4.1. Therapeutic indications

• Reduction in the risk or delay of the onset of type 2 diabetes mellitus in adult, overweight patients with IGT* and/or IFG*, and/or increased HbA1C who are:

- at high risk for developing overt type 2 diabetes mellitus (see section 5.1) and

- still progressing towards type 2 diabetes mellitus despite implementation of intensive lifestyle change for 3 to 6 months

Treatment with Xynox must be based on a risk score incorporating appropriate measures of glycaemic control and including evidence of high cardiovascular risk (see section 5.1).

Lifestyle modifications should be continued when metformin is initiated, unless the patient is unable to do so because of medical reasons.

*IGT: Impaired Glucose Tolerance; IFG: Impaired Fasting Glucose

• 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 may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

4.2. Posology and method of administration

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 Xynox 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 Xynox 500 mg 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 daily.

• 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 Xynox 2000mg once daily, Xynox 1000mg 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 Metformin 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 Xynox is not recommended.

• If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate Xynox at the dose indicated above.

• Xynox 750 mg and Xynox 1000 mg are intended for patients who are already treated with metformin tablets (prolonged or immediate release).

• The dose of Xynox 750 mg or Xynox 1000 mg should be equivalent to the daily dose of metformin tablets (prolonged or immediate release), up to a maximum dose of 1500 mg or 2000 mg respectively, given with the evening meal.

Combination with insulin

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Xynox is one 500 mg tablet once daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

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

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).

Benefit in the reduction of risk or delay of the onset of type 2 diabetes mellitus has not been established in patients 75 years and older (see section 5.1) and metformin initiation is therefore not recommended in these patients (see section 4.4).

Renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products 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.

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.

Paediatric population

In the absence of available data, Xynox should not be used in children.

Method of administration

For oral use. Swallow the tablets whole with a glass of water; do not chew the tablets.

4.3. Contraindications

• Hypersensitivity to metformin 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 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. 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).

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. 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.

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.

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.

For patients with acute and unstable heart failure, metformin is contraindicated (see section 4.3).

Elderly:

Due to the limited therapeutic efficacy data in the reduction of risk or delay of type 2 diabetes in patients 75 years and older, metformin initiation is not recommended in these patients.

Administration of iodinated contrast agents:

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of 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 epidural 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 never causes hypoglycaemia, although 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. Patients should be advised that this is normal.

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.

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 case 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 that renal 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 other drug and upon its discontinuation.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

• Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.

• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.

• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

4.6. Fertility, pregnancy and lactation

Pregnancy

Uncontrolled hyperglycaemia in the periconceptional phase and during pregnancy is associated with increased risk of congenital abnormalities, pregnancy loss, pregnancy-induced hypertension, preeclampsia, and perinatal mortality. It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy, to reduce the risk of adverse hyperglycaemia-related outcomes to the mother and her child.

Metformin crosses the placenta with levels that can be as high as maternal concentrations.

A large amount of data on pregnant women (more than 1000 exposed outcomes) from a register-based cohort study and published data (meta-analyses, clinical studies, and registries) indicates no increased risk of congenital abnormalities nor feto/neonatal toxicity after exposure to metformin in the periconceptional phase and/or during pregnancy.

There is limited and inconclusive evidence on the metformin effect on the long-term weight outcome of children exposed in utero. Metformin does not appear to affect motor and social development up to 4 years of age in children exposed during pregnancy although data on long term outcomes are limited.

If clinically needed, the use of metformin can be considered during pregnancy and in the periconceptional phase as an addition or an alternative to insulin.

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, breast-feeding 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.

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 meglinitides).

4.8. Undesirable effects

In post marketing data and in controlled clinical studies, adverse event reporting in patients treated with Xynox 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 adverse reactions may occur with Xynox.

Frequencies are defined as follows: very common: >1/10; common ≥1/100, <1/10; uncommon ≥1/1,000, <1/100; rare ≥1/10,000, <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

Common:

• Vitamin B12 decrease/deficiency (see section 4.4).

Very rare:

• Lactic acidosis (see 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

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 the Yellow Card Scheme at 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 doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin 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.