METFORMIN

Posology Adults with normal renal function (GFR ≥ 90 mL/min):

Reduction in the risk or delay of the onset of type 2 diabetes • Metformin should only be considered where intensive lifestyle modifications for 3 to 6 months have not resulted in adequate glycaemic control. • The therapy should be initiated with one tablet Metabet SR/Metformin prolonged release tablets 500 mg once daily with the evening meal.

• After 10 to 15 days dose adjustment on the basis of blood glucose measurements is recommended (OGTT and/or FPG and/or HbA1C values to be within the normal range). A slow increase of dose may improve gastro-intestinal tolerability.

The maximum recommended dose is 4 tablets (2000 mg) once daily with the evening meal. • It is recommended to regularly monitor (every 3-6 months) the glycaemic status (OGTT and/or FPG and/or HbA1c value) as well as the risk factors to evaluate whether treatment needs to be continued, modified or discontinued.

• A decision to re-evaluate therapy is also required if the patient subsequently implements improvements to diet and/or exercise, or if changes to the medical condition will allow increased lifestyle interventions to be possible. Monotherapy in Type 2 diabetes mellitus and combination with other oral antidiabetic agents The usual starting dose is one tablet of Metabet SR/Metformin prolonged release tablets 500 mg tablet once daily.

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 4 tablets of Metabet SR/Metformin prolonged release tablets 500 mg tablet daily.

Dosage increases should be made in increments of 500 mg every 10-15 days, up to a maximum of 2000 mg once daily with the evening meal. If glycaemic control is not achieved on 2000 mg of Metabet SR/Metformin prolonged release tablets once daily, of 1000 mg of Metabet SR/Metformin prolonged release tablets twice daily 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. In patients already treated with metformin tablets, the starting dose of Metabet SR/Metformin prolonged release tablets should be equivalent to the daily dose of metformin immediate release tablets.

In post marketing data and in controlled clinical studies, adverse event reporting in patients treated with Metabet SR / Metformin prolonged-release tablets was similar in nature and severity to that reported in patients treated with Metformin immediate release.

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite, which resolve spontaneously in most cases. The following undesirable effects may occur with Metabet SR/Metformin prolonged release tablets.

Frequencies are defined as follows:

Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders:

Very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders:

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 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 metformin-treated 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. 2. 3.

Cardiac function:

1. • Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis) • Diabetic pre-coma • Severe renal failure (GFR < 30 mL/min). • Acute conditions with the potential to alter renal function such as: - dehydration, - severe infection, - shock.

• Disease which may cause tissue hypoxia (especially acute or worsening of chronic disease) such as: - decomposed heart failure, - respiratory failure, - recent myocardial infarction, - shock. • Hepatic insufficiency, acute alcohol intoxication, alcoholism.