Consumer medicine information

APO-Metformin XR

Metformin hydrochloride

BRAND INFORMATION

Brand name

APO-Metformin XR

Active ingredient

Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Metformin XR.

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 XR is used to control blood glucose (sugar) in people with Type 2 diabetes mellitus, especially in those who are overweight. It is used when diet and exercise are not enough to control high levels of blood glucose.

Metformin XR can be used alone, or in combination with other medicines for treating diabetes.

Metformin belongs to a group of medicines called biguanides. It lowers high blood glucose levels by:

  • improving your body's sensitivity to insulin and restoring the way it normally uses glucose
  • reducing the amount of glucose your liver makes
  • delaying the amount of glucose your intestine absorbs.

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

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is also called Non-Insulin Dependent Diabetes Mellitus (NIDDM) or Maturity Onset Diabetes.

Insulin is a hormone that enables body tissues to take up glucose from the blood and to use it for energy or fat storage for future use.

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 (hyperglycaemia), which can lead to serious medical problems.

Long-term hyperglycaemia can lead to heart disease, blindness, kidney damage, poor blood circulation and gangrene.

Signs of hyperglycaemia may include:

  • tiredness or lack of energy
  • headache
  • thirst
  • passing large amounts of urine
  • blurred vision.

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.

Use in children

There is not enough information to recommend the use of this medicine for children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • any medicine containing 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 or have had any of the following:

  • Type 1 diabetes mellitus that is well controlled by insulin alone
  • Type 2 diabetes that is already well controlled by diet alone
  • serious complications with your diabetes or any type of metabolic acidosis such as lactic acidosis or diabetic ketoacidosis (a symptom of uncontrolled diabetes, in which substances called ketone bodies accumulate in the blood - you may notice this as an unusual fruity odour on your breath)
  • kidney failure or severe kidney disease
  • dehydration (for instance due to persistent or severe vomiting or diarrhoea)
  • shock from severe injury or blood loss
  • severe liver disease
  • acute alcohol intoxication or chronic alcohol dependence
  • certain heart or blood circulation problems, including a recent heart attack or heart failure (when the heart fails to pump blood effectively)
  • blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast heart rate) or severe breathing difficulties
  • inflammation of the pancreas (symptoms include severe upper stomach pain, often with nausea and vomiting) if associated with severe infection or hypoxia (lack of oxygen)
  • a severe infection or gangrene.

Do not take this medicine if you need to have major surgery or an examination such as an X-ray or a 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.

Do not take this medicine if you are pregnant. Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will replace metformin with insulin while you are pregnant.

Do not breastfeed if you are taking this medicine. Your doctor will discuss with you the options of either breast-feeding or using metformin.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

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

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

  • kidney problems – before starting metformin, your doctor will ask you to have a blood test to check your kidney function
  • liver problems
  • alcohol dependence
  • current dehydration
  • current infection
  • pancreatitis (inflammation of the pancreas)
  • heart or blood vessel problems, including 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. You should also avoid taking other medicines that contain alcohol.

Tell your doctor if you are planning to have any operations or radiographic procedures.

If you have not told your doctor about any of the above, tell him/her 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 and metformin may interfere with each other. 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
  • corticosteroids such as prednisolone, prednisone and cortisone
  • 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).
  • some medicines used to treat asthma such as salbutamol and terbutaline
  • diuretics, also called fluid or water tablets, such as amiloride, bumetanide, frusemide, hydrochlorothiazide and spironolactone
  • chlorpromazine, 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, including arthritis such as aspirin, diclofenac, meloxicam, naproxen and piroxicam
  • medicines used to treat ulcers and reflux, such as cimetidine
  • medicines used to prevent blood clots such as warfarin
  • 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 hydrochloride such as topiramate and other carbonic anhydrase inhibitors such as zonisamide, acetazolamide or diclorphenamide

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.

Other medicines not listed above may also interact with metformin.

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

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

How much to take

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.

The usual starting dose is 500 mg once daily with the evening meal. Your doctor may increase the dose slowly, depending on your blood glucose levels.

The maximum recommended dose is 2 grams once per day.

The elderly and people with kidney problems may need smaller doses.

How to take it

Swallow the tablets whole with a full glass of water.

Do not break, crush or chew the tablets. If you break, crush or chew the tablets, they will not work as well.

Metformin XR are modified release tablets. This means they have a special coating which allows the active ingredient, metformin, to be released slowly over time.

When to take it

Take your medicine at about the same time each day.

Taking the tablets during or with your evening meal will reduce the chance of a stomach upset.

Taking it 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

Continue taking your medicine for as long as your doctor tells you. Metformin will help control diabetes but will not cure it. Most people will need to take metformin for long periods of time.

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

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 an unwanted side effect.

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)

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 (telephone 13 11 26) for advice, or go to Accident and Emergency at the 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 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.

If you do experience any signs of hypoglycaemia, raise your blood glucose quickly by eating jelly beans, sugar or honey, drinking a non-diet soft drink or taking glucose tablets.

While you are taking this medicine

Things you must do

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

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

Tell your doctor that you are taking this medicine if you experience any of the following signs which may indicate a lifethreatening condition called lactic acidosis:

  • muscle cramps
  • stomach pain
  • feeling weak
  • problems breathing.

Tell your doctor if you plan to have any radiographic procedures requiring an injection of an iodinated contrast agent (dye). Your doctor will advise you when to stop taking metformin before you have these procedures and when to start again.

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 plan to breastfeed while taking this medicine, tell your doctor immediately.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may want to check your kidneys, liver, heart and blood levels while you are taking metformin.

Make sure you 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.

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 (for instance due to persistent or severe diarrhoea or recurrent vomiting)
  • you are injured
  • you have a fever
  • you have a serious infection such an influenza, respiratory tract infection or urinary tract infection

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.

Hypoglycaemia

Metformin does not normally cause hypoglycaemia (low blood sugar), although you may experience it while taking other medicines for diabetes such as insulin, sulfonylureas or glitinides. Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia (low blood sugar) and know how to treat them.

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 jellybeans
  • 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

If you experience any of the signs of hyperglycaemia (high blood sugar), contact your doctor immediately.

The risk of hyperglycaemia is increased in the following situations:

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

Things you must not do

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.

Do not skip any meals while taking metformin.

Things to be careful of

If you must 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.

Things to be aware of

After metformin is absorbed into your body, you may see the empty tablet shell in your faeces (bowel motions). This is normal and does not affect the way metformin works.

Side effects

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

Metformin helps most people with control blood glucose (sugar) inpeople with Type 2 diabetes mellitus, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

The above list includes the more common side effects of your medicine, which disappear after the first few weeks. Taking metformin with meals can help reduce nausea and diarrhoea.

Tell your doctor as soon as possible if you notice any of the following:

  • symptoms of liver disease such as nausea, vomiting, loss of appetite, feeling generally unwell, fever, yellowing of the skin and eyes (jaundice) and dark coloured urine.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • 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 (buildup 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 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. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell. It is very important that you speak to your doctor immediately if a side effect is severe, occurred suddenly or gets worse rapidly.

Other side effects not listed above may also occur in some people.

Some side effects (e.g. reduced vitamin B12 level) 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 it may not keep well.

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

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

Keep it 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, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Metformin XR tablets looks like

Metformin XR 500 contains 500 mg metformin hydrochloride as modified release tablets: White, capsule shaped uncoated tablet with XR 500 on one side and a plain on the other side. AUST R 281211.

It is available in blister packs of 120 tablets.

Metformin XR 1000 contains 1000 mg metformin hydrochloride as modified release tablets: White capsule shaped uncoated tablet with XR 1000 one side and a plain on the other side. AUST R 281210.

It is available in blister packs of 60 tablets.

* Not all strengths may be available.

Ingredients

Each modified release tablet contains either 500 mg or 1000 mg metformin hydrochloride as the active ingredient. It also contains the following inactive ingredients:

  • hypromellose
  • povidone
  • colloidal anhydrous silica
  • magnesium stearate

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

APO-Metformin XR

Active ingredient

Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Metformin hydrochloride.

2 Qualitative and Quantitative Composition

APO-Metformin XR 500 modified release tablets contain 500 mg metformin hydrochloride (HCl).
APO-Metformin XR 1000 modified release tablets contain 1000 mg metformin hydrochloride (HCl).
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release tablet.

APO-Metformin XR 500.

White, capsule shaped uncoated tablet with XR 500 on one side and plain on the other side.

APO-Metformin XR 1000.

White, capsule shaped uncoated tablet with XR 1000 one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. Metformin may be used as monotherapy or in combination with other oral hypoglycaemic agents, or with insulin.

4.2 Dose and Method of Administration

Dosage.

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 HCl (≥ 2 g per day).

Monotherapy and combination with other oral hypoglycaemic agents.

Initiating therapy with Metformin XR.

For patients new to metformin, the usual starting dose is one Metformin XR 500 tablet, once daily, with the evening meal. If the starting dose requires 750 mg modified release metformin HCl, then alternative brands will be required, as Metformin XR 500 cannot be divided.
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.
Dosage increases should be made in increments of 500 mg every 10-15 days, up to a maximum of 2000 mg once daily with the evening meal. If the dosage increases require 750 mg modified release metformin HCl, then alternative brands will be required, as Metformin XR 500 cannot be divided.

Combining different Metformin XR dosage strengths.

The combined use of different strengths of Metformin XR 500 and Metformin XR 1000 is not recommended, only one strength should be used at a time in order to avoid accidentally exceeding the recommended upper daily dose limit of 2000 mg.

Maintenance therapy with Metformin XR.

Metformin XR 1000 is intended as a maintenance therapy for patients currently treated with either 1000 mg or 2000 mg metformin HCl. In patients already treated with metformin HCl immediate release tablets, the starting dose of metformin HCl modified release tablets should be equivalent to the daily dose of metformin HCl immediate release tablets.
The maximum recommended dose is four tablets of Metformin XR 500 or two tablets of 750 mg modified release metformin HCl (alternative brands) or two tablets of Metformin XR 1000, once daily, with the evening meal.

Switching from Metformin XR to immediate release metformin.

If glycaemic control is not achieved with the maximum recommended dose of four Metformin XR 500 tablets or two tablets of 750 mg modified release metformin HCl (alternative brands) or two Metformin XR 1000 tablets, patients may be switched to metformin HCl immediate release tablets to a maximum dose of 3000 mg daily.

Switching from immediate release metformin to Metformin XR.

In patients already treated with metformin HCl immediate release tablets, the starting dose of Metformin XR 500 or Metformin XR 1000 should be equivalent to the daily dose of metformin HCl immediate release tablets. In patients treated with immediate release metformin HCl at a dose above 2000 mg daily, switching to Metformin XR 500 or Metformin XR 1000 is not recommended.

Transferring from other oral hypoglycaemic agents.

If transfer from another oral antidiabetic agent is intended, discontinue the other agent. Initiate with one Metformin XR 500 tablet, once daily, with the evening meal and titrate as described under Initiating therapy with Metformin XR.

Combination with insulin.

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose is one Metformin XR 500 tablet, once daily, with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements. If the starting dose requires 750 mg modified release metformin HCl, then alternative brands will be required, as Metformin XR 500 cannot be divided. After titration, switching to Metformin XR 1000 should be considered.

Elderly.

Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Children.

In absence of available data, Metformin XR 500 or Metformin XR 1000 should not be used in children.

4.3 Contraindications

Hypersensitivity to metformin or to any of the excipients.
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, Administration of iodinated contrast materials).
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.
Major surgery (see Section 4.4 Special Warnings and Precautions for Use, Surgery).
Severe hepatic insufficiency, acute alcohol intoxication, alcoholism.
Lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in 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 that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. 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.

Diagnosis.

The risk of lactic acidosis must be considered in the event of nonspecific 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).

Use in renal impairment.

As metformin 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 2-4 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 nonsteroidal 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 the patient 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. It should not be reinstituted until 48 hours after the test 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).

Surgery.

Metformin must be discontinued 48 hours before elective 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.

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.
Metformin alone does not cause hypoglycaemia; however, caution is advised when it is used in combination with other antidiabetic agents (sulfonylureas, glinides, insulin).
The tablet shells may be present in the faeces. Patients should be advised that this is normal.

Paediatric use.

In absence of available data, metformin HCl modified release tablets should not be used in children.

Use in the elderly.

Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function (see Section 4.2 Dose and Method of Administration, Elderly). Regular assessment of renal function is necessary.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Contraindicated combination.

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. It should not be reinstituted until 48 hours after the test and only after renal function has been re-evaluated and found to be normal (see Section 4.4 Special Warnings and Precautions for Use, Administration of iodinated contrast materials).

Inadvisable combination.

Alcohol.

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

Combinations requiring precautions for use.

Medicines with intrinsic hyperglycaemic activity.

[e.g. glucocorticoids and tetracosactides (systemic and local routes), β2-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.

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.

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 coadministered. Cessation of metformin in patients receiving vitamin K antagonists can cause marked increases in the prothrombin time.

Beta-blockers.

Coadministration of metformin and beta-blockers may result in a potentiation of the antihyperglycaemic 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.

Calcium channel blockers.

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

Cimetidine.

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

Diuretics, especially loop diuretics.

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

Nifedipine.

A single dose, metformin/nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration 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 had minimal effects on the pharmacokinetics of nifedipine.

Thyrotropin.

Reduction of thyrotropin (TSH) serum levels has been reported in diabetic patients with hypothyroidism when metformin therapy is initiated.

Organic cation transporters (OCT).

Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with:
Substrates/inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy.
Substrates/inhibitors of OCT2 (such as cimetidine, dolutegravir, crizotinib, olaparib, daclatasvir, vandetanib) may decrease the renal elimination of metformin and thus 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 lactic acidosis and adversely affect renal function.
Therefore, caution is advised when these drugs are co-administered with metformin and a dose adjustment may be considered, particularly in patients with renal impairment.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or foetal development, parturition or postnatal development.
When the patient plans to become pregnant and during pregnancy, 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 breast feeding or to discontinue metformin, taking into account the importance of the medicinal product 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 (sulfonylureas, glinides, insulin).

4.8 Adverse Effects (Undesirable Effects)

In postmarketing data and in controlled clinical studies, adverse event reporting in patients treated with metformin HCl modified release tablets (containing metformin 500 mg, 1000 mg) was similar in nature and severity to that reported in patients treated with metformin immediate release tablets.
The following undesirable effects may occur under treatment with metformin. 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, adverse effects are presented in order of decreasing seriousness.

Gastrointestinal disorders.

Very common: gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. A slow increase of the dose may improve gastrointestinal tolerability.

Hepatobiliary disorders.

Not known: isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation.

Metabolism and nutrition disorders.

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

Nervous system disorders.

Common: taste disturbance.

Skin and subcutaneous tissue disorders.

Very rare: skin reactions such as erythema, pruritus, urticaria.

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.

Although hypoglycaemia has not been seen with ingestion of up to 85 g of metformin alone, 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 nonspecific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may also 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 levels.
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 overalkalinization with sodium bicarbonate. As metformin 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 anti-diabetic agent; it is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.
Delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term and long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical trials.

Metformin HCl modified release tablet has been evaluated in three double blind, randomized, multicentre, parallel group clinical trials, two of which employed a placebo control. These studies were each followed by a 52 week open label extension study involving subjects who completed double blind treatment and/or were withdrawn for inadequate glycaemic control. The primary endpoint was the mean change in HbA1C from baseline in each case.
Both placebo controlled studies were in diet failed patients previously not exposed to metformin. One study evaluated once daily metformin HCl modified release tablet at daily doses of 500 mg, 2 x 500 mg, 3 x 500 mg and 4 x 500 mg, and also twice daily 2 x 500 mg, for 16 weeks. Treatment with once daily metformin HCl modified release tablet resulted in dose related reductions in indices of glycaemic control (HbA1C, fasting plasma glucose (FPG) and the proportions of patients achieving HbA1C < 7.0% at study end or last prior measurement) that were significant at all doses relative to placebo (Table 1). The results of a 52 week open label extension to this study (Table 1) showed that the antihyperglycaemic effects of metformin HCl modified release tablet were maintained over time. There was no weight gain in any treatment group.
The second placebo controlled study evaluated metformin HCl modified release tablet at a target dose of 2 x 500 mg once daily for a period of 12 weeks. Indices of glycaemic control (as above) improved significantly compared with placebo (Table 2). The magnitudes of improvements were comparable to those observed in the dose ranging study (Table 1). The accompanying 52 week open label study again showed that improvements in glycaemia were durable over time. No weight gain was associated with metformin HCl modified release tablet treatment.
The third randomized, double blind study evaluated the effects of switching from the immediate release formulation of metformin HCl to metformin HCl modified release tablet. Patients suboptimally controlled with metformin received immediate release metformin HCl 500 mg twice daily, were randomized to continue on immediate release metformin HCl or to receive once daily metformin HCl modified release tablet at a dose of 2 x 500 mg or 3 x 500 mg, for a period of 12 weeks. Indices of glycaemia were not markedly altered after switching between the formulations, either in the double blind study or an associated 52 week open label study (Table 3).
The prospective randomized study (UKPDS) has established the long-term benefit of intensive blood glucose control in overweight type 2 diabetes. The immediate release tablet form of metformin was used in the UKPDS.
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 a 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 formally established.

5.2 Pharmacokinetic Properties

Absorption.

At steady state, similar to the immediate release formulation, Cmax and AUC do not increase in proportion with the administered dose. The administration of two, three, or four tablets 500 mg modified release tablets results in a 1.8, 2.4 and 3.0-fold increase for Cmax and a 2.0, 2.7 and 3.2-fold increase in AUC.
Intrasubject variability of Cmax and AUC of metformin modified release tablets is comparable to that observed with metformin immediate release tablets.
No accumulation is observed after repeated administration of up to 2000 mg metformin hydrochloride as modified release tablets (administered as four 500 mg modified release tablets).
Metformin absorption from the modified release formulation is not altered by meal composition.
Pharmacokinetic parameters, from healthy volunteers, for this medicine, are presented in Table 4.
After an oral dose of the 500 mg modified release tablet, under fasted conditions, metformin absorption is slightly delayed compared to an immediate release tablet; delay is approximately an hour (tmax for the modified release tablet is 3½ hours and tmax for the immediate release tablet is 2½ hours).
AUC is decreased by ≈ 35% when the modified release tablet is administered under fasted conditions compared to fed, Cmax is unaffected and the tmax is reduced by 1-2 hours.

Distribution.

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution Vd ranged 6-276 L.

Metabolism.

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Excretion.

Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6½ hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

5.3 Preclinical Safety Data

Genotoxicity.

Preclinical data reveal no specific hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity.

Carcinogenicity.

Preclinical data reveal no specific hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, carcinogenic potential or reproductive toxicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hypromellose, povidone, colloidal anhydrous silica, magnesium stearate.

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. Store in original container.

6.5 Nature and Contents of Container

APO-Metformin XR 500.

Blister pack (PVC/Al) of 120 tablets: AUST R 281211.

APO-Metformin XR 1000.

Blister pack (PVC /Al) of 60 tablets: AUST R 281210.
APO and APOTEX are registered trademarks of Apotex Inc.
Not all strengths 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

White crystals easily soluble in water, sparingly soluble in alcohol and practically insoluble in acetone and methylene chloride.
Metformin is a strong base with a pKa greater than 12. At pH < 12, which is always the case in the body, metformin is very hydrophilic: the octanol/water partition coefficient is 0.05. The melting point of metformin hydrochloride is 224°C. Metformin hydrochloride is a very stable molecule.

Chemical structure.


Chemical Name: 1,1-dimethylbiguanide hydrochloride.
Molecular Formula: C4H12ClN5.
Molecular Weight: 165.63.

CAS number.

1115-70-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes