GLEMA

glimepiride is indicated for the treatment of type 2 diabetes when diet, physical exercise and weight reduction alone are not sufficient.

The simultaneous intake of glimépiride with certain other medicines may lead to an unwanted increase or decrease in the hypoglycemic effect of glimépiride. Therefore, the intake of any other medicine should only take place with the agreement (or on prescription) of a doctor.

Glimépiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be influenced by the concomitant administration of CYP2C9 inducers (such as rifampicin) or inhibitors (such as fluconazole).

Published results of an in vivo interaction study show that the area under the curve (AUC) of glimépiride is almost doubled in the presence of fluconazole, one of the most potent CYP2C9 inhibitors.

Based on the experience acquired with glimépiride and other sulfonylureas, the following interactions must be mentioned.

A potentiation of the hypoglycemic effect and therefore, in some cases, hypoglycemia may occur when one of the following medicines is taken, for example:

· phenylbutazone, azapropazone and oxyphenbutazone,

· insulin and oral antidiabetics, such as metformin,

· salicylates and para-aminosalicylic acid,

· anabolic steroids and male sex hormones,

· chloramphenicol, certain long-acting sulfonamides, tetracyclines, antibiotics of the quinolone family and clarithromycin,

· coumarin anticoagulants,

· fenfluramine,

· disopyramide

· fibrates,

· angiotensin-converting enzyme inhibitors,

· fluoxetine, MAOIs,

· allopurinol, probenecid, sulfinpyrazone,

· sympatholytics,

· cyclophosphamide, trophosphamide and iphosphamide,

· miconazole, fluconazole,

· pentoxifylline (at high dose parenterally),

· tritoqualine.

A decrease in the hypoglycemic effect and therefore, an increase in blood glucose levels may occur when one of the following medicines is taken, for example:

· estrogens and progestogens,

· salidiuretics and thiazide diuretics,

· thyroid-stimulating agents, glucocorticoids,

· phenothiazine derivatives, chlorpromazine,

· adrenaline and sympathomimetics,

· nicotinic acid (high doses) and nicotinic acid derivatives,

· laxatives (long-term use),

· phenytoin, diazoxide,

· glucagon, barbiturates and rifampicin,

· acetazolamide.

H2 antagonists, beta-blockers, clonidine, and reserpine may lead to either a potentiation or a decrease in the hypoglycemic effect.

Under the influence of sympatholytic medicines like beta-blockers, clonidine, guanethidine or reserpine, the signs of adrenergic counter-regulation to hypoglycemia may be decreased or absent.

Alcohol intake may potentiate or decrease the hypoglycemic effect of glimépiride in an unpredictable way.

Glimépiride may potentiate or attenuate the effects of coumarin anticoagulants.

Colesevelam binds to glimépiride and reduces its absorption from the gastrointestinal tract. No interaction was observed when glimépiride was taken at least 4 hours before colesevelam. Therefore, glimépiride must be administered at least 4 hours before colesevelam.

Pregnancy

Risks related to diabetes

Abnormal blood glucose levels during pregnancy are associated with an increased incidence of congenital malformations and perinatal mortality. To avoid a teratogenic risk, blood glucose must be closely monitored during pregnancy. In such circumstances, the use of insulin is required. Patients planning a pregnancy should inform their doctor.

Risks related to glimépiride

There is no sufficient data on the use of glimépiride in pregnant women. Animal studies have shown reproductive toxicity probably related to the pharmacological action (hypoglycemia) of glimépiride (see section 5.3).

As a consequence, glimépiride should not be used during the entire duration of pregnancy.

If a pregnancy is planned or in case of discovery of a pregnancy during treatment with glimépiride, the treatment must be replaced as quickly as possible by insulin.

Breastfeeding

The excretion of glimepiride in human breast milk is unknown. In rats, glimepiride is excreted in breast milk. Given that other sulfonylureas are excreted in human breast milk and considering the risk of hypoglycemia in breastfed children, breastfeeding is contraindicated in case of treatment with glimepiride.

Fertility

No data on fertility is available.

The effects on the ability to drive and use machines have not been studied.

The patient's ability to concentrate or react may be impaired due to hypoglycemia or hyperglycemia or, for example, due to visual disturbances. This may represent a risk in situations where these faculties are necessary (such as driving a car or using machines).

Patients must be informed of the precautions to take in order to avoid hypoglycemia while driving. This is particularly important in patients who have absent or diminished warning symptoms of hypoglycemia or in patients who have frequent episodes of hypoglycemia. In these circumstances, it should be considered whether it is recommended to drive or use machines or not.

The following adverse effects observed during clinical studies with glimepiride and other sulfonylureas are classified below by organ system class and in descending order of frequency:

· very frequent (≥1/10),

· frequent (≥1/100 to <1/10),

· uncommon (≥1/1000 to <1/100),

· rare (≥1/10 000 to <1/1000),

· very rare (<1/10 000),

· frequency unknown (cannot be estimated on the basis of available data).

Hematological and lymphatic system disorders

Rare: thrombocytopenia, leucopenia, neutropenia, agranulocytosis, erythropenia, hemolytic anemia and pancytopenia, which are, in general, reversible upon discontinuation of treatment.

Frequency unknown: severe thrombocytopenia with a platelet count lower than 10 000/µl and thrombocytopenic purpura.

Immune system disorders

Very rare: leukocytoclastic vasculitis, mild hypersensitivity reactions that may progress to serious reactions with dyspnea, blood pressure drop and sometimes shock.

Frequency unknown: cross-allergy with sulfonylureas, sulfonamides and their derivatives is possible.

Metabolism and nutrition disorders

Rare: hypoglycemia.

These hypoglycemic reactions most often appear immediately, can be severe and are not always easy to correct. The occurrence of such reactions depends, as with any hypoglycemic treatment, on individual factors such as dietary habits and the dose of the hypoglycemic agent (see section 4.4).

Eye disorders

Frequency unknown: visual disturbances, transient, may occur notably at the start of treatment, due to glycemic changes.

Gastrointestinal disorders

Rare: dysgeusia.

Very rare: nausea, vomiting, diarrhea, abdominal distension, abdominal discomfort and abdominal pains, which can rarely lead to discontinuation of treatment.

Hepatobiliary disorders

Very rare: abnormal liver function (with, for example, cholestasis and jaundice), hepatitis and liver failure.

Frequency unknown: elevation of liver enzymes.

Skin and subcutaneous tissue disorders

Rare: alopecia.

Frequency unknown: cutaneous hypersensitivity reactions may occur such as pruritus, skin rashes, urticaria and photosensitivity.

Investigations

Rare: weight gain.

Very rare: decreased blood sodium.

Reporting of suspected adverse effects

Reporting of suspected adverse effects after authorization of the medicinal product is important. It allows continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr