Metoprolol Tartrate 100mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metoprolol Tartrate 100 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 100 mg of metoprolol tartrate.
Excipient(s) with known effect:
Each tablet contains 166 mg of lactose.
For the full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Round, biconvex white tablet, engraved 4A6 with a breakline on reverse.
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Metoprolol tablets are indicated for the management of hypertension, angina pectoris and cardiac arrhythmias, especially supraventricular tachyarrhythmias.
They may also be used as an adjunct in the treatment of hyperthyroidism. In the early treatment of acute myocardial infarction, metoprolol may be used to reduce infarct size and the incidence of ventricular fibrillation. By providing pain relief, the need for opiate analgesics may be decreased. When administered to patients with acute myocardial infarction, metoprolol has been demonstrated to reduce mortality. Metoprolol is also indicated for the prevention of migraine.
4.2 Posology and method of administration
Posology
The dose must always be adjusted to the individual requirements of the patient
but should not exceed 400mg/day. The following are guidelines:
Adults The usual dosage for the following indications is given below.
Hypertension: The initial dosage is 100 mg per day in the morning,
which may be increased by 100 mg per day at weekly intervals to a maximum of 400 mg per day, depending on response. If control is not achieved with a single daily dose, twice daily dosing should be initiated. Over the dosage range most patients may be expected to respond rapidly and satisfactory. Combination therapy with a diuretic or another hypotensive agent may also be considered to attain a further reduction in blood pressure.
Metoprolol 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 Metoprolol added into the regime with adjustment of the previous therapy if necessary.
Angina: The usual dosage is 50 to 100 mg two 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: 50 mg two or three times daily usually controls the condition, but if necessary this can be increased to 300 mg per day in divided doses. Following treatment of acute arrhythmia with a Metoprolol injection, continuation therapy with Metoprolol tablets should be initiated 4 to 6 hours later at an initial dose not exceeding 50 mg three times daily.
Hyperthyroidism: 50 mg taken four times daily is the recommended
dosage. This should be reduced as the euthyroid state is achieved.
Myocardial infarction: For optimal benefits in the early intervention of
myocardial infarction, patients should present within 12 hours of the onset of chest pain. Oral therapy should commence within 15 minutes after administration of Metoprolol injection, with 50 mg 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 200 mg daily given in divided doses. The treatment should be continued for at least 3 months.
Migraine prophylaxis: The usual dosage is 100 to 200 mg daily, administered
in divided doses (morning and evening).
Children Metoprolol is not recommended for use in children.
Older people There is no evidence to suggest that dosage
requirements are different in otherwise healthy older patients. However, caution is indicated in older 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.
Initially the lowest possible dose should be used.
Hepatic dysfunction In patients with significant hepatic dysfunction, a
reduction in dosage may be necessary.
Method of administration
Metoprolol tablets should be administered orally and swallowed unchewed.
4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1
Metoprolol is contraindicated in severe asthma or history of severe bronchospasm, atrioventricular block of second or third degree, uncontrolled heart failure, severe bradycardia, cardiogenic shock, hypotension, severe peripheral arterial disease, sick-sinus syndrome, metabolic acidosis, untreated phaeochromocytoma and known hypersensitivity to Metoprolol and related derivatives or to any of the excipients.
Metoprolol is also contra-indicated when myocardial infarction is complicated by significant bradycardia, first degree heart block, systolic hypotension (<100 mmHg) and/or severe heart failure.
4.4 Special warnings and precautions for use
Beta blockers increase sensitivity to allergens and also the severity of anaphylactoid reactions; patients with a history of anaphylaxis to an antigen may be more reactive to repeated challenge with the antigen while taking beta blockers. Whenever possible, beta blockers, including Metoprolol, should be avoided for patients who are at increased risk of anaphylaxis.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The labelling for Metoprolol will state - Do not take this medicine if you have a history of wheezing or asthma.
Although cardioselective beta-blockers, including Metoprolol, may have less effect on lung function than non-selective beta blockers, as with all beta blockers, it is prudent to avoid Metoprolol in the treatment of patients with reversible obstructive pulmonary disease. If compelling clinical reasons necessitate Metoprolol therapy, concurrent use of a beta2-bronchodilator, e.g. terbutaline, may be advisable in some patients or current therapy requires adjustment.
Metoprolol may exacerbate bradycardia, symptoms of peripheral arterial circulatory disorders and anaphylactic shock. If patients develop increasing bradycardia, (heart rate less than 50 to 55 beats/min) Metoprolol 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.
Abrupt withdrawal of beta blockers has sometimes resulted in angina, myocardial infarction, ventricular arrhythmias, and death.
Abrupt cessation of beta-blocking therapy should be avoided, in particular those with known ischaemic heart disease. When possible, withdrawal of Metoprolol should be gradual over 10 days in decreasing doses, to 25 mg daily for the final 6 days. During the period of withdrawal, patients should be closely monitored and replacement therapy should be initiated where required.
Beta-blockers, including Metoprolol, should not be used in patients with untreated congestive heart failure (see section 4.3). Metoprolol may be administered when heart failure has been controlled. For patients with a history of heart failure or those known to have poor cardiac reserve, digitalisation and/or diuretic therapy should be considered. Metoprolol should be used with caution in patients where cardiac reserve is poor.
Because of their negative effect on atrioventricular conduction, beta-blockers, including Metoprolol, 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, Metoprolol should be administered with caution to patients having, or suspected of developing, thyrotoxicosis, and both thyroid and cardiac function should be monitored closely.
Metoprolol should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents (see section 4.5). It may be necessary to adjust hypoglycaemic therapy in labile and insulin-dependent diabetes. Metoprolol may mask some of the symptoms of hypoglycaemia by inhibition of sympathetic nerve functions and patients should be warned accordingly.
Beta blockers reduce the responses to the beta-adrenoceptor stimulating effects of adrenaline. Treatment must be started with the alpha blocker and only when alpha blockade is successfully established can tachycardia be controlled by the cautious use of a beta blocker.
In patients with a phaeochromocytoma, an alpha blocker should be given concurrently.
In the presence of cirrhosis of the liver, it may be necessary to adjust the dosage because Metoprolol undergoes biotransformation in the liver, the bioavailability of Metoprolol may be enhanced. The use of adrenaline in patients undergoing beta-blockade can result in a rise in blood pressure and bradycardia. The possibility of this occurrence is reduced by the use of beta1-selective drugs.
Prior to general anaesthesia, Metoprolol therapy should be reported to the anaesthetist. The benefits of continuing a treatment with a beta-blocker, including Metoprolol, should be balanced against the risk of withdrawing it in each patient. Should Metoprolol withdrawal be considered desirable, if possible, this should be completed at least 24 hours before anaesthesia. Conversely, in some individuals it may be desirable to employ a beta-blocker as pre-medication. By shielding the heart against stress, this may prevent excessive sympathetic stimulation provoking cardiac arrhythmias or acute coronary insufficiency. If a beta-blocker is administered for this purpose, an anaesthetic with little negative inotropic activity should be selected to minimise the risk of myocardial depression. 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 pi-receptor blockers, such as Metoprolol, can be used in such patients, but only with the utmost care.
Like all beta-blockers, careful consideration should be given to patients with psoriasis before Metoprolol is administered.
The full oculomucocutaneous syndrome, as described elsewhere with practolol, has not been reported with Metoprolol. However, part of this syndrome (dry eyes either alone or, occasionally, with skin rashes) has occurred. In most cases the symptoms cleared when Metoprolol treatment was withdrawn. Patients should be observed carefully for potential ocular effects. If such effects occur, discontinuation of Metoprolol should be considered. (see advice about discontinuation above).
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions may occur with drugs whose actions enhance or antagonise the various effects of beta blockers at betal and beta2 receptors, including their antihypertensive effect.
Metoprolol and other anti-hypertensive drugs have an additive effect on blood pressure and care should be taken to avoid hypotension. However, combinations of anti-hypertensive agents are often used with benefit to improve control of hypertension.
As beta-blockers may affect the peripheral circulation, care should be exercised with concurrent therapy of drugs with similar activity, e.g. ergotamine.
Prazosin
The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker.
Clonidine
If combination therapy with clonidine is to be terminated, Metoprolol should be withdrawn several days prior to 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
As with all beta-blockers, Metoprolol should not be administered in combination with verapamil or diltiazem as they may induce bradycardia, hypotension and asystole. A calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving Metoprolol 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 Metoprolol should be closely monitored.
Use of calcium-channel blockers with beta blockers has resulted in hypotension, bradycardia, conduction defects
Metoprolol can reduce myocardial contractility and impair intracardiac conduction and care should be exercised when drugs of similar activity are administered concomitantly e.g. antiarrhythmia agents, general anaesthetics.
CYP2D6 inhibitors
Potent inhibitors of this enzyme may increase the plasma concentration of Metoprolol (see section 5.2). Caution should therefore be exercised when coadministering 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 amiodarone
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
Nitroglycerin may enhance the hypotensive effect of Metoprolol.
Digitalis glycosides
Metoprolol should also not be administered with cardiac glycosides as they may induce bradycardia and/ or increase in atrioventricular conduction time.
Sympathomimetics
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. Enzyme inducing agents, e.g. rifampicin, may decrease plasma Metoprolol levels, whereas enzyme inhibitors, e.g. cimetidine, alcohol or hydralazine may enhance plasma concentrations.
Care should also be taken when beta-blockers are given concurrently with sympathomimetic ganglion blocking agents, other beta-blockers (e.g. eye drops) or MAO inhibitors.
Patients taking beta blockers may have an exaggerated hypertensive response to adrenaline
Insulin and oral hypoglycaemic agents
The dosages of oral anti-diabetic agents and also of insulin may have to be readjusted in patients receiving beta-blockers. 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 Metoprolol than with a non-selective beta-blocker. However, diabetic patients receiving Metoprolol should be monitored to ensure that diabetes control is maintained (see section 4.4).
Non-steroidal anti-inflammatory drugs
Indometacin and other prostaglandin synthetase inhibiting drugs may reduce the antihypertensive effect of beta-blockers.
Adrenaline
Metoprolol therapy can reduce the response to adrenaline during the treatment of an allergic reaction.
Anaphylactic reactions to stings and other antigens may be potentiated by beta blockers and the risk of serious reactions may be increased. In addition, beta blockers may antagonise the effects of adrenaline in the management of anaphylaxis (see Interactions under Sympathomimetics)
Lignocaine
The elimination of lidocaine may also be impaired by Metoprolol.
General anaesthetics
Some inhalation anaesthetics may enhance the cardiodepressant effect of beta-blockers (see section 4.4).
Hepatic enzyme inducers/inhibitors
Enzyme inducing agents (e.g. rifampicin) may reduce plasma concentrations of Metoprolol, whereas enzyme inhibitors (e.g. cimetidine) may increase plasma concentrations.
Alcohol
During concomitant ingestion of alcohol and Metoprolol the concentration of blood alcohol may reach higher levels and may decrease more slowly.
4.6 Fertility, pregnancy and lactation
Pregnancy
Metoprolol should not be used in pregnancy or nursing mothers unless the physician considers the benefits to outweigh the possible risks to the foetus or infant. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries.
However, Metoprolol has been used in pregnancy associated hypertension under close surveillance after 20 weeks gestation. Although Metoprolol crosses the placental barrier and is present in cord blood, there have been no reports of foetal abnormalities. Animal experiments have shown neither teratogenic potential nor other adverse events on the embryo and/or foetus relevant to the safety assessment of the product.
As with all beta-blockers, side effects may develop, including bradycardia and hypoglycaemia in the foetus, new born or breastfed infant. 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.
Breast-feeding
Breast-feeding is not recommended. If the breast-feeding mother is treated with normal therapeutic doses of Metoprolol, the amount of Metoprolol ingested via the breast milk should not produce significant beta-blocking effects in the neonate.
Effects on ability to drive and use machines
4.7
When driving or operating machines it should be taken into account that dizziness or fatigue may occasionally occur. Patients should be warned accordingly.
4.8 Undesirable effects
List of adverse reactions
Frequency estimates:
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),
Not known (cannot be estimated form the available data).
|
Blood and the lymphatic system disorders | |
|
Very rare |
thrombocytopenia |
|
Immune system disorders | |
|
Not known |
positive anti-nuclear antibodies |
|
Psychiatric disorders | |
|
Rare |
depression, nightmares |
|
Very rare |
Personality disorder, hallucinations |
|
Nervous system disorders | |
|
Common |
dizziness, headache |
|
Rare |
alertness decreased, somnolence or insomnia, paraesthesia |
|
Not Known |
amnesia/memory impairment, nervousness, anxiety, taste disturbance |
|
Eye disorders | |
|
Very rare |
visual disturbance (e.g. blurred vision), dry eyes and/or eye irritation |
|
Not known |
conjunctivitis |
|
Ear and labyrinth disorders | |
|
Very rare |
tinnitus, and, in doses exceeding those recommended, hearing disorders (e.g. 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 |
|
Not known |
Increase of pre-existing intermittent claudication |
|
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 |
|
Not Known |
arthralgia |
|
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 |
Post Marketing Experience
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 of suspected adverse reactions
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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Signs and symptoms
Poisoning due to an overdose of Metoprolol may result in 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.
Initial manifestations usually arise within 20 minutes to 2 hours of Metoprolol ingestion. The effects of massive overdose may persist for several days, despite declining plasma concentrations.
Treatment
Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiovascular, respiratory and renal function, and blood glucose and electrolytes. 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. If ingestion is recent, the induction of vomiting, gastric lavage or administration of activated charcoal may prevent further absorption. Cardiovascular complications should be treated symptomatically, which may require the use of sympathomimetic agents, eg. noradrenaline, metaraminol, atropine or inotropic agents, eg. dopamine, dobutamine. Temporary pacing may be required for AV block. An intravenous dose of 1 - 10 mg of glucagon can reverse the effects of excessive beta-blockade. Intravenous beta2-stimulants, e.g. terbutaline may be required to relieve bronchospasm.
Metoprolol cannot be effectively removed by haemodialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: beta blocking agents, selective ATC code: C07A B02.
Metoprolol is a cardioselective beta-adrenoceptor blocking agent.
Mechanism of Action
It has a relatively greater blocking effect on beta ^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.
5.2 Pharmacokinetic properties
Absorption
Metoprolol 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
Approximately 10% of Metoprolol in plasma is protein bound. Metoprolol crosses the placenta, and is found in breast milk (see section 4.6).
Biotransformation
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 betablocking effect.
Elimination
Elimination is mainly by hepatic metabolism and the average elimination halflife 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 Patients
Because 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 older people 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.
5.3 Preclinical safety data
Pre-clinical information has not been included because the safety profile of Metoprolol has been established after many years of clinical use. Please refer to section 4.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The tablets contain:
Microcrystalline cellulose (E460)
Lactose monohydrate Sodium starch glycolate Colloidal anhydrous silica Magnesium stearate
6.2. Incompatibilities
Not applicable.
Shelf-Life
6.3.
48 months.
6.4. Special Precautions for Storage
Store at or below 25°C. Protect from light.
6.5. Nature and Content of Container
HDPE or polypropylene containers with caps or child resistant closures in packs of 100 or 500 tablets.
Blister strips in packs of 28, 30, 56 or 60 tablets.
Not all pack sizes may be marketed.
6.6. Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited,
Brampton Road, Hampden Park,
Eastbourne, BN22 9AG.
8. MARKETING AUTHORISATION NUMBER(S)
PL 00289/0744
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 28/12/2005
10 DATE OF REVISION OF THE TEXT
31/03/2015