Metformin Hydrochloride

Indications

Metformin Hydrochloride is used for: Type 2 DM, Polycystic ovarian syndrome,

Adult Dose

Oral Type 2 diabetes mellitus Adult: Conventional preparation: Initially, 500 mg bid or tid, or 850 mg 1-2 times daily, may increase gradually to 2000 mg daily at intervals of at least 1 wk. Maximum daily dose of 2550 mg per day. Modified-release preparation: Initially, 500 mg once daily, may increase in increments of 500 mg at intervals of at least 1 wk to max 2000 mg once daily at night. If glycaemic control is not sufficient, dose may be divided to give 1000 mg bid. Not to exceed 2000 mg/day Polycystic ovary syndrome Initial: 500 mg/day in the morning for 1 wk, then 500 mg twice daily for 1 wk, then 1.5-1.7 g/day in 2-3 divided doses. Elderly: Initial and maintenance dosing should be conservative. Hepatic impairment: Avoid use; risk of lactic acidosis

Child Dose

Oral Type 2 diabetes mellitus Child: >10 yr Initially, 500 mg 1-2 times daily or 850 mg once daily, may increase gradually to max 2000 mg daily in 2 or 3 divided doses at intervals of at least 1 wk.

Renal Dose

Renal impairment Obtain eGFR before starting metformin eGFR <30 mL/min/1.73 m²: Contraindicated eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly) If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug

Administration

Should be taken with food.

Contra Indications

Acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis). Renal failure, severe renal or hepatic impairment, acute conditions which may affect renal function e.g. dehydration, severe infection or shock. Cardiac failure, CHF, IDDM, severe impairment of thyroid function; acute or chronic alcoholism. Acute or chronic diseases which may cause tissue hypoxia e.g. cardiac or respiratory failure, recent MI or shock. Pregnancy, lactation.

Precautions

Caution when used in patients with CHF especially in those with unstable or acute heart failure. Risk of lactic acid accumulation increases with the degree of renal impairment. May need to discontinue treatment in patients with stress-related states e.g. fever, trauma, infection or surgery. Metformin should be temporarily discontinued for 48 hr in patients undergoing radiologic studies involving intravascular admin of iodinated contrast materials. Elderly. Monitor renal function regularly. Because of possibility of hypoglycemia in combination therapy with a sulphonylurea or insulin, diabetic control should be monitored by blood sugar readings. Lactation: Enters breast milk; not recommended

Pregnancy-Lactation

Pregnancy Limited data with in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage; published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk; poorly-controlled diabetes mellitus in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications; poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity Human data Published data from post-marketing studies have not reported clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when used during pregnancy; however, these studies cannot definitely establish absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups Animal data Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day; this represents exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively; determination of fetal concentrations demonstrated a partial placental barrier to metformin Reproduction potential Discuss potential for unintended pregnancy with premenopausal women as therapy may result in ovulation in some anovulatory women Lactation Limited published studies report that metformin is present in human milk; however, there is insufficient information to determine effects of metformin on breastfed infant and no available information on effects of metformin on milk production; therefore, developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from the underlying maternal condition

Interactions

Additive effect w/ sulfonylureas. Thiazide diuretics, corticosteroids, phenothiazines, OC, sympathomimetics, niacin, Ca channel blockers and isoniazid may exacerbate loss of glycaemic control. ACE inhibitors may reduce fasting blood glucose concentrations. May increase serum level w/ cimetidine. Potentially Fatal: Concurrent use w/ iodinated contrast agents may increase the risk of metformin-induced lactic acidosis.

Side Effects

Side effects of Metformin Hydrochloride : Anorexia, nausea, vomiting, diarrhoea, wt loss, flatulence, occasional metallic taste; weakness; hypoglycaemia; rash, malabsorption of vit B12. Chest discomfort, flushing, palpitation, chills, headache, lightheadedness, indigestion, abdominal discomfort. Potentially Fatal: Lactic acidosis in presence of renal failure and alcoholism. Patients may experience a metallic taste and there may be weight loss, which in some diabetics could be an advantage.

Mode of Action

Metformin is a biguanide w/ antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It decreases hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; delays intestinal absorption of glucose; and enhances insulin sensitivity by increasing peripheral glucose uptake and utilisation.