NAME OF THE MEDICINAL PRODUCT
Glucophage XR 750mg extended release tablet
QUALITATIVE AND QUANTITATIVE COMPOSITION
One extended release tablet contains 750 mg metformin hydrochloride
corresponding to 585 mg metformin base. For a full list of excipients, see
List of excipients.
Extended release tablet
White to off-white capsule-shaped, biconvex tablet, debossed on one side
with '750' and on the other side with 'Merck'.
Treatment of type 2 diabetes mellitus in adults, when dietary management and
exercise alone does not result in adequate glycaemic control. Glucophage XR
may be used as monotherapy or in combination with other oral antidiabetic
agents, or with insulin.
A reduction of diabetic complications has been shown in overweight type 2
diabetic patients treated with immediate release metformin as first-line
therapy after diet failure (see Pharmacodynamic properties).
Posology and method of administration
Monotherapy and combination with other oral antidiabetic agents:
• The usual starting dose of Glucophage XR 750mg is one tablet daily given
with the evening meal.
• After 10 to 15 days the dose should be adjusted on the basis of blood
glucose measurements. A slow increase of dose may improve gastro-intestinal
tolerability. The maximum recommended dose is 2 tablets once daily with the
• In patients already treated with metformin tablets, the starting dose of
Glucophage XR should be equivalent to the daily dose of metformin immediate
• If transfer from another oral antidiabetic agent is intended: discontinue
the other agent and initiate Glucophage XR at the dose indicated above.
Combination with insulin:
Metformin and insulin may be used in combination therapy to achieve better
blood glucose control. The usual starting dose of Glucophage XR is one
tablet once daily with the evening meal, 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 Special
warnings and special precautions for use).
Children: In the absence of available data, Glucophage XR should not
be used in children.
• Hypersensitivity to metformin 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:
- severe infection,
• Acute or chronic disease which may cause tissue hypoxia such as:
- cardiac or respiratory failure,
- recent myocardial infarction,
• Hepatic insufficiency, acute alcohol intoxication, alcoholism
Special warnings and precautions for use
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.
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
• 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-
• a significant reduction in the absolute risk of myocardial infarction:
metformin 11 events/ 1000 patient-years, diet alone 18 events/ 1000
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.
Following a single oral administration of 1500 mg of Glucophage XR 750 mg, a
mean peak plasma concentration of 1193 ng/ml is achieved with a median value
of 5 hours and a range of 4 to 12 hours.
Glucophage XR 750 mg was shown to be bioequivalent to Glucophage XR 500
mg at a 1500 mg dose with respect to Cmax and AUC in healthy fed and fasted
The bioequivalent product shows the following properties:
At steady state, similar to the immediate release formulation, Cmax and AUC
are not proportionally increased to the administered dose. The AUC after a
single oral administration of 2000 mg of metformin extended release tablets
is similar to that observed after administration of 1000 mg of metformin
immediate release tablets b.i.d.
Intrasubject variability of Cmax and AUC of metformin extended release
tablets is comparable to that observed with metformin immediate release
When the extended release tablet is administered in fasting conditions
the AUC is decreased by 30% (both Cmax and Tmax are unaffected).
Metformin absorption from the extended release formulation is not altered
by meal composition.
No accumulation is observed after repeated administration
of up to 2000 mg of metformin extended release tablets.
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 I.
Metformin is excreted unchanged in the urine. No metabolites have been
identified in humans.
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.
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.
List of Excipients
Special precautions for storage
Protect from moisture, freezing and excessive heat.
Store below 30°C
Nature and contents of container
30 and 60 tablets in blister strips.
Not all pack sizes may be marketed.