4.1. Therapeutic indications

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. Metformin prolonged-release tablets may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

For study results with respect to effects on glycaemic control and diabetic complications, (see section 5.1).

4.2. Posology and method of administration

Posology

Adults with normal renal function (GFR ≥ 90 ml/min)

Monotherapy and combination with other oral anti-diabetic agents

The usual starting dose is one Metformin 500mg Prolonged-release Tablet once daily, taken 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 4 tablets of Metformin hydrochloride 500mg Prolonged- release Tablets daily with an evening meal.

Dosage increases should be made in increments of 500mg every 10-15 days, up to a maximum of 2000mg once daily with the evening meal. If glycaemic control is not achieved on 2000mg once daily, 1000mg twice daily should be considered, with both doses being given with food, at the time of the morning and evening meals. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000mg daily.

In patients already treated with metformin tablets, the starting dose of Metformin hydrochloride Prolonged-release Tablets should be equivalent to the daily dose of metformin immediate release tablets. In patients treated with metformin at a dose above 2000mg daily, switching to Metformin hydrochloride Prolonged-release Tablets is not recommended.

Metformin hydrochloride 750mg and 1000mg Prolonged-release Tablets are intended as maintenance therapy for patients currently treated with metformin tablets (prolonged or immediate release).

The dose of Metformin hydrochloride 750mg or 1000mg Prolonged-release Tablets should be equivalent to the daily dose of metformin tablets (prolonged or immediate release), up to a maximum dose of 1500mg or 2000mg respectively, given with the evening meal. After 10 to 15 days, it is recommended to check that the dose of Metformin hydrochloride 750mg or 1000mg Prolonged-release Tablets is adequate on the basis of blood glucose measurements.

In the event of transfer from another oral anti-diabetic agent: The other agent should be discontinued and titration should begin with Metformin hydrochloride 500mg Prolonged- release Tablets as indicated above, before switching to Metformin hydrochloride 750mg or Metformin hydrochloride 1000mg Prolonged –release Tablets.

Combination with insulin

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of metformin is one 500mg prolonged-release tablet once daily, taken with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements. After titration, switching to Metformin 1000mg Prolonged-release Tablet should be considered.

For patients already treated with metformin and insulin in combination therapy, the dose of Metformin hydrochloride 750mg or 1000mg Prolonged-release Tablets should be equivalent to the already used daily dose of metformin tablets up to a maximum of 1500mg or 2000mg respectively, given with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements.

Renal impairment

GFR should be assessed before initiation of treatment with Metformin hydrochloride Prolonged–release Tablets and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

GFR ml/min

Total maximum daily dose

Additional considerations

60-89

2000 mg

Dose reduction may be considered in relation to declining renal function. For patients with a GFR of 60-89 ml/min, the maximum total daily dose is the currently approved dose for adults with normal renal function.

45-59

2000 mg

Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin. The starting dose is at most half of the maximum dose.

30-44

1000 mg

<30

-

Metformin is contraindicated.

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 section 4.4).

Paediatric population

In the absence of available data, Metformin hydrochloride Prolonged-release Tablets should not be used in children.

Method of administration

The tablets should not be chewed, split or crushed and should be taken whole with a glass of water.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- 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 disease, or worsening of chronic disease such as:

- decompensated heart failure,

- respiratory failure,

- recent myocardial infarction,

- shock

- Hepatic insufficiency, acute alcohol intoxication, alcoholism

4.4. Special warnings and precautions for use

Lactic acidosis

Lactic acidosis, a very rare but serious, metabolic complication, most often occurs at acute worsening of renal function heart and respiratory disease 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.

In patients treated with metformin, caution should be exercised when initiating therapy with medicinal products that may cause acute renal insufficiency (such as antihypertensives, diuretics and non-steroidal anti-inflammatory drugs (NSAIDs)). Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Diagnosis

Patients and/or their 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. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (>5 mmol/l), and an increased anion gap and lactate/pyruvate ratio.

Renal function

GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2. Metformin is contraindicated in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function, see section 4.3.

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.

Metformin is contraindicated in patients with acute and unstable heart failure (see section 4.3).

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 for lactic acidosis. Metformin should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.5.

Surgery

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

Other precautions

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.

Metformin alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides).

The tablet shells may be present in the faeces. It is recommended that patients be advised that this is normal.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Metformin must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided thatrenal function has been re-evaluated and found to be stable see sections 4.2 and 4.4

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids (systemic and local routes) and sympathomimetics). More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon its discontinuation.

Organic cation transporters (OCT)

Metformin is the substrate for both the transporters OCT1 and OCT2. Concomitant use with metformin:

- OCT1 inhibitors (such as verapamil) can decrease the effectiveness of metformin.

- OCT1 inducers (such as rifampicin) can increase the absorption of metformin from the gastrointestinal tract and its effectiveness.

- OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) can decrease the renal excretion of metformin and may result in increased plasma concentrations of metformin.

- OCT1 and OCT2 inhibitors (such as crisotinib and olaparib) can alter the efficacy and the renal elimination of metformin.

Caution should therefore be used when these medicinal products are co-administered with metformin, especially in patients with renal impairment, as the plasma concentrations of metformin may be increased. If necessary, adjusting the dose of metformin should be considered, as OCT inhibitors/inducers can modify the effectiveness of metformin.

4.6. Fertility, pregnancy and lactation

Pregnancy

Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.

A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).

When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible to reduce the risk of malformations of the foetus.

Breast-feeding

Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breast- feeding should be made, taking into account the benefit of breast-feeding and the potential risk to adverse effects on the child.

Fertility

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Some clinical studies suggest that metformin can increase ovulation in women with polycystic ovarian syndrome (PCOS). However, there is no evidence to date that metformin increases the number of live births in women with PCOS.

4.7. Effects on ability to drive and use machines

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (e.g. sulphonylureas, insulin, or meglitinides).

4.8. Undesirable effects

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

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 adverse reactions may occur under treatment with metformin.

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.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Metabolism and nutrition disorders

Very rare: Lactic acidosis (see section 4.4).

Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

Nervous system disorders

Common: Altered taste

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. To prevent this, it is recommended to take metformin distributed over 2–3 doses per day, with or after a meal. 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

Very rare: Skin reactions such as erythema, pruritus, urticaria.

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. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.