GLUCOPHAGE XR Metformin Hydrochloride 500mg Extended-Release Tablet 1's

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/1.73m²) 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 500mg or 850mg metformin hydrochloride daily. The maximum daily dose is 1000mg. 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/1.73m² 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 (once daily dosage). 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 and combination with other oral antidiabetic agents: Unless otherwise prescribed, 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 can never replace insulin in Type 1 diabetes but concomitant administration with insulin makes it possible to reduce the insulin doses and obtain more stable blood glucose levels. In case metformin (Glucophage XR) is used in combination with insulin, the usual starting dose is one tablet of metformin (Glucophage XR) 500 mg or 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 1000mg to 1500mg 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.
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/1.73m²) 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/1.73m²; Every 3 months in patients with CrCl between 30 and 44 mL/min or eGFR between 30 and 44 mL/min/1.73m² If CrCl or eGFR fall below 30 mL/min or 30 mL/min/1.73m² 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 should be adjusted based on renal function. Regular assessment of renal function is necessary (see Precautions).
Children: Metformin (Glucophage XR) is not recommended for use in children.
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/1.73m² 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/1.73m² or receiving intra-arterial iodinated contrast materials with CrCl below 60 mL/min or eGFR below 60 mL/min/1.73m² 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.

Should be taken with food: XR tab: Swallow whole, do not chew/crush. Must be taken daily w/o interruption w/ evening meal.

Glucophage 500 mg/Glucophage Forte/Glucophage XR: Metformin (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/1.73m² for intravenous administration or in patients with CrCl below 60 mL/min or eGFR below 60 mL/min/1.73m² 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.

Glucophage 500 mg/Glucophage Forte: Renal function: As metformin is excreted by the kidney, it is recommended that creatinine clearance or GFR 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/1.73m² 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/1.73m².
In case creatinine clearance or eGFR is <30 mL/min/1.73m² respectively, metformin is contraindicated (see Contraindications).
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution is recommended 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).
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.
Other precautions: It is recommended that all patients 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 be performed regularly.
Metformin alone never causes hypoglycemia, although caution is advised when it is used in combination with insulin, sulphonylureas or meglitinides.
Glucophage 1 gram: Renal function: As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) 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/1.73m² 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/1.73m². In case CrCl is below 30 mL/min or eGFR is below 30 mL/min/1.73m² respectively, metformin is contraindicated (see Contraindications).
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised 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 antihypertensive therapy or diuretic therapy 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.
Children from 10 years of age and adolescents: The diagnosis of type 2 diabetes mellitus should 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.
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 should continue their energy-restricted diet.
It is recommended that the usual laboratory tests for diabetes monitoring should be performed regularly.
Metformin alone does not cause hypoglycemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).
Glucophage XR: Renal function: As metformin is excreted mainly 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/1.73m² 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/1.73m². In case CrCl is below 30 mL/min or eGFR is below 30 mL/min/1.73m² respectively, metformin is contraindicated (see Contraindications).
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised 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, 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 combinations with sulphonylureas or meglitinides.
Effect 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, patients should be alerted to the risk of hypoglycemia when metformin is used in combination with other antidiabetic agents (sulfonylureas, insulin, glinides or other hypoglycemic agents). It is important to be aware of the onset of hypoglycemia. Symptoms of hypoglycemia include weakness, dizziness, increased sweating, fast heartbeat, vision disorders or difficulty in concentration. When a patient starts to feel these symptoms, he should not drive or use machines.

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: Very rare: Lactic acidosis (see Precautions).
Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia.
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: As with all medications, metformin (Glucophage XR) can cause undesirable effects. 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. They are presented by frequencies which 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: Very rare: Lactic acidosis (see Precautions). Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia.
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.

Glucophage 500 mg/Glucophage 1 g/Glucophage Forte/Glucophage XR: Contraindicated combinations in patients with CrCL below 45 mL/min or eGFR below 45 mL/min/1.73m² for intravenous administration or in patients with CrCL below 45 mL/min or eGFR below 60 mL/min/1.73m² 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.

Antidiabetic Agents