Glucophage/Glucophage Forte/Glucophage XR

Metformin HCl.

Glucophage: Each Glucophage 500 mg film-coated tablet contains 500 mg Metformin hydrochloride corresponding to 390 mg metformin base.
Each Glucophage 1 gram film-coated tablet contains 1 gram Metformin hydrochloride corresponding to 780 mg metformin base.
Glucophage Forte: Each Glucophage Forte 850 mg film-coated tablet contains 850 mg Metformin hydrochloride corresponding to 663 mg metformin base.
Glucophage XR: Each Glucophage XR 500 mg extended release tablet contains 500 mg Metformin hydrochloride corresponding to 390 mg metformin base.
Each Glucophage XR 750 mg extended release tablet contains 750 mg Metformin hydrochloride corresponding to 585 mg metformin base.
Each Glucophage XR 1 gram extended release tablet contains 1 gram Metformin hydrochloride corresponding to 780 mg metformin base.

Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycemic effects on both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin may act via 3 mechanisms: (1) in the liver, reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization and (3) in the intestine, delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).
In humans, independently of its action on glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
A similar action has not been demonstrated with the extended release formulation, possibly due to the evening administration, and an increase in triglycerides may occur.
Effect on body weight: In contrast to other commonly used antihyperglycemic agents, such as sulphonylureas or thiazolinediones, treatment with metformin offers a considerable benefit for patients with type 2 diabetes by not causing an increase in body weight. By maintaining or reducing body weight, metformin limits other risk factors associated with increased weight. Over the long term this translates into more stable glycemic control and a decreased risk of diabetes complications. The clinical studies conducted with metformin in both adults and children fully support that metformin improves glycemic control without increasing body weight or even with a small weight loss.
Pharmacokinetics: Absorption: Glucophage/Glucophage Forte: After an oral dose, maximum plasma concentration (C_max) is reached in 2.5 hours (T_max) between 1.5 and 3.5). Absolute bioavailability of a 500 mg or 850 mg metformin immediate-release tablet is approximately 50 to 60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20 to 30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.
At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/mL. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 5 microgram/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the plasma concentration-time curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Glucophage XR: After an oral dose of metformin (Glucophage XR) 500 mg, metformin absorption is significantly delayed compared to the immediate-release tablet (T_max at 2.5 hours) with a T_max at 7 hours.
Following a single oral administration of 1500 mg of metformin (Glucophage XR) 750 mg, a mean peak plasma concentration of 1193 ng/mL is achieved with a median value of 5 hours and a range of 4 to 12 hours. Metformin (Glucophage XR) 750 mg was shown to be bioequivalent to metformin (Glucophage XR) 500 mg at a 1500 mg dose with respect to C_max and AUC in healthy fed and fasted subjects.
Following a single oral administration in the fed state of one tablet of metformin (Glucophage XR) 1 gram, a mean peak plasma concentration of 1214 ng/mL is achieved with a median time of 5 hours (range of 4 to 10 hours). Metformin (Glucophage XR) 1 gram was shown to be bioequivalent to metformin (Glucophage XR) 500 mg at a 1 gram dose with respect to C_max and AUC in healthy fed and fasted subjects.
At steady state, similar to the immediate-release formulation, C_max and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2 grams metformin extended release is similar to that observed after administration of 1 gram metformin immediate-release twice daily.
Intrasubject variability of C_max and AUC of metformin extended release is comparable to that observed with metformin immediate-release.
When 2 tablets of 500 mg metformin extended release is administered in fed conditions the AUC is increased by approximately 70% (both C_max and T_max are only slightly increased).
When the 1 gram extended-release tablet is administered in fed conditions the AUC is increased by 77% (C_max is increased by 26% and T_max is slightly prolonged by about 1 hour).
Metformin absorption from the extended-release formulation is not altered by meal composition.
No accumulation is observed after repeated administration of up to 2 grams metformin extended release.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63 to 276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Treatment of type 2 diabetes mellitus (non-insulin-dependent diabetes), particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycemic control: in adults, metformin (Glucophage) may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin; in children from 10 years of age and adolescents, metformin (Glucophage) may be used as monotherapy or in combination with insulin.
Intensive glucose control with metformin as first-line therapy in overweight type 2 diabetic adult patients has been shown to reduce diabetes complications.
Prevention of type 2 diabetes mellitus in patients with prediabetes and at least one additional risk factor in whom lifestyle modifications alone have not reached adequate glycemic control.

Glucophage/Glucophage Forte: Unless otherwise prescribed, the dosage and administration is as follows: Adults: Monotherapy or in combination with other oral antidiabetic agents: The usual starting dose is one tablet of metformin (Glucophage) 500 mg or one tablet of metformin (Glucophage Forte) 850 mg, 2 or 3 times daily given during or after meals. Metformin (Glucophage) must be taken daily without interruption, except if specifically indicated by the doctor. If the patient has forgotten to take metformin (Glucophage), the next dose should be taken at the usual time. Do not double the dose of metformin (Glucophage). If the patient has taken more metformin (Glucophage) tablets than indicated, the doctor or pharmacist must be consulted immediately.
After 10 to 15 days dose adjustment on the basis of blood glucose measurements is recommended. A slow increase of dose may improve gastrointestinal tolerability.
In patients receiving a high metformin dose (2 to 3 grams per day), it is possible to replace two metformin (Glucophage) 500 mg tablets with one metformin (Glucophage) 1 gram tablet.
The maximum recommended dose of metformin hydrochloride is 3 grams daily, taken as 3 divided doses.
If transfer from another oral antidiabetic is intended, discontinue the other agent and initiate metformin at the dose indicated previously.
Monotherapy in the indication prediabetes: The usual dose is 1000 to 1700 mg metformin hydrochloride per day divided in two doses given during or after meals. It is recommended to regularly monitor the glycemic status as well as the risk factors to evaluate whether treatment is still needed.
Combination with insulin: Metformin and insulin may be used in combination therapy to achieve better blood glucose control. Unless otherwise prescribed, metformin is given at the usual starting dose of one tablet of metformin (Glucophage) 500 mg or metformin (Glucophage Forte) 850 mg 2 or 3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.
Children from 10 years of age and adolescents: Monotherapy or in combination with insulin: Metformin (Glucophage) can be used in children from 10 years of age and adolescents as monotherapy or in combination with insulin.
The usual starting dose is one tablet of metformin (Glucophage) 500 mg or one tablet of metformin (Glucophage Forte) 850 mg once daily, given during or after meals.
After 10 to 15 days dose adjustment on the basis of blood glucose measurements is recommended. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 grams daily, taken as 2 or 3 divided doses.
Patients with renal impairment: Metformin may be used in patients with moderate renal impairment stage 3 (creatinine clearance [CrCl] between 30 and 59 mL/min or estimated glomerular filtration rate [eGFR] between 30 and 59 mL/min/1.73 m²) only in the absence of other conditions that may increase the risk of lactic acidosis (see Contraindications) and with the following dose adjustments: The starting dose is 500 mg or 850 mg metformin hydrochloride daily. The maximum daily dose is 1000 mg. The renal function should be closely monitored: Every 3-6 months in patients with CrCl between 45 and 59 mL/min or eGFR between 45 and 59 mL/min/1.73 m²; Every 3 months in patients with CrCl between 30 and 44 mL/min or eGFR between 30 and 44 mL/min/1.73 m².
If CrCl or eGFR fall below 30 mL/min or 30 mL/min/1.73 m² respectively, metformin must be discontinued immediately.
Elderly: Due to the potential for decreased renal function in elderly subjects, it is recommended that the metformin dosage be adjusted based on renal function. Regular assessment of renal function is necessary (see Precautions).
Combination with iodinated contrast materials: Iodinated contrast materials may be administered intravenously in metformin-treated patients with creatinine clearance equal or greater than 45 mL/min or eGFR equal or greater than 45 mL/min/1.73 m² without discontinuation of metformin before the test (see Contraindications).
Patients receiving intravenous iodinated contrast materials with a CrCl below 45 mL/min or eGFR <45 mL/min/1.73 m² or receiving intra-arterial iodinated contrast materials with a CrCl below 60 mL/min or eGFR of <60 mL/min/1.73 m² should stop taking metformin 48 hours before the test. Renal function should be re-assessed 48 hours after contrast material administration and metformin should only be restarted if it has not deteriorated further.
Glucophage XR: The dosage of metformin (Glucophage XR) is determined by the doctor on an individual basis according to the results of laboratory blood glucose measurement. The tablets are swallowed whole, without chewing and must be taken daily without interruption with the evening meal. Metformin (Glucophage XR) should always be taken with food. This will avoid the patient having gastrointestinal discomfort (see Adverse Reactions). Patients who have stopped the treatment must contact their doctor. In case the patient has forgotten to take metformin (Glucophage XR), the next dose should be taken at the usual time. Do not double the dose of metformin (Glucophage XR) unless otherwise prescribed by the doctor. If the patient has taken more metformin (Glucophage XR) than indicated, the doctor or pharmacist should be consulted immediately.
Monotherapy or in combination with other oral antidiabetic agents: Unless otherwise prescribed, the usual starting dose is one tablet metformin (Glucophage XR) 500 mg or one tablet metformin (Glucophage XR) 750 mg once daily with the evening meal. Metformin (Glucophage XR) 1 gram is intended as a maintenance therapy for patients treated with either 1 gram or 2 grams of metformin hydrochloride and should be taken once daily with the evening meal.
After 10 to 15 days dose adjustment on the basis of blood glucose measurements is recommended. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin (Glucophage XR) 500 mg is four (4) tablets daily. The recommended dose of metformin (Glucophage XR) 750 mg is 2 tablets once daily. If glycemic control is not achieved on 2 tablets of metformin (Glucophage XR) 750 mg once daily, metformin (Glucophage XR) 750 mg may be increased to a maximum dose of 3 tablets daily. The maximum recommended dose of metformin (Glucophage XR) 1 gram is two (2) tablets daily.
Dosage increase is recommended in increments of 500 mg every 10 to 15 days, up to 2 grams once daily. If glycemic control is not achieved on 3 tablets of metformin (Glucophage XR) 750 mg or 2 grams metformin hydrochloride (Glucophage XR) extended release once daily, patients may be switched to metformin hydrochloride (Glucophage) immediate-release to a maximum dose of 3 grams daily. In patients already treated with metformin immediate-release, a starting dose of metformin extended release equivalent to the daily dose of the metformin immediate-release is recommended. In patients treated with metformin immediate-release at a dose above 2 grams daily, switching to metformin hydrochloride extended release is not recommended.
If transfer from another oral antidiabetic agent is intended, discontinue the other agent and initiate metformin (Glucophage XR) at the dose indicated previously. Titration should begin with metformin (Glucophage XR) 500 mg before switching to metformin (Glucophage XR) 1 gram as indicated previously.
Combination with insulin: Metformin and insulin may be used in combination therapy to achieve better blood glucose control. Unless otherwise prescribed, the usual starting dose is one tablet of metformin (Glucophage XR) 500 mg or one tablet of metformin (Glucophage XR) 750 mg once daily, while insulin dosage is adjusted on the basis of blood glucose measurements. After titration, switch to metformin (Glucophage XR) 1 gram should be considered.
Monotherapy in the indication prediabetes: The usual dose is 1000 to 1500 mg metformin hydrochloride once daily during or after meals. It is recommended to regularly monitor the glycemic status as well as the risk factors to evaluate whether treatment is still needed.
Children: In the absence of data, metformin (Glucophage XR) is not recommended for use in children.
Patients with renal impairment: Metformin may be used in patients with moderate renal impairment stage 3 (creatinine clearance [CrCl] between 30 and 59 mL/min or estimated glomerular filtration rate [eGFR] between 30 and 59 mL/min/1.73 m²) only in the absence of other conditions that may increase the risk of lactic acidosis (see Contraindications) and with the following dose adjustments: The starting dose is 500 mg or 850 mg metformin hydrochloride daily. The maximum daily dose is 1000 mg. The renal function should be closely monitored: Every 3 - 6 months in patients with CrCl between 45 and 59 mL/min or eGFR between 45 and 59 mL/min/1.73 m²; Every 3 months in patients with CrCl between 30 and 44 mL/min or eGFR between 30 and 44 mL/min/1.73 m².
If CrCl or eGFR fall below 30 mL/min or 30 mL/min/1.73 m² respectively, metformin must be discontinued immediately.
Elderly: Due to the potential for decreased renal function in elderly subjects, it is recommended that the metformin dosage be adjusted based on renal function. Regular assessment of renal function is necessary (see Precautions).
Combination with iodinated contrast materials: Iodinated contrast materials may be administered intravenously in metformin-treated patients with CrCl equal or greater than 45 mL/min or eGFR equal or greater than 45 mL/min/1.73 m² without discontinuation of metformin before the test (see also Contraindications).
Patients receiving intravenous iodinated contrast materials with CrCl below 45 mL/min or eGFR below 45 mL/min/1.73 m² or receiving intra-arterial iodinated contrast materials with CrCl below 60 mL/min or eGFR below 60 mL/min/1.73 m² should stop taking metformin 48 hours before the test. Renal function should be re-assessed 48 hours after contrast material administration and metformin should only be restarted if it has not deteriorated further.

Hypoglycemia has not been seen with metformin 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 a hospital. The most effective method to remove lactate and metformin is hemodialysis.

Metformin (Glucophage/Glucophage XR) MUST NOT BE USED in the following cases: Hypersensitivity to metformin hydrochloride or to any of the excipients. Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis); Diabetic pre-coma; Severe renal failure (CrCl below 30 mL/min or eGFR below 30 mL/min/1.73m²; Acute conditions with the potential to alter renal function such as dehydration, severe infection or shock. Disease (especially acute disease or worsening of chronic disease) which may cause tissue hypoxia such as unstable congestive heart failure, respiratory failure, recent myocardial infarction or shock. Hepatic insufficiency, acute alcohol intoxication, alcoholism.
Intravascular administration of iodinated contrast materials in radiodiagnostic examinations can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Therefore, metformin must be discontinued 48 hours before the test in patients with CrCl below 45 mL/min or eGFR below 45 mL/min/1.73 m² for intravenous administration or in patients with CrCl below 60 mL/min or eGFR below 60 mL/min/1.73 m² for intra-arterial administration. Metformin may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and has not deteriorated further.
Metformin must be discontinued 48 hours prior to elective major surgical interventions and may not be reinstated until 48 hours afterwards, and only after renal function has been re-evaluated and has not deteriorated further.

Lactic acidosis: Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication. Risk factors include poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, severe infection, hepatic insufficiency, and any condition associated with hypoxia (such as decompensated cardiac failure, acute myocardial infarction) or the concomitant use of medications which might cause lactic acidosis (such as NRTIs), (see also Contraindications).
Lactic acidosis can occur due to metformin accumulation. Reported cases of lactic acidosis in patients treated with metformin have occurred primarily in diabetic patients with acute renal failure or acute worsening of renal function.
Special caution should therefore be paid to situations where renal function may become acutely impaired (see also Contraindications), for example in case of dehydration (severe or prolonged diarrhea or vomiting) or when initiating drugs which can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs).
In the acute conditions listed, metformin must be immediately and temporarily discontinued.
The following non-specific symptoms could be signs of lactic acidosis: such as muscle cramps, digestive disorders as abdominal pain and severe asthenia.
Diagnosis: Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH (below 7.35), plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. In case of lactic acidosis, the patient should be immediately hospitalized (see also Overdosage).
Physicians must alert the patients on the risk and on the symptoms of lactic acidosis. Patients should be instructed to immediately seek medical attention and to stop taking metformin. Metformin must be immediately discontinued, at least temporarily, until the situation is clarified. Reintroduction of metformin should then be discussed taking into account the benefit/risk ratio on an individual basis as well as renal function.
Renal function: As metformin is excreted by the kidney, it is recommended that CrCl (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) or eGFR should be determined before initiating treatment and regularly thereafter: At least annually in patients with normal renal function, at least every 3 to 6 months in patients with CrCl between 45 and 59 mL/min or eGFR between 45 and 59 mL/min/1.73 m² and in elderly subjects, at least every 3 months in patients with CrCl between 30 and 44 mL/min or eGFR between 30 and 44 mL/min/1.73 m². In case CrCl is below 30 mL/min or eGFR is below 30 mL/min/1.73 m² respectively, metformin is contraindicated (see Contraindications).
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution is needed in situations where renal function may become acutely impaired, for example due to dehydration (severe or prolonged diarrhea or vomiting), or when initiating drugs which can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs). In the acute conditions listed, metformin must be immediately and temporarily discontinued. In these cases, it is also recommended to check renal function before initiating treatment with metformin.
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 Contraindications).
Other precautions: It is recommended that all patients should continue their diet with a regular distribution of carbohydrate intake during the day and that overweight patients continue their energy-restricted diet.
It is recommended that the usual laboratory tests for diabetes monitoring should be performed regularly.
Metformin alone never causes hypoglycemia, although caution is advised when it is used in combination with insulin, sulphonylureas or meglitinides.
Effects on the Ability to Drive and to Use Machines: Metformin monotherapy does not cause hypoglycemia and therefore has no effect on the ability to drive or to use machines. However, it is recommended that patients should be alerted to the risk of hypoglycemia when metformin is used in combination with other antidiabetic agents such as sulphonylureas, insulin or meglitinides.
Glucophage/Glucophage Forte: 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 anemia 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.
Use in Children: Children from 10 years of age and adolescents: The diagnosis of type 2 diabetes mellitus must be confirmed before treatment with metformin is initiated.
No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children, is recommended.
Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although metformin efficacy and safety in children below 12 did not differ from efficacy and safety in older children, particular caution is recommended when prescribing to children aged between 10 and 12 years.
Glucophage XR: 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 anemia 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. The tablet shells may be present in the feces. It is recommended that patients be advised that this is normal and this is not linked with a decrease in therapeutic activity.

Pregnancy: Uncontrolled hyperglycemia 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 hyperglycemia‑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.
Lactation: Metformin is excreted into human breast milk in very small amounts. 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 breastfeeding or to discontinue metformin needs to take into account the benefit of breastfeeding, the importance of the medicinal product to the mother, and the potential risk of adverse effects in the infant.

Glucophage/Glucophage Forte: The following undesirable effects may occur under treatment with metformin. 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; frequency not known: cannot be estimated from the available data.
Metabolism and nutrition disorders: Common: Vitamin B12 decrease/ deficiency (see Precautions).
Very rare: Lactic acidosis (see Precautions).
Nervous system disorders: Common: Taste disturbance.
Gastrointestinal disorders: Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain 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 tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and subcutaneous tissue disorders: Very rare: Skin reactions such as erythema, pruritus, urticaria.
Children from 10 years of age and adolescents: In published and post marketing data and in controlled clinical studies in a limited pediatric population aged 10 to 16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.
At the first sign of any adverse drug reaction, patient must seek medical attention immediately.
Glucophage XR: The following undesirable effects observed in patients treated with metformin (Glucophage XR) extended release tablets were similar in nature and severity to those observed in patients treated with metformin (Glucophage) immediate-release tablets. The following undesirable effects may occur under treatment with metformin. 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; frequency not known: cannot be estimated from the available data.
Metabolism and nutrition disorders: Common: Vitamin B12 decrease/deficiency (see Precautions). Very rare: Lactic acidosis (see Precautions).
Nervous system disorders: Common: Taste disturbance.
Gastrointestinal disorders: Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain 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 tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and subcutaneous tissue disorders: Very rare: Skin reactions such as erythema, pruritus, urticaria.
At the first sign of any adverse drug reaction, patient must seek medical attention immediately.

Contraindicated combinations: In patients with CrCL below 45 mL/min or eGFR below 45 mL/min/1.73 m² for intravenous administration or in patients with CrCL below 45 mL/min or eGFR below 60 mL/min/1.73 m² for intra-arterial administration of iodinated contrast materials, metformin must be discontinued 48 hours before the test (see Contraindications).
Combinations to be used with caution: Medicinal products with intrinsic hyperglycemic activity (e.g. glucocorticoids and tetracosactides [systemic and local routes], beta-2-agonists, danazol, and chlorpromazine at high dosages of 100 mg per day, diuretics): 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. Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to their potential to decrease renal function (further to their intrinsic hyperglycemic effect).
Organic cation transporters (OTC): Metformin is a substrate of both transporters OCT1 and OCT2. Co-administration of metformin with Substrates/inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin; Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy; Substrates/inhibitors of OCT2 (such as cimetidine, dolutegravir, crizotinib, olaparib, daclatasvir, vandetanib) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
Therefore, caution is advised when these drugs are co-administered with metformin and a dose adjustment may be considered, particularly in patients with renal impairment.
Interaction with alcohol: The risk of lactic acidosis is increased in acute alcohol intoxication, particularly in case of fasting or malnutrition or hepatic insufficiency. It is recommended that consumption of alcohol and alcohol-containing medicinal products be avoided.

Glucophage: Store at temperatures not exceeding 30°C.
Glucophage Forte: Store at temperatures not exceeding 25°C.
Glucophage XR: Store at temperatures not exceeding 30°C.
Do not use after the expiry date.

Antidiabetic Agents

A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.

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