Glibenclamide + metformin

Oral
Type 2 diabetes mellitus
Adult: Available preparations: Glibenclamide 1.25 mg and metformin 250 mg tab Glibenclamide 2.5 mg and metformin 500 mg tab Glibenclamide 5 mg and metformin 500 mg tab Patients with inadequate glycaemic control on diet and exercise: Initially, 1.25 mg/250 mg once daily or bid. In patients with HbA_1c >9% or FPG >200 mg/dL, may give an initial dose of 1.25 mg/250 mg bid. May adjust dose in increments of 1.25 mg/250 mg daily every 2 weeks or longer. Patients with inadequate glycaemic control on diet, exercise and initial treatment with sulfonylurea or metformin monotherapy: Initially, 2.5 mg/500 mg or 5 mg/500 mg bid. Titrate daily dose in increments of not more than 5 mg/500 mg every 2 weeks or longer. Initial dose must not exceed the daily dose of sulfonylurea and metformin already being taken. Gradually increase doses based on glycaemic control and tolerance. Max: 20 mg/2,000 mg daily. Dosage recommendations may vary among countries (refer to detailed product guideline).
Elderly: Initiate at a lower dose. Treatment recommendations may vary among countries (refer to detailed product guideline).
Renal impairment: CrCl <60 mL/min: Contraindicated.

CrCl (ml/min)	Dosage Recommendation
<60	Contraindicated.

Hepatic impairment: Contraindicated.

Should be taken with food.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma; acute conditions that may alter renal function (e.g. severe infection, shock, dehydration); acute or chronic disease which may cause tissue hypoxia (e.g. unstable CHF, respiratory failure, recent MI, acute significant blood loss, sepsis, gangrene); elective major surgery (discontinue use 48 hours before surgery and until 48 hours afterwards), porphyria. Acute alcohol intoxication or alcoholism. Renal (CrCl <60 mL/min) or hepatic impairment. Concomitant use with bosentan, miconazole and intravascular iodinated contrast agents.

Patient with thyroid insufficiency, impaired adrenal and/or pituitary function; stable heart failure, other risk factors for lactic acidosis (e.g. inadequately controlled diabetes, ketosis, prolonged fasting, concomitant use of drugs that may cause lactic acidosis). Avoid use in patients with G6PD deficiency. Malnourished or debilitated patients. Elderly. Pregnancy and lactation. Not indicated for use in patients with type 1 diabetes mellitus. Patient Counselling This drug may cause dizziness or impaired mental alertness and capacity to react, if affected, do not drive or operate machinery. Monitoring Parameters Monitor blood glucose, HbA_1c twice yearly (in patients with stable glycaemic control and are meeting treatment goals) or quarterly (in patients not meeting treatment goals or with treatment change); renal function prior to initiation, annually during treatment and when clinically indicated; haematologic parameters (e.g. Hb/haematocrit, RBC indices) and hepatic function prior to initiation, periodically during treatment or at least annually once on maintenance therapy; vitamin B₁₂ level periodically during prolonged use and folate (if megaloblastic anaemia is suspected). Monitor for signs and symptoms of hypoglycaemia.

Significant: Hypoglycaemia (may be severe), vitamin B₁₂ deficiency (long-term use), haemolytic anaemia. Very rarely, disulfiram-like reactions. Gastrointestinal disorders: Diarrhoea, nausea, vomiting, abdominal pain, taste disturbance, heartburn, dyspepsia. Hepatobiliary disorders: Hepatocellular, mixed hepatocellular, and cholestatic liver injury. Rarely, cholestatic jaundice and hepatitis which may progress to liver failure. Investigations: Liver function abnormalities (e.g. elevated transaminase). Metabolism and nutrition disorders: Loss of appetite. Nervous system disorders: Headache, dizziness. Skin and subcutaneous tissue disorders: Pruritus, erythema, urticaria, maculopapular or morbilliform eruptions.
Potentially Fatal: Lactic acidosis, increased risk for CV mortality.

Symptoms: Mild to severe hypoglycaemia; lactic acidosis. Management: Mild hypoglycaemia without loss of consciousness or neurological findings may be treated with oral glucose and adjustments in drug dose and/or meal patterns. Severe hypoglycaemic reactions with coma, seizure or other neurological impairment require administration of glucagon or rapid IV inj of glucose 50% solution. Closely monitor patient for at least 24-48 hours. May perform haemodialysis in case of metformin overdosage.

May result in impaired glucose tolerance with thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, oral contraceptives, estrogen, phenytoin, nicotinic acid, sympathomimetics, Ca channel blockers, and isoniazid. Glibenclamide: May enhance hypoglycaemic effect with chloramphenicol, ciprofloxacin, sulfamethoxazole/trimethoprim combination, sulfonamides, tetracyclines, disopyramide, MAOIs, NSAIDs (e.g. phenylbutazone), salicylates, coumarin derivatives, clofibrate, probenecid, ACE inhibitors (e.g. captopril, enalapril), anabolic steroids. β-blockers may mask the symptoms of hypoglycaemia (e.g. palpitations, tachycardia); majority of the non-cardioselective β-blockers may increase the severity and incidence of hypoglycaemia. May reduce hypoglycaemic effect with rifampicin and diazoxide. Increased half-life with fluconazole. Reduced plasma concentration and exposure with bile acid sequestrants (e.g. colesevelam); administer glibenclamide + metformin at least 4 hours before bile acid sequestrants. Reduced antidiuretic effect of desmopressin. Metformin: May increase the risk of lactic acidosis with carbonic anhydrase inhibitors (e.g. acetazolamide, dichlorphenamide), NSAIDs, ACE inhibitors, angiotensin II receptor blockers, diuretics (particularly loop diuretics). May reduce efficacy with organic cationic transporter (OCT)-1 inhibitors (e.g. verapamil). Increased plasma concentration and reduced clearance with OCT2 inhibitors (e.g. cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole). May increase absorption and efficacy with OCT1 inducers (e.g. rifampicin). May decrease the anticoagulant effect of vitamin K antagonists.
Potentially Fatal: Increased risk of hepatotoxicity (elevated liver enzymes) with bosentan. May increase the risk of severe hypoglycaemia with miconazole (systemic route, oromucosal gel). Concomitant administration of intravascular iodinated contrast agents may result in renal failure and occurrence of lactic acidosis.

Alcohol may potentiate the risk of lactic acidosis; avoid concomitant use.

Glibenclamide and metformin have different, but complementary, mechanisms of action in improving glycaemic control in patients with type 2 diabetes mellitus. Glibenclamide, a 2nd generation sulfonylurea, stimulates insulin release from pancreatic β-cells, reduces glucose output from the liver and increases insulin sensitivity at peripheral target sites. Metformin, a biguanide antidiabetic, improves the glucose tolerance by lowering both basal and postprandial plasma glucose. It reduces hepatic glucose production by inhibiting gluconeogenesis, reduces intestinal glucose absorption and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation. Synonym: glibenclamide: glyburide.
Onset: Glibenclamide: Increase in serum insulin levels: 15-60 minutes. Metformin: Within days; max effect up to 2 weeks.
Duration: Glibenclamide: ≤24 hours.
Absorption: Glibenclamide: Very readily absorbed from the gastrointestinal tract. Time to peak plasma concentration: Within 2-4 hours. Metformin: Slowly and incompletely absorbed from the gastrointestinal tract. Bioavailability: Approx 50-60% (fasted state). Time to peak plasma concentration: 2.5 hours.
Distribution: Glibenclamide: Crosses the placenta. Plasma protein binding: 99%, primarily to albumin. Metformin: Partitions into erythrocytes; concentrates in the kidney, liver and gastrointestinal tract. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: 654 ± 358 L. Plasma protein binding: Negligible.
Metabolism: Glibenclamide: Almost completely metabolised in the liver. Metformin: Not metabolised in the liver.
Excretion: Glibenclamide: Via urine (approx 50%) and faeces (approx 50%) as metabolites. Terminal elimination half-life: 4-11 hours. Metformin: Via urine (approx 90%, as unchanged drug). Elimination half-life: 4-9 hours (plasma); approx 17.6 hours (blood).

Oral: Store below 30°C. Protect from light.

Antidiabetic Agents

A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.
A10BB01 - glibenclamide ; Belongs to the class of sulfonylureas. Used in the treatment of diabetes.