Glimepiride

Glimepiride is an oral hypoglycaemic agent of the sulfonylurea group. It acts mainly by stimulating the release of insulin from the beta cells of the pancreas, and it appears to have pronounced extrapancreatic effects as well.

Mechanism of Action

• Insulin release: like other sulfonylureas, glimepiride closes ATP-sensitive potassium channels in the beta-cell membrane. The cell depolarises, calcium channels open, and the calcium that enters triggers exocytosis of insulin. It increases the response of the beta cells to the physiological glucose stimulus.
• Binding: glimepiride binds, with a high exchange rate, to a membrane protein associated with the potassium channel that is distinct from the usual sulfonylurea binding site. According to DrugBank it acts on the SUR1 and SUR2A subunits of the channel.
• Extrapancreatic activity: it raises the sensitivity of peripheral tissue to insulin and lowers hepatic uptake of insulin. These effects, postulated for other sulfonylureas too, improve the uptake of blood glucose into muscle and fat tissue.

Pharmacokinetics

• Absorption: bioavailability after oral dosing is complete. Food has no relevant influence on absorption and only slightly slows its rate. Peak serum concentrations are reached about 2.5 hours after an oral dose, and Cmax and AUC rise in a linear relationship with the dose.
• Distribution: the volume of distribution is very small (about 8.8 litres, similar to the albumin space), protein binding is above 99%, and clearance is low (about 48 mL/min). In animals glimepiride passes into milk and across the placenta; its ability to cross the blood-brain barrier is low.
• Metabolism: hepatic, mainly through CYP2C9, to a hydroxy derivative and a carboxy derivative. Their terminal half-lives were 3 to 6 and 5 to 6 hours respectively.
• Elimination: the dominant serum half-life is about 5 to 8 hours, slightly longer after higher doses. After a radiolabelled dose, 58% of the radioactivity was recovered in urine and 35% in faeces, and no unchanged substance was found in urine. Single and multiple once-daily doses showed no significant pharmacokinetic differences, intra-individual variability was very low, and there was no relevant accumulation.
• Special populations: pharmacokinetics were similar in men and women and in younger and older (over 65) patients. In patients with reduced creatinine clearance, glimepiride clearance tended to be higher and mean serum concentrations lower, probably through faster elimination caused by lower protein binding; renal elimination of both metabolites was also affected. No additional risk of accumulation is generally assumed in these patients.

• Type 2 diabetes mellitus, when diet, physical exercise and weight reduction alone are not adequate.

Glimepiride is also an ingredient of a fixed-dose combination with pioglitazone (Tandemact), which is covered on its own product page. This page follows the Spanish (AEMPS) SmPC of the 2 mg and 4 mg tablets; other national SmPCs can differ in wording, strengths and doses.

• Hypersensitivity to glimepiride, to other sulfonylureas or sulfonamides, or to any of the excipients.
• Type 1 diabetes mellitus.
• Diabetic coma.
• Ketoacidosis.
• Severe renal or hepatic function disorders; a change to insulin is required in these cases.

The reactions below are based on clinical trial experience with glimepiride and other sulfonylureas. The SmPC lists no reaction as very common, common or uncommon. Hypoglycaemia is listed as rare, but it mostly occurs immediately, can be severe and is not always easy to correct. It depends on individual factors such as eating habits and dose.

Rare (≥1/10,000 to <1/1,000): thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and pancytopenia (generally reversible when treatment stops); hypoglycaemia; taste disturbance (dysgeusia); hair loss (alopecia); weight gain.

Very rare (<1/10,000): leukocytoclastic vasculitis; mild hypersensitivity reactions that may progress to serious ones with breathlessness, a fall in blood pressure and sometimes shock; nausea, vomiting, diarrhoea, abdominal distension, abdominal discomfort and abdominal pain (in very few cases leading to stopping treatment); impaired liver function (for example with cholestasis and jaundice), hepatitis and liver failure; decreased blood sodium.

Not known: severe thrombocytopenia (platelet count below 10,000 per µL) and thrombocytopenic purpura; cross-allergy with sulfonylureas, sulfonamides or related substances; transient visual disturbances, especially at the start of treatment, due to changes in blood glucose; raised liver enzymes; skin hypersensitivity reactions such as pruritus, rash, urticaria and photosensitivity.

Taking other medicines together with glimepiride can cause unwanted rises or falls in its glucose-lowering effect, so other medicines should be taken only with the knowledge, or on the prescription, of the doctor.

• CYP2C9: glimepiride is metabolised by CYP2C9, so inducers (for example rifampicin) and inhibitors (for example fluconazole) change its metabolism. In an interaction study reported in the literature, fluconazole, one of the most potent CYP2C9 inhibitors, roughly doubled the AUC of glimepiride.
• Increased glucose-lowering effect (hypoglycaemia may occur): phenylbutazone, azapropazone and oxyphenbutazone; other oral antidiabetic agents and insulin, such as metformin; salicylates and p-aminosalicylic acid; anabolic steroids and male sex hormones; chloramphenicol, certain long-acting sulfonamides, tetracyclines, quinolone antibiotics and clarithromycin; coumarin anticoagulants; fenfluramine; disopyramide; fibrates; ACE inhibitors; fluoxetine and MAO inhibitors; allopurinol, probenecid and sulfinpyrazone; sympatholytics; cyclophosphamide, trofosfamide and ifosfamides; miconazole and fluconazole; pentoxifylline (high-dose parenteral); tritoqualine.
• Reduced glucose-lowering effect (blood glucose may rise): oestrogens and progestogens; saluretics and thiazide diuretics; thyroid-stimulating agents and glucocorticoids; phenothiazine derivatives and chlorpromazine; adrenaline and sympathomimetics; nicotinic acid (high doses) and derivatives; laxatives (long-term use); phenytoin and diazoxide; glucagon, barbiturates and rifampicin; acetazolamide.
• H2-receptor antagonists, beta-blockers, clonidine and reserpine: may either potentiate or weaken the blood glucose-lowering effect. Sympatholytics (beta-blockers, clonidine, guanethidine, reserpine) may reduce or abolish the signs of adrenergic counter-regulation to hypoglycaemia.
• Alcohol: may potentiate or weaken the glucose-lowering effect unpredictably. Avoid alcohol.
• Coumarin derivatives: glimepiride may potentiate or weaken their effects.
• Colesevelam: it binds glimepiride and reduces absorption. No interaction was seen when glimepiride was taken at least 4 hours before colesevelam, so glimepiride should be taken at least 4 hours before it.

Treatment of diabetes rests on a good diet, regular physical activity and routine blood and urine checks; tablets or insulin cannot make up for a diet that is not followed. The dose is set from the results of blood and urine glucose tests. A single daily dose is usually enough, taken shortly before or during a substantial breakfast or, if no breakfast is eaten, shortly before or during the first main meal. The tablets are swallowed without chewing, with a little liquid.

Recommended Dose

• Starting dose: 1 mg once a day. If control is satisfactory, the same dose is used for maintenance.
• Titration: if control is not satisfactory, increase gradually according to glycaemic control, with 1 to 2 weeks between steps, to 2, 3 or 4 mg a day.
• Higher doses: more than 4 mg a day gives better results only in exceptional cases. The maximum recommended dose is 6 mg a day.
• Falling needs: as diabetes control improves and insulin sensitivity rises, the dose requirement may fall. To avoid hypoglycaemia, consider reducing the dose or stopping. A correction may also be needed when body weight, lifestyle or other factors that raise the risk of hypoglycaemia or hyperglycaemia change.
• A hypoglycaemic reaction on 1 mg a day means the patient can be controlled by diet alone.

Combination Treatment

• With metformin: if control is not adequate at the maximum daily dose of metformin, glimepiride can be added. The metformin dose is kept, glimepiride starts low and is increased to the maximum daily dose according to the control wanted. The combination is started under close medical supervision.
• With insulin: if control is not adequate at the maximum daily dose of glimepiride, insulin can be added. The glimepiride dose is kept, insulin starts low and is increased according to the control wanted. The combination is started under close medical supervision.

Switching from Other Treatments

• From another oral antidiabetic: usually possible. The potency and half-life of the previous medicine are taken into account. With long half-life agents (for example chlorpropamide) a washout of a few days is advisable to reduce the risk of additive hypoglycaemia. The recommended starting dose is 1 mg a day, increased gradually.
• From insulin: in exceptional cases in patients with type 2 diabetes controlled on insulin, under strict medical supervision.

Special Populations

• Renal or hepatic impairment: severe impairment is a contraindication; see Contraindications.
• Children and adolescents: there are no data below 8 years. For ages 8 to 17 there are few data on glimepiride as monotherapy. The data on safety and efficacy are insufficient, so use in this population is not recommended.

Missed Dose

A missed dose must not be made up by taking a larger dose later.

Hypoglycaemia

• Glimepiride is taken shortly before or during a meal. When meals are irregular or skipped, it can lead to hypoglycaemia.
• Possible symptoms: headache, intense hunger, nausea, vomiting, lassitude, sleepiness, sleep disorders, restlessness, aggression, poor concentration, alertness and reaction time, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, convulsions, drowsiness and loss of consciousness that may progress to coma, rapid breathing and bradycardia. Signs of adrenergic counter-regulation may also occur: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.
• A severe attack can resemble a stroke. Symptoms can almost always be controlled quickly by immediate carbohydrate (sugar); artificial sweeteners have no effect. Hypoglycaemia can recur even when the first measures worked. A severe or prolonged episode that sugar controls only temporarily needs immediate medical treatment and sometimes hospitalisation.
• Factors that favour hypoglycaemia: a patient unwilling, or (more often in the elderly) unable, to cooperate; undernutrition, irregular or skipped meals or fasting; diet changes; an imbalance between exercise and carbohydrate intake; alcohol, especially with skipped meals; impaired kidney function; severe liver dysfunction; overdose; some endocrine disorders that affect carbohydrate metabolism or counter-regulation (some thyroid disorders, adrenocortical or anterior pituitary insufficiency); and other medicines.

Monitoring

Treatment requires regular monitoring of blood and urine glucose, and measuring glycosylated haemoglobin is recommended. Blood counts (especially white cells and platelets) and liver function should be checked regularly.

Stress Situations

In situations of stress (for example accidents, surgery, febrile infections), a temporary change to insulin may be indicated.

Severe Liver or Kidney Disorders

There is no experience with glimepiride in severe hepatic disorders or in dialysis. A change to insulin is indicated in severe hepatic or renal disorders.

G6PD Deficiency

Sulfonylureas can cause haemolytic anaemia in patients with G6PD deficiency. Take care in these patients and consider an alternative that is not a sulfonylurea.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: altered blood glucose in pregnancy is linked to a high incidence of congenital abnormalities and perinatal mortality, so blood glucose should be monitored during pregnancy and insulin used. Women considering pregnancy should tell their doctor. There are insufficient data on glimepiride in pregnant women; animal studies show reproductive toxicity related to its pharmacological action (hypoglycaemia). Glimepiride should not be used throughout pregnancy. If a patient plans a pregnancy or finds she is pregnant, treatment should be changed to insulin as soon as possible.
• Breastfeeding: it is not known whether glimepiride passes into human milk; it passes into rat milk. Other sulfonylureas pass into breast milk and there is a risk of hypoglycaemia in breast-fed infants, so breastfeeding is not advised during treatment.
• Fertility: no data are available.

Lactose and Sodium

The tablets contain lactose monohydrate (137.2 mg in the 2 mg tablet and 135.9 mg in the 4 mg tablet). Patients with hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each dose contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

No studies on the ability to drive and use machines have been done. Concentration and reaction can be impaired by hypoglycaemia or hyperglycaemia, or by a visual disorder, which is a risk where these abilities matter, for example when driving or operating machinery. Patients should take precautions to avoid hypoglycaemia while driving. This matters most for patients with reduced or absent awareness of the warning symptoms of hypoglycaemia, or with frequent episodes. Whether driving or operating machinery is advisable should then be considered.

Do not store above 30 °C. Keep the tablets in the original package to protect them from moisture. They are supplied in PVC/aluminium blisters; not all pack sizes may be marketed. Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the packaging.

Prescription only (Rx). Glimepiride tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.