- Metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults & children (10 years & above) with type 2 diabetes mellitus. A reduction of diabetic complications has been shown in overweight type-2 diabetic adult patient treated with Metformin as first-line therapy after diet failure.
- Obesity & Insulin Resistance
- Polycystic Ovary Syndrome
- Gestational Diabetes
Dosage & Administration
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin. Dosage of Metformin must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Metformin is 2550 mg in adults and 2000 mg 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, both 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 titration fasting plasma glucose should be used to determine the therapeutic response to Metformin and identify the minimum effective dose for the patient. There after, glycosylated hemoglobin should be measured at intervals of approximately 3 months. Short-term administration of Metformin may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Recommended Dosing Schedule
In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. The usual starting dose of Metformin tablets is 500 mg twice a day or 850 mg once a day, given with meals. 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. 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.
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.
Polycystic Ovary Syndrome:
Polycystic ovary syndrome, initially 500 mg with breakfast for 1 week, then 500 mg with breakfast and evening meal for 1 week, then 1.5-1.7 g daily in 2-3 divided doses.
Transfer from Other Antidiabetic Therapy:
When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant Metformin Oral Sulfonylurea Therapy in Adult Patients:
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. With concomitant Metformin and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. 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.
Concomitant Metformin and Insulin Therapy in Adult Patients:
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 500 mg every week there after until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Metformin. It is recommended that the insulin dose to be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin. Further adjustment should be individualized based on glucoselowering response.
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.
Use of Concomitant Medications that May Affect Renal Function or Metformin Disposition:
Concomitant medications that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of Metformin, such as cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) 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. Therefore, in patients in whom any such study is planned, Metformin should be temporarily discontinued at the time of or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
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 therapy, the drug should be promptly discontinued.
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 is known to potentiate the effect of Metformin on lactate metabolism. Patients, therefore, should be warned 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 diseases.
Vitamin B12 Deficiency:
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.
US FDA Approved Pregnancy Category B. During pregnancy, women with pre-existing diabetes can be treated with Metformin, either alone or in combination with insulin.
Metformin can be continued during breast-feeding for those with pre-existing diabetes.
Women with gestational diabetes may be treated with or without concomitant insulin with glibenclamide from 11 weeks gestation or with Metformin. Women with gestational diabetes should discontinue hypoglycaemic treatment after giving birth.