Keep out of reach of children.
Read the directions carefully before use.
For prescription only.
QUALITATIVE AND QUANTITATIVE COMPOSITION:
Active ingredient: Metformin hydrochloride ...............500 mg
Excipients: q.s …………………………………………………… 1 tablet
Box of 10 blisters x 10 extended release tablets.
Glumeform 500 XR is an antihyperglycemic agent including active ingredient - metformin. It belongs to biguanide class. Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both fasting and postprandial plasma glucose. Its mechanisms of action are explained as follows: metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, enhances cellular glucose utilization, improves insulin binding to receptors, and stimulates glucose disintegration via anaerobic pathway. Glumeform 500 XR reduces hyperglycemia in patients suffering from diabetes, but does not produce hypoglycemia (except for cases of fasting or combination with other synergic drugs). The drug also does not produce hypoglycemia in normal subjects.
Metformin not only has antihyperglycemic effect but also usefully influences lipemic components in patients with type 2 diabetes. The drug diminishes the concentration of triglyceride, total cholesterol and LDL cholesterol. The activities of increased fibrinogenolysis and decreased platelet aggregation are recorded in diabetic patients after treatment with metformin.
Absorption and bioavailability
Following a single oral dose of Glumeform 500 XR, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin immediate release tablets, however, the extent of absorption (as measured by AUC) is similar to metformin immediate release tablets. At steady state, the AUC and Cmax are less than dose proportional for Glumeform 500 XR within the range of 500 mg to 2000 mg administered once daily. The extent of metformin absorption from metformin extended release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as a dose of 1000 mg twice daily. After repeated administration of Glumeform 500 XR, metformin did not accumulate in plasma. Within-subject variability in Cmax and AUC of metformin extended release tablets is comparable to that with immediate release tablets. Although the extent of metformin absorption (as measured by AUC) from metformin increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Glumeform 500 XR.
Distribution
Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas. Metformin partitions into erythrocytes. Steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 µg/ml.
Metabolism and elimination
Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination.
Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents.
Metformin is not recommended for use in pregnancy. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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 COX2 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 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.
During treatment initiation, the most common adverse reactions are allergic reactions, nausea, vomiting, diarrhoea, abdominal pain and loss of appetite, which resolve spontaneously in most cases.
Frequencies are defined as follows: very common: (≥1/10); common (≥ 1/100, < 1/10); uncommon (≥1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Metabolism and nutrition disorders
Very rare: Lactic acidosis, decrease of vitamin B12 absorption with decrease of serum levels. Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia.
Nervous system disorders
Common: Taste disturbance.
Gastrointestinal disorders
Very common: Nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. A slow increase of the dose may also improve gastrointestinal tolerability.
Hepatobiliary disorders
Very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritus, urticaria.
Please inform your doctor of all undesirable effects upon drug administration.
Hypoglycemia has not been seen even with ingestion of up to 85 grams of metformin, although lactic acidosis has occurred in such circumstances. Metformin is dialyzable with a clearance of up to 170 ml/min. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Store in dry places, not exceeding 30°C, protect from light.
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 (diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients.
Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis.
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.
Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmia. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anyhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Posology and method of administration, Contraindications, Special warnings and precautions for use, Interactions and Use in special populations).
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin. In metformin treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue metformin and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Posology and method of administration, Clinical Pharmacology]:
- Before initiating metformin, obtain an estimated glomerular filtration rate (eGFR).
- Metformin is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications].
- Initiation of metformin is not recommended in patients with eGFR between 30 - 45 mL/min/1.73 m2.
- Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
- In patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
Drug Interactions: The concomitant use of metformin with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Interactions]. Therefore, consider more frequent monitoring of patients.
Age 65 or greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
Radiological studies with contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin if renal function is stable.
Surgery and other procedures:
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.
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Metformin should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic states: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue metformin.
Excessive alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving metformin.
Hepatic impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin in patients with clinical or laboratory evidence of hepatic disease.
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.
Other precautions: All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides).
Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. Metformin may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.
Severe renal failure (eGFR below 30 mL/min/1.73 m2) [see Special warnings and precautions for use].
Hypersensitivity of any components of the drug. Known hypersensitivity to metformin.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
Diabetic pre-coma.
Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents.
Acute or chronic disease which may cause tissue hypoxia such as: cardiac failure, recent myocardial infarction, respiratory failure, pulmonary embolism, shock, acute significant blood loss, sepsis, gangrene, pancreatitis.
Regular surgery (with cautions).
Severe hepatic insufficiency, acute alcohol intoxication, alcoholism.
Lactation.
Note: Glumeform 500 XR should be taken the whole tablet. Do not break or chew the tablet.
Recommended dosage:
The starting dose of metformin in patients who are not currently taking metformin is 500 mg orally, once daily. Increase the dose in 500 mg increments every 1-2 weeks if a higher dose of metformin is needed and there are no gastrointestinal adverse reactions. The dosage of metformin must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg.
Adults: The therapy should be initiated with one tablet Glumeform 500 XR once daily with the evening meal. After 1 to 2 weeks dose adjustment on the basis of blood glucose measurements is recommended. Dosage increases should be made in increments of 500 mg every 1 to 2 weeks. A slow increase of dose may improve gastro-intestinal tolerability. The maximum recommended dose is 4 tablets of Glumeform 500 XR once daily with the evening meal.
If transfer from another oral antidiabetic agent is intended: Discontinue the other agent and initiate Glumeform 500 XR at the dose indicated above. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Elderly: The metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.
Paediatric population: In the absence of available data, Glumeform 500 XR should not be used in children.
Concomitant metformin and oral sulfonylurea therapy:
If patients have not responded to four weeks of the maximum dose of metformin monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin at the maximum dose. If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin.
Combination with insulin:
Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Glumeform 500 XR is one tablet once daily with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements.
Recommendations for use in renal impairment:
Assess renal function prior to initiation of metformin and periodically thereafter.
Metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.
Initiation of metformin in patients with an eGFR between 30-45 mL/min/1.73 m2 is not recommended.
In patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.
Discontinue metformin if the patient's eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications, Special warnings and precautions for use].
Discontinuation for iodinated contrast imaging procedures.
Discontinue metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable [see Special warnings and precautions for use].
Or as prescribed by the physician.
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