Glibenclamide + Metformin


Generic Medicine Info
Indications and Dosage
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

In patients with inadequate glycaemic control on diet and exercise alone: Initially, 1.25 mg/250 mg once daily or bid. In patients with HbA1c >9% or fasting plasma glucose (FPG) >200 mg/dL, an initial dose of 1.25 mg/250 mg bid may be given. May adjust dose in increments of 1.25 mg/250 mg daily every 2 weeks or longer. In patients with inadequate glycaemic control on diet, exercise and initial treatment with glibenclamide (or other 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 glibenclamide (or another sulfonylurea) and metformin already being taken. Gradually increase doses based on individual glycaemic control and tolerance. Max: 20 mg glibenclamide and 2,000 mg metformin 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 (mL/min) Dosage
<60 Contraindicated.
Hepatic Impairment
Contraindicated.
Administration
Should be taken with food.
Contraindications
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.
Special Precautions
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.
Adverse Reactions
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.
Patient Counseling Information
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, HbA1c 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.
Overdosage
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.
Drug Interactions
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.
Food Interaction
Alcohol may potentiate the risk of lactic acidosis; avoid concomitant use.
Action
Description: 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.
Pharmacokinetics:
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).
Chemical Structure

Chemical Structure Image
Glibenclamide

Source: National Center for Biotechnology Information. PubChem Database. Glyburide, CID=3488, https://pubchem.ncbi.nlm.nih.gov/compound/Glyburide (accessed on Jan. 22, 2020)


Chemical Structure Image
Metformin

Source: National Center for Biotechnology Information. PubChem Database. Metformin, CID=4091, https://pubchem.ncbi.nlm.nih.gov/compound/Metformin (accessed on Jan. 20, 2020)

Storage
Store below 30°C. Protect from light.
MIMS Class
ATC Classification
A10BD02 - metformin and sulfonylureas ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
References
Anon. Glibenclamide (Glyburide) and Metformin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 06/05/2021.

Anon. Glibenclamide (Glyburide). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 06/05/2021.

Anon. Metformin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 06/05/2021.

Buckingham R (ed). Glibenclamide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 06/05/2021.

Buckingham R (ed). Metformin Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 06/05/2021.

Glucovance 500 mg/2.5 mg; 500 mg/5 mg Film-Coated Tablets (Merck Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 06/05/2021.

Glucovance 500 mg/2.5 mg; 500 mg/5 mg Tablets (Merck Pte Ltd). MIMS Singapore. http://www.mims.com/singapore. Accessed 23/07/2021.

Glucovance Film-Coated Tablet (Merck, Inc.). MIMS Philippines. http://www.mims.com/philippines. Accessed 23/07/2021.

Glyburide and Metformin Hydrochloride Tablet, Film-Coated (Aurobindo Pharma Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 23/07/2021.

Disclaimer: This information is independently developed by MIMS based on Glibenclamide + Metformin from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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