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SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

Metformin 500 mg Tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 500 mg corresponding to 390 mg of metformin.
For a full list of excipients, see section 6. 1.
3. PHARMACEUTICAL

Film-coated tablet.
White to off-white film-coated oval shaped tablet, debossed with “93” on one side and “48”
on the other.
4. CLINICAL
PARTICULARS

4.1. Therapeutic indications
Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when
dietary management and exercise alone does not result in adequate glycaemic control.
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 (see section 5. 1.).
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 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 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 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).
Children & adolescents:

Monotherapy and combination with insulin
-
Metformin 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.
4.3. Contraindications
-
Hypersensitivity to metformin hydrochloride or to any of the excipients. Diabetic ketoacidosis, diabetic pre-coma. Renal failure or renal dysfunction (e.g., creatinine clearance < 60 ml/min). Acute conditions with the potential to alter renal function such as: intravascular administration of iodinated contrast agents (see section 4.4) Acute or chronic disease which may cause tissue hypoxia such as: Hepatic insufficiency, acute alcohol intoxication, alcoholism
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:
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).
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 radiological 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 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.
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 & 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 or sulphonylureas.
4.5. Interaction with other medicinal products and other forms of interaction
Concomitant use not recommended

Alcohol
Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of
-
Avoid consumption of alcohol and alcohol-containing medicinal products.
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 treatment. If necessary, adjust the dosage of the
antidiabetic medicinal product during therapy with the other medicinal product and upon its
discontinuation.
ACE-inhibitors
ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the
antidiabetic medicinal product during therapy with the other medicinal product and upon its
discontinuation.
4.6. Pregnancy and lactation
To date, no relevant epidemiological data are available. Animal studies do not indicate
harmful effects with respect to pregnancy, embryonic or foetal development, parturition or
postnatal development (see also 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 (sulphonylureas, insulin, repaglinide).
4.8. Undesirable effects
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 and isolated cases.
Metabolism and nutrition disorders
Very rare: Decrease 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 megaloplastic anaemia.
Very rare: Lactic acidosis (see section 4.4.).
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 be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose
may also improve gastrointestinal tolerability.
Hepatobiliary disorders
Isolated reports: Liver function test abnormalities or hepatitis resolving upon metformin
discontinuation.
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritus, urticaria.
In published and post marketing data and in controlled clinical studies in a limited paediatric
population aged between 10 – 16 years treated during 1 year, adverse event reporting was
similar in nature and severity to that reported in adults.


4.9. Overdose

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.
5. PHARMACOLOGICAL
PROPERTIES

5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Oral blood glucose lowering drugs, biguanides
ATC code: A10BA02

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, 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.
5.2. Pharmacokinetic properties
Absorption:
After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a
500 mg or 850 mg 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 is 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 mgn 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
7days 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

Preclinical data reveal no special hazard for humans based on conventional studies on safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity
reproduction.
6. PHARMACEUTICAL
PARTICULARS

6.1. List of excipients
Core
Povidone K30
Povidone K90
Anhydrous colloidal silica
Magnesium stearate
Coating
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400.
6.2. Incompatibilities
Not applicable
6.3. Shelf-life
3 years
6.4. Special precautions for storage

This medicinal product does not require any special storage conditions.
6.5. Nature and contents of the container

PVC/PVdC/aluminium blisters.
Pack sizes: 20, 28, 30, 50, 56, 60, 84, 90, 100, 120, 200 & 500 film-coated tablets.
Not all pack sizes may be marketed.
6.6. Special precautions for disposal

No special requirements
MARKETING AUTHORISATION HOLDER
TEVA UK Limited
Brampton Road
Hampden Park
Eastbourne
East Sussex, BN22 9AG
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
04/08/00
10. DATE OF REVISION OF THE TEXT

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