Metformin 500mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metformin 500mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains metformin hydrochloride 500mg.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
White coloured, film-coated, round biconvex tablets embossed with ‘M 500’ on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic 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,metformin 850mg tablets 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, Metformin tablets may be used as monotherapy or in combination with insulin.
A reduction of diabetic complications has been shown in overweight type 2 diabetic patients treated with metformin as first-line therapy after diet failure (see 5.1 pharmacodynamic properties).
4.2 Posology and method of administration
Adults:
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 3g daily, taken as 3 divided doses.
• If transfer from another oral anti-diabetic 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.
Elderly: Due to 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)
Children and adolescents:
Monotherapy and combination with insulin
• Metformin 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 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.
4.3 Contraindications
• Hypersensitivity to metformin hydrochloride 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 (see section 4.4)
• 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
4.4 Special warnings and precautions for use 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 5mmol/L and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, Metformin hydrochloride should be discontinued and patient should be hospitalised immediately (see section 4.9).
Renal Function:
As metformin is excreted by the kidneys, 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 iodine contrast agent:
As the intravenous administration of iodinated contrast material in radiologic studies can lead to renal failure, metformin should be discontinued prior to, or at the time of the test and not to be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5)
Surgery:
Metformin Hydrochloride should 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 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 to 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.
• Metformin alone never causes hypoglycaemia, although caution is
advised when it is used in combination with insulin and sulfonylureas.
4.5 Interaction with other medicinal products and other forms of interaction Concomitant use not recommended:
Alcohol
Increased risk of lactic acidosis in acute intoxication, particularly in case of :
• fasting or malnutrition
• hepatic insufficiency
Avoid consumption of alcohol and alcohol-containing medications.
Iodinated contrast agents (see section 4.4)
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 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 the 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.
4.6 Fertility, pregnancy and lactation Fertility, pregnancy and lactation
To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or foetal development, parturition or postnatal development (see section 5.3)
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 foetal malformations associated with abnormal blood glucose levels.
Metformin is excreted into milk in lactating rats. Similar data is 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.
4.7 Effects on Ability to Drive and Use Machines
Metformin monotherapy does not cause hypoglycaemia and therefore has no effect 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 (sulfonylureas, insulin, repaglinide)
4.8 Undesirable effects
The following undesirable effects may occur under treatment with metformin hydrochloride. Frequencies are defined as follows: very common: 1/10; common>1/100, <1/10; uncommon> 1/1,0000, <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 disturbance
Gastrointestinal 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 Hydrochloride 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, urticaria
Metabolism and nutrition disorders:
Very rare: Lactic acidosis (see section 4.4).
Decrease of vitamin B12 absorption with decrease of serum levels during long term use of metformin hydrochloride. Consideration of such aetiology is recommended if a patient present with megaloblastic anaemia.
Hepatobiliary disorders:
Not known: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin hydrochloride discontinuation.
In published and post marketing data and in controlled climical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse events 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 products 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 has not been seen with metformin doses up to 85g, 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Biguanide oral hypoglycaemic agents-ATC code: A10BA02
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and post-prandial 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 (GLUTs) known to date.
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 triglycerides levels.
Clinical Efficacy:
The prospective randomised (UKPDS) study has established long-term benefit of intensive blood glucose control in type 2 diabetes.
Analysis of the results of the overweight patients treated with metformin after failure of diet alone showed:
• A significant reduction of the absolute risk of any diabetes-related complications in metformin group (29.8 events/1000 patients-years) versus diet alone (43.3 events/1000 patient-years), p= 0.0023, and versus the combined sulphonylurea and insulin monotherapy groups(4.01 events/1000 patients-years), p=0.0034.
• A significant reduction of the absolute risk of the diabetes-related mortality: Metformin hydrochloride 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-year, p=0.017
• A significant reduction of the absolute risk of overall mortality: metformin hydrochloride 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 hydrochloride 11 events/1000 patients-years, diet alone 18 events/1000 patients-years (p=0.01)
Benefit regarding clinical outcome has not been shown for metformin hydrochloride used as secondline therapy, in combination with a sulfonylurea.
In type I 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.
5.2 Pharmacokinetic properties
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 5060% 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 usual metformin doses and the dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1pg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4pg/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride.
Following administration of a dose of 850mg, 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 was 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 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 urine. No metabolites has been identified in humans.
Elimination:
Renal clearance of metformin is >400ml/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.
Children and adolescents:
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 titrated based on glycaemic control, this is of limited clinical relevance.
5.3 Preclinical Safety Data
Preclinical data reveals no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core
Sodium starch glycollate Maize starch Povidone
Colloidal anhydrous silica Magnesium Stearate
Film-coating Hypromellose Titanium dioxide (E171)
Propylene Glycol Macrogol 6000 Purified talc
6.2. Incompatibilities
Not applicable
6.3. Shelf life
3 Years
6.4
Special precautions for storage
Do not store above 25 °C. Store in the original package. Keep the containers tightly closed.
6.5. Nature and contents of container
Blister: Transparent PVC /PVdC/Aluminium foil. Packs of 28, 84 and 504’s tablets in a carton
Opaque PVC /PVdC/Aluminium foil. Packs of 28, 84 and 504’s tablets in a carton
Plastic securitainers with a tamper proof closures; 500 tablets Not all pack sizes may be marketed.
6.6. Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Milpharm Limited,
Ares,
Odyssey Business Park,
West End Road,
South Ruislip HA4 6QD,
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 16363/0111
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19/02/2009
10 DATE OF REVISION OF THE TEXT
27/11/2015