Glucophage XR 500mg. 750mg. 1000mg Tablet

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone do not result in adequate glycaemic control. Glucophage XR can be given alone as initial therapy or can be administered in combination with other oral antidiabetic agents or with insulin.

Glucophage XR 500 mg: The usual starting dose 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 dosage is 4 tablets daily. Dosage increases should be made in increments of 500 mg every 10 to 15 days, up to a maximum of 2000 mg once daily with an evening meal. If glycaemic control is not achieved with Glucophage XR 500 mg 4 tablets once daily, Glucophage XR 500mg 2 tablets twice daily should be considered, with both doses given with food. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000 mg daily.

Glucophage XR 750 mg: The usual starting dose 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 recommended dosage is 2 tablets once daily, with the evening meal. If glycaemic control is not achieved with Glucophage XR 750 mg 2 tablets once daily Glucophage XR 750 mg may be increased to a maximum dose of 3 tablets once daily with the evening meal. If glycaemic control is not achieved on Glucophage XR 750 mg 3 tablets once daily, one tablet of Glucophage XR 750 mg in the morning and two tablets of Glucophage XR 750 mg in the evening should be considered, with both doses being given with food. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000 mg daily.

Glucophage XR 1000 mg: Glucophage XR 1000 mg is intended as maintenance therapy for patients already treated with either 1000 mg (2 tablets of Glucophage XR 500) or 2000 mg (4 tablets of Glucophage XR 500) of sustained release metformin hydrochloride. If glycaemic control is not achieved, patients may be switched to standard metformin hydrochloride tablets to a maximum daily dose of 3000 mg daily.

Switching patients already treated with metformin tablets: In patients already treated with metformin tablets, the starting dose of Glucophage XR prolonged release tablets should be equivalent to the daily dose of metformin immediate release tablets. In patients treated with metformin at a dose above 2000 mg daily, switching to Glucophage XR prolonged release tablets is not recommended.

Switching patients from other oral antidiabetic agents: If transfer from another oral antidiabetic agent is intended, discontinue the other agent and initiate Glucophage XR prolonged release tablets at the doses indicated above.

Combination therapy with insulin: Glucophage XR prolonged release tablets and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose is Glucophage XR 500 mg once daily with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements. After titration, switch to Glucophage XR 1000 mg may be considered.

Other combination therapy: See Warnings and special precautions.

Elderly: Due to the potential for decreased renal function in elderly subjects, the dosage for the Glucophage XR range should be adjusted based on renal function. Regular assessment of renal function is necessary. (See Warnings and special precautions.)

Children: In the absence of available data, the Glucophage XR range should not be used in children.

• Hypersensitivity to metformin hydrochloride or any of the other ingredients.
• Diabetic ketoacidosis, diabetic pre-coma.
• Renal failure or renal dysfunction (creatinine clearance < 60 ml/min).
• Acute conditions with the potential to alter renal function e.g. dehydration, severe infection, shock, intravascular administration of iodinated contrast media.
• Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, pancreatitis, recent myocardial infarction, shock.
• Hepatic insufficiency, acute alcohol intoxication, alcoholism (acute or chronic).
• The use of Glucophage XR during pregnancy is not advised.

Lactic acidosis: Lactic acidosis is associated with the use of Glucophage XR range. Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to Glucophage XR administration. In patients presenting with a metabolic acidosis and not having evidence of ketoacidosis (ketonuria and ketonaemia), lactic acidosis should be suspected and Glucophage XR range therapy should be stopped. Lactic acidosis is a medical emergency, which must be treated in hospital. Glucophage XR range is excreted by the kidney and regular monitoring of renal function is advised in all diabetic patients with type 2 diabetes mellitus. The incidence of lactic acidosis may be reduced by assessing also other associated risk factors such as poorly controlled diabetes mellitus, type 2: ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Diagnosis: Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by a coma. Diagnostic laboratory findings include a decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, Glucophage XR should be discontinued and the patient should be hospitalised immediately.

Renal function: As Glucophage XR 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 a NSAID. Glucophage XR range therapy should be stopped 2-3 days before surgery and before clinical investigations such as intravenous urography and intravenous angiography, and reinstated only after control of renal function has been regained.

The use of Glucophage XR formulations is not advised in conditions which may cause dehydration, or in patients suffering from serious infections, trauma or on low calorie intake.

Patients on long-term treatment with Glucophage XR formulations should have an annual estimation of vitamin B12 levels, since Glucophage XR range may cause mal-absorption of vitamin B12, which may result in megaloblastic anaemia.

Administration of iodinated contrast agent: As the intravascular administration of iodinated contrast materials in radiological studies (such as intravenous urography and intravenous angiography) can lead to renal failure, Glucophage XR 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: Glucophage XR should be discontinued 48 hours before elective surgery with general anaesthesia and should not be resumed earlier than 48 hours afterwards. During concomitant treatment with a sulphonylurea, blood glucose should be monitored because combination therapy may cause hypoglycaemia. Stabilisation of diabetic patients with Glucophage XR and insulin should be carried out in hospital because of the possibility of hypoglycaemia until the ratio of the two medicines has been obtained (see Contra-Indications). Contraindications should be carefully observed.

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. The tablet shells may be present in the faeces. Patients should be advised that this is normal.

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 Glucophage XR accumulation and a risk of lactic acidosis. Glucophage XR 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. Medical practitioners should inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, the dosage of the antidiabetic medicines should be adjusted during therapy with the other medicine and upon its discontinuation.
• ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the antidiabetic medicine should be adjusted during therapy with the other medicine and upon its discontinuation.
• Cimetidine: Reduced renal clearance of Glucophage XR has been reported during cimetidine therapy, so a dose reduction should be considered.
• Anticoagulants: Glucophage XR has been reported to diminish the activity of warfarin, and so dose adjustments and increased frequency of INR determinations should be considered.
• Sulphonylurea: Concomitant therapy of Glucophage XR with sulphonylurea may cause hypoglycaemia.
• Vitamins: Long-term treatment with Glucophage XR may cause vitamin B12 mal-absorption in the gastro-intestinal tract, thus a dose reduction of Glucophage XR should be considered.

The use of Glucophage XR during pregnancy is not advised. There is no information available concerning the safety of Glucophage XR during lactation.

Glucophage XR monotherapy does not cause hypoglycaemia and therefore is not expected to have an effect on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycaemia when Glucophage XR range is used in combination with other antidiabetic agents such as (sulphonylureas, insulin, repaglinide).

Side-effects: Adverse reactions reported are listed below by system organ class and by frequency. Frequencies are defined as: very common (> 1/10), common (> 1/100, 1/1000, < 1/100), rare (< 1/10 000), 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 the Glucophage XR range. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia. Lactic acidosis (see Warnings and Special Precautions).

Nervous system disorders: Common: Taste disturbance.

Gastro-intestinal disorders: Very common: Nausea, vomiting, diarrhoea, abdominal pain and loss of appetite.

Hepato-biliary disorders: Isolated reports: Liver function test abnormalities or hepatitis resolving on Glucophage XR range discontinuation.

Skin and subcutaneous tissue disorders: Very rare: Skin reactions such as erythema, pruritus and urticaria.

Hypoglycaemia can occur when Glucophage XR range is given concomitantly with a sulphonylurea, insulin or alcohol. In excessive dosage, and particularly if there is a possibility of accumulation, lactic acidosis may develop. Intense symptomatic and supportive therapy is recommended which should be particularly directed at correcting fluid loss and correcting blood glucose levels. Treatment of overdosage: There is no specific antidote for overdose with Glucophage XR range. Treatment is supportive and symptomatic and should be directed at correcting fluid loss and metabolic disturbances. Haemodialysis is the most effective way to remove lactate and metformin.