Consumer medicine information

Chemmart Metformin

Metformin hydrochloride

BRAND INFORMATION

Brand name

Chemmart Metformin

Active ingredient

Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Chemmart Metformin.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine 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 this medicine is used for

Metformin 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.

Metformin belongs to a group of medicines called biguanides.

It 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.

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.

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 an allergy to:


metformin or any other biguanide

any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue or other parts of the body

rash, itching or hives on the skin

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

type 1 diabetes that is well controlled by insulin alone

type 2 diabetes that is already well controlled by diet alone

any type of metabolic acidosis such as lactic acidosis, 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 or alcohol dependence

severe kidney disease or kidney failure

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)

dehydration, severe blood loss or shock

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

Do not take this medicine if 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 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.

Do not take this medicine if you are pregnant or plan to become pregnant.

Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will replace metformin with insulin while you are pregnant.

Do not take this medicine if you are breast-feeding.

Metformin may pass into human breast milk. Your doctor will discuss the options available to you.

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

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

kidney problems

  • heart failure

Tell your doctor if 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.

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

Do not take this medicine whilst pregnant or breastfeeding until you and your doctor have discussed the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

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

Some medicines may interact with metformin. These include:

other medicines used to treat diabetes such as insulin, glitinides (repaglinide) and sulfonylureas (e.g. gliclazide or glibenclamide)

iodinated contrast agents (dyes)

  • medicines that contain alcohol, such as cough and cold syrups
  • tetracosactrin, used in people with multiple sclerosis, and in young children to treat some types of seizures (fits)
  • danazol, used to treat endometriosis
  • medicines used to treat high blood pressure and some heart conditions, such as beta-blockers (metoprolol), calcium channel blockers (nifedipine, amlodipine) and ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, perindopril, ramipril, quinapril and trandolapril).
  • medicines used to prevent blood clots such as warfarin
  • diuretics, also called fluid or water tablets, such as amiloride, bumetanide, frusemide, hydrochlorothiazide and spironolactone
  • thyroid hormones, such as thyroxine
  • chlorpromazine, a medicine used to treat schizophrenia and other mental illnesses
  • NSAIDs (non-steroidal anti-inflammatory drugs), medicines used to relieve pain, swelling and other symptoms of inflammation, such as aspirin, diclofenac, ibuprofen, meloxicam, naproxen or piroxicam
  • cimetidine, a medicine commonly used to treat reflux and ulcers
  • corticosteroids such as prednisolone, prednisone and cortisone
  • some medicines used to treat asthma such as salbutamol or terbutaline
  • medicines that are substrates/ inhibitors of organic cation transporters – OCT 1 such as verapamil; OCT 2 such as dolutegravir, crizotinib, olaparib, daclatasvir or vandetanib
  • medicines that are inducers of OCT 1 such as rifampicin
  • medicines that may increase the risk of lactic acidosis when concomitantly used with metformin such as topiramate and other carbonic anhydrase inhibitors (zonisamide, acetazolamide or dichlorphenamide)

These medicines may be affected by metformin or may affect how well it works. You may need 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 this medicine.

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.

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

How much to take

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

Adults:

The usual starting dose for adults is 500mg 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 1000mg 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 500mg or 850mg once daily. Your doctor may increase or decrease the dose, depending on your blood glucose levels.

The maximum recommended dose is 2000mg 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.

If you forget to take it

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

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

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

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

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

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. 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 these extra carbohydrates will prevent a second drop in your blood glucose level.

HYPERGLYCAEMIA

Hyperglycaemia 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

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

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked.

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.

Tell your doctor if any of the following happen:

  • you become ill
  • you become dehydrated
  • you are injured
  • you have a fever
  • you have a serious infection such an influenza, respiratory tract infection or urinary tract infection
  • you are having surgery (including dental surgery) or are going into hospital
  • you are having an examination such as an X-ray or a scan requiring an injection of an iodinated contrast agent (dye)

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.

Things you must not do

Do not skip meals while taking this medicine.

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

If you need 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

Side effects

Tell your doctor as soon as possible if you do not feel well while you are this medicine.

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 you may have an increased chance of getting side effects.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

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.

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

  • symptoms of an allergic reaction including 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

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 heartbeat

LACTIC ACIDOSIS IS A VERY RARE BUT SERIOUS SIDE EFFECT REQUIRING URGENT MEDICAL ATTENTION OR HOSPITALISATION. ALTHOUGH RARE, IF IT DOES OCCUR, LACTIC ACIDOSIS CAN BE FATAL. THE RISK OF LACTIC ACIDOSIS IS HIGHER IN THE ELDERLY, OR PEOPLE WITH POORLY CONTROLLED DIABETES, PROLONGED FASTING, CERTAIN HEART CONDITIONS, SEVERE LIVER OR KIDNEY PROBLEMS OR PEOPLE WHO DRINK ALCOHOL.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

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

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

Some side effects (e.g. reduced vitamin B12 levels) can only be found when your doctor does tests from time to time to check your progress.

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 they 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 the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What Chemmart Metformin 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. AUST R 174817.

Available in blister packs of 100 tablets.

850 mg tablets:

White coloured, film-coated, round biconvex tablets plain on one side and '850' embossed on the other side. AUST R 174818.

Available in blister packs of 60 tablets.

1000 mg tablets:

White, film-coated, capsule-shaped, biconvex tablet, plain on one side and a break-line on the other. AUST R 176510.

Available in blister packs of 10, 30, 60 and 90 tablets.

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

Ingredients

Each tablet contains 250 mg 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
  • colloidal anhydrous silica
  • sodium starch glycollate
  • maize starch
  • purified talc
  • titanium dioxide.

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

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia
Tel: (02) 8877 8333
Web: www1.apotex.com/au

APO and APOTEX are registered trademarks of Apotex Inc

This leaflet was last updated in June 2020.

Published by MIMS August 2020

BRAND INFORMATION

Brand name

Chemmart Metformin

Active ingredient

Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Metformin hydrochloride.

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.

Chemmart Metformin 500 tablets.

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

Chemmart Metformin 850 tablets.

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

Chemmart Metformin 1000 tablets.

White, film-coated, capsule-shaped, biconvex tablet with a central breakline on one side.

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.

4.2 Dose and Method of Administration

Chemmart 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 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.

4.3 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.
Chemmart 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 precoma.
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.

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 incidence of lactic acidosis can and should be reduced by assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
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.

Diagnosis.

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders such as abdominal pain and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately (see Section 4.9 Overdose, Treatment).

Renal function.

As metformin hydrochloride is excreted by the kidney, it is recommended that creatinine clearance and/or serum creatinine levels be determined before initiating treatment and regularly thereafter:
At least annually in patients with normal renal function;
At least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.
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).

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.

The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. 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. 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

Contraindicated combinations.

Iodinated contrast materials.

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 (see Section 4.4 Special Warnings and Precautions for Use, Administration of iodinated contrast materials).

Inadvisable combinations.

Alcohol.

Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of fasting or malnutrition, hepatic insufficiency.
Avoid the consumption of alcohol and alcohol-containing medications. 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.

Combinations requiring precautions for use.

Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids and tetracosactides (systemic and local routes), beta-2-agonists, danazol, chlorpromazine at high dosages of 100 mg per day and diuretics:
More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon discontinuation.

Diuretics, especially loop diuretics.

May increase the risk of lactic acidosis due to their potential to decrease renal function.

Pharmacokinetic interactions.

Cimetidine.

Reduced clearance of metformin has been reported during cimetidine therapy, so a dose reduction should be considered.

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.

Co-administration 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.

ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin hydrochloride may be necessary when such medicinal products are added or discontinued.

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 (OCT).

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, crizotinib, olaparib, daclatasvir, vandetanib) may decrease renal elimination of metformin and this lead to an increase metformin plasma concentration.

Carbonic anhydrase inhibitors.

Topiramate or other carbonic anhydrase inhibitors (e.g. zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Metformin hydrochloride tablet may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

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.
Metformin is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.

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).

4.8 Adverse Effects (Undesirable Effects)

The following undesirable effects may occur under treatment with metformin hydrochloride. Frequencies are defined as follows: very common > 1/10; common > 1/100, < 1/10; uncommon > 1/1,000, < 1/100; rare > 1/10,000, < 1/1,000; very rare < 1/10,000; not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Gastrointestinal disorders.

Very common: Gastrointestinal disorders such as diarrhoea, nausea, vomiting, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Metabolism and nutrition disorders.

Very rare: lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use).
Decrease of vitamin B12 absorption with a decrease in serum levels has been observed in patients treated long-term with metformin. Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia. Therefore, serum B12 levels should be appropriately monitored or periodic parenteral B12 supplementation should be considered (see Section 4.4 Special Warnings and Precautions for Use, Other precautions).

Nervous system disorders.

Common: taste disturbance.

Skin and subcutaneous tissue disorders.

Very rare: Skin reactions such as erythema, pruritus and urticaria.

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.

4.9 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).

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.

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

Chemmart Metformin 500 tablets.

PVC/PVDC/Al blister packs of 100 tablets: AUST R 174817.

Chemmart Metformin 850 tablets.

PVC/PVDC/Al blister packs of 60 tablets: AUST R 174818.

Chemmart Metformin 1000 tablets.

PVC/PVDC/Al blister packs of 10, 30 60 and 90 tablets: AUST R 176510.
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.

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 structure.


Chemical Name: 1,1-dimethylbiguanide hydrochloride.
Molecular Formula: C4H11N5.HCl.
Molecular Weight: 165.6.

CAS number.

1115-70-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes