Consumer medicine information

Terry White Chemists Metformin Tablets

Metformin hydrochloride

BRAND INFORMATION

Brand name

Terry White Chemists Metformin Tablets

Active ingredient

Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Terry White Chemists Metformin Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

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

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

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up-to-date leaflet from www.apotex.com.au.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is Terry White Chemists Metformin 500, 850 or 1000 tablets. It contains the active ingredient metformin (as metformin hydrochloride).

It is used to treat type 2 diabetes (also called non-insulin dependent diabetes mellitus or maturity onset diabetes) in adults and children over 10 years of age.

It is especially useful in those who are overweight, when diet and exercise are not enough to lower high blood glucose levels (hyperglycaemia).

For adult patients, metformin can be used alone, or in combination with other oral diabetic medicines or in combination with insulin in insulin requiring type 2 diabetes.

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

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

How it works

Metformin belongs to a group of medicines called biguanides.

Metformin lowers high blood glucose by helping your body make better use of the insulin produced by your pancreas.

If your blood glucose is not properly controlled, you may experience hypoglycaemia (low blood glucose) or hyperglycaemia (high blood glucose).

People with type 2 diabetes are unable to make enough insulin or their body does not respond properly to the insulin it does make. This causes a build up of glucose in the blood, which can lead to serious medical problems with your heart, eyes, circulation or kidneys.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children under 10 years of age.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have or have had any of the following:
    - type 1 diabetes that is well controlled by insulin alone
    - type 2 diabetes that is already well controlled by diet alone
    - diabetic ketoacidosis (a symptom of uncontrolled diabetes, in which substances called ketone bodies build up in the blood - you may notice this as an unusual fruity odour on your breath, difficulty breathing, confusion and frequent urination)
    - severe liver disease
    - excessive alcohol intake, binge drinking, alcohol dependence
    - severe kidney disease or kidney failure
    - dehydration, severe blood loss, shock
    - a severe infection
    - certain heart or blood vessel problems, including a recent heart attack or severe heart failure (when the heart fails to pump blood effectively)
    - severe breathing difficulties
    - blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast heart rate)
    - gangrene
    - inflammation of the pancreas (pancreatitis), symptoms include severe upper stomach pain, often with nausea and vomiting.
  • You need to have major surgery or an examination such as an X-ray or scan requiring an injection of iodinated contrast (dye).
    You must stop taking metformin for a certain period of time before and after the examination or the surgery. Your doctor will decide whether you need any other treatment for this time. It is important that you follow your doctor's instructions precisely.
  • You are breast-feeding.
    Metformin may pass into human breast milk.
  • You are hypersensitive to, or have had an allergic reaction to, metformin, other biguanides or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  2. You have or have had any medical conditions, especially the following:
    - kidney problems
    - heart failure.
  3. You drink alcohol.
    Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with metformin may also lead to serious side effects. Your doctor may suggest you stop drinking or reduce the amount of alcohol you drink.
  4. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  5. You are currently breast-feeding or you plan to breast-feed. Do not take this medicine whilst breast-feeding.
  6. You are planning to have surgery or an anaesthetic.
  7. You are currently receiving or are planning to receive dental treatment.
  8. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with metformin. These include:

  • other medicines used to treat diabetes, such as sulfonylureas or repaglinide
  • some medicines used to treat high blood pressure and some heart conditions, including beta-blockers, calcium channel blockers and ACE inhibitors; some examples include metoprolol, nifedipine and enalapril
  • medicines used to prevent blood clots such as warfarin
  • diuretics, also called fluid tablets
  • thyroid preparations such as thyroxine
  • cimetidine, a medicine commonly used to treat reflux and ulcers
  • glucocorticoids such as prednisone and cortisone
  • some medicines used to treat asthma such as salbutamol or terbutaline.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with metformin.

How to take this medicine

Follow carefully all directions given to you by your doctor.

Their instructions may be different to the information in this leaflet.

How much to take

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

Do not stop taking your medicine or change your dosage without first checking with your doctor.

Adults

The usual starting dose for adults is 500 mg one to two times a day. Your doctor may increase or decrease the dose, depending on your blood glucose levels. The maximum recommended dose is 1000 mg three times a day.

People over 65 years of age or those with kidney problems may need smaller doses.

Children & Adolescents

The usual starting dose for children from 10 years of age and adolescents is one tablet of 500 mg or 850 mg once daily. Your doctor may increase or decrease the dose, depending on your blood glucose levels.

The maximum recommended dose is 2000 mg daily, taken as two or three divided doses.

How to take it

Swallow the tablets with a glass of water.

When to take it

Take your medicine during or immediately after a meal, at about the same time each day.

This will reduce the chance of a stomach upset.

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

How long to take it for

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

Metformin will help control your diabetes but will not cure it. Most people will need to take metformin on a long-term basis.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise take it as soon as you remember (with or immediately after a meal) and then go back to taking your medicine as you would normally.

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

This may increase the chance of you getting low blood sugar levels (hypoglycaemia).

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

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

If you take too much metformin you may feel sleepy, very tired, sick, vomit, have trouble breathing and have unusual muscle pain, stomach pain or diarrhoea. These may be early signs of a serious condition called lactic acidosis (build up of lactic acid in the blood).

You may also experience symptoms of hypoglycaemia (low blood glucose). This usually only happens if you take too much metformin together with other medicines for diabetes or with alcohol.

While you are taking this medicine

Things you must do

Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia and hyperglycaemia and know how to treat them.

HYPOGLYCAEMIA

Metformin does not normally cause hypoglycaemia, although you may experience it if you also take other medicines for diabetes such as sulfonylureas or repaglinide; or if you also use insulin.

Hypoglycaemia can occur suddenly. Initial signs may include:

  • weakness, trembling or shaking
  • sweating
  • light-headedness, dizziness, headache or lack of concentration
  • irritability, tearfulness or crying
  • hunger
  • numbness around the lips and tongue.

If not treated promptly, these may progress to:

  • loss of co-ordination
  • slurred speech
  • confusion
  • fits or loss of consciousness.

If you experience any of the symptoms of hypoglycaemia, you need to raise your blood glucose immediately.

You can do this by doing one of the following:

  • eating 5 to 7 jelly beans
  • eating 3 teaspoons of sugar or honey
  • drinking half a can of non-diet soft drink
  • taking 2 to 3 concentrated glucose tablets.

Unless you are within 10 to 15 minutes of your next meal or snack, follow up with extra carbohydrates such as plain biscuits, fruit or milk.

Taking this extra carbohydrate will prevent a second drop in your blood glucose level.

HYPERGLYCAEMIA

Hyperglycemia is often asymptomatic (doesn't cause any immediate symptoms) in many people. However some people will develop symptoms. Those people who develop symptoms may experience the following:

  • high levels of sugar in the urine
  • frequent urination
  • increased thirst.

If you develop any signs of hyperglycaemia, contact your doctor immediately.

Your doctor may need to consider additional or other treatments for your diabetes.

The risk of hyperglycaemia is increased in the following situations:

  • uncontrolled diabetes
  • illness, infection or stress
  • taking less metformin than prescribed
  • taking certain other medicines
  • too little exercise
  • eating more carbohydrates than normal.

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breast-feeding or are planning to breast-feed
  • you are about to have any blood tests

You must also tell your doctor if:

  • you become ill
  • you become dehydrated
  • you are injured
  • you have a fever
  • you have a serious infection
  • you are having surgery (including dental surgery) or are going into hospital

Your blood glucose may become difficult to control at these times. You may also be more at risk of developing a serious condition called lactic acidosis. At these times, your doctor may replace metformin with insulin.

Go to your doctor regularly for a check-up. Your doctor may want to perform blood tests to check your kidneys, liver, heart and vitamin B12 level while you are taking this medicine.

Check your blood glucose levels regularly.

This is the best way to tell if your diabetes is being controlled properly. Your doctor or diabetes educator will show you how and when to do this.

When you start treatment with metformin, it can take up to two weeks for your blood glucose levels to be properly controlled.

Carefully follow the advice of your doctor and dietician on diet, drinking alcohol and exercise.

Things you must not do

  • Do not skip meals while taking this medicine.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not take your medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not stop taking your medicine, or change the dosage, without checking with your doctor.

Things to be careful of

If you have to be alert, for example when driving, be especially careful not to let your blood glucose levels fall too low.

Low blood glucose levels may slow your reaction time and affect your ability to drive or operate machinery. Drinking alcohol can make this worse. However, metformin by itself is unlikely to affect how you drive or operate machinery.

If you become sick with a cold, fever or flu, it is very important to continue taking metformin even if you feel unable to eat your normal meal.

Your diabetes educator or dietician can give you a list of foods to use for sick days.

If you are travelling, it is a good idea to:

  • wear some form of identification (e.g. bracelet) showing you have diabetes
  • carry some form of sugar to treat hypoglycaemia if it occurs, for example, sugar sachets or jelly beans
  • carry emergency food rations in case of a delay, for example, dried fruit, biscuits or muesli bars
  • bring your medicine with you, so you don't miss any doses.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking metformin.

Metformin helps most people with diabetes, but it may have unwanted side effects in a few people.

If you are over 65 years of age, report any side effects to your doctor immediately.

People over his age may have an increased chance of getting side effects.

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

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

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

  • stomach upset such as feeling sick (nausea)
  • vomiting
  • taste disturbance
  • loss of appetite
  • diarrhoea
  • skin reactions such as redness of the skin, itching or an itchy rash (urticaria)

These are generally mild side effects. Stomach upset and diarrhoea are common but usually short-lived. Taking your medicine with meals can help reduce nausea and diarrhoea. Skin rash has been reported rarely.

Tell your doctor immediately or go to Accident or Emergency at the nearest hospital if you notice any of the following symptoms of Lactic Acidosis (build up of lactic acid in the blood):

  • nausea, vomiting, stomach pain
  • trouble breathing
  • feeling weak, tired or generally unwell
  • unusual muscle pain
  • sleepiness
  • dizziness or light-headedness
  • shivering, feeling extremely cold
  • slow heart beat.

Lactic acidosis is a very rare but serious side effect requiring urgent medical attention or hospitalisation.

Although rare, if lactic acidosis does occur it can be fatal. The risk of lactic acidosis is higher in the elderly, those whose diabetes is poorly controlled, those with prolonged fasting, those with certain heart conditions, those who drink alcohol and those with kidney and liver problems.

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Allergic reactions

If you think you are having an allergic reaction to metformin, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

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

Keep this medicine where children cannot reach it.

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

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What Terry White Chemists Metformin 500, 850 or 1000 looks like

  • 500 mg tablets:
    White coloured, film-coated biconvex capsule shaped tablet with central break-line on one side and '500' embossed on the other side.
    They are packaged in a blister pack of 100 tablets.
  • 850 mg tablets:
    White coloured, film-coated, round biconvex tablets plain on one side and '850' embossed on the other side.
    They are packaged in a blister pack of 60 tablets.
  • 1000 mg tablets:
    White, film-coated, capsule-shaped, biconvex tablet, plain on one side and a breakline on the other.
    They are packed in a blister pack of 10, 30, 60 and 90 tablets.

* Not all strengths and/or pack sizes may be available.

Ingredients

Each tablet 500 mg, 850 mg or 1000 mg of metformin hydrochloride as the active ingredient.

It also contains the following inactive ingredients:

  • hypromellose
  • macrogol 6000
  • magnesium stearate
  • povidone
  • propylene glycol
  • silica - colloidal anhydrous
  • sodium starch glycollate
  • starch - maize
  • talc- purified
  • colloidal anhydrous silica
  • titanium dioxide.

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

  • Terry White Chemists Metformin 500 tablets (blister pack):
    AUST R 174819.
  • Terry White Chemists Metformin 850 tablets (blister pack):
    AUST R 174820.
  • Terry White chemists Metformin 1000 tablets (blister pack):
    AUST R 176511

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was last updated in:
June 2013

BRAND INFORMATION

Brand name

Terry White Chemists Metformin Tablets

Active ingredient

Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Metformin hydrochloride.

6.7 Physicochemical Properties

Metformin hydrochloride is a white, crystalline powder which is almost odourless and hygroscopic. It is freely soluble in water, slightly soluble in ethanol (96%) and practically insoluble in chloroform and in ether.
Chemical Name: 1,1-dimethylbiguanide hydrochloride.
Molecular Formula: C4H11N5.HCl.
Molecular Weight: 165.6.

Chemical structure.


CAS number.

1115-70-4.

2 Qualitative and Quantitative Composition

Each tablet contains 500 mg, 850 mg or 1000 mg metformin hydrochloride, as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablet.

Terry White Chemists Metformin 500 tablets

.White coloured, film-coated biconvex capsule shaped tablet with central breakline on one side and '500' embossed on the other side.

Terry White Chemists Metformin 850 tablets.

White coloured, film-coated, round biconvex tablets plain on one side and '850' embossed on the other side.

Terry White Chemists Metformin 1000 tablets.

White, film-coated, capsule-shaped, biconvex tablet, plain on one side and a breakline on the other.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Metformin is an oral biguanide hypoglycaemic agent. It causes an increased peripheral uptake of glucose by increasing the biological efficiency of available exogenous or endogenous insulin.
The mode of action of metformin may be linked to an increase of insulin sensitivity. It does not stimulate insulin release but does require the presence of insulin to exert its anti-hyperglycaemic effect. Possible mechanisms of action include inhibition of gluconeogenesis in the liver, delay in glucose absorption from the gastrointestinal tract and an increase in peripheral uptake of glucose.
Metformin has an antiketogenic activity which is comparable, though somewhat inferior, to insulin itself. Metformin lowers both basal and postprandial blood glucose in diabetic patients but does not cause hypoglycaemia in either diabetics or normal individuals.

Clinical trials.

The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes.
Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p = 0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p = 0.0034;
a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p = 0.017;
a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p = 0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p = 0.021);
a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p = 0.01).
For metformin used as second-line therapy, in combination with sulfonylurea, benefit regarding clinical outcome has not been shown.
In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not been fully established.

Paediatrics.

In a double-blind, placebo-controlled study in 82 paediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 10.1 mmol/L), treatment with metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 3.6 mmol/L, compared with placebo.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, metformin hydrochloride is absorbed along the entire gastrointestinal mucosa. Studies using single oral doses of metformin tablets indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption of metformin rather than an increase in elimination. After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are non-linear.
At usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations are reached in 24 to 48 hours and are generally less than 1 microgram/mL. During controlled clinical trials, maximum metformin plasma levels did not generally exceed 5 microgram/mL, even at maximum doses.

Distribution.

Metformin is not bound to plasma proteins.

Metabolism.

Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.

Excretion.

In patients with significantly decreased renal function (based on measured creatinine clearance), the plasma half-life of metformin is prolonged and renal clearance is decreased in proportion to the decrease in creatinine clearance, e.g. if creatinine clearance is 10-30 mL/min, renal clearance is reduced to 20% of normal.

Paediatrics.

Following an oral dose, children 12 years and older, have shown similar pharmacokinetic profile of metformin to that observed in adults. Pharmacokinetic data in children between 10 and 12 years are not available.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of a mutagenic potential of metformin was found in the Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes), or in vivo micronuclei formation test (mouse bone marrow).

Carcinogenicity.

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. Three doses are both approximately two to three times the recommended human daily dose on a body surface area basis. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumourigenic potential observed with metformin in male rats. However, an increased incidence of benign stromal uterine polyps was seen in female rats treated with 900 mg/kg/day.

4 Clinical Particulars

4.1 Therapeutic Indications

Metformin is indicated in the treatment of type 2 diabetes mellitus in adults, children from 10 years of age and adolescents, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.
For adult patients, metformin may be used as initial treatment or in sulfonylurea failures either alone or in combination with a sulfonylurea and other oral agents or as adjuvant therapy in insulin requiring type 2 diabetes.

4.3 Contraindications

Juvenile diabetes mellitus that is uncomplicated and well regulated on insulin.
Diabetes mellitus regulated by diet alone.
During or immediately following surgery where insulin is essential.
Terry White Chemists Metformin 500/850/1000 should not be given to patients who have experienced hypersensitivity to the product or any of its ingredients.
Hypersensitivity to biguanides.
Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis.
Diabetic pre-coma.
Renal failure or renal dysfunction (creatinine clearance < 60 mL/min).
Acute conditions with the potential to alter renal function such as dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see Section 4.4 Special Warnings and Precautions for Use).
Acute or chronic disease which may cause tissue hypoxia such as cardiac failure, recent myocardial infarction, respiratory failure, pulmonary embolism, shock, acute significant blood loss, sepsis, gangrene, pancreatitis.
Elective major surgery (see Section 4.4 Special Warnings and Precautions for Use).
Severe hepatic insufficiency: acute alcohol intoxication; alcoholism.
Lactation.

Risk of lactic acidosis.

Because of the danger of lactic acidosis, metformin should not be used in the presence of the following conditions: diminished renal function; cardiovascular disease (e.g. coronary insufficiency, myocardial infarction, and hypertension); conditions which may be associated with tissue hypoxia (e.g. gangrene, circulatory shock, acute significant blood loss); pulmonary embolism; severe hepatic dysfunction; pancreatitis; excessive alcohol intake; concomitant use of diuretics.

4.4 Special Warnings and Precautions for Use

Lactic acidosis.

Lactic acidosis is a rare but serious [high mortality in the absence of prompt treatment] metabolic complication which can occur due to accumulation of metformin during treatment. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis is a medical emergency and must be treated in hospital immediately. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Special caution should be taken in the elderly due to the decrease of renal function with age.
The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases per 1000 patient years, with approximately 0.015 fatal cases per 1000 patient years). The onset is often subtle and accompanied by non-specific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and non-specific abdominal distress. Lactic acidosis may also occur in association with a number of pathophysiological conditions, including diabetes mellitus, and when there is significant tissue hypoperfusion and hypoxaemia.

Heart failure.

Type 2 diabetic patients with heart failure are at an increased risk of hypoperfusion and possible renal insufficiency. Renal insufficiency is a risk factor for systemic accumulation of metformin and consequently lactic acidosis. Careful monitoring of renal function is recommended when metformin is used in patients with cardiac failure. The major risk of cardiac insufficiency is hypoxia.
When metformin is implicated as the cause of lactic acidosis, metformin plasma levels greater than 5 microgram/mL are generally found (see Section 5.2 Pharmacokinetic Properties). Underlying renal disease, or a deterioration in renal function, result in reduced clearance of metformin and drug accumulation and are therefore major risk factors in lactic acidosis. The risk of lactic acidosis may therefore be significantly decreased by regular monitoring of renal function in patients taking metformin and those patients on concomitant diuretics. The use of minimum effective dose of metformin is recommended. In addition, metformin therapy should be temporarily stopped in the presence of any condition associated with hypoxaemia or dehydration, in patients suffering from serious infections or trauma (particularly if gastrointestinal disturbances are noted or acidosis is suspected) and in those undergoing surgery.

Surgery.

Metformin hydrochloride must be discontinued 48 hours before elective major surgery. Therapy may be restarted no earlier than 48 hours following surgery and only after renal function has been re-evaluated and found to be normal.

Other precautions.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should; therefore, be warned against excessive alcohol intake, acute or chronic, while taking metformin.
All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
Periodic assessment of renal, hepatic and cardiovascular function is recommended during prolonged periods of treatment with metformin.
Metformin hydrochloride alone does not cause hypoglycaemia; however, caution is advised when it is used in combination with other antidiabetic agents (sulphonylureas, glinides, insulin).
In patients receiving continuous metformin therapy, it is recommended that serum vitamin B12 levels be measured prior to initiation treatment with metformin, after 6 months treatment and thereafter annually because of reports of decreased vitamin B12 absorption associated with metformin administration.

Use in the elderly.

The risk of lactic acidosis, in association with metformin, is increased in elderly patients on long-term therapy due to the physiological alteration of the renal function and the possible accumulation of metformin.
Metformin may be used in the elderly if Contraindications and Special Warnings and Precautions for Use (see Section 4.3; Section 4.4) are respected, the dosage is frequently reviewed and renal function monitored.
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).

Administration of iodinated contrast materials.

Radiological studies involving the use of intravascular iodinated contrast materials (for example intravenous urogram, intravenous cholangiography, angiography, any computed tomography scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients with normal renal function, metformin should be stopped at the time of the study and not recommenced for 48 hours and only after renal function has been re-evaluated and found to be normal.
Therefore, metformin must be discontinued either 48 hours before the test when renal function is known to be impaired or from the time of the test when renal function is known to be normal. Metformin may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Section 4.5 Interactions with Other Medicines and other Forms of Interactions).

Paediatric use.

Metformin is not recommended for use in children under 10 years of age.
The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated.
No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but clinical data in relation to the long-term effect of metformin on the development of skeletal and reproductive system in children and adolescents are not available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children, is recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Alcohol.

Avoid the consumption of alcohol and alcohol-containing medications. The risk of lactic acidosis increases with acute intoxication, particularly in cases of fasting or malnutrition and hepatic insufficiency. Alcohol may make the signs of hypoglycaemia less clear, and delayed hypoglycaemia can occur. The CNS depressant effects of alcohol plus hypoglycaemia can make driving and operation of dangerous machinery much more hazardous.

Pharmacokinetic interactions.

Cimetidine.

Co-administration of cimetidine with metformin may lead to reduced renal clearance of metformin and hence increased plasma metformin concentrations. Dose reductions should therefore be considered in patients being treated with cimetidine.

Anticoagulants.

Metformin increases the elimination rate of vitamin K antagonists. Consequently, the prothrombin time should be closely monitored in patients in whom metformin and vitamin K antagonists are being co-administered. Cessation of metformin in patients receiving vitamin K antagonists can cause marked increases in the prothrombin time.

Nifedipine.

A single dose, metformin/nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of metformin and nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in the urine. Tmax and half-life of metformin were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin has minimal effects on the pharmacokinetics of nifedipine.

Pharmacodynamic interactions.

Sulfonylureas and repaglinide.

During concomitant therapy with either sulfonylureas or repaglinide, blood glucose should be monitored because combined therapy may cause hypoglycaemia.

Other hypoglycaemics.

During combined therapy of metformin with other hypoglycaemics, blood glucose should be monitored because of the possibility of hypoglycaemia.

Beta-blockers.

Coadministration of metformin and beta-blockers may result in a potentiation of the anti-hyperglycaemic action. In addition, some of the premonitory signs of hypoglycaemia, in particular tachycardia, may be masked. Monitoring of blood glucose should be undertaken during dosage adjustment of either agent.

ACE inhibitors.

Coadministration of metformin and ACE inhibitors may result in a potentiation of the hypoglycaemic action. Monitoring of blood glucose should be undertaken during dosage adjustment of either agent.

Calcium channel blockers.

Calcium channel blockers may affect glucose control in diabetic patients; regular monitoring of glycaemic control is recommended.

Thiazide diuretics.

Thiazide therapy may impair glucose tolerance. Dosage adjustment of metformin may be required.

Thyroid products.

Thyroid products tend to produce hyperglycaemia and may lead to loss of control.

Glucocorticoids (systemic and local routes), beta-2-antagonists and diuretics.

Glucocorticoids (systemic and local routes), beta-2-antagonists and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the anti-diabetic medicinal product during therapy with the other medicinal product and upon its discontinuation.

Iodinated contrast media.

Metformin should be temporarily withheld in patients undergoing radiological studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function (see Section 4.4 Special Warnings and Precautions for Use).

Organic cation transporters.

Metformin is a substrate of both transporters OCT1 and OCT2.
Coadministration of metformin with:
Substrates/inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
Inducers of OCT2 (such as rifampicin) may increase gastrointestinal absorption and efficacy.
Substrates/inhibitors of OCT2 (such as cimetidine, dolutegravir, cizotinib, olaparib, dalclatasvir, vandetanid) may decrease renal elimination of metformin and this lead to an increase metformin plasma concentration.

NSAID.

May increase the risk of acidosis and adversely affect renal function.
Therefore, caution is advised when these drugs are coadministered with metformin and a dose adjustment may be considered, particularly with renal impairment.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility of male or female rats was unaffected by metformin administration at doses up to 600 mg/kg/day, or approximately twice the maximum recommended daily dose on a body surface area basis.
(Category C)
To date, no relevant epidemiological data is available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or foetal development, parturition or postnatal development.
Oral hypoglycaemics may enter the foetal circulation and cause neonatal hypoglycaemia. It is important to achieve strict normoglycaemia during pregnancy. Oral anti-hyperglycaemic agents should be replaced by insulin.
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, or about two times the maximum recommended human daily dose on a body surface area basis. Determination of foetal concentrations demonstrated a partial placental barrier to metformin. Because animal reproduction studies are not always predictive of human response, any decision to use this drug should be balanced against the benefits and risks. The safety of metformin in pregnant women has not been established.
Because information available suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, there is a consensus among experts that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers, but caution should be exercised in such patients, and a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

Gastrointestinal.

Very common: mild gastrointestinal symptoms (such as diarrhoea, nausea, vomiting, abdominal pain and loss of appetite) are the most frequent reactions to metformin (> 1/10), especially during the initial treatment period. These symptoms are generally transient and resolve spontaneously during continued treatment.
Gastrointestinal side effects can possibly be avoided if metformin is taken with meals and if the dose is increased slowly. Occasionally, a temporary dose reduction can be considered. Occurrence of gastrointestinal symptoms, once a patient is stabilised on any dose of metformin, could be due to lactic acidosis or other serious disease.

Systemic/ metabolic.

Very rare: lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use) is a very rare (< 1/10,000) but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin.
The onset of lactic acidosis is often subtle and accompanied by non-specific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Lactic acidosis should be suspected in any diabetic patient with a metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia).
Lactic acidosis is a medical emergency that must be treated in hospital. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted.

Nervous system disorders.

Common: taste disturbance (3%) is common.

Dermatological.

Very rare: skin reactions such as erythema, pruritus and urticaria have been reported, but the incidence is rare (< 1/10,000).

Haematological.

Very rare: a decrease in vitamin B12 absorption with a decrease in serum levels has been observed in patients treated long-term with metformin (< 1/10,000). Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia. Therefore, serum B12 levels should be appropriately monitored and periodic parenteral B12 supplementation considered.

Hepatobiliary disorders.

Isolated reports: liver function tests abnormalities or hepatitis resolving upon metformin discontinuation, have been reported.
In clinical trials in children and adolescents with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Terry White Chemists Metformin 500/850/1000 tablets are intended for oral administration.
Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment; other risk factors include old age associated with reduced renal function and high doses of metformin above 2 g per day.

Dosage.

It is important that the tablets are taken in divided doses with meals.
Initially 500 mg should be taken once or twice a day and if necessary increased over a few weeks up to 1 g three times per day. The dose should be titrated with gradual dose increments until the desired effect is obtained. 500 mg three times a day is often sufficient to obtain diabetic control. If necessary, the dose can be increased to 1 g three times daily, which is the maximum recommended daily dose. Control may be attained within a few days but occasionally requires up to two weeks. Once control has been obtained, the dosage should be reviewed and reduced to the lowest maintenance level consistent with good diabetic control.
Metformin dosage should be frequently reviewed in patients stabilised on metformin, especially if they develop an illness, as they may tolerate the drug less well, particularly if the illness is accompanied by a decrease in renal function. If necessary, metformin should be ceased for a few days during an illness and then restarted at low dosage, as for initial therapy.
The action of metformin is progressive and no final assessment of the patient's real response should be made before the 21st day of treatment; blood sugar estimations are recommended during the initial 15 days of stabilisation. Metformin will not produce a hypoglycaemic state when used alone; however, due to its action in increasing insulin effectiveness, care must be taken when metformin is initially administered with parenteral doses of insulin.

Elderly.

The initial and maintenance dosing of metformin should be conservative in elderly patients, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin.

Use in children and adolescents.

Metformin can be used as monotherapy in children from 10 years of age and adolescents. The usual starting dose is one tablet of 500 mg or 850 mg once daily, given during meals or after meals.
After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.
The maximum recommended dose of metformin is 2 g daily, taken as two or three divided doses.

In debilitated or malnourished patients.

The dosing should be conservative and based on a careful assessment of renal function.

4.7 Effects on Ability to Drive and Use Machines

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machinery. However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulphonylureas, glinides, insulin).

4.9 Overdose

Symptoms.

Hypoglycaemia has not been seen with ingestion of up to 85 g of metformin alone, although lactic acidosis has occurred in such circumstances. This disorder is a medical emergency and must be treated in hospital. The onset of lactic acidosis is often subtle and accompanied only by non-specific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and non-specific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia).

Treatment.

Lactic acidosis may develop in diabetic metformin-treated patients with overdose. Lactic acidosis is diagnosed and monitored by measurement of serum electrolytes, arterial pH and pCO2 and arterial lactate plasma level.
The aim of treatment is to manage any underlying disorder and in some cases this will be sufficient to enable the body's homeostatic mechanism to correct the acid-base imbalance. The advantages of more active treatment of the acidosis must be balanced against the risks, including over alkalinisation with sodium bicarbonate. Because metformin hydrochloride is dialysable (with a clearance of up to 170 mL/min under good haemodynamic conditions), prompt haemodialysis is recommended to correct the acidosis and remove the accumulated metformin.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hypromellose, macrogol 6000, magnesium stearate, povidone, propylene glycol, colloidal anhydrous silica, sodium starch glycollate, maize starch, purified talc, titanium dioxide.

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.

6.5 Nature and Contents of Container

Terry White Chemists Metformin 500 tablets.

Blister packs of 100 tablets: AUST R 174819.

Terry White Chemists Metformin 850 tablets.

Blister packs of 60 tablets: AUST R 174820.

Terry White Chemists Metformin 1000 tablets.

Blister packs of 10, 30 60 and 90 tablets: AUST R 176511. Not all strengths and/or pack sizes may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes