Consumer medicine information

Metoprolol-WGR Tablets

Metoprolol tartrate

BRAND INFORMATION

Brand name

Metoprolol-WGR

Active ingredient

Metoprolol tartrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Metoprolol-WGR Tablets.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

The name of your medicine is METOPROLOL-WGR tablets. It contains the active ingredient metoprolol.

It is used:

  • to treat high blood pressure, also called hypertension
  • to prevent a type of chest pain, also called angina
  • after a heart attack
  • to prevent migraine headaches.

Metoprolol belongs to a group of medicines called beta-blockers. It works by affecting the body's response to some nerve impulses, especially in the heart.

As a result, it decreases the heart's need for blood and oxygen and reduces the amount of work that the heart must do. It also widens the blood vessels in the rest of the body.

Metoprolol can be used alone or in combination with other medicines to treat your condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Metoprolol is only available with a doctor's prescription.

There is no evidence that this medicine is addictive.

Use in children

Metoprolol is not recommended for use in children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have or have had any of the following medical conditions:

  • sudden losses of consciousness
  • asthma, wheezing, difficulty breathing or other severe lung problems
  • a history of allergic problems, including hayfever
  • a very slow heartbeat (less than 45 to 50 beats per minute)
  • low blood pressure
  • a severe blood vessel disorder causing poor circulation in the arms and legs, severe drops in blood pressure, dizziness, fast heartbeat, rapid and shallow breathing or cold clammy skin
  • phaeochromocytoma (a rare tumour of the adrenal gland) which is not already being treated with other medicines
  • sudden and oppressive chest pain, a sign of heart attack
  • irregular heartbeat (without functioning pacemaker)
  • other heart disorders
  • swollen ankles and/or tiredness due to heart disease or certain other heart conditions
  • poor blood circulation in your limbs (e.g. very cold, pale hands or feet, or pain in your leg muscles when you walk)
  • shock

If you are not sure whether any of the above medical conditions apply to you, check with your doctor.

Do not take this medicine if you have an allergy to:

  • any medicine containing metoprolol
  • any other beta-blocker medicines
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are pregnant.

Metoprolol should not be used throughout pregnancy, especially during the first 3 months of pregnancy, unless clearly necessary.

Metoprolol may affect your baby, especially if you take it in the last few days before your baby is born.

Your doctor can discuss with you the risks and benefits involved.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives, dyes or bee or wasp stings.

Your doctor will want to know if you are prone to allergies. Beta-blocker medicines can make an allergic reaction worse.

Tell your doctor if you have or have had any of the following medical conditions:

  • diabetes
  • an overactive thyroid gland
  • kidney problems
  • liver problems
  • a heart attack
  • chest pain when you are at rest, or certain types of angina, such as Prinzmetal angina or variant angina
  • oculomucocutaneous syndrome (signs include severe conjunctivitis and skin rash and ear infection)

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

Metoprolol passes into breast milk and there is a possibility that your baby could be affected.

Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interact with metoprolol. These include:

  • other beta-blocker medicines, including beta-blocker eye drops
  • other medicines used to treat high blood pressure e.g. calcium channel blockers (such as verapamil or diltiazem), clonidine and hydralazine
  • some medicines used to treat angina
  • adrenaline or similar substances, which are often found in eye or nose drops, or in some cough and cold medicines
  • other medicines used to treat irregular heart beat (arrhythmias), e.g. amiodarone, flecainide, disopyramide and quinidine
  • medicines for diabetes
  • quanethidine, used to treat certain heart conditions
  • some local and general anaesthetics used during surgery
  • warfarin or dipyridamole, used to prevent blood clots
  • non-steroidal anti-inflammatory drugs (NSAIDs), used to relieve pain or inflammation e.g. ibuprofen or indomethacin
  • cimetidine, used for stomach ulcers
  • some antibiotics (e.g. rifampicin)
  • some antivirals (e.g. ritonavir)
  • some antihistamines (e.g. diphenhydramine)
  • some antidepressant medications (e.g. fluoxetine, paroxetine or bupropion)
  • monoamine-oxidase inhibitor (MAOI) medicines
  • some antifungals (e.g. terbinafine)
  • ergot alkaloids, used in the prevention and treatment of migraine headaches

These medicines may be affected by metoprolol or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

High blood pressure:
The usual dose is from 50 mg to 200 mg each day, either as a single dose or divided into two doses.

Angina:
The usual dose is from 100 mg to 300 mg each day, divided into two or three doses.

After a heart attack:
The usual dose is 200 mg each day, divided into two doses.

To prevent migraine:
The usual dose is from 100 mg to 150 mg each day, divided into two doses (morning and evening).

How to take it

Swallow the tablets whole with a full glass of water.

It does not matter if you take metoprolol before or after food.

How long to take it

Continue taking metoprolol for as long as your doctor tells you.

Metoprolol helps to control your symptoms, but it does not cure your condition. Your doctor will check your progress to make sure the medicine is working and will decide how long your treatment should continue.

Talk to your doctor if you are not sure how long you need to take your medicine for.

If you forget to take it

If it is almost time for your next dose, skip the missed dose and take your next dose at the usual time.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the one that you missed. This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include feeling sick and vomiting, bluish skin and nails, very low blood pressure, slow heartbeat, difficulty breathing, fainting, convulsions (fits), coma or death.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

If you have an allergic reaction to a food, another medicine or an insect sting while you are taking this medicine, tell your doctor immediately. There is a chance that metoprolol could make the allergic reaction worse or harder to treat.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

You may feel light-headed or dizzy when you start to take metoprolol.

This is because your blood pressure is falling suddenly. If this problem doesn't go away, talk to your doctor.

To avoid symptoms of low blood pressure, here are some hints that may help:

  • Stand up slowly to help your body get used to the change in position and blood pressure
  • If you feel dizzy, sit or lie down until you feel better
  • If you feel faint, breathe deeply and bend forward with your head between your knees
  • Take extra care when exercising, driving or standing for long periods, especially in hot weather. Drink plenty of fluids, especially if you sweat a lot.

If you are being treated for diabetes, make sure you check your blood sugar regularly and report any problems to your doctor. Metoprolol may change how well your diabetes is controlled. It may also prevent some of the warning signs of low blood sugar, such as fast heartbeat and may make low blood sugar last longer. The dose of your diabetes medicines may need to be changed.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Make sure you drink enough water during exercise and hot weather when you are taking this medicine, especially if you sweat a lot. If you do not drink enough water while taking metoprolol, you may feel faint or lightheaded or sick. This is because your blood pressure is dropping too much. If you continue to feel unwell, tell your doctor.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. Your doctor may want to gradually reduce the amount of metoprolol you are taking before stopping it completely. This helps to reduce the chance of your condition becoming worse or keep other unwanted heart problems from happening.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking this medicine until you know how it affects you.

As with other beta-blocker medicines, metoprolol may cause dizziness, light-headedness or decreased alertness in some people.

If you have any of these symptoms, do not drive or do anything else that could be dangerous.

Be careful drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness or light-headedness may be worse.

Be careful to dress warmly during cold weather, especially if you will be outside for a long time. Like other beta-blocker medicines, metoprolol may make you more sensitive to cold temperatures, especially if you have problems with your blood circulation. These medicines tend to decrease blood circulation in the skin, fingers and toes.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking this medicine.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

If you are over 65 years of age, you may have an increased chance of getting side effects.

Tell your doctor if you notice any of the following and they worry you:

  • tiredness, drowsiness or decreased alertness
  • dizziness, spinning sensation (vertigo) or light-headedness
  • headache or other aches and pains
  • sleepiness during the day, difficulty sleeping or nightmares
  • stomach ache or upset, nausea (feeling sick) or vomiting
  • diarrhoea or constipation
  • dry or irritated eyes; blurred vision
  • dry mouth
  • increased sweating
  • runny or blocked nose
  • abnormal triglycerides, cholesterol values or liver function tests during treatment with metoprolol

Tell your doctor as soon as possible if you notice any of the following:

  • fainting
  • depression or other changes in mood
  • confusion or loss of memory
  • buzzing or ringing in the ears, or other difficulty hearing
  • problems with sexual function
  • weight gain
  • hair thinning
  • worsening of psoriasis
  • muscle cramps or painful joints
  • a tingling sensation

The above list includes serious side effects that may require medical attention.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • shortness of breath, sometimes with tiredness, weakness or reduced ability to exercise
  • swelling of the feet or legs due to fluid build-up
  • coldness, burning, numbness or pain in arms and legs
  • chest pain
  • pain behind the breastbone (different from angina)
  • changes in heart rate (fast, slow or irregular)
  • yellowing of the skin or eyes (jaundice), sometimes with pain in the abdomen
  • constant "flu-like" symptoms (chills, fever, sore throat, aching joints, swollen glands, tiredness or lack of energy)
  • unusual bleeding or bruising
  • skin reactions (rash, itching or worsening of psoriasis)
  • symptoms of sunburn (redness, itching, swelling or blistering) that happen much more quickly than normal
  • abnormal thinking or hallucinations (seeing or hearing things that are not there)
  • symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

Other side effects not listed above may occur in some patients.

Storage and Disposal

Storage

Keep your tablets in the original pack, away from direct light, until it is time to take them. If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it in the car or on windowsills. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What METOPROLOL-WGR looks like

Metoprolol 50 mg tablets:

Pink, round, biconvex film-coated tablets with notch break line on one side and '50' debossed on the other side. AUST R 234003.

A blister pack contains 10 tablets or 100 tablets.

Metoprolol 100 mg tablets:

White to off white, round, biconvex film-coated tablets with notch break line on one side and '100' debossed on the other side. AUST R 234004.

A blister pack contains 10 tablets or 60 tablets.

* Not all strengths and pack sizes may be available.

Ingredients:

Metoprolol contains 50 mg or 100 mg of metoprolol tartrate as the active ingredient.

The tablets also contain the following in-active ingredients:

  • Lactose monohydrate
  • Microcrystalline cellulose
  • Sodium starch glycollate
  • Colloidal anhydrous silica
  • Croscarmellose sodium
  • Pregelatinised maize starch
  • Purified talc
  • Magnesium stearate
  • Hypromellose
  • Macrogol 400
  • Titanium dioxide
  • Iron oxide - red (50 mg only)

Metoprolol tablets contains sugars as lactose.

Sponsor

Wagner Pharmaceuticals Pty Ltd
6 Albert Street
Preston VIC 3072
Tel: 1800 936 140

This leaflet was last updated in September 2024.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Metoprolol-WGR

Active ingredient

Metoprolol tartrate

Schedule

S4

 

1 Name of Medicine

Metoprolol tartrate.

2 Qualitative and Quantitative Composition

Metoprolol-WGR contain either 50 mg or 100 mg of metoprolol tartrate.

Excipients with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets 50 mg.

Pink, round, biconvex film-coated tablets with notch break line on one side and '50' debossed on other side.

Tablets 100 mg.

White to off-white, round, biconvex film-coated tablets with notch break line on one side and '100' debossed on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension: as monotherapy or for use in combination with other antihypertensives.
Angina pectoris: for long-term prophylaxis. Glyceryl trinitrate should be employed if necessary for alleviating acute attacks.
Confirmed or suspected myocardial infarction.
Prevention of migraine.

4.2 Dose and Method of Administration

Dosage.

The maximum daily dose should not exceed 400 mg.
Although twice daily dosage is optimal, in those patients whose maintenance dosage is 150 mg daily or less, it may be administered as a single dose.
It is advisable to individualise the dosage.

Method of administration.

The film coated tablets should be swallowed whole with a glass of water.
Metoprolol-WGR tablets should always be taken in standard relation to meals. For example, if it is decided that the patient should take Metoprolol-WGR Tablets with breakfast, the patient should continue to take it with breakfast throughout the course of therapy.
Hypertension.

Mild.

50 or 100 mg, given once daily for one week.

Moderate to severe.

50 or 100 mg, given twice daily for one week.

Maintenance.

50 or 100 mg, given once or twice daily.
Some patients may respond to 50 mg. A larger number will respond to 100 mg, given once daily as initial and maintenance therapy. Response is rarely improved by increasing the dose beyond 200 mg daily.
Angina pectoris. 50 mg to 100 mg, given two or three times daily.
Myocardial infarction. The recommended dosage can be reduced depending on the haemodynamic status of the patient.

Initially.

Therapy should commence with 50 mg twice daily and be continued for 48 hours.

Maintenance.

Generally 100 mg, given twice daily.
Prevention of migraine. 100 to 150 mg, given in two divided doses (morning and evening).

4.3 Contraindications

Known hypersensitivity to metoprolol and related derivatives.
Hypersensitivity to any of the excipients in Metoprolol-WGR.
Sensitivity to other beta-blockers (cross-sensitivity between beta-blockers can occur).
Atrioventricular block of second or third degree.
Congestive heart failure.
Sinus bradycardia (less than 45 to 50 beats/minute).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Shock (including cardiogenic and hypovolaemic shock).
Myocardial infarction patients with a heart rate of < 45 beats/min, a P-R interval of > 0.24 sec, a systolic blood pressure of < 100 mmHg, and/or moderate to severe heart failure.
Right ventricular failure secondary to pulmonary hypertension.
Significant right ventricular hypertrophy.
Hypotension.
Untreated phaeochromocytoma (see Section 4.4 Special Warnings and Precautions for Use).
Continuous or intermittent inotropic therapy acting through β-receptor agonism.
Allergic disorders (including allergic rhinitis) which may suggest a predisposition to bronchospasm.
Severe bronchial asthma or history of severe bronchospasm.
Beta-adrenergic blockade of the smooth muscle of bronchi and bronchioles may result in an increased airways resistance. These drugs also reduce the effectiveness of asthma treatment. This may be dangerous in susceptible patients. Therefore, beta-blockers are contraindicated in any patient with a history of airways obstruction or a tendency to bronchospasm. Use of cardio-selective beta-blockers can also result in severe bronchospasm. Metoprolol-WGR should not be used in patients with severe bronchospastic disease (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Use in special patient groups.

Bronchospastic disease. In general, patients with bronchospastic disease should not be given beta-blockers of any type (e.g. selective or non-selective), including Metoprolol-WGR. If such therapy must be used, great caution should be exercised. Alternative therapy should be considered.
Cardiac failure. Beta-blockade depresses myocardial contractility and may precipitate cardiac failure in some patients with a history of cardiac failure, chronic myocardial insufficiency or unsuspected cardiomyopathy. In patients without a history of cardiac failure, continuing depression of the myocardium may lead to cardiac failure. If signs of cardiac failure are present, the patient should be fully digitalised and/or given a diuretic and carefully monitored. If cardiac failure persists, the beta-blocker should be withdrawn gradually (see statement below regarding abrupt withdrawal).

Note.

Although congestive heart failure has been considered to be a contraindication to the use of beta-blockers, there is a growing literature on the experimental use of beta-adrenergic blocking drugs in heart failure. As further trials are needed to identify which patients are likely to respond to which drugs, beta-blockers should not normally be prescribed for heart failure outside of specialist centres.
Beta-blockers, including Metoprolol-WGR, should not be used in patients with untreated congestive heart failure. This condition should first be stabilised.
Myocardial infarction. In patients with myocardial infarction, if significant hypotension occurs, Metoprolol tartrate 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.
Prinzmetal angina. There is a risk of exacerbating the number and duration of coronary artery spasms if patients with Prinzmetal angina or variant angina pectoris are treated with a beta-blocker, including Metoprolol-WGR. If this treatment is essential, it should only be undertaken in a coronary or intensive care unit.
Conduction disorders. Very rarely a pre-existing A-V conduction disorder of moderate degree may become aggravated (possibly leading to A-V block). Metoprolol-WGR should be administered with caution to patients with first degree A-V block (see Section 4.3 Contraindications).
Phaeochromocytoma. In patients known to be, or suspected to be, suffering from a phaeochromocytoma, metoprolol tartrate should always be given in combination with an alpha-blocker (e.g. phentolamine or phenoxybenzamine) and only after the alpha blocker has been initiated to avoid exacerbation of hypertension.
Diabetes. Metoprolol-WGR should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents. Diabetic patients should be warned that beta-blockers, including Metoprolol-WGR, affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia.
In patients with insulin or non-insulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia, beta-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need adjustment. Diabetic patients receiving Metoprolol-WGR should be monitored to ensure that diabetes control is maintained.
Allergic conditions. Allergic conditions may be exaggerated by beta-blockade (e.g. allergic rhinitis during the pollen season and allergic reactions to bee and wasp stings). Beta-blockers, including Metoprolol-WGR, should be avoided if there is a risk of bronchospasm.
In patients taking beta-blockers, including Metoprolol-WGR, anaphylactic shock assumes a more severe form and may be resistant to normal doses of adrenaline. Whenever possible, beta-blockers, including Metoprolol-WGR, should be avoided in patients who are at increased risk of anaphylaxis.
Hyperthyroidism. Because beta-blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomatic improvement without any change in thyroid status, special care should be exercised in those patients who are hyperthyroid and are also receiving beta-blockers. Where Metoprolol-WGR is administered to patients having, or suspected of developing thyrotoxicosis, both thyroid and cardiac function should be monitored closely.
Interactions. Calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving metoprolol tartrate because there is a risk of cardiac arrest in this situation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Peripheral circulatory disorders. Beta-blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral vascular disease (for example, Raynaud's disease or phenomenon, intermittent claudication) (see Section 4.3 Contraindications).
Use in hepatic impairment. Metoprolol is mainly eliminated by means of hepatic metabolism (see Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties). Therefore, hepatic impairment may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to increased plasma concentrations. Metoprolol tartrate blood levels are likely to increase substantially in patients with hepatic impairment. The elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h), in patients with liver impairment. Therefore, metoprolol tartrate should be initiated at low doses with cautious gradual dose titration according to clinical response.
Use in renal impairment. Patients with renal impairment may usually be treated with normal doses. In patients with severe renal disease, haemodynamic changes following beta-blockade may impair renal function further. Beta-blockers which are excreted mainly by the kidney may require dose adjustment in patients with renal failure. Caution in metoprolol tartrate dosing is recommended in patients with severe renal impairment. There is a possibility of accumulation of one of metoprolol tartrate's less active metabolites in patients with a creatinine clearance below 5 mL/min but this accumulation would not influence the beta-blocking properties of metoprolol.

Possible effects of treatment.

Effects on the heart rate.

If the patient develops increasing bradycardia (heart rate less than 50 to 55 beats/min), the dosage of Metoprolol-WGR should be gradually reduced or treatment gradually withdrawn (see Section 4.3 Contraindications).

Effects on the thyroid.

The effects of beta-blockers on thyroid hormone metabolism may result in elevations of serum free thyroxine (T4) levels. In the absence of any signs or symptoms of hyperthyroidism, additional investigation is necessary before a diagnosis of thyrotoxicosis can be made.

Other metabolic effects.

Beta-adrenoceptors are involved in the regulation of lipid as well as carbohydrate metabolism. Some drugs affect the lipid profile adversely although the long-term clinical significance of this change is unknown and the effect appears to be less for drugs with intrinsic sympathomimetic activity.

Effects on the eye and skin.

Various rashes and conjunctival xeroses have been reported with beta-blocking agents. Cross reactions may occur between beta-blockers, therefore substitutions within the group may not necessarily preclude occurrence of symptoms.
During long-term treatment with the beta-blocking drug, practolol, a specific rash bearing a superficial resemblance to psoriasis was occasionally described. In a number of patients affected, this rash was accompanied by adverse effects on the eye (xerophthalmia and/or keratoconjunctivitis) of varying severity. This condition is called the oculomucocutaneous syndrome or practolol syndrome. On a few rare occasions, serous otitis media, sclerosing peritonitis, pericarditis and pleurisy have been reported.
The full oculomucocutaneous syndrome has not been reported with metoprolol. However, part of the 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-WGR should be considered.
More recently, an association between Peyronie's disease (a fibrosing induration of the penis) and various beta-blockers has been suggested but is not proven.

Abrupt withdrawal.

Care should be taken if beta-blockers have to be discontinued abruptly in patients with coronary artery disease. Severe exacerbation of angina and precipitation of myocardial infarction and ventricular arrhythmias have occurred following abrupt discontinuation of beta-blockade in patients with ischaemic heart disease. Therefore, it is recommended that the dosage be reduced gradually over a period of about 8-14 days, during which time the patient's progress should be assessed. Metoprolol-WGR (metoprolol tartrate) should be temporarily reinstituted if the angina worsens markedly or if acute coronary insufficiency develops. If the drug must be withdrawn abruptly, close observation is required. In the perioperative period, beta-blockers should not be withdrawn unless indicated.

Women of child-bearing potential.

Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.

Use in the elderly.

Caution in dosing is recommended due to increased likelihood of adverse events (see Section 5 Pharmacological Properties, Pharmacokinetics in the elderly).

Paediatric use.

No paediatric studies have been performed. The safety and efficacy of metoprolol in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on metoprolol.

The effects of Metoprolol-WGR and other antihypertensive drugs on blood pressure are usually additive. Metoprolol enhances the effects of other antihypertensive drugs. Particular care is required when initiating administration of a beta-blocker and prazosin together.

Sympathetic ganglion blocking agents, other beta-blockers or monoamine oxidase (MAO) inhibitors.

Patients receiving concurrent treatment with sympathetic ganglion blocking agents, catecholamine depleting drugs, other beta-blockers (including those in form of eye drops), 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.

The following medicinal products may increase the effect or plasma concentrations of metoprolol.

Antiarrhythmic drugs.

Beta-blockers may enhance the negative inotropic and negative chronotropic effect of antiarrhythmic agents of the quinidine type. Care should be taken when prescribing beta-blockers with antiarrhythmic drugs. Interactions have been reported during concomitant beta-blocker therapy with the Class IA agents, disopyramide and less frequently quinidine; Class IB agents, tocainide, mexiletine and lignocaine; Class IC agents, flecainide and propafenone (not available in Australia); the Class III agent, amiodarone; and the Class IV agents (e.g. verapamil).
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.

Antihypertensive drugs.

Metoprolol-WGR enhances the effect of other antihypertensive drugs. The combined effects of Metoprolol-WGR and other antihypertensive drugs on blood pressure are usually additive.

Calcium antagonists.

The concomitant use of beta-blockers and calcium antagonists with myocardial depressant and sinus node activity, e.g. verapamil and to a lesser extent diltiazem, may cause hypotension, bradycardia and asystole. Extreme caution is required if these drugs have to be used together. A calcium channel blocker of the phenylalkylamine type (e.g. verapamil) should not be administered intravenously to patients receiving Metoprolol-WGR because there is a risk of cardiac arrest in this situation. 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 this type in combination with Metoprolol-WGR should be closely monitored.
The dihydropyridine calcium antagonists (e.g. nifedipine) have a weaker myocardial depressant effect and can be administered cautiously with beta-blockers. If excessive hypotension develops, the calcium antagonist should be stopped or the dosage reduced.

CYP2D6 inhibitors.

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 metaboliser. 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, 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 and medications for stomach ulcers such as cimetidine.

Hydralazine.

Concomitant administration of hydralazine may inhibit pre-systemic metabolism of metoprolol leading to increased concentrations of metoprolol.

General anaesthetics.

The necessity or desirability of withdrawing beta-blocking agents prior to major surgery is controversial. The impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anaesthesia and surgical procedures. The benefits of continuing a treatment with a beta-blocker should be balanced against the risk of withdrawing it in each patient.
In patients receiving beta-blocker therapy, inhalation anaesthetics may enhance the cardiodepressant effect. Beta-blockade may have beneficial effects in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the postoperative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthetist must be made aware of beta-blockade because of the potential for interactions with other drugs, resulting in severe bradyarrhythmias and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and the increased propensity for vagal-induced bradycardia. Incidents of protracted severe hypotension or difficulty restoring normal cardiac rhythm during anaesthesia have been reported.
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.
Modern inhalational anaesthetic agents are generally well tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were sometimes associated with severe circulatory depression in the presence of beta-blockade. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.
Metoprolol may also reduce the clearance of other drugs (i.e. lignocaine).

Glyceryl trinitrate.

Glyceryl trinitrate may enhance the hypotensive effect of Metoprolol-WGR.

Hepatic enzyme inhibitors.

Enzyme-inhibiting substances may exert an influence on the plasma concentration of metoprolol. The plasma concentration of metoprolol may be raised by cimetidine.

The following medicinal products may decrease the effect or plasma concentration of metoprolol.

Digitalis glycosides.

Concurrent use of digitalis glycosides (e.g. digoxin) may result in excessive bradycardia and/or increase in atrioventricular conduction time. Monitoring heart rate and PR interval is recommended.

Hepatic enzyme inducers.

Enzyme-inducing drugs may affect plasma concentrations of metoprolol. For example, the plasma concentration of metoprolol is lowered by rifampicin.

Non-steroidal anti-inflammatory drugs.

Concurrent treatment with non-steroidal anti-inflammatory drugs including COX-2 inhibitors with a beta-blocker such as indomethacin 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 anti-inflammatory drugs.

Prazosin.

Particular caution is called for when administering a beta-blocker and prazosin together for the first time.

Sympathomimetics.

Adrenaline or other sympathomimetic agents such as adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine, phenylpropanolamine, and xanthine derivatives (including, in antitussives or nose and eye drops) may provoke hypertensive reactions when used concomitantly with beta-blockers; however, this is less likely with therapeutic doses of beta1-selective drugs than with non-selective beta-blockers.
A watch should be kept for possible negative inotropic and chronotropic effects when metoprolol is given together with calcium antagonists and/or anti-arrhythmic agents.
Patients receiving concurrent treatment with sympathetic nervous system inhibitors, other beta-blockers (also in the form of eye drops), or MAO inhibitors should be kept under surveillance.

Effect of metoprolol on other medicinal products.

Alcohol.

Metoprolol may modify the pharmacokinetic behaviour of alcohol when taken concomitantly. The plasma level of metoprolol may be raised by alcohol.

Catecholamine-depleting agents.

Concomitant use of drugs such as reserpine and guanethidine requires careful monitoring since the added effect of a beta-blocker may produce an excessive reduction of the resting sympathetic nervous tone.

Anti-adrenergic agents.

Antihypertensive effect of alpha-adrenergic blockers such as guanethidine, betanidine, reserpine, alpha-methyldopa 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. Concurrent use of beta-blockers and clonidine should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If administered concomitantly, the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker (the rebound hypertension associated with clonidine withdrawal can be exacerbated by the presence of a beta-blocker). Furthermore, if both drugs are withdrawn simultaneously, marked rise in blood pressure, and/or arrhythmias may result.

Antidiabetic drugs and insulin.

Beta-blockers may interfere with the usual hemodynamic response to hypoglycemia and produce a rise in blood pressure associated with severe bradycardia. When treating diabetics with beta-blockers, caution is indicated and the dosage of antidiabetic medication may need to be adjusted.

Lignocaine.

Metoprolol may reduce the clearance of other drugs (e.g. lignocaine, leading to increased lignocaine effects).

Warfarin.

A limited number of reports have demonstrated a rise in AUC and concentration of warfarin when taken with another beta-blocker. This could potentially increase the anti-coagulant effect of warfarin.

Ergot alkaloid.

Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.

Dipyridamole.

In general, administration of a beta-blocker should be withheld before dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of metoprolol tartrate on the fertility of humans have not been studied. While metoprolol tartrate showed reversible adverse effects on spermatogenesis (altered morphology and motility) in male rats at less than therapeutic doses, it had no effect on rates of conception in animal fertility studies at up to 11 times the maximum recommended daily dose on a body surface area adjusted basis.
(Category C)
Metoprolol has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the foetus when metoprolol is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity.
There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly indicated.
Reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for metoprolol tartrate. Embryotoxicity and/or fetotoxicity in rats and rabbits were noted as increases in preimplantation loss, decreases in the number of viable foetuses per doe, and/or decreases in neonatal survival starting at dose of about 300 mg/m2 (on a body surface area adjusted basis), similar to the maximum recommended therapeutic dose. High doses were associated with some maternal toxicity, and growth delay of the offspring in utero, which was reflected in minimally lower weights at birth.
Experience with metoprolol in the first trimester of pregnancy is limited, but no foetal malformations attributable to metoprolol have been reported. 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.
Metoprolol should not be given during pregnancy unless its use is considered essential.
Beta-blockers may reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion and early labour, and cause bradycardia in the foetus and new-born infant. It is therefore suggested that appropriate maternofetal monitoring be performed in pregnant women treated with metoprolol.
Metoprolol crosses the placental barrier in pregnant women; in one study the concentration in the umbilical vein was almost the same as in maternal vein plasma.
During the later stages of pregnancy, these drugs should only be given after weighing the needs of the mother against the risk to the foetus. 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 (e.g. bradycardia, hypoglycaemia).
 The concentration of metoprolol in breast milk is approximately three times higher than in the mother's plasma. In the normal dose range, the amount of metoprolol ingested via human milk seems to be negligible with regard to its beta-blocking effect on the infant. Nevertheless, breast-fed infants should be closely observed for signs or symptoms of beta-blockade.

4.7 Effects on Ability to Drive and Use Machines

Metoprolol-WGR may cause dizziness, fatigue or visual disturbances (see Section 4.8 Adverse Effects (Undesirable Effects)) and, therefore, may adversely affect the patient's ability to drive or use machinery.

4.8 Adverse Effects (Undesirable Effects)

Cardiovascular adverse effects (related, possibly related, unassessable or unknown) reported by ≥ 1% in 1,395 patients during randomised clinical trials of metoprolol and placebo, see Table 1.
Adverse effects are ranked under the following frequency estimates: very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%.

Blood and the lymphatic system disorders.

Rare: agranulocytosis.
Very rare: thrombocytopenia.

Psychiatric disorders.

Uncommon: depression, impaired concentration, somnolence or insomnia, nightmares.
Rare: nervousness, anxiety, impotence/sexual dysfunction
Very rare: personality disorder, hallucinations, mental confusion, amnesia/memory impairment.

Nervous system disorders.

Common: dizziness, headache.
Uncommon: paraesthesia.
Rare: depressed level of consciousness alertness decreased, somnolence or insomnia, short term memory loss.

Eye disorders.

Rare: visual disturbance (e.g. blurred vision), dry eyes and/or eye irritation, conjunctivitis (see Section 4.4 Special Warnings and Precautions for Use).

Ear and labyrinth disorders.

Very rare: tinnitus, and, in doses exceeding those recommended, hearing disorders (e.g. hypoacusis or deafness).

Cardiac disorders.

Common: bradycardia, palpitation, postural disorders (very rarely with syncope).
Uncommon: heart failure, precordial pain, cardiogenic shock in patients with acute myocardial infarction*.
Rare: cardiac arrhythmias, conduction disorders.
* 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.

Vascular disorders.

Common: orthostatic hypotension (occasionally with syncope), peripheral oedema, hypertension (mild and transient), cold extremities (Raynaud's phenomenon), arterial insufficiency.
Uncommon: oedema.
Very rare: gangrene in patients with pre-existing severe peripheral circulatory disorders, angina (mild and transient), intermittent claudication.

Respiratory, thoracic and mediastinal disorders.

Common: dyspnoea, exertional dyspnoea.
Uncommon: bronchospasm (which may occur in patients without a history of obstructive lung disease).
Rare: rhinitis.

Gastrointestinal disorders.

Common: nausea and vomiting, diarrhoea, constipation, abdominal pain, heartburn, flatulence, gastric pain.
Rare: dry mouth.
Very rare: retroperitoneal fibrosis (relationship to metoprolol has not been definitely established), unstable diabetes.

Hepatobiliary disorders.

Very rare: hepatitis.

Skin and subcutaneous tissue disorders.

Common: pruritus.
Uncommon: skin rash (in the form of urticaria, psoriasiform and dystrophic skin lesions).
Rare: loss of hair.
Very rare: photosensitivity, hyperhydrosis, reversible alopecia, worsening of psoriasis, sweating increased.

Musculoskeletal, connective tissue disorders.

Uncommon: muscle cramps.
Very rare: arthritis, musculoskeletal pain, arthralgia.

Reproductive system and breast disorders.

Very rare: erectile dysfunction, libido and potency, Peyronie's disease (relationship to metoprolol has not been definitely established).

Immune system disorders.

Hypersensitivity.

General disorders and administration site conditions.

Very common: fatigue, tiredness.
Very rare: taste disturbance.

Investigations.

Uncommon: weight gain.
Rare: liver function test abnormal.
Discontinuation of the drug should be considered if any such reaction is not otherwise explicable.
The oculomucocutaneous syndrome associated with the beta-blocker, practolol, has not been reported with metoprolol (see Section 4.3 Contraindications).

Post-marketing data.

In addition to the adverse events reported in the clinical trials, the following events have been reported during post-marketing surveillance of metoprolol*:

Nervous system disorders.

Confusional state.

Investigations.

Increase in blood triglycerides, 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.

Potential adverse reactions.

A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Metoprolol-WGR.

Cardiac disorders.

Intensification of AV block (see Section 4.3 Contraindications).

Blood and the lymphatic system disorders.

Nonthrombocytopenic purpura, thrombocytopenic purpura.

Nervous system disorders.

Reversible mental depression progressing to catatonia, an acute reversible syndrome characterised by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance in neuropsychometrics.

Hypersensitivity reactions.

Fever combined with aching and sore throat, laryngospasm, and respiratory distress.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

Poisoning due to an overdosage of Metoprolol-WGR may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiac insufficiency, bradyarrhythmia, cardiac conduction disturbances, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness (or even coma), convulsions, nausea, vomiting and cyanosis and death. The main clinical signs of overdosage are cardiovascular and in some cases decompensation may be rapid.
Concomitant ingestion of alcohol, antihypertensives, quinidine or barbiturates aggravate the signs and symptoms.
The first manifestations of overdosage can appear in 20 minutes but are more commonly seen within 1 to 2 hours after the drug's ingestion. The effects of massive overdosage may persist for several days despite declining plasma concentrations.
Cases of overdosage in paediatric patients need to be given extra attention even if the patient appears well on presentation and even if only a small number of tablets have apparently been taken.

Treatment.

Patients suffering from overdosage of a beta-blocker should always be hospitalised so that vital functions can be monitored. In general, patients with acute or recent myocardial infarction may be more haemodynamically unstable than other patients and should be treated accordingly. Induction of vomiting or gastric lavage should be undertaken.
In the presence of severe hypotension, bradycardia, and impending heart failure, administers a beta1-stimulant (e.g. isoprenaline) intravenously at 2 to 5 minute intervals until the desired effect is achieved. Where a beta1-stimulant is not available, administer 0.5 to 2.0 mg atropine sulphate i.v. in order to block the vagus nerve. If a satisfactory effect is not achieved, agents such as dopamine, dobutamine, or noradrenaline may be administered.
Further measures: 1 to 5 (max 10) mg glucagon (glucagon activates the adenylcyclase system independently of the beta-receptor, augmenting contractility in the presence of beta-blockade); transvenous intracardiac pacemaker. To combat bronchospasm, a beta2-stimulant (e.g. salbutamol) or aminophylline can be given. i.v.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: cardio-selective beta-blocker; ATC Code: C07A B02.

Mechanism of action.

Metoprolol, the active substance of Metoprolol-WGR, is a relatively cardio-selective beta-blocker, i.e. it acts on beta1-receptors mainly located in the heart at lower doses than those needed to influence the beta2-receptors mainly located in the bronchi and peripheral vessels.
Metoprolol has little membrane-stabilising effect nor does it display partial agonist activity (i.e. intrinsic sympathomimetic activity = ISA) at doses required to produce beta-blockade.
Pharmacodynamics (PD)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.
Metoprolol lowers elevated blood pressure in both the standing and lying position. It also reduces the extent of rises in blood pressure occurring in response to physical and mental stress.
In angina pectoris, metoprolol reduces the frequency and severity of the attacks and the need for glyceryl trinitrate relief, and increases exercise tolerance. In cases of supraventricular tachycardia or atrial fibrillation, and in the presence of ventricular extrasystoles, metoprolol has a regulating effect on the heart rate. In patients with a suspected or confirmed myocardial infarction, metoprolol lowers mortality. This effect may possibly be attributable to a decrease in the incidence of severe ventricular arrhythmias, as well as to limitation of infarct size. Metoprolol has also been shown to reduce the incidence of recurrent myocardial infarction.
Due to its beta-blocking effect, metoprolol is suitable for the prevention of migraine.
Metoprolol has been shown to reduce diuretic-induced increase in plasma renin activity. It inhibits catecholamine-induced insulin secretion to a far lesser degree than non-selective beta-blockers.
Orthostatic reactions or disturbances of electrolyte balance have not been observed.
Metoprolol-WGR has less effect than non-selective beta-blockers on peripheral circulation and the bronchial muscles in therapeutic doses. However, it should be used with caution in patients with asthma, and concomitant use of an adrenergic bronchodilator, e.g. terbutaline or salbutamol, is recommended. Patients already on beta2-stimulants for reversible airways obstruction may require adjustment of dosage if metoprolol therapy is subsequently introduced.
Metoprolol-WGR inhibits catecholamine-induced lipolysis.
The active metabolite of metoprolol (2-hydroxymetoprolol) does not contribute significantly to the therapeutic effect.
Metoprolol-WGR is a relatively lipid soluble compound i.e. less soluble than propranolol and more lipid soluble than atenolol.

Clinical trials.

Based on four studies of metoprolol in healthy males (n=69), the mean maximal β1 blockade (Emax) measured by reduction in exercise heart rate was 28%, 95% CI [25%, 31%]. The mean metoprolol plasma concentration at 50% of Emax (C50) was 105 nanomol/L, 95% CI [74, 135]. β1 blockade of 30% of maximum was arbitrarily considered the lower limit to obtain a significant effect and was achieved with a mean plasma concentration (C30) of 45 nanomol/L, 95% CI [32, 58].

5.2 Pharmacokinetic Properties

Absorption.

Metoprolol is rapidly and almost completely (more than 95%) absorbed from the gastrointestinal tract. Metoprolol exhibits stereo-specific pharmacokinetics.

Distribution.

Metoprolol is rapidly and extensively distributed to the extra-vascular tissue. The volume of distribution is 5.6 L/kg. The apparent volume of distribution at steady state (Vss) in extensive metabolisers (4.84 L/kg) is relatively higher than poor metabolizers (2.83 L/kg). At therapeutic concentrations, approximately 12 % of the active ingredient in Metoprolol-WGR (metoprolol tartrate) is bound to human serum proteins. Metoprolol crosses the placenta and is found in breast milk (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation). Metoprolol is not a significant P-glycoprotein substrate indicating that interindividual variability in pharmacokinetics of metoprolol can be majorly due to CYP2D6 metabolism.

Metabolism.

Metoprolol is extensively metabolised by enzymes of the cytochrome P450 system in the liver. The main metabolic pathways of metoprolol are alpha-hydroxylation, O-demethylation, and oxidative deamination. Alpha-hydroxylation of metoprolol is stereo-selective. 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 metabolizers phenotype. Approximately 7% of Caucasians and less than 1% Orientals are poor metabolisers. CYP2D6 poor metabolizers exhibit several-fold higher plasma concentrations of metoprolol than extensive metabolizers with normal CYP2D6 activity. Although the cytochrome P450 2D6 dependent metabolism of metoprolol seems to have little or no effect on safety or tolerability of the drug, caution should be exercised when administering metoprolol to poor metabolisers. Long-term studies have shown that metoprolol neither enhances nor inhibits its own metabolism.

Excretion.

Metoprolol-WGR is excreted mainly by glomerular filtration. Studies with radioactively labelled drug have shown that more than 90% of the dose is excreted in the urine in 72 hours, mainly in the form of known metabolites. Only about 3% of the administered dose is excreted unchanged in the urine in 72 hours. The rate of renal excretion of metoprolol has a linear relationship to its plasma concentration. The elimination half-life of metoprolol is between 3 and 5 hours. Following single oral administration of 100 mg metoprolol the median clearances were 31, 168, and 367 L/h in poor metabolizers, extensive metabolizers, and ultra-rapid metabolizers, respectively. The renal clearance of the stereo-isomers does not exhibit stereo-selectivity in renal excretion.

Dose proportionality.

Metoprolol exhibits saturable pre-systemic metabolism leading to non-proportionate increase in the exposure with increased dose.

Food effect.

In a study in healthy volunteers (n=8), food significantly increased the extent of absorption of metoprolol after a single 100 mg dose (p < 0.05). The average increase in the plasma concentration time AUC was 40% (range -28% to 132%). There was considerable variability. There was also a trend to higher and earlier peak plasma concentrations of metoprolol with food, although the differences compared with fasting were not significant. It is recommended that metoprolol tartrate be taken in standard relation to meals to minimise variations in effects (see Section 4.2 Dose and Method of Administration).

Dose-response.

The duration of the beta-blocking effect is dose dependent (as measured by reduction of exercise heart rate). For instance, in healthy subjects the effect of 20 mg metoprolol given intravenously is halved after about 6 hours.

Pharmacokinetics in the elderly.

The geriatric population may show slightly higher plasma concentrations of metoprolol and the active metabolite alpha-hydroxymetoprolol than the young as a combined result of a decreased elimination of metoprolol and the metabolite in elderly population and a decreased hepatic blood flow. However, this increase is not clinically significant or therapeutically relevant. Whilst the pharmacokinetics of metoprolol are similar in the young and elderly, there may be pharmacodynamic changes in the elderly such as changes in the number of receptors or decreased receptor sensitivity; therefore, caution in dosing is recommended.

5.3 Preclinical Safety Data

Genotoxicity.

Metoprolol tartrate was devoid of mutagenic/genotoxic potential in the bacterial cell system (Ames) test and in vivo assays involving mammalian somatic cells or germinal cells of male mice.

Carcinogenicity.

Metoprolol tartrate was not carcinogenic in mice and rats after oral administration of doses up to 800 mg/kg for 21 to 24 months.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, colloidal anhydrous silica, microcrystalline cellulose, croscarmellose sodium, pregelatinised maize starch, sodium starch glycollate, magnesium stearate, hypromellose, purified talc, macrogol 400, titanium dioxide.
The 50 mg strength tablets also contain iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light and moisture, store in the original packaging. Keep out of reach of children.

6.5 Nature and Contents of Container

50 mg tablet.

Blister packs (PVC/Al) of 100's and 10's (AUST R 234003).

100 mg tablet.

Blister packs (PVC/Al) of 60's and 10's (AUST R 234004).
Not all strengths or pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Metoprolol tartrate is an aryloxypropanolamine derivative. It is a white, odourless or almost odourless, crystalline powder with a melting point of 120°C. It is very soluble in water, soluble in chloroform, methylene chloride and alcohol, and almost insoluble in benzene, diethyl ether and acetone.

Chemical structure.


Chemical name: Bis [(2RS)-11[4- (2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino] propan-2-ol](2R,3R)-2,3-dihydroxybutanedioate.
Molecular weight: 685.
Molecular formula: C34H56N2O12.

CAS number.

56392-17-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes