Glimepiride is a sulfonylurea antidiabetic. It is given orally for the treatment of type 2 diabetes

mellitus when diet, physical activity and weight control alone are not adequate.      

The basis for successful management of diabetes is a proper diet, regular physical activity, as well as

routine checks of blood and urine. Tablets or insulin cannot compensate if the patient does not keep to

the recommended diet.

Initial doses is 1 mg daily.

For the different dosage regimens other strengths are existing.

If control is unsatisfactory the dosage should be modified, based on the glycaemic control, in a

stepwise manner with an interval of about 1 to 2 weeks between each step, to 2, 3 or 4 mg glimepiride

per day.

A dosage of more than 4 mg glimepiride per day gives acceptable results only in exceptional cases.

The highest suggested dose is 6 mg glimepiride per day.

In patients not adequately controlled with the highest daily dose of metformin, simultaneous

glimepiride therapy can be initiated.

While maintaining the metformin dose, the glimepiride therapy is initiated with a low dose, and is then

titrated up based on the desired level of control up to the maximum daily dose. The combination

therapy should be taken under close medical supervision.

In patients not adequately controlled with the maximum daily dose of Glide, simultaneous insulin

therapy can be started if required. While maintaining the glimepiride dose, insulin treatment is started

       

at low dose and increased depending on the desired level of metabolic control. The combination

therapy should be taken under close medical supervision.

Normally one daily dose of glimepiride is enough. It is advised that this dose be administered shortly

before or during a substantial breakfast or if none is taken - shortly before or during the first main

meal.

If a dose is missed, this should not be corrected by increasing the next dose.

Tablets should be swallowed completely without crushing or chewing with 100 ml liquid.

If a patient has a hypoglycaemic reaction on 1 mg glimepiride daily, this be a sign of that they can be

controlled by diet alone.

In the course of treatment, as an enhancement in control of diabetes is related with higher insulin

sensitivity, glimepiride requirements may decrease. To avoid hypoglycaemia timely dose reduction or

cessation of therapy must therefore be considered. Modification in dosage may also be required, if there

are changes in weight or life style of the patient, or other factors that increase the risk of hypo-or

hyperglycaemia.

Switch over from other oral hypoglycaemic agents to Glide:

A switch over from other oral hypoglycaemic agents to Glide can usually be done. For the switch over

to Glide the strength and the half-life of the previous drug has to be considered. In some cases,

especially in antidiabetics with a long half-life (e.g. chlorpropamide), a wash out period of a few days

is recommended in order to minimise the risk of hypoglycaemic reactions due to the additive effect.

The recommended starting dose is 1 mg glimepiride per day. Based on the response the glimepiride

dosage may be increased stepwise, as indicated earlier.

Switch over from Insulin to Glide

In exceptional cases, where type 2 diabetic patients are regulated on insulin, a changeover to Glide may

be recommended. The changeover should be undertaken under close medical supervision.

Special Populations

Patients with renal or hepatic impairment:

See section 4.3.

Children and adolescents:

There are no data available on the use of glimepiride in patients under 8 years of age. For children aged

8 to 17 years, there are limited data on glimepiride as monotherapy (see sections 5.1 and 5.2).

The available data on safety and efficacy are insufficient in the paediatric population and therefore such

use is not advised.

Route of Administration:

Oral administration.

Sequence SPC - 2 Glimepiride is contraindicated in patients with the following conditions: • Hypersensitivity to glimepiride, other sulfonylureas or sulfonamides or to any of the excipients • insulin dependent diabetes, • diabetic coma, • ketoacidosis, • severe renal or hepatic function disorders. In case of severe renal or hepatic function disorders, a change over to insulin is required.

Glimepiride must be taken shortly before or during a meal. When meals are taken at irregular hours or

skipped altogether, treatment with Glimepiride may lead to hypoglycaemia. Possible symptoms of

hypoglycaemia include: headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered

sleep, restlessness, aggressiveness, impaired concentration, alertness and reaction time, depression,

confusion, speech and visual disorders, aphasia, tremor, paresis, 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 such as 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. Symptoms can almost always be promptly

controlled by immediate intake of carbohydrates (sugar). Artificial sweeteners have no effect. It is

known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may

recur. Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual

amounts of sugar, require immediate medical treatment and occasionally hospitalisation.

Factors favouring hypoglycaemia include:

- Unwillingness or (more commonly in older patients) incapacity of the patient to cooperate,

- Undernutrition, irregular mealtimes or missed meals or periods of fasting,

- Alterations in diet,

- Imbalance between physical exertion and carbohydrate intake,

- Consumption of alcohol, especially in combination with skipped meals,

- Impaired renal function,

- Serious liver dysfunction,

- Overdosage with Glimepiride,

- Certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or

counterregulation of hypoglycaemia (as for example in certain disorders of thyroid function and in

anterior pituitary or adrenocortical insufficiency),

- Concurrent administration of certain other medicinal products.

       

Sequence SPC - 3

Treatment with Glimepiride requires regular monitoring of glucose levels in blood and urine. In

addition determination of the proportion of glycosylated haemoglobin is recommended.

Regular hepatic and haematological monitoring (especially leucocytes and thrombocytes) are required

during treatment with Glimepiride.

In stress-situations (e.g. accidents, acute operations, infections with fever, etc.) a temporary switch to

insulin may be indicated.

No experience has been gained concerning the use of Glimepiride in patients with severe impairment

of liver function or dialysis patients. In patients with severe impairment of renal or liver function

change over to insulin is indicated.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic 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.

Glimepiride contains lactose . Patients with rare hereditary problems of galactose intolerance, the Lapp

lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Many interactions have been reported with the sulfonylureas, largely representing either

pharmacokinetic interactions (due to the displacement of the antidiabetic from plasma proteins or

alteration in its metabolism since it is metabolized by Cytochrome P450 2 C9 (CYP2C9) or excretion)

or pharmacological interactions with drugs having an independent effect on blood glucose.

A diminished hypoglycaemic effect, possibly requiring an increased dose of sulfonylurea, has been

seen or might be expected on theoretical grounds with adrenaline and sympathomimetics ,

aminoglutethimide, chlorpromazine, corticosteroids, diazoxide, oral contraceptives (oestrogens and

progestogens), rifamycins, nicotinc acid and its derivatives, long term use of laxatives, phenytoin,

barbiturates, glucagon, acetazolamide, thiazide diuretics, and thyroid hormones and thyroid

stimulating agents.

An increased hypoglycaemic effect has occurred or might be expected with insulin , oral antidiabetics,

ACE inhibitors, alcohol, sympatholytics, allopurinol, probencid, disopyramide, fenfluramine, some

analgesics (notably azapropazone, phenylbutazone, oxyphenbutazone, p-aminosalicylic acid and the

salicylates), azole antifungals (fluconazole, ketoconazole, and miconazole), chloramphenicol,

cimetidine, clofibrate and related compounds, coumarin anticoagulants, clarithromycin,

fluoroquinolones, heparin, fluoxetine, MAOIs, phosphamides, , parentral high doses of pentoxipylline,

tritoqualine, octreotide (although this may also produce hyperglycaemia), ranitidine, anabolic steroids

a, male sex hormones, sulfinpyrazone, sulfonamides (including co-trimoxazole), tetracyclines, and

tricyclic antidepressants.

       

Sequence SPC - 4

H2 antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of

the blood glucose lowering effect.

Under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine

and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.

Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable

fashion.

Glimepiride may either potentiate or weaken the effects of coumarin derivatives.

Pregnancy

Pregnancy risk factor C

Risk related to the diabetes

Abnormal blood glucose levels during pregnancy are related with a higher rate of congenital

abnormalities and perinatal mortality, so the blood glucose level must be closely monitored during

pregnancy in order to avoid the teratogenic possibility. The use of insulin is prefered under such

situation. Patients who consider pregnancy should notify their physician.

Risk related to glimepiride

There are no adequate data from the use of glimepiride in pregnant women. Animal studies have

shown reproductive toxicity which likely was related to the pharmacologic action (hypoglycaemia) of

glimepiride

Consequently, glimepiride should not be used during the whole pregnancy.

In case of treatment by glimepiride, if the patient plans to become pregnant or if a pregnancy is

discovered, the treatment should be switched as quickly as possible to insulin therapy.

Lactation

The excretion in human milk is unknown. Glimepiride is excreted in rat milk. As other sulfonylureas

are excreted in human milk and because there is a risk of hypoglycaemia in nursing infants, breastfeeding

is advised against during treatment with glimepiride.

Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemics are

required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess

their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard

driving licences; those treated with insulin receive restricted licences which must be renewed (with

appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic

attacks while driving, and should be counselled in appropriate management of the situation (stopping

driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and

       

Sequence SPC - 5

removing the ignition key from the car) should such an event occur. Patients who have lost

hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition,

eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated

with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy

goods vehicles or passenger carrying vehicles; those treated with insulin may not drive such vehicles,

and are restricted in driving some other vehicles such as small lorries and minibuses.

Gastrointestinal disturbances such as nausea, vomiting, heartburn, anorexia, diarrhoea, and a metallic

taste may occur with sulfonylureas and are usually mild and dose-dependent; increased appetite and

weight gain may occur. Skin rashes and pruritus may occur and photosensitivity has been reported.

Rashes are usually hypersensitivity reactions and may progress to more serious disorders Other severe

effects may be manifestations of a hypersensitivity reaction. They include altered liver enzyme values,

hepatitis and cholestatic jaundice, leucopenia, thrombocytopenia, aplastic anaemia, agranulocytosis,

haemolytic anaemia, erythema multiforme or the Stevens- Johnson syndrome, exfoliative dermatitis,

and erythema nodosum

After ingestion of an overdosage hypoglycaemia may occur, lasting from 12 to 72 hours, and may

recur after an initial recovery. Symptoms may not be present for up to 24 hours after ingestion. In

general observation in hospital is recommended. Nausea, vomiting and epigastric pain may occur. The

hypoglycaemia may in general be accompanied by neurological symptoms like restlessness, tremor,

visual disturbances, co-ordination problems, sleepiness, coma and convulsions. Treatment primarily

consists of preventing absorption by inducing vomiting and then drinking water or lemonade with

activated charcoal (adsorbent) and sodium-sulphate (laxative). If large quantities have been ingested,

gastric lavage is indicated, followed by activated charcoal and sodium-sulphate. In case of (severe)

overdosage hospitalisation in an intensive care department is indicated. Start the administration of

glucose as soon as possible, if necessary by a bolus intravenous injection of 50 ml of a 50% solution,

followed by an infusion of a 10% solution with strict monitoring of blood glucose. Further treatment

should be symptomatic.

In particular when treating hypoglycaemia due to accidental intake of Glimepiride in infants and young

children, the dose of glucose given must be carefully controlled to avoid the possibility of producing

dangerous hyperglycaemia. Blood glucose should be closely monitored.

ATC code: A10BB12.

5.1 Pharmacodynamic properties

Gimepiride is a orally active sulfonamides blood glucose lowering agent . It could be

       

Sequence SPC - 6

prescribed for non-insulin dependent diabetes mellitus.

Sulfonylureas acts by stimulating insulin release from pancreatic beta cells mainly, this is

occurred an increase of responsiveness of the pancreatic beta cells to the physiological

glucose stimulus.

Glimepiride has pronounced extrapancreatic effects also postulated for other sulfonylureas.

Insulin release

Sulfonylureas regulate insulin secretion by closing the ATP-sensitive potassium channel in

the beta cell membrane. Closing the potassium channel induces depolarisation of the beta

cell and results - by opening of calcium channels - in an increased influx of calcium into the

cell which leads to insulin release through exocytosis.

Glimepiride binds with a high exchange rate to a beta cell membrane protein which is

associated with the ATP-sensitive potassium channel but which is different from the usual

sulfonylurea binding site.

Extrapancreatic activity

The extrapancreatic effects are for example an improvement of the sensitivity of the

peripheral tissue for insulin and a decrease of the insulin uptake by the liver.

The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special

transport proteins, located in the cells membrane. The transport of glucose in these tissues

is the rate limiting step in the use of glucose. Glimepiride increases very rapidly the number

of active glucose transport molecules in the plasma membranes of muscle and fat cells,

resulting in stimulated glucose uptake.

Glimepiride increases the activity of the glycosyl-phosphatidylinositol-specific

phospholipase C which may be correlated with the drug-induced lipogenesis and

glycogenesis in isolated fat and muscle cells.

Glimepiride inhibits the glucose production in the liver by increasing the intracellular

concentration of fructose-2, 6-bisphosphate, which in its turn inhibits the gluconeogenesis.

General

In healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of

glimepiride is dose-dependent and reproducible. The physiological response to acute

physical exercise, reduction of insulin secretion, is still present under glimepiride.

There was no significant difference in effect regardless of whether the medicinal product

was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic

control over 24 hours can be achieved with a single daily dose.

Although the hydroxy metabolite of glimepiride caused a small but significant decrease in

serum glucose in healthy persons, it accounts for only a minor part of the total drug effect.

       

Sequence SPC - 7

Combination therapy with metformin

Improved metabolic control for concomitant glimepiride therapy compared to metformin

alone in patients not adequately controlled with the maximum dosage of metformin has

been shown in one study.

Combination therapy with insulin

Data for combination therapy with insulin are limited. In patients not adequately controlled

with the maximum dosage of glimepiride, concomitant insulin therapy can be initiated. In

two studies, the combination achieved the same improvement in metabolic control as

insulin alone; however, a lower average dose of insulin was required in combination

therapy.

Special populations

Children and adolescents

An active controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg

daily) of 24 weeks duration was performed in 285 children (8-17 years of age) with type 2

diabetes.

Both glimepiride and metformin exhibited a significant decrease from baseline in HbA1c

(glimepiride -0.95 (se 0.41); metformin -1.39 (se 0.40)). However, glimepiride did not

achieve the criteria of non-inferiority to metformin in mean change from baseline of HbA1c.

The difference between treatments was 0.44% in favour of metformin. The upper limit

(1.05) of the 95% confidence interval for the difference was not below the 0.3% noninferiority

margin.

Following glimepiride treatment, there were no new safety concerns noted in children

compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety

data are available in paediatric patients

5.2 Pharmacokinetic properties

Glimepiride is completely absorbed from the gastrointestinal tract. Peak plasma concentrations occur

in 2 to 3 hours, and it is highly protein bound. The drug is extensively metabolised to two main

metabolites, a hydroxy derivative and a carboxy derivative. The half-life after multiple doses is about 9

hours. About 60% of a dose is eliminated in the urine and 40% in the faeces.

       

Sequence SPC - 8

5.2 Preclinical safety data

Preclinical effects observed occurred at exposures sufficiently in excess of the maximum human

exposure as to indicate little relevance to clinical use, or were due to the pharmacodynamic action

(hypoglycaemia) of the compound. This finding is based on conventional safety pharmacology,

repeated dose toxicity, genotoxicity, carcinogenicity, and reproduction toxicity studies. In the latter

(covering embryotoxicity, teratogenicity and developmental toxicity), adverse effects observed were

considered to be secondary to the hypoglycaemic effects induced by the compound in dams and in

offspring.

6.1 List of excipients

Glimepiride 1 tablets contains iron oxide red, Glimepiride 2 tablets contains iron oxide yellow and

Blue lake No. 2, Glimepiride 3 tablets contains iron oxide yellow and Glimepiride 4 tablets contains

Blue lake No. 2.

Not applicable

2 years

Store below 30 degree.

S.No. Materials

1. Lactose

2. Sodium Starch Glycolate

3. Povidone

4. Sodium Lauryl Sulphate

5. Magnesium Stearate

Glimepiride 1 tablets : box contains 3 strips, each of 10 tablets (transparent PVDC/Aluminum

blisters).

Glimepiride 2 tablets : box contains 3 strips, each of 10 tablets (transparent PVDC/Aluminum

blisters).

Glimepiride 3 tablets : box contains 3 strips, each of 10 tablets (transparent PVDC/Aluminum

blisters).

Glimepiride 4 tablets : box contains 3 strips, each of 10 tablets (transparent PVDC/Aluminum

blisters).

Keep out of reach of children.