of the patient. The following are guidelines:
The recommended maintenance dosage in patients with hypertension is 100mg-200mg daily, given as a single dose in the morning or in divided doses (morning and evening). Begin with 50mg twice daily or 100mg once daily. Dose increments should be at intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily. Doses up to 400mg daily have been used. If needed, other antihypertensive agents may be added.
Long-term antihypertensive treatment with metoprolol in daily doses of 100-200mg has been shown to reduce total mortality, including sudden cardiovascular death, stroke, and coronary events in hypertensive patients.
The recommended dosage is 100-200mg daily, given in divided doses (morning and evening). Begin with 50mg twice daily. Dose increments should be at intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily (in divided doses). Doses up to 300mg daily (in divided doses) have been used. If needed, other antianginal agents may be added.
The recommended dosage is 100-200mg daily given in divided doses (morning and evening). If needed, other antiarrhythmic agents may be added.
The recommended dosage is 50mg four times a day.
To achieve optimal benefits from intravenous Metoprolol suitable patients should present within 12 hours of the onset of chest pain. Therapy should commence with 5mg i.v. every 2 minutes to a maximum of 15mg total as determined by blood pressure and heart rate. The second or third dose should not be given if the systolic blood pressure is <90mmHg, the heart rate is <40 beats/min and the P-Q time is >0.26 seconds, or if there is any aggravation of dyspnoea or cold sweating. Oral therapy should commence 15 minutes after the last injection with 50mg every 6 hours for 48 hours. Patients who fail to tolerate the full intravenous dose should be given half the suggested oral dose.
The usual maintenance dose is 200mg daily, given in divided doses.
The recommended dosage is 100-200mg daily, given in divided doses (morning and evening).
Dose adjustment is generally not needed in patients with impaired renal function.
Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has a low protein binding (5-10%). However, a reduction in dosage may be necessary, according to the severity of hepatic impairment.
Several studies indicate that age-related physiological changes have negligible effects on the pharmacokinetics of metoprolol.
There is limited experience with metoprolol treatment in children.
4.3 Contraindications
1. 2nd or 3rd degree atrioventricular block.
2. Severe bradycardia.
3. Uncontrolled digitalis-/diuretic-refractory heart failure.
4. Cardiogenic shock.
5. Asthma/chronic obstructive airways disease
6. Known sensitivity to metoprolol tartrate or to any of the excipients; hypersensitivity to other beta-blocker (cross-sensitivity between beta-blockers can occur).
Metoprolol, as with other beta-blockers, should not be used in patients with any of the following:
- AV block of second- or third-degree,
- Unstable decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension),
- Continuous or intermittent inotropic therapy acting through beta-receptor agonism,
- Bradycardia, (<45bpm),
- Sick sinus syndrome,
- Cardiogenic shock,
- Severe peripheral arterial circulatory disorder,
- Untreated phaeochromocytoma,
- Metabolic acidosis.
Known hypersensitivity to any component of Metoprolol or other beta-blockers.
Metoprolol is also contra-indicated when suspected acute myocardial infarction is complicated by bradycardia (<45bpm), first degree heart block (the P-Q interval is >0.24 sec) or systolic blood pressure <100mmHg.
4.4 Special Warnings and Precautions for Use
Sudden withdrawal of beta-adrenoceptor blocking agents in patients with ischaemic heart disease may result in the appearance of anginal attacks of increased frequency or severity or deterioration in cardiac state. Discontinuation of therapy should be gradual.
In the event that a patient receiving the beta-blocker requires anaesthesia the anaesthetist should be informed of the use of the medication prior to the use of a general anaesthetic to permit his taking the necessary precautions.
The beta-blocker should only be used with caution in patients with controlled congestive cardiac failure or with a family history of asthma. Evidence of development of either condition should be regarded as a signal to discontinue therapy.
The initial treatment of severe malignant hypertension should be so designed as to avoid sudden reduction in diastolic blood pressure with impairment of autoregulatory mechanisms.
Some cases of ocular changes (conjunctivitis and ‘dry eye’) and/or skin rashes (including a psoriasiform type) have been reported in association with the use of beta-adrenoceptor blockers. Until their significance is known it is recommended that consideration be given to discontinuing such therapy if these effects appear.
Metoprolol tartrate can be administered to patients with obstructive respiratory disorders provided that adequate supervision is maintained to permit any necessary adjustment of dosage of the bronchodilator employed.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Metoprolol as with other beta-blockers:
• should not be withdrawn abruptly. When possible, Metoprolol should be withdrawn gradually over a period of 10-14 days, in diminishing doses to 25mg daily for the last 6 days. During its withdrawal patients should be kept under close surveillance, especially those with known ischaemic heart disease. The risk for coronary events, including sudden death, may increase during the withdrawal of beta-blockade.
• must be reported to the anaesthetist prior to general anaesthesia. It is not generally recommended to stop Metoprolol treatment in patients undergoing surgery.
• although contra-indicated in severe peripheral arterial circulatory disturbances (see Section 4.3), may also aggravate less severe peripheral arterial circulatory disorders.
• may be administered when heart failure has been controlled. Digitalisation and/or diuretic therapy should also be considered for patients with a history of heart failure, or patients known to have a poor cardiac reserve.
• may cause patients to develop increasing bradycardia, in such cases the Metoprolol dosage should be reduced or gradually withdrawn.
• due to the negative effect on conduction time, may aggravate pre-existing conduction time disorders of moderate degree, which may lead to AV block, and should only be given with caution to patients with first degree heart block.
• may increase the number and duration of angina attacks in patients with Prinzmetal's angina, due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Metoprolol is a beta1-selective beta-blocker; consequently, its use may be considered although utmost caution must be exercised.
• may mask the early signs of acute hypoglycaemia, in particular tachycardia. During treatment with Metoprolol, the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is less than with non-selective beta-blockers.
• may mask the symptoms of thyrotoxicosis.
• may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.
Although cardioselective beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers, these should be avoided in patients with reversible obstructive airways disease unless there are compelling clinical reasons for their use. When administration is necessary, these patients should be kept under close surveillance. The use of a beta2-bronchodilator (e.g. terbutaline) may be advisable in some patients. The dosage of the beta2-agonist may require an increase when treatment with Metoprolol is commenced.
As with all beta-blockers, careful consideration should be given to patients with psoriasis before Metoprolol is administered.
In the presence of liver cirrhosis the bioavailability of Metoprolol may be increased.
In patients with a phaeochromocytoma, an alpha-blocker should be given concomitantly.
In labile and insulin-dependent diabetes it may be necessary to adjust the hypoglycaemic therapy.
Intravenous administration of calcium antagonists of the verapamil-type should not be given to patients treated with beta-blockers.
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products and Other Forms of Interaction
The beta-blocker should be used with great caution in patient who are receiving concomitant myocardial depressants such as halogenated anaesthetics or verapamil or class I antiarrhythmic agents such as disopyramide. Caution is also advised in patients who are receiving beta stimulants such as isoprenaline or adrenergic stimulants such as noradrenaline or adrenaline, which also stimulate alpha-adrenoceptors and thus increase vasoconstrictor activity and reverse the hypotensive effect. The effect of Metoprolol on the beta2-stimulant effects of these agents is less pronounced than is the case for non-selective beta-blockers such as propranolol.
Adrenergic neurone blocking agents such as guanethidine; reserpine, diuretics and other anti-hypertensive agents, including the vasodilator group, will have an additive effect on the hypotensive action of the drug.
The beta-blocker may mask the symptoms of thyrotoxicosis and hypoglycaemia by inhibition of sympathetic nerve functions.
If the beta-blocker and clonidine are given concurrently the clonidine should not be discontinued until several days after withdrawal of the beta-blocker.
Metoprolol can reduce myocardial contractility and impair intracardiac conduction. Care should be exercised when drugs with similar activity, e.g. antiarrhythmic agents (of the quinidine type and amiodarone), or general anaesthetics, are given concurrently.
Increased negative inotropic and chronotropic effects may occur when Metoprolol is given together with calcium antagonists of the verapamil and diltiazem type, causing bradycardia, hypotension and asystole. In patients treated with beta-blockers intravenous administration of calcium antagonists of the verapamil-type should not be given in combination.
Digitalis glycosides, in association with beta-blockers, may increase atrioventricular conduction time and may induce bradycardia.
Patients receiving concomitant treatment with sympathetic ganglion blocking agents, other beta-blockers (i.e. eye drops), or Mono Amine Oxidase (MAO) inhibitors should be kept under close surveillance.
If concomitant treatment with clonidine is to be discontinued, Metoprolol should be withdrawn several days before clonidine.
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.
The administration of adrenaline (epinephrine) to patients undergoing beta-blockade can result in an increase in blood pressure and bradycardia although this is less likely to occur with beta1-selective drugs.
Metoprolol may impair the elimination of lidocaine.
Metoprolol is a metabolic substrate for the Cytochrome P450 isoenzyme CYP2D6. Drugs that act as enzyme-inducing and enzyme-inhibiting substances may exert an influence on the plasma level of metoprolol. Plasma levels of metoprolol may be raised by co-administration of compounds metabolised by CYP2D6, e.g. antiarrhythmics, antihistamines, histamine-2-receptor antagonists, antidepressants, antipsychotics, and COX-2-inhibitors. The plasma concentration of metoprolol is lowered by rifampicin and may be raised by alcohol and hydralazine.
As with other beta-blockers, concomitant therapy with dihydropyridines e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.
Concomitant treatment with indometacin or other prostaglandin synthetase inhibiting drugs may decrease the antihypertensive effect of beta-blockers.
The beta-blocker may mask some of the symptoms of thyrotoxicosis and of hypoglycaemia by inhibition of sympathetic nerve functions. The effects of hypoglycaemic agents may be increased, particularly by the non-cardioselective beta-blockers. The dosages of oral antidiabetics and also of insulin may have to be readjusted in patients receiving beta-blockers. The tachycardia of hypoglycaemia may be modified.
As beta-blockers may affect the peripheral circulation, care should be exercised when drugs with similar activity e.g. ergotamine are given concurrently.
The effects of Metoprolol and other antihypertensive drugs on blood pressure are usually additive. Care should be taken when combining with other antihypertensive drugs or drugs that might reduce blood pressure, such as tricyclic antidepressants, barbiturates and phenothiazines. However, combinations of antihypertensive drugs may often be used with benefits to improve control of hypertension.
4.6 Pregnancy and Lactation
The beta-blocker should not be given during pregnancy or lactation unless it is considered essential by the physician. Animal studies do not suggest a teratogenic effect with the drug. As with all beta-blockers Metoprolol may cause side effects e.g. bradycardia, hypoglycemia in the foetus and in the new born and breast-fed infant. The beta-blocker has been given in pregnancy-associated hypertension after 20 weeks gestation. Although the drug crosses the placental barrier and is present in cord blood, there is no evidence up to the present time of foetal abnormalities. Nonetheless the possibility cannot be excluded and the drug should only be used if considered essential and with the patient under close supervision. The drug is excreted in breast milk. This should be kept in mind if it is intended for use in nursing mothers.
Metoprolol should not be used in pregnancy or nursing mothers unless the physician considers that the benefit outweighs the possible hazard to the foetus/infant. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries.
As with all beta-blockers, Metoprolol may cause side-effects especially bradycardia and hypoglycaemia in the foetus, and in the newborn and breastfed infant. Metoprolol has, however, been used in pregnancy associated hypertension under close supervision, after 20 weeks gestation. Although Metoprolol crosses the placental barrier and is present in the cord blood, as yet no evidence of foetal abnormalities has been reported.
The amount of metoprolol ingested via breast milk should not produce significant beta-blocking effects in the neonate if the mother is treated with the normal therapeutic doses.
4.7 Effects on Ability to Drive and Use Machines
None stated.
Patients should know how they react to Metoprolol before they drive or use machines because occasionally dizziness or fatigue may occur.
4.8 Undesirable Effects
Side effects include gastrointestinal upset, bradycardia, headache, Raynaud’s phenomena, paraesthesia, depression and sleep disorders.
4.9 Overdose
Overdosage may lead to hypotension and bradycardia. Such effects can be counteracted by using atropine sulphate 0.25 - 2.0 mg. If the desired effect is not achieved dopamine or dobutamine can be administrated. Glucagon in a dose of 1-10 mg can also be administered for treatment of overdosage of beta-blockers.
Poisoning due to an overdose of Metop may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, nausea, vomiting, cyanosis, hypoglycaemia and, occasionally, hyperkalaemia.
Concomitant ingestion of alcohol, antihypertensives, quinidine or barbiturates may aggravate the patient's condition.
The first manifestations usually appear 20 minutes to 2 hours after drug ingestion.
Treatment should include close monitoring of cardiovascular, respiratory and renal function, and blood glucose and electrolytes. Further absorption may be prevented by induction of vomiting, gastric lavage or administration of activated charcoal if ingestion is recent. Cardiovascular complications should be treated symptomatically. In the presence of severe hypotension, bradycardia, and impending heart failure, administer a beta1-agonist until the desired effect is achieved. Where a selective beta1-agonist is not available, dopamine may be used; or atropine sulphate iv may be used in order to block the vagus nerve. If a satisfactory effect is not achieved, other sympathomimetic agents (e.g. noradrenaline [norepinephrine], metaraminol), or inotropic agents (e.g. dobutamine) may be used. Temporary pacing may be required for AV block. Glucagon can reverse the effects of excessive beta-blockade, given in a dose of 1-10mg intravenously.
Intravenous beta2-stimulants e.g. terbutaline may be required to relieve bronchospasm.
It should be noted that the dosages of drugs (antidotes) needed to treat overdose of beta-blockade are much higher than normally recommended therapeutic dosages. This is because the beta-receptors are occupied by the beta-blocker.
Metop cannot be effectively removed by haemodialysis.
5.1 PHARMACODYNAMIC PROPERTIES
Metoprolol a beta1 adrenoceptor blocking agent. It has a relatively greater effect on beta1 receptors (i.e. those mediating adrenergic stimulation of heart rate and contractility and the release of free fatty acids from fat stores) than on beta2 receptors involved in bronchodilation and vasoconstriction.
Metoprolol is a competitive β-adrenoceptor antagonist. It acts preferentially to inhibit β1-adrenoceptors (conferring some cardioselectivity), is devoid of intrinsic sympathomimetic activity (partial agonist activity) and possesses β-adrenoceptor blocking activity comparable in potency with propranolol.
A negative chronotropic effect on the heart is a consistent feature of metoprolol administration. Thus, cardiac output and systolic blood pressure rapidly decrease following acute administration.
5.2 Pharmacokinetic Properties
Metoprolol tartrate readily absorbed after oral dosage with significant first pass metabolism in the liver to metabolites, only one of which has some beta blocking activity. Excretion is mainly through the kidney. The parent drug has a half life of 3-4 hours but a longer duration of biological activity.
Metoprolol tablets dissolve rapidly which results in a rapid and complete absorption with tmax within 2 hours and consistent bioavailability data between different study populations.
Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme.
Elimination is mainly via hepatic metabolism (>90%). Terminal half life is about 3-4 hours.
5.3 Preclinical Safety Data
There are no preclinical safety data of relevance to the prescriber.
10. DATE OF REVISION OF THE TEXT
May 2009
February 2010
Summary of Product Characteristics
1. Trade Name of the Medicinal Product
METOP 50 mg Tablets 50mg
METOP 100 mg Tablets 100mg
2. Qualitative and Quantitative Composition
Metoprolol Tartrate 50 mg
50mg:
Each tablet contains 50mg Metoprolol Tartrate.
Excipients: Each tablet contains 39mg Lactose monohydrate.
100mg:
Each tablet contains 100mg Metoprolol Tartrate.
Excipients: Each tablet contains 35mg Lactose monohydrate.
For a full list of excipients, see Section 6.1
3. Pharmaceutical Form
Tablet
White, uncoated, biconvex tablet marked ‘ML’ breakline ‘50’ on one side and ‘G’ on the reverse.
White, uncoated, biconvex tablet marked ‘ML’ breakline ‘100’ on one side and ‘G’ on the reverse.
The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4. Clinical Particulars
ADULTS:
ELDERLY PERSONS:
CHILDREN, INFANTS AND NEONATES:
6. Known sensitivity to metoprolol tartrate or to any of the excipients; hypersensitivity to other beta-blockers (cross-sensitivity between beta-blockers can occur).
4.5 Interaction With Other Medicinal Products and Other Forms of Interactions
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group:
Cardioselective beta-blocker (ATC code: C07A B02).
6. Pharmaceutical Particulars
6.1 List of Excipients
Lactose monohydrate
Microcrystalline cellulose
Povidone
Silica colloidal anhydrous
Colloidal anhydrous silica
Magnesium stearate
Sodium starch glycolate type A
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
36 months 3 years in polypropylene containers with polyethylene caps
24 months 2 years in PVdC/Aluminium foil blisters
6.4 Special Precautions for Storage
Store below 25ºC.
Do not store above 25oC
6.5 Nature and Contents of Container
Polypropylene containers with polyethylene caps in packs of 100 or 500 tablets AND
PVdC/Aluminium foil blister packs of 100 or 500 tablets packed in a carton.
Not all pack sizes may be marketed.
6.6 Instructions for Use/Handling
6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product.
No special requirements
7. Marketing Authorisation Holder
Generics [UK] Limited
12 Station Close
Potters Bar
Hertfordshire EN6 1TL,
United Kingdom
8. Marketing Authorisation Number
50 mg: PA 405/24/1
100mg: PA 405/24/2
9. Date of First Authorisation/Renewal of the Authorisation
18th May 1988/ 18th May 2003
Date of first authorisation: 18th May 1988
Date of last renewal: 18th May 2008
10. Date of Revision of the Text
December 2003
May 09