Metformin Tablets 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metformin Tablets 500mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Metformin Hydrochloride 500 mg Excipient with known effect:
Lactose.
For a full list of excipients see section 6.1.
3. PHARMACEUTICAL FORM
Film-Coated Tablet
Biconvex white film-coated tablet marked MP8 on one side and METF 500 mg on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of type 2 (maturity onset) diabetes mellitus, particularly in overweight patients when dietary management and exercise alone has failed to result in adequate glycaemic control
Metformin may be used as monotherapy or;
• In adults; in combination with other oral anti-diabetic agents or with insulin
• In children from 10 years of age and adolescents: in combination with insulin
Obese diabetic patients who are not well controlled on insulin but who are insulin-dependent may occasionally benefit when Metformin is used as an adjunct.
4.2 Posology and method of administration
Posology
Adults:
Monotherapy and combination with other oral antidiabetic agents:
The usual starting dose is one 500 mg tablet 2 or 3 times a day to be taken with or after meals. After 10-15 days should control of diabetes be incomplete, based on blood glucose measurements, a gradual increase in dosage to a maximum of 3 g daily in 3 divided doses taken together with meals may be instituted. This dosage regimen should not be increased above 3 g.
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 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.
Paediatric population:
Over 10 years of age, and adolescents; Monotherapy and combination with insulin
The usual starting dose is one tablet (500 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.
Under 10 years of age:
Not recommended.
Elderly:
Metformin, while indicated in the elderly, due to the potential for decreased renal function, the dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section 4.4).
Renal impairment:
Metformin may be used in patients with moderate renal impairment, stage 3a (creatinine clearance [CrCl] 45- 59 mL/min or estimated glomerular filtration rate [eGFR] 45 -59 mL/min/1.73m ) only in the absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments:
The starting dose is 500 mg or 850 mg metformin hydrochloride, once daily. The maximum dose is 1000 mg daily, given as 2 divided doses. The renal function should be closely monitored (every 3-6 months). If CrCl or eGFR fall <45 ml/min or <45 ml/min/1.73m respectively, metformin must be discontinued immediately.
Method of administration
Oral
4.3 Contraindications
• Chronic liver disease, acute or chronic alcoholism
• Impaired renal function (creatinine clearance < 45 mL/min or eGFR < 45 mL/min/1.73m2) including proteinuria; if this is suspected Metformin should be withdrawn.
• Acute or chronic disease which may cause tissue hypoxia such as;
o Cardiac failure even if controlled o Recent myocardial infarction o Those conditions associated with hypoxaemia.
o Peripheral vascular disease.
o History of or conditions associated with lactic acidosis such as shock or pulmonary insufficiency
• Diabetic pre-coma, ketoacidosis or history of ketoacidosis
• Acute conditions with the potential to alter renal function such as;
o Severe infection or trauma o Dehydration o Shock
o Intravascular administration of iodinated contrast agents (see section 4.4)
• Lactation
• Hypersensitivity to the drug, Metformin hydrochloride or any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Lactic acidosis:
Lactic acidosis is a very 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 impaired renal failure or acute worsening of renal function. Special caution should be paid to situations where renal function may become impaired, for example in case of dehydration (severe diarrhoea or vomiting), or when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal antiinflammatory drug (NSAID). In the acute conditions listed, metformin should be temporarily discontinued.
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 (such as decompensated cardiac failure, acute myocardial infarction) (see also section 4.3).
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. Patients should be instructed to notify these signs immediately to their physicians if they occur, notably if patients had a good tolerance to metformin before. Metformin should be discontinued, at least temporarily, until the situation is clarified. Reintroduction of metformin should then be discussed taking into account the benefit/risk ratio in an individual basis as well as renal function.
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).
Physicians should alert the patients on the risk and on the symptoms of lactic acidosis.
Renal function:
Regular monitoring of renal function should be undertaken as Metformin is renally excreted. Serum creatinine levels (this can be estimated from serum creatinine levels by using Cockcroft-gault formula) or eGFR 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 lower limit of normal and in elderly subjects.
In case CrCl is <45 ml/min (eGFR < 45 ml/min/1.73m2), metformin is contraindicated (see section 4.3).
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. Particular care is required with elderly patients who are more likely to have diminished renal function, which may be asymptomatic.
Metformin should not be used in conditions which may cause dehydration. Cardiac function
Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, metformin is contraindicated (see section 4.3).
Administration of iodinated contrast media
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore in patients in whom any such studies are planned, Metformin should be discontinued at the time of, or prior to, the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal (see section 4.5).
In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m2), metformin must be discontinued 48 hours before administration of iodinated contrast media and not be reinstituted until at least 48 hours afterwards and only after renal function has been re-evaluated and has not deteriorated further (see section 4.5).
Surgery:
Metformin hydrochloride should be discontinued 48 hours before elective surgery with general, spinal or peridural anaesthesia. Therapy should not be usually resumed earlier than 48 hours afterwards or resumption of oral nutrition and only if normal renal function has been established.
Paediatric population:
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 prepubescent 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:
• In any of the above conditions Metformin should be temporarily suspended and particularly if acidosis is suspected. Only after lactic acidosis or ketoacidosis have been excluded should treatment be resumed.
• 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.
• Annual measurement of vitamin BJ2 in patients on continuous therapy since reduced BJ2 has been reported.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Precaution must be taken with medicinal products with intrinsic hyperglycaemic activity and more frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon its discontinuation. There may be interactions between Metformin and
- Anticoagulants: prothrombin time should be monitored; accordingly patients receiving the two drugs may need adjustment of the anticoagulant dosage.
- Sulphonylurea: possibly enhance the hypoglycaemia.
- Alcohol: enhances the hypoglycaemic effect and increases the risk of lactic acidosis, particularly in case of fasting or malnutrition, hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medicinal product.
- Insulin: therapy stabilisation should be carried out in hospital, blood glucose levels should be monitored; possibly enhance the hypoglycaemic effect.
- Cimetidine: reduced renal clearance of Metformin has been reported and accordingly a dose reduction should be considered.
- ACE inhibitors: possibly enhance the hypoglycaemic effect.
- Anti-depressants: MAOIs enhance the hypoglycaemic effect.
- Anti-hypertensives: diazoxide may antagonise the hypoglycaemic effect; beta-blockers enhance the hypoglycaemic effect and can mask warning signs such as tremor.
- Corticosteroids: antagonism of hypoglycaemic effect.
- Oral contraceptives: antagonism of hypoglycaemic effect.
- Diuretics: antagonism of hypoglycaemic effect by loop diurectics. Also increased risk of lactic acidosis due to their potential to decrease renal function.
- Clofibrates: may improve glucose tolerance and have an additive effect.
- Iodinated contrast media: Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin accumulation and an increased risk of lactic acidosis.
In patients with eGFR > 60 ml/min/1.73m ,metformin must be discontinued prior to, or at the time of the test and not be reinstituted until at least 48 hours afterwards, and only after renal function has been reevaluated and has not deteriorated further (see section 4.4).
In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m ), metformin must be discontinued 48 hours before administration of iodinated contrast media and not be reinstituted until at least 48 hours afterwards and only after renal function has been reevaluated and has not deteriorated further.
4.6 Fertility, pregnancy and lactation
Pregnancy
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.
Metformin should not be used in pregnancy unless there are compelling reasons for its use. Insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.
A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).
Breast-feeding
Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, do not use during lactation unless considered absolutely essential. A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effects on the child.
Fertility
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
4.7 Effects on ability to drive and use machines
Metformin monotherapy does not cause hypoglycaemia and therefore has no known effects on the ability to drive or to use machines.
However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulphonylureas, insulin, repaglinide).
4.8 Undesirable effects
During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take metformin in 2 or 3 daily doses and to increase slowly the doses.
The following adverse events 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) including isolated reports, not known (cannot be estimated from the available data)]
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Metabolism and nutrition disorders
Very rare:
Lactic acidosis (see section 4.4)
Decrease vitamin BJ2 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.
Not known: Anorexia
Nervous system disorders
Common: Taste disturbance
Hepato-biliary disorders
Very rare: Isolated reports of abnormal liver functional tests, hepatitis (resolving upon discontinuation)
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritus, urticaria
Gastrointestinal disorders
Very Common: Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite
While Metformin is usually well tolerated, gastro-intestinal disturbances sometimes occur and although they are usually minor they can normally be avoided by taking Metformin with or after food. It may, however, be necessary temporarily to lower the dose of Metformin. Metformin treatment should not be abandoned at the first sign of intolerance because this has been found to resolve spontaneously. Normally, gastrointestinal upsets disappear within the period which diabetic control is achieved. It is unusual for such symptoms to return and if they do, an alternative cause such as lactic acidosis should be suspected.
Paediatric population
In 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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard
4.9 Overdose
Hypoglycaemia does not occur if Metformin is taken alone in overdosage, (up to 85g), but it can occur when Metformin is given concomitantly with a sulphonylurea, insulin or alcohol. In excessive dosage lactic acidosis may develop. Lactic acidosis is a medical emergency and must be treated in hospital.
The treatment includes intensive supportive therapy and correcting fluid loss and metabolic disturbance. The most effective method to remove lactate and metformin is haemodialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Blood glucose lowering drugs. Biguanides; ATC code: A10BA02
Mechanism of action
Metformin is a biguanide oral anti-hyperglycaemic agent which lowers both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via 3 mechanisms:
• reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
• in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation.
• 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 (GLUTs) known to date.
Pharmacodynamic effects
In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.
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 study (UKPDS) has established the long-term benefit of intensive blood glucose control in adult patients with 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 sulfonylurea 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 sulfonylurea 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).
Benefit regarding clinical outcome has not been shown for metformin used as second-line therapy, in combination with a sulfonylurea.
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.
Paediatric population
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.
5.2 Pharmacokinetic properties
Absorption
After an oral dose of metformin hydrochloride tablet, maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride 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 is non-linear.
At the recommended metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following oral administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings 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 volume of distribution (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.
Characteristics in specific groups of patients Renal impairment
The available data in subjects with moderate renal insufficiency are scarce and no reliable estimation of the systemic exposure to metformin in this subgroup as compared to subjects with normal renal function could be made. Therefore, the dose adaptation should be made upon clinical efficacy/tolerability considerations (see section 4.2).
Paediatric population
Single dose study: After single doses of metformin hydrochloride 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 twice daily 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 twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose
Silica, colloidal anhydrous Gelatin
Sodium starch glycollate Purified Water Magnesium Stearate Hypromellose Ethylcellulose Titanium Dioxide E171 Diethylphthalate
6.2. Incompatibilities
Not applicable.
6.3. Shelf Life
36 months for all packs.
6.4. Special Precautions for Storage
Blister packs: Do not store above 25°C. Store in the original package. Containers: Do not store above 25°C. Keep the container tightly closed.
6.5. Nature and Contents of Container
High density polystyrene containers with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polyurethane/polythene inserts.
Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000.
250 micron PVC glass-clear/bluish rigid PVC (pharmaceutical grade). 20 micron hard-tempered aluminium foil coated on the dull side with 6-7 gsm heat seal lacquer and printed on the bright side.
Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000.
6.6
7.
8.
9
10
Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
MARKETING AUTHORISATION HOLDER
Metwest Pharmaceuticals Limited
15 Runnelfield
Harrow on the Hill
Middlesex
HA1 3NY
United Kingdom
MARKETING AUTHORISATION NUMBER(S) PL 17521/0008
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/01/2009