- metformin hydrochloride
POM: Prescription only medicine
This information is intended for use by health professionals
Monotherapy and combination with other oral antidiabetic agents:• The usual starting dose is one tablet 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. The maximum recommended dose of metformin is 3 g daily.• If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin at the dose indicated above.
Combination with insulinMetformin and insulin may be used in combination therapy to achieve better blood glucose control. Metformin is given at the usual starting dose of one tablet 2-3 times 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 (see section 4.4 Special warnings and precautions for use).
Children and adolescents
Monotherapy and combination with insulin:• Metformin film-coated tablets can be used in children from 10 years of age and adolescents. • The usual starting dose is one tablet of 500 mg or 850 mg once daily, given during meals 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 is 2 g daily, taken as 2 or 3 divided doses.
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: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 (see section 4.9 Overdose).
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 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.
Surgery:Metformin hydrochloride should be discontinued 48 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards.
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 metformin efficacy and safety in children below 12 did not differ from efficacy and safety in older children, 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.• Metormin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulphonylureas.
Concomitant use not recommended
Alcohol:Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:• fasting or malnutrition• hepatic insufficiencyAvoid consumption of alcohol and alcohol-containing medications.
Iodinated contrast agents (see section 4.4 Special warnings and precautions for use):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.
Combinations requiring precautions for useGlucocorticoids (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.
Gastrointestinal Disorders:Very common: Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite are very common: these occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, 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.
Nervous system disorders:Common: Taste disturbance Metabolism and nutrition disorders:Very rare: Decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin and appears generally to be without clinical significance. Consideration of such aetiology is recommended if a patient presents with megaloplastic anaemia.Lactic acidosis is very rare (see 4.4 Special warnings and precautions for use).
Skin and subcutaneous tissue disorders:Very rare: Skin reactions such as erythema, pruritus, urticariaIn 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.
Hepatobiliary disorders:Isolated reports: Liver function test abnormalities or hepatitis resolving upon metformin discontinuation .
Pharmacotherapeutic group: Oral blood glucose lowering drugs, A10B A02Metformin 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, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
Clinical efficacy:The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes.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.Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.
Absorption:After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500mg or 850mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are non-linear.At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/ml, even at maximum doses.Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Distribution:Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.
Metabolism:Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination:Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Paediatrics:Single dose study: After single doses of metformin 500 mg, paediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg BID for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg BID for 14 days. As the dose is individually titratedbased on glycaemic control, this is of limited clinical relevance.
CoreSodium starch glycollateMaize starchPovidoneColloidal anhydrous silicaMagnesium stearate
Film-coatingMethylhydroxypropylcelluloseTitanium dioxide E 171Propylene glycolMacrogol 6000Purified talc