Boxed Warnings
Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment; other risk factors include old age associated with reduced renal function and high doses of metformin above 2 g per day.
1 Name of Medicine
Metformin hydrochloride and glibenclamide.
2 Qualitative and Quantitative Composition
Glucovance contains metformin hydrochloride and glibenclamide combination as the active ingredients and is available in three strength combinations:
Each Glucovance 250/1.25 tablet contains 250 mg metformin hydrochloride and 1.25 mg glibenclamide.
Each Glucovance 500/2.5 tablet contains 500 mg metformin hydrochloride and 2.5 mg glibenclamide.
Each Glucovance 500/5 tablet contains 500 mg metformin hydrochloride and 5 mg glibenclamide.
Excipients with known effect. Trace amounts of Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Oral. Film-coated tablets.
Glucovance 250/1.25. Yellow film-coated, capsule-shaped, biconvex tablets, engraved with "250" on one side and "1.25" on the other side.
Glucovance 500/2.5. Pale orange film-coated, capsule-shaped, biconvex tablets, engraved with "2.5" on one side.
Glucovance 500/5. Yellow film-coated, capsule-shaped, biconvex tablets, engraved with "5" on one side.
4 Clinical Particulars
4.9 Overdose
High overdose or the existence of concomitant risk factors may lead to lactic acidosis due to the presence of metformin (see Section 4.4 Special Warnings and Precautions for Use). Overdose may also precipitate hypoglycaemia due to the presence of the sulfonylurea (see Section 4.4 Special Warnings and Precautions for Use).
Since hypoglycaemia and its clinical symptoms may recur after apparent clinical recovery (even after several days), close and continued medical supervision and, possibly, referral to a hospital are indicated. In particular, significant overdosage and severe reactions, e.g. with unconsciousness or other neurological dysfunction, are emergency cases and require immediate care and hospitalisation.
If hypoglycaemic coma is diagnosed or suspected, administer glucagon (adults: 0.5 to 1 mg) intravenously, subcutaneously or intramuscularly; or an intravenous infusion of a 20% glucose solution (adults: 40 to 100 mL) until the patient recovers consciousness. In infants, glucose must be dosed very carefully, accompanied by close monitoring of blood glucose, taking into account the risk of potentially severe hyperglycaemia. Other symptomatic therapies (e.g. anticonvulsants) should be administered as necessary.
Lactic acidosis is a medical emergency and must be treated in hospital. The most effective treatment is to remove lactate and metformin by haemodialysis. The plasma clearance of glibenclamide may be prolonged in patients suffering from liver disease. Since glibenclamide is extensively bound to proteins, it is not eliminated by dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
No animal studies have been conducted with the combination of metformin and glibenclamide.
Genotoxicity. Metformin. Metformin was not genotoxic in assays for gene mutations (S. typhimurium, mouse lymphoma cells) or chromosomal damage (chromosomal aberrations test in human lymphocytes or in vivo micronuclei formation test).
Glibenclamide. Glibenclamide was not genotoxic in a limited set of in vitro assays for gene mutations (S. typhimurium) and other genotoxic effects (DNA damage/alkaline elution assay). The clastogenic potential of glibenclamide has not been investigated.
Carcinogenicity. Metformin. Long-term carcinogenicity studies with metformin alone have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at oral doses up to 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are approximately 3 to 4 times the maximum recommended daily dose on a body surface area basis. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumourigenic potential observed with metformin in male rats. However, an increased incidence of benign stromal uterine polyps was seen in female rats at 900 mg/kg/day.
Glibenclamide. A study with glibenclamide alone in a small number of rats (15/sex/group) at doses up to 300 mg/kg/day (approximately 136 times the maximum recommended daily dose on a body surface area basis) for 18 months showed no carcinogenic effects.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Chemical structure. Metformin hydrochloride.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSMETFOH.gif Chemical name: 1,1-dimethylbiguanide hydrochloride.
Molecular formula: C4H11N5, HCl.
Molecular weight: 165.6.
Metformin hydrochloride is a white, crystalline powder, which is odourless or almost odourless and hygroscopic. It is freely soluble in water, slightly soluble in ethanol (96%), and practically insoluble in chloroform and in ether.
Glibenclamide.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSGLIBEN.gif Chemical name: 1-{4-[2-(5-chloro- 2-methoxybenzamido) ethyl]benzene-sulphonyl}- 3-cyclohexylurea.
Molecular formula: C23H28ClN3O5S.
Molecular weight: 494.
Glibenclamide is a white or almost white crystalline powder; odourless or almost odourless. It is practically insoluble in water and in ether, slightly soluble in ethanol and methanol and sparingly soluble in chloroform.
CAS number. Metformin hydrochloride. 1115-70-4.
Glibenclamide. 10238-21-8.
7 Medicine Schedule (Poisons Standard)
S4 (Prescription Only Medicine).
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/GLUCOVST.gif
