Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Metoprolol 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.
A warning stating “Do not take this medicine if you have a history of wheezing or asthma” will appear on the label.
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 airway disease unless there are compelling clinical reasons for their use. Therapy with a beta2-stimulant may become necessary or current therapy may require adjustment.
Metoprolol may aggravate bradycardia and symptoms of peripheral arterial circulatory disorders. If the patient develops increasing bradycardia, (heart rate less than 50 to 55 brats/min) Denex should be given in lower doses or gradually withdrawn.
In addition, anaphylactic reactions precipitated by other agents may be particularly severe in patients taking beta-blockers and may be resistant to normal doses of adrenaline. Whenever possible, beta-blockers should be avoided for patients who are at increased risk of anaphylaxis.
Abrupt cessation of therapy with a beta-blocker should be avoided, especially in patients with ischaemic heart disease. When possible, Denex should be withdrawn gradually over a period of 10 days, the doses diminishing to 25 mg for the last 6 days. During its withdrawal, the patient should be kept under close surveillance and replacement therapy should be initiated where required.
Beta-blockers, including Denex, should not be used in patients with untreated congestive heart failure (see section 4.3). This condition should first be stabilized. Additional therapy should also be considered for patients with a history of heart failure or patients who are known to have a poor cardiac reserve, e.g. diuretics and/or digitalization.
Because of their negative effect on atrioventricular conduction, beta-blockers should be given only with caution to patients with first degree atrioventricular block (see section 4.3).
Beta-blockers mask some of the clinical signs of thyrotoxicosis. Therefore, Denex should be administered with caution to patients having or suspected of developing thyrotoxicosis and both thyroid and cardiac function should be monitored closely.
Denex should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents (see section 4.5). In labile and insuli-dependent diabetes it may be necessary to adjust the hypoglycaemic therapy. Denex may mask some of the symptoms of hypoglycaemia by inhibition of sympathetic nerve functions and patients should be warned accordingly.
In patients with a treated phaeochromocytoma, an alpha-blocker should be given concomitantly.
In patients with significant hepatic dysfunction it may be necessary to adjust the dosage because metoprolol undergoes biotransformation in the liver.
The administration of adrenaline 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.
Denex therapy should be brought to the attention of the anaesthetist prior to general anaesthesia. When it has been decided to interrupt a beta-blockade in preparation for surgery, therapy should be discontinued for at least 48 hours. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation. However, the risk of hypertension may be increased. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs. In a patient under beta-blockade, the anaesthetic selected should be one exhibiting as little negative inotropic activity as possible (halothane/nitrous oxide). The patient may be protected against vagal reactions by intravenous administration of atropine.
Beta-blockers may increase the number and duration of angina attacks in patients with Prinzmetal’s angina (variant angina pectoris). However, relatively selective β1-receptor blockers, such as Denex can be used in such patients, but only with the utmost care.
Patients with anamnestically known psoriasis should take beta-blockers only after careful consideration.
The full oculomucocutaneous syndrome, as described elsewhere with practolol, has not been reported with Denex. However, part of this syndrome (dry eyes either alone or, occasionally, with skin rashes) has occurred. In most cases the symptoms cleared when Denex treatment was withdrawn. Patients should be observed carefully for potential ocular effects. If such effects occur discontinuation of Denex should be considered (see advice about discontinuation above).
The effects of 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 benefit improve control of hypertension.
As beta-blockers may affect the 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.
The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta blocker.
If 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 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 Denex 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 Denex should be closely monitored.
Potent inhibitors of this enzyme may increase the plasma concentration of 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.
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 may enhance the hypotensive effect of Denex.
Concurrent use of digitalis glycosides may result in excessive bradycardia and/or increase in atrioventricular conduction time.
Metoprolol will antagonize the beta1 effects of sympathomimetic agents but should have little influence on the bronchodilator effects of beta2- agonists at normal therapeutic doses.
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 beta-selective drug such as metoprolol than with a non-selective beta-blocker. However, diabetic patients receiving Denex should be monitored to ensure that diabetes control is maintained (see section 4.4).
Concurrent treatment with non-steroidal anti-inflammatory drugs such as indomethacin may decrease the antihypertensive effect of metoprolol.
Metoprolol may impair the elimination of lidocaine.
Some inhalation anaesthetics may enchance the cardiodepressant effect of beta-blockers (see section 4.4).
Enzyme inducing agents (e.g. rifampicin) may reduce plasma concentrations of metoprolol, whereas enzyme inhibitors (e.g. cimetidine) may increase plasma concentrations.
During concomitant ingestion of alcohol and metoprolol the concentration of blood alcohol may reach higher levels and may decrease more slowly.
Beta-blockers reduce placental perfusion which may result in intrauterine foetal death, immature and premature deliveries. Denex should not be used in pregnancy or lactation unless it is considered that the benefit outweighs the possible risk to the foetus/infant.
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 foetal abnormalities have been reported. Animal experiments have shown neither teratogenic potential nor other adverse events on the embryo and/or foetus relevant of the safety assessment of the product.
The amount of 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.
If Denex is used during pregnancy and lactation special attention should be paid to the foetus, neonate and breast-fed infant for undesirable effects of the drug’s beta-blocking action (e.g. bradycardia, hypoglycaemia). 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 effects of beta-blockade in the newborn baby.
As with all beta-blockers, metoprolol may affect patients' ability to drive and operate machinery. Patients should be warned accordingly.
The following definitions of frequencies are used: 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) and not known (cannot be estimated from the available data).
| Blood and the lymphatic system disorders | |
| Very rare | thrombocytopenia |
| Psychiatric disorders | |
| Rare | depression, nightmares |
| Very rare | personality disorder, hallucinations |
| Nervous system disorders | |
| Common | dizziness, headache |
| Rare | alertness decreased, somnolence or insomnia, paraesthesia |
| Eye disorders | |
| Very rare | visual disturbance (eg. blurred vision), dry eyes |
| Ear and labyrinth disorders | |
| Very rare | tinnitus, and, in doses exceeding those recommended, hearing disorders (eg. hypoacusis or deafness) |
| Cardiac disorders | |
| Common | bradycardia |
| Rare | heart failure, cardiac arrhythmias, palpitation |
| Very rare | cardiac conduction disorders, precordial pain |
| Vascular disorders | |
| Common | orthostatic hypotension (occasionally with syncope) |
| Rare | oedema, Raynaud’s phenomenon |
| Very rare | gangrene in patients with pre-existing severe peripheral circulatory disorders |
| Respiratory, thoracic and mediastinal disorders | |
| Common | exertional dyspnoea |
| Rare | bronchospasm (which may occur in patients without a history of obstructive lung disease) |
| Very rare | rhinitis |
| Gastrointestinal disorders | |
| Common | nausea and vomiting, abdominal pain |
| Rare | diarrhoea or constipation |
| Very rare | dry mouth |
| Not known | retroperitoneal fibrosis (relationship to metoprolol has not been definitely established) |
| Hepatobiliary Disorders | |
| Not known | hepatitis |
| Skin and subcutaneous tissue disorders | |
| Rare | skin rash (in the form of urticaria, psoriasiform and dystrophic skin lesions) |
| Very rare | photosensitivity, hyperhydrosis, alopecia, worsening of psoriasis |
| Musculoskeletal and connective tissue disorders | |
| Rare | muscle cramps |
| Very rare | arthritis |
| Reproductive system and breast disorders | |
| Very rare | disturbances of libido and potency |
| Not known | Peyronie’s disease (relationship to metoprolol has not been definitely established) |
| General disorders and administration site conditions | |
| Common | fatigue |
| Investigations | |
| Very rare | weight increase, liver function test abnormal |
The following adverse reactions have been reported during post-approval use of metoprolol: 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 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 to Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.
No known incompatibilities.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
