DOSAGE AND ADMINISTRATION
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.)
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