A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Glucotrol Warnings, Precautions, Pregnancy, Nursing, Abuse - Glipizide
Glucotrol Warnings, Precautions, Pregnancy, Nursing, Abuse - Glipizide
WARNINGS
Immediate and Extended Release Tablets
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 2 ½ 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 findings of the UGDP study provide an adequate basis
for this warning. The patient
should be informed of the potential
risks and advantages of glipizide
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.
As with any other non-deformable material, caution should be used when
administering glipizide
extended-release tablets in patients with preexisting severe gastrointestinal
narrowing (pathologic or
iatrogenic). There have been rare reports of obstructive symptoms in patients
with known structures in association
with the ingestion of another
drug in this non-deformable sustained
release formulation.
PRECAUTIONS
General
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.
Hypoglycemia: All sulfonylurea
drugs are capable of producing severe hypoglycemia. Proper patient
selection, dosage, and instructions are important to avoid hypoglycemic
episodes. Renal or hepatic
insufficiency may cause elevated
blood levels of glipizide
and the latter may also diminish gluconeogenic capacity, both of which
increase the risk of serious
hypoglycemic reactions. Elderly, debilitated or malnourished patients,
and those with adrenal or pituitary insufficiency are particularly susceptible
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. 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.
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 discontinue glipizide
and administer insulin.
The effectiveness of
any oral hypoglycemic drug, including
glipizide, 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. Adequate adjustment of dose and adherence to diet should
be assessed before classifying a patient as a secondary failure.
Laboratory Tests: Blood and urine
glucose should be monitored
periodically. Measurement of glycosylated hemoglobin
may be useful.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
A twenty month study in rats and an eighteen 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 on fertility.
Pregnancy, Teratogenic Effects, Pregnancy Category C
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. There are no adequate and well controlled studies
in pregnant women. Glipizide should be used during pregnancy only if the
potential benefit justifies the potential
risk to the fetus.
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 blood glucose
levels as close to normal as
possible.
Nonteratogenic Effects
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. If glipizide
is used during pregnancy, it should be discontinued at least one month
before the expected delivery date.
Nursing Mothers
Although it is not known whether glipizide
is excreted in human milk, some
sulfonylurea drugs are
known to be excreted in human
milk. Because the potential
for hypoglycemia in nursing
infants may exist, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the
drug to the mother. If the drug
is discontinued and if diet alone
is inadequate for controlling blood
glucose, insulin therapy should be considered.
Pediatric Use: Safety and effectiveness
in pediatric patients have
not been established.
Immediate Release Tablets
Information for the Patient: Patients should be informed
of the potential risks and
advantages of glipizide
and of alternative modes of therapy. They should also be informed about
the importance of adhering to dietary instructions, of a regular
exercise program, and of
regular testing of urine and/or
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. Primary
and secondary failure should
also be explained.
Extended Release Tablets
GI Disease: Markedly reduced GI
retention times of the glipizide
extended-release tablets may influence the pharmacokinetic profile and
hence the clinical efficacy
of the drug.
Adequate adjustment of
dose and adherence
to diet should be assessed before
classifying a patient as a
secondary failure.
Information for the Patient: Patients should be informed
that glipizide extended-release
tablets should be swallowed whole. Patients should not chew, divide or
crush tablets. Patients should not be concerned if they occasionally notice
in their stool something that
looks like a tablet. In the glipizide
extended-release tablet, the medication
is contained within a shell
that has been specially designed to slowly release
the drug so the body can absorb
it. When this process is completed,
the empty tablet is eliminated from the body.
Patients should be informed of the potential
risks and advantages of glipizide extended-release and of alternative
modes of therapy. They should also be informed about the importance of
adhering to dietary instructions, of a regular
exercise program, and of
regular testing of urine
and/or blood glucose.
The risk of hypoglycemia, its
symptoms and treatment, and conditions that predispose to its development
should be explained to patients and responsible family members. Primary
and secondary failure also
should be explained.
Geriatric Use: Of the total number
of patients in clinical studies of glipizide
extended-release 33 percent
were 65 and over. No overall differences in effectiveness
or safety were observed between these patients and younger patients, but
greater sensitivity of some individuals cannot be ruled out. Approximately
1-2 days longer were required to reach steady state in the elderly. (See
CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION).
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