There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with GLUCOPHAGE or GLUCOPHAGE XR or any other pharmacologic agent. Dosage of GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose of GLUCOPHAGE XR in adults is 2000 mg.

GLUCOPHAGE should be given in divided doses with meals while GLUCOPHAGE XR should generally be given once daily with the evening meal. GLUCOPHAGE or GLUCOPHAGE XR 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 (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, either 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 response after an initial period of effectiveness.

Short-term administration of GLUCOPHAGE or GLUCOPHAGE XR may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

GLUCOPHAGE XR tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of GLUCOPHAGE XR will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)

Recommended Dosing Schedule

Adults

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 GLUCOPHAGE (metformin hydrochloride) 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, GLUCOPHAGE 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 GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on GLUCOPHAGE XR 2000 mg once daily, a trial of GLUCOPHAGE XR 1000 mg twice daily should be considered. If higher doses of metformin are required, GLUCOPHAGE should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. (See CLINICAL PHARMACOLOGY: Clinical Studies.)

In a randomized trial, patients currently treated with GLUCOPHAGE were switched to GLUCOPHAGE XR. Results of this trial suggest that patients receiving GLUCOPHAGE treatment may be safely switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from GLUCOPHAGE to GLUCOPHAGE XR, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY: Clinical Studies).

Pediatrics

The usual starting dose of GLUCOPHAGE 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. Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have not been established.

Transfer From Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to GLUCOPHAGE or GLUCOPHAGE XR, 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 GLUCOPHAGE or GLUCOPHAGE XR and Oral Sulfonylurea Therapy in Adult Patients

If patients have not responded to 4 weeks of the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on GLUCOPHAGE 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg, or 2500/20 mg of GLUCOPHAGE and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c, and plasma glucose response (see CLINICAL PHARMACOLOGY: Clinical Studies). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)

If patients have not satisfactorily responded to 1 to 3 months of concomitant therapy with the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without GLUCOPHAGE or GLUCOPHAGE XR.

Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Insulin Therapy in Adult Patients

The current insulin dose should be continued upon initiation of GLUCOPHAGE or GLUCOPHAGE XR therapy. GLUCOPHAGE or GLUCOPHAGE XR therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of GLUCOPHAGE or GLUCOPHAGE XR should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for GLUCOPHAGE and 2000 mg for GLUCOPHAGE XR. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and GLUCOPHAGE or GLUCOPHAGE XR. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations

GLUCOPHAGE or GLUCOPHAGE XR are not recommended for use in pregnancy. GLUCOPHAGE is not recommended in patients below the age of 10 years. GLUCOPHAGE XR is not recommended in pediatric patients (below the age of 17 years).

The initial and maintenance dosing of GLUCOPHAGE or GLUCOPHAGE XR 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. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)