WARNINGS
Special Warning on Increased Risk of Cardiovascular
Mortality
The administration of oral hypoglycemic drugs has been
reported to be associated with increased cardiovascular
mortality as compared to treatment with diet alone or
diet plus insulin. This warning is based on the study
conducted by the University Group Diabetes Program (UGDP),
a long-term, prospective clinical trial designed to evaluate
the effectiveness of glucose-lowering drugs in preventing
or delaying vascular complications in patients with non-insulin-dependent
diabetes. The study involved 823 patients who were randomly
assigned to one of four treatment groups.1
UGDP reported that patients treated for 5 to 8 years
with diet plus a fixed dose of tolbutamide (1.5 grams
per day) had a rate of cardiovascular mortality approximately
2½ times that of patients treated with diet alone.
A significant increase in total mortality was not observed,
but the use of tolbutamide was discontinued based on the
increase in cardiovascular mortality, thus limiting the
opportunity for the study to wshow an increase in overall
mortality. Despite controversy regarding the interpretation
of these results, the finding of the UGDP study provide
an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of glimepiride
tablets and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide)
was included in this study, it is prudent from a safety
standpoint to consider that this warning may also apply
to other oral hypoglycemic drugs in this class, in view
of their close similarities in mode of action and chemical
structure.
PRECAUTIONS
General
Hypoglycemia: All sulfonylurea drugs are
capable of producing severe hypoglycemia. Proper patient
selection, dosage, and instructions are important to avoid
hypoglycemic episodes. Patients with impaired renal function
may be more sensitive to the glucose-lowering effect of
glimepiride. A starting dose of 1 mg once daily followed
by appropriate dose titriation is recommended in those patients.
Debilitated or malnourished patients, and those with adrenal,
pituitary, or hepatic insufficiency are particularly susceptive
to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia
may be difficult to recognize in the elderly and in people
who are taking beta-adrenergic blocking drugs or other sympatholytic
agents. Hypoglycemia is more likely to occur when caloric
intake is deficient, after severe or prolonged exercise,
when alcohol is ingested, or when more than one glucose-lowering
drug is used. Combined use of glimepiride with insulin or
metformin may increase the potential for hypoglycemia.
Loss of Control of Blood Glucose: When
a patient stabilized on any diabetic regimen is exposed
to stress such as fever, trauma, infection, or surgery,
a loss of control may occur. At such times, it may be necessary
to add insulin in combination with glimepiride or even use
insulin monotherapy. The effectiveness of any oral hypoglycemic
drug, including glimepiride, in lowering blood glucose to
a desired level decreases in many patients over a period
of time, which may be due to progression of the severity
of the diabetes or to diminished responsiveness to the drug.
This phenomenon is known as secondary failure, to distinguish
it from primary failure in which the drug is ineffective
in an individual patient when first given. Should secondary
failure occur with glimepiride or metformin monotherapy,
combined therapy with glimepiride and metformin or glimepiride
and insulin may result in a response. Should secondary failure
occur with combined glimepiride/metformin therapy, it may
be necessary to initiate insulin therapy.
Information for the Patient
Patients should be informed of the potential risks and
advantages of glimepiride and of alternative modes of
therapy. They should also be informed about the importance
of adherence to dietary instructions, of a regular exercise
program, and of regular testing of blood glucose.
The risks of hypoglycemia, its symptoms and treatment,
and conditions that predispose to its development should
be explained to patients and responsible family members.
The potential for primary and secondary failure should
also be explained.
Laboratory Tests
Fasting blood glucose should be monitored periodically
to determine therapeutic response. Glycosylated hemoglobin
should also be monitored, usually every 3 to 6 months,
to more precisely assess long-term glycemic control.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Studies in rats at doses of up to 5000 ppm in complete
feed (approximately 340 times the maximum recommended
human dose, based on surface area) for 30 months showed
no evidence of carcinogenesis. In mice, administration
of glimepiride for 24 months resulted in an increase in
benign pancreatic adenoma formation which was dose related
and is thought to be the result of chronic pancreatic
stimulation. The no-effect dose for adenoma formation
in mice in this study was 320 ppm in complete feed, or
46 to 54 mg/kg body weight/day. This is about 35 times
the maximum human recommended dose of 8 mg once daily
based on surface area.
Glimepiride was non-mutagenic in a battery of in vitro
and in vivo mutagenicity studies (Ames test, somatic cell
mutation, chromosomal aberration, unscheduled DNA synthesis,
mouse micronucleus test).
There was no effect of glimepiride on male mouse fertility
in animals exposed up to 2500 mg/kg body weight (>1700
times the maximum recommended human dose based on surface
area). Glimepiride had no effect on the fertility of male
and female rats administered up to 4000 mg/kg body weight
(approximately 4000 times the maximum recommended human
dose based on surface area).
Pregnancy
Teratogenic Effects, Pregnancy Category C
Glimepiride did not produce teratogenic effects in rats
exposed orally up to 4000 mg/kg body weight (approximately
4000 times the maximum recommended human dose based on
surface area) or in rabbits exposed up to 32 mg/kg body
weight (approximately 60 times the maximum recommended
human dose based on surface area). Glimepiride has been
shown to be associated with intrauterine fetal death in
rats when given in doses as low as 50 times the human
dose based on surface area and in rabbits when given in
doses as low as 0.1 times the human dose based on surface
area. This fetotoxicity, observed only at dose inducing
maternal hypoglycemia, has been similarly noted with other
sulfonylureas, and is believed to be directly related
to the pharmacologic (hypoglycemic) action of glimepiride.
There are no adequate and well-controlled studies in
pregnant women. On the basis of results from animal studies,
glimepiride tablets should not be used during pregnancy.
Because recent information suggests that abnormal blood
glucose levels during pregnancy are associated with a
higher incidence of congenital abnormalities, many experts
recommend that insulin be used during pregnancy to maintain
glucose levels as close to normal as possible.
Nonteratogenic Effects
In some studies in rats, offspring of dams exposed to
high levels of glimepiride during pregnancy and lactation
developed skeletal deformities consisting of shortening,
thickening, and bending of the humerus during the postnatal
period. Significant concentrations of glimepiride were
observed in the serum and breast milk of the dams as well
as in the serum of the pups. These skeletal deformations
were determined to be the result of nursing from mothers
exposed to glimepiride.
Prolonged severe hypoglycemia (4 to 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. Patients who are planning a pregnancy
should consult their physician, and it is recommended
that they change over to insulin for the entire course
of pregnancy and lactation.
Nursing Mothers
In rat reproduction studies, significant concentrations
of glimpiride were observed in the serum and breast milk
of the dams, as well as in the serum of the pups. Although
it is not known whether glimepiride is excreted in human
milk, other sulfonylureas are excreted in human milk. Because
the potential for hypoglycemia in nursing infants may exist,
and because of the effects on nursing animals, glimepiride
should be discontinued in nursing mothers. If glimepiride
is discontinued, and if diet and exercise alone are inadequate
for controlling blood glucose, insulin therapy should be
considered. (See Nonteratogenic Effects
above)
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
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