- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AdultsHypertension: initially a dose of 100mg per day should be prescribed either as single or divided doses. Depending upon the response the dosage may be increased by 100mg per day at weekly intervals to 200mg daily given in single or divided doses. Over the dosage range most patients may be expected to respond rapidly and satisfactorily. A further reduction in blood pressure may be achieved if Lopresor is used in conjunction with an antihypertensive diuretic or other hypotensive agent. Lopresor may be administered with benefit both to previously untreated patients with hypertension and to those in whom the response to previous therapy is inadequate. In the latter type of patient the previous therapy may be continued and Lopresor added into the regime with adjustment of the previous therapy if necessary. Angina Pectoris: 50-100mg 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 50-100mg twice daily. Cardiac Arrhythmias: A dosage of 50mg two or three times daily is usually sufficient. If necessary the dose can be increased up to 300mg per day administered in divided doses. Hyperthyroidism: 50mg four times daily. The dosage should be progressively reduced as euthyroid state is slowly achieved.
Myocardial Infarction:Early intervention: 50mg every 6 hours for 48 hours, preferably within 12 hours of the onset of chest pain. Maintenance: the usual maintenance dose is 200mg daily given in divided doses. The treatment should be continued for at least 3 months. Prophylaxis of Migraine: 100-200mg daily, given in divided doses (morning and evening).
ElderlyThere is no evidence to suggest that dosage requirements are different in otherwise healthy elderly patients. However, caution is indicated in elderly patients as an excessively pronounced decrease in blood pressure or pulse rate may cause the blood supply to vital organs to fall to inadequate levels. In patients with significant hepatic dysfunction the lower dosage recommendations will be more appropriate.
PrazosinThe acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker.
ClonidineIf combination treatment with clonidine is to be discontinued 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 blockersCalcium 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 Lopresor 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 Lopresor should be closely monitored.
CYP2D6 inhibitorsPotent inhibitors of this enzyme may increase the plasma concentration of metoprolol (see section 5.2. Pharmacokinetic properties). 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 amiodaroneAmiodarone, 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.
NitroglycerinNitroglycerin may enhance the hypotensive effect of Lopresor.
Digitalis glycosidesConcurrent use of digitalis glycosides may result in excessive bradycardia and/or increase in atrioventricular conduction time.
SympathomimeticsMetoprolol 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 drugsIn diabetic patients who use insulin, beta-blocker treatment may be associated with increased or prolonged hypoglycaemia. Beta-blockers may also antagonise the hypoglycaemic effects of sulfonylureas. The risk of either effect is less with a beta1-selective drug such as Lopresor than with a non-selective beta-blocker. However, diabetic patients receiving Lopresor should be monitored to ensure that diabetes control is maintained (see also Special warnings and special precautions for use).
Non-steroidal anti-inflammatory drugsConcurrent treatment with non-steroidal anti-inflammatory drugs such as indomethacin may decrease the antihypertensive effect of metoprolol.
LignocaineMetoprolol may impair the elimination of lignocaine.
General anaestheticsSome inhalation anaesthetics may enhance the cardiodepressant effect of beta-blockers (see Special warnings and special precautions for use).
Hepatic enzyme inducers/inhibitorsEnzyme inducing agents (e.g. rifampicin) may reduce plasma concentrations of metoprolol, whereas enzyme inhibitors (e.g. cimetidine) may increase plasma concentrations.
AlcoholDuring concomitant ingestion of alcohol and metoprolol the concentration of blood alcohol may reach higher levels and may decrease more slowly.
Blood and the lymphatic system disorders
personality disorder, hallucinations
Nervous system disorders
alertness decreased, somnolence or insomnia, paraesthesia
visual disturbance (eg. blurred vision), dry eyes and/or eye irritation
Ear and labyrinth disorders
tinnitus, and, in doses exceeding those recommended, hearing disorders (eg. hypoacusis or deafness)
heart failure, cardiac arrhythmias, palpitation
cardiac conduction disorders, precordial pain,
orthostatic hypotension (occasionally with syncope)
oedema, Raynaud's phenomenon
gangrene in patients with pre-existing severe peripheral circulatory disorders
Respiratory, thoracic and mediastinal disorders
bronchospasm (which may occur in patients without a history of obstructive lung disease)
nausea and vomiting, abdominal pain
diarrhoea or constipation
retroperitoneal fibrosis (relationship to Lopresor has not been definitely established)
Skin and subcutaneous tissue disorders
skin rash (in the form of urticaria, psoriasiform and dystrophic skin lesions)
photosensitivity, hyperhydrosis, alopecia, worsening of psoriasis
Musculoskeletal and connective tissue disorders
Reproductive system and breast disorders
disturbances of libido and potency
Peyronie's disease (relationship to Lopresor has not been definitely established)
General disorders and administration site conditions
weight increase, liver function test abnormal
Post Marketing ExperienceThe following adverse reactions have been reported during post-approval use of Lopresor: 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.
Signs and symptomsIn more severe cases an overdosage of 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.The first manifestations of overdosage appear 20 minutes to 2 hours after ingestion of Lopresor. The effects of massive overdose may persist for several days, despite declining plasma concentrations.
TreatmentPatients 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 Lopresor) and/or activated charcoal to remove the drug from the gastrointestinal tract. Metoprolol can not 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. Diazepam is the drug of choice for controlling seizures. A β2-agonist or aminophylline can be used to reverse bronchospasm; patients should be monitored for evidence of cardiac arrhythmias during and after administration of the bronchodilator.
Pharmacotherapeutic groupLopresor is a cardioselective beta-adrenergic blocking agent.
Mechanism of ActionIt 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-stabilising effect nor partial agonist (intrinsic sympathomimetic) activity. The stimulant effect of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac contractility and cardiac output.
AbsorptionMetoprolol 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 metoprolol is given with food.
Distribution and BiotransformationApproximately 10% of metoprolol in plasma is protein bound. Metoprolol crosses the placenta, and is found in breast milk (see Pregnancy and lactation). Metoprolol is extensively metabolised by enzymes of the cytochrome P450 system in the liver. The oxidative metabolism of 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 metabolisers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Orientals are PMs.CYP2D6 poor metabolisers exhibit several-fold higher plasma concentrations of metoprolol than extensive metabolisers with normal CYP2D6 activity. None of the metabolites of metoprolol contribute significantly to its beta-blocking effect.
EliminationElimination 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 metabolisers (approximately 10%) showing higher plasma concentrations and slower elimination than extensive metabolisers. Within individuals, however, plasma concentrations are stable and reproducible.
Characteristics in PatientsBecause of variation in rates of metabolism, the dose of metoprolol should always be adjusted to the individual requirements of the patient. As the therapeutic response, adverse effects and relative cardioselectivity are related to plasma concentration, poor metabolisers may require lower than normal doses. Dosage adjustment is not routinely required in the elderly or in patients with renal failure, but dosage may need to be reduced in patients with significant hepatic dysfunction when metoprolol elimination may be impaired.
Recordati Pharmaceuticals Limited
Isis House, 43 Station Road, Henley-on-Thames, Oxfordshire, RG9 1AT, UK
+44 (0)1491 576 336
+44 (0)1491 576 336
+44 (0)1491 576 336