Each tablet contains: Metformin Hydrochloride BP 500mg.
Pharmacology: Pharmacodynamics: Mechanism of Action: Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypogylycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacokinetics: The absolute bioavailability of Metformin tablet given under fasting conditions is approximately 50-60%. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower under the plasma concentration time curve (AUC) and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850mg tablet of metformin with food, compared to the same tablet strength administered fasting. The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin averaged 654+/- 358 L/Metformin is negligibly bound to plasma proteins in contrast to sulfonylureas which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time.
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 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
For the treatment of type II diabetes mellitus. In adults, it may be used as monotherapy or in combinations with other oral antidiabetic agents or with insulin. In children from 10 years of age and adolescents, it may be used as monotherapy or in combination with insulin.
The maximum recommended daily dose of Metformin is 2550mg in adults and 200mg in pediatric patients (10-16 years of age). Metformin should be given in divided doses with meals. Metformin should be started at a low dose with gradual dose escalation to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
During treatment initiation and dose tritration, fasting plasma glucose should be used to determine the therapeutic response to Metformin and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 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 sulfonylurea or insulin. Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication and secondary failure, i.e., loss of an adequate blood glucose lowering responses after an initial period of effectiveness. Short-term administration of metformin may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Adults: The usual starting dose of metformin tablets is 500 mg twice a day or 850 mg once a day, given with meals. In general, clinically significant responses are not seen at doses below 1500 mg per day. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. The dosage of metformin must be individualized on the basis of both effectiveness and tolerability. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given 3 times a day with meals.
Pediatrics: The usual starting dose of Metformin is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. The dosage of Metformin must be individualized on the basis of both effectiveness and tolerability.
Renal impairment: Assess renal function prior to initiation of Metformin and periodically thereafter.
Contraindicated in patients with estimated glomelular filtration rate below 30mL/minute/1.73m2.
In patients with glomelular filtration rate between 30-45 mL/minute/1.73m2 is not recommended.
In patients whose glomelular filtration rate later falls below 45 mL/minute/1.73m2, assess the benefit risk of continuing therapy.
Discontinue if the patient's glomelular filtration rate later falls below 30 mL/minute/1.73m2.
Discontinue Metformin at the time of or prior to an iodinated contrast imaging procedure in patients with an glomelular filtration rate between 30 and 601 mL/min/1.73m2; in patients with history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate glomelular filtration rate 48 hours after the imaging procedure; restart metformin if renal function is stable.
If patients have not responded to 4 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, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).
With concomitant Metformin and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial patients with type 2 diabetes and prior failure on glyburide, patients started on metformin 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of Metformin and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response. However attempts should be made to identify the minimum effective dose of each drug to achieve this goal with concomitant metformin and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken.
If patients have not satisfactorily responded to 1 to 3 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.
The current insulin dose should be continued upon initiation of metformin therapy. Metformin therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin should be increased by 500 mg after approximately 1 week and by 500mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for metformin. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120mg/dL in patients receiving concomitant insulin and metformin. Further adjustment should be individualized based on glucose-lowering response.
Pregnancy: Metformin is not recommended for use in pregnancy.
Metformin is not recommended in patients below the age of 10 years.
The initial maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function.
Symptoms: Hypoglycemia is not normally a problem encountered with metformin when used alone. In combination therapy with a sulfonylurea or insulin with alcohol, hypoglycemia can occur. In excessive dosage particularly, if there is a possibility of accumulation, lactic acidosis should be suspected. Some of the signs and symptoms suggestive of this condition are nausea, diarrhea, abdominal pain and dyspnea.
Treatment: Intensive supportive therapy is recommended which should be particularly directed at correcting fluid loss and metabolic disturbance. The most effective method to remove lactate and metformin is hemodialysis.
Metformin is contraindicated in patients with: Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5mg/dL (males), ≥1.4 mg/dL (females) or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse shock), acute myocardial infarction, and septicemia.
Congestive heart failure requiring pharmacologic treatment.
Known hypersensitivity to metformin hydrochloride.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration iodinated contrast materials, because use of such products may result in acute alteration of renal function.
Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during treatment with Metformin when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus and whenever there is significant tissue hypoperfusion and hypoxemia. In case of dehydration (severe diarrhea or vomiting, fever or reduced fluid intake), metformin should be temporary discontinued and contact with a health care professional is recommended. Lactic acidosis is characterized by acidotic dyspnea, 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 (>5mmol/L), increased anion gap & lactate/pyruvate ratio.
General: Monitoring of renal function: 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. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin. In patients with advanced age, Metformin should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those 80 years of age, renal function should be monitored regularly and generally, Metformin should not be titrated to the maximum dose. Before initiation of Metformin therapy and at least annually thereafter, renal function should be assessed and verified as normal.
In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution. Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography and computed tomography (CT) scans with intravascular contrast materials). Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin.
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. When such events occur in patients on Metformin, the drug should be promptly discontinued.
Surgical procedures: metformin therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warmed against excessive alcohol intake, acute or chronic, while receiving metformin.
Impaired hepatic function: Since impaired hepatic function has been associated with some cases of lactic acidosis, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Measurement of hematologic parameters on an annual basis is adviced in patients on metformin and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two to three year intervals may be useful.
Lactic acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation.
Metformin is not recommended for use in pregnancy.
Metformin is normally well tolerated, although as with all drugs, unwanted adverse effects sometimes occur. The most common adverse effects are gastrointestinal disturbances, generally lasting only for the first few days of treatment. This can usually be avoided by starting with a low dose and by taking metformin with meal. Very rarely, lactic acidosis has been associated with Metformin treatment. Virtually all reported cases, however, have involved patients with contraindications to treatment or in acute overdose. It is therefore important that the contraindications are strictly adhered to. Other common adverse effect is taste disturbance and very rarely, decrease of Vit. B12 absorption with decrease of serum levels during long-term use of metformin, hepatitis and skin reactions (i.e., erythema, pruritus, urticaria).
Glyburide: In a single dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide does not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed but were highly variable. The single dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain.
Furosemide: A single dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone and the terminal half-life was decreased by 32% without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
Nifedipine: A single dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9% respectively and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metfomin. Metformin had minimal effects on nifedipine.
Cationic drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between and oral cimetidine has been observed in normal healthy volunteers in both single and multiple dose, metformin-cimetidine drug interaction studies with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in single dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine) careful patient monitoring and dose adjustment of metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving metformin, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, the patient should be observed closely for hypoglycemia.
In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when co-administered in single dose interaction studies.
Metformin is negligibly bound to plasma proteins and is therefore less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol and probenecid as compared to the sulfonylureas which are extensively bound to serum proteins.
Store at temperatures not exceeding 30°C. Protect from light.
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.