Consumer medicine information

Metformin Sandoz

Metformin hydrochloride

BRAND INFORMATION

Brand name

Metformin Sandoz 500 mg and 850 mg

Active ingredient

Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

Metformin Sandoz®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Metformin Sandoz?

Metformin Sandoz contains the active ingredient metformin hydrochloride. Metformin Sandoz is used to control blood glucose (the amount of sugar in the blood) in people with diabetes mellitus. For more information, see Section 1. Why am I using Metformin Sandoz? in the full CMI.

2. What should I know before I use Metformin Sandoz?

Do not use if you have ever had an allergic reaction to Metformin Sandoz or any of the ingredients listed at the end of the CMI. Talk to your doctor or pharmacist if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Metformin Sandoz? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Metformin Sandoz and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Metformin Sandoz?

  • The dose varies from person to person.
  • The usual starting dose for adults in 500 mg one to two times a day. Your doctor may increase or decrease the dose, depending on your blood glucose levels. More instructions can be found in Section 4. How do I use Metformin Sandoz? in the full CMI.

5. What should I know while using Metformin Sandoz?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Metformin Sandoz.
  • Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia and hyperglycaemia and know how to treat them.
Things you should not do
  • Do not take Metformin Sandoz to treat any other complaints unless your doctor tells you to.
  • Do not skip meals while taking Metformin Sandoz.
  • Do not stop taking your medicine or change the dosage without checking with your doctor.
Driving or using machines
  • Metformin Sandoz by itself is unlikely to affect how you drive or operate machinery.
  • Low blood glucose levels may slow your reaction time and affect your ability to drive or operate machinery.
Drinking alcohol
  • Alcohol can affect the control of your diabetes.
  • Drinking excessive amounts of alcohol while you are being treated with Metformin Sandoz may also lead to serious side effects.
Looking after your medicine
  • Keep the pack in a cool, dry place (below 25°C) in its original packaging.
  • Do not store Metformin Sandoz in the bathroom, near a sink, on a window sill or in the car.
  • Keep your tablets where children cannot reach it.

For more information, see Section 5. What should I know while using Metformin Sandoz? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist if you notice any of the following and they worry you: nausea, vomiting, diarrhoea, stomach pain, taste disturbance, loss of appetite, skin rash, itching, and redness of the skin. Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following symptoms: trouble breathing, feeling weak, tired or generally unwell, unusual muscle pain severe nausea, sleepiness, dizziness, shivering, feeling extremely cold or slow heartbeat. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Metformin Sandoz®

Active ingredient(s): metformin hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Metformin Sandoz. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Metformin Sandoz.

Where to find information in this leaflet:

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

1. Why am I using Metformin Sandoz?

Metformin Sandoz contains the active ingredient metformin hydrochloride. Metformin Sandoz belongs to a group of medicines called biguanides. Metformin Sandoz lowers high blood glucose (hyperglycaemia) by helping your body make better use of the insulin produced by your pancreas.

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 buildup of glucose in the blood, which can lead to serious medical problems.

Metformin Sandoz is used to control blood glucose (the amount of sugar in the blood) in people with diabetes mellitus.

Metformin Sandoz can be used in type 2 diabetes in adults and children over 10 years of age. It is especially useful in those who are overweight, when diet and exercise are not enough to lower high blood glucose levels (hyperglycaemia).

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

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 Metformin Sandoz has been prescribed for you.

Your doctor may have prescribed Metformin Sandoz for another reason.

Metformin Sandoz is available only with a doctor's prescription.

There is no evidence that Metformin Sandoz is addictive.

2. What should I know before I use Metformin Sandoz?

Warnings

Do not use Metformin Sandoz if:

  • you are allergic to metformin, or any other biguanide, or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include:
    - skin rash, itching or hives
    - swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
    - wheezing or shortness of breath.
    Always check the ingredients to make sure you can use this medicine.
  • you have any of the following conditions:
    - type 1 diabetes mellitus 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, alcohol dependence
    - kidney failure or severe kidney disease
    - dehydration, severe blood loss, shock
    - a severe infection
    - certain heart or blood vessel problems, including a recent heart attack or severe heart failure (when the heart fails to pump blood effectively)
    - severe breathing difficulties
    - blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast heart rate)
    - gangrene
    - inflammation of the pancreas (pancreatitis), symptoms include severe upper stomach pain, often with nausea and vomiting
  • you need to have a 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 Sandoz 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 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.

Check with your doctor or pharmacist if you:

  • are allergic to any other medicines or any foods, preservatives or dyes.
  • have or have had any of the following medical conditions:
    - heart failure
    - kidney problems
    Your doctor may want to take special care if you have any of these conditions.
  • drink alcohol
    Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with Metformin Sandoz may also lead to serious side effects. Your doctor may suggest you stop drinking or reduce the amount of alcohol you drink.

If you have not told your doctor about any of the above, tell him/her before you start taking Metformin Sandoz.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

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

The safety of Metformin Sandoz in pregnant women has not been established.

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

Do not take Metformin Sandoz if you are breastfeeding.

Metformin Sandoz is not recommended while you are breastfeeding. Your doctor will discuss the options available to you.

3. What if I am taking other medicines?

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

Some medicines and Metformin Sandoz may interact with each other. These include:

  • other medicines used to treat diabetes
  • medicines that contain alcohol, such as cough and cold syrups
  • tetracosactrin, a medicine used in people with multiple sclerosis, and in young children to treat some types of seizures (fits)
  • danazol, a medicine used to treat endometriosis
  • some medicines used to treat high blood pressure and some heart conditions, including beta-blockers, calcium channel blockers and ACE inhibitors
  • medicines used to prevent blood clots, such as warfarin
  • diuretics, also called fluid tablets
  • 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 used to treat reflux and ulcers
  • corticosteroids such as prednisone or 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 hydrochloride such as topiramate and other carbonic anhydrase inhibitors

These medicines may be affected by Metformin Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Metformin Sandoz.

4. How do I use Metformin Sandoz?

Follow all directions given to you by your doctor and 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

  • The dose varies from person to person. Your doctor will decide the right dose for you.
  • The usual starting dose for adults is 500 mg one to two times a day. Your doctor may increase or decrease the dose, depending on your blood glucose levels. The maximum recommended dose is 1000 mg three times a day.
  • The elderly and people with kidney problems may need smaller doses.

Children and Adolescents

  • The usual starting dose for children from 10 years of age and adolescents is one tablet of 500 mg or 850 mg once daily. Your doctor may increase or decrease the dose, depending on your blood glucose levels.
  • The maximum recommended dose is 2 g taken as two or three divided doses.
  • If your child has diabetes that is resistant to insulin and is being treated in hospital, your child's doctor will decide the dose.

How to take it

  • Swallow the tablets with a glass of water.
  • The 500mg and 1000 mg tablets can be divided in half along the break line, if advised by your doctor or pharmacist.

When to take Metformin Sandoz

  • Take Metformin Sandoz during or immediately after food.
    This will reduce the chance of a stomach upset.
  • Take your medicine at the same time each day.
    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 for

  • Continue taking your medicine for as long as your doctor tells you to.
    This medicine will help control diabetes but does not cure it. Most people will need to take Metformin Sandoz on a long-term basis.

If you forget to take Metformin Sandoz

Metformin Sandoz should be taken regularly at the same time each day.

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

Otherwise, take the missed dose as soon as you remember (with food), and then go back to taking your tablets as you would normally.

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

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

If you use too much Metformin Sandoz

If you think that you have used too much Metformin Sandoz, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too much Metformin Sandoz, 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 (buildup 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 Sandoz 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.

5. What should I know while using Metformin Sandoz?

Things you should do

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

HYPOGLYCAEMIA

Metformin Sandoz does not normally cause hypoglycaemia, although you may experience it if you 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
  • lightheadedness, dizziness, headache or lack of concentration
  • irritability, tearfulness or crying
  • hunger
  • numbness around the lips and tongue.

If not treated promptly, these may progress to:

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

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

You can do this by doing one of the following:

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

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

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

HYPERGLYCAEMIA

If you notice the return of any of the 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 Sandoz than prescribed
  • taking certain other medicines
  • too little exercise
  • eating more carbohydrates than normal.

Tell your doctor if you:

  • become ill
  • become dehydrated
  • are injured
  • have a fever
  • have a serious infection
  • are having surgery (including dental surgery)

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 Sandoz with insulin.

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

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

If you become pregnant while taking Metformin Sandoz, tell your doctor immediately.

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
  • you are having major surgery
  • you are having an examination such as an X-ray or as can 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 Sandoz with insulin.

Visit your doctor regularly for check-ups.
Your doctor may want to perform blood tests to check your kidneys, liver, heart and vitamin B12 level while you are taking Metformin Sandoz.

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 Sandoz, it can take up to two weeks for your blood glucose levels to be properly controlled.

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

Things you should not do

Do not take Metformin Sandoz 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 skip meals while taking Metformin Sandoz.

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

Things to be careful of

If you become sick with a cold, fever or flu, it is very important to continue eating your normal meals.

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

When 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 enough Metformin Sandoz with you, so you don't miss any doses

Lifestyle measures that help reduce heart disease risk.

By following these simple measures, you can further reduce the risk from heart disease.

  • Quit smoking and avoid second-hand smoke
  • Limit alcohol intake
  • Enjoy healthy eating by:
    - eating plenty of vegetables and fruit;
    - reducing your saturated fat intake (eat less fatty meats, full fat dairy products, butter, coconut and palm oils, most take-away foods, commercially baked products)
  • Be active. Progress, over time, to at least 30 minutes of moderate-intensity physical activity on 5 or more days each week. Can be accumulated in shorter bouts of 10 minutes duration. If you have been prescribed anti-angina medicine, carry it with you when being physically active.
  • Maintain a healthy weight
  • Discuss your lifestyle and lifestyle plans with your doctor
  • For more information and tools to improve your heart health, call Heartline, the Heart Foundation's national telephone information service, on 1300 36 27 87 (local call cost).

Know warning signs of heart attack and what to do:

  • Tightness, fullness, pressure, squeezing, heaviness or pain in your chest, neck, jaw, throat, shoulders, arms or back
  • You may also have difficulty breathing, or have a cold sweat or feel dizzy or light headed or feel like vomiting (or actually vomit)

If you have heart attack warning signs that are severe, get worse or last for 10 minutes even if they are mild, call triple zero (000). Every minute counts.

Driving or using machines

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

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

Drinking alcohol

Tell your doctor or pharmacist if you drink alcohol.

Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with Metformin Sandoz may also lead to serious side effects. Your doctor may suggest you stop drinking or reduce the amount of alcohol you drink.

Looking after your medicine

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

If you take the tablets out of the pack, they may not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place where the temperature stays below 25°C, away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

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

Getting rid of any unwanted medicine

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

6. Are there any side effects?

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

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

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

If you are over 65 years of age, you may have an increased chance of getting side effects.

Do not be alarmed by the following list of side effects.

You may not experience any of them.

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

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

Less serious side effects

Less serious side effectsWhat to do
Gut or Gastrointestinal related:
  • feeling sick (nausea)
  • vomiting
  • diarrhoea
  • stomach pain
  • taste disturbance
  • loss of appetite
Skin related:
  • skin rash, itching, and redness of the skin
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

These are generally mild side effects which disappear after the first few weeks. Taking Metformin Sandoz with meals can help reduce stomach pain, nausea and diarrhoea. Skin reactions have been reported rarely.

Serious side effects

Serious side effectsWhat to do
Gut or Gastrointestinal related:
  • nausea, vomiting, stomach pain
Muscle-joint related:
  • unusual muscle pain
Heart related:
  • slow heart beat
Other:
  • trouble breathing
  • feeling weak, tired, or generally unwell
  • sleepiness
  • dizziness, light-heartedness
  • shivering, feeling extremely cold
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Lactic acidosis is a very rare but serious side effect requiring urgent medical attention or hospitalisation. Although rare, if lactic acidosis does occur, it can be fatal. The risk of lactic acidosis is higher in the elderly, those whose diabetes is poorly controlled, those with prolonged fasting, those with certain heart conditions, those who drink alcohol and those with kidney or liver problems.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

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.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Metformin Sandoz contains

Active ingredient
(main ingredient)		Each Metformin Sandoz tablet contains 500 mg, 850 mg or 1000 mg of metformin hydrochloride.
Other ingredients
(inactive ingredients)
  • sodium starch glycollate
  • maize starch
  • povidone
  • colloidal anhydrous silica
  • magnesium stearate
  • hypromellose
  • titanium dioxide
  • propylene glycol
  • macrogol 6000
  • purified talc
Potential allergensThis medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

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

What Metformin Sandoz looks like

Metformin Sandoz comes in 3 strengths:

Metformin Sandoz 500 mg - white, film coated, biconvex capsule shaped tablet with central break line on one side and '500' embossed on the other side. Available in blisters (AUST R 125661) and bottles of 100 tablets (Aust R 148268).

Metformin Sandoz 850 mg - white, film coated, round, biconvex tablet plain on one side and '850' embossed on the other side. Available in blisters (AUST R 125662) and bottles (AUST R 148270) of 60 tablets.

Metformin Sandoz 1000 mg - white, capsule -shaped filmcoated tablets, with a break line on one side. Available in blisters of 10, 30, 60 and 90 tablets (Aust R 292865).

Who distributes Metformin Sandoz

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia Tel: 1800 726 369

This leaflet was revised in October 2022.

Published by MIMS January 2023

BRAND INFORMATION

Brand name

Metformin Sandoz 500 mg and 850 mg

Active ingredient

Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Metformin hydrochloride.

2 Qualitative and Quantitative Composition

Each 500 mg film coated tablet contains 500 mg of metformin hydrochloride.
Each 850 mg film coated tablet contains 850 mg of metformin hydrochloride.
Each 1000 mg film coated tablet contains 1000 mg of metformin hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Metformin Sandoz film coated tablets 500 mg.

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

Metformin Sandoz film coated tablets 850 mg.

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

Metformin Sandoz film coated tablets 1000 mg.

White, film coated, capsule-shaped, biconvex tablet plain on one side and central breakline 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 initial treatment, or in sulfonylurea failures, either alone or in combination with a sulfonylurea and other oral agents or as adjuvant therapy in insulin dependent type 2 diabetes.

4.2 Dose and Method of Administration

Dosage.

Life threatening lactic acidosis can occur due to accumulation of metformin. Risk factors include renal impairment, old age and high doses of metformin above 2 g/day.
Initially 500 mg should be taken once or twice a day with breakfast and evening meal. If necessary, the dose may be 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 a 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 obtained 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.
If dose titration has been achieved with one tablet strength, then the patient's response should be reassessed if a different strength or dose schedule is commenced.
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.

Method of administration.

It is important that the tablets are taken in divided doses with meals.

Dosage adjustment.

Elderly.

The initial 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.

Debilitated patients.

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.
Hypersensitivity to metformin hydrochloride or to any of the excipients listed (see Section 6.1 List of Excipients).
Diabetic ketoacidosis, lactic acidosis, diabetic precoma.
Renal failure or renal dysfunction (creatinine clearance < 60 mL/minute).
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

Hypoglycaemia.

Hypoglycaemia does not occur in patients receiving metformin hydrochloride alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose lowering agents (such as sulfonylureas) or ethanol.
Elderly, debilitated or malnourished patients, and those with adrenal pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycaemic effects.
The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to a diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with metformin hydrochloride or sulfonylurea monotherapy, combined therapy with metformin hydrochloride and sulfonylurea may result in a response. Should secondary failure occur with combined metformin hydrochloride/ sulfonylurea therapy, it may be necessary to initiate insulin therapy.
Metformin hydrochloride alone does not usually cause hypoglycaemia, although it may occur when metformin hydrochloride is used in conjunction with other antidiabetic agents (oral sulfonylureas, glinides, insulin). When initiating combination therapy, the risks of hypoglycaemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients.

Lactic acidosis.

Lactic acidosis is a rare but serious (high mortality in the absence of prompt treatment) metabolic complication, which can occur due to metformin accumulation during treatment with metformin. 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.
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.
Special caution should be taken in the elderly due to the decrease of renal function with age.
The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases per 1,000 patient years, with approximately 0.015 fatal cases per 1,000 patient years). The onset is often subtle and accompanied by nonspecific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and nonspecific 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. Lactic acidosis is characterised by acidosis (decreased blood pH), elevated lactate levels with increased lactate/ pyruvate ratio and electrolyte disturbances with increased anion gap.

Diagnosis.

The risk of lactic acidosis must be considered in the event of nonspecific signs such as muscle cramps with digestive disorders 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 is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) should 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, diuretic therapy or when starting therapy with a nonsteroidal anti-inflammatory drug (NSAID).

Surgery.

Metformin 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.

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 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, patients taking concomitant diuretics and by the use of the minimum effective dose of metformin. 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.

Administration of iodinated contrast agent.

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 impaired renal function, metformin must be discontinued 48 hours before the test and in patients with normal renal function, metformin should be stopped at the time of the study and not recommended for 48 hours and only after renal function has been re-evaluated and found to be normal. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

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.
Alcohol is known to potentiate the effects of metformin on lactate metabolism. Patients should therefore be warned against excessive alcohol intake, acute or chronic, while taking metformin.
Periodic assessment of renal, hepatic and cardiovascular function is recommended during prolonged periods of treatment with metformin.

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 hepatic impairment.

Since impaired hepatic function has been associated with some cases of lactic acidosis, metformin should be avoided in patients with clinical or laboratory evidence of hepatic disease.

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 precautions 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.

Paediatric use.

Metformin is not recommended for use in children except those with insulin resistant diabetes who are being treated in hospital.
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 no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin treated children, especially prepubescent children, is recommended.

Effects on laboratory tests.

No information is available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Cimetidine.

Reduced clearance of metformin has been reported during cimetidine therapy, so a dose reduction should be considered. Other cationic drugs such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin are eliminated by renal tubular secretion and theoretically have the potential to compete for common renal tubular transport systems with metformin. Careful patient monitoring is recommended in situations where cationic medications which are excreted via the proximal renal tubular secretory system are coadministered with metformin.

Anticoagulants.

Metformin increased 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.

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 has minimal effects on the pharmacokinetics of nifedipine.

Sulfonylureas and meglitinides.

During concomitant therapy with other antidiabetic agents, such as sulfonylureas or meglitinides, blood glucose should be monitored because combined therapy may cause hypoglycaemia.

Beta-blockers.

Coadministration of metformin and β-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.

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.

Alcohol.

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

Thiazide diuretics.

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

Thyroid products.

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

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.

Iodinated contrast media.

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).

Other.

Phenothiazines, oestrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics and isoniazid tend to produce hyperglycaemia and patients receiving concomitant administration of any of these drugs with metformin hydrochloride should be closely observed to maintain glycaemic control.

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.

Fertility of male or female rats was unaffected by metformin administration at doses of up to 600 mg/kg/day, or approximately twice the maximum recommended daily dose on a body surface area basis.
(Category C)
Australian Category C Definition: Drugs, which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
It is important to achieve strict normoglycaemia during pregnancy. Oral hypoglycaemic 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 fetal 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.
Recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Oral hypoglycaemics may enter the fetal circulation and cause neonatal hypoglycaemia. There is a consensus among experts that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
 Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers, but caution should be exercised in such patients, and a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

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)

Gastrointestinal disorders.

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

Metabolism and nutrition disorders.

Very rare: Lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use) is a very rare (< 1/10,000) but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin.
The onset of lactic acidosis is often subtle and accompanied by nonspecific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's doctor should be instructed to notify the doctor immediately if they occur. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia).
Lactic acidosis is a medical emergency that must be treated in hospital. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures should be instituted promptly.
A decrease of vitamin B12 absorption with a decrease in serum levels has been observed in patients treated too long-term with metformin and appears to be generally without clinical significance (< 1/10,000). 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 considered. (See Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Very rare: Skin reactions such as mild erythema, pruritus and urticaria have been reported in some hypersensitive individuals, but the incidence is very rare (< 1/10,000).

Hepatobiliary disorders.

Very rare: Isolated reports. Liver function tests abnormalities or hepatitis resolving upon metformin discontinuation, have been reported.

Nervous system disorders.

Common: Taste disturbance (3%) is common.

Reporting suspected adverse effects.

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

4.9 Overdose

Symptoms.

Hypoglycaemia has not been seen with ingestion of up to 85 g of metformin alone, although lactic acidosis has occurred in such circumstances. 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 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, such as ketonuria and ketonaemia.

Treatment.

Lactic acidosis should be feared in diabetic metformin treated patients with overdose. Lactic acidosis is diagnosed and monitored by measuring 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 overalkalinisation 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 Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Metformin is an antihyperglycaemic agent, which improves glucose tolerance in NIDDM subjects, lowering both basal and postprandial plasma glucose. Metformin 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 increased insulin sensitivity. It does not stimulate insulin release but does require the presence of insulin to exert its antihyperglycaemic 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 has a modest favourable effect on serum lipids, which are often abnormal in NIDDM patients.

Clinical trials.

The prospective randomised (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 the following:
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.

A randomised, open, balanced, crossover bioequivalence study using metformin tablets 500 mg film coated tablets in 26 healthy subjects showed that peak plasma concentrations occurred at between 2 to 3 hours after a single dose of 500 mg. The mean peak plasma concentration was 0.721 mg/mL for the test product. Metformin was detected in plasma for 36 hours postdose in all subjects. The Tmax values were comparable for both reference and test formulations. The 90% confidence limit for AUC0-t and AUC0-inf (as a measure of the extent of absorption) of the test product metformin tablets compared to the reference product (metformin 500 mg Diabex Alphapharm) was within acceptable limits. No adverse events were reported.
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 rather than increase in elimination.
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. Food decreases the extent and slightly delays the absorption of metformin. However, the clinical relevance of this is unknown. During controlled trials, maximum metformin plasma levels did not generally exceed 5 microgram/mL even at maximum doses.

Distribution.

Metformin is negligibly bound to plasma proteins.

Metabolism.

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

Excretion.

In patients with 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. No pharmacokinetic data is available for hepatic insufficiency.

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 104 weeks) and mice (dosing duration 91 weeks) at doses up to and including 900 and 1500 mg/kg/day, respectively. These doses are 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 tumorigenic 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

Sodium starch glycollate, maize starch, povidone, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide, propylene glycol, macrogol 6000 and purified talc.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Metformin Sandoz tablets 500 mg: 100's in PVC/PE/PVDC/Al blister packs and HDPE bottles.
Metformin Sandoz tablets 850 mg: 60's in PVC/PE/PVDC/Al blister packs and HDPE bottles.
Metformin Sandoz 1000 mg: 10's, 30's, 60's and 90's in PVC/PE/PVDC/Al blister packs.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Metformin hydrochloride is a white crystalline powder which is odourless or almost odourless and hygroscopic. It is freely soluble in water, slightly soluble in alcohol and practically insoluble in acetone and in methylene chloride.

Chemical structure.


Chemical formula: 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