GLUCOPHAGE

Metformin hydrochloride

Presentation

Tablets: 500mg - White to off white round biconvex film coated tablets, 11mm diameter, with GL500 debossed on one side.

Tablets: 850mg - White to off white round biconvex film coated tablets, 13.5mm diameter, with GL850 debossed on one side.

Uses

Actions

Metformin is a biguanide oral anti-hyperglycaemic agent. Does not lower blood sugar in non-diabetics and in diabetics does not cause hypoglycaemia when used alone. (In combination therapy please see Warnings and Precautions). Reduces overweight. Lowers levels of plasma insulin; cholesterol; triglycerides and pre-beta-lipoproteins. Improves glucose assimilation.

Pharmacokinetics

Absorption from GI tract is about 50-60 percent but it is thought that absorption decreases as the dose of GLUCOPHAGE increases. GLUCOPHAGE is not significantly bound to plasma proteins and is excreted almost unchanged in the urine.

Indications

Diet-failed, maturity onset diabetics especially if overweight: (a) alone as initial therapy; (b) combination therapy with a sulphonylurea.

Adjuvant therapy in insulin-dependent diabetics especially if overweight.

Dosage and Administration

It is important that GLUCOPHAGE tablets should be taken in divided doses with meals. The dose should be increased gradually. One 850mg tablet twice a day or one 500mg tablet three times a day is often enough to give good diabetic control. This may be achieved within a few days, but it is not unusual for the full effect to be delayed for up to two weeks. If control is incomplete a cautious increase in dosage to a maximum of 3g daily is justified. Once control has been obtained it may be possible to reduce the dosage.

GLUCOPHAGE therapy with a sulphonylurea or insulin should be monitored by blood-sugar readings because combined therapy may cause hypoglycaemia. If it is decided to stabilise diabetic patients with GLUCOPHAGE and insulin therapy it is recommended that this is carried out in hospital because of the possibility of hypoglycaemia until the correct ratio of the two medicines is determined.

Children: GLUCOPHAGE is not recommended for use in children.

Elderly: GLUCOPHAGE is indicated in the elderly, but not when renal function is significantly impaired.

Contraindications

Diabetic coma and ketoacidosis. Significant renal impairment (serum creatinine >0.16 mmol/L). Chronic hepatic disease. Alcoholism (acute or chronic). Conditions associated with hypoxia (e.g. recent myocardial infarction, cardiac failure, pulmonary disease and surgery). States associated with lactic acidosis such as shock or pulmonary insufficiency. History of lactic acidosis.

Warnings and Precautions

METFORMIN is excreted by the kidney and care is consequently necessary in patients with decreased renal function. METFORMIN therapy should be stopped at least 48 hours prior to a procedure (or on admission for an emergency procedure) predisposing to dehydration and clinical investigations such as intravenous urography and intravenous angiography because of an increased risk of lactic acidosis. METFORMIN should be reinstated only after the patient is eating and drinking normally.

It is prudent to stop METFORMIN therapy temporarily if any of the above conditions exist, particularly if gastrointestinal disturbances are noted or acidosis is suspected. Advise doctor if current infection is present. After ketoacidosis and lactic acidosis have been excluded METFORMIN treatment may be resumed.

Patients receiving continuous METFORMIN therapy should have an annual estimation of B₁₂ absorption. However, it should be stressed that no case of overt pernicious anaemia has been reported.

Blood glucose levels should be monitored when patients are in catabolic states (e.g sepsis or in the post-operative period) or during concomitant therapy with a sulphonylurea as combined therapy may cause hypoglycaemia. Stabilisation of diabetic patients with METFORMIN and short term insulin therapy should be carried out in hospital because of the possibility of hypoglycaemia until the correct ratio of the two medicines has been obtained. Other risk factors for lactic acidosis include sepsis, high dosage of metformin, increasing age and dehydration.

Pregnancy and Lactation: The use of METFORMIN is not advised in pregnancy, where decompensation has occurred temporarily as a result of infection, trauma or surgery, or in conditions which may cause dehydration.

Adverse Effects

GLUCOPHAGE is well tolerated but gastrointestinal upsets (e.g. diarrhoea) which are usually minor and transient are often avoided by taking GLUCOPHAGE with meals (which is always recommended). Occasionally a temporary lowering of the dose may be needed. Only 3% of patients have to discontinue GLUCOPHAGE therapy because of this complication. Therefore, it is important that treatment is not abandoned at the first sign of intolerance since this has been found to resolve spontaneously, and it is usual for gastrointestinal upsets to disappear within the period during which diabetic control is achieved. It is unusual for them to return and if such symptoms occur an alternative reason should be sought.

Lactic acidosis is a serious and often fatal metabolic complication which has been reported in a number of diseases including diabetes. It is characterised by acidosis (decreased blood pH), electrolyte disturbances with an increased anion gap and an increased lactate level with altered lactate/pyruvate ratio. Azotaemia may also be present. Lactic acidosis often has an insidious onset and non-specific symptomatology. Marked anorexia or unexplained weight loss may indicate the onset and precede the full clinical manifestations of lactic acidosis presenting with nausea, vomiting, hyperventilation, malaise and/or abdominal pain. In the majority of fatal cases patients with these early symptoms have not been investigated for lactic acidosis. In patients with a metabolic acidosis lacking evidence of ketoacidosis (ketoacidosis and ketonaemia) lactic acidosis should be suspected. Lactic acidosis is a medical emergency which must be treated in hospital immediately.

The few cases of lactic acidosis reported with GLUCOPHAGE therapy have occurred in patients with complications included in the contraindications. The problem of lactic acidosis with GLUCOPHAGE is unusual provided that patients are correctly selected and attention paid to the correct diet and dosage.

Interactions

As with a number of medicines interaction between GLUCOPHAGE and anticoagulants is a possibility. Thus patients receiving the two medicines may need adjustment of the anticoagulant dosage.

Reduced renal clearance of GLUCOPHAGE has been reported during cimetidine therapy, so a dose reduction should be considered.

Overdosage

Signs and Symptoms: Hypoglycaemia does not occur with GLUCOPHAGE monotherapy (fifty tablets have been ingested with no untoward effects on blood glucose levels). However, in combination with a sulphonylurea or insulin or alcohol, hypoglycaemia can occur.

In excessive dosage and particularly if there is a possibility of accumulation lactic acidosis should be suspected. Some signs and symptoms suggestive of this condition are nausea, diarrhoea, abdominal pain, dyspnoea.

Treatment: Intensive supportive therapy is recommended which should be particularly directed at correcting fluid loss and abdominal pain, dyspnoea.

Pharmaceutical Precautions

Store below 25°C.

Medicine Classification

Prescription Medicine.

Package Quantities

500mg Tablets: Blister packs of 100.

850mg Tablets: Blister packs of 60.

Further Information

GLUCOPHAGE does not lower blood glucose levels in non-diabetics and does not cause hypoglycaemia in diabetics when used as monotherapy. Weight loss often occurs during therapy and levels of plasma cholesterol, triglycerides and pre-beta-lipoproteins may be lowered. GLUCOPHAGE has been shown to improve peripheral glucose metabolism