AstraZeneca Pharmaceuticals (Ireland) Ltd

Betaloc 50mg Tablets

Betaloc 100mg Tablets

Betaloc 50mg Tablets:

Each tablet contains Metoprolol tartrate 50mg

Each tablet contains 17.5mg lactose monohydrate

Betaloc 100mg Tablets:

Each tablet contains Metoprolol tartrate 100mg

Each tablet contains 35mg lactose monohydrate

For a full list of excipients, see Section 6.1.

Tablet.

Betaloc 50mg Tablets: White to offwhite, circular, biconvex tablet, scored and engraved 'A/BB' on one side.

Betaloc 100mg Tablets: White to offwhite, circular, biconvex tablet, scored and engraved 'A/ME' on one side.

In the management of hypertension and angina pectoris. Cardiac arrhythmias, especially supraventricular tachyarrhythmias.

Adjunct to the treatment of hyperthyroidism.

Early intervention with Betaloc in acute myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics.

Betaloc has been shown to reduce mortality when administered to patients with acute myocardial infarction.

Prophylaxis of migraine.

The tablets should be taken on an empty stomach.

The dose must always be adjusted to the individual requirements of the patient. The following are guidelines:

Hypertension

The recommended maintenance dosage in patients with hypertension is 100mg200mg daily, given as a single dose in the morning or in divided doses (morning and evening). Begin with 50mg twice daily or 100mg once daily. Dose increments should be at intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily. Doses up to 400mg daily have been used. If needed, other antihypertensive agents may be added.

Longterm antihypertensive treatment with metoprolol in daily doses of 100200mg has been shown to reduce total mortality, including sudden cardiovascular death, stroke, and coronary events in hypertensive patients.

Angina Pectoris

The recommended dosage is 100200mg daily, given in divided doses (morning and evening). Begin with 50mg twice daily. Dose increments should be at intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily (in divided doses). Doses up to 300mg daily (in divided doses) have been used. If needed, other antianginal agents may be added.

Cardiac Arrhythmias

The recommended dosage is 100200mg daily given in divided doses (morning and evening). If needed, other antiarrhythmic agents may be added.

Hyperthyroidism

The recommended dosage is 50mg four times a day.

Myocardial Infarction

Early intervention

To achieve optimal benefits from intravenous Betaloc suitable patients should present within 12 hours of the onset of chest pain. Therapy should commence with 5mg i.v. every 2 minutes to a maximum of 15mg total as determined by blood pressure and heart rate. The second or third dose should not be given if the systolic blood pressure is <90mmHg, the heart rate is <40 beats/min and the PQ time is >0.26 seconds, or if there is any aggravation of dyspnoea or cold sweating. Oral therapy should commence 15 minutes after the last injection with 50mg every 6 hours for 48 hours. Patients who fail to tolerate the full intravenous dose should be given half the suggested oral dose.

Maintenance

The usual maintenance dose is 200mg daily, given in divided doses.

Migraine Prophylaxis

The recommended dosage is 100200mg daily, given in divided doses (morning and evening).

Impaired Renal Function

Dose adjustment is generally not needed in patients with impaired renal function.

Impaired Hepatic Function

Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has a low protein binding (510%). However, a reduction in dosage may be necessary, according to the severity of hepatic impairment.

Elderly

Several studies indicate that agerelated physiological changes have negligible effects on the pharmacokinetics of metoprolol.

Children

There is limited experience with metoprolol treatment in children.

Betaloc, as with other betablockers, should not be used in patients with any of the following:

- AV block of second- or thirddegree,

- Unstable decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension),

- Continuous or intermittent inotropic therapy acting through betareceptor agonism,

- Bradycardia, (<45bpm),

- Sick sinus syndrome,

- Cardiogenic shock,

- Severe peripheral arterial circulatory disorder,

- Untreated phaeochromocytoma,

- Metabolic acidosis.

Known hypersensitivity to any component of Betaloc or other betablockers.

Betaloc is also contraindicated when suspected acute myocardial infarction is complicated by bradycardia (<45bpm), first degree heart block (the PQ interval is >0.24 sec) or systolic blood pressure <100mmHg.

Betaloc as with other betablockers:

• should not be withdrawn abruptly. When possible, Betaloc should be withdrawn gradually over a period of 1014 days, in diminishing doses to 25mg daily for the last 6 days. During its withdrawal patients should be kept under close surveillance, especially those with known ischaemic heart disease. The risk for coronary events, including sudden death, may increase during the withdrawal of betablockade.

• must be reported to the anaesthetist prior to general anaesthesia. It is not generally recommended to stop Betaloc treatment in patients undergoing surgery. Acute initiation of high-dose metoprolol to patients undergoing non-cardiac surgery should be avoided, since it has been associated with bradycardia, hypotension and stroke including fatal outcome in patients with cardiovascular risk factors.

• although contraindicated in severe peripheral arterial circulatory disturbances (see Section 4.3), may also aggravate less severe peripheral arterial circulatory disorders.

• may be administered when heart failure has been controlled. Digitalisation and/or diuretic therapy should also be considered for patients with a history of heart failure, or patients known to have a poor cardiac reserve.

• may cause patients to develop increasing bradycardia, in such cases the Betaloc dosage should be reduced or gradually withdrawn.

• due to the negative effect on conduction time, may aggravate preexisting conduction time disorders of moderate degree, which may lead to AV block, and should only be given with caution to patients with first degree heart block.

• may increase the number and duration of angina attacks in patients with Prinzmetal's angina, due to unopposed alphareceptor mediated coronary artery vasoconstriction. Betaloc is a beta₁selective betablocker; consequently, its use may be considered although utmost caution must be exercised.

• may mask the early signs of acute hypoglycaemia, in particular tachycardia. During treatment with Betaloc, the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is less than with nonselective betablockers.

• may mask the symptoms of thyrotoxicosis.

• may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.

Although cardioselective betablockers may have less effect on lung function than nonselective betablockers, as with all betablockers, these should be avoided in patients with reversible obstructive airways disease unless there are compelling clinical reasons for their use. When administration is necessary, these patients should be kept under close surveillance. The use of a beta₂bronchodilator (e.g. terbutaline) may be advisable in some patients. The dosage of the beta₂agonist may require an increase when treatment with Betaloc is commenced.

As with all betablockers, careful consideration should be given to patients with psoriasis before Betaloc is administered.

In the presence of liver cirrhosis the bioavailability of Betaloc may be increased.

In patients with a phaeochromocytoma, an alphablocker should be given concomitantly.

In labile and insulindependent diabetes it may be necessary to adjust the hypoglycaemic therapy.

Intravenous administration of calcium antagonists of the verapamiltype should not be given to patients treated with betablockers.

The initial treatment of severe malignant hypertension should be so designed as to avoid sudden reduction in diastolic blood pressure with impairment of autoregulatory mechanisms.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.

Betaloc 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.

Increased negative inotropic and chronotropic effects may occur when Betaloc is given together with calcium antagonists of the verapamil and diltiazem type, causing bradycardia, hypotension and asystole. In patients treated with betablockers intravenous administration of calcium antagonists of the verapamiltype should not be given in combination.

Digitalis glycosides, in association with betablockers, may increase atrioventricular conduction time and may induce bradycardia.

Patients receiving concomitant treatment with sympathetic ganglion blocking agents, other betablockers (i.e. eye drops), or Mono Amine Oxidase (MAO) inhibitors should be kept under close surveillance.

If concomitant treatment with clonidine is to be discontinued, Betaloc should be withdrawn several days before clonidine.

Betaloc will antagonise the beta₁effects of sympathomimetic agents but should have little influence on the bronchodilator effects of beta₂agonists at normal therapeutic doses.

The administration of adrenaline (epinephrine) to patients undergoing betablockade can result in an increase in blood pressure and bradycardia although this is less likely to occur with beta₁selective drugs.

Betaloc may impair the elimination of lidocaine.

Metoprolol is a metabolic substrate for the Cytochrome P450 isoenzyme CYP2D6. Drugs that act as enzymeinducing and enzymeinhibiting substances may exert an influence on the plasma level of metoprolol. Plasma levels of metoprolol may be raised by coadministration of compounds metabolised by CYP2D6, e.g. antiarrhythmics, antihistamines, histamine2receptor antagonists, antidepressants, antipsychotics, and COX2inhibitors. The plasma concentration of metoprolol is lowered by rifampicin and may be raised by alcohol and hydralazine.

As with other betablockers, concomitant therapy with dihydropyridines e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Concomitant treatment with indometacin or other prostaglandin synthetase inhibiting drugs may decrease the antihypertensive effect of betablockers.

The betablocker may mask some of the symptoms of thyrotoxicosis and of hypoglycaemia by inhibition of sympathetic nerve functions. The effects of hypoglycaemic agents may be increased, particularly by the noncardioselective betablockers. The dosages of oral antidiabetics and also of insulin may have to be readjusted in patients receiving betablockers. The tachycardia of hypoglycaemia may be modified.

As betablockers may affect the peripheral circulation, care should be exercised when drugs with similar activity e.g. ergotamine are given concurrently.

The effects of Betaloc and other antihypertensive drugs on blood pressure are usually additive. Care should be taken when combining with other antihypertensive drugs or drugs that might reduce blood pressure, such as tricyclic antidepressants, barbiturates and phenothiazines. However, combinations of antihypertensive drugs may often be used with benefits to improve control of hypertension.

Pregnancy

Betaloc should not be used in pregnancy or nursing mothers unless the physician considers that the benefit outweighs the possible hazard to the foetus/infant. Betablockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries.

As with all betablockers, Betaloc may cause sideeffects especially bradycardia and hypoglycaemia in the foetus, and in the newborn and breastfed infant.

Betaloc has, however, been used in pregnancy associated hypertension under close supervision, after 20 weeks gestation. Although Betaloc crosses the placental barrier and is present in the cord blood, as yet no evidence of foetal abnormalities has been reported.

Lactation

The amount of metoprolol ingested via breast milk should not produce significant betablocking effects in the neonate if the mother is treated with the normal therapeutic doses.

Patients should know how they react to Betaloc before they drive or use machines because occasionally dizziness or fatigue may occur.

Betaloc is well tolerated and adverse reactions have generally been mild and reversible. The following events have been reported as adverse events in clinical trials or reported from routine use. A relationship to treatment with metoprolol has not always been established.

The following definitions of frequencies are used:

Very common (>10%), common (19.9%), uncommon (0.10.9%), rare (0.010.09%) and very rare (<0.01%).

*Excess frequency of 0.4% compared with placebo in a study of 46,000 patients with acute myocardial infarction where the frequency of cardiogenic shock was 2.3% in the metoprolol group and 1.9% in the placebo group in the subset of patients with low shock risk index. The shock risk index was based on the absolute risk of shock in each individual patient derived from age, sex, time delay, Killip class, blood pressure, heart rate, ECG abnormality, and prior history of hypertension. The patient group with low shock risk index corresponds to the patients in which metoprolol is recommended for use in acute myocardial infarction.

The symptoms of overdose may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

General treatment should include:

Close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Excessive bradycardia can be countered with atropine 1-2 mg intravenously and/or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10 mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10 mg/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta adrenoceptor stimulant such as dobutamine 2.5 to 10 micrograms/kg/minute by intravenous infusion may be given.

Dobutamine, because of its positive inotropic effect could also be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.

Metoprolol is a competitive β-adrenoceptor antagonist. It acts preferentially to inhibit β₁-adrenoceptors (conferring some cardioselectivity), is devoid of intrinsic sympathomimetic activity (partial agonist activity) and possesses β-adrenoceptor blocking activity comparable in potency with propranolol.

A negative chronotropic effect on the heart is a consistent feature of metoprolol administration. Thus, cardiac output and systolic blood pressure rapidly decrease following acute administration.

Metoprolol tablets dissolve rapidly which results in a rapid and complete absorption with t_max within 2 hours and consistent bioavailability data between different study populations.

Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme.

Elimination is mainly via hepatic metabolism (>90%). Terminal half life is about 34 hours.

The acute toxicity of metoprolol is low to moderate. Signs of toxicity are nonspecific and do not indicate any target organ. Signs in rats and dogs indicate that metoprolol can exert a cardiopressive action at high plasma concentrations. Acute toxicity after oral administration is lower in rodents than in dogs.

There is no specific general toxicity after repeated administration to rats or dogs. Reproduction and mutagenicity studies have revealed no evidence of adverse effects. Carcinogenicity studies in rats and mice have shown no increased incidence of neoplasms related to metoprolol.

Microcrystalline cellulose

Lactose monohydrate

Sodium starch glycollate

Colloidal anhydrous silica

Povidone

Magnesium stearate

Not applicable.

5 years.

Do not store above 25°C.

Polypropylene securitainer with polyethylene cap - 56, 100 and 500 tablets

Thermoformed PVC/aluminium blister packs:

100 (10 x 10 blisters)

56 (4 x 14 blisters)

50 (5 x 10 blisters)

Not all pack sizes may be marketed.

No special requirements.

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

Betaloc 50mg Tablets: PA 970/32/2

Betaloc 100mg Tablets: PA 970/32/3

Betaloc 50mg Tablets: 4^th July 1975 / 26^th May 2010

Betaloc 100mg Tablets: 4^th June 1975 / 26^th May 2010

28^th May 2010