Glumet/Glumet-XR

Glumet tab: 500 mg: White, round, plain on one side and with "LRII" logo on the other side.
850 mg: White to off-white, oval, film-coated, scored on one side and plain on the other side.
1 g: White to off-white, elliptical, bisected on one side and plain on the other side.
Each tablet contains: Metformin hydrochloride 500 mg, 850 mg or 1 g.
Glumet-XR XR tab: White, elliptical, plain, biconvex.
Each extended-release tablet contains: Metformin hydrochloride 500 mg.
Glumet-XR PR tab: White to off-white, oval, biconvex, bevel-edged, uncoated tablet with occasionally mottled appearance, debossed '089' on one side and plain on other side.
Each prolonged-release tablet contains: Metformin hydrochloride 1,000 mg (equivalent to 780 mg Metformin).

Oral Hypoglycemic.
Pharmacology: Pharmacodynamics: Metformin is a biguanide antidiabetic agent that reduces both basal and postprandial plasma glucose concentrations in patients with type 2 diabetes mellitus by improving both peripheral and hepatic sensitivity to insulin. It does not stimulate insulin secretion and therefore does not produce hypoglycemia when used alone. Fasting insulin levels and day-long insulin response remain the same or may even decrease with metformin therapy.
Metformin may act via three mechanisms: It reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; increases insulin sensitivity in the skeletal muscles and adipocytes, improving peripheral glucose uptake and utilization; delays intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. It also increases the transport capacity of all types of membrane glucose transporters.
Metformin has demonstrated modest favorable effects on lipid metabolism in patients with type 2 diabetes. It lowers total cholesterol, mean fasting serum triglycerides and low density lipoprotein cholesterol levels; it has no adverse effects on other lipid levels.
Pharmacokinetics: Metformin HCl is slowly and incompletely absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of metformin HCl tablet under fasting conditions is approximately 50 to 60% with metformin HCl doses of 500 mg to 1,500 mg. Single doses of metformin HCl 500 mg to 1,500 mg show lack of dose proportionality with increasing doses which is due to decreased absorption rather than altered elimination.
Metformin distributes rapidly to peripheral body tissues and fluids. It also appears to distribute slowly into erythrocytes and into a deep tissue compartment. Metformin is negligibly bound to plasma proteins. Steady-state plasma concentrations of metformin are generally <1 mcg/mL and are reached within 24 to 48 hours at usual clinical doses and dosing schedules.
Renal elimination of metformin is via glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug. The principal plasma elimination half-life of metformin is about 6.2 hours with 90% of the total dose being cleared within 24 hours in patients with normal renal function. In the blood, the elimination half-life is about 17.6 hours.
Special Populations: Renal Insufficiency: The plasma and blood half-life of metformin is prolonged and the renal clearance decreased in proportion to the decrease in creatinine clearance in patients with decreased renal function (based on measured creatinine levels).
Geriatrics: The limited pharmacokinetic data of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, half-life is prolonged, and C_max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily related to a change in renal function.
Pediatrics: After oral administration of a single metformin HCl 500 mg tablet with food, C_max and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years old) compared with healthy adults (20 to 45 years old), all with normal renal function.
The safety and efficacy of metformin HCl extended-release and prolonged-release tablet has not been established in pediatric patients. Pharmacokinetic studies have not been conducted in these patients.
Glumet tab 500 mg and 1 g/Glumet-XR XR tab: Metformin HCl immediate-release (Glumet) 1 g tablet and extended-release (Glumet-XR) 500 mg tablet were shown to be bioequivalent to the reference product (innovator) in adults under fasting conditions. The following are important pharmacokinetic parameters of metformin in adult volunteers who received immediate-release metformin HCl (Glumet) 1 g tablet (as a single oral dose) and extended-release metformin HCl (Glumet-XR) 500 mg tablet (two 500-mg tablets given once a day for three days) under fasting conditions: See Tables 1 and 2.

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Metformin HCl extended-release tablet is intended for once-a-day dosing. Once-a-day dosing is possible through control of metformin release rate and prolonging absorption in the upper gastrointestinal tract.
Glumet-XR PR tab: Metformin HCl prolonged-release tablet is intended for once-a-day dosing. Once-a-day dosing is possible through control of metformin release rate and prolonging absorption in the upper gastrointestinal tract.
At steady-state, after administration of metformin HCl prolonged-release tablet, the AUC and peak plasma concentrations are not dose proportional within the range of 500 mg to 2,000 mg. Time to reach maximum plasma concentrations (T_max) is approximately 7 hours (range from 4 to 8 hours). The extent of metformin absorption (based on AUC) for metformin HCl prolonged-release tablet at 2,000 mg once a day dose is similar as that for metformin HCl immediate-release tablet at 1,000 mg twice a day dose.

Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.
Metformin may be used as monotherapy or in combination with other oral antidiabetic agents or with insulin.

General Dosing Recommendations: There is usually no fixed dosage regimen with any antidiabetic agent for the management of hyperglycemia in patients with diabetes mellitus. Dosage of metformin HCl tablets must be individualized based on both effectiveness and tolerance while not exceeding the maximum recommended daily doses.
During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to metformin HCl tablet and identify the minimum effective dose. Thereafter, glycosylated hemoglobin (HbA_1c) should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin when used as monotherapy or in combination with other oral antidiabetic agents or insulin.
Monitoring of glycemic control through frequent measurements of fasting blood glucose and periodic testing of HbA_1c will detect primary failure (i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication), and secondary failure (i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness).
It is recommended that metformin HCl be administered with meals to ensure optimum delivery of metformin to the systemic circulation and minimize gastric intolerance. Administration of metformin in the fed state has been shown to significantly increase the systemic delivery of metformin compared to the fasted state.
Transfer from Metformin HCl Immediate-Release Tablet to Metformin HCl Extended-Release or Sustained-Release Tablet or Metformin HCl Prolonged-Release Tablet: In patients already treated with metformin HCl immediate-release tablet, the starting dose of metformin HCl extended-release or sustained-release or prolonged-release tablet should be equivalent to the daily dose of metformin HCl immediate-release tablet. Switching to metformin HCl extended-release or sustained-release or prolonged-release is not recommended in patients treated with metformin HCl immediate-release at doses above 2,000 mg per day. If glycemic control is still not achieved with metformin HCl extended-release or sustained-release or prolonged-release tablets 2,000 mg per day, patients may be switched to metformin HCl immediate-release up to a maximum dose of 3,000 mg (Glumet tab 500 mg & 1 g/Glumet-XR XR tab) or 2,550 mg (Glumet tab 850 mg/Glumet-XR PR tab) per day.
Transfer from Other Antidiabetic Therapy: No transition period is generally necessary when transferring patients from standard oral hypoglycemic agents other than chlorpropamide. When transferring patients from chlorpropamide, exercise caution during the first two weeks because overlapping drug effects and hypoglycemia may occur due to prolonged retention of chlorpropamide in the body.
Concomitant Metformin and Oral Sulfonylurea Therapy: Gradual addition of an oral sulfonylurea while continuing maximum dose metformin therapy may be considered in patients who have not responded to four weeks of maximum dose metformin therapy.
Consider alternative therapies such as insulin (with or without metformin) if response to 1 to 3 months maximum dose of sulfonylurea and metformin combination therapy remains unsatisfactory.
Glumet tab 500 mg & 1 g/Glumet-XR XR tab: See Table 3.

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Recommended Oral Dose of Immediate-Release Metformin Tablet in Children 10 to 16 years Old with Type 2 Diabetes Mellitus: Usual starting dose: 500 mg twice a day, given with meals.
Dosage may be increased by 500 mg weekly up to a maximum of 2,000 mg daily given in divided doses.
The efficacy and safety of extended-release metformin in pediatric patients have not been established.
Concomitant Metformin and Insulin Therapy: The current insulin dose should be continued upon initiation of metformin therapy.
Initial Oral Dose of Metformin HCl Tablet: 500 mg once a day.
Metformin dose may be increased by 500 mg after approximately one week and by 500 mg every week thereafter until adequate glycemic control is achieved.
Maximum Recommended Daily Dose with Insulin: 2,500 mg.
It is recommended that the insulin dose be reduced by 10 to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL. Individualize further dose adjustments based on patient response in patients receiving metformin with insulin.
Or, as prescribed by a physician.
Glumet tab 850 mg: See Table 4.

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Recommended Oral Dose in Children 10 to 16 Years Old: Usual starting dose: 500 mg two times a day or 850 mg once a day with meals.
Dosage may be increased by 500 mg weekly up to a maximum of 2,000 mg per day given in divided doses.
The efficacy and safety of extended-release or sustained-release metformin in pediatric patients have not been established.
Concomitant Metformin and Insulin Therapy: The current insulin dose should be continued upon initiation of metformin therapy.
Initial Oral Dose of Metformin HCl Tablet: 500 mg or 850 mg once a day.
Metformin dose may be increased by 500 mg after approximately one week and by 500 mg every week thereafter until adequate glycemic control is achieved.
Maximum Recommended Daily Dose with Insulin: 2,550 mg.
It is recommended that the insulin dose be reduced by 10 to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL. Individualize further dose adjustments based on patient response in patients receiving metformin with insulin.
Glumet-XR PR tab: See Table 5.

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Dosage in Patients with Renal Impairment: Metformin HCl may be used in patients with moderate renal impairment [estimated glomerular filtration rate (eGFR) between 30 and <60 mL/min/1.73 m²)] only in the absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments: See Table 6.

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Concomitant Metformin and Insulin Therapy: The current insulin dose should be continued upon initiation of metformin therapy.
Initial Oral Dose of Metformin HCl Tablet: 500 mg once a day.
Metformin dose may be increased by 500 mg after approximately one week and by 500 mg every week thereafter until adequate glycemic control is achieved.
Maximum Recommended Daily Dose with Insulin: 2,000 mg.
It is recommended that the insulin dose be reduced by 10 to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL. Individualize further dose adjustments based on patient response in patients receiving metformin with insulin.

There were no cases of overdose reported in clinical studies. Symptoms of metformin overdose include extensions of the common adverse effects (e.g., epigastric discomfort, nausea, vomiting, diarrhea, drowsiness, weakness, dizziness, malaise, and headache). Should these symptoms occur, lactic acidosis should be excluded. Metformin therapy should be discontinued and proper supportive therapy should be instituted.
Metformin ingestion of up to 50 g has been reported. Hypoglycemia was reported in 10% of cases, but no causal relationship with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Hypersensitivity to metformin HCl or to any ingredient in the product.
Unstable and/or type 1 (insulin-dependent) diabetes mellitus.
History of lactic acidosis irrespective of precipitating factors.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Treat diabetic ketoacidosis with insulin.
Severe renal impairment (eGFR <30 mL/min/1.73 m²).
Acute conditions with the potential to alter renal function such as: Dehydration due to persistent or severe diarrhea, recurrent vomiting; Severe infection; Diagnostic examinations (e.g., intravenous urography, angiography) that would involve the use of iodinated contrast agents/media.
Acute or chronic disease which may cause tissue hypoxia such as: Cardiac or respiratory failure; Recent myocardial infarction; Shock.
Acute or chronic alcoholism.
Severe liver disease.
Pregnancy or breastfeeding.

Warning on Lactic Acidosis: Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation during treatment. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, and any condition associated with hypoxia.
Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), reduced blood pH, electrolyte disturbance with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
Lactic acidosis is usually accompanied by nonspecific symptoms such as acidotic dyspnea, vomiting, abdominal pain with muscle cramps, and/or a general feeling of malaise with severe fatigue. Hypothermia followed by coma, hypotension, and resistant bradyarrhythmias may be seen with marked acidosis. Instruct patients to immediately alert their physicians if these symptoms occur. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful.
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialyzable, prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.
Do not use metformin in patients with congestive heart failure receiving drugs such as digoxin and furosemide because of the risk of hypoperfusion and hypoxemia which may lead to lactic acidosis.
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. 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 anhydrase 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.
If metformin-associated lactic acidosis is suspected, immediately discontinue metformin HCl and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that occurs due to metformin accumulation during treatment. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of the drug. 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 is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
The risk factors for the development of metformin-associated lactic acidosis and the recommendations to reduce and manage metformin-associated lactic acidosis include the following: Renal Impairment: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function.
Before initiating metformin therapy, obtain the patient's eGFR. The eGFR should be determined at least annually in all patients taking metformin. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently (e.g., every 3 to 6 months).
Initiating metformin therapy in patients with eGFR between 30 to 45 mL/min/1.73 m² is not recommended. In patients taking metformin whose eGFR falls below 45 mL/min/1.73 m², the benefits and risks of continuing treatment should be assessed. Discontinue metformin if the patient's eGFR later falls below 30 mL/min/1.73 m². Metformin is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².
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. Consider more frequent monitoring of patients.
Age 65 Years or Older: 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.
Radiologic 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. 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 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: 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 cause prerenal azotemia. Promptly discontinue metformin when such events occur.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism. Excessive alcohol intake on an acute or chronic basis should be avoided in patients receiving metformin.
Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Avoid use of metformin in patients with clinical or laboratory evidence of hepatic disease.
Monitoring of Renal Function: Impaired renal function would increase the risk of metformin accumulation and lactic acidosis. Renal function should be assessed and verified as normal before initiation of metformin therapy. Estimated glomerular filtration rate (eGFR) should be determined 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.
Initiating metformin HCl therapy in patients with eGFR between 30 to 45 mL/min/1.73 m² is not recommended. In patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m², the benefits and risks of continuing treatment should be assessed. Discontinue metformin if the patient's eGFR later falls below 30 mL/min/1.73 m².
Medications which may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin (i.e., cationic drugs) should be used with caution since these drugs are eliminated by renal tubular secretion.
Macrovascular Outcomes: Macrovascular risk reduction with the use of metformin or any antidiabetic drug has not been established in clinical studies.
Radiologic Studies: Administration of parenteral iodinated contrast agents has led to an acute decrease in renal function and the occurrence of lactic acidosis in patients receiving metformin. 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, 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, and restart metformin if renal function is stable.
Hypoxic States: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. Promptly discontinue metformin when such events occur in patients on metformin HCl therapy.
Surgical Procedures: Temporarily discontinue metformin use in patients undergoing surgery associated with restricted food or fluid intake. Metformin therapy may be reinstituted when the patient's oral intake has resumed and renal function has been found normal.
Impaired Hepatic Function: Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease since impaired hepatic function has been associated with lactic acidosis.
Alcohol: Combined use of alcohol and metformin may increase the risk of hypoglycemia and lactic acidosis since alcohol decreases lactate clearance and hepatic gluconeogenesis, and may increase insulin secretion. Excessive alcohol intake on an acute or chronic basis should be avoided in patients receiving metformin.
Vitamin B₁₂ Levels: Evaluate hematologic parameters prior to initiation of metformin therapy and at least annually. Impairment of vitamin B₁₂ absorption has been reported in some patients, and long-term treatment with metformin has been associated with reductions in vitamin B₁₂ serum levels. Periodic measurements of serum vitamin B₁₂ levels should be performed in patients on long-term treatment with metformin, particularly in patients with anemia or neuropathy.
Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemia. It may be difficult to recognize hypoglycemic states in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Maintaining Adequate Glycemic Control during Periods of Stress: Temporary discontinuation of metformin and administration of insulin may be necessary in periods of stress such as fever, trauma, infection, or surgery to maintain adequate glucose control. Metformin may be reinstituted after the acute episode is resolved.
Hypothyroidism: Metformin induces a reduction in thyrotropin [thyroid stimulating hormone (TSH)] levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism.
Effects on Ability to Drive and Use Machines: Patients should be warned about driving a vehicle or operating machinery under conditions where risk of hypoglycemia is present.
Use in Children: The use of metformin HCl immediate-release tablet has been established in pediatric patients 10 to 16 years old with type 2 diabetes.
The safety and efficacy of metformin HCl extended-release, prolonged-release or sustained-release tablet have not been established in these patients.
Use in the Elderly: Aging is associated with reduced renal function and metformin is known to be substantially excreted in the kidney. The risk of serious adverse reactions to metformin is greater in patients with reduced/impaired renal function especially in the elderly. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, dose of elderly patients should not be titrated to the maximum dose. Metformin treatment should not be initiated in patients ≥80 years old unless creatinine clearance demonstrates that renal function is not reduced.

Pregnancy: Pregnancy Category B. Oral hypoglycemic agents (including metformin) are not recommended during pregnancy. Maintaining blood glucose levels as close to normal as possible is necessary during pregnancy since abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is recommended during pregnancy.
Lactation: Metformin is excreted into human milk and should therefore not be used by breastfeeding mothers. The importance of metformin HCl to the mother should be considered when deciding whether to discontinue breastfeeding or discontinue metformin because the potential for hypoglycemia in breastfeeding infants may exist. Consider insulin therapy for adequate glycemic control if metformin HCl is discontinued.

Metformin may provoke or augment lactic acidosis particularly if it is present in high concentrations in the blood. Some of the symptoms of lactic acidosis may mimic certain adverse effects of metformin. Physicians should instruct their patients to recognize the onset of symptoms of lactic acidosis to avoid this adverse reaction.
The most frequent adverse effects reported with metformin include nausea, vomiting, diarrhea, abdominal pain and loss of appetite. These adverse effects occur during initiation of treatment and resolve spontaneously in most cases.
Blood and lymphatic system disorders: Decrease in serum vitamin B₁₂, hemolytic anemia, megaloblastic anemia (rare); serum folic acid concentrations do not appear to decrease substantially in patients receiving metformin.
Metabolism and nutrition disorders: Hyperglycemia, hypoglycemia (may occur when metformin is given concomitantly with sulfonylureas and/or alcohol), hypomagnesemia, lactic acidosis, loss of appetite, weight decreased.
Nervous system disorders: Agitation, dizziness, headache, lightheadedness, peripheral neuropathy (in patients with vitamin B₁₂ deficiency).
Cardiac disorders: Chest discomfort, palpitations.
Vascular disorders: Flushing, hypertension.
Respiratory, thoracic and mediastinal disorders: Dyspnea, flu syndrome, pneumonitis with vasculitis, rhinitis, upper respiratory infection.
Gastrointestinal disorders: Abdominal discomfort (e.g., bloating, abdominal cramps), abdominal distention, abdominal pain, abnormal stools/loose stools, anorexia, constipation, dry mouth, dyspepsia/heartburn, epigastric discomfort, flatulence, gastric disorder, gastric ulcer, gastrointestinal disorder, indigestion, nausea, vomiting, taste disturbance specifically metallic taste in the mouth.
Hepatobiliary disorders: Abnormal liver function tests, autoimmune hepatitis, cholestasis, cholestatic, hepatocellular, and mixed hepatocellular liver injury, hepatic injury, hepatitis, pancreatitis.
Skin and subcutaneous tissue disorders: Dermatitis, erythema, nail disorder, photosensitivity, pruritus, rash, skin lesion, urticaria.
Musculoskeletal and connective tissue disorders: Asthenia, chills, musculoskeletal pain, myalgia.
Renal and urinary disorders: Urinary tract infection.
General disorders and administration site conditions: Fatigue, increased sweating.
Investigations: Increased blood lactic acid, decreased thyrotropin level (in patients with treated or untreated hypothyroidism).
Glumet-XR PR tab: Nervous system disorders: Agitation, dizziness, encephalopathy, headache, lightheadedness, peripheral neuropathy (in patients with vitamin B₁₂ deficiency).
Gastrointestinal disorders: Abdominal discomfort (e.g., bloating, abdominal cramps), abdominal distention, abdominal pain, abnormal stools/loose stools, anorexia, constipation, diarrhea, dry mouth, dyspepsia/heartburn, epigastric discomfort, flatulence, gastric disorder, gastric ulcer, gastrointestinal disorder, indigestion, nausea, vomiting, taste disturbance specifically metallic taste in the mouth.

Carbonic Anhydrase Inhibitors: Carbonic anhydrase inhibitors (e.g., topiramate, zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
Organic Cation Transporters (OCT)/Multidrug and Toxin Extrusion (MATE) Inhibitors: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.
Coadministration of metformin with inhibitors of OCT1 (e.g., verapamil) may reduce efficacy of metformin. Inducers of OCT1 (e.g., rifampicin) may increase gastrointestinal absorption and efficacy of metformin. Inhibitors of OCT2 (e.g., 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 (e.g., crizotinib, olaparib) may alter efficacy and renal elimination of metformin. Therefore, caution is advised particularly in patients with renal impairment, when these drugs are coadministered with metformin, as metformin plasma concentration may increase. Dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.
Cationic Drugs: Cationic drugs such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin that are eliminated by renal tubular secretion, theoretically may cause an increase in metformin peak plasma concentrations, whole blood concentrations and whole blood AUC by competing with metformin for common renal tubular transport systems. Concomitant administration of metformin and cimetidine has been observed to result in reduced urinary metformin excretion and increased plasma metformin concentrations.
Other Antidiabetic Agents: Hypoglycemia may occur when metformin is used concomitantly with other antidiabetic agents such as sulfonylureas, meglitinides, glitazones, or insulin.
Diuretics: Thiazide diuretics may exacerbate diabetes mellitus and may result in increased requirements of oral antidiabetic agents, metformin included. Temporary loss of diabetic control or secondary failure to the antidiabetic agent may also occur. Potassium-sparing diuretics, which are less diabetogenic, may be considered as a substitute.
Furosemide may increase metformin plasma and blood concentrations and blood AUC without significantly affecting metformin renal clearance.
Nifedipine: Nifedipine increases the absorption, C_max and AUC of metformin, and increases metformin excretion in the urine. Metformin has minimal effects on nifedipine pharmacokinetics.
β-Adrenergic Blocking Agents: β-adrenergic blocking agents (e.g., propranolol, nadolol) may impair glucose tolerance and mask the true frequency or severity of hypoglycemia, block hypoglycemia-induced tachycardia but not hypoglycemic sweating, delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia, and impair peripheral circulation. Use these drugs with caution in patients with type 2 diabetes.
Protein-Bound Drugs: Interaction of metformin and highly protein-bound drugs (e.g., salicylates, sulfonamides, chloramphenicol, probenecid) is unlikely because metformin is negligibly bound to plasma proteins.
Angiotensin-Converting Enzyme (ACE) Inhibitors: ACE inhibitors (e.g., captopril, enalapril) may reduce fasting blood glucose concentrations. These drugs have also been associated with unexplained hypoglycemia in diabetic patients. Caution should be exercised when administering metformin together with ACE inhibitors to prevent severe hypoglycemia.
Alcohol: There is an increased risk of hypoglycemia and lactic acidosis when alcohol and metformin are used concomitantly since alcohol decreases lactate clearance and hepatic gluconeogenesis, and may increase insulin secretion. Acute or chronic intake of alcohol should be avoided in patients receiving metformin therapy.
Clomifene: Ovulatory response may be increased when clomifene and metformin are used concomitantly in premenopausal patients with polycystic ovary syndrome.
Anticoagulants: Metformin may affect the pharmacokinetic properties of coumarin anticoagulants when administered concomitantly. An increase in prothrombin time may occur upon cessation of metformin therapy, with an increased risk of hemorrhage. Patients receiving phenprocoumon or other vitamin K anticoagulants should be carefully monitored.
Iodinated Contrast Media: Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin accumulation with the risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the procedure, and withheld for 48 hours afterwards. Metformin may be reinstituted only after renal function has been re-evaluated and found to be normal.
Glibenclamide (Glyburide): Concomitant administration of metformin and glyburide produced no changes in metformin pharmacokinetics and pharmacodynamics. Decreases in C_max, blood AUC of glyburide were observed, but were highly variable. The clinical significance of this finding was unclear.
Levothyroxine: Levothyroxine may reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and metformin dosage adjusted as necessary.
Drugs Affecting Glycemic Control: Drugs that may cause hyperglycemia and may exacerbate loss of glycemic control in patients with diabetes include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. Close monitoring of glycemic control and metformin dose adjustments are recommended when such drugs are administered or withdrawn in patients.
Drugs Affecting Renal Function: Drugs that may adversely affect renal function and may increase the risk of lactic acidosis include nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics (particularly loop diuretics). When starting or using these drugs in combination with metformin, close monitoring of renal function is required.
Others: The pharmacokinetics of propranolol and ibuprofen were not affected by metformin when coadministered in single-dose interaction studies in healthy volunteers.

Store at temperatures not exceeding 30°C.
Glumet-XR PR tab: Protect from light and moisture.

Antidiabetic Agents

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

Rx