Consumer medicine information

Lopresor

Metoprolol tartrate

BRAND INFORMATION

Brand name

Lopresor

Active ingredient

Metoprolol tartrate

Schedule

What is in this leaflet

This leaflet answers some common questions about Lopresor.

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

The information in this leaflet was last updated on the date listed on the final page. Some more recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

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

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

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

What Lopresor is used for

Lopressor is used:

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

Hypertension
Everyone has blood pressure. This pressure helps to move your blood around your body. Your blood pressure may be different at various times of the day, depending on how busy you are. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed. If high blood pressure is not treated it can lead to serious health problems, including stroke, heart disease and kidney failure.

There are usually no symptoms of hypertension. The only way of knowing that you have it is to have your blood pressure checked on a regular basis. You may feel fine and have no symptoms but, if high blood pressure is not treated, it can lead to serious health problems. Lopresor helps to lower your blood pressure.

Angina
Angina is a pain or uncomfortable feeling in the chest, often spreading to the arms or neck and sometimes to the shoulders and back. This may be caused by too little blood and oxygen getting to the heart. The pain of angina is usually brought on by exercise or stress but it can also happen while you are resting. Lopresor helps to prevent angina from happening. It is not used to treat a sudden attack.

Reducing heart complications after heart attack
After a heart attack there is a chance of developing complications such as an irregular heartbeat (also called an arrhythmia) or another heart attack. Lopresor helps to prevent these conditions from happening.

Migraine
This is a throbbing headache, usually affecting one side of the head and often accompanied by nausea, vomiting and sensitivity to light.

Lopresor belongs to a group of medicines called beta-blockers. It works by affecting the body's response to some nerve impulses, especially in the heart. As a result, it decreases the heart's need for blood and oxygen and reduces the amount of work that the heart has to do. It also widens the blood vessels in the rest of the body.

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

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

Lopresor is not recommended for use in children.

Lopresor is only available with a doctor's prescription.

It is not addictive.

Before you take Lopresor

When you must not take it

Do not take Lopresor if you have an allergy to:

metoprolol (the active ingredient) or to any of the other ingredients of Lopresor listed at the end of this leaflet
any other beta-blocker medicines

Some of the symptoms of an allergic reaction may include:

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

Do not take Lopresor if you have any of the following medical conditions:

sudden loss of consciousness sometimes
asthma, wheezing, difficulty breathing or other severe lung problems, or you have had these problems in the past
a history of allergic problems, including hay fever
a very slow heartbeat, less than 45 to 50 beats per minute
low blood pressure
a severe blood vessel disorder causing poor circulation in the arms and legs
severe drop in blood pressure, dizziness, fast heartbeat, rapid and shallow breathing, cold clammy skin
phaeochromocytoma (a rare tumour of the adrenal gland) which is not already being treated with other medicines
sudden and oppressive chest pain, sign of heart attack
irregular heart beat
swollen ankles and/or tiredness due to heart disease or certain other heart conditions
heart disorders
poor blood circulation in your limbs (for example, very cold, pale hands or feet, or pain in your leg muscles when you walk).
undergo an operation where an anesthetic is used during treatment with
respiratory diseases such as asthma
oculomucocutaneous syndrome (signs include severe conjunctivitis and skin rash and ear infection)

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

Do not take Lopresor after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Do not give this medicine to a child. There is not enough information on its use in children.

Before you start to take it

Tell your doctor if you are allergic to:

any other medicines, foods, dyes or preservatives
bee or wasp stings

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

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

diabetes
an overactive thyroid gland
kidney problems
liver problems
chest pain when you are at rest, or certain types of angina, such as Prinzmetal angina or variant angina

Your doctor may want to take special precautions if you have any of the above conditions.

Tell your doctor if you are pregnant or intend to become pregnant. Lopresor should not be used throughout pregnancy, especially during the first 3 months of pregnancy, unless clearly necessary. Lopresor may affect your baby, especially if you take it in the last few days before your baby is born. Your doctor can discuss the risks and benefits of taking this medicine during pregnancy.

Tell your doctor if you are breast-feeding or intend to breast-feed. The active ingredient in Lopresor passes into breast milk and there is a possibility that your baby could be affected.

If you have not told your doctor about any of these things, tell him/her before you take Lopresor.

Taking other medicines

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

Other medicines and Lopresor may interfere with each other. These medicines include:

other beta-blocker medicines
other medicines used to treat high blood pressure such as calcium channel blockers and clonidine
some medicines used to treat angina
adrenaline or similar substances, which are often found in eye or nose drops, or in some cough and cold medicines
other medicines used to treat irregular heart beat (arrhythmias)
medicines for diabetes
quanethidine, a medicine used to treat certain heart conditions
some local and general anaesthetics used during surgery
monoamine-oxidase inhibitor (MAOI) medicines
warfarin, a medicine used to prevent blood clots
non-steroidal anti-inflammatory drugs such as COX-2 inhibitors to relieve pain or inflammation
cimetidine, a medicine for stomach ulcers
some antibiotics (e.g. rifampicin)
some antivirals (e.g. ritonavir)
some antihistamines (e.g. diphenhydramine)
some antidepressant medications (e.g. fluoxetine, paroxetine or bupropion)
some antifungals (e.g. terbinafine)
ergot alkaloids, a class of medicines used in the prevention and treatment of migraine headaches
dipyridamole, a medicine use to reduce the risk of blood clots
other medicines that may cause a decrease in heart rate (e.g fingolimod, a medicine used to treat multiple sclerosis)
other medicines that may cause a decrease in blood pressure (e.g. aldesleukin, a medicine used to treat kidney cancer)

You may need to take different amounts of your medicines or you may need to take different medicines.

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

How to take Lopresor

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

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

How much to take

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

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

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

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

How to take it

Swallow the tablets whole with a full glass of water or other liquid.

It does not matter if you take Lopresor before or after food, but it is important to take it in the same way each day. For example, if you always take Lopresor with food, continue taking it with food every day.

How long to take it

Continue taking Lopresor for as long as your doctor tells you to. Lopresor helps to control your symptoms but it does not cure your condition. Your doctor will check your progress to make sure the medicine is working and will decide how long your treatment should continue.

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

If you forget to take it

If it is almost time for your next dose (eg. within 2 or 3 hours), skip the dose you missed and take your next dose when you are meant to.

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

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

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

If you take too much

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

Keep the telephone numbers for these places handy.

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

While you are taking Lopresor

Things you must do

Be sure to keep all of your doctor's appointments so that your progress can be checked. This helps your doctor to give you the best treatment and to prevent unwanted side effects from happening.

If you become pregnant while taking Lopresor, tell your doctor. Your doctor can discuss with you the risks and benefits of taking it while you are pregnant.

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

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. You may feel light-headed or dizzy when you start to take Lopresor. This is because your blood pressure is falling suddenly. If this problem doesn't go away, talk to your doctor.

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

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

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

If you plan to have surgery and will need an anaesthetic, tell your doctor or dentist that you are taking Lopresor. This will help your doctor to prevent unwanted side effects such as a sudden drop in blood pressure.

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

Tell any other doctor, dentist or pharmacist who treats you that you are taking Lopresor.

Things you must not do

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

Do not use Lopresor to treat any other complaints unless your doctor says you can.

Do not give this medicine to anyone else, even if their symptoms seem to be similar to yours.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking Lopresor until you know how it affects you. As with other beta-blocker medicines, Lopresor may cause dizziness, light-headedness or decreased alertness in some people.

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

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Lopresor. All medicines 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.

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 side effects and they worry you:

tiredness, drowsiness, decreased alertness
dizziness, spinning sensation (vertigo), light-headedness or fainting
headache or other aches and pains
difficulty sleeping, nightmares
depression or other changes in mood
confusion or loss of memory
stomach ache or upset, nausea (feeling sick) or vomiting
diarrhoea or constipation
dry or irritated eyes, blurred vision
buzzing or ringing in the ears, or other difficulty hearing
dry mouth
increased sweating
runny or blocked nose
problems with sexual function
numbness, tingling in the extremities
weight gain
hair thinning
worsening of psoriasis
muscle cramps or painful joints
a tingling sensation
abnormal triglycerides or cholesterol values, or liver function tests sleepiness during the day or troubled sleep
diarrhoea or constipation

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

signs of allergy such as swelling of the face, lips or tongue which may cause problems with swallowing or breathing
chest tightness, wheezing, rattly breathing
shortness of breath, sometimes with tiredness, weakness or reduced ability to exercise
swelling of the feet or legs due to fluid build-up
coldness, burning, numbness or pain in arms and legs
chest pain
pain behind the breastbone (different from angina)
changes in heart rate (fast, slow, irregular)
yellowing of the skin or eyes (jaundice), sometimes with pain in the abdomen
constant "flu-like" symptoms (chills, fever, sore throat, aching joints, swollen glands, tiredness or lack of energy)
unusual bleeding or bruising
skin reactions (rash, itching, worsening of psoriasis)
symptoms of sunburn (redness, itching, swelling, blistering) that happen much more quickly than normal
abnormal thinking or hallucinations (seeing or hearing things that are not there)
breathlessness, difficulty breathing when lying down, swelling of the feet or legs, signs of heart disorders

The above side effects could be serious. You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may happen in some people.

After taking Lopresor

Storage

Keep your tablets in the original container until it is time to take them.

Store the tablets in a cool dry place.

Do not store Lopresor or any other medicine in the bathroom or near a sink.

Do not leave the tablets in the car or on window sills. Heat and dampness can destroy some medicines. Lopresor will keep well if it is cool and dry.

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

Disposal

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

Product description

What it looks like

Lopressor comes in two types of tablets:

Lopresor 50 - rose pink, heart- shaped, film coated tablet, marked HM on one side and CIBA on the other; one carton contains 100 tablets.
Lopresor 100 - light blue, heart- shaped, film coated, scored tablet, marked IP on one side and CIBA on the other; one carton contains 60 tablets.

Ingredients

Active Ingredient

Lopresor 50 - 50 mg metoprolol tartrate per tablet
Lopressor 100 - 100 mg metoprolol tartrate per tablet.

Inactive Ingredients

Lopresor 50 also contains:

silica-colloidal anhydrous
cellulose-microcrystalline (E 460)
povidone (E1201)
sodium starch glycollate
magnesium stearate (E 572)
hypromellose (E 464)
titanium dioxide (E 171)
talc-purified (E 553b)
lactose
polysorbate 80
iron oxide red CI77491 (E 172)

Lopressor 100 also contains:

silica-colloidal anhydrous
cellulose-microcrystalline (E 460)
povidone (E1201)
sodium starch glycollate
magnesium stearate (E 572)
hypromellose (E 464)
titanium dioxide (E 171)
shellac (E 904)
indigo carmine CI73015 (E 132)

Lopressor tablets do not contain sucrose, tartrazine or any other azo dyes.

Sponsor

Lopresor is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
North Ryde NSW 2113
Telephone 1-800-671-203
Web site: www.novartis.com.au

® = Registered Trademark

This leaflet was prepared in March 2020.

Australian Registration Number.

Lopresor 50 mg AUST R 11041

Lopresor 100 mg AUST R 11042

(lpp100320c.doc) based on (lpp100320i.doc)

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Lopresor

Active ingredient

Metoprolol tartrate

Schedule

1 Name of Medicine

Metoprolol tartrate.

2 Qualitative and Quantitative Composition

Lopresor tablets contain either 50 mg or 100 mg of metoprolol tartrate.
Excipients with known effect: 50 mg tablets contain lactose.
They also contain silica-colloidal anhydrous, cellulose-microcrystalline, povidone, sodium starch glycollate, magnesium stearate, hypromellose, and titanium dioxide. The 100 mg strength tablets also contain shellac and indigo carmine CI73015. The 50 mg strength tablets also contain lactose, polysorbate 80, talc-purified, and iron oxide red CI77491.

3 Pharmaceutical Form

Tablets 50 mg.

Rose pink, heart-shaped, film-coated, marked HM, CIBA on reverse.

Tablets 100 mg.

Light blue, heart-shaped, film-coated, scored, marked IP, CIBA on reverse.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Dosage.

The maximum daily dose should not exceed 400 mg.
Although twice daily dosage is optimal, in patients whose maintenance dosage is 150 mg daily or less, it may be administered as a single dose.
The dosage should be adapted to the requirements of the individual patient. The following dosage recommendations may be taken as a guide.
Hypertension.

Mild.

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

Moderate to severe.

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

Maintenance.

50 or 100 mg, given once or twice daily. Some patients may respond to 50 mg. A larger number will respond to 100 mg, given once daily as initial and maintenance therapy. Response is rarely improved by increasing the dose beyond 200 mg daily.
Angina pectoris. 50 to 100 mg, given two or three times daily.
Myocardial infarction. The recommended dosage can be reduced depending on the haemodynamic status of the patient. Initially, therapy should commence with 50 mg twice daily and be continued for 48 hours.

Maintenance.

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

Method of administration.

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

4.3 Contraindications

Known hypersensitivity to metoprolol and related derivatives;
hypersensitivity to any of the excipients in Lopresor;
sensitivity to other beta-blockers (cross sensitivity between beta-blockers can occur);
atrioventricular block of second or third degree;
congestive heart failure; sinus bradycardia (< 45 to 50 beats/minute);
sick sinus syndrome;
severe peripheral arterial circulatory disorders;
shock (including cardiogenic and hypovolaemic shock);
myocardial infarction patients with a heart rate of < 45 beats/minute, a PR interval > 0.24 seconds, a systolic blood pressure of < 100 mmHg and/or moderate to severe heart failure;
right ventricular failure secondary to pulmonary hypertension;
significant right ventricular hypertrophy;
hypotension;
untreated phaeochromocytoma (see Section 4.4 Special Warnings and Precautions for Use);
allergic disorders (including allergic rhinitis) which may suggest a predisposition to bronchospasm;
severe bronchial asthma or history of severe bronchospasm.
Beta-adrenergic blockade of the smooth muscle of bronchi and bronchioles may result in increased airways resistance. These drugs also reduce the effectiveness of asthma treatment. This may be dangerous in susceptible patients. Therefore, beta-blockers are contraindicated in any patient with a history of airways obstruction or a tendency to bronchospasm. Use of cardioselective beta-blockers can also result in severe bronchospasm. Lopresor should not be used in patients with severe bronchospastic disease (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Use in special patient groups.

Bronchospastic disease.

In general, patients with bronchospastic disease should not be given beta-blockers of any type (e.g. selective or nonselective), including Lopresor. If such therapy must be used, great caution should be exercised. Alternative therapy should be considered.

Cardiac failure.

Beta-blockade depresses myocardial contractility and may precipitate cardiac failure in some patients with a history of cardiac failure, chronic myocardial insufficiency or unsuspected cardiomyopathy. In patients without a history of cardiac failure, continuing depression of the myocardium may lead to cardiac failure. If signs of cardiac failure are present, the patient should be fully digitalised and/or given a diuretic and carefully monitored. If cardiac failure persists, the beta-blocker should be withdrawn gradually (see statement below regarding abrupt withdrawal).

Note.

Although congestive heart failure has been considered to be a contraindication to the use of beta-blockers, there is growing literature on the experimental use of beta-adrenergic blocking drugs in heart failure. As further trials are needed to identify which patients are likely to respond to which drugs, beta-blockers should not normally be prescribed for heart failure outside of specialist centres.
Beta-blockers, including Lopresor, should not be used in patients with untreated congestive heart failure. This condition should first be stabilised.

Myocardial infarction.

In patients with myocardial infarction, if significant hypotension occurs, Lopresor should be discontinued, and the hemodynamic status of the patient and the extent of myocardial ischemia carefully assessed. Intensive hemodynamic monitoring may be required and appropriate treatment modalities should be instituted. If hypotension is associated with significant bradycardia or atrioventricular block, treatment should be directed at reversing these.

Prinzmetal angina.

There is a risk of exacerbating the number and duration of coronary artery spasms if patients with Prinzmetal angina or variant angina pectoris are treated with a beta-blocker, including Lopresor. If this treatment is essential, it should only be undertaken in a coronary or intensive care unit.

Conduction disorders.

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

Phaeochromocytoma.

In patients known to be, or suspected to be, suffering from a phaeochromocytoma, Lopresor should always be given in combination with an alpha-blocker (e.g. phentolamine or phenoxybenzamine) and only after the alpha blocker has been initiated to avoid exacerbation of hypertension.

Diabetes.

Lopresor should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents. Diabetic patients should be warned that beta-blockers, including Lopresor, affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia.
In patients with insulin or noninsulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia, beta-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need adjustment. Diabetic patients receiving Lopresor should be monitored to ensure that diabetes control is maintained.

Allergic conditions.

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

Hyperthyroidism.

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

Interactions.

Calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving Lopresor because there is a risk of cardiac arrest in this situation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Peripheral circulatory disorders.

Beta-blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral arterial circulatory disorders (for example, Raynaud's disease or phenomenon, intermittent claudication) (see Section 4.3 Contraindications).

Use in renal impairment.

Patients with renal impairment may usually be treated with normal doses. In patients with severe renal disease, haemodynamic changes following beta-blockade may impair renal function further. Caution in Lopresor dosing is recommended in patients with severe renal impairment. There is a possibility of accumulation of one of Lopresor's less active metabolites in patients with a creatinine clearance below 5 mL/min but this accumulation would not influence the beta-blocking properties of metoprolol.

Use in hepatic impairment.

Metoprolol is mainly eliminated by hepatic metabolism (see Section 5.2 Pharmacokinetic Properties). Therefore, hepatic impairment may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to increased plasma concentrations. Lopresor blood levels are likely to increase substantially in patients with hepatic impairment. The elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h), in patients with liver impairment. Therefore, Lopresor should be initiated at low doses with cautious gradual dose titration according to clinical response.

Possible effects of treatment.

Effects on the heart rate.

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

Effects on the thyroid.

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

Other metabolic effects.

Beta-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.

Effects on the eye and skin.

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

Abrupt withdrawal.

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

Women of childbearing potential.

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

Use in the elderly.

Caution in dosing is recommended due to increased likelihood of adverse events (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in the elderly).

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on metoprolol.

The effects of Lopresor and other antihypertensive drugs on blood pressure are usually additive. Patients receiving concurrent treatment with catecholamine depleting drugs, other beta-blockers (including those in the form of eye drops, such as timolol) or monoamine oxidase (MAO) inhibitors should be carefully monitored. In addition, possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor.

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

Antiarrhythmic drugs.

Beta-blockers may enhance the negative inotropic and negative chronotropic effect of antiarrhythmic agents of the quinidine type. Care should be taken when prescribing beta-blockers with antiarrhythmic drugs. Interactions have been reported during concomitant beta-blocker therapy with the class IA agents, disopyramide, procainamide, ajmaline and less frequently quinidine; class IB agents, tocainide, mexiletine and lignocaine; class IC agents, flecainide and propafenone (not available in Australia); the class III agent, amiodarone; and the class IV agents (e.g. verapamil). Particularly, in patients with pre-existing sinus node dysfunction, concomitant administration of amiodarone may result in additive electrophysiologic effects including bradycardia, sinus arrest, and atrioventricular block.

Antihypertensive drugs.

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

Calcium antagonists.

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

CYP2D6 inhibitors.

Potent inhibitors of this enzyme may increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 would result in the change of phenotype into poor metaboliser. Caution should, therefore, be exercised when coadministering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluvoxamine, fluoxetine, paroxetine, sertraline, bupropion, clomipramine, desipramine, antipsychotics such as chlorpromazine, fluphenazine, haloperidol, thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.

Hydralazine.

Concomitant administration of hydralazine may inhibit presystemic metabolism of metoprolol leading to increased concentrations of metoprolol.

General anaesthetics.

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

Glyceryl trinitrate.

Glyceryl trinitrate may enhance the hypotensive effect of Lopresor.

Hepatic enzyme inhibitors.

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

Other drugs causing decrease in heart rate.

Concomitant administration of beta-blockers with other drugs known to decrease heart rate such as sphingosine-1-phosphate receptor modulators (e.g. fingolimod) may result in additive heart rate lowering effects.

Other drugs causing decrease in blood pressure.

Concomitant administration of beta-blockers with other drugs known to decrease blood pressure such as aldesleukin may result in an enhanced hypotensive effect.

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

Digitalis glycosides.

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

Hepatic enzyme inducers.

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

Nonsteroidal anti-inflammatory drugs.

Concomitant administration of nonsteroidal anti-inflammatory drugs, such as indomethacin, including COX-2 inhibitors with a beta-blocker may decrease the antihypertensive effect of metoprolol, possibly as a result of the inhibition of renal prostaglandin synthesis and sodium and fluid retention caused by nonsteroidal anti-inflammatory drugs.

Prazosin.

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

Sympathomimetics.

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

Interactions resulting in effects on other medicines.

Alcohol.

Metoprolol may modify the pharmacokinetic behaviour of alcohol when taken concomitantly.

Catecholamine depleting agents.

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

Anti-adrenergic agents.

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

Antidiabetic drugs and insulin.

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

Lignocaine.

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

Warfarin.

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

Ergot alkaloid.

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

Dipyridamole.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Lopresor on the fertility of humans have not been studied. While metoprolol tartrate showed reversible adverse effects on spermatogenesis (altered morphology and motility) in male rats at less than therapeutic doses, it had no effect on rates of conception in animal fertility studies at up to 11 times the maximum recommended daily dose on a body surface area adjusted basis.
(Category C)
There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly indicated.
Reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for metoprolol tartarate. Embryotoxicity and/or fetotoxicity in rats and rabbits were noted as increases in preimplantation loss, decreses in the number of viable foetuses per doe, and/or decreses in neonatal survival starting at does of about 300 mg/m² (on a body surface area adjusted basis), similar to the maximum recommended therapeutic dose. High doses were associated with some maternal toxicity, and growth delay of the offspring in utero, which was reflected in minimally lower weights at birth.
There is a limited amount of data on the use of metoprolol in pregnant women. Experience with metoprolol in the first trimester of pregnancy is limited, but no foetal malformations attributable to metoprolol have been reported.
Beta-blockers may reduce placental perfusion and cause bradycardia in the foetus. During the later stages of pregnancy, these drugs should only be given after weighing the needs of the mother against the risk to the foetus. The lowest possible dose should be used and treatment should be discontinued at least 2 to 3 days before delivery to avoid increased uterine contractility and the effects of beta-blockade in the newborn (e.g. bradycardia, hypoglycaemia).
The concentration of metoprolol in breast milk is approximately three times higher than in the mother's plasma. However, in the normal dose range, the amount of metoprolol ingested via human milk seems to be negligible with regard to its beta-blocking effect on the infant. Nevertheless, breastfed infants should be closely observed for signs or symptoms of β-blockade.

4.7 Effects on Ability to Drive and Use Machines

Dizziness, fatigue or visual impairment may occur during treatment with Lopresor (see Section 4.8 Adverse Effects (Undesirable Effects)) and may adversely affect the patient's ability to drive or use machinery.

4.8 Adverse Effects (Undesirable Effects)

Cardiovascular adverse effects (related, possibly related, unassessable or unknown) reported by ≥ 1% in 1,395 patients during randomised clinical trials of Lopresor and placebo are shown in Table 1.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions from clinical trials (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Discontinuation of the drug should be considered if any such reaction is not otherwise explicable.
The oculomucocutaneous syndrome associated with the beta-blocker, practolol, has not been reported with Lopresor (see Section 4.4 Special Warnings and Precautions for Use).

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

The following adverse reactions have been derived from postmarketing experience with Lopresor via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Nervous system disorders.

Confusional state.

Investigations.

Increase in blood triglycerides, decrease in high density lipoprotein (HDL).

Potential adverse reactions.

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

Cardiac disorders.

Intensification of atrioventricular (AV) block (see Section 4.3 Contraindications).

Blood and the lymphatic system disorders.

Nonthrombocytopenic purpura, thrombocytopenic purpura.

Nervous system disorders.

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

Hypersensitivity reactions.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Signs and symptoms.

An overdosage of Lopresor may lead to severe hypotension, sinus bradycardia, atrioventricular block, myocardial infarction, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness (or even coma), convulsions, nausea, vomiting and cyanosis and death.
Concomitant ingestion of alcohol, antihypertensives, quinidine or barbiturates aggravate the signs and symptoms.
The first manifestations of overdosage can appear in 20 minutes but are more commonly seen within 1 to 2 hours after the drug's ingestion. The effects of massive overdosage may persist for several days despite declining plasma concentrations.

Treatment.

Contact the Poisons Information Centre on 131 126 for advice on management.
Patients suffering from overdosage of a beta-blocker should always be hospitalised so that vital functions can be monitored. In general, patients with acute or recent myocardial infarction may be more haemodynamically unstable than other patients and should be treated accordingly. Induction of vomiting or gastric lavage should be undertaken.
Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care.
In the presence of severe hypotension, bradycardia and impending heart failure, administer a beta₁-stimulant (e.g. isoprenaline) intravenously at 2 to 5 minute intervals until the desired effect is achieved. Where a beta₁-stimulant is not available, administer 0.5 to 2.0 mg atropine sulphate i.v. in order to block the vagus nerve. If a satisfactory effect is not achieved, agents such as dopamine, dobutamine or noradrenaline may be administered.
Further measures: 1 to 5 (max 10) mg glucagon (glucagon activates the adenylcyclase system independently of the β-receptor, augmenting contractility in the presence of beta-blockade); transvenous intracardiac pacemaker. To combat bronchospasm, a beta₂-stimulant (e.g. salbutamol) or aminophylline can be given i.v.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: cardioselective beta-blocker; ATC code: C07AB02.
The stimulant effect of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac contractility and cardiac output.
Metoprolol lowers elevated blood pressure in both the standing and lying position. It also reduces the extent of rises in blood pressure occurring in response to physical and mental stress.
In angina pectoris, metoprolol reduces the frequency and severity of the attacks, and the need for glyceryl trinitrate relief, and increases exercise tolerance. In cases of supraventricular tachycardia or atrial fibrillation, and in the presence of ventricular extrasystoles, metoprolol has a regulating effect on the heart rate. In patients with a suspected or confirmed myocardial infarction, metoprolol lowers mortality. This effect may possibly be attributable to a decrease in the incidence of severe ventricular arrhythmias, as well as to limitation of infarct size. Metoprolol has also been shown to reduce the incidence of recurrent myocardial infarction.
Due to its beta-blocking effect, metoprolol is suitable for the prevention of migraine.
Metoprolol has been shown to reduce diuretic induced increase in plasma renin activity. It inhibits catecholamine induced insulin secretion to a far lesser degree than nonselective beta-blockers.
Orthostatic reactions or disturbances of electrolyte balance have not been observed.
Lopresor has less effect than nonselective beta-blockers on peripheral circulation and the bronchial muscles in therapeutic doses. However, it should be used with caution in patients with asthma, and concomitant use of an adrenergic bronchodilator, e.g. terbutaline or salbutamol, is recommended. Patients already on beta₂-stimulants for reversible airways obstruction may require adjustment of dosage if metoprolol therapy is subsequently introduced.
Lopresor inhibits catecholamine induced lipolysis.
The active metabolite of metoprolol (2-hydroxymetoprolol) does not contribute significantly to the therapeutic effect.
Lopresor is a relatively lipid soluble compound, i.e. less soluble than propranolol and more lipid soluble than atenolol.
Based on four studies of metoprolol in healthy males (n = 69), the mean maximal beta₁ blockade (Emax) measured by reduction in exercise heart rate was 28%, 95% CI [25%, 31%]. The mean metoprolol plasma concentration at 50% of Emax (C₅₀) was 105 nanomol/L, 95% CI [74, 135]. β₁ blockade of 30% of maximum was arbitrarily considered the lower limit to obtain a significant effect and was achieved with a mean plasma concentration (C₃₀) of 45 nanomol/L, 95% CI [32, 58].

Mechanism of action.

Metoprolol, the active substance of Lopresor, is a relatively cardioselective beta-blocker, i.e. it acts on beta₁-receptors mainly located in the heart at lower doses than those needed to influence the beta₂-receptors mainly located in the bronchi and peripheral vessels.
Metoprolol has little membrane stabilising effect, nor does it display partial agonist activity, i.e. intrinsic sympathomimetic activity (ISA), at doses required to produce beta-blockade.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

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

Distribution.

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

Metabolism.

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

Excretion.

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

Dose proportionality.

Metoprolol exhibits saturable presystemic metabolism leading to nonproportionate increase in the exposure with increased dose.

Food effect.

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

Dose response.

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

Pharmacokinetics in the elderly.

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

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

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

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Protect from moisture. Keep out of reach of children.

6.5 Nature and Contents of Container

Tablets 50 mg: bottle pack of 100's.
Tablets 100 mg: bottle pack of 60's.

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

Chemical name: di-[(±)-1-(isopropylamino)-3 -[ρ-(2-methoxyethyl)phenoxy]-2 -propanol] l(+)-tartrate.
Molecular weight: 684.81.
Molecular formula: (C₁₅H₂₅NO₃)₂(C₄H₆O₆).

Chemical structure.

CAS number.

56392-17-7.

7 Medicine Schedule (Poisons Standard)

S4.

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Lopresor

Metoprolol tartrate

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Lopresor 100 mg

Lopresor 50 mg