Section 4.2
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The dose must always be adjusted to the individual requirements of the patient. The following are guidelines:
Control of Tachyarrhythmias changed to Cardiac arrhythmias.
I.V changed to intravenously
Such treatment should be initiated in a coronary care or similar unit immediately after the patients haemodynamic condition has stabilised
Text added to 6th paragraph of section 4.2
Impaired Renal Function: Dose adjustment is generally not needed in patients with impaired renal function.
Significant dysfunction changed to Impaired Hepatic Function
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A reduction in dosage may be necessary.
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Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has a low protein binding (5‑10%). However, in patients with severe hepatic dysfunction a reduction in dosage may be necessary,
according to the severity of hepatic impairment.
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Initially the lowest possible dose should be used, especially in the elderly
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Several studies indicate that age‑related physiological changes have negligible effects on the pharmacokinetics of metoprolol. Dose adjustment is not needed in the elderly, but careful dose titration is important in all patients.
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There is limited experience with metoprolol treatment in children.
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The safety and efficacy of metoprolol in children has not been established.
Section 4.3
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Betaloc Injection, as with other beta‑blockers, should not be used in patients with any of the following:
- Hypotension,
- AV block of second- or third‑degree,
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- Uncontrolled heart failure Unstable
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- Decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension),
- Continuous or intermittent inotropic therapy acting through beta‑receptor agonism,
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b-blockers or to any of the constituents of Betaloc i.v.
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any component of Betaloc Injection or other beta‑blockers
Section 4.4
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If patients develop increasing bradycardia, Betaloc i.v. should be given in lower doses or gradually withdrawn. Symptoms of peripheral arterial circulatory disorders may be aggravated by Betaloc.
In cases where the systolic blood pressure is below 100mmHg, Betaloc should only be given intravenously if special precautions are observed, because there is a risk that administration of the drug by this route may cause a further fall in blood pressure (i.e. in patients with cardiac arrhythmias).
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When treating patients with suspected or definite myocardial infarction the haemodynamic status of the patient should be carefully monitored after each of the three 5mg intravenous doses. The second or third dose should not be given if the heart rate is <40 beats/min, the systolic blood pressure is <90mmHg and the P‑Q time is >0.26 sec, or if there is any aggravation of dyspnoea or cold sweating.
Betaloc, as with other beta‑blockers:
Abrupt interruption of b-blockers is to be avoided.
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should not be withdrawn abruptly during oral treatment. When possible, Betaloc should be withdrawn gradually over a period of 10‑14 days, in diminishing doses to 25mg daily for the last 6 days.
The risk for coronary events, including sudden death, may increase during the withdrawal of beta‑blockade.
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It is not generally recommended to stop Betaloc treatment in patients undergoing surgery. If withdrawal of metoprolol is considered desirable, this should, if possible, be completed at least 48 hours before general anaesthesia. However, in some patients it may be desirable to employ a beta-blocker as premedication. By shielding the heart against the effects of stress, the beta-blocker may prevent excessive sympathetic stimulation provoking cardiac arrhythmias or acute coronary insufficiency. If a beta-blocker is given for this purpose, an anaesthetic with little negative inotropic activity should be selected to minimise the risk of myocardial depression.
although contra‑indicated in severe peripheral arterial circulatory disturbances (see Section 4.3), may also aggravate less severe peripheral arterial circulatory disorders.
Betaloc should be used with caution in patients where cardiac reserve is poor.
may cause patients to develop increasing bradycardia, in such cases the Betaloc Injection dosage should be reduced or gradually withdrawn.
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may aggravate pre‑existing conduction time disorders of moderate degree, which may lead to AV block, and
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due to the negative effect on conduction time, should only be given with caution to patients with first-degree heart block.
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In patients with Prinzmetal’s angina b1 selective agents should be used with care.
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may increase the number and duration of angina attacks in patients with Prinzmetal’s angina, due to unopposed alpha‑receptor mediated coronary artery vasoconstriction. Betaloc Injection is a beta1‑selective beta‑blocker; consequently, its use may be considered although utmost caution must be exercised.
Exisiting text
As with other b-blockers, Betaloc i.v. may mask the symptoms of thyrotoxicosis and the early signs of acute hypoglycaemia in patients with diabetes mellitus. However, the risk of this occurring is less than with non-selective b-blockers.
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may mask the early signs of acute hypoglycaemia, in particular tachycardia. During treatment with Betaloc Injection, the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is less than with non‑selective beta‑blockers.
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may mask the symptoms of thyrotoxicosis.
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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 Betaloc Injection is commenced.
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The elderly should be treated with caution, starting with a lower dose.
The administration of adrenaline to patients undergoing b-blockade can result in an increase in blood pressure and bradycardia although this is less likely to occur with b1-selective drugs.
Section 4.5
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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.
Existing text
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.
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Enzyme inducing agents (e.g. rifampicin) may reduce plasma concentrations of Betaloc i.v., whereas enzyme inhibitors (e.g. cimetidine, alcohol and hydralazine) may increase plasma concentrations.
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Care should also be exercised when b-blockers are given in combination with sympathomimetic ganglion blocking agents, other b-blockers (i.e. eye drops) or MAO inhibitors.
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.
Exisiting text
Like all other b-blockers, Betaloc i.v. should not be given in combination with verapamil, diltiazem or digitalis glycosides. A watch should be kept for possible negative effects when metoprolol is given in combination with calcium antagonists, since this may cause bradycardia, hypotension and asystole.
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Increased negative inotropic and chronotropic effects may occur when Betaloc metoprolol is given together with calcium antagonists of the verapamil and diltiazem type,In patients treated with beta‑blockers intravenous administration of calcium antagonists of the verapamil‑type should not be given.
Betaloc i.v. Injection 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.
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Beta-blockers may enhance the negative inotropic and negative dromotropic effect of antiarrhythmic agents (of the quinidine type and amiodarone).
Digitalis glycosides, in association with beta-blockers, may increase atrioventricular conduction time and may induce bradycardia.
In patients receiving beta-blocker therapy, inhalation anaesthetics enhance the cardiodepressant effect.
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.
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.
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when combining with other antihypertensive drugs or drugs that might reduce blood pressure
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to avoid hypotension ould be the result of concomitant administration with dihydropyridine derivatives,
Section 4.6
Pregnancy added to beginning of section and metoprolol changed to Betaloc Injection.
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Use during
Section 4.8
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Metoprolol is usually well tolerated and adverse reactions have generally been mild and reversible.
A relationship to treatment with metoprolol has not always been established.
As in the case of other b-blockers, a marked fall in blood pressure may sometimes occur following intravenous injection of Betaloc. Other side effects are usually mild and infrequent. The most common appear to be lassitude, GI disturbances (nausea, vomiting or abdominal pain) and disturbances of sleep pattern. In many cases these effects have been transient or have disappeared after a reduction in dosage.
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Effects related to the CNS which have been reported occasionally are dizziness and headache and rarely paraesthesia, muscle cramps, depression, decreased mental alertness. There have also been isolated reports of personality disorders like amnesia, memory impairment, confusion, hallucination, nervousness and anxiety.
Cardiovascular effects which have been reported occasionally are bradycardia, postural hypotension and rarely, heart failure, increased existing AV block, palpitations, cardiac arrhythmias, Raynauds phenomenon, peripheral oedema and precordial pain. There have also been isolated reports of cardiac conduction abnormalities, gangrene in patients with pre-existing severe peripheral circulatory disorders and increase of pre-existing intermittent claudication.
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Common gastro-intestinal disturbances have been described above but rarely diarrhoea or constipation also occur and there have been isolated cases of dry mouth and abnormal liver function.
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Skin rashes (urticaria, psoriasiform, dystrophic skin lesions) and positive anti-nuclear antibodies (not associated with SLE) occur rarely. Isolated cases of photosensitivity, psoriasis exacerbation, increased sweating and alopecia have been reported. Respiratory effects include occasional reports of dyspnoea on exertion and rare reports of bronchospasm and isolated cases of rhinitis.
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Rarely impotence/sexual dysfunction. Isolated cases of weight gain, thrombocytopenia, disturbances of vision, conjunctivitis, tinnitus, dry or irritated eyes, taste disturbance and arthralgia have also been reported.
The reported incidence of skin rashes and/or dry eyes is small and in most cases the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable.
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Th following definitions of frequencies are used:
Very common (>10%), common (1‑9.9%), uncommon (0.1‑0.9%), rare (0.01‑0.09%) and very rare (<0.01%).
Infections and infestations
Very rare: Gangrene in patients with pre‑existing severe peripheral circulatory disorders.
Blood and lymphatic system disorders
Very rare: Thrombocytopenia.
Psychiatric disorders
Uncommon: Depression, insomnia, nightmares.
Rare: Nervousness, anxiety.
Very rare: Confusion, hallucinations.
Nervous system disorders
Common: Dizziness, headache.
Uncommon: Concentration impairment, somnolence, paraesthesiae.
Very rare: Amnesia/memory impairment, taste disturbances.
Eye disorders
Rare: Disturbances of vision, dry and/or irritated eyes, conjunctivitis
Ear and labyrinth disorders
Very rare: Tinnitus.
Cardiac disorders
Common: Bradycardia, palpitations.
Uncommon: Deterioration of heart failure symptoms, first‑degree heart block.
Rare: Disturbances of cardiac conduction, cardiac arrhythmias, increased existing AV block.
Vascular disorders
Common: Postural disorders (very rarely with syncope).
Rare: Raynauds phenomenon.
Very rare: Increase of pre-existing intermittent claudication.
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea on exertion.
Uncommon: Bronchospasm.
Rare: Rhinitis
Gastrointestinal disorders
Common: Nausea, abdominal pain, diarrhoea, constipation.
Uncommon: Vomiting.
Rare: Dry mouth.
Hepato-biliary disorders
Very rare: Hepatitis.
Skin and subcutaneous tissue disorders
Uncommon: Rash (in the form of psoriasiform urticaria and dystrophic skin lesions), increased sweating.
Rare: Loss of hair.
Very rare: Photosensitivity reactions, aggravated psoriasis.
Musculoskeletal and connective tissue disorders
Very rare: Arthralgia.
Uncommon: Muscle cramps.
Reproductive system and breast disorders
Rare: Impotence/sexual dysfunction.
General disorders and administration site disorders
Very common: Fatigue.
Common: Cold hands and feet.
Uncommon: Precordial pain, oedema.
Investigations
Uncommon: Weight gain.
Rare: Liver function test abnormalities, positive anti-nuclear antibodies (not associated with SLE).
Section 4.9
Symptoms added to beginning of section 4.9
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Concomitant ingestion of alcohol, antihypertensives, quinidine, or barbiturates or other drugs and combinations of drugs that might negatively affect the circulatory system and/or the central nervous system, may aggravate the patient’s condition.
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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 i.v. may be used in order to block the vagus nerve. If a satisfactory effect is not achieved, other
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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.
The use of haemodialysis or haemoperfusion may be considered.
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Betaloc Injection cannot be effectively removed by haemodialysis.
Section 5.2
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Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme.
Section 10
Change date to 21st March 2007
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