Consumer medicine information

Glyade MR

Gliclazide

BRAND INFORMATION

Brand name

Glyade MR

Active ingredient

Gliclazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Glyade MR.

What is in this leaflet

This leaflet answers some common questions about GLYADE MR.

It does not contain all the available information

Reading this leaflet does not take the place of talking to your doctor, pharmacist, or diabetes educator.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking GLYADE MR against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

What GLYADE MR is

The name of your medicine is GLYADE MR.

GLYADE MR contains the active ingredient 'gliclazide'.

Gliclazide belongs to a group of medicines called sulphonylureas.

The medicine releases the active ingredient gliclazide progressively over 24 hours.

What GLYADE MR is used for

GLYADE MR is used to control blood glucose (sugar) in patients with Type II diabetes mellitus. This type of diabetes is also known as non-insulin-dependent diabetes (NIDDM), or maturity-onset diabetes).

Why GLYADE MR is used for Type II diabetes mellitus

GLYADE MR is used when diet and exercise are not enough to control your blood glucose.

GLYADE MR can be used alone or together with insulin or other medicines for treating diabetes.

How it works

Glucose is used by the body as fuel, and all people have glucose circulating in their blood. In diabetes, levels of blood glucose are higher than is needed, which is also known as hyperglycaemia. If your blood glucose is not properly controlled, you may experience hypoglycaemia (low blood glucose) or hyperglycaemia (high blood glucose). High blood glucose can lead to serious problems with our heart, circulation and/or kidneys.

It is very important to control high blood glucose whether or not you feel unwell. This really helps to avoid serious long-term health problems, which can involve the heart, eyes, circulation, and/or kidneys.

A section at the end of this leaflet contains advice about recognising and treating hyperglycaemia.

GLYADE MR is used when diet and exercise are not enough to control your blood glucose properly. It lowers blood glucose by increasing the amount of insulin (a hormone that controls blood glucose levels) produced by your pancreas.

As with many medicines used for the treatment of diabetes, there is a possibility that blood glucose levels may become very low during treatment with GLYADE MR. This is known as hypoglycaemia.

A section at the end of this leaflet contains advice about recognising and treating hypoglycaemia.

GLYADE MR is available only with a doctor's prescription.

GLYADE MR is not addictive

Ask your doctor if you have any questions about why GLYADE MR has been prescribed for you.

Before you take GLYADE MR

There are some people who should not take GLYADE MR. Please read the lists below.

If you think any of these situations apply to you, or you have any questions, please consult your doctor, pharmacist, or diabetes educator.

Do not take GLYADE MR if

  • you are allergic to: gliclazide, or any of the other ingredients listed at the end of this leaflet.
  • you have had an allergic reaction to any other sulphonylureas, or GLYADE MR related medicines such as sulfa antibiotics or to thiazide diuretics (a type of "fluid" or "water" tablet).
    Symptoms of an allergic reaction to GLYADE MR or to these medicines may include skin rash, itchiness or hives, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain.
    If you are not sure if you have an allergy to GLYADE MR, check with your doctor.
  • are pregnant or trying to become pregnant.
    GLYADE MR may affect your developing baby if you take it during pregnancy. Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will usually replace GLYADE MR with insulin while you are pregnant.
  • are breastfeeding or plan to breast-feed.
    GLYADE MR is not recommended while you are breastfeeding. It is not known whether GLYADE MR passes into breast milk.
  • you have Type 1 diabetes mellitus (also known as insulin-dependent diabetes (IDDM), or juvenile-onset diabetes).
  • you have unstable diabetes
  • you have diabetic ketoacidosis (a problem which affects the acidity of your blood and can lead to coma - which is mainly associated with Type 1 diabetes).
  • you have severe kidney disease
  • you have severe liver disease
  • you are taking an antibiotic medicine containing the active ingredient miconazole
  • the expiry date (EXP) printed on the pack.
    If you take it after the expiry date has passed, it may not work as well.
  • the packaging is torn or shows signs of tampering.
    If it is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking GLYADE MR, talk to your doctor.

For children

Do not give GLYADE MR to a child. There is no experience with the use of GLYADE MR in children.

For older people

Elderly people can generally use GLYADE MR safely.

There are no special instructions for older people taking GLYADE MR.

Tell your doctor straight away if:

  • you are pregnant or plan to become pregnant or are breast-feeding.
    Your doctor can discuss with you the risks and benefits involved.
  • you are allergic to any of the ingredients listed at the end of this leaflet; to any other medicines; or to any other substances, such as foods, preservatives or dyes
  • If you have a family history of or know you have the hereditary condition glucose-6-phosphate dehydrogenase (G6PD) deficiency (abnormality of red blood cells), lowering of the haemoglobin level and breakdown of red blood cells (haemolytic anaemia) can occur.
  • you have had any of the following medical conditions:
    - kidney disease
    - liver disease
    - a history of diabetic coma.
    - adrenal, pituitary or thyroid problems
    - heart failure
  • you have any medical condition, or do anything, that may increase the risk of hyperglycaemia - for example:
    - you are ill or feeling unwell (especially with fever or infection)
    - you are injured
    - you are having surgery.
    - you are taking less GLYADE MR than prescribed
    - you are taking less exercise than normal
    - you are eating more carbohydrate than normal.
    - drinking alcoholic drinks.
    - not eating regular meals.
    - taking more exercise than usual.

If you have not told your doctor, pharmacist or diabetes educator about any of the above, tell them before you start taking GLYADE MR.

Taking other medicines

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

Taking GLYADE MR may change the effect of some medicines, and some medicines may affect how well GLYADE MR works. You may need different amounts of your medication or to take different medicines.

Some medicines may lead to low blood glucose (hypoglycaemia) by increasing the blood-glucose-lowering effect of GLYADE MR.

These include:

  • some medicines used to treat fungal or yeast infections (miconazole which is contraindicated)
  • alcohol
  • other medicines used to treat diabetes (such as biguanides and insulin)
  • some medicines used to treat high blood pressure and other heart conditions (including angiotensin receptor blocker, beta-blockers)
  • some medicines used to treat depression and other mental illness (MAOIs)
  • some cholesterol-lowering
  • medicines (clofibrate)
  • some medicines used to treat arthritis, pain and inflammation (including high dose aspirin, ibuprofen, phenylbutazone)
  • some antibiotics (chloramphenicol; tetracyclines; long-acting sulphonamides)
  • some medicines used to treat acid reflux and stomach ulcers

Some medicines may lead to high blood glucose levels (hyperglycaemia) by weakening the blood glucose-lowering effect of GLYADE MR.

These include:

  • alcohol
  • some medicines for epilepsy (danazol)
  • some medicines used to treat depression and other mental illness (chlorpromazine)
  • St John's Wort (Hypericum perforatum) preparations used to treat depression
  • some hormones used in hormone replacement therapy and oral contraceptives (oestrogen, progesterone)
  • some medicines for asthma (salbutamol, intravenous terbutaline).
  • barbiturates, medicines used for sedation
  • glucocorticoids

Some medicines may lead to unstable blood glucose (low blood sugar and high blood sugar) when taken at the same time as GLYADE MR, especially in elderly patients.

  • These include:
  • A class of antibiotics called fluoroquinolones.

GLYADE MR may change the effects of some other medicines.

These include:

  • some medicines used to prevent blood clots (warfarin)

You may need different amounts of your medicine or you may need to take different medicines. Your doctor, pharmacist or diabetes educator can tell you what to do if you are taking any of these medicines. They also have a more complete list of medicines to be careful with or avoid while taking GLYADE MR.

Ask your doctor or pharmacist if you are not sure if you are taking any of these medicines.

How to take GLYADE MR

Follow all directions given to you by your doctor, pharmacist, and diabetes educator carefully. They may differ from the information contained in this leaflet.

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

Your doctor will tell you how many tablets to take each day. They may increase or decrease the dose, depending on your blood glucose levels.

When to take it

Swallow the tablets whole with a glass of water. GLYADE MR tablets should not be broken in half, crushed or chewed. Breaking, crushing or chewing the tablets may change the effectiveness of the tablet.

It is important to take your GLYADE MR at the same time each day - usually with breakfast. Taking GLYADE MR with food can help to minimise the risk of hypoglycaemia.

Do not skip meals while taking GLYADE MR.

How long to take it

Continue taking GLYADE MR for as long as your doctor recommends. Make sure you keep enough GLYADE MR to last over weekends and holidays.

GLYADE MR will help control your diabetes but will not cure it. Therefore, you may have to take it for a long time.

If you forget to take it

If 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 you remember (with food), then go back to taking your tablets as you would normally. Missed doses can cause high blood glucose (hyperglycaemia).

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not take a double dose to make up for the dose you have missed. If you double a dose, this may cause low blood glucose (hypoglycaemia).

If you take too much (overdose)

Immediately telephone your doctor, Diabetes Australia or Poisons Information Centre (telephone in Australia: 13 11 26) for advice if you think that you or anyone else may have taken too much GLYADE MR. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much GLYADE MR together with other medicines for diabetes or alcohol, you may experience symptoms of low blood glucose (hypoglycaemia).

If not treated quickly, these symptoms may progress to loss of co-ordination, slurred speech, confusion, loss of consciousness and fitting.

At the first signs of hypoglycaemia, raise your blood glucose quickly by following the instructions at the end of this leaflet.

If you experience any of these symptoms, immediately get medical help.

While you are taking GLYADE MR

Things you must do

If you become pregnant while you are taking GLYADE MR, tell your doctor.

Tell all doctors, dentists, pharmacists and diabetes educators who are involved with your treatment that you are taking GLYADE MR.

If you are about to start taking any new medicines, tell you doctor and pharmacist that you are taking GLYADE MR.

Take GLYADE MR exactly as your doctor has prescribed. Otherwise you may not get the full benefits from treatment.

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.

Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia and hyperglycaemia and know how to treat them. Instructions at the end of this leaflet can help you with this.

Visit your doctor regularly so that they can check on your progress.

Carefully follow your doctor's and dietician's advice on diet, drinking alcohol and exercise.

Tell your doctor immediately if you notice the return of any symptoms of hyperglycaemia that you had before starting GLYADE MR.

These may include lethargy or tiredness, headache, thirst, passing large amounts of urine and blurred vision.

These may be signs that GLYADE MR is no longer working, even though you may have been taking it successfully for some time.

Things you must not do

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

Do not use GLYADE MR to treat other complaints unless your doctor tells you to.

Do not stop taking GLYADE MR, or change the dosage, without checking with your doctor.

Do not skip meals while taking GLYADE MR.

Things to be careful of

If you drink alcohol while taking GLYADE MR, you may get flushing, headache, breathing difficulties, rapid heart beat, stomach pains or feel sick and vomit.

Protect your skin when you are in the sun, especially between 10am and 3pm. Sulphonylureas (the group of medicines that GLYADE MR belongs to) may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness, or a severe sunburn.

If outdoors, wear protective clothing and use a 30+ sunscreen. If your skin does appear to be burning, tell your doctor immediately.

Be careful driving or operating machinery until you know how GLYADE MR affects you.

Also, be especially careful not to let your blood glucose levels fall too low.

GLYADE MR may cause dizziness and drowsiness in some people. Low blood glucose levels may also slow your reaction time and affect your ability to drive or operate machinery. A section at the end of this leaflet contains advice about recognising and treating hypoglycaemia.

Drinking alcohol can make this worse. If either of these occurs, do not drive, operate machinery or do anything else that could be dangerous.

If you are travelling, it is a good idea to:

  • wear some form of identification 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
  • keep GLYADE MR readily available

If you become sick with a cold, fever or flu, it is very important to continue taking GLYADE MR, even if you fell unable to eat your normal meal. If you have trouble eating solid food, use sugar-sweetened drinks as a carbohydrate substitute or eat small amounts of bland food.

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

Side Effects

If you do not feel well while you are taking GLYADE MR then tell your doctor, pharmacist, or diabetes educator as soon as possible.

All medicines can have side effects. Most of the time they are not serious but sometimes they can be.

GLYADE MR helps most people with Type 2 diabetes, but it may sometimes have unwanted side effects. These can include:

  • Hypoglycaemia and hyperglycaemia. A section at the end of this leaflet contains advice about recognising and treating hypoglycaemia and hyperglycaemia
  • runny or blocked nose, sneezing, facial pressure or pain, bronchitis, sore throat and discomfort when swallowing, upper respiratory infection, coughing,
  • back pain, arthralgia, arthrosis,
  • high blood pressure, chest pain,
  • Headache, unusual weakness,
  • Viral infection, urinary tract infection,
  • dizziness
  • stomach upset with symptoms like feeling sick, stomach pain, vomiting, diarrhoea or constipation.
  • decrease in the number of cells in the blood (e.g. platelets, red and white blood cells) which may cause paleness, prolonged bleeding, bruising, sore throat and fever have been reported. These symptoms usually vanish when the treatment is discontinued.
  • Increase of some hepatic enzymes levels, and exceptionally a liver disease,
  • your vision may be affected for a short time especially at the start of treatment. This effect is due to changes in blood sugar levels.

Other side effects are usually mild when they occur. Do not be alarmed by this list of possible side effects. You may not experience any of them.

However if you do - or if you notice anything else that is making you feel unwell - you should consult your doctor or pharmacist.

Other uncommon side effects have been reported and you may wish to discuss this issue with your doctor, pharmacist, or diabetes educator.

If any of the signs below occur stop taking GLYADE MR then tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital:

  • Skin rash, redness itching and/ or hives, blisters, angioedema (rapid swelling of tissues such as eyelids, face, lips, mouth, tongue or throat that may result in breathing difficulty) have been reported. Rash may progress to widespread blistering or peeling of the skin and may be the first sign of rare life threatening conditions (e.g. Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and severe hypersensitivity reactions (DRESS). Exceptionally, DRESS have been reported: initially as flu-like symptoms and a rash on the face then an extended rash with a high temperature.

As for other sulphonylureas, the following adverse events have been observed: cases of severe changes in the number of blood cells and allergic inflammation of the wall of blood vessels, reduction in blood sodium (hyponatraemia), symptoms of liver impairment (e.g. jaundice) which in most cases disappeared after withdrawal of the sulfonylurea, but may lead to life-threatening liver failure in isolated cases.

After taking GLYADE MR

Storage

Keep your tablets in the pack until it is time to take them. GLYADE MR will not keep as well outside its blister packaging.

Keep them in a cool dry place where the temperature stays below 30°C.

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

Keep GLYADE MR tablets where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking GLYADE MR, or the tablets have passed their expiry date, return any leftover tablets to your pharmacist for disposal.

Product description

What it looks like

GLYADE MR tablets are white, oblong tablets with "DIA 30" engraved on one face and the Servier logo on the other.

GLYADE MR tablets come in a blister strip. Each box contains 100 tablets.

Ingredients

Each tablet of GLYADE MR contains 30 mg of gliclazide as the active ingredient and a number of inactive ingredients.

The inactive ingredients in GLYADE MR tablets include calcium hydrogen phosphate, maltodextrin, hypromellose, magnesium stearate, colloidal anhydrous silica.

The tablets are gluten free and lactose free.

Manufacturer/Distributor

GLYADE MR is a product discovered and developed by Servier Research International.

It is distributed in Australia by:

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

GLYADE MR is registered on the Australian Register of Therapeutic Goods.

Australian Register Number:
AUST R 139728

Recognising and treating hyPOglycaemia (very LOW blood sugar levels)

Hypoglycaemia may occur during GLYADE MR treatment.

The first signs of hypoglycaemia
are usually weakness, trembling or shaking, sweating, lightheadedness, dizziness, headache or lack of concentration, irritability, tearfulness, hunger, and/ or numbness around the lips and tongue.

At the first signs of hypoglycaemia take some sugar to raise your blood sugar level quickly. Do this by eating 5 to 7 jelly beans, 3 teaspoons of sugar or honey, drinking half a can of non-diet soft drink, taking 2-3 glucose tablets or a tube of glucose gel.

Then take some extra carbohydrates -
such as plain biscuits, fruit or milk - unless you are within 10-15 minutes of your next meal. Taking this extra carbohydrate will help to prevent a second drop in your blood glucose level.

If not treated quickly, hypoglycaemia symptoms may progress to loss of co-ordination, slurred speech, confusion, fits or loss of consciousness.

If hypoglycaemia symptoms do not get better straight away after taking sugar then go to the Accident and Emergency department at your nearest hospital - if necessary by calling an ambulance.

Contact your doctor or diabetes educator for advice if you are concerned about hypoglycaemia.

Recognising and treating hyPERglycaemia (HIGH blood sugar levels)

Some people may feel fine when their glucose levels are high. Others notice symptoms of hyperglycaemia like tiredness, lack of energy, thirst, passing large amounts of urine, headache, and/or blurred vision.

If you notice symptoms of hyperglycaemia , or your blood sugar levels are high, tell your doctor immediately. You may need adjustments of the dose or type of medicines you are taking.

It is very important to control high blood glucose whether or not you feel unwell. This really helps to avoid serious long-term health problems, which can involve the heart, eyes, circulation, and/or kidneys.

If you experience any of the signs of hyperglycaemia (high blood glucose) contact your doctor or diabetes educator for advice immediately.

This leaflet was prepared in July 2019.

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Glyade MR

Active ingredient

Gliclazide

Schedule

S4

 

1 Name of Medicine

Gliclazide.

6.7 Physicochemical Properties

Gliclazide has the chemical name 1-(3-azabicyclo [3.3.0]oct-3-yl)- 3-p-tolylsulphonylurea. It is a white or almost white powder, practically insoluble in water, freely soluble in dichloromethane, sparingly soluble in acetone and slightly soluble in ethanol 96%. The melting point of gliclazide is approximately 168°C.
Molecular formula: C15H21N3O3S.

Chemical structure.


CAS number.

21187-98-4.

2 Qualitative and Quantitative Composition

Each Glyade MR tablet contains 30 mg of gliclazide.
Gliclazide is an oral hypoglycaemic sulphonylurea which differs from other related compounds by an N-containing heterocyclic ring with an endocyclic bond.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet, modified release: white, oblong, with an engraving of "DIA 30" on one face and Servier logo on the other face.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacodynamics.

Gliclazide reduces blood glucose levels by stimulating insulin secretion from the β-cells of the islets of Langerhans. Gliclazide shows high affinity, strong selectivity and reversible binding to the β-cell KATP channels with a low affinity for cardiac and vascular KATP channels. Increased postprandial insulin and C-peptide secretion persists after two years of treatment.
In type II diabetes, gliclazide restores the first peak of insulin secretion in response to glucose and increases the second phase of insulin secretion. A significant increase in insulin release is seen in response to stimulation induced by a meal or glucose.
Gliclazide also has extrapancreatic effects and haemovascular properties.
It has been shown to increase peripheral insulin sensitivity:
In muscle, euglycaemic hyperinsulinaemic clamp studies with gliclazide have demonstrated significantly increased (35%) insulin mediated glucose uptake which may improve diabetes control. Gliclazide potentiates insulin action on muscle glycogen synthase. These effects are consistent with a post-transcriptional action of gliclazide on GLUT4 glucose transporters.
Studies on glucose turnover have further shown that gliclazide decreases hepatic glucose production, leading to an improvement in fasting blood glucose levels.
Gliclazide has been shown in some studies to have actions independent of that on glucose levels. These haemovascular effects of gliclazide include:
Partial inhibition of platelet aggregation and adhesion with a decrease in markers of platelet activation (beta-thromboglobulin, thromboxane B2).
Increased vascular endothelial fibrinolytic activity (increased tPA activity).
Antioxidant properties, notably a reduction in plasma lipid peroxides and increased erythrocyte superoxide dismutase activity.
Inhibition of the increased adhesiveness of type II diabetic patients' monocytes to endothelial cells in vitro.
The antioxidant, platelet inhibiting and fibrinolytic actions of gliclazide involve processes which have been implicated in the pathogenesis of vascular complications of type II diabetes. There is no clinical evidence that the haemovascular effects of gliclazide are of therapeutic benefit in type II diabetes patients.

5.2 Pharmacokinetic Properties

Absorption.

Hydration of the tablets induces formation of a gel to activate drug release. Plasma levels increase progressively, resulting in a plateau shaped curve from the sixth to the twelfth hour after administration. Intraindividual variability is low. Gliclazide is completely absorbed and food intake does not affect the rate or degree of absorption.

Distribution.

Plasma protein binding is approximately 95%. The relationship between the dose administered and the area under the concentration curve as a function of time is linear for doses of gliclazide up to 90 mg/day. At the highest evaluated dose (135 mg/day), the AUC increases slightly more than proportionally to the dose.

Metabolism.

Gliclazide is mainly metabolised in the liver, the products of which are extensively excreted in the urine.

Excretion.

Less than 1% of unchanged drug is recovered in the urine. No active metabolites have been detected in plasma. The clearance of gliclazide has been found to be slightly reduced as a function of age. This reduction, however, is not considered to be clinically significant. The elimination half-life of gliclazide is approximately 16 hours.

Use in elderly.

No clinically significant modifications in the pharmacokinetic parameters have been observed in elderly patients.

5.3 Preclinical Safety Data

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Type II diabetes in association with dietary measures when dietary measures alone are inadequate to control blood glucose.
During controlled clinical trials in patients with type II diabetes, Glyade MR, taken as a single daily dose, was shown to be effective long-term in controlling blood glucose levels, based on monitoring of HbA1c.

4.3 Contraindications

This medication is contraindicated in the following cases.
hypersensitivity to gliclazide, other sulphonylureas, sulfonamides, or to any of the excipients;
type I diabetes, diabetic ketoacidosis, diabetic precoma and coma;
severe renal or hepatic impairment: in these cases the use of insulin is recommended;
treatment with miconazole (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

The risks of hypoglycaemia, together with its symptoms, treatment and conditions that predispose to its development, should be explained to the patient and to family members. The patient should be informed of the importance of following dietary advice, of taking regular exercise, and of regular monitoring of blood glucose levels.

Hypoglycaemia.

Hypoglycaemia may occur following administration of sulphonylureas. Rarely cases may be severe and prolonged. This may involve hospitalisation and glucose infusion may need to be continued for several days.
Careful selection of patients and of the dose used, as well as provision of adequate information to the patient are necessary to avoid hypoglycaemic episodes. The following factors may increase the risk of hypoglycaemia:
patient does not follow the doctor's treatment advice (particularly elderly patients);
malnutrition;
irregular mealtimes, skipping meals, periods of fasting or dietary changes;
imbalance between physical exercise and carbohydrate intake;
renal impairment;
severe hepatic impairment;
overdose of antidiabetic agents;
certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal impairment, concomitant administration of certain other medicines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Gliclazide should only be prescribed if the patient is likely to have a regular food intake (including breakfast). It is important to have a regular carbohydrate intake due to the increased risk of hypoglycaemia if a meal is delayed, an inadequate amount of food is consumed or the food is low in carbohydrate. Hypoglycaemia is more likely to occur during periods of low calorie diet, following prolonged or strenuous exercise, following alcohol intake or during treatment with a combination of hypoglycaemic agents.

Poor blood glucose control.

Blood glucose control in treated patients may be affected by St John's wort (Hypericum perforatum) preparations (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), fever, trauma, infection or surgical intervention. It may be necessary to discontinue treatment and to administer insulin in these cases.
The efficacy of oral antidiabetic agents often decreases in the long-term. This may be due to progression in the severity of the diabetes, or to a reduced response to treatment. This phenomenon is known as secondary failure and should be distinguished from primary failure, when the drug is ineffective as first line treatment. However, before classifying the patient as a secondary failure, dose adjustment and reinforcement of dietary measures should be considered.

Unstable blood glucose level (dysglycaemia).

Disturbances in blood glucose, including hypoglycaemia and hyperglycaemia have been reported, in diabetic patients receiving concomitant treatment with fluoroquinolones, especially in elderly patients. Indeed, careful monitoring of blood glucose is recommended in all patients receiving gliclazide and a fluoroquinolone at the same time.

Renal and hepatic impairment.

Severe renal or hepatic impairment may affect the distribution of gliclazide and hepatic impairment may also reduce the capacity for neoglucogenesis. These two effects increase the risk of severe hypoglycaemic reactions. A hypoglycaemic episode in these patients may be prolonged and appropriate management should be initiated.

Glucose-6-phosphate dehydrogenase deficiency (G6PD).

Treatment of patients with G6PD deficiency with sulphonylurea agents can lead to haemolytic anaemia. Since gliclazide belongs to the chemical class of sulphonylurea drugs, caution should be used in patients with G6PD deficiency and a nonsulphonylurea alternative should be considered.

Patients with porphyria.

Cases of acute porphyria have been described with the class of sulfonylurea drugs, in patients who have porphyria.

Use in elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

Not recommended for paediatric use, see Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

Glycated haemoglobin should be monitored regularly. Blood glucose measurement may also be useful.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Blood glucose monitoring during and after treatment is necessary when Glyade MR is used with medicines which can interact with gliclazide. It may also be necessary to adjust the dose of Glyade MR during and after treatment with such medicines.

1) The following medications are likely to increase the risk of hypoglycaemia.

Concomitant use which is contraindicated.

Miconazole (systemic route, oromucosal gel).

Increases the hypoglycaemic effect with possible onset of hypoglycaemia symptoms, or even coma.

Concomitant use which is not recommended.

Phenylbutazone (systemic route).

Increases the hypoglycaemic effect of sulphonylureas (displaces their binding to plasma proteins and/or reduces their elimination). It is preferable to use a different anti-inflammatory agent, or else to warn the patient and emphasise the importance of self monitoring. Where necessary, adjust the dose during and after treatment with the anti-inflammatory agent.

Alcohol.

Acute alcohol intoxication potentiates the hypoglycaemic action of all sulphonylurea agents by inhibiting compensatory reactions. This can lead to the onset of hypoglycaemic coma. Ingestion of alcohol may also cause a disulfiram-like reaction with characteristic flushing of the face, throbbing headache, giddiness, tachypnoea, tachycardia or angina pectoris. Chronic alcohol abuse may, as a result of liver enzyme induction, increase the metabolism of sulphonylurea drugs, shortening the plasma half-life and duration of action.
Avoid alcohol or medicines containing alcohol.

Concomitant use which requires special care.

Potentiation of the blood glucose lowering effect and therefore in some instances, hypoglycaemia may occur when one of the following medications is taken.

Other antidiabetic agents (insulins, acarbose, biguanides, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists), sulfonamides, clarithromycin, clofibrate, salicylates (high doses), chloramphenicol, MAOIs, β-blockers, H2-receptor antagonists, ACE inhibitors, fluconazole and nonsteroidal anti-inflammatory agents.

2) The following medications may cause an increase in blood glucose levels.

Advise the patient and emphasise the importance of glucose monitoring.

Concomitant use which is not recommended.

Danazol.

If the use of danazol cannot be avoided, it may be necessary to adjust the dose of Glyade MR during and after treatment with danazol.

Concomitant use which requires special care.

Chlorpromazine.

High doses (> 100 mg per day of chlorpromazine) can increase blood glucose levels (reduced insulin release). Advise the patient and emphasise the importance of glucose monitoring. It may be necessary to adjust the dose of Glyade MR during and after treatment with chlorpromazine.

Glucocorticoids (systemic and local route: intra-articular, cutaneous and rectal preparations) and tetracosactrin.

Concomitant use may increase blood glucose levels with possible ketosis (glucocorticoids cause reduced tolerance to carbohydrates). Emphasise the importance of blood glucose monitoring, particularly at the start of treatment. It may be necessary to adjust the dose of Glyade MR during and after treatment with glucocorticoids.

Salbutamol, terbutaline (intravenous).

May cause increased blood glucose levels due to beta-2 agonist effects. If necessary, switch to insulin.

Barbiturates, oestrogens and progestogens.

May adversely affect blood sugar control with hypoglycaemic agents in some patients by causing increased blood glucose levels.

St John's wort (Hypericum perforatum) preparations.

Gliclazide exposure is decreased by St John's wort (Hypericum perforatum).

3) The following products may cause unstable blood glucose.

Concomitant use which requires special care.

Fluoroquinolones.

In case of a concomitant use of gliclazide and a fluoroquinolone, the patient should be warned of the risk of unstable blood glucose, and the importance of blood glucose monitoring should be emphasised.

Concomitant use to be taken into consideration.

Anticoagulant therapy (warfarin).

Sulphonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of warfarin may be necessary.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
In animal studies embryotoxicity and/or birth defects have been demonstrated with some sulfonylureas.
Gliclazide should not be used in pregnant women. From a clinical point of view, there are limited data (less than 300 pregnancies) to allow evaluation of the possible malformative or foetotoxic effects of gliclazide, when administered during pregnancy. Animal studies of gliclazide have not shown any teratogenic effect.
Glyade MR is contraindicated during pregnancy and insulin is the drug of first choice for treatment of diabetes during pregnancy. Treatment should be changed from Glyade MR to insulin therapy before pregnancy is attempted, or as soon as pregnancy is discovered. Control of diabetes should be achieved before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes.
It is not known whether gliclazide or its metabolites are excreted in breast milk. Given the risk of neonatal hypoglycaemia, Glyade MR is contraindicated in women who are breastfeeding. A risk to newborns/ infants cannot be excluded.

4.8 Adverse Effects (Undesirable Effects)

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.
Good clinical acceptability of gliclazide, has been established in many studies as well as in medical practice.
The safety of Glyade MR has been evaluated in controlled clinical trials in 955 patients, of which 728 patients were treated in long-term comparative trials, against gliclazide 80 mg tablets, for up to ten months. In these comparative trials, the overall incidence and type of adverse events were similar in both Glyade MR and gliclazide 80 mg groups. Adverse events were generally mild and transient, not requiring discontinuation of therapy.
However, where patients did discontinue due to adverse events, the percentage was lower in the Glyade MR group (2.9%) than in the gliclazide 80 mg group (4.5%).

Hypoglycaemia (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

The most frequent adverse reaction with gliclazide is hypoglycaemia.
As is the case with all sulphonylurea drugs, hypoglycaemic reactions have been reported following gliclazide administration. However, a number of studies have shown that hypoglycaemia is less common with gliclazide than with glibenclamide.
Possible symptoms of hypoglycaemia are: headache, intense hunger, nausea, vomiting, lassitude, sleep disorders, agitation, aggression, poor concentration, reduced awareness and slowed reactions, depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disorders, dizziness, feeling of powerlessness, loss of self control, delirium, convulsions, shallow respiration, bradycardia, drowsiness and loss of consciousness, possibly resulting in coma and/or death. In addition, signs of adrenergic counter regulation may be observed: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.
Usually, symptoms disappear after intake of carbohydrate such as sugar (artificial sweeteners have no effect). Experience with other sulphonylureas shows that hypoglycaemia can recur even when these measures are initially effective. If a hypoglycaemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalisation is required.
In long-term comparative studies, the percentage of patients experiencing hypoglycaemic episodes was similar between patients treated with Glyade MR (11.6%) and those treated with gliclazide 80 mg (11.1%). However, the number of hypoglycaemic episodes per 100 patient months was lower in the Glyade MR group (3.5) than in the gliclazide 80 mg group (4.8).
Analysis of elderly patients (over 65 years old) showed less hypoglycaemia than in the general population, with a prevalence of hypoglycaemic episodes lower in the Glyade MR group (2.6 hypoglycaemic episodes for 100 patient months) than in the gliclazide 80 mg group (4.1).
The percentage of patients experiencing hypoglycaemic episodes in the subpopulation with renal failure, was similar to that observed in the general population.
Adverse events reported during controlled clinical trials with Glyade MR were those expected in an ageing population with diabetes.
Adverse events that were reported in at least 2.0% of patients, in long-term controlled clinical studies, are presented in Table 1. The most frequent adverse events were not specifically related to the disease (such as respiratory infections or back pain).
Analysis of adverse events in subpopulations showed a similar pattern to that seen in the general population. Gender, age and renal impairment had no significant influence on the safety profile of Glyade MR.

Other adverse effects.

Gastrointestinal disturbances (reported with gliclazide), including nausea, dyspepsia, diarrhoea, abdominal pain, vomiting, and constipation may be avoided or minimised if gliclazide is taken with breakfast.
The following adverse effects have been rarely reported.

Skin and subcutaneous tissue disorders.

Pruritus, urticaria, maculopapular rashes, rash, angioedema, erythema and bullous reactions (such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) (as with other sulfur containing medications) and autoimmune bullous disorders and exceptionally, drug rash with eosinophilia and systemic symptoms (DRESS).

Blood and lymphatic system disorders (as with other sulphonylurea medications).

Anaemia, leucopenia, thrombocytopenia and agranulocytosis. These are in general reversible upon discontinuation of medication.

Hepatobiliary disorders.

Elevations of serum bilirubin and hepatic enzymes (AST, ALT, alkaline phosphatase) levels, and exceptionally, hepatitis (isolated reports). Treatment should be discontinued if cholestatic jaundice appears. These symptoms usually disappear after discontinuation of treatment.

Investigations.

Occasional elevations of serum creatinine, blood urea nitrogen.

Eye disorders.

Transient visual disturbances may occur due to changes in blood glucose levels, particularly on initiation of treatment. As with any glucose lowering medication, transient visual disturbances may occur on initiation of treatment due to changes in blood glucose levels.

Class effects.

The following adverse events have been observed with sulphonylureas: cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia and allergic vasculitis, hyponatremia, elevated liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulphonylurea or led to life threatening liver failure in isolated cases.

4.2 Dose and Method of Administration

For adult use only.
Glyade MR tablets are modified release tablets and therefore should be neither broken nor chewed.
Glyade MR should be taken with food because there is increased risk of hypoglycaemia if a meal is taken late, if an inadequate amount of food is consumed or if the food is low in carbohydrate. It is recommended that the medication be taken at breakfast time. If a dose is forgotten, the dose taken on the next day should not be increased.
The daily dose may vary from 30 to 120 mg taken orally, once daily. The initial recommended dose is 30 mg daily, even in elderly patients (≥ 65 years). It should not exceed 120 mg.
As with all hypoglycaemic agents, the dose should be titrated according to the individual patient's response. Titration should be carried out in steps of 30 mg, according to the fasting blood glucose response. Each step should last for at least two weeks.
Previously untreated patients should commence with a dose of 30 mg and will benefit from dose titration until the appropriate dose is reached.
Glyade MR can replace gliclazide 80 mg tablets, tablet for tablet, for doses of one to four tablets per day.
Glyade MR may be used to replace other antidiabetic treatments without any transitional period. If a patient is switched from a hypoglycaemic sulphonylurea with a prolonged half-life he/she should be carefully monitored (for one to two weeks) in order to avoid hypoglycaemia due to possible residual effects of the previous therapy.
Glyade MR may be given in combination with biguanides, alpha-glucosidase inhibitors or insulin.

Elderly patients.

The efficacy and tolerance of Glyade MR has been confirmed in clinical trials in patients over 65 years who were given the same dosage regimen as the general population. The dosage is therefore identical to that recommended for adults under the age of 65 years.

Renal impairment.

The efficacy and tolerance of Glyade MR has been confirmed in clinical trials of patients with mild to moderate renal failure (creatinine clearance of between 15 and 80 mL/min) who were given the same dosage regimen as the general population. No dosage adjustment is therefore required in patients with mild to moderate renal impairment. Use of Glyade MR in patients with severe renal impairment is contraindicated (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Patients should be made aware of the symptoms of hypoglycaemia and should be careful if driving or operating machinery, especially at the beginning of treatment.

4.9 Overdose

Advice on overdose management can be obtained from the national Poisons Information Centre by telephoning 131126.
Overdose of sulphonylureas may cause hypoglycaemia.
Moderate symptoms of hypoglycaemia (without loss of consciousness or neurological signs) should be corrected by carbohydrate intake, dose adjustment and/or modification of diet. Strict monitoring should be continued until the doctor is sure that the patient is out of danger.
Severe hypoglycaemic reactions are possible (with coma, convulsions or other neurological disorders) and must be treated as a medical emergency, requiring immediate hospitalisation.
If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid IV injection of 50 mL of concentrated glucose solution (20 to 30%). This should be followed by continuous infusion of a more dilute glucose solution (10%) at a rate necessary to maintain blood glucose levels above 5 mmol/L. It is recommended that patients should be monitored closely for a 48 hour period at least.
Plasma clearance of gliclazide may be prolonged in patients with hepatic disease. However, due to the strong binding of gliclazide to proteins, dialysis is not effective in these patients.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Calcium hydrogen phosphate dihydrate, colloidal anhydrous silica, hypromellose, maltodextrin, 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 30°C.

6.5 Nature and Contents of Container

Glyade MR tablets are supplied in aluminium/PVC blister strips containing 100 tablets enclosed in an outer carton.1
1 The 20 tablet pack is not currently supplied in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes