Glucophage XR

Glucophage XR

metformin

Manufacturer:

PT. Merck Tbk
Full Prescribing Info
Contents
Metformin HCl.
Description
Glucophage XR 500 mg prolonged release tablet contains 500 mg Metformin hydrochloride corresponding to 390 mg Metformin base.
Glucophage XR 750 mg prolonged release tablet contains 750 mg Metformin hydrochloride corresponding to 585 mg Metformin base.
Glucophage XR 1000 mg prolonged release tablet contains 1000 mg Metformin hydrochloride corresponding to 780 mg Metformin base.
Excipients/Inactive Ingredients: Magnesium stearate, Hypromellose, Sodium carmellose.
Action
Pharmacotherapeutic group: Oral blood glucose lowering drugs. Biguanides. ATC code: A10BA02.
Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate Insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via 3 mechanisms: reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
in muscle, by increasing Insulin sensitivity, improving peripheral glucose uptake and utilization.
and 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 (GLUTs) known to date.
In clinical studies, use of Metformin was associated with either a stable body weight or modest weight loss. In humans, independently of its action on glycaemia, Metformin immediate-release has favourable 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.
Clinical Efficacy: The prospective randomised study (UKPDS) has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes. Analysis of the results for overweight patients treated with Metformin after failure of diet alone showed: a significant reduction of the absolute risk of any diabetes-related complication in the Metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined Sulfonylurea and Insulin monotherapy groups (40.1 events/1000 patient -years), p=0.0034;
a significant reduction of the absolute risk of diabetes-related mortality: Metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;
a significant reduction of the absolute risk of overall mortality: Metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined Sulfonylurea and Insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);
a significant reduction in the absolute risk of myocardial infarction: Metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Benefit regarding clinical outcome has not been shown for Metformin used as second-line therapy, in combination with a Sulfonylurea.
In type 1 diabetes, the combination of Metformin and Insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Pharmacokinetics: Absorption: After an oral dose of Glucophage XR 500, Metformin absorption is significantly delayed compared to the immediate-release tablet (Tmax at 2.5 hours) with a Tmax at 7 hours. Following a single oral administration of 1500 mg of Glucophage XR 750, a mean peak plasma concentration of 1193 mg/mL is achieved with a median value of 5 hours and a range of 4 to 12 hours. Glucophage XR 750 was shown to be bioequivalent to Glucophage XR 500 at a 1500 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.
Following a single oral administration in the fed state of one tablet of Glucophage XR 1000, a mean peak plasma concentration of 1214 ng/mL is achieved with a median time of 5 hours (range of 4 to 10 hours). Glucophage XR 1000 was shown to be bioequivalent to Glucophage XR 500 at a 1000 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.
At steady state, similar to the immediate-release formulation, Cmax and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000 mg Metformin prolonged-release is similar to that observed after administration of 1000 mg Metformin immediate release twice daily.
Intrasubject variability of Cmax and AUC of Metformin prolonged-release is comparable to that observed with Metformin immediate-release.
When 2 tablets of 500 mg Metformin prolonged-release is administered in fed conditions the AUC is increased by approximately 70% (both Cmax and Tmax are only slightly increased).
When the 1000 mg prolonged release tablet are administered in fed conditions the AUC is increased by 77% (Cmax is increased by 26% and Tmax is slightly prolonged by about 1 hour).
Metformin absorption from the prolonged-release formulation is not altered by meal composition.
No accumulation is observed after repeated administration of up to 2000 mg Metformin prolonged 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 63-276 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.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity reproduction.
Indications/Uses
Reduction in the risk or delay of the onset of type 2 diabetes mellitus in adult, overweight patients with IGT* (Prediabetes) and/or IFG*, and/or increased HbA1C who are: at high risk for developing overt type 2 diabetes mellitus and still progressing towards type 2 diabetes mellitus despite implementation of intensive lifestyle change 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 dietary management and exercise alone does not result in adequate glycaemic control. Glucophage XR may be used as monotherapy or in combination with other oral antidiabetic agents, or with Insulin.
Dosage/Direction for Use
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 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 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 of Glucophage XR 500 mg, 750 and 1000 mg: The usual starting dose is one tablet of Glucophage XR 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 2000 mg XR once daily with the evening meal.
Dosage increases should be made in increments of 500 mg every 10-15 days, up to a maximum of 2000 mg once daily with the evening meal. If glycaemic control is not achieved on 2000 mg once daily, Glucophage XR 1000 mg twice daily should be considered, with both doses being given with food. If glycaemic control is still not achieved, patients may be switched to Metformin tablets IR tablets to a maximum dose of 3000 mg daily.
Glucophage XR 750 mg and 1000 mg is intended for patients who are already treated with Metformin tablets (prolonged or immediate release). The dose of Glucophage XR 750 mg or 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.
In patients already treated with Metformin tablets, the starting dose of Glucophage XR should be equivalent to the daily dose of Metformin IR tablets. In patients treated with Metformin at a dose above 2000 mg daily, switching to Glucophage XR is not recommended.
If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate Glucophage XR at the dose indicated as previously mentioned.
Combination with Insulin: Metformin hydrochloride and Insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Glucophage XR is 500 mg once daily with the evening meal, while Insulin dosage is adjusted on the basis of blood glucose measurements. After titration, switch to Glucophage XR 1000 mg should be considered.
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 Precautions).
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 and Metformin initiation is therefore not recommended in these patients.
Patients with Renal Impairment: Metformin may be used in patients with moderate renal impairment (creatinine clearance or glomerular filtration rate (GFR) between 30 and 59 mL/min) only in the absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments: Patients with creatinine clearance or a GFR between 45 and 59 mL/min: the starting dose is 500 mg or 750 mg Metformin hydrochloride, once daily. The maximum dose is 1000 mg daily. The renal function should be closely monitored (every 3 - 6 months).
Patients with creatinine clearance or a GFR between 30 and 44 mL/min: it is not recommended to initiate Metformin hydrochloride, but Metformin can be maintained in patients already treated, provided that the maximum daily dose is not higher than 1000 mg. The renal function should be closely monitored every 3 months.
If creatinine clearance or GFR fall below 30 mL/min, Metformin must be discontinued immediately.
Children: In the absence of available data, Glucophage XR should not be used in children.
Overdosage
Hypoglycaemia has not been seen with Metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of Metformin hydrochloride 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.
Contraindications
Hypersensitivity to Metformin or to any of the excipients.
Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis).
Diabetic pre-coma.
Severe renal failure or renal dysfunction (creatinine clearance or GFR <30 mL/min).
Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see Precautions).
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.
Elective major surgery (see Precautions).
Hepatic insufficiency, acute alcohol intoxication, alcoholism.
Special Precautions
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 diarrhoea 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 characterised by acidotic dyspnoea, 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 hospitalised (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 creatinine clearance or GFR be determined before initiating treatment and regularly thereafter: at least annually in patients with normal renal function,
at least two to four times a year in patients with creatinine clearance or GFR at the lower limit of normal or between 45 and 59 mL/min and in elderly subjects.
at least four times a year in patients with creatinine clearance or GFR between 30 and 44 mL/min. In case creatinine clearance or GFR is <45 mL/min, it is not recommended to initiate Metformin.
In case creatinine clearance or GFR is <30 mL/min, Metformin is contraindicated (see Contraindications). Special caution should be exercised in situations where renal function may become impaired, for example in the elderly, in case of dehydration, or when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). 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).
Administration of Iodinated Contrast Materials: The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce Metformin accumulation and may expose to lactic acidosis. Therefore, depending on the renal function, Metformin must be discontinued 48 hours before the test or from the time of the test and may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Interactions).
Surgery: Metformin must be discontinued 48 hours before elective major surgery. Therapy may be restarted no earlier than 48 hours following surgery and only after renal function has been re-evaluated and found to be normal.
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. Sulfonylureas or Meglitinides).
The tablet shells may be present in the feces. It is recommended that patients be advised that this is normal.
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. Sulfonylureas, Insulin, or Meglitinides).
Use In Pregnancy & 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 fetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
However, when the patient plans to become pregnant and during pregnancy, diabetes should not be treated with Metformin but Insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.
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 should be made whether to discontinue breast-feeding or to discontinue Metformin, taking into account the benefit of breast-feeding and the potential risk to adverse effect in the infant.
Adverse Reactions
The following adverse 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.
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 aetiology is recommended if a patient presents with megaloblastic anaemia.
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: Liver function tests abnormalities or hepatitis resolving upon Metformin discontinuation.
Skin and Subcutaneous Tissue Disorders: Very rare: Skin reactions such as erythema, pruritus, urticaria.
Drug Interactions
Contraindicated Combinations: Iodinated contrast materials: Depending on the renal function, Metformin must be discontinued 48 hours before the test or from the time of the test and may not be reinstituted until 48 hours afterwards (see Contraindications and Precautions).
Concomitant Use Not Recommended: Alcohol: The risk of lactic acidosis is increased in acute alcohol intoxication, particularly in case of fasting or malnutrition, hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medicinal product.
Combinations Requiring Precautions for Use: Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids and tetracosactides (systemic and local routes), beta-2-agonists, Danazol, Chlorpromazin at high dosages of 100 mg per day and 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 discontinuation.
Diuretics especially loop diuretics: They may increase the risk of lactic acidosis due to their potential to decrease renal function.
Organic cation transporters (OCT): 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 Metformin plasma concentration.
Inhibitors of both OCT1 and OCT2 (such as Crizotinib, Olaparib) may alter efficacy and renal elimination of Metformin.
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.
Storage
Store below 30°C.
MIMS Class
ATC Classification
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.
Presentation/Packing
PR tab 500 mg x 8 x 15's. 750 mg x 8 x 15's. 1,000 mg x 12 x 10's.
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