Drug Class Description
Biguanides.

Generic Name
Metformin

Drug Description
Each 500mg sachet contains 500 mg metformin hydrochloride corresponding to 390 mg metformin base.Each 1000mg sachet contains 1000 mg metformin hydrochloride corresponding to 780 mg metformin base.Excipients: contains aspartame.

Presentation
Powder for oral solution. White, odourless powder

Indications
Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.• In adults, Glucophage may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin.• In children from 10 years of age and adolescents, Glucophage may be used as monotherapy or in combination with insulin. A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with metformin as first-line therapy after diet failure.

Adult Dosage
Monotherapy and combination with other oral antidiabetic agents:The usual starting dose is 500 mg or 850mg metformin hydrochloride 2 or 3 times daily given during or after meals.After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. In patients receiving a high metformin hydrochloride dose (2 to 3 grams per day), it is possible to replace two Glucophage 500 mg doses with one Glucophage 1000 mg dose.The maximum recommended dose of metformin hydrochloride is 3 g daily, taken as 3 divided doses.If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin at the dose indicated above.Combination with insulin:Metformin and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of 500 mg or 850mg 2 or 3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Child Dosage
Monotherapy and combination with insulinGlucophage can be used in children from 10 years of age and adolescents. The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during or after meals. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.Preparation:The powder should be poured into a glass and 150 ml water should be added to obtain a clear to slightly opalescent solution. The solution should be taken immediately after being prepared. If necessary, the solution may be stirred.

Elderly Dosage
Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Contra Indications
Hypersensitivity to metformin or to any of the excipients. Diabetic ketoacidosis, diabetic pre-coma. Renal failure or renal dysfunction (creatinine clearance < 60 ml/min). Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents. Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock. Hepatic insufficiency, acute alcohol intoxication, alcoholism. Lactation.

Special Precautions
Lactic acidosis: Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. Diagnosis: The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders as abdominal pain and severe asthenia. Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately.Renal function:As metformin is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:at least annually in patients with normal renal function,at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug.Administration of iodinated contrast agent:As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal.Surgery:Metformin must be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function has been established.Children and adolescents:The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated.No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children, is recommended.Children aged between 10 and 12 years:Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.Other precautions:All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.The usual laboratory tests for diabetes monitoring should be performed regularly.Metformin alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or sulfonylureas.Glucophage powder for oral solution contains aspartame, a source of phenylalanine. It is recommended to consider this fact before treatment is initiated in patients with phenylketonuria.

Interactions
Concomitant use not recommended:Alcohol:Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of:fasting or malnutrition, hepatic insufficiency.Avoid consumption of alcohol and alcohol-containing medicinal product.Iodinated contrast agents:Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and an increased risk of lactic acidosis.Metformin must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal.Combinations requiring precautions for use:Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabeticmedicinal product during therapy with the other medicinal product and upon its discontinuation.ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin may be necessary during and after addition or discontinuation of such medicinal products.

Adverse Reactions
The following undesirable effects may occur under treatment with metformin. Frequencies are defined as follows: very common: 1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000, not known (cannot be estimated from the available data).Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Nervous system disorders:Common: Taste disturbanceGastrointestinal disorders:very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.Skin and subcutaneous tissue disorders:very rare: Skin reactions such as erythema, pruritus, urticariaMetabolism and nutrition disorders:very rare: Lactic acidosisDecrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.Hepatobiliary disorders:very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.Children and adolescentsIn published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

Manufacturer
Merck

Drug Availability
(POM)

Updated
26 June 2009