Consumer medicine information

APO-Metoprolol Tablets

Metoprolol tartrate

BRAND INFORMATION

Brand name

APO-Metoprolol

Active ingredient

Metoprolol tartrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

APO-METOPROLOL TABLETS

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using APO-METOPROLOL tablets?

APO-METOPROLOL tablets contains the active ingredient metoprolol tartrate. APO-METOPROLOL tablets are used to lower high blood pressure (also called hypertension), prevent angina, treat or prevent heart attacks, or reduce your risk of heart complications following a heart attack or to prevent migraine headaches

For more information, see Section 1. Why am I using APO-METOPROLOL tablets? in the full CMI.

2. What should I know before I use APO-METOPROLOL tablets?

Do not use if you have ever had an allergic reaction to APO-METOPROLOL or any of the ingredients listed at the end of the CMI, if you have asthma, wheezing, difficulty breathing or other lung problems, or have had them in the past, you have a history of allergic problems, including hayfever, you have low blood pressure, you have a very slow heartbeat (less than 45-50 beats/minute), you have certain other heart conditions, you have phaeochromocytoma (a rare tumour of the adrenal gland) which is not being treated already with other medicines, you have a severe blood vessel disorder causing poor circulation in the arms and legs or if you are receiving/having emergency treatment for shock or severely low blood pressure.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use APO-METOPROLOL tablets? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-METOPROLOL tablets and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use APO-METOPROLOL tablets?

  • APO-METOPROLOL tablets are available as either 50mg or 100mg tablets. The dose of APO-METOPROLOL tablets depends on what condition you are being treated for. Your doctor will tell you what dose to take.
  • Swallow the tablet with a glass of fluid.

More instructions can be found in Section 4. How do I use APO-METOPROLOL tablets? in the full CMI.

5. What should I know while using APO-METOPROLOL tablets?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APO-METOPROLOL.
  • Be sure to keep all of your doctor's appointments so that your progress can be checked.
  • If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.
  • Make sure you drink enough water during exercise and hot weather when you are taking APO-METOPROLOL, especially if you sweat a lot.
  • If you are being treated for diabetes, make sure you check your blood sugar level regularly and report any changes to your doctor.
Things you should not do
  • Do not stop using this medicine suddenly without checking with your doctor.
Looking after your medicine
  • Keep your tablets in the blister pack until it is time to take them.

For more information, see Section 5. What should I know while using APO-METOPROLOL? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience side effects, most of them are minor and temporary. However, some side effects may be serious and could require urgent medical attention or hospitalization. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APO-METOPROLOL TABLETS

Active ingredient(s): metoprolol tartrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-METOPROLOL tablets. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using APO-METOPROLOL tablets.

Where to find information in this leaflet:

1. Why am I using APO-METOPROLOL tablets?
2. What should I know before I use APO-METOPROLOL tablets?
3. What if I am taking other medicines?
4. How do I use APO-METOPROLOL tablets?
5. What should I know while using APO-METOPROLOL tablets?
6. Are there any side effects?
7. Product details

1. Why am I using APO-METOPROLOL tablets?

APO-METOPROLOL tablets contains the active ingredient metoprolol tartrate. APO-METOPROLOL tablets belongs to a group of medicines called beta-blockers.

APO-METOPROLOL tablets are used to:

  • lower high blood pressure, also called hypertension
  • prevent angina
  • treat or prevent heart attacks, or reduce your risk of heart complications following a heart attack
  • prevent migraine headaches

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 therefore reduces the amount of work that the heart has to do. It also widens the blood vessels in the rest of the body, as well as helping the heart to beat more regularly.

2. What should I know before I use APO-METOPROLOL tablets?

Warnings

Do not use APO-METOPROLOL tablets if:

  • you are allergic to metoprolol tartrate, or any of the ingredients listed at the end of this leaflet, or any other beta-blocker medicine.
    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 or you may feel faint.
  • you have asthma, wheezing, difficulty breathing or other severe lung problems, or have had them in the past
  • you have a history of allergic problems, including hayfever
  • you have low blood pressure
  • you have a very slow heartbeat (less than 45 to 50 beats per minute)
  • you have certain other heart conditions
  • you have phaeochromocytoma (a rare tumour of the adrenal gland) which is not already being treated with other medicines
  • you have a severe blood vessel disorder causing poor circulation in the arms and legs
  • you are receiving/having emergency treatment for shock or severely low blood pressure.

Check with your doctor if you:

  • are not sure whether any of the above apply to you
  • have any other medical conditions
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Like most beta-blocker medicines, APO-METOPROLOL is not recommended for use during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

The active ingredient in APO-METOPROLOL passes into breast milk and therefore there is a possibility that the breastfed baby may be affected.

Children and Adolescent

Do not give APO-METOPROLOL to children.

The safety and effectiveness of APO-METOPROLOL in children has not been established.

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

  • asthma, wheezing, difficulty breathing or other lung problems
  • diabetes
  • an overactive thyroid gland
  • liver problems
  • certain types of angina
  • any other heart problems
  • phaeochromocytoma, a rare tumour of the adrenal gland
  • any blood vessel disorder causing poor circulation in the arms and legs

3. What if I am taking other medicines?

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

Some medicines may interfere with APO-METOPROLOL tablets and affect how it works. These include:

  • Other beta-blocker medicines, including beta-blocker eye drops
  • calcium channel blockers or calcium antagonists, medicines used to treat high blood pressure and angina for example verapamil or diltiazem
  • medicines used to treat high blood pressure, for example clonidine, hydrazine, and prazosin
  • medicines used to treat abnormal or irregular heart beat for example amiodarone, disopyramide and quinidine
  • adrenaline or similar substances, which are often found in eye or nose drops, or in some cough and cold medicines
  • medicines used to treat arthritis, pain, or inflammation for example indomethacin and ibuprofen
  • warfarin, a medicine used to prevent blood clots
  • digoxin, a medicine used to treat heart failure
  • medicines used to treat diabetes
  • quanethidine, used to treat certain heart conditions
  • some local and general anaethetics used during surgery
  • cimetidine, a medicine used to treat for stomach ulcers
  • medicines used to treat bacterial infections, for example rifampicin
  • some antivirals for example ritonavir
  • some antihistamines for example diphenhydramine
  • some antidepressant medications for example fluoxetine, paroxetine or bupropion
  • medicines used to treat depression
  • monoamine-oxidase inhibitors (MAOIs)
  • some antifungals for example terbinafine
  • ergot alkaloids, used in the prevention and treatment of migraine headaches.

These medicines may be affected by APO-METOPROLOL or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking APO-METOPROLOL.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APO-METOPROLOL tablets.

4. How do I use APO-METOPROLOL tablets?

How much to take

For high blood pressure:

  • The usual starting dose is one 50mg or 100mg tablet once a day for one week.
  • The dose is then usually increased to 50mg or 100mg once or twice daily.
  • Your doctor may tell you to take a different amount of APO-METOPROLOL.
    Follow your doctors the instructions carefully.
  • If you are taking other prescription medicines which lower blood pressure, your doctor may need to change the dose of them to obtain the best results for you.

For angina pectoris:

  • The usual starting dose is one 50mg or 100mg taken two or three times a day.

After myocardial infarction (heart attack):

  • The usual starting dose is 100mg taken twice a day, often starting with a lower dose for 2 days.

For migraine prevention:

  • The usual dose is 100-150mg taken twice a day, taken in divided doses morning and evening.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

How to take APO-METOPROLOL

Swallow the tablet with a full glass of water.

When to take APO-METOPROLOL

Take your medicine at about the same time each day before or after food.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take APO-METOPROLOL

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but it does not cure it.

It is important to keep taking your medicine even if you feel well.

DO NOT STOP TAKING APO-METOPROLOL TABLETS SUDDENLY.

The dose needs to be reduced slowly over 7 to 14 days to make sure that your condition does not get worse. Your doctor will tell you how to gradually reduce the dose before stopping completely.

If you forget to use APO-METOPROLOL tablets

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

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

If you use too much APO-METOPROLOL tablets

If you think that you have used too much APO-METOPROLOL tablets, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too many APO-METOPROLOL tablets your blood pressure may drop too far. You will feel faint, and your heart rate will also slow down. You may also have nausea, vomiting, and convulsions. In extreme cases, serious heart and lung problems may occur.

5. What should I know while using APO-METOPROLOL tablets?

Things you should do

Be sure to keep all of your doctor's appointments so that your progress can be checked.

Elderly patients especially need to be monitored to stop their blood pressure falling too far.

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 begin to take APO-METOPROLOL.

This is because your blood pressure has fallen suddenly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to change in position and blood pressure. If this problem gets worse or continues, talk to your doctor.

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 this medicine, you may feel faint or light headed or sick. This is because your blood pressure is dropping too much. If you continue to feel unwell, tell your doctor.

If you are being treated for diabetes, make sure you check your blood sugar level regularly and report any changes to your doctor.

APO-METOPROLOL may change how well your diabetes is controlled. It may also cover up some of the symptoms of low blood sugar (hypoglycaemia). APO-METOPROLOL may increase the time your body takes to recover from low blood sugar. Your doses of diabetic medicines, including insulin, may need to change.

Call your doctor straight away if you:

  • become pregnant while taking APO-METOPROLOL
  • have a severe allergic reaction to foods, medicines or insect stings

If you have a history of allergies, there is a chance that APO-METOPROLOL may cause allergic reactions to be worse and harder to treat.

If you are about to be started on a new medicine, remind your doctor and pharmacist that you are taking APO-METOPROLOL.

  • Tell any doctors, dentists, and pharmacists who are treating you that you are taking APO-METOPROLOL.
  • If you plan to have a surgery (even at the dentist) that need an anaesthetic, tell your doctor or dentist that you are taking APO-METOPROLOL.
  • If you have to have any medical tests while you are taking APO-METOPROLOL, tell your doctor.
    APO-METOPROLOL may affect the results of some tests.

Things you should not do

  • Do not stop using this medicine suddenly without checking with your doctor.
    Your doctor may want you to gradually reduce the amount of APO-METOPROLOL you are taking before stopping completely. This may help reduce the possibility of your condition getting worse.
  • Do not give APO-METOPROLOL to anyone else even if they have the same condition as you.
  • Do not use APO-METOPROLOL to treat any other complaints unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-METOPROLOL tablets affects you.

As with other beta-blocker medicines, APO-METOPROLOL may cause dizziness, light-headedness, tiredness, or drowsiness in some people. Make sure you know how you react to APO-METOPROLOL before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol, dizziness or light-headedness may be worse.

Dress warmly during cold weather, especially if you will be outside for a long time (for example when playing winter sports).

APO-METOPROLOL like other beta-blocker medicines, may make you more sensitive to cold temperatures especially if you have circulation problems.

Looking after your medicine

Keep your tablets in the blister pack until it is time to take them.

If you take APO-METOPROLOL out of the blister pack it will not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place where the temperature stays below 30°C, away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

When to discard your medicine

Do not take APO-METOPROLOL if the expiry date printed on the pack has passed 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.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • headache, tiredness, drowsiness, weakness, or lack of energy
  • aches and pains, painful joints
  • nausea (feeling sick), vomiting
  • stomach upset, diarrhoea or constipation, weight gain
  • dry mouth, changes in taste sensation
  • difficulty sleeping, nightmares
  • mood changes
  • confusion, short-term memory loss, inability to concentrate
  • increased sweating, runny or blocked nose
  • hair loss
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • dizziness, lightheadedness or fainting especially on standing up, which may be due to low blood pressure
  • tingling or “pins and needles”
  • coldness, burning, numbness or pain in arms and/or legs
  • skin rash or worsening of psoriasis
  • sunburn happening more quickly than usual
  • abnormal thinking or hallucinations
  • buzzing or ringing in the ears, deafness
  • irritated eyes or blurred vision
  • sexual problems
  • constant "flu-like" symptoms with tiredness or lack of energy
  • unusual bleeding or bruising
Serious side effects are rare.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
  • shortness of breath, being less able to exercise
  • swelling of the ankles, feet or legs
  • chest tightness, wheezing, noisy breathing, difficulty breathing
  • chest pain, changes in heart rate or palpitations
  • swelling of the face, lips, tongue or throat which may cause difficulty swallowing or breathing
  • yellowing of the skin or eyes (jaundice), generally feeling unwell
These side effects are rare.		Call your doctor straight away, or go straight to the Emergency at your nearest hospital if you notice any of these very serious side effects.
You may need urgent medical attention or hospitalization.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What APO-METOPROLOL tablets contains

Active ingredient
(main ingredient)		metoprolol tartrate
Other ingredients
(inactive 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)
Potential allergenssugars as lactose

Do not take this medicine if you are allergic to any of these ingredients.

What APO-METOPROLOL tablets looks like

APO-METOPROLOL 50mg tablets is pink, round, biconvex film-coated tablets with notch break line on one side and '50' debossed on the other side. AUST R 192766.

A blister pack contains 10 tablets or 100 tablets.

APO-METOPROLOL 100mg tablets is 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 192772.

A blister pack contains 10 tablets or 60 tablets.

* Not all strengths and pack sizes may be available.

Who distributes APO-METOPROLOL tablets

Arrotex Pharmaceuticals
15-17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in February 2025.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

APO-Metoprolol

Active ingredient

Metoprolol tartrate

Schedule

S4

 

1 Name of Medicine

Metoprolol tartrate.

2 Qualitative and Quantitative Composition

Each tablet contains either 50 mg or 100 mg of metoprolol tartrate as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

50 mg tablet.

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

100 mg tablet.

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.
Suspected or definite myocardial infarction.
Migraine prophylaxis.

4.2 Dose and Method of Administration

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.
The film coated tablets should be swallowed whole.

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 once daily. However, a large number of patients 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.

Migraine prophylaxis.

100 to 150 mg, given in two divided doses (morning and evening).

4.3 Contraindications

Bronchospasm. Beta-adrenergic blockade of the smooth muscle of bronchi and bronchioles may result in an increased airways resistance. These medicines 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 cardioselective beta-blockers can also result in severe bronchospasm. If such therapy must be used, great caution should be exercised. Alternative therapy should be considered.
Allergic disorders (including allergic rhinitis) which may suggest a predisposition to bronchospasm.
Right ventricular failure secondary to pulmonary hypertension.
Significant right ventricular hypertrophy.
Sinus bradycardia (less than 45-50 beats/minute).
Second or third degree atrioventricular (A-V) block.
Shock (including cardiogenic and hypovolaemic shock).
Hypersensitivity to metoprolol, related derivatives or any of the excipients in metoprolol. Cross-sensitivity between beta-blockers can occur.
Congestive heart failure (see Section 4.4 Special Warnings and Precautions for Use).
Sick-sinus syndrome (unless a permanent, appropriately functioning pacemaker is in place).
Severe peripheral arterial circulatory disorders.
Myocardial infarction patients with a heart rate of < 45 beats/min., a P-R interval of ≥ 0.24 seconds, a systolic blood pressure of < 100 mmHg and/or moderate to severe heart failure.
Hypotension.
Untreated phaeochromocytoma (see Section 4.4 Special Warnings and Precautions for Use).
Continuous or intermittent inotropic therapy acting through beta-receptor agonism.

4.4 Special Warnings and Precautions for Use

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, metoprolol should be discontinued gradually (see Section 4.4 Special Warnings and Precautions for Use, Abrupt withdrawal).
Beta-blockers should not be used in patients with untreated congestive heart failure. This condition should first be stabilised. 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 medicines in heart failure. As further trials are needed to identify which patients are most likely to respond to which medication, beta-blockers should not normally be prescribed for heart failure outside of specialist centres.

Myocardial infarction.

In patients with myocardial infarction, if significant hypotension occurs, metoprolol 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. 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 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 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 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, 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 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, should be avoided if there is a risk of bronchospasm.
In patients taking beta-blockers, including metoprolol, anaphylactic shock assumes a more severe form and may be resistant to normal doses of adrenaline. Whenever possible, beta-blockers, including metoprolol, should be avoided in patients who are at increased risk of anaphylaxis.

Hyperthyroidism.

Special care should be exercised in those patients who are hyperthyroid and are also receiving beta-blockers, because beta-blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomatic improvement without any change in thyroid status. Where metoprolol is administered to patients having, or suspected of developing thyrotoxicosis, both thyroid and cardiac function should be monitored closely.

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 renal impairment.

In patients with severe renal disease, haemodynamic changes following beta-blockade may impair renal function further. Caution in metoprolol's dosing is recommended in patients with severe renal impairment. There is a possibility of accumulation of one of metoprolol'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. Beta-blockers which are excreted mainly by the kidney may require dose adjustment in patients with renal failure.

Use in hepatic impairment.

Metoprolol is mainly eliminated by means of hepatic metabolism (see Section 5 Pharmacological Properties, Section 5.2 Pharmacokinetic Properties). Therefore, liver cirrhosis may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to increased plasma concentrations. Metoprolol 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 should be initiated at low doses with cautious gradual dose titration according to clinical response.

Concomitant therapy with calcium antagonists.

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

Clonidine.

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.

Antiarrhythmic drugs.

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 antiarrhythmic agents (e.g. verapamil).

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.

General anaesthesia.

Beta-blockade may have beneficial effects in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the post-operative 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 surgery (see Section 4.4 Special Warnings and Precautions for Use, Abrupt withdrawal).

Possible effects of treatment.

Effects on the heart rate.

If the patient develops increasing bradycardia (heart rate less than 50-55 beats/min), the dosage of metoprolol 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 medicines affect the lipid profile adversely although the long-term clinical significance of this change is unknown and the effect appears to be less for medicines with intrinsic sympathomimetic activity.

Effects on the eye and skin.

Various skin rashes and conjunctival xerosis 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 medicine, practolol, a specific rash bearing a superficial resemblance to psoriasis was occasionally described. In a number of the 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, serious otitis media, sclerosing peritonitis, pericarditis and pleurisy have been reported as part of this syndrome.
The oculomucocutaneous syndrome as reported with practolol has not been reported with metoprolol. However, dry eyes and skin rash have been reported with metoprolol. In most cases the symptoms cleared when metoprolol treatment was withdrawn. Patients should be observed carefully for potential ocular effects. If such symptoms occur, discontinuation of metoprolol 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 should be temporarily reinstituted if the angina worsens.
If the medicine must be withdrawn abruptly in these patients, close observation is required. In the peri-operative period metoprolol should not be withdrawn, unless withdrawal is specifically indicated.

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 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

Antiarrhythmic medicines.

Beta-blockers may enhance the negative inotropic and negative chronotropic effect of anti-arrhythmic agents of the quinidine type. Care should be taken when prescribing beta-blockers with antiarrhythmic medicines. Interactions have been reported during concomitant beta-blocker therapy with the Class IA agents, disopyramide and less frequently, quinidine; Class IB agents, 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.
When metoprolol is given together with anti-arrhythmic agents the patient should be monitored for possible negative inotropic and chronotropic effects. The negative inotropic and negative chronotropic effects of antiarrhythmic agents of the quinidine type and amiodarone may be enhanced by beta-blockers.

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

Patients receiving concomitant treatment with sympathetic ganglion blocking agents, other beta-blockers (also in the form of eye drops) or monoamine oxidase (MAO) inhibitors should be kept under surveillance. Possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor.

Antihypertensive medicines.

Metoprolol enhances the effect of other antihypertensive medicines. Particular care is required when initiating administration of a beta-blocker and prazosin together.

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.

Clonidine.

Concurrent use of beta-blockers and clonidine should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If concomitant treatment with clonidine is to be discontinued, the beta-blocker medication should be withdrawn several days before clonidine. The rebound hypertension associated with clonidine withdrawal can be exacerbated by the presence of a beta-blocker. If both medicines are withdrawn simultaneously, a marked rise in blood pressure and/or arrhythmias may result.

Catecholamine-depleting agents.

Concomitant use of medicines 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.

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 medicines 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 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 should be closely monitored. When metoprolol is given together with calcium antagonists of the verapamil and diltiazem type the patient should be monitored for possible negative inotropic and chronotropic effects.
The combination of beta-blockers with dihydropyridine calcium channel blockers with a weak myocardial depressant effect (e.g. felodipine, nifedipine) can be administered together with caution. If excessive hypotension develops, the calcium antagonist should be stopped or the dosage reduced.

Prostaglandin synthetase inhibiting agents.

Concomitant treatment with indomethacin or other prostaglandin synthetase inhibiting agents may decrease the antihypertensive effect of beta-blockers.

Alcohol.

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

Hepatic enzyme effects.

Enzyme-inducing and enzyme-inhibiting substances may change the plasma concentration of metoprolol. The plasma level of metoprolol is lowered by rifampicin and may be raised by cimetidine, alcohol, hydralazine and selective serotonin re-uptake inhibitors (SSRIs) e.g. paroxetine, fluoxetine and sertraline.

Oral antidiabetic agents.

Beta-blockers may interfere with the usual haemodynamic response to hypoglycaemia 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 (see Section 4.4 Special Warnings and Precautions for Use).

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.
Beta-blockade may have beneficial effects in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the post-operative 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 medicines, 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.
Inhalation anaesthetics may enhance the cardio-depressant effect of beta-blocker therapy. 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 surgery (see Section 4.4 Special Warnings and Precautions for Use, Abrupt withdrawal).
Metoprolol may reduce the clearance of other medicines (e.g. lignocaine).

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.

Digitalis glycosides.

Digitalis glycosides, in association with beta-blockers, may increase atrioventricular conduction time and may induce bradycardia. Monitoring of the heart rate and PR interval is recommended.

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 SSRIs (see Hepatic enzyme effects) or bupropion, clomipramine, 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 presystemic metabolism of metoprolol leading to increased concentrations of metoprolol.

Glyceryl trinitrate.

Glyceryl trinitrate may enhance the hypotensive effect of metoprolol.

Sympathomimetics.

Concomitant administration of sympathomimetic 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 medicines 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.

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 on the fertility of humans have not been studied. While metoprolol 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)
Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.
Metoprolol should not be given during pregnancy unless its use is considered essential.
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.
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.
There is a limited amount of data on the use of metoprolol in pregnant women. Experiences with metoprolol in the first trimester of pregnancy is limited, but no foetal malformations attributable to metoprolol have been reported.
In general, beta-blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion and early labour. It is therefore suggested that appropriate maternofetal monitoring be performed in pregnant women treated with metoprolol. Beta-blockers may cause bradycardia in the foetus and newborn infant.
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 discontinuation of treatment should be considered at least 2-3 days before delivery to avoid increased uterine contractility and effects of beta-blockade in the newborn (e.g. bradycardia, hypoglycaemia).
 Metoprolol is excreted in human breast milk. The concentration of metoprolol in breast milk is approximately three times higher than in the mother's plasma. Beta-blockers taken by the mother may cause side effects, e.g. bradycardia, in the breast fed infant. However, 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. Experience suggests that metoprolol only need to be discontinued during lactation if the infant's hepatic function is severely impacted.

4.7 Effects on Ability to Drive and Use Machines

Metoprolol 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)

Occasionally, especially at the start of treatment, beta-blockers may give rise to gastro-intestinal upsets, sleep disturbances or exertional tiredness. These effects, however, are of a mild nature and seldom necessitate a reduction in the dosage.
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).
The following events have been reported as adverse events in clinical trials or reported from routine use. In many cases a relationship with metoprolol has not been established.
The following definitions of frequency are used: very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%.

Central nervous system.

Very common: fatigue.
Common: dizziness, headache.
Uncommon: paraesthesia, muscle cramps.
Rare: depressed level of consciousness.

Cardiovascular.

Common: bradycardia, postural disorders (very rarely with syncope), cold hands and feet (Raynaud's phenomenon), palpitations, clinically significant falls in blood pressure after intravenous administration.
Uncommon: transient deterioration of heart failure symptoms, A-V block I, oedema, precordial pain, cardiogenic shock in patients with acute myocardial infarction*.
Rare: disturbances of cardiac conduction, cardiac arrhythmias.
Very rare: gangrene in patients with pre-existing severe peripheral circulatory 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.

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.

Haematological.

Rare: agranulocytosis.
Very rare: thrombocytopenia.

Hepatobiliary disorders.

Rare: liver function test abnormalities.
Very rare: hepatitis.

Immune system disorders.

Hypersensitivity.

Musculoskeletal, connective tissue disorders.

Uncommon: muscle cramps.
Rare: muscle spasms.
Very rare: arthritis, musculoskeletal pain.

Metabolic.

Uncommon: weight gain.

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.

Respiratory.

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

Reproductive system.

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

Sense organs.

Rare: disturbances of vision, dry eyes and/or eye irritation, conjunctivitis.
Very rare: tinnitus, hearing disorders when exceeding recommended doses (e.g. hypoacusis or deafness), taste disturbances.

Skin.

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

Vascular disorders.

Common: postural disorders (occasionally with syncope), clinically significant falls in blood pressure after intravenous administration, peripheral oedema, hypertension (mild and transient), cold hands and feet (Raynaud's phenomenon), arterial insufficiency.
Rare: oedema.
Very rare: gangrene in patients with pre-existing severe peripheral circulatory disorders, angina (mild and transient), intermittent claudication.

General disorders.

Common: tiredness.

Miscellaneous.

Very rare: arthralgia.

Post-marketing data - adverse drug reactions from spontaneous reports and literature cases (frequency not known).

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.

Cardiac disorders.

Intensification of AV block (see Section 4.3 Contraindications).

Blood and the lymphatic system disorders.

Non-thrombocytopenic 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 http://www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Poisoning due to an overdosage of metoprolol may lead to severe hypotension, cardiac insufficiency, bradyarrhythmia, cardiac conduction disturbances, bradycardia, atrioventricular block, heart failure, 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. Overdosage with metoprolol can lead to death.
Concomitant ingestion of alcohol, antihypertensives, quinidine or barbiturates aggravates the signs and symptoms.
The first manifestations of overdosage can appear in 20 minutes but are more commonly seen within 1-2 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.
Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care.
In the presence of severe hypotension, bradycardia and impending heart failure, administer a beta1-stimulant (e.g. isoprenaline) intravenously at 2-5 minute intervals until the desired effect is achieved. Where a beta1-stimulant is not available, administer 0.5-2.0 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: 1-5 (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 intravenously.
For information on the management of overdose, contact the Poison 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 is a relatively cardioselective beta-adrenoceptor blocking medicine without intrinsic sympathomimetic activity. 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 reduces the blood pressure in patients with hypertension, in both the standing and supine 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.
Metoprolol has been shown to reduce mortality in patients with suspected or definite myocardial infarction. 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.
In cases of supraventricular tachycardia or atrial fibrillation, and in the presence of ventricular extrasystoles, metoprolol has a regulating effect on the heart rate.
Orthostatic reactions or disturbances of electrolyte balance have not been observed.
In therapeutic doses, metoprolol has less effect on the peripheral circulation and the bronchial muscles than non-selective beta-blockers. However, it should be used with caution in patients with asthma and concomitant use of an adrenergic bronchodilator, e.g. terbutaline or salbutamol, is advisable. Patients with reversible airways obstruction who are already on beta2-stimulants may require adjustment of the dosage of these if metoprolol therapy is subsequently introduced.
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 will inhibit catecholamine-induced lipolysis.
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.
Metoprolol is practically devoid of membrane-stabilising activity and does not display partial agonist activity (i.e. intrinsic sympathomimetic activity = ISA) at doses required to produce beta-blockade.
Metoprolol forms an active metabolite (2-hydroxymetoprolol), which does not contribute significantly to the therapeutic effect.
Metoprolol is considered a relatively lipid soluble compound i.e. less soluble than propranolol and more lipid soluble than atenolol.
Metoprolol has been shown to exert a prophylactic effect in both classical and common migraine.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Metoprolol is rapidly and almost completely (more than 95%) absorbed from the gastro-intestinal 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. At therapeutic concentrations, approximately 12% of the active ingredient in metoprolol tablets (metoprolol tartrate) is bound to human serum proteins.

Metabolism.

Long-term studies have shown that metoprolol neither enhances nor inhibits its own metabolism. 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 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 medicine, caution should be exercised when administering metoprolol to poor metabolisers.

Excretion.

Studies with radioactively labelled drug have shown that more than 90% of the dose is excreted in the urine within 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.
Metoprolol is excreted mainly by glomerular filtration.

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 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 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 was not carcinogenic in mice and rats after oral administration of doses up to 800 mg/kg for 21-24 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, and 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. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.5 Nature and Contents of Container

50 mg tablet.

Blister packs (PVC/Aluminium silver foil) of 10 or 100 tablets (AUST R 192766).

100 mg tablet.

Blister packs (PVC/Aluminium silver foil) of 10 or 60 tablets (AUST R 192772).
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 a white, crystalline powder with a melting point of approximately 120°C. The powder is practically odourless. It is very soluble in water, soluble in chloroform, methylene chloride and alcohol, and almost insoluble in benzene, diethylether and acetone. Metoprolol tartrate is structurally related to other cardioselective beta-blockers.

Chemical structure.

Structural Formula:
Chemical Name: di-[(±)-1-(isopropylamino)-3- [p-(2-methoxyethyl) phenoxy]-2-propanol] L(+)-tartrate.
Molecular Weight: 684.81.
Molecular Formula: (C15H25NO3)2.(C4H6O6).

CAS number.

56392-17-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes