METFORMIN HYDROCHLORIDE

Posology Adults with normal renal function (GFR ≥90 mL/min) Monotherapy and combination with other oral antidiabetic agents Initially, 500 mg every 8 hours or 850 mg every 12 hours, with or after food. Diabetic control may be achieved within a few days but the full effect can be delayed for up to 2 weeks.

If control is incomplete, the dosage may be increased with care up to a maximum of 3 g daily taken as 3 divided doses 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.

Once adequate control has been achieved a reduction in dosage may be possible. 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 hydrochloride is given at the usual starting dose of 500 mg or 850 mg 2 or 3 times daily, while insulin dosage is adjusted based on blood glucose measurements. Elderly Metformin should be used with caution in elderly patients whose renal function may be reduced.

4).

In cases of metabolic decompensation:

The metformin dosage may be reduced in cases of metabolic decompensation. If only small daily doses are administered an omission of one metformin dose should be tried. This is of importance in elderly patients to reduce the risk of lactic acidosis.

Patients with renal impairment A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. g. every 3-6 months. GFR mL/min Total maximum daily dose (to be divided into 2- 3 daily doses) Additional considerations 60-89 3000 mg Dose reduction may be considered in relation to declining renal function.

4) should be reviewed before considering initiation of metformin. The starting dose is at most half of the maximum dose. <30 - Metformin is contraindicated. Paediatric population Monotherapy and combination with insulin • Metformin can be used in children from 10 years of age and adolescents.

• The usual starting dose is 500 mg or 850 mg metformin hydrochloride once 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 hydrochloride is 2 g daily, taken as 2 or 3 divided doses.

Further dosage information Combination with sulphonylureas:

Metformin hydrochloride may be used in combination with sulphonylureas if monotherapy with metformin does not lead to a satisfactory response. However, it should be noted that metformin and sulphonylureas have a different mode of action and therefore an additive or potentiating effect of these drugs might cause a hypoglycaemic shock.

Substitution for sulphonylureas:

Metformin hydrochloride may be used instead of sulphonylureas in patients who formerly have been treated with sulphonylureas. Method of administration For oral administration. Monitoring advice See special warnings and precautions for use.

Metabolism & Nutrition Disorders:

The following convention has been utilised for the classification of frequency: Very common, ≥ 1/10; common, ≥1/100 and < 1/10; uncommon, ≥1/1000 and < 1/100; rare, ≥ 1/10000 and < 1/1000; very rare, < 1/10000; not known (cannot be estimated from the available data) There are no modern clinical studies available that can be used to determine the frequency of undesirable effects.

Gastrointestinal disturbances occur in 5-20% of patients at the beginning of metformin therapy. These effects are generally of minor importance and do not require termination of metformin therapy. The frequency and severity can be reduced markedly by starting with a low dose and gradually increasing the dose and by administration of metformin with or after meals.

About 5% of all patients do not tolerate metformin therapy. Persisting gastrointestinal disturbances require the termination of metformin therapy.

Nervous System Disorders:

Common: Taste disturbance Immune System Disorders: Very rare: Hypersensitivity (including hypersensitivity reactions of the skin). 4).

Very rare:

Lactic acidosis (symptoms include gastrointestinal disorders, muscle pains, muscle spasms, fatigue, dyspnoea, hyperthermia, hyperventilation, decrease of blood pH, increase of lactate value, clouding of consciousness and coma). On suspicion of lactic acidosis, metformin therapy must be immediately stopped and the patient must be treated at once as an emergency in hospital.

Gastro-intestinal disorders:

Very common: nausea, vomiting, abdominal pain, diarrhoea, anorexia and metallic taste 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:

Very Rare: liver function test abnormal; hepatitis resolving upon discontinuation of Metformin.

Skin & Subcutaneous Tissue Disorders:

Very rare: erythema, pruritus, urticaria.

Paediatric population:

In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10 to 16 years treated for 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Lactic acidosis:

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin tablets should be temporarily discontinued and contact with a health care professional is recommended. Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformintreated patients.

5). Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention.

35), increased plasma lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

Patients with known or suspected mitochondrial diseases:

In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.

Surgery:

Metformin must be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been reevaluated and found to be stable.

2. 3. Cardiac function Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function. 3). Administration of iodinated contrast agent Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis.

2 and

1 • Severe renal failure (GFR <30 ml/min) • Chronic liver disease or hepatic insufficiency • Severe cardiovascular impairment • Acute or chronic disease which may cause tissue hypoxia such as decompensated heart failure or respiratory failure, recent myocardial infarction, shock • Severe peripheral vascular disease • Acute conditions with the potential to alter renal function, for example infections with fever, pancreatitis or trauma • Dehydration, severe infection, shock • History of or conditions associated with lactic acidosis such as shock or pulmonary insufficiency, alcoholism (acute or chronic), acute alcohol intoxication • Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis) • Reduced diet (< 1000kcal or 4,200kJ per day)