Dosage and administration	Dosage: Dosage should be individualized on the basis of both response and tolerance. Initial dose is 1mg once daily. If adequate glycemic control is not achieved, the dose should be gradually increased at no more than 1–2 mg at 1- to 2-week intervals to 2 mg – 4 mg – 6 mg once daily until blood glucose is controlled. Mamximum dose is 6 mg once daily. Normally, patients respond to doses of 1-4 mg daily. A dosage of more than 4 mg glimepiride per day gives better results only in exceptional cases. In patients with uncontrolled glucose with a maximum daily dose of metformin, the treatment can be combined with glimepiride. Metformin dose is still maintained, glimepiride therapy is started with a low dose, then adjusted gradually until the desired metabolic control is achieved. The combination must be closely monitored by the physician. In patients not adequately controlled with the maximum daily dose of glimepiride, concomitant insulin therapy can be considered. While maintaining the dose of glimepiride, insulin therapy is initiated at low doses and adjusted for the desired level of glycemic control. Coordination with insulin must be closely monitored by the physician. While maintaining the glimepiride dose, insulin treatment is started at a low dose and titrated up depending on the desired level of blood glucose control. The combination therapy should be initiated under close medical supervision. Switch over from other oral hypoglycaemic agents to glimepiride. A switch over from other oral hypoglycaemic agents to glimepiride can generally be done. For the switch over to glimepiride, the strength and half-life of the previous drug must be taken into account. In some cases, especially in antidiabetics with a long half-life (e.g. chlorpropamide), it takes several days for changeover to minimize the risk of hypoglycaemia due to the additive effect. The recommended starting dose is 1mg glimepiride daily. Depending on the patient's response, the dose may be increased gradually as described above. Switch over from insulin to glimepiride. In exceptional cases, where patients with type II diabetes have taken insulin, a changeover to glimepiride may be indicated. The changeover should be closely monitored by physician. Patient with liver failure or kidney failure. There is limited experience available on the use of glimepiride in patients with hepatic or renal insufficiency or patients on hemodialysis. It is recommended that insulin be used in patients with hepatic or renal insufficiency. Children: Data on safety and efficacy in children are inadequate, therefore glimepiride is not recommended. Administration: Glimegim®4 should be taken whole with adequate liquid shortly before breakfast or lunch. Do not chew tablets. The general principle: For initial and long-term treatment, it is necessary to follow your doctor’s instructions very closely. The dosage of glimepiride must be the lowest which is sufficient to achieve the desired blood glucose level. Do not skip meals while taking glimepiride tablets.
Contraindications	Hypersensitivity to glimepiride or to any of the excipients, or to other sulfonylureas, or to sulfonamide derivatives. Insulin– dependent diabetes (type I). Diabetic ketoacidosis. Diabetic coma. Severe renal or hepatic impairment. Pregnant women or breastfeeding mothers.
Warnings and precautions for use	Glimepiride must be taken immediately before or during meals. Patients should be fully instructed on the nature of diabetes and what to do to prevent and detect complications. The goal of treatment is good blood sugar control, so patients have to take the drug regularly, accompanied by diet, appropriate exercise, and weight loss, if necessary. Close supervision is required because hypoglycaemia may occur during initial weeks of the therapy. In case of irregular meals or skipping meals, treatment with glimepiride can lead to hypoglycemia. Common symptoms of hypoglycemia include: Headache, hunger, weakness, sweating, tremor, discomfort, impaired concentration (see Overdose and management). The clinical picture of a severe hypoglycaemic attack may be similar to that of a stroke. Symptoms can almost be controlled quickly by immediate sugar intake. Artificial sweeteners have no effect. Although this measure may initially be effective, but hypoglycemia may recur. Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual amounts of sugar, requires immediate medical treatment and, in some circumstances, in-patient hospital care. Factors contributing to hypoglycemia include: – Non-compliance with or non-cooperation with drug therapy (commonly seen in the elderly patients). – Malnutrition, irregular mealtimes or skipped meals or being on a diet. – Alterations in diet. – Imbalance between consumption of carbohydrates and physical performance. – Consumption of alcohol, especially in combination with skipped meals. – Impaired renal function. – Severe hepatic dysfunction. – Glimepiride overdosage. – Certain disorders of the endocrine system affect the carbohydrate metabolism or regulation of blood glucose (such as certain disorders of thyroid function, pituitary or adrenocortical insufficiency). – Concurrent administration of certain other medicines (see Interaction with other medicinal products and other forms of interaction). During glimepiride therapy, glucose levels in blood and urine must be monitored regularly. Regular hepatic and hematological monitoring (especially leucocytes and thrombocytes) are required during treatment with glimepiride tablets. In stressful situations (eg, accidents, acute operations, infections with fever etc), a temporary switch to insulin may be indicated. Glimepiride should not be administered to pediatric patients under 18 years of age. Treatment of patients with G6PD deficiency with sulfonylurea agents may lead to hemolytic anemia. Because glimepiride belongs to the sulfonylurea group, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered. There are limited experiences on the use of glimepiride tablets in patients with impaired hepatic function or kidney disease. In patients with severely impaired renal or hepatic function, insulin is indicated. This drug contains lactose and tartrazine. Lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Tartrazine (E102): May cause an allergic reaction.
Recommendation for pregnancy and breastfeeding	Pregnancy: There are no adequate data from the use of glimepiride in pregnant women. Therefore, glimepiride is contraindicated in pregnant women. If patient become pregnant during glimepiride therapy, she must inform the treating doctor to change over to insulin and insulin dosage should be adjusted to keep blood glucose level in a normal range. Lactation: It is not known whether the drug can pass breast milk. Therefore, glimepiride is contraindicated for breastfeeding; Use insulin instead. If glimepiride is required, breastfeeding must be stopped.
Effects on ability to drive and use machines	There is no information about the effects of glimepiride on ability to drive or use machine. However, caution should be exercised when using the drug for the driver or the operator because their ability to concentrate and their response may be reduced due to high or low blood glucose levels and visual impairment. Patients should be advised to take precautions to avoid hypoglycaemia whilst driving.
Interactions, incompatibilities of medicine	Concurrent administration of glimepiride with other drugs may result in increased or decreased effects of glimepiride. Therefore, patient should consult the treating doctor before taking another medicine. Glimepiride is metabolized in the liver by cytochrome P450 (CYP2C9). Its metabolism will be altered by concomitant administration of CYP2C9 inducers (e.g. rifampicin) or with inhibitors (e.g. fluconazole). The following interactions should be noted: Potentiation of the blood-glucose-lowering effect: Hypoglycaemia may occur when glimepiride is used concurrently with following medicinal products: – Phenylbutazone, azapropazone and oxyphenbutazone. – Insulin and oral antidiabetic products, such as metformin. – Antibiotics such as ciprofloxacin, pefloxacin etc. – Salicylates and para-aminosalicylic acid, some nonsteroidal anti-inflammatory drugs (NSAIDs). – Anabolic steroids and male sex hormones. – Chloramphenicol, certain long acting sulfonamides, tetracyclines. – Coumarin anticoagulants. – Fenfluramine. – Fibrates. – ACE inhibitors. – Fluoxetine, MAO-inhibitors. – Allopurinol, probenecid, sulfinpyrazone. – Sympatholytics. – Cyclophosphamide, trophosphamide and iphosphamides. – Miconazole, fluconazole. – Pentoxifylline (high dose parenteral). – Tritoqualine. Weakening of the blood-glucose-lowering effect: Increase in blood glucose levels may occur when one of the following medicinal products is taken: – Estrogen and progestogens. – Saluretics, thiazide diuretics. – Thyroid stimulating agents, glucocorticoids. – Phenothiazine derivatives, chlorpromazine. – Adrenaline and sympathicomimetics. – Nicotinic acid (high dosages) and nicotinic acid derivatives. – Laxatives (long term use). – Phenytoin, diazoxide. – Glucagon, barbiturates and rifampicin. – Acetazolamide. Potentiation or weakening of the blood-glucose-lowering effect: – H2 antagonists. – Beta-blockers, clonidine, guanethidine and reserpine. 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.
Undesirable effects (ADRs)	The most important ADR is hypoglycemia. Common, ADR > 1/100 Neurological: Vertigo, dizziness, headache. Rare, ADR < 1/1000 Blood and lymphatic system disorders: Mild thrombocytopenia, hemolytic anemia, erythropenia, leukopenia, agranulocytosis. Vascular: Allergic vasculitis. Metabolism and nutrition disorders: Hypoglycaemia. These hypoglycaemic reactions mostly occur immediately, may be severe and are not always easy to correct. The occurrence of such reactions depends, as with other hypoglycaemic therapies, on individual factors such as dietary habits and dosage Very rare, ADR < 1/10.000 Immune system disorders: Leukocytoclastic vasculitis, mild hypersensitivity reactions that may develop into serious reactions with dyspnea, fall in blood pressure and sometimes shock. Gastrointestinal disorders: Nausea, vomiting, sensations of pressure or fullness in the epigastrium, abdominal pain and diarrhea. Hepato-biliary disorders: Hepatic function abnormal (e.g. with cholestasis and jaundice), hepatitis and hepatic failure. Investigations: Blood sodium decrease. Not known Blood and lymphatic system disorders: Severe thrombocytopenia with platelet count less than 10, 000/µl and thrombocytopenic purpura. Immune system disorders: Cross-allergenicity with sulfonylureas, sulfonamides or related substances is possible. Visual disorders: Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels. Hepato-biliary disorders: Hepatic enzymes increased. Skin and subcutaneous tissue disorders: Hypersensitivity reactions of the skin may occur as pruritus, rash, urticaria and photosensitivity. Guidelines for ADR management In general, undesirable effects mentioned above will decrease gradually and resolve themselves during the therapy. If they become severe, the therapy must be discontinued.
Overdose and management	Symptoms: Glimepiride overdose can cause severe hypoglycemia with symptoms: Headache, lethargy, tremor, sweating, clammy skin, restlessness, anxiety, tachycardia, hypertension, palpitation, irritability, chest pain, arrhythmia, ravenous hunger, nausea, vomiting, sleepiness, impaired concentration, alertness and reaction time, speech and visual disorders, paresis, sensory disturbances, dizziness, depression, confusion, loss of consciousness leading to coma. In case of coma, shallow respiration and bradycardia were observed. The clinical picture of a severe hypoglycaemic attack may be similar to that of a stroke. Symptoms may not be present for up to 24 hours after ingestion. Treatment: In case of mild hypoglycemia: Oral administration of glucose or table sugar solution (dissolve about 20 – 30g in a glass of water), and monitoring blood glucose level. Sugar is taken at 15-minute intervals until the blood glucose level are within normal range. If severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur: Patients should be immediately moved to health facilities to be treated with glucagon or concentrated glucose solution. In cases of acute intake of large amounts of glimepiride, detoxification (e.g. by gastric lavage and administration of medicinal charcoal) is indicated.
Pharmacodynamic properties	Glimepiride is a sulphonylurea agent used in the treatment of non-insulin-dependent (type II) diabetes mellitus. Glimepiride acts mainly by stimulating beta-cells of the pancreatic islets of Langerhans to release insulin, thus, it works only if the pancreas remains active (beta cells still produce insulin). Glimepiride acts by binding to receptors in the pancreatic beta cell membrane, leading to closure of the ATP-sensitive potassium channel. Closing the potassium channel induces depolarisation of the beta cell membrane and results – by opening of calcium channels – in an increased influx of calcium into the cell. This leads to insulin release through exocytosis. As with other sulfonylurea hypoglycemics, glimepiride lowers blood glucose levels in both patients with diabetes and in healthy people without diabetes. On long term use, glimepiride also has some extrapancreatic effects, contributing significantly to the hypoglycemic effect of the drug. Among these effects, principal effect is to improve the sensitivity of peripheral tissues for insulin and decrease the production of glucose by the liver. Glimepiride has a synergistic effect with metformin or insulin.
Pharmacokinetic properties	The bioavailability of glimepiride is very high. Food intake does not alter significantly the absorption, only the absorption rate is slightly slower. Maximum plasma concentrations are reached approximately 2.5 hours after oral administration. Glimepiride has a very low distribution volume (approx 8.8 litres) which is roughly equal to the albumin distribution space, high protein binding (>99%), and a low clearance (approx 48 ml/min). The plasma half- life of glimepiride is within 5 – 8 hours, but after high doses, slightly longer half-lives are noted. After a single dose of radiolabelled glimepiride, 58% of the metabolites was recovered in the urine, and 35% in the feces. No unchanged metabolite was detected in the urine. Glimepiride is metabolized in the liver, mainly by CYP2C9. Two metabolites of glimepiride, the hydroxy derivative and the carboxy derivative, were identified both in urine and feces.
Storage conditions, shelf-life, quality specification of the medicine	Storage conditions: Protect from humidity and light, below 30 degrees C. Shelf – life: 36 months from the manufacture date. Quality specification: In house specification.

GLIMEGIM 4

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