Consumer medicine information

Diapride

Glimepiride

BRAND INFORMATION

Brand name

Diapride

Active ingredient

Glimepiride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Diapride.

What is in this leaflet

This leaflet answers some common questions about DIAPRIDE.

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

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

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

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

What DIAPRIDE is used for

DIAPRIDE is used to control blood glucose in patients with diabetes mellitus.

There are two types of diabetes mellitus:

  • type 1, also called insulin dependent diabetes
  • type 2, also called non-insulin dependent diabetes mellitus or maturity onset diabetes.

DIAPRIDE is used in the treatment of type 2 diabetes mellitus. It is used when diet and exercise are not enough to control your blood glucose levels.

It is available only with a doctor's prescription.

How DIAPRIDE works

DIAPRIDE belongs to a group of medicines called sulphonylureas. The medicine lowers 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, lack of concentration
  • irritability, tearfulness, crying
  • hunger
  • numbness around the lips and tongue.

If not treated promptly, these may progress to:

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

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

  • lethargy or tiredness
  • headache
  • thirst
  • passing large amounts of urine
  • blurred vision.

Hyperglycaemia can lead to serious problems with your heart, eyes, circulation or kidneys.

Before you take it

When you must not take it

Do not take DIAPRIDE if you are allergic to:

  • medicines containing glimepiride or any other sulphonylureas
  • sulphonamide (sulphur) antibiotics
  • thiazide diuretics
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to DIAPRIDE may include skin rash, itchiness, shortness of breath, or difficulty breathing.

Do not take DIAPRIDE if you have any of the following medical conditions:

  • type 1 diabetes mellitus
  • unstable diabetes
  • diabetic acidosis
  • diabetic coma or pre-coma
  • severe kidney disease or undergoing dialysis
  • severe liver disease.

Ask your doctor if you are not sure whether you should start taking this medicine.

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

Do not take it if you are breastfeeding. This medicine can pass into breast milk and may harm your baby.

Do not take it if the expiry date (Exp.) printed on the pack has passed.

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

Before you start to take it

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

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

  • liver problems
  • kidney problems
  • a history of diabetic coma
  • adrenal, pituitary or thyroid problems
  • heart failure
  • glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Tell your doctor if:

  • you drink alcohol in any amount
  • you do not eat regular meals
  • you do a lot of exercise or you do heavy exercise at work
  • you are ill or feeling unwell

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

Discuss this with your doctor.

If you have not told your doctor about any of the above, tell them before you start taking DIAPRIDE.

Taking other medicines

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

Some medicines may lead to low blood glucose (hypoglycaemia) by increasing the blood glucose-lowering effect of DIAPRIDE. These include:

  • alcohol
  • other medicines used to treat diabetes
  • anabolic steroids
  • some antibiotics
  • some antidepressants
  • some medicines used to treat reflux and stomach ulcers
  • some anti-inflammatory agents, such as ibuprofen and naproxen
  • some medicines used to treat arthritis and gout
  • some blood pressure lowing medicines, such as beta-blockers and ACE inhibitors
  • medicines used to prevent or treat blood clots, blood vessel problems, and irregular heart rhythms
  • some cholesterol-lowering and weight reduction medicines
  • some cancer and organ transplant treatments.

Some medicines may lead to loss of control of your diabetes by weakening the blood glucose-lowering effects of DIAPRIDE. These include:

  • alcohol
  • some antibiotics such as rifampicin
  • some blood pressure, cholesterol and heart medications
  • some medicines used to treat reflux and stomach ulcers
  • thyroid medication
  • some medicines used to treat epilepsy
  • corticosteroids, glucagon, adrenaline and other hormonal therapies
  • oral contraceptives
  • some asthma medicines, preparations for coughs and colds, and weight reduction medicines
  • some fluid and glaucoma medications
  • large loses of laxatives
  • some psychiatric and sedating medications

DIAPRIDE may change the effects of other medicines. These include:

  • coumarin derivatives, which are used to prevent blood clots.

Some medicines may hide the symptoms of low blood glucose (hypoglycaemia). These include:

  • alcohol
  • certain heart medications, such as beta-blockers

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 more information on medicines to be careful with or avoid while taking DIAPRIDE.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

How to take DIAPRIDE

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

How much to take

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

The usual starting dose for adults is one 1 mg tablet each day. Your doctor may increase this dose up to four tablets a day, depending on your blood glucose levels.

How to take DIAPRIDE

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

It should be taken immediately before a meal. If you only eat a light breakfast, you should delay taking the tablet until the first main meal of the day (eg. lunch).

If you forget to take DIAPRIDE

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

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

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

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

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

How long to take it for

Keep taking this medicine for as long as your doctor recommends.

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

If you take too much DIAPRIDE (overdose)

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

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

If you do experience any symptoms 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 it

Things you must do

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

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

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

Make sure that you, your friends, family and work colleagues can recognise the signs of hypoglycaemia and hyperglycaemia and know how to treat them. Provide them with the telephone number for your doctor, the Poisons Information Centre (13 11 26 in Australia) and Emergency Services.

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

You can do this by doing one of the following:

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

Unless you are within 10 to 15 minutes of your next meal or snack, follow up with extra carbohydrates such as plain biscuits, fruit or milk. Taking this extra carbohydrate will prevent a second drop in your blood glucose level.

Always carry some sugary food or drink with you. Diet and low calorie soft drinks do NOT contain sugar and are unsuitable to take for hypoglycaemia.

If you are elderly or are taking other medicines for diabetes, the risk of hypoglycaemia is increased.

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

  • too much DIAPRIDE
  • too much or unexpected exercise
  • delayed meal or snack
  • too little food.

If you experience any symptoms of hyperglycaemia, contact your doctor immediately.

The risk of hyperglycaemia is increased in the following situations:

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

Tell your doctor if any of the following happen:

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

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

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

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

Things you must not do

Do not skip meals while taking DIAPRIDE.

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

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

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. DAIPRIDE 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.

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. However, DIAPRIDE by itself is unlikely to affect how you drive or operate machinery.

Make sure you know how you react to DIAPRIDE before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or lightheaded. If this occurs, do not drive.

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 e.g. sugar sachets or jelly beans
  • carry emergency food rations in case of delay e.g. dried fruit, biscuits or muesli bars
  • keep DIAPRIDE readily available.

If you become sick with a cold, fever or flu, it is important to continue taking DIAPRIDE, even if you feel unable to eat your normal meal. If you have trouble eating solid foods, use sugar-sweetened drinks as a carbohydrate substitute or eat some small amounts of bland food. Your diabetes educator or dietician can give you a list of food to use for sick days.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking DIAPRIDE. DIAPRIDE helps most people with diabetes but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

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

  • signs to 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
  • stomach upset including nausea and vomiting
  • abdominal pain or discomfort, diarrhoea, or a feeling of fullness in the stomach
  • eye problems including blurred or double vision.

Tell your doctor immediately or go to Accident and Emergency if you notice any of the following symptoms:

  • rash, sores, redness or itching of the skin, itchy hives-like rash or spots
  • symptoms of sunburn such as redness, itching, swelling or blistering which may occur more quickly than normal
  • bleeding or bruising more easily than normal, or reddish or purplish blotches under the skin
  • yellowing of the skin or eyes, also called jaundice
  • 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.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice anything that is making you feel unwell.

After using DIAPRIDE

Storage

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

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

Do not keep DIAPRIDE in a car, on a window sill, in a bathroom or near a sink. Heat and dampness can destroy some medicines.

Disposal

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

Product description

What it looks like

DIAPRIDE comes in 4 strengths of tablets:

  • DIAPRIDE 1 - pink, round tablet, G1 on one side and plain on the other
  • DIAPRIDE 2 – green, capsule-shaped tablet, G2, scoreline, G2 on one side and scoreline on the other
  • DIAPRIDE 3 –pale yellow, capsule-shaped tablet, G3, scoreline, G3 on one side and scoreline on the other
  • DIAPRIDE 4 –blue, capsule- shaped tablet, G4, scoreline, G4 on one side and scoreline on the other.

Each pack contains 30 tablets.

Ingredients

The active ingredient in DIAPRIDE is glimepiride:

  • each DIAPRIDE 1 tablet contains 1 mg of glimepiride
  • each DIAPRIDE 2 tablet contains 2 mg of glimepiride
  • each DIAPRIDE 3 tablet contains 3 mg of glimepiride
  • each DIAPRIDE 4 tablet contains 4 mg of glimepiride.

The tablets also contain:

  • lactose monohydrate
  • microcrystalline cellulose
  • povidone
  • sodium starch glycollate
  • magnesium stearate
  • iron oxide red CI77491 (1 mg tablets) (172)
  • iron oxide yellow CI77492 (2 mg, 3 mg tablets) (172)
  • indigo carmine CI73015 (2 mg, 4 mg tablets) (120).

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

Supplier

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

Australian registration numbers:

DIAPRIDE 1: Aust R 107344

DIAPRIDE 2: Aust R 107345

DIAPRIDE 3: Aust R 107346

DIAPRIDE 4: Aust R 107347

This leaflet was revised in October 2018

Published by MIMS December 2018

BRAND INFORMATION

Brand name

Diapride

Active ingredient

Glimepiride

Schedule

S4

 

1 Name of Medicine

Glimepiride.

6.7 Physicochemical Properties

Glimepiride is a white odourless, crystalline powder, practically insoluble in methanol and water, slightly soluble in ethanol and sparingly soluble in methylene chloride.
The chemical name for glimepiride is trans-1- {4-[2-(3-ethyl-4- methyl-2-oxo-3- pyrroline-1-carboxamido)ethyl] phenylsulfonyl}-3- (4-methylcyclohexyl) urea.
C24H34N4O5S. Molecular weight: 490.63.

Chemical structure.

Its structural formula is:

CAS number.

93479-97-1.

2 Qualitative and Quantitative Composition

Diapride tablets come in four strengths and contain either 1 mg, 2 mg, 3 mg or 4 mg of glimepiride.
Excipients of known effect: lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Diapride 1.

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

Diapride 2.

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

Diapride 3.

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

Diapride 4.

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Diapride tablets contain glimepiride which is a member of the sulfonylurea group of oral antidiabetic agents. 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, extra pancreatic 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 non-fasting 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.

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 an 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 bd (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.

5.2 Pharmacokinetic Properties

The pharmacokinetics of glimepiride are similar in males and females and also in young and elderly (> 65 years) patients. Intra-individual 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 Section 4.3 Contraindications; Section 4.2 Dose and Method of 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.

5.3 Preclinical Safety Data

Genotoxicity.

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

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.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.3 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 Use in pregnancy).
Lactation (see 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.

4.4 Special Warnings and Precautions for Use

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), blood glucose regulation may deteriorate and a temporary change to insulin may become necessary to maintain good metabolic control.
Diapride 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, in-patient 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 non-sulfonylurea alternative should be considered.

Use in the elderly.

No data available.

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Glimepiride is metabolised by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is co-administered 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(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.
 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.

4.8 Adverse Effects (Undesirable 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.
Dysgeusia, (taste disturbance or loss of taste) has been reported.

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 post-marketing experience (frequency not known). Anaemia, eosinophilia and aplastic anaemia have been reported with sulfonylureas.

Dermatologic reactions.

Allergic or pseudo-allergic skin reactions (e.g. itching, pruritus, erythema, urticaria, rashes, erythematous and maculo-papular 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 pseudo-allergic 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. Cases of alopecia and weight gain have also been reported.

Reporting suspected adverse effects.

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

4.2 Dose and Method of 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.

Dosage adjustment.

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 Section 5.2 Pharmacokinetic Properties, 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.

4.7 Effects on Ability to Drive and Use Machines

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.

4.9 Overdose

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 cases of acute intake of large amounts of glimepiride, detoxification (e.g. by gastric lavage and administration of medicinal charcoal) is indicated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain the following excipients: lactose monohydrate, 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). The tablets are gluten free.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Blister pack (PVC/PCTFE (Aclar)/Al) of 30 tablets.

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