ATC subcategoryOral hypoglycemic agents
Each tablet contains:
active ingredient: metformin hydrochloride – 500 mg (equivalent to 390 mg metformin);
excipients: microcrystalline cellulose, povidone, sodium starch glycolate, magnesium stearate, maize starch.
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and Postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin may act via 3 mechanisms:
(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation
(3) and delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT). In humans, independently of its action on glycaemia, immediate-release metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: immediate-release metformin reduces total cholesterol, LDL cholesterol and triglyceride levels. A similar action has not been demonstrated with the prolonged-release formulation, possibly due to the evening administration, and an increase in triglycerides may occur.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in overweight type 2 diabetic patients treated with immediate-release metformin as first-line therapy after diet failure. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
• a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/ 1000 patient-years) versus diet alone (43.3 events/ 1000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/ 1000 patient-years), p=0.0034.
• a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/ 1000 patient-years, p=0.017;
• a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/ 1000 patient-years versus diet alone 20.6 events/ 1000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/ 1000 patient-years (p=0.021);
• a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/ 1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)
For metformin used as second-line therapy, in combination with a sulphonylurea, benefit regarding clinical outcome has not been shown.
In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
• In adults, Metformin may be used as monotherapy or in combination with other oral antidiabetic agents or with insulin.
• In children from 10 years of age and adolescents, Metformin 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.
Monotherapy and combination with other oral antidiabetic agents:
• The usual starting dose is 500 mg once daily.
• After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastro-intestinal tolerability. The maximum recommended dose is 2000 mg daily.
• Dosage increases should be made in increments of 500 mg every 10-15 days, up to a maximum of 2000 mg once daily with the evening meal. If glycaemic control is not achieved on 2000 mg of Metformin once daily, 1000 mg of Metformin twice daily should be considered, with both doses being given with food. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000 mg daily.
In patients already treated with metformin tablets, the starting dose of Metformin should be equivalent to the daily dose of metformin immediate-release tablets. In patients treated with metformin at a dose above 2000 mg daily, switching to Metformin is not recommended.
• 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. The usual starting dose of Metformin is 500 mg once daily, while insulin dosage is adjusted on the basis of blood glucose measurements.
Elderly: 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.
Children: In the absence of available data, Metformin should not be used in children.
Method of administration
The tablets should be swallowed whole with a drink of water. They should not be chewed or crushed.
Very rare: Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia.
Nervous system disorders
Common: Taste disturbance
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. A slow increase of the dose may also improve gastrointestinal tolerability.
Not known: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritus, urticaria.
Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.
• 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:
– severe infection,
– intravascular administration of iodinated contrast agents (see section 4.4).
• Acute or chronic disease which may cause tissue hypoxia such as:
– cardiac or respiratory failure,
– recent myocardial infarction,
• Hepatic insufficiency, acute alcohol intoxication, alcoholism
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.
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.
As metformin is excreted by the kidney, creatinine clearance and/or 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 creatinine clearance levels at the 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 an NSAID.
Administration of iodinated contrast agent:
As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
Metformin hydrochloride should be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy should be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if renal function has been established.
• 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 never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulphonylureas.
Each tablet contains up to 10.8mg sodium (0.5mmol) which should be taken into consideration for patients on a controlled sodium diet
To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development.
When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.
Metformin is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the compound to the mother.
Concomitant use not recommended
Avoid simultaneous administration with danazol, as it possesses hyperglycemic action. If treatment by danazol is needed, it is necessary to adjust the dosage of metformin drug during therapy by danazole and upon its discontinuation.
Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:
• fasting or malnutrition,
• hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medications.
Chlorpromazine: high-doses of chlorpromazine (100 mg daily) raise glycemia,reducing the release of insulin. If necessary, adjust the dosage of the Metformin during therapy with the other drug and upon its discontinuation.
Diuretics: concomitant use of loop diuretics could increase the risk of lactic acidosis in those with impaired renal function. Metformin should not be prescribed if creatinine clearance below 60 ml /min.
Iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis.
Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
Associations 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 antidiabetic drug during therapy with the other drug and upon its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.
Sulfonylureas, insulin, acarbose, salicylates may increase the risk of hypoglycemia.
White biconvex tablets.
10 Tablets are packed into PVC-Aluminum blister packet (inside package).
3 Blister inserted together with the leaflet into cardboard boxes (outer package).
3 years. Do not use after the expiration date.
To be dispensed with prescription.
Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.