Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2020 Publisher: Novartis New Zealand Limited, PO Box 99102, Newmarket, Auckland 1149, Telephone: 0800 354 335
Hypersensitivity to metoprolol and related derivatives, or to any of the excipients; hypersensitivity to other beta-blockers (cross-sensitivity between beta-blockers can occur).
For oral use: severe bronchial asthma or history of severe bronchospasm (see Section 4.4 Special warnings and precautions for use).
For intravenous use: bronchial asthma and history of bronchospasm.
Use of Lopresor or Slow Lopresor is contraindicated in patients with myocardial infarction who have a heart rate of less than 45 to 50 beats/min, P-R interval of greater than 0.24 sec, a systolic blood pressure of less than 100 mmHg, and/or severe heart failure.
In general, patients with bronchospastic diseases should not be given beta-blockers, including Lopresor or Slow Lopresor. However, because of its relative cardioselectivity, oral Lopresor or Slow Lopresor may be administered with caution to patients with mild or moderate bronchospastic diseases who do not respond to, or cannot tolerate, other suitable treatments. Since beta1-selectivity is not absolute, a beta2- agonist should be administered concomitantly, and the lowest possible dose of Lopresor or Slow Lopresor should be used.
Lopresor or Slow Lopresor should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents (see Section 4.5 Interaction with other medicines and other forms of interaction).. Diabetic patients should be warned that beta-blockers, including Lopresor or Slow Lopresor, may mask the tachycardia occurring with hypoglycaemia; however, other manifestations of hypoglycaemia such as dizziness and sweating may not be significantly suppressed, and sweating may be increased.
Beta-blockers, including Lopresor or Slow Lopresor, should not be used in patients with untreated congestive heart failure (see Section 4.3 Contraindications). This condition should first be stabilised.
Because of their negative effect on atrioventricular conduction, beta-blockers, including Lopresor or Slow Lopresor, should be given only with caution to patients with first degree atrioventricular block (see Section 4.3 Contraindications).
If the patient develops increasing bradycardia (heart rate less than 50 to 55 beats/min), the dosage should be gradually reduced, or treatment gradually withdrawn (see Section 4.3 Contraindications).
In patients with myocardial infarction, if significant hypotension occurs, Lopresor or Slow Lopresor should be discontinued, and the hemodynamic status of the patient and the extent of myocardial ischemia carefully assessed. Intensive hemodynamic monitoring may be required and appropriate treatment modalities should be instituted. If hypotension is associated with significant bradycardia or atrioventricular block, treatment should be directed at reversing these.
Lopresor or Slow Lopresor should be used with caution in patients with peripheral arterial circulatory disorders (for example, Raynaud’s disease or phenomenon, intermittent claudication), because betablocker treatment may aggravate such conditions (see Section 4.3 Contraindications).
In patients known to have, or suspected of having, a phaeochromocytoma, Lopresor or Slow Lopresor should always be given in combination with an alpha-blocker and only after the alpha-blocker has been initiated (see Section 4.3 Contraindications).
The necessity, or desirability, of withdrawing beta-blocking agents, including Lopresor or Slow Lopresor, prior to major surgery is controversial. The impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The benefits of continuing a treatment with a beta-blocker, including Lopresor, or Slow Lopresor should be balanced against the risk of withdrawing it in each patient. If a patient treated with Lopresor or Slow Lopresor needs general anaesthesia, the anaesthetist should be informed that the patient is receiving a beta-blocker. An anaesthetic agent with as little cardiodepressant effect as possible should be used (see Section 4.5 Interaction with other medicines and other forms of interaction). If it is thought necessary to withdraw beta-blocker, including Lopresor or Slow Lopresor, therapy before surgery, this should be done gradually and completed about 48 hours before the general anaesthetic.
Lopresor or Slow Lopresor treatment should not be stopped suddenly, especially in patients with ischaemic heart disease. To prevent exacerbation of angina pectoris, the dosage should be gradually reduced over 1 to 3 weeks and, if necessary, replacement therapy should be initiated at the same time.
Anaphylactic reactions precipitated by other agents may be particularly severe in patients taking betablockers, and may be resistant to normal doses of adrenaline. Whenever possible, beta-blockers, including Lopresor or Slow Lopresor, should be avoided for patients who are at increased risk of anaphylaxis.
Beta-blockers may increase the number and duration of angina attacks in patients with Prinzmetal’s angina (variant angina pectoris). Relatively selective beta1-receptor blockers, such as Lopresor or Slow Lopresor, can be used in such patients, but only with the utmost care.
Beta-blockers mask some of the clinical signs of thyrotoxicosis. Therefore, where Lopresor or Slow Lopresor is administered to patients having, or suspected of developing, thyrotoxicosis, both thyroid and cardiac function should be monitored closely.
The full oculomucocutaneous syndrome, as described elsewhere with practolol, has not been reported with Lopresor or Slow Lopresor. However, part of this syndrome (dry eyes either alone or, occasionally, with skin rashes) has occurred. In most cases the symptoms cleared when Lopresor or Slow Lopresor treatment was withdrawn. Patients should be observed carefully for potential ocular effects. If such effects occur, gradual discontinuation of Lopresor or Slow Lopresor should be considered.
Calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving Lopresor or Slow Lopresor because there is a risk of cardiac arrest in this situation (see Section 4.5 Interaction with other medicines and other forms of interaction).
Metoprolol undergoes substantial hepatic first-pass metabolism, and is mainly eliminated by hepatic metabolism (see Section 5 Pharmacological properties, and 5.2 Pharmacokinetic properties). Therefore, hepatic impairment may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to increased plasma concentrations.
Elderly patients should be treated cautiously. An excessive decrease in blood pressure or pulse rate may reduce the blood supply to vital organs to inadequate levels.
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 Lopresor or Slow Lopresor because there is a risk of cardiac arrest in this situation (see Section 4.4 Special warnings and precautions for use)
The effects of Lopresor or Slow Lopresor and other antihypertensive drugs on blood pressure are usually additive. Patients receiving concurrent treatment with catecholamine depleting drugs, other betablockers (including those in form of eye drops, such as timolol), or monoamine oxidase (MAO) inhibitors, should be carefully monitored. In addition, possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor.
Concomitant administration of a beta-adrenergic antagonist with a calcium channel blocker may produce an additive reduction in myocardial contractility due to negative chronotropic and inotropic effects. Patients taking an oral calcium channel blocker of the verapamil type in combination with Lopresor or Slow Lopresor should be closely monitored.
Beta-blockers may potentiate the negative inotropic effect of anti-arrhythmic agents and their effect on atrial-conduction time. Particularly, in patients with pre-existing sinus node dysfunction, concomitant administration of amiodarone may result in additive electro-physiologic effects including bradycardia, sinus arrest, and atrioventricular block anti-arrhythmic agents such as quinidine tocainide, procainamide, ajmaline amiodarone, flecainide and disopyramide may potentiate the effects of Lopresor or Slow Lopresor on heart rate and atrioventricular conduction.
Nitroglycerin may enhance the hypotensive effect of Lopresor or Slow Lopresor.
Concomitant administration of beta-blockers with other drugs known to decrease heart rate such as sphingosine-1-phosphate receptor modulators (e.g. fingolimod) may result in additive heart rate lowering effects.
Concomitant administration of beta-blockers with other drugs known to decrease blood pressure such as aldesleukin may result in an enhanced hypotensive effect.
Some inhalation anaesthetics may enhance the cardiodepressant effect of beta-blockers (see Section 4.4 Special warnings and precautions for use).
Potent inhibitors of this enzyme may increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 would result in the change of phenotype into poor metabolizer phenocopying, (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 fluvoxamine, fluoxetine, paroxetine, sertraline, bupropion, clomipramine, desipramine antipsychotics such as chlorpromazine, fluphenazine, haloperidol, thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine.
Concomitant administration of hydralazine may inhibit presystemic metabolism of metoprolol leading to increased concentrations of metoprolol.
Concurrent use of digitalis glycosides may result in excessive bradycardia and/or increase in atrioventricular conduction time. Monitoring heart rate and PR interval is recommended.
Concomitant administration of sympathomimetic drugs such as adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine, phenylpropanolamine, and xanthine derivatives (including antitussives or nose and eye drops) with a beta-blocker may enhance the pressor response resulting in hypertension due to mutual inhibition of therapeutic effects. However, this is less likely with therapeutic doses of beta1- selective drugs than with non-selective beta-blockers.
Concomitant administration of non-steroidal anti-inflammatory drugs including COX-2 inhibitors with a beta-blocker may decrease the antihypertensive effect of metoprolol, possibly as a result of the inhibition of renal prostaglandin synthesis and sodium and fluid retention caused by non-steroidal antiinflammatory drugs.
Enzyme-inducing drugs may affect plasma concentrations of metoprolol. For example, the plasma concentration of metoprolol is lowered by rifampicin.
Antihypertensive effect of alpha-adrenergic blockers such as guanethidine, betanidine, reserpine, alphamethyldopa or clonidine may be potentiated by beta-blockers. Beta- adrenergic blockers may also potentiate the postural hypotensive effect of the first dose of prazosin, probably by preventing reflex tachycardia. On the contrary, beta adrenergic blockers may also potentiate the hypertensive response to withdrawal of clonidine as patients receiving concomitant clonidine and beta-adrenergic blocker. If a patient is treated with clonidine and Lopresor or Slow Lopresor concurrently, and clonidine treatment is to be discontinued, Lopresor or Slow Lopresor should be stopped several days before clonidine is withdrawn.
Beta-blockers may interfere with the usual hemodynamic response to hypoglycemia and produce a rise in blood pressure associated with severe bradycardia In 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 or Slow Lopresor than with a non-selective beta-blocker. However, diabetic patients receiving Lopresor or Slow Lopresor should be monitored to ensure that diabetes control is maintained (see also Section 4.4 Special warnings and precautions for use).
Metoprolol may reduce the clearance of lidocaine, leading to increased lidocaine effects.
The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker, including Lopresor or Slow Lopresor.
Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.
In general, administration of a beta- blocker should be withheld before dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection.
Metoprolol may modify the pharmacokinetic parameters of alcohol.
Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.
In general, no drug should be taken during the first 3 months of pregnancy, and the relative benefits and risks of treatment should be carefully considered throughout pregnancy.
There is a limited amount of data on the use of metoprolol in pregnant women. Experience with metoprolol in the first trimester of pregnancy is limited, but no fetal malformations attributable to metoprolol have been reported. However, beta-blockers may reduce placental perfusion.
In the case of treatment with Lopresor or Slow Lopresor during the pregnancy 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 (for example, bradycardia, hypoglycaemia).
Small quantities of metoprolol are secreted into breast milk: with therapeutic doses, an infant consuming 1 L of breast milk daily would receive a dose of less than 1 mg of metoprolol. Nevertheless, breast-fed infants should be closely observed for signs of beta-blockade.
Dizziness, fatigue or visual impairment may occur during treatment with Lopresor or Slow Lopresor (see Section 4.8 Undesirable effects), and may adversely affect the patient’s ability to drive or use machines.
Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).
| 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 | depressed level of consciousness, somnolence or insomnia, paraesthesia |
| Eye disorders | |
| Very rare | visual impairment (e.g. blurred vision), dry eyes, eye irritation |
| Ear and labyrinth disorders | |
| Very rare | tinnitus1 hearing disorders (e.g. hypoacusis or deafness) |
| Cardiac disorders | |
| Common | bradycardia |
| Rare | cardiac failure, arrhythmias, palpitation |
| Very rare | conduction disorders, chest pain |
| Vascular disorders | |
| Common | orthostatic hypotension (occasionally with syncope) |
| Rare | oedema, Raynaud’s phenomenon |
| Very rare | Gangrene2 |
| Respiratory, thoracic and mediastinal disorders | |
| Common | exertional dyspnoea |
| Rare | Bronchospasm3 |
| Very rare | rhinitis |
| Gastrointestinal disorders | |
| Common | nausea and vomiting, abdominal pain |
| Rare | diarrhoea or constipation |
| Very rare | dry mouth, retroperitoneal fibrosis4 |
| Hepatobiliary disorders | |
Very rare hepatitis
| Skin and subcutaneous tissue disorders | |
| Rare | rash (in the form of urticaria, psoriasiform and dystrophic skin lesions) |
| Very rare | Photosensitivity reaction, hyperhydrosis, alopecia, worsening of psoriasis. |
| Musculoskeletal, connective tissue disorders | |
| Rare | muscle spasms |
| Very rare | arthritis |
| Reproductive system and breast disorders | |
| Very rare | erectile dysfunction, libido disorder, Peyronie’s disease4 |
| General disorders and administration site conditions | |
| Common | fatigue |
| Investigations | |
| Very rare | weight increase, liver function test abnormalities |
1 and, in doses exceeding those recommended
2 in patients with pre-existing severe peripheral circulatory disorders
3 which may occur in patients without a history of obstructive lung disease
4 relationship to Lopresor has not been definitely established
Adverse drug reactions from spontaneous reports and literature cases (frequency not known). The following adverse reactions have been derived from post-marketing experience with Lopresor via spontaneous case reports and literature cases: Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.
Nervous system disorders: confusional state
Investigations: blood triglycerides increased, High Density Lipoprotein (HDL) decreased
Reporting suspected adverse reactions after authorization of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via https://nzphvc.otago.ac.nz/reporting/
Not applicable.
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