Consumer medicine information

Topreloc-XL

Metoprolol succinate

BRAND INFORMATION

Brand name

Topreloc-XL

Active ingredient

Metoprolol succinate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Topreloc-XL.

SUMMARY CMI

TOPRELOC-XL

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 TOPRELOC-XL?

TOPRELOC-XL contains the active ingredient metoprolol succinate. It belongs to a group of medicines called beta-blockers, which used to treat heart failure.

For more information, see Section 1. Why am I using TOPRELOC-XL? in the full CMI.

2. What should I know before I use TOPRELOC-XL?

Do not use if you have ever had an allergic reaction to TOPRELOC-XL or any of the ingredients listed at the end of the CMI.

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 TOPRELOC-XL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TOPRELOC-XL 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 TOPRELOC-XL?

Take TOPRELOC-XL exactly as your doctor has prescribed. Your doctor will tell you how much TOPRELOC-XL tablets to take each day.

More instructions can be found in Section 4. How do I use TOPRELOC-XL? in the full CMI.

5. What should I know while using TOPRELOC-XL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using TOPRELOC-XL
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking TOPRELOC-XL
  • Stop taking TOPRELOC-XL and contact your doctor immediately if you become pregnant while you are taking TOPRELOC-XL
Things you should not do
  • Do not give this medicine to anyone else, even if their condition seems similar to yours.
  • Do not use it 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 TOPRELOC-XL affects you
  • TOPRELOC-XL may affect your ability to drive a car or operate machinery
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep TOPRELOC-XL tablets in a cool dry place where the temperature stays below 25°C. It may be stored in a refrigerator but should not be frozen.

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

6. Are there any side effects?

  • Mild side effects: 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.
  • Serious side effects: 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.

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

TOPRELOC-XL

Active ingredient(s): metoprolol succinate

Consumer Medicine Information (CMI)

This leaflet provides important information about using TOPRELOC-XL. 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 TOPRELOC-XL.

Where to find information in this leaflet:

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

1. Why am I using TOPRELOC-XL?

TOPRELOC-XL contains the active ingredient metoprolol succinate.

TOPRELOC-XL belongs to a group of medicines called beta-blockers.

TOPRELOC-XL tablets are used to treat heart failure. It is used in combination with other medicines to treat your condition.

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.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor will have explained why you are being treated with TOPRELOC-XL and told you what dose to take.

Your doctor may have prescribed this medicine for another reason.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

TOPRELOC-XL is not addictive.

2. What should I know before I use TOPRELOC-XL?

Warnings:

Do not use TOPRELOC-XL if:

  • you are allergic to any medicine containing metoprolol succinate 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 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 TOPRELOC-XL after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

  • If it has expired or is damaged, return it to your pharmacist for disposal.

Do not give TOPRELOC-XL to children.

  • The safety and effectiveness of TOPRELOC-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 are allergic to:

  • metoprolol succinate or any of the ingredients listed at the end of this leaflet
  • any other medicine including other beta-blocker medicines
  • any other substances, such as foods, preservatives or dyes

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

  • asthma or other lung problems, even if you have had them in the past
  • allergic problems, including hayfever
  • diabetes
  • very slow heart beat (less than 45-50 beats/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)

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

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

Tell your doctor if you are breastfeeding or plan to breastfeed.

  • The active ingredient in TOPRELOC-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 or pharmacist about any of the above, tell them before you start taking TOPRELOC-XL

3. What if I am taking other medicines?

Taking other medicines

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

Some medicines and TOPRELOC-XL may interfere with each other. 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 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 TOPRELOC-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.

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

4. How do I use TOPRELOC-XL?

Take TOPRELOC-XL exactly as your doctor has prescribed.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

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

How much to take / use

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.

How to take it

TOPRELOC-XL tablets may be broken in half or swallowed whole with a glass of water as directed by your doctor. TOPRELOC-XL tablets should not be chewed or crushed.

If you are taking other medicines your doctor may need to change the dose of them to obtain the best results for you.

How long to take it

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

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

DO NOT STOP TAKING TOBETA XL 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 take it

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

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

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

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

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

If you take too much (overdose)

Telephone your doctor, the Poisons Information Centre (13 11 26) or go to casualty at your nearest hospital immediately if you think that you or anyone else may have taken too much TOPRELOC-XL. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too many TOPRELOC-XL tablets 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.

5. What should I know while using TOPRELOC-XL?

Things you should do

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

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

Some people may experience an apparent worsening of their condition in the early stages of treatment with TOPRELOC-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 taking TOPRELOC-XL, especially if you sweat a lot.

If you do not drink enough water while taking TOPRELOC-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.

TOPRELOC-XL may change how well your diabetes is controlled. It may also cover up some of the symptoms of low blood sugar (hypoglycaemia). TOPRELOC-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.

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

Tell any doctors, dentists, and pharmacists who are treating you that you are taking TOPRELOC-XL.

If you plan to have surgery (even at the dentist) that needs an anaesthetic, tell your doctor or dentist that you are taking TOPRELOC-XL.

If you have to have any medical tests while you are taking TOPRELOC-XL, tell your doctor.

TOPRELOC-XL may affect the results of some tests.

Things you should not do

Do not stop taking TOPRELOC-XL without checking with your doctor.

Your doctor may want you to gradually reduce the amount of TOPRELOC-XL you are taking before stopping completely. This may help reduce the possibility of your condition worsening or other heart complications occurring.

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

Do not use TOPRELOC-XL to treat any other complaints unless your doctor tells you to.

Things to be careful of

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TOPRELOC-XL affects you.

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

Drinking alcohol

Be careful drinking alcohol while you are taking TOPRELOC-XL.

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).

TOPRELOC-XL, like other beta-blocker medicines, tends 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.

Looking after your medicine

Storage

Keep your TOPRELOC-XL tablets in the blister & bottle until it is time to take them.

If you take the tablets out of the box or blister pack they may not keep well.

Store below 25°C. Protect from moisture

Do not store TOPRELOC-XL or any other medicine in the bathroom or near a sink or stove. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep TOPRELOC-XL where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

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?

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

If you get any side effects, do not stop taking TOPRELOC-XL without first talking to your doctor.

All medicines can have side effects. 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.

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

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

Mild side effects

Mild 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
Tell your doctor or pharmacist if you have any of the these mild side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • 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 or pharmacist immediately 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 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.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.

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.

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 TOPRELOC-XL contains

Active ingredient
(main ingredient)		TOPRELOC-XL 23.75 mg-23.75 mg metoprolol succinate per tablet
TOPRELOC-XL 47.5 mg-47.5 mg metoprolol succinate per tablet
TOPRELOC-XL 95 mg-95 mg metoprolol succinate per tablet
TOPRELOC-XL 190 mg-190 mg metoprolol succinate per tablet
Other ingredients
(inactive ingredients)
  • Microcrystalline Cellulose
  • Silicon dioxide
  • Povidone
  • Ethyl Cellulose
  • Methacrylic Acid Copolymer
  • Triethyl Citrate
  • Talc
  • Macrogol 6000
  • Silicified Microcrystalline Cellulose
  • Croscarmellose Sodium
  • Sodium Stearyl Fumarate
  • Opadry YS-1R-7006 Clear (ARTG # 13068)
  • Opadry 02F280014 White (ARTG # 123088)

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

What TOPRELOC-XL looks like

  • TOPRELOC-XL 23.75 mg tablets are white to off white, oval shape, biconvex film coated tablet with breakline on one side and debossed with 'A' and '3' on each side of breakline on other side.
  • TOPRELOC-XL 47.5 mg tablets are white to off white, round shape, biconvex film coated tablet with breakline on one side and debossed with 'A50' on other side.
  • TOPRELOC-XL 95 mg tablets are white to off white, round shape, biconvex film coated tablet with breakline on one side and debossed with 'A100' on other side.
  • TOPRELOC-XL 190 mg tablets are white to off white, oval shape, biconvex film coated tablet with breakline on one side and debossed with 'A200' on other side.

TOPRELOC-XL available in a

23.75 mg:

  • PVC/PVDC Blister Pack of 15's Tablets
  • HDPE Bottle Pack of 15's, 30's, & 90's Tablets.

47.5 mg/95 mg/190 mg:

  • PVC/PVDC Blister Pack of 15's & 30's Tablets
  • HDPE Bottle Pack of 15's, 30's & 90's Tablets.

Who distributes TOPRELOC-XL

Pharmacor Pty Ltd.
Chatswood, NSW, 2067
Australia

TOPRELOC-XL
23.75 mg: Blister pack: 356239
Bottle pack: 356235

TOPRELOC-XL
47.5 mg: Blister pack: 356233
Bottle pack: 356240

TOPRELOC-XL
95 mg: Blister pack: 356243
Bottle pack: 356236

TOPRELOC-XL
190 mg: Blister pack: 356232
Bottle pack: 356238

This leaflet was prepared in 03/2022

Published by MIMS June 2022

BRAND INFORMATION

Brand name

Topreloc-XL

Active ingredient

Metoprolol succinate

Schedule

S4

 

1 Name of Medicine

Metoprolol succinate.

2 Qualitative and Quantitative Composition

Topreloc-XL 23.75 mg.

Each modified release tablet contains 23.75 mg metoprolol succinate.

Topreloc-XL 47.5 mg.

Each modified release tablet contains 47.5 mg metoprolol succinate.

Topreloc-XL 95 mg.

Each modified release tablet contains 95 mg metoprolol succinate.

Topreloc-XL 190 mg.

Each modified release tablet contains 190 mg metoprolol succinate.

Excipient with known effect.

None.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Topreloc-XL 23.75 mg.

White to off white, oval shape, biconvex film coated tablet with breakline on one side and debossed with 'A' and '3' on each side of breakline on other side.

Topreloc-XL 47.5 mg.

White to off white, round shape, biconvex film coated tablet with breakline on one side and debossed with 'A50' on other side.

Topreloc-XL 95 mg.

White to off white, round shape, biconvex film coated tablet with breakline on one side and debossed with 'A100' on other side.

Topreloc-XL 190 mg.

White to off white, oval shape, biconvex film coated tablet with breakline on one side and debossed with 'A200' on other 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

Dosage.

Topreloc-XL has 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.
Topreloc-XL is recommended for once daily treatment and is preferably taken together with the morning meal. Topreloc-XL tablets should be swallowed with liquid and should not be chewed or crushed.
The dose of Topreloc-XL 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).
Topreloc-XL 47.5 mg, Topreloc-XL 95 mg and Topreloc-XL 190 mg tablets may only be broken in half for ease of swallowing and not to divide into equal doses.
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 Topreloc-XL. If this occurs, the patient should be monitored very closely and the dose of Topreloc-XL should be reduced if symptoms continue to worsen. Topreloc-XL 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).

Special patient populations.

Impaired renal and hepatic function.

Dose adjustment is not needed in patients with impaired renal function.
Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol is low protein binding (5-10%). 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 with Topreloc-XL treatment 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 45-50 beats/minute).
Non-compensated 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.
Suspected acute myocardial infarction with a heart rate of < 45 beats/minute, a P-R interval of > 0.24 seconds or a systolic blood pressure of < 100 mmHg, and/or moderate to severe noncompensated heart failure.
Hypotension.
Untreated phaeochromocytoma (see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity to any component of Topreloc-XL 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, Topreloc-XL should be discontinued gradually (see Section 4.4 Special Warnings and Precautions for Use, Abrupt withdrawal).

Bronchospasm.

Where Topreloc-XL is 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 Topreloc-XL 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).

Anti-arrhythmic 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.

Topreloc-XL 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 Topreloc-XL should be monitored to ensure diabetes control is maintained.

Other metabolic effects.

Beta 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). Topreloc-XL 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, Topreloc-XL 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 Topreloc-XL is 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 Topreloc-XL 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 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.
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 Topreloc-XL, 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 Topreloc-XL is 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 of Topreloc-XL should be gradually reduced or treatment gradually withdrawn (see Section 4.3 Contraindications).

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 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 the elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

The safety and efficacy of metoprolol in children has 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 anti-hypertensive 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 Topreloc-XL is 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 re-uptake inhibitors (SSRIs) e.g. paroxetine, fluoxetine, and sertraline, 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 antidiabetic agents.

The dosages of oral antidiabetics 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 anti-coagulant 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 Topreloc-XL 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% cf. 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 drugs, metoprolol succinate 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 foetus and new-born. 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. During the late 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 to 3 days before delivery to avoid increased uterine contractility and effects of β-blockade in the newborn (e.g. bradycardia, hypoglycaemia).
Metoprolol succinate was shown to increase foetal loss in rabbits at 25 mg/kg/day PO (2 times the MRCD 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 drugs, Topreloc-XL 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 breast-fed 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 succinate at up to 500 mg/kg/day PO (23 times the MRCD on a mg/m2 basis).

4.7 Effects on Ability to Drive and Use Machines

Topreloc-XL may occasionally cause dizziness, visual disturbances or fatigue (see Section 4.8 Adverse Effects (Undesirable Effects)) hence patients should know how they react to Topreloc-XL before they drive or use machinery, particularly when starting or changing treatment.

4.8 Adverse Effects (Undesirable Effects)

Topreloc-XL is well tolerated and adverse reactions have generally been mild and reversible. The following events have been reported as adverse events in clinical trials or reported from routine use, mostly with conventional metoprolol (metoprolol succinate). In many cases a relationship with metoprolol has not been established.
The following definitions of frequency are used: very common ≥ 10%; common 1 - 9.9%; uncommon 0.1 - 0.9%; rare 0.01 - 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 46000 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.

Haematologic.

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

4.9 Overdose

Symptoms.

Symptoms of overdosage may include severe hypotension, cardiac insufficiency, bradycardia and bradyarrhythmia, cardiac conduction disturbances, cardiogenic shock, cardiac arrest, impairment of consciousness/coma, convulsions and bronchospasm. The main clinical signs of overdosage are cardiovascular and in some cases decompensation may be rapid. Overdosage with Topreloc-XL can lead to death.
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.

Management.

For information on management of overdose, contact the Poisons Information Centre on 131126 (Australia).
Care should be provided at a facility that can provide appropriate supporting measures, monitoring, and supervision.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Syrup of ipecac and gastric lavage are no longer considered to be standard therapy for gut decontamination.
Atropine, adreno stimulating drugs or pacemaker to treat bradycardia and conduction disorders.
Hypotension, acute cardiac failure, and shock to be treated with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adreno stimulating drugs such as dobutamine, with α1 receptor agonistic drugs added in presence of vasodilation. Intravenous use of calcium salts (Ca2+) can also be considered.
Bronchospasm can usually be reversed by bronchodilators.

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 succinate 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 succinate formulations.
When given together with a β2-agonist, metoprolol succinate in therapeutic doses interferes less than non-selective 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 non-selective 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 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 class II-IV and decreased ejection fraction (≤ 0.40) on optimal standard therapy at enrolment. Patients were randomised to receive either metoprolol succinate (n=1990) or placebo (n=2001) once daily. The dose of metoprolol succinate was titrated during 6-8 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 60-79 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. 10-20% 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 compared to placebo.
The numbers needed to treat (NNT) to achieve a reduction of 1 case of all cause mortality, cardiac death and non-fatal AMI, mortality from cardiovascular causes and from sudden death are as follows (see Table 3).
Metoprolol succinate was generally well tolerated. Treatment was ceased due to adverse events in 10.3% of patients taking metoprolol succinate 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, but the difference did not reach statistical significance.

5.2 Pharmacokinetic Properties

Absorption and distribution.

Topreloc-XL consists of several hundred beads of metoprolol succinate, each coated with a polymeric membrane which controls 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.

Metabolism and excretion.

Metoprolol undergoes oxidative metabolism in the liver, primarily by CYP2D6. Due to polymorphism of CYP2D6, about 5-10% 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. Co-administration 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 beta-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 shows no significant differences in the pharmacokinetics of metoprolol as compared with younger persons.

5.3 Preclinical Safety Data

Genotoxicity.

Metoprolol succinate 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 succinate. 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 histologic 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

Each Topreloc-XL Tablet contains: microcrystalline cellulose, silicon dioxide, povidone, ethylcellulose, methacrylic acid copolymer, triethyl citrate, macrogol 6000, silicified microcrystalline cellulose, croscarmellose sodium, sodium stearylfumarate, purified talc, Opadry complete film coating system YS-1R-7006 Clear (ARTG PI No. 13068), Opadry complete film coating system 02F280014 (ARTG PI No. 123088).

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.

6.5 Nature and Contents of Container

23.75 mg.

PVC/PVDC/Al blister packs containing 15 tablets.
HDPE bottles with polypropylene child-resistant screw caps containing 15, 30 and 90 tablets.

47.5 mg/95 mg/190 mg.

PVC/PVDC/Al blister packs containing 15 and 30 tablets.
HDPE bottles with polypropylene child-resistant screw caps containing 15, 30 and 90 tablets.

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 succinate is a white, crystalline powder with a melting point of approximately 138°C. It is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, slightly soluble in dichloromethane and 2-propanol, and practically insoluble in ethyl acetate, acetone, diethyl ether and heptane.

Chemical structure.


Chemical name.

Di-(±)-1-(isopropylamine)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate.

CAS number.

98418-47-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes