Consumer medicine information

Diabex XR

Metformin hydrochloride

BRAND INFORMATION

Brand name

Diabex XR

Active ingredient

Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Diabex XR.

What is in this leaflet

This leaflet answers some common questions about Diabex XR.

It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or diabetes educator.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Diabex XR against the benefits expected for you.

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

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

What Diabex XR is used for

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

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

TYPE 2 DIABETES MELLITUS
Type 2 diabetes mellitus is also called non-insulin dependent diabetes mellitus (NIDDM) or maturity onset diabetes.

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

People with Type 2 diabetes are unable to make enough insulin or their body does not respond properly to the insulin it does make. This causes a build-up of glucose in the blood (hyperglycaemia), which can lead to serious medical problems.

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

Signs of hyperglycaemia may include:

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

How Diabex XR works

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

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

Ask your doctor if you have any questions about why Diabex XR has been prescribed for you.

Diabex XR is not recommended in children as its safety and effectiveness have not been established in this age group.

Diabex XR is available only with a doctor's prescription.

There is no evidence that Diabex XR is addictive.

This medicine has been prescribed for you personally and you should not pass it onto others even if their symptoms are the same as yours.

Before you take Diabex XR

When you must not take it

Do not take Diabex XR if you are allergic to:

  • medicines containing metformin (such as Diaformin, Glucophage) or any other biguanide
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include 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 Diabex XR if you have any of the following medical conditions:

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

Do not take Diabex XR if you need to have major surgery or an examination such as an X-ray or a scan requiring an injection of iodinated contrast (dye). You must stop taking Diabex XR for a certain period of time before and after the examination or the surgery. Your doctor will decide whether you need any other treatment for this time. It is important that you follow your doctor's instructions precisely.

Do not take this medicine if you are pregnant or plan to become pregnant. Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will replace Diabex XR with insulin while you are pregnant.

Do not take Diabex XR if you are breastfeeding. Your doctor will discuss the options available to you.

Do not take this medicine after the expiry date (EXP) 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 Diabex XR, ask your doctor.

Before you start to take it

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

Before starting Diabex XR your doctor will ask you to have a blood test to check your kidney function.

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

  • kidney problems
  • liver problems
  • heart or blood vessel problems including heart failure.

Tell your doctor if you drink alcohol.

Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with Diabex XR 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 Diabex XR.

Taking other medicines

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

Some medicines and Diabex XR may interfere with each other.

These include:

  • other medicines used to treat diabetes such as insulin, glitinides (Novonorm), and sulfonylureas (e.g. Amaryl, Daonil, Diamicron, Glimel, Glyade, Melizide, Minidiab)
  • iodinated contrast agents (dyes)
  • medicines that contain alcohol, such as cough and cold syrups
  • corticosteroids such as prednisone (Panafacort, Sone) and cortisone (Cortate)
  • tetracosactide (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
  • medicines used to treat high blood pressure and some heart conditions, such as beta-blockers, metoprolol (e.g. Betaloc, Minax), calcium channel blockers such as nifedipine (e.g. Adalat, Adefin), ACE inhibitors such as captopril (e.g. Capoten, Acenorm), enalapril (e.g. Alphapril, Amprace, Renitec) fosinopril (Monopril), lisinopril (e.g. Lisodur, Prinivil, Zestril), perindopril (Coversyl), quinapril (Accupril, Asig).
  • Some medicines used to treat asthma such as salbutamol (Ventolin) or terbutaline (Bricanyl).
  • diuretics, also called fluid tablets, such as amiloride (Midamor, Kaluril), bumetanide (Burinex), furosemide (frusemide (Lasix, Uremide, Urex)), hydrochlorothiazide (Dithiazide), spirinolactone (Aldactone, Spiractin).
  • 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, including arthritis such as aspirin (e.g. Disprin, Solprin), diclofenac (e.g. Voltaren, Fenac), ibuprofen (e.g. Actiprofen, Brufen, Rafen), meloxicam (Mobic), naproxen (e.g. Naprogesic, Naprosyn, Inza) and piroxicam (e.g. Feldene, Mobilis)
  • medicines used to treat ulcers and reflux, such as cimetidine (e.g. Tagamet, Magicul)
  • medicines used to prevent blood clots such as warfarin (e.g. Coumadin, Marevan)
  • thyroid hormones, such as levothyroxine (e.g. Oroxine, Eutroxsig)
  • 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

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

How to take Diabex XR

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.

How much to take

Diabex XR comes in two strengths

Diabex XR 500 (500 mg Tablets) and Diabex XR 1000 (1000 mg Tablets).

The dose varies from person to person. Your doctor will decide the right dose for you.

The usual starting dose is 1 tablet (500 mg) once daily with the evening meal. Your doctor may increase the dose slowly, depending on your blood glucose levels.

The maximum recommended dose is 2 grams once per day.

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

How to take Diabex XR

Swallow the tablets whole with a glass of water.

Do not break, crush or chew the tablets. If you break, crush or chew Diabex XR, they will not work as well. Diabex XR are extended release tablets. This means they have a special coating which allows the active ingredient, metformin, to be released slowly over time.

When to take Diabex XR

Take your medicine everyday with the evening meal. Taking Diabex XR during or with your evening meal will reduce the chance of a stomach upset.

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

How long to take Diabex XR for

Keep taking Diabex XR for as long as your doctor recommends.

Diabex XR will help control diabetes but will not cure it. Most people will need to take Diabex XR for long periods of time.

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

If you forget to take Diabex XR

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

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

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

If you take too much Diabex XR (overdose)

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

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

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

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

While you are taking Diabex XR

Things you must do

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

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

If you become pregnant while taking this medicine, tell your doctor.

Tell your doctor if you plan to have:

  • surgery with general anaesthesia
  • any x-ray procedures requiring an injection of an iodinated contrast agent (dye).

Your doctor will advise you when to stop taking Diabex XR before you have these procedures and when to start again.

HYPOGLYCAEMIA

Diabex XR does not normally cause hypoglycaemia (low blood sugar), although you may experience it while taking other medicines for diabetes such as insulin, sulfonylureas or glinide.

Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia (low blood sugar) and know how to treat them.

Hypoglycaemia can occur suddenly. Initial signs may include:

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

If not treated promptly, these may progress to:

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

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

You can do this by doing one of the following:

  • eating 5 to 7 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 experience any of the signs of hyperglycaemia (high blood sugar), contact your doctor immediately.

The risk of hyperglycaemia is increased in the following situations:

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

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).
  • you become pregnant.

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 Diabex XR with insulin.

Visit your doctor regularly for check-ups. Your doctor may want to check your kidneys, liver, heart and blood levels while you are taking Diabex XR.

Make sure you check your blood glucose levels regularly. This is the best way to tell if your diabetes is being controlled properly. Your doctor or diabetes educator will show you how and when to do this.

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

Things you must not do

Do not use Diabex XR 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 Diabex XR.

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

Things to be careful of

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

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

Things to be aware of

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

Side effects

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

Diabex XR 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 treatment if you get some of the side effects.

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

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

  • stomach upset such as 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 (urticaria).

These are generally mild side effects which disappear after the first few weeks. Taking Diabex XR with meals can help reduce nausea and diarrhoea.

Tell your doctor as soon as possible if you notice any of the following:
Symptoms of liver disease such as nausea, vomiting, loss of appetite, feeling generally unwell, fever, yellowing of the skin and eyes (jaundice) and dark coloured urine

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 heartbeat.

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 SEVERE KIDNEY OR LIVER PROBLEMS.

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

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

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

After taking Diabex XR

Storage

Keep Diabex XR where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

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

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

Do not leave Diabex XR in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

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

Product description

What it looks like

Diabex XR comes in 2 strengths. Diabex XR 500 (500 mg Tablets) and Diabex XR 1000 (1000 mg Tablets).

  • Diabex XR 500 is a white to off-white, round, biconvex tablet, debossed "500" on one side. It is available in blister packs of 120 tablets.
  • Diabex XR 1000 is a white to off-white, capsule-shaped tablet, marked on one side with "1000". It is available in blister packs of 60 tablets.

Ingredients

The active ingredient in Diabex XR is metformin hydrochloride.

Each Diabex XR 500 extended release tablet contains 500 mg of metformin hydrochloride.

The tablets also contain the following inactive ingredients:

  • carmellose sodium
  • hypromellose
  • magnesium stearate

The tablets do not contain sucrose, lactose, gluten, tartrazine or any other azo dyes.

Each Diabex XR 1000 extended release tablet contains 1000 mg of metformin hydrochloride.

The tablets also contain the following inactive ingredients:

  • carmellose sodium
  • hypromellose
  • magnesium stearate.

The tablets do not contain sucrose, lactose, gluten, tartrazine or any other azo dyes.

Both tablet strengths contain trace amounts of sulfites.

Supplier

Diabex XR 500 and Diabex XR 1000 are supplied in Australia by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers are:
Diabex XR 500 - AUST R 318081
Diabex XR 1000 - AUST R 153699

This leaflet was prepared on 2 June 2020.

* Registered trade mark of Merck Sante S.A.S.

DiabexXR_cmi\Jun20/00

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Diabex XR

Active ingredient

Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Metformin hydrochloride.

2 Qualitative and Quantitative Composition

Each Diabex XR 1000 extended release tablet contains 1000 mg of metformin hydrochloride.
Diabex XR also contains trace amounts of sulfites. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Metformin hydrochloride 1000 mg extended release tablets: white to off-white, capsule-shaped, biconvex tablet, debossed '1000' on one face.
Diabex XR 1000 is gluten free.
The tablet shells may be present in the faeces. Patients should be advised that this is normal.

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. Diabex XR 1000 may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

4.2 Dose and Method of Administration

Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment, other risk factors include old age associated with reduced renal function.

Monotherapy and combination with other oral antidiabetic agents.

Initiating therapy with Diabex XR.

For patients new to metformin, the usual starting dose of Diabex XR is one tablet of Diabex XR 500 or Diabex XR 750 once daily taken with the evening meal.
After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastro-intestinal tolerability. Dosage increases should be made in increments of 500 mg or 750 mg every 10-15 days.

Combining Diabex XR dosage strengths.

The combined use of different strengths of Diabex XR 500, Diabex XR 750 or Diabex XR 1000 is not recommended. Only one strength (Diabex XR 500, Diabex XR 750 or Diabex XR 1000) should be used at a time in order to avoid accidentally exceeding the recommended upper daily dose limit of 2000 mg.

Maintenance therapy with Diabex XR.

Diabex XR 1000 is intended as a maintenance therapy for patients currently treated with either 1000 mg or 2000 mg of metformin. In patients already treated with metformin tablets, the starting dose of Diabex XR should be equivalent to the daily dose of metformin immediate release tablets.
The maximum recommended dose is either 4 tablets of Diabex XR 500, 2 tablets of Diabex XR 750 or 2 tablets of Diabex XR 1000 once daily with the evening meal.

Switching from Diabex XR to immediate release metformin.

If glycaemic control is not achieved with the maximum recommended dose of Diabex XR 500 (2000 mg), Diabex XR 750 (1500 mg) or Diabex XR 1000 (2000 mg) patients may be switched to metformin immediate release tablets to a maximum dose of 3000 mg daily.

Switching from immediate release metformin to Diabex XR.

In patients already treated with metformin tablets, the starting dose of Diabex XR 500, Diabex XR 750 or Diabex XR 1000 should be equivalent to the daily dose of metformin immediate release tablets. In patients treated with metformin at a dose above 2000 mg daily, switching to Diabex XR 500, Diabex XR 750 or Diabex XR 1000 is not recommended.

Transferring from other oral agents.

If transfer from another oral antidiabetic agent is intended: discontinue the other agent. Titration should begin with Diabex XR 500 before switching to Diabex XR 750 or Diabex XR 1000 and initiate Diabex XR at the dose indicated above.

Combination with insulin.

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Diabex XR is 500 mg or 750 mg once daily with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements. After titration, switch to Diabex XR 1000 should be considered.

Elderly.

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

Children.

In the absence of available data, Diabex XR 500, Diabex XR 750 or Diabex XR 1000 should not be used in children.

4.3 Contraindications

Hypersensitivity to metformin hydrochloride or to any of the excipients.
Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis).
Diabetic pre-coma.
Renal failure or renal dysfunction (creatinine clearance < 60 mL/min).
Acute conditions with the potential to alter renal function such as: dehydration; severe infection; shock; intravascular administration of iodinated contrast agents (see Section 4.4 Special Warnings and Precautions for Use).
Acute or chronic disease which may cause tissue hypoxia such as: cardiac failure; recent myocardial infarction; respiratory failure; pulmonary embolism; shock; acute significant blood loss; sepsis; gangrene; pancreatitis.
Major surgery (see Section 4.4 Special Warnings and Precautions for Use).
Severe hepatic insufficiency, acute alcohol intoxication, alcoholism.
Lactation.

4.4 Special Warnings and Precautions for Use

Lactic acidosis.

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Diagnosis.

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

Renal function.

As metformin is excreted by the kidney, it is recommended that creatinine clearance and/or serum creatinine levels be determined before initiating treatment and regularly thereafter:
at least annually in patients with normal renal function;
at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).

Administration of iodinated contrast materials.

The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose the patient to lactic acidosis. Therefore, metformin must be discontinued either 48 hours before the test when renal function is known to be impaired or from the time of the test when renal function is known to be normal; and may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Surgery.

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

Other precautions.

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
Metformin hydrochloride alone does not cause hypoglycaemia; however, caution is advised when it is used in combination with other antidiabetic agents (sulphonylureas, glinides, and insulin).
The tablet shells may be present in the faeces. Patients should be advised that this is normal.

Use in the elderly.

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

Paediatric use.

In absence of available data, Diabex XR 1000 should not be used in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Contraindicated combinations.

Iodinated contrast materials.

Metformin must be discontinued either 48 hours before the test when renal function is known to be impaired, or from the time of the test when renal function is known to be normal (see Section 4.4 Special Warnings and Precautions for Use, Administration of iodinated contrast materials).
Metformin should not be reinstituted until 48 hours after the test, and only after renal function has been re-evaluated and found to be normal (see Section 4.4 Special Warnings and Precautions for Use).

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.

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.

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

Thyrotropin.

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

Cimetidine.

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

Anticoagulants.

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

Nifedipine.

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

Organic cation transporters (OCT).

Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with:
substrates/inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin;
inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy;
substrates/inhibitors of OCT2 (such as cimetidine, dolutegravir, crizotinib, olaparib, daclatasvir, vandetanib) may decrease the renal elimination of metformin and thus lead to an increase metformin plasma concentration.

Carbonic anhydrase inhibitors.

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

NSAID.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
To date, no relevant epidemiological data is available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or foetal development, parturition or postnatal development.
When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.
Australian Categorisation Definition of Category C: 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.
Metformin is excreted into milk in lactating rats. Similar data is 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 medicinal product to the mother.

4.7 Effects on Ability to Drive and Use Machines

Diabex XR 1000 monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machinery.
However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulphonylureas, glinides, insulin).

4.8 Adverse Effects (Undesirable Effects)

In post marketing data and in controlled clinical studies, adverse event reporting in patients treated with Diabex XR 1000 were similar in nature and severity to that reported in patients treated with Diabex immediate release.
The following undesirable effects may occur under treatment with metformin. Frequencies are defined as follows: very common: > 1/10; common: > 1/100, < 1/10; uncommon: > 1/1,000, < 1/100; rare: > 1/10,000, < 1/1,000; very rare: < 1/10,000; not known (cannot be estimated from the available data).
Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.

Nervous system disorders.

Common: Taste disturbance.

Gastrointestinal disorders.

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

Skin and subcutaneous tissue disorders.

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

Metabolism and nutrition disorders.

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

Hepatobiliary disorders.

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

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.

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

Treatment.

Lactic acidosis may develop in diabetic metformin-treated patients with overdose. Lactic acidosis is diagnosed and monitored by measurement of serum electrolytes, arterial pH and pCO2 and arterial lactate plasma levels.
The aim of treatment is to manage any underlying disorder, and in some cases this will be sufficient to enable the body's homeostatic mechanism to correct the acid-base imbalance. The advantages of more active treatment of the acidosis must be balanced against the risks, including over-alkalinisation with sodium bicarbonate. Because metformin hydrochloride is dialysable (with a clearance of up to 170 mL/min under good haemodynamic conditions), prompt haemodialysis is recommended to correct the acidosis and remove the accumulated metformin.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Diabex XR 1000 is an oral anti-diabetic agent.
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:
Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation.
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.

Clinical trials.

Metformin modified release tablet has been evaluated in three double-blind, randomised, multicentre, parallel-group clinical trials, two of which employed a placebo control. These studies were each followed by a 52-week open-label extension study involving subjects who completed double-blind treatment and/or were withdrawn for inadequate glycaemic control. The primary endpoint was the mean change in HbA1C from baseline in each case.
Both placebo-controlled studies were in diet-failed patients previously not exposed to metformin. One study evaluated once-daily metformin modified release tablet at daily doses of 500 mg, 2 x 500 mg, 3 x 500 mg, and 4 x 500 mg, and also twice-daily 2 x 500 mg, for 16 weeks. Treatment with once-daily metformin modified release tablet resulted in dose-related reductions in indices of glycaemic control (HbA1C, fasting plasma glucose [FPG] and the proportions of patients achieving HbA1C < 7.0% at study end or last prior measurement) that were significant at all doses relative to placebo (Table 1). The results of a 52-week open-label extension to this study (Table 1) showed that the antihyperglycaemic effects of metformin modified release tablet were maintained over time. There was no weight gain in any treatment group.
The second placebo-controlled study evaluated metformin modified release tablet at a target dose of 2 x 500 mg, once-daily for a period of 12 weeks. Indices of glycaemic control (as above) improved significantly compared with placebo (Table 2). The magnitudes of improvements were comparable to those observed in the dose-ranging study (Table 1). The accompanying 52-week open-label study again showed that improvements in glycaemia were durable over time. No weight gain was associated with metformin modified release tablet treatment.
The third randomised, double-blind study evaluated the effects of switching from the immediate-release formulation of metformin to metformin modified release tablet. Patients sub-optimally controlled with metformin received immediate-release metformin 500 mg twice daily, were randomised to continue on immediate-release metformin or to receive once-daily metformin modified release tablet at a dose of 2 x 500 mg or 3 x 500 mg for a period of 12 weeks. Indices of glycaemia were not markedly altered after switching between the formulations, either in the double-blind study or an associated 52-week open-label study (Table 3).
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in overweight type 2 diabetes. The immediate release tablet form of metformin was used in the UKPDS.
Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
A significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulphonylurea 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 sulphonylurea 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).
Benefit regarding clinical outcome has not been shown for metformin used as second-line therapy, in combination with a sulphonylurea.
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.

After an oral dose of the extended release tablet Diabex XR 500, metformin absorption is significantly delayed compared to the immediate release tablet with a Tmax at 7 hours (Tmax for the immediate release tablet is 2.5 hours).
Table 4 gives an overview on the main pharmacokinetic parameters of the three Diabex XR strengths under fed conditions.
Diabex XR 750 was shown to be bioequivalent to Diabex XR 500 at a 1500 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.
In addition, bioequivalence of the Diabex XR 1000 and Diabex XR 500 was demonstrated following single doses at a 1000 mg dose.
Steady-state bioequivalence data of Diabex XR 750 and of Diabex XR 1000 are not available.
The bioequivalent products show the following properties:
At steady state, similar to the immediate release formulation, Cmax and AUC do not increase in proportion with the administered dose. The administration of two, three, or four tablets Diabex XR 500 (500 mg tablets) results in a 1.8, 2.4, and 3.0 increase for Cmax and a 2.0, 2.7, and 3.2-fold increase in AUC.
The AUC after a single oral administration of 2000 mg of metformin extended release tablets, administered as four tablets of 500 mg Diabex XR 500, is similar to that observed after administration of 1000 mg of metformin immediate release tablets twice daily.
Intrasubject variability of Cmax and AUC of metformin extended release is comparable to that observed with metformin immediate release tablets.
Although the AUC is decreased by 30% following single dose administration of Diabex XR 500 administered as four tablets of 500 mg in fasting conditions, both Cmax and Tmax are unaffected.
In fasting conditions after administration of Diabex XR 750 extended release tablet the AUC is decreased by approximately 49% compared to fed state; Cmax is decreased by about 21% and Tmax is reduced by approximately 1.5 hours.
When Diabex XR 1000 (1000 mg) extended release tablet is administered in fasting conditions the AUC is decreased by approximately 40% compared to fed state (Cmax is decreased by 10 to 20% and Tmax is reduced by 1 hour).
Metformin absorption from the extended release formulation is not altered by meal composition.
No accumulation is observed after repeated administration of up to 2000 mg of metformin administered as four extended-release tablets of 500 mg Diabex XR 500. Steady state studies have not been conducted with Diabex XR 750 and Diabex XR 1000.

Distribution.

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution Vd ranged between 63 to 276 L.

Metabolism.

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

Excretion.

Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

See Genotoxicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Diabex XR 1000 tablets contain the following excipients: carmellose sodium, hypromellose, and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

PVC/PVDC/Al Blister packs of 10 (starter pack), 30, 60, 90, 100 and 120 tablets.
Some pack sizes may not be marketed.
AUST R 153699.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 1,1-dimethylbiguanide hydrochloride.
Molecular formula: C4H12ClN5.
Molecular weight: 165.63.
Metformin hydrochloride are white crystals easily soluble in water, sparingly soluble in alcohol, practically insoluble in acetone and methylene chloride.
Metformin is a strong base with a pKa greater than 12. At pH < 12, which is always the case in the body, metformin is very hydrophilic: the octanol/water partition coefficient is 0.05. The melting point of metformin hydrochloride is 224°C. Metformin hydrochloride is a very stable molecule.

CAS number.

1115-70-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes