Glucophage XR

/ Merck Serono LTD, Israel

The therapy should be initiated with one tablet Glucophage XR 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 dosemay improve gastro-intestinal tolerability. The maximum recommended dose is 4 tablets (2000mg) once daily with the evening meal.
See prescribing information for full details.

Reduction in the risk or delay of the onset of type 2 diabetes mellitus in adult, overweight patientswith IGT* and/or IFG*, and/or increased HbA1C with:
* High risk for developing overt type 2 diabetes mellitus
* Progression toward type 2 diabetes mellitus despite implementation of intensive lifestyle changes for 3 to 6 months
Treatment with Glucophage XR must be based on a risk score incorporating appropriate measures of glycaemic control and including evidence of high cardiovascular risk.
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 dietarymanagement and exercise alone does not result in adequate glycaemic control. Glucophage XR maybe used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

* Hypersensitivity to metformin or to any of the excipients
* 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 (dehydration, severe infection, shock)
* Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease); decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
* Hepatic insufficiency, acute alcohol intoxication, alcoholism

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.
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.
Renal function: GFR should be assessed before treatment initiation and regularly thereafter. Metformin is contraindicated in patients with GFR<30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function.
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.
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.
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:
* 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.
* 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).
See prescribing information for full details.

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.
Common: Vitamin B12 decrease/deficiency, Taste disturbance.
See prescribing information for full details.

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.
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.

Pregnancy: 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.
Lactation: 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 effect on the child.
Women of childbearing potential:
In premenopausal women, treatment with Glucophage XR may result in ovulation in anovulatory women, which may lead to unintended pregnancy.

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.