Consumer medicine information

GLUCOBETE

Metformin hydrochloride

BRAND INFORMATION

Brand name

Glucobete Tablets

Active ingredient

Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using GLUCOBETE.

What is in this leaflet

This leaflet answers some common questions about GLUCOBETE. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist or diabetes educator.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking GLUCOBETE against the benefits it is expected for you.

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

Keep this leaflet with your medicine.

You may need to read it again.

What GLUCOBETE is used for

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

GLUCOBETE 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). For adult patients, GLUCOBETE 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 GLUCOBETE has been prescribed for you.

Your doctor may have prescribed GLUCOBETE for another reason.

GLUCOBETE is available only with a doctor’s prescription.

There is no evidence that GLUCOBETE is addictive.

How GLUCOBETE works

GLUCOBETE belongs to a group of medicines called biguanides. GLUCOBETE 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 build up of glucose in the blood, 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.

Before you take GLUCOBETE

When you must not take it

Do not take GLUCOBETE if you are allergic to:

  • Medicines containing metformin or any other biguanide.
  • Any of the ingredients listed toward 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.

Do not take GLUCOBETE if 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.
  • 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
  • dehydratiion, 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.

Do not take GLUCOBETE if you plan to have major surgery or an X-ray or a scan requiring an injection of iodinated contrast (dye).

You must stop taking GLUCOBETE 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 GLUCOBETE if you are pregnant or plan to become pregnant.

The safety of GLUCOBETE in pregnant woman has not been established.
Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will replace GLUCOBETE with insulin while you are pregnant.

Do not take GLUCOBETE if you are breast feeding.

GLUCOBETE is not recommended while you are breast feeding. Your doctor will discuss the options available to you.

Do not take GLUCOBETE if the expiry date (EXP) printed on the pack has passed.

If you take this medicine after the expiry date it may not work as well.

Do not take GLUCOBETE if the packaging shows signs of tampering or the tablets do not look quite right.

If you are not sure whether you should start taking GLUCOBETE, ask your doctor.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, food, dyes or preservatives

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

  • heart failure
  • kidney problems

Your doctor may want to take special care if you have any of these conditions.

Tell to 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 GLUCOBETE may 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 these things, tell him/her before you start taking GLUCOBETE.

Taking other medicines

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

Some medicines may be affected by GLUCOBETE or may affect how well it works. 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
  • Repaglinide (Novonorm), another type of medicine used to treat diabetes.
  • some medicines used to treat high blood pressure and some heart conditions, including betablockers, calcium channel blockers and ACE inhibitors.
  • medicines used to prevent blood clots such as warfarin.
  • diuretics,alsocalledfluidtablets.
  • chlorpromazine, a medicine used to treat schizophrenia and other mental illness.
  • NSAIDs(non-steroidal antiinflammatory drugs), medicines used to relieve pain, swelling and other symptoms of inflammation, such as aspirin, diclofenac, ibuprofen, meloxicam, naproxen or piroxicam.
  • cimetidine, a medicine commonly used to treat reflux and ulcers.
  • corticosteroids such as prednisone or cortisone.
  • some medicines used to treat asthma such as salbutamol or terbutaline

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

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

How to take GLUCOBETE

Follow all directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in the leaflet.

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

How much to take GLUCOBETE

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 GLUCOBETE

Swallow the tablet with a glass of water.

When to take GLUCOBETE

Take GLUCOBETE during or immediately after food.

This will reduce the chance of a stomach upset.

Take your medicine at about the same time each day.

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

How long to take GLUCOBETE for

Keep taking GLUCOBETE for as long as your doctor recommends.

GLUCOBETE will help control diabetes but will not cure it. Most people will need to take GLUCOBETE on long term basis.

If you forget to take GLUCOBETE

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 take too much GLUCOBETE (Overdose)

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

If you take too much of GLUCOBETE, you may feel sleepy, very tired, sick, vomit, have trouble breathing and have unusual muscle pain, stomach pain or diarrhoea. These may be the 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 of GLUCOBETE together with other medicines for diabetes or with alcohol.

If you 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 GLUCOBETE

Things you must do

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

HYPOGLYCAEMIA
GLUCOBETE 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, head ache 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 GLUCOBETE 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 GLUCOBETE with insulin.

Before starting any new medicine, tell your doctor or pharmacist that you are taking GLUCOBETE.

Tell all the doctors, dentists and Pharmacists who are treating you that you are taking GLUCOBETE.

If you become pregnant while taking GLUCOBETE, 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 a scan requiring an injection of an iodinated contrast agent (dye)

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

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

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

Things you must not do

Do not skip meals while taking GLUCOBETE.

Do not stop taking GLUCOBETE or change the dose without checking with your doctor.

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

Do not use GLUCOBETE to treat any other conditions unless your doctor tells you to.

Things to be careful of

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

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

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

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

When you are traveling, 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 GLUCOBETE 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.

Side Effects

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

GLUCOBETE helps most people with diabetes but it may have unwanted side effects in some 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.

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.

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

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

These are generally mild side effects which disappear after the first few weeks. Taking GLUCOBETE with meals can help reduce nausea and diarrhoea. Skin rash has been reported rarely.

TELL YOUR DOCTOR IMMEDIATELY OR GO TO ACCIDENT AND EMERGENCY AT THE NEAREST HOSPITAL IF YOU NOTICE ANY OF THE FOLLOWING SYMPTOMS OF LACTIC ACIDOSIS (BUILD UP OF LACTIC ACID IN THE BLOOD):

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

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

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

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.

After taking GLUCOBETE

Storage

Keep the medication where children cannot reach it.

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

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.

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

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

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking GLUCOBETE, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product Description

What it looks like

  • GLUCOBETE 500 is presented in blister packs of 30 & 100 and bottle pack of 100.
  • GLUCOBETE 850 is presented in blister packs of 20 & 60 and bottle packs of 60 & 100.
  • GLUCOBETE 1000 is presented in blister packs of 20 & 90 and bottle pack of 100.

GLUCOBETE 500
White, biconvex, circular shaped, film coated tablets with ‘A’ debossed on one side and ‘60’ debossed on the other side.

GLUCOBETE 850
White, biconvex, circular shaped, film coated tablets with ‘A’ debossed on one side and ‘61’ debossed on the other side.

GLUCOBETE 1000
White, biconvex, oval shaped, film coated tablets with a score line in between ‘6’ and ‘2’ on one side and ‘A’ debossed on the other side.

Ingredients

Active ingredients
Metformin hydrochloride
Each tablet contain either 500, 850 or 1000 mg of Metformin hydrochloride.

Inactive ingredients

  • Povidone
  • Magnesium stearate
  • Opadry complete film coating system YS-1R-7006 Clear (PIARTG No. 13068).

Name and Address of the Sponsor

Aurobindo Pharma Australia Pty Ltd
Unit 3, North Rydelink
277-283 Lane Cove Road
Macquarie Park
NSW 2113 Australia

Date of Approval
22 November 2011

Date of most recent amendment
31 May 2012

BRAND INFORMATION

Brand name

Glucobete Tablets

Active ingredient

Metformin hydrochloride

Schedule

S4

 

Name of the medicine

Metformin hydrochloride.

Excipients.

Povidone, magnesium stearate and Opadry complete film coating system YS-1R-7006 Clear (PI-ARTG No. 13068).

Description

Chemical name: 1,1-dimethyldiguanide hydrochloride. Molecular formula: C4H11N5.HCl. MW: 165.6. CAS: 1115-70-4. Metformin hydrochloride is a white, crystalline powder. It is freely soluble in water, slightly soluble in ethanol and practically insoluble in acetone and in methylene chloride.

Pharmacology

Metformin 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 3 mechanisms: 1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; 2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation; 3) 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 or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

Pharmacokinetics.

Absorption.

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

Distribution.

Metformin is not bound to plasma proteins.

Metabolism.

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

Excretion.

In patients with 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.
A randomised, open label bioequivalence study in 16 healthy volunteers showed, on the basis of Cmax and AUC determinations, that one tablet of metformin 1000 mg can replace two tablets of metformin 500 mg. The relative bioavailability of metformin 1000 mg compared to metformin 500 mg tablets is 92.6% for AUC and 88% for Cmax

Paediatrics.

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

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:
a significant reduction of the absolute risk of any diabetes related complication in the metformin group (29.8 events/1,000 patient years) versus diet alone (43.3 events/1,000 patient years), p = 0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1,000 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 /1,000 patient years, diet alone 18 events /1,000 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.

Paediatrics.

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

Indications

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

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.
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 materials (see Precautions).
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.
Severe hepatic insufficiency, acute alcohol intoxication, alcoholism.
Lactation.
Elective major surgery (see Precautions).

Precautions

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 Overdosage, Treatment).

Renal function.

As metformin hydrochloride is excreted by the kidney, it is recommended that creatinine clearance and/or serum creatinine levels be determined before initiating treatment and regularly thereafter: at least annually in patients with normal renal function; at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a 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 to lactic acidosis. Therefore, metformin must be discontinued either 48 hours before the test when renal function is known to be impaired or from the time of the test when renal function is known to be normal. Metformin may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Interactions with Other Medicines).

Surgery.

Metformin hydrochloride must be discontinued 48 hours before elective major surgery. Therapy may be restarted no earlier than 48 hours following surgery and only after renal function has been reevaluated 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 hydrochloride alone does not cause hypoglycaemia; however, caution is advised when it is used in combination with other antidiabetic agents (sulphonylureas, glinides, insulin).
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.

Carcinogenicity.

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

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).

Effects on fertility.

Fertility of male or female rats was unaffected by metformin administration at doses up to 600 mg/kg/day, or approximately twice the maximum recommended daily dose on a body surface area basis.

Use in pregnancy.

(Category C)
To date, no relevant epidemiological data is available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or foetal development, parturition or postnatal development.
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, or about two times the maximum recommended human daily dose on a body surface area basis. Determination of foetal concentrations demonstrated a partial placental barrier to metformin. Because animal reproduction studies are not always predictive of human response, any decision to use this drug should be balanced against the benefits and risks. The safety of metformin in pregnant women has not been established.
When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

Use in lactation.

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

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

Effects on ability to drive or operate machinery.

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

Interactions

Contraindicated combinations.

Iodinated contrast materials.

Metformin must be discontinued either 48 hours before the test when renal function is known to be impaired, or from the time of the test when renal function is known to be normal (see Precautions, Administration of iodinated contrast materials).

Inadvisable combinations.

Alcohol.

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

Combinations requiring precautions for use.

Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids and tetracosactides (systemic and local routes), beta-2 agonists, danazol, chlorpromazine at high dosages of 100 mg per day and diuretics.

More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon discontinuation.

Diuretics, especially loop diuretics.

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

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.

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.

Cimetidine.

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

Anticoagulants.

Metformin increases the elimination rate of vitamin K antagonists. Consequently, the prothrombin time should be closely monitored in patients in whom metformin and vitamin K antagonists are being 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 had minimal effects on the pharmacokinetics of nifedipine.

Effects on laboratory tests.

No information is available.

Adverse Effects

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

Nervous system disorders.

Common: taste disturbance.

Gastrointestinal disorders.

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

Skin and subcutaneous tissue disorders.

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

Metabolism and nutrition disorders.

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

Hepatobiliary disorders.

Very rare: isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation.
In clinical trials in children and adolescents with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

Dosage and Administration

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

Elderly.

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

Use in children and adolescents.

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

Note.

Do not break GLUCOBETE 1000 mg tablets in half.

Overdosage

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 (ketonuria and ketonaemia).

Treatment.

Lactic acidosis may develop in diabetic metformin treated patients with overdose. Lactic acidosis is diagnosed and monitored by measurement of serum electrolytes, arterial pH and pCO2 and arterial lactate plasma level.
The aim of treatment is to manage any underlying disorder and in some cases this will be sufficient to enable the body's homeostatic mechanism to correct the acid base imbalance. The advantages of more active treatment of the acidosis must be balanced against the risks, including over alkalinisation with sodium bicarbonate. Because metformin hydrochloride is dialysable (with a clearance of up to 170 mL/min under good haemodynamic conditions), prompt haemodialysis is recommended to correct the acidosis and remove the accumulated metformin.
In the event of an overdosage contact the Poisons Information Centre on 131 126 for advice and management.

Presentation

Tablets (white, biconvex, film coated), 500 mg (circular, marked A, 60 on reverse): 30's*, 100's (blister pack, AUST R 180430), 100's* (bottle, AUST R 180445); 850 mg (circular, marked A, 61 on reverse): 20's*, 60's (blister pack, AUST R 180438), 60's*, 100's* (bottle, AUST R 180433); 1000 mg (oval, scored, marked A, 6/2 on reverse): 20's*, 90's (blister pack, AUST R 180444), 100's* (bottle, AUST R 180437).
*Not currently marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.