Consumer medicine information

APO-Glimepiride

Glimepiride

BRAND INFORMATION

Brand name

APO-Glimepiride Tablets

Active ingredient

Glimepiride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about APO-Glimepiride. It does not contain all of the available information.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits this medicine is expected to have for you.

Ask your doctor or pharmacist if you have any concerns about taking this medicine.

Keep this leaflet with the medicine.

You may need to read it again.

What this medicine is used for

The name of your medicine is APO-Glimepiride. It contains the active ingredient glimepiride.

This type of diabetes is also known as non-insulin-dependent diabetes mellitus (NIDDM) or maturity onset diabetes.

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

Glimepiride can be used alone, or together with insulin or other medicines for treating diabetes.

How it works

Glimepiride belongs to a group of medicines called sulphonylureas.

Glimepiride lowers high blood glucose by increasing the amount of insulin produced by your pancreas.

If your blood glucose is not properly controlled, you may experience hypoglycaemia (low blood glucose) or hyperglycaemia (high blood glucose).

Hypoglycaemia (low blood glucose) can occur suddenly. Signs may include:

  • Weakness, trembling or shaking
  • Sweating
  • Lightheadedness, dizziness, headache or lack of concentration
  • Tearfulness or crying
  • Irritability
  • Hunger
  • Numbness around the lips and tongue

If not treated promptly, these may progress to:

  • Loss of co-ordination
  • Slurred speech
  • Confusion
  • Loss of consciousness or seizures

Hyperglycaemia (high blood glucose) usually occurs more slowly than low blood glucose. Signs of high blood glucose may include:

  • Lethargy or tiredness
  • Headache
  • Thirst
  • Passing large amounts of urine
  • Blurred vision

High blood glucose can lead to serious problems with your heart, eyes, circulation or kidneys.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

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

There is no evidence that this medicine is addictive.

Before you take this medicine

When you must not take it

Do not take this medicine if you have had an allergic reaction to:

  • glimepiride or other sulfonylureas
  • antibiotics called sulphonamides
  • thiazide diuretics (a type of fluid or water tablets)
  • lactose (these tablets contain lactose)
  • any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • muscle pain or tenderness or joint pain or rash
  • itching or hives on the skin.

Check with your doctor if you are not sure if you have any of the above.

Do not take this medicine if you have, or have had any of the following conditions:

  • type 1 diabetes mellitus (insulin dependent diabetes mellitus, also known as IDDM, or juvenile or growth onset diabetes)
  • a history of ketoacidosis
  • unstable diabetes
  • diabetic ketoacidosis
  • diabetic coma or pre-coma
  • severe kidney disease or undergoing dialysis
  • severe liver disease
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency

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

Glimepiride 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 glimepiride with insulin while you are pregnant.

Do not take this medicine of you are breast-feeding or planning to breast-feed.

Glimepiride can pass into the breast milk and harm your baby.

Do not give this medicine to children.

There is not enough experience with the use of glimepiride in children.

Do not take this medicine past the expiry date (EXP) printed on the pack.

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

Do not take this medicine if the packaging is torn, shows signs of tampering or if it does not look quite right.

If it has expired or is damaged, return it to your pharmacist for disposal.

Talk to your doctor or pharmacist if you are not sure whether you should start taking this medicine.

Before you start to take it

Tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - lactose
    - any other substances such as food, preservatives, or dyes
  2. You have or have had any medical conditions, especially the following:
    - liver problems
    - kidney problems
    - a deficiency in the enzyme in your body called glucose-6-phosphate dehydrogenase (G6PD)
    - a history of diabetic coma
    - adrenal, pituitary or thyroid problems
    - heart failure
  3. You drink alcohol in any amount
  4. You do not eat regular meals
  5. You do a lot of exercise or you do heavy exercise or work
  6. You are ill or feeling unwell
  7. You plan to become pregnant of breast-feed
  8. You are taking any other anti-diabetic treatments

Alcohol, diet, exercise, and your general health all strongly affect the control of your diabetes.

If you have not told you doctor, pharmacist, of diabetes educator about any of the above, tell them before you start taking this medicine.

Taking other medicines

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

Some medicines may interfere with glimepiride. These include:

  • other medicines used to treat diabetes (tablets and insulin)
  • some medicines used to treat high blood pressure or heart conditions, eg. beta blockers, ACE inhibitors, calcium channel blockers, amiodarone, disopyramide, reserpine or guanethidine
  • some hormones used in hormone replacement therapy and oral contraceptives (oestrogen and progestogens)
  • monoamine oxidase inhibitors (MAOIs), used for treating depression, Parkinson's Disease or infections
  • some medicines used for mental illness (eg. phenothiazines)
  • barbiturates, used for epilepsy and sedation during anaesthetics
  • phenytoin, used for epilepsy
  • medicines for treating high cholesterol / blood fats
  • some medicines used to treat arthritis, pain and inflammation (diclofenac, naproxen, ibuprofen, azapropazone, fenyramidol, oxyphenbutazone, phenylbutazone, salicylates)
  • antibiotics called sulfonamides, quinolones, sulfinpyrazone, tetracyclines, rifampicin, isoniazid, clarithromycin or chloramphenicol
  • miconazole, or fluconazole, used to treat fungal infections
  • some medicines used to prevent or treat blood clots (warfarin and similar medicines)
  • cimetidine, famotidine, nizatidine and ranitidine, used to treat acid reflux and stomach ulcers
  • medicines called corticosteroids (e.g. prednisolone, cortisone)
  • anabolic steroids, male sex hormones
  • thyroid hormones, used to treat thyroid problems
  • oxpentifylline used to prevent or treat blood vessel problems
  • clonidine, used for high blood pressure or migraine
  • diuretics, also known as fluid tablets (e.g. chlorothiazide)
  • diazoxide, used mainly for treating very high blood pressure
  • acetazolamide, used to treat glaucoma, epilepsy and oedema (swelling due to fluid)
  • some antidepressants
  • weight reduction medicines
  • tritoqualine, an antihistamine
  • trofosfamide, cyclophosphamide, ifosfamide, used for treating certain cancers
  • laxatives (long-term use)
  • probenecid, used for treating gout
  • glucagon, used to help balance blood sugar levels
  • medicines used in asthma medicines and cold remedies.

These medicines may be affected by glimepiride or may affect how well it works. This may result in levels of blood sugar which are too high or too low.

In addition, alcohol, certain heart medications such as beta- blockers, clonidine, guanethidine or reserpine, may hide the symptoms of low blood glucose (hypoglycaemia).

You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist can tell you if you are taking any of these medicines. They may also have more information on medicines to be careful with or avoid while taking glimepiride.

Drinking alcohol can also affect your blood sugar levels and how well glimepiride works.

Other interactions not listed above may also occur.

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

How to take this medicine

Follow all directions given to you by your doctor, pharmacist or 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.

How much to take

Your doctor or pharmacist will tell you how many tablets you will need to take. This depends on your condition and whether or not you are taking any other medicines. Your doctor may increase or decrease the dose, depending on your blood glucose levels.

How to take it

Swallow the tablets whole with a glass of water. Do not chew tablets.

When to take it

Take glimepiride immediately before or with a meal.

Glimepiride tablets are usually taken once a day, immediately before breakfast. If you only eat a light breakfast, you should delay taking the tablet until the first main meal of the day (e.g. lunch).

Do not skip meals while taking glimepiride tablets.

Take it at about the same time each day.

It will also help you remember when to take them.

It is important that you eat regular meals.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Glimepiride will help control your Type 2 diabetes but will not cure it. Most people will need to take glimepiride for long periods of time.

Make sure you have enough to last over weekends and holidays.

Do not skip meals while taking glimepiride tablets.

Take it at about the same time each day.

It will also help you remember when to take them.

It is important that you eat regular meals.

If you forget to take it

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 (immediately before food), and then go back to taking it as you would normally.

Skipping a dose may result in hyperglycaemia. If you experience any symptoms of hyperglycaemia, contact your doctor immediately.

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 that you missed.

If you double dose this may cause low blood glucose (hypoglycaemia).

Ask you pharmacist for some hints if you have trouble remembering to take your medicine.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital. Also report any other medicine or alcohol which has been taken.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much glimepiride, you may experience symptoms of hypoglycaemia (low blood glucose).

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 eating jelly beans, sugar or honey, drinking non-diet soft drink or taking glucose tablets.

While you are taking this medicine

Things you must do

Take your tablets exactly as your doctor has prescribed.

Tell all doctors, dentists and pharmacists who are treating you that you are taking glimepiride.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking glimepiride.

Tell your doctor immediately if you become pregnant.

Tell your doctor if you feel APO-Glimepiride is not helping your condition.

Tell your doctor that you are taking this medicine if you are about to have any blood tests.

Tell your doctor and pharmacist that you are taking glimepiride if you are about to start taking any new medicines.

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

Make sure you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia (low blood glucose) and hyperglycaemia (high blood glucose) and know what to do. Provide them with the telephone number for your doctor, the Poisons Information Centre (13 11 26 in Australia).

Always carry some sugary food or drink with you.

Tell your doctor immediately if you notice the return of any symptoms of hyperglycaemia that you had before starting glimepiride, or if your blood sugar levels are high.

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

If you are elderly or are taking other medicines for diabetes (e.g. insulin or metformin), the risk of hypoglycaemia (low blood sugar) is increased.

The risk of hypoglycaemia is also increased in the following situations:

  • too much glimepiride
  • too much unexpected exercise
  • delayed meal or snack
  • too little food

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

The risk of hyperglycaemia is increased in the following situations:

  • undiagnosed or uncontrolled diabetes
  • illness, infection or stress
  • too little glimepiride
  • taking certain medicines
  • too little exercise
  • eating more carbohydrates than normal
  • sudden immobilisation, e.g. after an accident

Tell your doctor if you:

  • become ill
  • become dehydrated
  • are excessively stressed
  • are injured
  • have a fever
  • have serious infection
  • are having surgery.

Your blood glucose may become difficult to control at these times. Your doctor may decide to replace glimepiride with insulin.

Visit your doctor for regular blood tests and checks of your eyes, feet, kidneys, heart, circulation, blood, and blood pressure.

Make sure you check your blood glucose levels regularly.

This is the best way to tell if your diabetes is being controlled properly. You doctor of diabetes educator will show you how and when to do this.

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

Things you must not do

Do not skip meals while taking glimepiride.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

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

Do not take your medicine to treat any other complaints unless your doctor or pharmacist tells you to.

Things to be careful of

Protect your skin when you are outdoors or in the sun, especially between 10 am and 3 pm, wear protective clothing and use a 15+ sunscreen. If your skin appears to be burning, tell your doctor immediately.

Glimepiride may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight may cause skin rash, itching, redness or severe sunburn.

Be careful while driving or operating machinery until you know how glimepiride affects you.

If you have to be alert, e.g. 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. Your vision may also be temporarily affected.

If you are travelling it is a good idea to:

  1. Wear some form of identification showing you have diabetes
  2. Carry some form of sugar to treat hypoglycaemia (low blood glucose) if it occurs, for example, sugar sachets or jelly beans
  3. Carry emergency food rations in case of a delay, for example, dried fruit, biscuits or muesli bars
  4. Keep glimepiride tablets readily available.

If you become sick with a cold, fever or flu, it is very important to continue taking glimepiride, even if you feel 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.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Glimepiride, or if you have any questions or concerns.

All medicines may 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.

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

  • signs of hypoglycaemia, which may include weakness, trembling or shaking, sweating, light-headedness, headache, dizziness, lack of concentration, tearfulness or crying, irritability, hunger and numbness around the lips and fingers
  • nausea
  • vomiting
  • abdominal pain of discomfort
  • diarrhoea or feeling of fullness in the stomach
  • blurred or double vision

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

These may be serious side effects and you may need medical attention:

  • hypoglycaemia or hyperglycaemia, symptoms of sunburn such as redness, itching, swelling or blistering which may occur more quickly than normal after being in the sun
  • bleeding or bruising more easily than normal, or reddish or purplish blotches under the skin
  • signs of frequent or worrying infections, such as fever, severe chills, sore throat or mouth ulcers
  • signs of anaemia, such as tiredness, being short of breath and looking pale.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • rash, sores, redness or itching of the skin, itchy hives-like rash of spots (this could mean that you are allergic to glimepiride)
  • yellowing of the skin or eyes, also called jaundice

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

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

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Storage and disposal

Storage

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

If you take the tablets out of the box or the blister pack they may not keep well.

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

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

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

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Glimepiride looks like

APO-Glimepiride 1 mg Tablets:
Pink, round tablet, G1 on one side and plain on the other.

APO-Glimepiride 2 mg Tablets:
Green, capsule-shaped tablet, G2, scoreline, G2 on one side and scoreline, on the other.

APO-Glimepiride 3 mg Tablets:
Pale yellow, capsule-shaped tablet, G3, scoreline, G3 on one side and scoreline, on the other.

APO-Glimepiride 4 mg Tablets:
Blue, capsule-shaped tablet, G4, scoreline, G4 on one side and scoreline on the other.

Blister packs of 30 tablets.

Ingredients

Each tablet contains 1, 2, 3 or 4 mg of glimepiride as the active ingredient.

It also contains the following inactive ingredients:

  • lactose
  • microcrystalline cellulose
  • povidone
  • sodium starch glycollate
  • magnesium stearate
  • iron oxide red CI77491 (1 mg tablets)
  • iron oxide yellow CI77492 (2 mg, 3 mg tablets)
  • indigo carmine CI73015 (2 mg, 4 mg tablets)

Australian Registration Numbers

APO-Glimepiride 1 mg tablets
Blister pack
AUST R 151570

APO-Glimepiride 2 mg tablets
Blister pack
AUST R 151571

APO-Glimepiride 3 mg tablets
Blister pack
AUST R 151572

APO-Glimepiride 4 mg tablets
Blister pack
AUST R 151573

APO-Glimepiride does not contain gluten, sucrose, tartrazine or any other azo dyes.

Sponsor

Aspen Pharma Pty Ltd
34-36 Chandos Street,
St. Leonards NSW 2065
Australia

Distributor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in:
June 2014

BRAND INFORMATION

Brand name

APO-Glimepiride Tablets

Active ingredient

Glimepiride

Schedule

S4

 

Name of the medicine

Glimepiride.

Excipients.

Lactose, microcrystalline cellulose, sodium starch glycollate, povidone, magnesium stearate, iron oxide red (1 mg tablets only), iron oxide yellow (2 mg and 3 mg tablets only) and indigo carmine (2 mg and 4 mg tablets only).

Description

Chemical name: trans-1-{4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl]phenylsulfonyl}-3-(4-methylcyclohexyl) urea. Molecular formula: C24H34N4O5S. MW: 490.63. CAS: 93479-97-1. APO-Glimepiride tablets contain glimepiride which is a member of the sulfonylurea group of oral antidiabetic agents. Glimepiride is a white odourless, crystalline powder, practically insoluble in methanol and water, slightly soluble in ethanol and sparingly soluble in methylene chloride.

Pharmacology

Pharmacodynamics.

Mechanism of action.

Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentrations. The primary mechanism of action of glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion in the rhythm of meals. In addition, extrapancreatic effects (e.g. reduction of basal hepatic glucose production and increased peripheral tissue sensitivity to insulin and glucose uptake) may also play a limited role in the activity of glimepiride.
In nonfasting diabetic patients, the hypoglycaemic action of a single dose of glimepiride persists for 24 hours.
Evidence from in vitro and animal studies suggests that there is lower glucagon secretion with glimepiride than glibenclamide and this may give rise to a prolonged reduction of blood glucose levels without increased plasma insulin levels. The clinical significance of these findings is yet to be clarified. A long-term, randomised, placebo controlled clinical trial demonstrated that glimepiride therapy improves postprandial insulin/C-peptide responses and overall glycaemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels.
The efficacy of glimepiride is not affected by age, gender or weight. Glimepiride therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profile of patients. The physiological response to acute exercise (i.e. reduction of insulin secretion) is still present during glimepiride therapy.

Pharmacokinetics.

The pharmacokinetics of glimepiride are similar in males and females and also in young and elderly (> 65 years) patients. Intraindividual variability is low.

Absorption.

Glimepiride is completely absorbed after oral administration. The peak serum concentration (Cmax) is reached in about 2.5 hours. There is a linear relationship between dose and both Cmax and AUC (area under the plasma concentration time curve). Food does not significantly affect the rate or extent of absorption of glimepiride.

Distribution.

After intravenous dosing in normal subjects, the volume of distribution was 8.8 litres (113 mL/kg) and the total body clearance was 48 mL/minute. Protein binding was greater than 99%.
Glimepiride is likely to be only minimally removed by haemodialysis due to its high protein binding.
Multiple dose studies with glimepiride in diabetic patients demonstrated plasma concentration time curves similar to single dose studies, indicating that there is no accumulation of drug in tissue depots.

Metabolism.

The elimination half-life of glimepiride at steady state is about five to eight hours after oral administration. However, results of a pharmacokinetic study on patients with type 2 diabetes mellitus indicated that higher doses may be associated with a longer half-life.
Glimepiride is completely metabolised by oxidative biotransformation. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). In vitro studies indicate that cytochrome P450 2C9 is the principal enzyme involved in the biotransformation of glimepiride to M1. M1 has been found to have about 40% of the pharmacological activity of glimepiride. It is eliminated via the urine and also by further metabolism to M2 via one or several cytosolic enzymes. M1 has a terminal elimination half-life of three to six hours after an oral dose. The formation of M1 is linear up to a dose of glimepiride 16 mg. The kinetics of M2 have not been fully elucidated due to low plasma levels. Its terminal elimination half-life after an oral dose is about five to six hours.

Excretion.

Following an oral dose of glimepiride, 35% of the dose is excreted in faeces and 58% in urine.

Renal impairment.

In a single dose, open label study conducted in 15 patients with renal impairment, glimepiride (3 mg) was administered to three groups of patients with different levels of mean creatinine clearance (CrCl); (group I, CrCl = 77.7 mL/minute, n = 5), (group II, CrCl = 27.4 mL/minute, n = 3), and (group III, CrCl = 9.4 mL/minute, n = 7). Glimepiride was found to be well tolerated in all three groups. The results showed that glimepiride serum levels decreased as renal function decreased. However, M1 and M2 serum levels (mean AUC (area under the curve) values) increased 2.3 and 8.6 times from group I to group III. The apparent terminal half-life (t1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4, 21.9 and 9.3% for group I to III).
Results from a multiple dose titration study conducted in 16 patients with renal impairment using doses ranging from 1 to 8 mg daily for three months were consistent with the results after a single dose. All patients with a CrCl < 22 mL/minute had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of glimepiride 1 mg may be given to a patient with type 2 diabetes mellitus with renal disease, and the dose may be titrated based on fasting blood glucose levels (see Contraindications, Dosage and Administration).
It is not known if glimepiride is dialysable.

Hepatic impairment.

The effects of hepatic failure on the clearance of glimepiride have not been systematically examined.

Clinical Trials

A placebo controlled study using fixed daily doses of 1 mg, 4 mg and 8 mg glimepiride found that all three doses were effective at reducing blood glucose levels. However, there was no significant difference in the reduction in fasting plasma glucose (FPG) between the 4 mg and 8 mg doses at any timepoint throughout the study.
In another placebo controlled dose ranging study of glimepiride (1, 2, 3, 4, 6 and 8 mg/day), the majority of patients were controlled in the dose range of 1 to 4 mg daily. There was only a very small difference in the reduction in median FPG levels between the 4 mg and 8 mg doses (-3.08 mmol/L versus -3.16 mmol/L). The greatest change of -3.27 mmol/L was seen with the 2 mg dose. This supports the results of the aforementioned clinical study.
Two large multicentre studies involving approximately 1,900 patients were conducted to examine the dose response effect of glimepiride on blood glucose and HbA1c levels. In both these studies, a large proportion of patients achieved a FPG level below 8.32 mmol/L at the 1 mg/day dose, with a further 10% of patients achieving this level at the 2 mg/day dose. Some patients benefited by an increase in dose to 4 mg/day, but only a few patients, mainly those with very high baseline FPG levels, required higher doses. Based on the results of these studies, the World Health Organization (WHO) has set the defined daily dose (DDD) of glimepiride to be 2 mg.
An additional 161 patient, randomised, double blind crossover study, including four weeks active treatment each with 3 mg b.d. (twice daily) or 6 mg daily of glimepiride, indicated that some patients may have improved results when glimepiride is given twice daily. However, for the majority of patients, once daily dosing provided adequate control. It is important to note that the treatment period in this study was only four weeks and, as such, the long-term safety benefit of twice daily dosing has not been established.

Indications

As an adjunct to diet, exercise and weight loss, to lower the blood glucose in patients with noninsulin dependent (type 2) diabetes mellitus.

Contraindications

Hypersensitivity to glimepiride, other sulfonylureas, other sulfonamides or any excipient.
Severe impairment of renal function (CrCl < 30 mL/minute).
Dialysis patients.
Severe hepatic dysfunction.
Pregnancy (see Precautions, Use in pregnancy).
Lactation (see Precautions, Use in lactation).
Glimepiride is not suitable for the treatment of insulin dependent (type 1) diabetes mellitus (e.g. for the treatment of patients with a history of ketoacidosis), nor for the treatment of diabetic ketoacidosis, nor for the treatment of diabetic precoma or coma.
In patients with severe impairment of hepatic function, changeover to insulin is indicated to achieve optimal metabolic control.

Precautions

Patients receiving glimepiride should be monitored with regular clinical and laboratory evaluations, including blood and urine glucose determinations, to determine the minimum effective dosage and to detect primary failure (inadequate lowering of blood glucose concentration at the maximum recommended dosage) or secondary failure (loss of control of blood glucose concentration following an initial period of effectiveness) to the drug. Glycosylated haemoglobin measurements may also be useful for monitoring the patient's response to glimepiride therapy.
Some improvement in glucose tolerance may take place after a few weeks of treatment with glimepiride. The clinical status should be checked within the first four to eight weeks and at regular intervals thereafter to ascertain whether it is possible to reduce the dose.
The treatment of diabetes requires regular checks. Alertness and reactions may be impaired due to hypoglycaemia or hyperglycaemia, especially when beginning or after altering treatment, or when glimepiride is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.
In cases of unusual stress (e.g. emergency or elective surgery, febrile infection), a temporary change to insulin may become necessary to maintain good metabolic control.
APO-Glimepiride tablets must not be used beyond the expiry date marked on the pack and must be stored out of reach of children.

Hypoglycaemic reactions.

Hypoglycaemia is a potential risk from treatment with any sulfonylurea, particularly in the first month of treatment or when dosage is increased.
Debilitated patients, malnourished patients and patients with adrenal, pituitary, renal or hepatic insufficiency are particularly susceptible to the hypoglycaemic action of sulfonylureas and should therefore be carefully monitored. The dosage of glimepiride should be carefully adjusted in these patients.
Hepatic insufficiency may cause increased serum concentrations of glimepiride and may diminish gluconeogenic capacity, both of which increase the risk of severe hypoglycaemic reactions.
Alcohol ingestion, severe or prolonged exercise, deficient caloric intake or use of more than one antidiabetic agent may predispose patients to the development of hypoglycaemia.
If risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the patient's lifestyle changes.
Hypoglycaemia may be difficult to recognise in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents.
Patients and responsible family members should be made aware of the signs and symptoms of hyperglycaemia (severe thirst, dry mouth, frequent micturition, dry skin) and hypoglycaemia (intense hunger, sweating, tremor, restlessness, irritability, depression, headache, disturbed sleep or transient neurological disorders) and the prompt action to be taken if either event should occur.
The potential for primary and secondary failure should also be explained.
Hypoglycaemia can almost always be promptly controlled by the intake of carbohydrates (glucose or sugar). It is known from other sulfonylureas that, despite initial successful countermeasures, hypoglycaemia may recur. Patients must therefore remain under close observation. Severe hypoglycaemia requires immediate treatment and follow-up by a physician and, in some circumstances, inpatient hospital care.

Haemolytic anaemia.

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a nonsulfonylurea alternative should be considered.

Use in pregnancy.

(Category C)
It is important to achieve strict normoglycaemia during pregnancy. Glimepiride must not be taken during pregnancy. Otherwise there is risk of harm to the child. The patient must change over to insulin during pregnancy. Patients planning a pregnancy must inform their physician. It is recommended that such patients change over to insulin.
The sulfonylureas may enter the foetal circulation and cause neonatal hypoglycaemia. In rats, dietary glimepiride at high doses (approximately 82 mg/kg) during gestation caused limb deformations. In rabbits, effects on pregnancy were characterised by increased incidences of abortions/ total resorptions and malformations. Similar foetal wastage was not seen in rats although the finding of anophthalmia in a proportion of foetuses may be indicative of a treatment related effect as eye malformations were found in the rabbit study. Adverse pregnancy outcomes in the rat and rabbit are probably due to the pharmacodynamic effects of glimepiride at excessive doses and are not substance specific. Glimepiride had no recognisable effects on the rearing, physical development, functional and learning behaviour, memory or fertility of the progeny.

Use in lactation.

Studies in rats showed that glimepiride is excreted in milk. High doses caused hypoglycaemia in suckling young rats. Dietary administration of glimepiride (120 to 206 mg/kg) during lactation caused limb deformations in adolescent pups from day 4 of lactation onwards. To prevent possible ingestion of glimepiride with the breast milk, and possible harm to the child, glimepiride must not be taken by breastfeeding women. Nursing mothers must either be changed over to insulin or cease breastfeeding.

Paediatric use.

The safety and efficacy of glimepiride in children have not been established. Glimepiride is not recommended for use in this age group.

Carcinogenicity.

In a two year carcinogenicity study in mice receiving glimepiride in the diet up to 813 mg/kg/day, there was an increase in the incidence of pancreatic islet cell hyperplasia and islet cell adenomas; these are regarded to be the result of chronic stimulation of the pancreatic beta cells. In a 30 month carcinogenicity study in rats receiving glimepiride in the diet up to 345 mg/kg/day, there was an increased incidence of pancreatic islet cell adenomas, however these were considered incidental as there was no dose relationship in either sex. There were no malignant tumours in rats or mice.

Genotoxicity.

A standard battery of laboratory tests did not reveal any genotoxic or mutagenic potential for glimepiride.

Effects on ability to drive and machinery.

Alertness and reactions may be impaired due to hypo- or hyperglycaemia, especially when beginning or after altering treatment or when glimepiride is not taken regularly. This may affect the ability to drive or to operate machinery.

Interactions

Glimepiride is metabolised by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is coadministered with inducers, inhibitors or substrates of CYP2C9 (e.g. rifampicin, fluconazole, amiodarone, tolbutamide, diclofenac, ibuprofen, naproxen).
Based on experience with glimepiride and known interactions for other sulfonylureas, the following interactions must be considered.
In addition to insulin and other oral antidiabetic agents, drugs which may potentiate the hypoglycaemic action of glimepiride include ACE inhibitors, aminosalicylic acid, anabolic steroids and male sex hormones, azapropazone, chloramphenicol, clarithromycin, clofibrate, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, MAO inhibitors, miconazole, oxpentifylline (high dose parenteral), oxyphenbutazone, para-aminosalicylic acid, phenylbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, sulfonamide antibiotics, tetracyclines, tritoqualine, trofosfamide.
Drugs which may attenuate the hypoglycaemic action of glimepiride include acetazolamide, barbiturates, calcium channel blockers, corticosteroids, diazoxide, diuretics, glucagon, isoniazid, laxatives (protracted use), nicotinic acid (high doses), oestrogens, phenothiazines, phenytoin, progestogens, rifampicin, adrenaline and other sympathomimetic agents, thyroid hormones.
H2-receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose lowering effect.
Concomitant treatment with a beta-receptor blocker, clonidine, guanethidine or reserpine may mask the warning symptoms of a hypoglycaemic attack.
Acute and chronic alcohol intake may either potentiate or attenuate the activity of glimepiride in an unpredictable fashion.
The effect of coumarin derivatives may be potentiated or weakened.

Adverse Effects

Glimepiride is generally well tolerated. Clinical experience has shown that adverse reactions serious enough to compel discontinuation of therapy are uncommon, even during long-term treatment.

Hypoglycaemia.

Hypoglycaemia is the greatest potential risk with all sulfonylureas. Based on what is known of other sulfonylureas, hypoglycaemia may be prolonged.
Possible symptoms of hypoglycaemia include headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, impaired alertness and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia.
In addition, signs of adrenergic counter regulation may be present, including sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.
The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.
The symptoms nearly always subside when hypoglycaemia is corrected.

Visual reactions.

Especially at the start of treatment, there may be temporary visual impairment (e.g. changes in accommodation and/or blurred vision) due to the change in blood glucose levels. The cause is a temporary alteration in the turgidity and hence the refractive index of the lens, this being dependent on blood glucose level.

Gastrointestinal reactions.

Occasionally (0.1 to 1% of patients), gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fullness in the epigastrium, abdominal pain and diarrhoea may occur.

Haematologic reactions.

Changes in the blood picture may occur: thrombocytopaenia, leucopaenia, haemolytic anaemia, erythrocytopaenia, granulocytopaenia, agranulocytosis or pancytopaenia may develop. Cases of severe thrombocytopaenia with platelet count less than 10,000/microliter and thrombocytopaenic purpura have been reported in postmarketing experience (frequency not known). Anaemia, eosinophilia and aplastic anaemia have been reported with sulfonylureas.

Dermatologic reactions.

Allergic or pseudoallergic skin reactions (e.g. itching, pruritus, erythema, urticaria, rashes, erythematous and maculopapular and bullous skin eruptions or psoriasiform drug eruption) may occur in patients treated with sulfonylureas. If skin reactions persist, the drug should be discontinued. Mild reactions in the form of urticaria may develop into serious and even life threatening reactions with dyspnoea and hypotension, sometimes progressing to shock. In the event of urticaria, the physician must be notified immediately. In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur. Porphyria cutanea tarda and pellagra-like changes have been reported with sulfonylureas. It should be noted that cross reactivity exists between sulfonylureas and sulfonamides.

Hepatic reactions.

In isolated cases, increased liver enzymes (AST, ALT), abnormal liver function, cholestasis, cholestatic hepatitis, granulomatous hepatitis, bilirubinaemia and liver failure have been reported with sulfonylureas. In isolated cases, there may be hepatitis, elevation of liver enzymes and/or cholestasis and jaundice which may progress to life threatening liver failure but can regress after withdrawal of glimepiride.

Electrolyte disturbance.

In isolated cases, hyponatraemia has been reported in patients receiving glimepiride and other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatraemia or to increase release of antidiuretic hormone.

Other.

Occasionally, allergic or pseudoallergic reactions may occur, e.g. in the form of itching, urticaria or rashes. Such mild reactions may develop into serious reactions with dyspnoea and a fall in blood pressure, sometimes progressing to shock. In the event of urticaria a physician must therefore be notified immediately. In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.

Dosage and Administration

In the management of type 2 diabetes mellitus, administration of an oral antidiabetic agent is not a substitute for appropriate dietary control.
In initiating treatment for type 2 diabetes mellitus diet should be emphasised as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycaemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.
If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea should be considered. Use of glimepiride must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glimepiride. During maintenance programs, glimepiride should be discontinued and insulin therapy initiated if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.
The dosage of glimepiride must be the lowest which is sufficient to achieve the desired metabolic control. Dosage must be based on regular blood and urine glucose determinations, and must be carefully individualised to obtain optimum therapeutic effect. Periodic measurement of glycosylated haemoglobin is also recommended to monitor the patient's response to treatment. If appropriate glimepiride dosage regimens are not followed, hypoglycaemia may be precipitated.
Measures for dealing with errors in dosage such as forgetting to take a dose, skipping a meal or inability to take a dose at the prescribed time should be discussed with the patient at the time of initiating therapy. A missed dose must never be corrected by subsequently taking a larger dose.
Short-term administration of glimepiride may be sufficient during periods of transient loss of metabolic control in patients usually well controlled on diet.
Food does not alter the bioavailability or other pharmacokinetic parameters of glimepiride.

Initial dose and dose titration.

The initial dose of glimepiride is one 1 mg tablet once daily. The tablet should be swallowed whole without chewing with adequate liquid (e.g. half a glass of water) immediately before breakfast. Patients who eat only a light breakfast should defer the first dose of the day until the first main meal of the day (e.g. lunch). It is very important that meals are not skipped after the tablet has been taken.
If good metabolic control is achieved within the first week of treatment (as determined by blood and urine glucose), continue the daily dose of one 1 mg tablet as maintenance therapy.
If metabolic control is unsatisfactory after one to two weeks of treatment, increase the daily dose in increments of 1 mg at one to two week intervals, until satisfactory metabolic control is achieved. Most patients will achieve optimum control at doses of 1 mg to 4 mg once daily. Only in exceptional cases will doses of more than glimepiride 4 mg/day give better results. Normally, a single daily dose will maintain good blood glucose control for 24 hours.

Secondary dosage adjustment.

Glimepiride requirements may fall as treatment proceeds because an improvement in diabetes control results in greater insulin sensitivity. To avoid hypoglycaemia, timely dose reduction or cessation of therapy should be considered.
Correction of glimepiride dosage must also be considered whenever the patient's weight or lifestyle changes or other factors arise which affect glycaemic control.
Patients should be reminded to monitor glucose levels when switching between different brands of glimepiride tablets.
Secondary failures should be treated by discontinuing glimepiride and starting insulin.

Changeover from other antidiabetic agents to glimepiride.

There is no exact dosage relationship between glimepiride and other oral antidiabetic agents. When transferring patients from another oral antidiabetic drug to glimepiride, it is recommended to begin with the usual starting dose of 1 mg once daily. This recommendation applies even in cases where the patient is being switched from the maximum dose of another antidiabetic agent.
Depending on the pharmacokinetic and pharmacodynamic characteristics of the previous medication, a drug free transition period may be necessary in order to avoid overlapping drug effects possibly resulting in hypoglycaemia.

Renal impairment.

There is limited information available on the use of glimepiride in renal insufficiency. Patients with impaired renal function may be more sensitive to the glucose lowering effect of glimepiride (see Pharmacokinetics, Renal impairment). In patients with mild (CrCl > 50 mL/minute) to moderate (CrCl 30 to 50 mL/minute) renal impairment, a starting dose of 1 mg once daily must not be exceeded. The dose may then be carefully titrated upwards if necessary based on fasting blood glucose levels according to the protocol mentioned above (i.e. in increments of 1 mg at intervals of one to two weeks).
No experience has been gained in the use of glimepiride in dialysis patients. These patients should be changed over to insulin therapy to achieve optimum metabolic control.

Hepatic impairment.

No experience has been gained in the use of glimepiride in patients with severe hepatic impairment. These patients should be changed over to insulin therapy to achieve optimum metabolic control.

Overdosage

Symptoms.

Accidental or intentional overdose may cause severe and prolonged hypoglycaemia which may be life threatening.

Management.

In case of overdosage with glimepiride, a doctor must be notified immediately. At the first signs of hypoglycaemia, the patient must immediately take sugar, preferably glucose, unless a doctor has already started care.
Since hypoglycaemia and its clinical symptoms may recur after apparent clinical recovery (even after several days), close and continued medical supervision and possibly referral to a hospital are indicated. In particular, significant overdosage and severe reactions, e.g. with unconsciousness or other neurological dysfunctions, are emergency cases and require immediate care and hospitalisation.
If hypoglycaemic coma is diagnosed or suspected intravenous infusion of a 20% glucose solution (adults: 40 to 100 mL) is indicated. Alternatively, intravenous, subcutaneous or intramuscular administration of glucagon (adults: 0.5 to 1 mg) may be considered. In infants, glucose must be dosed very carefully and close monitoring of blood glucose is required to minimise the risk of potentially severe hyperglycaemia. Other symptomatic therapy (e.g. anticonvulsants) should be administered as necessary.
After acute glucose replacement has been completed, it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days.
In cases of acute intake of large amounts of glimepiride, detoxification (e.g. by gastric lavage and administration of medicinal charcoal) is indicated.
Contact the Poisons Information Centre on 131 126 (Australia) for advice on the management of overdosage.

Presentation

Tablets, 1 mg (pink, round, marked G1 on one side, plain on reverse, AUST R 151570); 2 mg (green, capsule shaped, scored, marked G2/G2 on one side, scored on reverse, AUST R 151571); 3 mg (pale yellow, capsule shaped, scored, marked G3/G3 on one side, scored on reverse, AUST R 151572); 4 mg (blue, capsule shaped, scored, marked G4/G4 on one side, scored on reverse, AUST R 151573): 30's (blister pack).
APO-Glimepiride tablets are intended for oral administration.

Storage

Store below 25°C.

Poison Schedule

S4.