Glucophage® 850 mg

GLUCOPHAGE® 850 mg
Summary of product characteristics


1. NAME OF THE MEDICINAL PRODUCT
GLUCOPHAGE® 850 mg film-coated tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION OF THE ACTIVE
INGREDIENT
Each film-coated tablet of GLUCOPHAGE® 850 mg contains metformin hydrochloride 850
mg corresponding to metformin base 663 mg.
3. PHARMACEUTICAL FORM
Film-coated tablet.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Treatment of type 2 diabetes mellitus, when dietary management and exercise alone does not
result in adequate glycemic control.
·
In adults, GLUCOPHAGE® 850 mg film-coated tablet 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, GLUCOPHAGE® 850 mg film- coated tablet 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 5.1
Pharmacodynamic properties).
In Type 1 diabetes, GLUCOPHAGE® may be given as an adjuvant to patients whose diabetic
are poorly controlled.
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.
Children and adolescents
Monotherapy and combination with insulin
·
GLUCOPHAGE® 850 mg film-coated tablet can be used in children from 10 years of The usual starting dose is one tablet of 500 mg or 850 mg once daily, given during 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 (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 4.4 Warnings and special
precautions for use).
- 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 special 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 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.
- Metformin alone never causes hypoglycaemia, although caution is advised when it is used in
combination with insulin or sulfonylureas.
- 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).

4.5. Interaction with other medicinal products and other forms of interaction
Inadvisable combinations
Alcohol
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.
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.

4.6. 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 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 are not available in humans and
a decision should be made whether to discontinue nursing or to discontinue metformin, taking
into account the compound to the mother.
4.7. Effects on ability to drive and to use machines
GLUCOPHAGE® 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 reports.
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 megaloblastic anaemia.
very rare: Lactic acidosis (see 4.4. Special warnings and precautions for use).
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 tests 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 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
ORAL ANTI-DIABETICS
(A10BA02: Gastrointestinal tract and metabolism) 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 and (3) 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 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 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.
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
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.

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 nonlinear. 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
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, toxicity
reproduction.

6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Polyvidone K30, magnesium stearate, hypromellose (film-coating), q.s. one film coated tablet
of 899.3 mg.

6.2. Shelf-life
5 years

6.3. Special precautions for storage
Store below 25 ºC
6.4. Instructions for use, handling and disposal
No special requirements

6.5. Packing
50, 100 & 500 tablets in blister packs (PVC- aluminium)
Not all package sizes may be sold
7. NAME & ADDRESS OF MANUFACTURER
Merck Santé s.a.s.
2 rue du Pressoir vert
45400 SEMOY - FRANCE

Source: http://www.diabetes.org.my/file_dir/8258219424626608fda153.pdf