Consumer medicine information

ARX-Metoprolol XL (was Metrol XL)

Metoprolol succinate

BRAND INFORMATION

Brand name

ARX-Metoprolol XL (was Metrol-XL)

Active ingredient

Metoprolol succinate

Schedule

What is in this leaflet

This leaflet answers some common questions about ARX-Metoprolol XL.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ARX-Metoprolol XL against the benefits they expect it will have for you.

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

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

What ARX-Metoprolol XL is used for

ARX-Metoprolol XLis used to treat heart failure. It helps to increase survival, reduce hospitalisation and improve symptoms. It is used in combination with other medicines to treat your condition.

ARX-Metoprolol XL 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 therefore reduces the amount of work the heart has to do. It also helps the heart to beat more regularly.

Your doctor may have prescribed ARX-Metoprolol XL for another reason. Ask your doctor if you have any questions about why ARX-Metoprolol XL has been prescribed for you.

ARX-Metoprolol XL is not recommended for use in children, as there have been no studies of its effects in children

ARX-Metoprolol XL is available only with a doctor's prescription.

There is no evidence that ARX-Metoprolol XL is addictive.

Before you take ARX-Metoprolol XL

When you must not take it

Do not take ARX-Metoprolol XL if:

you are allergic to medicines containing metoprolol or 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 or you may feel faint.
you have or have had asthma difficulty in breathing, wheezing, bronchitis or other lung problems 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
you are receiving/having emergency treatment for shock or severely low blood pressure.

If you are not sure whether any of these apply to you, check with your doctor.

Do not take ARX-Metoprolol XL if the expiry date (Exp.) printed on the pack has passed.

Do not take ARX-Metoprolol XL if the packaging is torn or shows signs of tampering.

Do not give ARX-Metoprolol XL to children.

The safety and effectiveness of ARX-Metoprolol XL in children has not been established.

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:

metoprolol succinate or any of the ingredients listed at the end of this leaflet
any other medicines, especially other beta-blockers
any other substances, such as foods, preservatives or dyes.

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

asthma or other lung problem, even is you had them in the past
allergic problems, including hayfever
diabetes
very slow heart beat (less than 45-50 beats per minute)
severe blood vessel disorder causing poor circulation in the arms and legs
liver problems
kidney problems
certain types of angina
any other heart problems
phaeochromocytoma (a rare tumour of the adrenal gland)
hyperthyroidism (an overactive thyroid gland).

Your doctor may want to take special care if you have any of these conditions.

Tell your doctor, if you are pregnant or intend to become pregnant.

Like most beta- blocker medicines, ARX-Metoprolol XL is not recommended for use during pregnancy.

Tell your doctor, if you are breastfeeding or plan to breast-feed.

The active ingredient in ARX-Metoprolol XL passes into breast milk and therefore there is a possibility that the breast-fed baby may be affected.

If you have not told your doctor about any of the above, tell them before you start taking ARX-Metoprolol XL.

Taking other medicines

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

Some medicines may be affected by ARX-Metoprolol XL, or may affect how well 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 and diltiazem
medicines used to treat high blood pressure, for example clonidine, hydralazine, and prazosin medicines used to treat heart problems
medicines used to treat abnormal or irregular heartbeat, for example amiodarone, disopyramide and quinidine
medicines used to treat arthritis, pain, or inflammation, for example indomethacin and ibuprofen
digoxin, a medicine used to treat heart failure
medicines used to treat diabetes
medicines used to treat bacterial infections, for example rifampicin
cimetidine, a medicine used to treat stomach ulcers
medicines used to treat depression
warfarin, a medicine used to prevent blood clots
monoamine-oxidase inhibitors (MAOIs)

These medicines may be affected by ARX-Metoprolol XL 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 ARX-Metoprolol XL.

If you have not told your doctor about any of these things, tell them before you take any ARX-Metoprolol XL.

How to take ARX-Metoprolol XL

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How much to take

The dose varies from patient to patient.

The usual starting dose is half a 23.75 mg or a whole 23.75 mg tablet once a day for one to two weeks. The dose is then usually doubled every second week up to a maximum dose of 190 mg once daily or to the highest tolerated dose.

Your doctor will tell you how many tablets you need to take each day and when to take them. This depends on your condition and whether or not you are taking any other medicines. Your doctor may adjust the dose of other medicines you are taking to obtain the best results for you.

Follow all directions given to you by your doctor and pharmacist carefully.

DO NOT STOP TAKING ARX-Metoprolol XL SUDDENLY, WITHOUT BEING TOLD BY YOUR DOCTOR.

Stopping ARX-Metoprolol XL suddenly may cause your symptoms to worsen. The dose needs to be reduced slowly over at least 14 days. Your doctor will tell you how to do this.

How to take ARX-Metoprolol XL

Swallow the tablets with a glass of water.

Do not crush or chew the tablets. If you crush or chew ARX-Metoprolol XL tablets, they will not work as well.

ARX-Metoprolol XL tablets can be broken in half if your doctor has prescribed half a tablet.

If you forget to take ARX-Metoprolol XL

If you miss a dose of ARX-Metoprolol XL and your next dose is more than 12 hours away, take the missed dose right away.

If your next dose is less than 12 hours away take only half the dose.

Take your next dose when you are meant to.

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.

How long to take ARX-Metoprolol XL for

To properly control your condition, ARX-Metoprolol XL must be taken every day.

Keep taking ARX-Metoprolol XL for as long as your doctor recommends.

If you take too much ARX-Metoprolol XL (overdose)

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

If you take too much ARX-Metoprolol XL, your blood pressure may drop too far. You will feel faint or may faint, and your heart rate will also slow down. You may also have nausea, vomiting and shortness of breath. In extreme cases, serious heart and lung problems may occur.

While you are taking ARX-Metoprolol XL

Things you must do

Visit your doctor regularly and keep all of your appointments so that your doctor can check on your progress.

If you become pregnant while taking ARX-Metoprolol XL, tell your doctor immediately.

If you have a severe allergic reaction to foods, medicines or insect stings, tell your doctor immediately. If you have a history of allergies, there is a chance that ARX-Metoprolol XL may cause allergic reactions to be worse and 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 begin to take ARX-Metoprolol XL. 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 the change in position and blood pressure. If this problem gets worse or continues, talk to your doctor.

If you feel a worsening of your condition in the early stages of taking ARX-Metoprolol XL Some people may experience an apparent worsening of their condition in the early stages of treatment with ARX-Metoprolol XL. It is important to tell your doctor if this happens to you, although it is usually temporary. If your condition continues to worsen, you should see your doctor as soon as possible.

Make sure you drink enough water during exercise and hot weather when you are takingARX-Metoprolol XL, especially if you sweat a lot. If you do not drink enough water while taking ARX-Metoprolol XL, 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. ARX-Metoprolol XL may change how well your diabetes is controlled. It may also cover up some of the symptoms of low blood sugar (hypoglycaemia). ARX-Metoprolol XL may increase the time your body takes to recover from low blood sugar. Your doses of diabetic medicines, including insulin, may need to change.

Before starting any new medicine, tell your doctor or pharmacist that you are taking ARX-Metoprolol XL.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking ARX-Metoprolol XL.

If you plan to have surgery, including dental surgery, tell your doctor or dentist that you are taking ARX-Metoprolol XL. Your blood pressure may drop suddenly if ARX-Metoprolol XL interacts with the anaesthetic.

If you have to have any medical tests while you are taking ARX-Metoprolol XL, tell your doctor. ARX-Metoprolol XL may affect the results of some tests.

Things you must not do

Do not stop taking ARX-Metoprolol XL, without checking with your doctor. Your doctor may want you to gradually reduce the amount of ARX-Metoprolol XL you are taking before stopping completely. This will help reduce the possibility of your condition worsening or other heart complications occurring.

Do not use ARX-Metoprolol XL to treat any other conditions unless your doctor tells you to.

Do not give ARX-Metoprolol XL to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how ARX-Metoprolol XL affects you. As with other beta-blocker medicines, ARX-Metoprolol XL may cause drowsiness, dizziness or lightheadedness in some people. Make sure you know how you react to ARX-Metoprolol XL before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed.

Be careful when drinking alcohol while taking ARX-Metoprolol XL. If you feel dizzy or lightheaded when you take ARX-Metoprolol XL, drinking alcohol may make you fell more dizzy or lightheaded.

Dress warmly during cold weather, especially if you will be outside for a long time (for example when playing winter sports). ARX-Metoprolol XL, like other beta-blocker medicines, tend to decrease blood circulation in the skin, fingers and toes. It may make you more sensitive to cold weather, especially if you have circulation problems.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ARX-Metoprolol XL.

Like all other medicines, ARX-Metoprolol XL may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

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

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

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.

These side effects are usually mild.

Tell your doctor immediately if you notice any of the following:

dizziness, light headedness or fainting especially on standing up, which may be a sign of low blood pressure
tingling or "pins and needles"
coldness, burning, numbness or pain in the 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
problems with sexual function
constant "flu-like" symptoms with tiredness or lack of energy
unusual bleeding or bruising.

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

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

shortness of breath, being less able to exercise
swelling of the ankles, feet or legs
chest tightness, wheezing, noisy breathing
chest pain, changes in heart rate or palpitations
swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing, which may be signs of a serious allergic reaction
yellowing of the skin or eyes (jaundice), generally feeling unwell

These are very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

After using ARX-Metoprolol XL

Storage

Keep ARX-Metoprolol XL 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.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

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

Do not store ARX-Metoprolol XL or any other medicine in the bathroom or near a sink.

Do not leave ARX-Metoprolol XL in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking ARX-Metoprolol XL, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ARX-Metoprolol XL comes in 4 strengths of tablets:

ARX-Metoprolol XL 23.75 – white, oval tablet, scored on both sides
ARX-Metoprolol XL 47.5 – white, oval tablet, scored on both sides, marked ‘A’ on one side.
ARX-Metoprolol XL 95 – white, oval tablet, scored on both sides, marked ‘B’ on one side.
ARX-Metoprolol XL 190 – white, oval tablet, scored on both sides, marked ‘C’ on one side.

ARX-Metoprolol XL 23.75 packs contain 15 tablets. Packs of the other strengths contain 30 tablets.

Ingredients

The active ingredient in ARX-Metoprolol XL is metoprolol succinate.

each ARX-Metoprolol XL 23.75 tablet contains 23.75 mg of metoprolol succinate
each ARX-Metoprolol XL 47.5 tablet contains 47.5 mg of metoprolol succinate
each ARX-Metoprolol XL 95 tablet contains 95 mg of metoprolol succinate
each ARX-Metoprolol XL 190 tablet contains 190 mg of metoprolol succinate.

The tablets also contain:

microcrystalline cellulose
methylcellulose
glycerol
maize starch
ethylcellulose
magnesium stearate
Sepifilm LP 770 (ARTG PI No.: 109200)

The tablets do not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Supplier

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

www.arrotex.com.au

Australian registration numbers:

ARX-METOPROLOL XL 23.75:
AUST R 172299

ARX-METOPROLOL XL 47.5:
AUST R 172300

ARX-METOPROLOL XL 95:
AUST R 172306

ARX-METOPROLOL XL 190:
AUST R 172304

Date of preparation:
07/2024

Published by MIMS September 2024

BRAND INFORMATION

Brand name

ARX-Metoprolol XL (was Metrol-XL)

Active ingredient

Metoprolol succinate

Schedule

1 Name of Medicine

Metoprolol succinate.

2 Qualitative and Quantitative Composition

ARX-Metoprolol XL modified release tablets come in four strengths and contain 23.75 mg, 47.5 mg, 95 mg or 190 mg of metoprolol succinate.
Each ARX-Metoprolol XL 23.75 modified release tablet contains 23.75 mg metoprolol succinate.
Each ARX-Metoprolol XL 47.5 modified release tablet contains 47.5 mg metoprolol succinate.
Each ARX-Metoprolol XL 95 modified release tablet contains 95 mg metoprolol succinate.
Each ARX-Metoprolol XL 190 modified release tablet contains 190 mg metoprolol succinate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

ARX-Metoprolol XL 23.75.

White, oval, biconvex tablet, 9 x 5 mm, scored on both sides.

ARX-Metoprolol XL 47.5.

White, oval, biconvex tablet, 11 x 6 mm, scored on both sides, marked 'A' on one side.

ARX-Metoprolol XL 95.

White, oval, biconvex tablet, 16 x 8 mm, scored on both sides, marked 'B' on one side.

ARX-Metoprolol XL 190.

White, oval, biconvex tablet, 19 x 10 mm, scored on both sides, marked 'C' on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Stable, chronic heart failure as an adjunct to other heart failure therapy.

4.2 Dose and Method of Administration

Metoprolol succinate modified release tablets have not been established to be clinically equivalent to immediate release forms of metoprolol, and should not be used for treatment of conditions other than stable, chronic heart failure.
Metoprolol succinate modified release tablets is recommended for once daily treatment and is preferably taken together with the morning meal. The tablets may be broken in half. Metoprolol succinate modified release tablets should be swallowed with liquid and should not be chewed or crushed.
The dose of Metoprolol succinate modified release tablets should be individually adjusted in patients with chronic heart failure stabilised on other heart failure treatment. It is recommended that patients be titrated from an initial low dose in accordance with the following titration schedule (see Table 1).
The patient should be carefully evaluated at each dose level with regard to tolerability. If the patient experiences hypotension a decreased dose of concomitant heart failure medication may be necessary. Initial hypotension does not necessarily mean that the dose cannot be tolerated during chronic treatment but the patient should be kept at the lower dose until their blood pressure has stabilised.
Some patients may experience an initial, usually transient, worsening of the symptoms and signs of heart failure when starting treatment with metoprolol succinate modified release tablets. If this occurs, the patient should be monitored very closely and the dose should be reduced if symptoms continue to worsen. Metoprolol succinate modified release tablets should not be ceased abruptly due to the risk of rebound hypertension and tachycardia. If treatment is to be discontinued, it should be reduced gradually (see Section 4.4 Special Warnings and Precautions for Use).

Renal insufficiency.

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

Hepatic insufficiency.

Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol is low protein binding (5 to 10%). When there are signs of serious impairment of liver function (e.g. patients who have had a shunt operation), a dose reduction should be considered.

Elderly.

Dose adjustment is not needed in the elderly.

Children.

There is limited experience of treatment with metoprolol succinate modified release tablets in children.

4.3 Contraindications

Predisposition to bronchospasm. β-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, β-blockers are contraindicated in any patient with a history of airways obstruction or a tendency to bronchospasm. Use of cardioselective β-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.
Second- and third-degree atrioventricular block.
Shock (including cardiogenic and hypovolaemic shock).
Unstable decompensated congestive heart failure (pulmonary oedema, hypoperfusion or hypotension).
Continuous or intermittent inotropic therapy acting through β-receptor agonism.
Clinically relevant sinus bradycardia (less than 45 to 50 beats/minute).
Non-compensated congestive heart failure (see Section 4.4 Special Warnings and Precautions for Use).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Suspected acute myocardial infarction with a heart rate of < 45 beats/minute, a PR interval of > 0.24 seconds or a systolic blood pressure of < 100 mmHg, and/or moderate to severe non-compensated heart failure.
Hypotension.
Untreated phaeochromocytoma (see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity to any component of ARX-Metoprolol XL (see Section 6.1 List of Excipients) and related derivatives.
Cross sensitivity between β-blockers can occur.

4.4 Special Warnings and Precautions for Use

Symptomatic cardiac failure.

β-Blockers should not be used in patients with unstabilised heart failure. This condition should first be stabilised with appropriate treatment (e.g. angiotensin converting enzyme inhibitors, digoxin, diuretics). If cardiac failure persists, the tablets should be discontinued gradually (see Section 4.4 Special Warnings and Precautions for Use, Abrupt withdrawal).

Bronchospasm.

Where metoprolol succinate modified release tablets are prescribed for patients known to be suffering from asthma, an inhaled β₂-agonist should be administered. The dosage of β₂-agonists may require adjustment (increase), however the risk of the tablets interfering with β₂-receptors is less than with conventional tablet formulations of β₁-selective blockers.

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 β-blockers may cause bradycardia, hypotension and asystole. Extreme caution is required if these drugs have to be used together (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Antiarrhythmic drugs.

Care should be taken when prescribing β-blockers with antiarrhythmic drugs as they may enhance the negative inotropic and chronotropic effects (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Diabetes.

Metoprolol succinate modified release tablets 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 β-blockers 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, β-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need to be adjusted. Diabetic patients receiving metoprolol succinate modified release tablets should be monitored to ensure diabetes control is maintained.

Other metabolic effects.

β-Adrenoreceptors 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.

Conduction disorders.

Very rarely a pre-existing A-V conduction disorder of moderate degree may become aggravated (possibly leading to A-V block). Metoprolol succinate modified release tablets should be administered with caution to patients with first degree A-V block (see Section 4.3 Contraindications).

Peripheral vascular disease.

β-Blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral vascular disease (see Section 4.3 Contraindications).

Bradycardia.

If patients develop increasing bradycardia, metoprolol succinate modified release tablets should be given in lower doses or gradually withdrawn.

Prinzmetal angina.

There is a risk of exacerbating coronary artery spasm if patients with Prinzmetal or variant angina are treated with a β-blocker. If this treatment is essential, it should only be undertaken in a coronary or intensive care unit.

Effects on the thyroid.

The effects of β-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.

Phaeochromocytoma.

Where metoprolol succinate modified release tablets are prescribed for a patient known to be suffering from phaeochromocytoma, an α-blocker should be given concomitantly to avoid exacerbation of hypertension.

Effects on the eye and skin.

Various skin rashes and conjunctival xerosis have been reported with β-blocking agents. Cross-reactions may occur between β-blockers, therefore substitutions within the group may not necessarily preclude occurrence of symptoms.
During long-term treatment with the β-blocking drug 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 or practolol syndrome. On a few rare occasions, serious otitis media, sclerosing peritonitis 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. If such symptoms occur, discontinuation of metoprolol should be considered.
Recently, an association between Peyronie's disease (a fibrosing induration of the penis) and various β-blockers has been suggested but is not proven.

General anaesthesia.

Prior to surgery the anaesthetist should be informed that the patient is receiving metoprolol succinate modified release tablets because of the potential for interactions with other drugs, resulting in severe bradyarrhythmias and hypotension, decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and decreased propensity for vagal induced bradycardia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). It is not recommended to stop β-blocker treatment in patients undergoing surgery. Acute initiation of high dose metoprolol to patients undergoing noncardiac surgery should be avoided, since it has been associated with bradycardia, hypotension and stroke including fatal outcome in patients with cardiovascular risk factors.
If it is thought necessary to withdraw β-blocker therapy before surgery, this should be done gradually and completed about 48 hours before surgery. (See Abrupt withdrawal below.)

Abrupt withdrawal.

Abrupt withdrawal of β-blockade is hazardous, especially in high risk patients, and should not be done. If there is a need to discontinue treatment with metoprolol succinate modified release tablets, this should be done gradually over at least two weeks with the dose reduced by half in each step, down to a final dose of half a 23.75 mg tablet. The final dose should be taken for at least four days before discontinuation. Close observation of the patient is required during the withdrawal phase. If symptoms occur, a slower withdrawal rate is recommended. Sudden withdrawal of β-blockade may aggravate chronic heart failure and also increase the risk of myocardial infarction and sudden death.

Allergic conditions.

Allergic reactions may be exaggerated by β-blockade (e.g. allergic rhinitis during the pollen season and allergic reactions to bee and wasp stings). β-Blockers should be avoided if there is a risk of bronchospasm.
In patients taking β-blockers, anaphylactic shock assumes a more severe form and may be resistant to usual doses of adrenaline. Whenever possible, β-blockers should be avoided in patients who are at increased risk of anaphylaxis.

Hyperthyroidism.

Because β-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 hyperthyroid patients who are also receiving β-blockers. Where metoprolol succinate modified release tablets are administered to patients having, or suspected of developing thyrotoxicosis, both thyroid and cardiac function should be closely monitored.

Effects on the heart rate.

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

Use in hepatic impairment.

Metoprolol is mainly eliminated by hepatic metabolism (see Section 5.2 Pharmacokinetic Properties). Therefore, liver cirrhosis may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to increased plasma levels.

Use in renal impairment.

In patients with severe renal disease haemodynamic changes following β-blockade may impair renal function further. β-Blockers which are excreted mainly by the kidney may require dose adjustment in patients with renal failure.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Elderly; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in the elderly.

Paediatric use.

The safety and efficacy of metoprolol in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

CYP2D6 inhibitors.

Coadministration of drugs which inhibit CYP2D6 such as quinidine, fluoxetine and paroxetine may cause increased exposure to metoprolol and consequent increased pharmacological effects.
Concomitant administration of the CYP2D6 inhibitor quinidine has been shown to substantially increase systemic exposure of both enantiomers of metoprolol. In healthy subjects with CYP2D6 extensive metaboliser phenotype, coadministration of quinidine 100 mg and immediate release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. These increases in plasma concentration are highly likely to be associated with exaggerated pharmacological effects and decrease in the cardioselectivity of metoprolol. Interactions with hydroxychloroquine and diphenhydramine, although smaller, could still be clinically significant.

Other antihypertensive agents.

Metoprolol enhances the effects of other antihypertensive drugs. Particular care is required when initiating administration of a β-blocker and prazosin together.

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

Patients receiving concomitant treatment with sympathetic ganglion blocking agents, other β-blockers (including eye drops), or monoamine oxidase (MAO) inhibitors should be kept under close surveillance.

Clonidine.

Concurrent use of β-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 β-blocker medication should be withdrawn several days before the gradual withdrawal of clonidine. The rebound hypertension associated with clonidine withdrawal can be exacerbated by the presence of a β-blocker. If both drugs are withdrawn simultaneously, a marked rise in blood pressure and/or arrhythmias may result.
If replacing clonidine by β-blocker therapy, the introduction of β-blockers should be delayed for several days after clonidine administration has stopped.

Calcium antagonists.

If metoprolol succinate modified release tablets are given with calcium antagonists of the verapamil and diltiazem type the patient should be monitored for possible negative inotropic and chronotropic effects. Calcium antagonists of the phenylalkylamine type (e.g. verapamil) should not be given by intravenous administration to patients treated with 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 β-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.

Antiarrhythmic agents.

When metoprolol is given together with antiarrhythmic agents, the patients 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 β-blockers. Interactions have been reported during concomitant β-blocker therapy with the class IA agents disopyramide, and less frequently quinidine; class IB agents tocainide, mexiletine and lignocaine; the class IC agent flecainide; the class III agent amiodarone; and the class IV antiarrhythmic agents (e.g. verapamil).

Anaesthetics.

In patients receiving β-blocker therapy, inhalation anaesthetics enhance the cardiodepressant effect (see Section 4.4 Special Warnings and Precautions for Use). Metoprolol may also reduce the clearance of other drugs (e.g. lignocaine).
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 β-blockage.

Liver enzyme effects.

Enzyme inducing and enzyme inhibiting substances may exert an influence on the plasma level of metoprolol. The plasma concentration of metoprolol is lowered by rifampicin and may be raised by cimetidine, alcohol, hydralazine and selective serotonin reuptake inhibitors (SSRIs), e.g. paroxetine, fluoxetine and sertraline, and quinidine, verapamil and diphenhydramine.

Prostaglandin synthetase inhibiting agents.

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

Alcohol.

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

Oral hypoglycaemic agents.

The dosages of oral hypoglycaemic may need to be adjusted in patients receiving β-blockers (see Section 4.4 Special Warnings and Precautions for Use).

Warfarin.

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

Catecholamine depleting agents.

Concomitant use of catecholamine depleting drugs such as reserpine, monoamine oxidase (MAO) inhibitors and guanethidine have an additive effect when given with β-blocking agents. Patients treated with metoprolol succinate modified release tablets plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension, since the added effect of a β-blocker may produce an excessive reduction of the resting sympathetic nervous tone.

Digitalis glycosides.

Digitalis glycosides, in association with β-blockers, may increase atrioventricular conduction time and may induce bradycardia.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In rats dosed with 500 mg/kg/day (23 times the MRCD on a mg/m² basis), there was a slight decrease in insemination rate (75% compared with 95% in untreated controls) with signs of maternal toxicity. There was no evidence of impaired fertility at 50 mg/kg/day (2.3 times the MRCD).
(Category C)
As with most medicines, metoprolol succinate modified release tablets should not be given during pregnancy unless its use is considered essential. As with all antihypertensive agents, β-blockers may cause side effects (e.g. reduced placental perfusion and bradycardia) in the fetus and newborn. Reduced placental perfusion has been associated with growth retardation, intrauterine death, abortion and early labour. It is therefore suggested that appropriate maternofoetal monitoring be performed in pregnant women treated with metoprolol succinate modified release tablets. During the late stages of pregnancy these drugs should only be given after weighing the needs of the mother against the risk to the fetus.
The lowest possible dose should be used and discontinuation of treatment should be considered at least two to three days before delivery to avoid increased uterine contractility and effects of β-blockade in the newborn (e.g. bradycardia, hypoglycaemia).
Metoprolol tartrate was shown to increase fetal loss in rabbits at 25 mg/kg/day PO (per oral) (two times the MRCD (maximum recommended clinical dose) on a mg/m² basis), and increase still births and decrease neonatal survival in rats at 500 mg/kg/day PO (23 times the MRCD on a mg/m² basis). These studies revealed no evidence of teratogenicity.
As with most medicines, metoprolol succinate modified release tablets should not be given during lactation unless its use is considered essential. As with all antihypertensive agents, β-blockers may cause side effects (e.g. bradycardia), in the breastfed infant. The amount of metoprolol ingested via breast milk seems to be negligible, in regard to β-blocking effect in the infant, if the mother is treated with metoprolol in doses within the normal therapeutic range.
Postnatal growth was not affected in lactating rats dosed with metoprolol tartrate at up to 500 mg/kg/day PO (per oral) (23 times the MRCD (maximum recommended clinical dose) on a mg/m² basis).

4.7 Effects on Ability to Drive and Use Machines

Metoprolol succinate modified release tablets may occasionally cause dizziness, visual disturbances or fatigue (see Section 4.8 Adverse Effects (Undesirable Effects)), hence patients should know how they react to the medicine before they drive or use machinery, particularly when starting or changing treatment.

4.8 Adverse Effects (Undesirable Effects)

Metoprolol succinate modified release tablets are well tolerated and adverse reactions have generally been mild and reversible. The following events have been reported as adverse events in clinical trials or reported from routine use, mostly with conventional metoprolol (metoprolol tartrate). In many cases a relationship with metoprolol has not been established.
The following definitions of frequency are used. Very common: ≥ 10%; common: 1 to 9.9%; uncommon: 0.1 to 0.9%; rare: 0.01 to 0.09%; very rare: < 0.01%.

Cardiovascular.

Common: bradycardia, postural disorders (very rarely with syncope), cold hands and feet (Raynaud's phenomenon), palpitations.
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.

Central nervous system.

Very common: fatigue.
Common: dizziness, headache.
Uncommon: paraesthesia, muscle cramps.

Gastrointestinal.

Common: nausea, diarrhoea, constipation, abdominal pain.
Uncommon: vomiting.
Rare: dry mouth.

Haematological.

Very rare: thrombocytopenia.

Hepatic.

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

Metabolic.

Uncommon: weight gain.

Psychiatric.

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

Respiratory.

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

Sense organs.

Rare: disturbances of vision, dry and/or irritated eyes, conjunctivitis.
Very rare: tinnitus, taste disturbances.

Skin.

Uncommon: rash (in the form of urticaria, psoriasiform and dystrophic skin lesions), increased sweating.
Rare: loss of hair.
Very rare: photosensitivity reactions, aggravated psoriasis.

Miscellaneous.

Very rare: arthralgia.

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 medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Overdosage of metoprolol succinate modified release tablets may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness/ coma, convulsions, nausea, vomiting and cyanosis. Concomitant ingestion of alcohol, antihypertensives, quinidine or barbiturates may aggravate the patient's condition. The first manifestations of overdose may be observed 20 minutes to two hours after the drug is ingested.

Treatment.

Induction of vomiting or gastric lavage. In the presence of severe hypotension, bradycardia, and impending heart failure, administer a β₁-agonist (e.g. isoprenaline) intravenously at two to five minute intervals or as continuous infusion until the desired effect is achieved. Where a selective β₁-agonist is not available, dopamine or atropine sulfate IV (intravenously) may be used in order to block the vagus nerve. If a satisfactory effect is not achieved, other sympathomimetic agents, such as dobutamine, may be used, or noradrenaline may be given.
Glucagon in a dose of 1 to 10 mg can also be administered. Glucagon activates the adenylcyclase system independently of the β-receptor, augmenting the contractility in the presence of β-blockade. A pacemaker may be necessary.
To combat bronchospasm, a β₂-agonist can be given intravenously.
Observe that the dosage of drugs (antidotes) needed to treat overdose of β-blockade are much higher than normally recommended therapeutic dosages. This is because β-receptors are occupied by the β-blocker.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Metoprolol is a β₁-selective β-blocker, i.e. it blocks β₁-receptors at doses lower than those needed to block β₂-receptors.
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 β-blockade. The stimulant effect of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac output, cardiac contractility and blood pressure.
Controlled release metoprolol succinate and the immediate release metoprolol tartrate are not bioequivalent. Controlled release metoprolol succinate gives an even plasma concentration time profile and effect (β₁-blockade) over 24 hours in contrast to conventional tablet formulations of β₁-selective blockers including metoprolol tartrate formulations.
When given together with a β₂-agonist, metoprolol succinate in therapeutic doses interferes less than nonselective β-blockers with β₂ mediated bronchodilation (see Section 4.4 Special Warnings and Precautions for Use). When clinically necessary, metoprolol succinate, in combination with a β₂-agonist, may be given to patients with symptoms of obstructive pulmonary disease. Metoprolol succinate also interferes less with insulin release than nonselective β-blockers.

Clinical trials.

Three randomised, double blind, placebo controlled studies and one randomised, open crossover study had been conducted to establish the efficacy and safety of metoprolol succinate modified release tablets in patients with chronic heart failure.
The pivotal study, MERIT-HF (n = 3991), was a survival study in patients with NYHA (New York Heart Association) functional classes II to IV and decreased ejection fraction (≤ 0.40) on optimal standard therapy at enrolment. Patients were randomised to receive either metoprolol succinate modified release tablets (n = 1990) or placebo (n = 2001) once daily. The dose of metoprolol succinate modified release tablets was titrated during six to eight weeks to the target of 200 mg. Treatment ranged from 0 to 622 days with a mean duration of one year.
Participants were predominantly male (76%), Caucasian (94%), previous (55%) or current (19%) smokers, aged 60 to 79 years (66%; mean age 64), with heart failure secondary to ischaemia (65%). Most had mild to moderate symptomatic heart failure at baseline: 41% in NYHA class II, 56% in class III and 4% in class IV. The mean ejection fraction was 0.28. About half the patients had a history of hypertension (44%) and/or myocardial infarction (48%). 25% had a history of diabetes mellitus. 10 to 20% had peripheral oedema, jugular venous distension, pulmonary rales and/or hepatomegaly. 23% had a third heart sound, 34% had a heart murmur, 25% had an irregular heart beat and 16% were in atrial fibrillation. 90% of patients were on one or more diuretics, 89% on an angiotensin converting enzyme inhibitor, 7% on an angiotensin II blocker, 63% on digitalis, 36% on long acting nitrates, 54% on aspirin, 37% on an oral anticoagulant and 23% on a statin.
Table 2 summarises the results of the efficacy variables for metoprolol succinate modified release tablets compared to placebo.

The numbers needed to treat (NNT) to achieve a reduction of one case of all cause mortality, cardiac death and nonfatal AMI, mortality from cardiovascular causes and from sudden death are as follows (see Table 3).

Metoprolol succinate modified release tablets were generally well tolerated. Treatment was ceased due to adverse events in 10.3% of patients taking metoprolol succinate modified release tablets compared to 12.3% of those taking placebo. Compared to placebo, the overall rate of treatment withdrawal and withdrawal due to worsening heart failure tended to be less with metoprolol succinate modified release tablets, but the difference did not reach statistical significance.

5.2 Pharmacokinetic Properties

ARX-Metoprolol XL consists of granules of metoprolol succinate, each coated to control the rate of metoprolol release. After rapid disintegration within the gastrointestinal tract, metoprolol is continuously released for approximately 20 hours, and a stable metoprolol plasma concentration is achieved over a dosage interval of 24 hours. Approximately 12% of metoprolol is bound to human serum proteins.
Metoprolol undergoes oxidative metabolism in the liver, primarily by CYP2D6. Due to polymorphism of CYP2D6, about 5 to 10% of Caucasians and a lower percentage of Asian and African populations are poor metabolisers of metoprolol. Such people experience higher plasma concentrations of metoprolol for a given dose. Because of these differences between individuals, gradual dose titration is important. Coadministration of drugs which inhibit CYP2D6 may increase plasma concentrations of metoprolol, particularly in extensive metabolisers (the majority of the population). Three main metabolites have been identified, although none have a β-blocking effect of clinical importance.
Over 95% of an oral dose can be recovered in the urine. Only approximately 5% of the administered dose is excreted unchanged, with this figure rising to 30% in isolated cases.

Pharmacokinetics in the elderly.

The elderly show no significant differences in the pharmacokinetics of metoprolol as compared with younger persons.

5.3 Preclinical Safety Data

Genotoxicity.

Metoprolol tartrate was not mutagenic in a bacterial assay, nor did it induce chromosomal damage in Chinese hamsters (bone marrow micronucleus and chromosome aberration assays) or in mice (dominant lethal assay).

Carcinogenicity.

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In rats at dietary doses of up to 800 mg/kg/day (36 times the maximum recommended clinical dose (MRCD) on a mg/m² basis) for 18 months, there was no increase in the incidence of neoplasms. The only histological changes that appeared to be drug related were an increased incidence of focal accumulation of foamy macrophages in pulmonary alveoli and an increased incidence of biliary hyperplasia.
In a 21 month study in CD-1 mice at dietary doses of up to 750 mg/kg/day (17 times the MRCD on a mg/m² basis), benign lung tumours (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumours, nor in the overall incidence of tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Metoprolol succinate contains the following excipients: microcrystalline cellulose, methylcellulose, glycerol, maize starch, ethylcellulose, magnesium stearate, and Sepifilm LP 770 (ARTG PI No.: 109200). The tablets are gluten free.

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 25°C. Protect from moisture.