There have been no clinical studies establishing conclusive evidence of macrovascular
risk reduction with METAGLIP (glipizide and metformin) or any other antidiabetic drug.
Metaglip (glipizide and metformin)
METAGLIP (glipizide and metformin) is capable of producing hypoglycemia; therefore, proper patient selection,
dosing, and instructions are important to avoid potential hypoglycemic episodes.
The risk of hypoglycemia is increased when caloric intake is deficient, when
strenuous exercise is not compensated by caloric supplementation, or during
concomitant use with other glucose-lowering agents or ethanol. Renal insufficiency
may cause elevated drug levels of both glipizide and metformin hydrochloride.
Hepatic insufficiency may increase drug levels of glipizide and may also diminish
gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions.
Elderly, debilitated, or malnourished patients and those with adrenal or pituitary
insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic
effects. Hypoglycemia may be difficult to recognize in the elderly and people
who are taking beta-adrenergic blocking drugs.
Renal and hepatic disease
The metabolism and excretion of glipizide may be slowed in patients with impaired
renal and/or hepatic function. If hypoglycemia should occur in such patients,
it may be prolonged and appropriate management should be instituted.
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency
with sulfonylurea agents can lead to hemolytic anemia. Because METAGLIP (glipizide and metformin) belongs
to the class of sulfonylurea agents, caution should be used in patients with
G6PD deficiency and a non-sulfonylurea alternative should be considered. In
postmarketing reports, hemolytic anemia has also been reported in patients who
did not have known G6PD deficiency.
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 METAGLIP (glipizide and metformin) . In patients with
advanced age, METAGLIP (glipizide and 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, METAGLIP (glipizide and metformin) should
not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION).
Before initiation of METAGLIP (glipizide and 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 METAGLIP (glipizide and metformin) discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin
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 (see PRECAUTIONS:
DRUG INTERACTIONS), 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 (see CONTRAINDICATIONS). Therefore, in patients in
whom any such study is planned, METAGLIP (glipizide and 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 reevaluated
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 METAGLIP (glipizide and metformin) therapy, the drug should
be promptly discontinued.
METAGLIP (glipizide and 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 METAGLIP (glipizide and metformin) . Due to its effect on the gluconeogenic
capacity of the liver, alcohol may also increase the risk of hypoglycemia.
Impaired hepatic function
Since impaired hepatic function has been associated with some cases of lactic
acidosis, METAGLIP (glipizide and metformin) should generally be avoided in patients with clinical or
laboratory evidence of hepatic disease.
Vitamin B12 levels
In controlled clinical trials with metformin of 29 weeks duration, a decrease
to subnormal levels of previously normal serum vitamin B12, without clinical
manifestations, was observed in approximately 7% of patients. Such decrease,
possibly due to interference with B12 absorption from the B12-intrinsic factor
complex is, however, very rarely associated with anemia and appears to be rapidly
reversible with discontinuation of metformin or vitamin B12 supplementation.
Measurement of hematologic parameters on an annual basis is advised in patients
on metformin and any apparent abnormalities should be appropriately investigated
and managed (see PRECAUTIONS: Laboratory Tests).
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 2- to 3-year intervals
may be useful.
Change in clinical status of patients with previously controlled type 2
A patient with type 2 diabetes previously well controlled on metformin who
develops laboratory abnormalities or clinical illness (especially vague and
poorly defined illness) should be evaluated promptly for evidence of ketoacidosis
or lactic acidosis. Evaluation should include serum electrolytes and ketones,
blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin
levels. If acidosis of either form occurs, METAGLIP (glipizide and metformin) must be stopped immediately
and other appropriate corrective measures initiated (see also WARNINGS).
Information for Patients
Metaglip (glipizide and metformin)
Patients should be informed of the potential risks and benefits of METAGLIP (glipizide and metformin)
and alternative modes of therapy. They should also be informed about the importance
of adherence to dietary instructions; a regular exercise program; and regular
testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic
The risks of lactic acidosis associated with metformin therapy, its symptoms,
and conditions that predispose to its development, as noted in the WARNINGS
and PRECAUTIONS sections, should be explained to patients. Patients should be
advised to discontinue METAGLIP (glipizide and metformin) immediately and promptly notify their health
practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence,
or other nonspecific symptoms occur. Once a patient is stabilized on any dose
level of METAGLIP (glipizide and metformin) , gastrointestinal symptoms, which are common during initiation
of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal
symptoms could be due to lactic acidosis or other serious disease.
The risks of hypoglycemia, its symptoms and treatment, and conditions that
predispose to its development should be explained to patients and responsible
Patients should be counseled against excessive alcohol intake, either acute
or chronic, while receiving METAGLIP. (See PATIENT INFORMATION.)
Periodic fasting blood glucose (FBG) and HbA1c measurements should be performed
to monitor therapeutic response.
Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit
and red blood cell indices) and renal function (serum creatinine) should be
performed, at least on an annual basis. While megaloblastic anemia has rarely
been seen with metformin therapy, if this is suspected, vitamin B12 deficiency
should be excluded.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted with the combined products in METAGLIP (glipizide and metformin) .
The following data are based on findings in studies performed with the individual
A 20-month study in rats and an 18-month study in mice at doses up to 75 times
the maximum human dose revealed no evidence of drug-related carcinogenicity.
Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in
rats of both sexes at doses up to 75 times the human dose showed no effects
Long-term carcinogenicity studies were performed with metformin alone in rats
(dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses
up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses
are both approximately 4 times the maximum recommended human daily (MRHD) dose
of 2000 mg of the metformin component of METAGLIP (glipizide and metformin) based on body surface area
comparisons. No evidence of carcinogenicity with metformin alone was found in
either male or female mice. Similarly, there was no tumorigenic potential observed
with metformin alone in male rats. There was, however, an increased incidence
of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of
There was no evidence of a mutagenic potential of metformin alone in the following
in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse
lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results
in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin alone when administered
at doses as high as 600 mg/kg/day, which is approximately 3 times the MRHD dose
of the metformin component of METAGLIP (glipizide and metformin) based on body surface area comparisons.
Teratogenic Effects - Pregnancy Category C
Recent information strongly suggests that abnormal blood glucose levels during
pregnancy are associated with a higher incidence of congenital abnormalities.
Most experts recommend that insulin be used during pregnancy to maintain blood
glucose as close to normal as possible. Because animal reproduction studies
are not always predictive of human response, METAGLIP (glipizide and metformin) should not be used during
pregnancy unless clearly needed. (See below.)
There are no adequate and well-controlled studies in pregnant women with METAGLIP (glipizide and metformin)
or its individual components. No animal studies have been conducted with the
combined products in METAGLIP (glipizide and metformin) . The following data are based on findings in studies
performed with the individual products.
Glipizide was found to be mildly fetotoxic in rat reproductive studies at all
dose levels (5- 50 mg/kg). This fetotoxicity has been similarly noted with other
sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and
believed to be directly related to the pharmacologic (hypoglycemic) action of
glipizide. In studies in rats and rabbits, no teratogenic effects were found.
Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day.
This represents an exposure of about 2 and 6 times the MRHD dose of 2000 mg
of the metformin component of METAGLIP (glipizide and metformin) based on body surface area comparisons
for rats and rabbits, respectively. Determination of fetal concentrations demonstrated
a partial placental barrier to metformin.
Prolonged severe hypoglycemia (4-10 days) has been reported in neonates born
to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives.
It is not recommended that METAGLIP (glipizide and metformin) be used during pregnancy. However, if it
is used, METAGLIP (glipizide and metformin) should be discontinued at least 1 month before the expected
delivery date. (See Pregnancy: Teratogenic Effects: Pregnancy
Although it is not known whether glipizide is excreted in human milk, some
sulfonylurea drugs are known to be excreted in human milk. Studies in lactating
rats show that metformin is excreted into milk and reaches levels comparable
to those in plasma. Similar studies have not been conducted in nursing mothers.
Because the potential for hypoglycemia in nursing infants may exist, a decision
should be made whether to discontinue nursing or to discontinue METAGLIP (glipizide and metformin) , taking
into account the importance of the drug to the mother. If METAGLIP (glipizide and metformin) is discontinued,
and if diet alone is inadequate for controlling blood glucose, insulin therapy
should be considered.
Safety and effectiveness of METAGLIP (glipizide and metformin) in pediatric patients have not been established.
Of the 345 patients who received METAGLIP (glipizide and metformin) 2.5 mg/250 mg and 2.5 mg/500 mg in
the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%)
were aged 75 and older. Of the 87 patients who received METAGLIP (glipizide and metformin) in the second-line
therapy trial, 17 (19.5%) were aged 65 and older while 1 (1.1%) was at least
aged 75. No overall differences in effectiveness or safety were observed between
these patients and younger patients in either the initial therapy trial or the
second-line therapy trial, and other reported clinical experience has not identified
differences in response between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
Metformin hydrochloride is known to be substantially excreted by the kidney
and because the risk of serious adverse reactions to the drug is greater in
patients with impaired renal function, METAGLIP (glipizide and metformin) should only be used in patients
with normal renal function (see CONTRAINDICATIONS, WARNINGS, and
CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated
with reduced renal function, METAGLIP (glipizide and metformin) should be used with caution as age increases.
Care should be taken in dose selection and should be based on careful and regular
monitoring of renal function. Generally, elderly patients should not be titrated
to the maximum dose of METAGLIP (see also WARNINGS and DOSAGE AND