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
Apidra Warnings, Precautions, Pregnancy, Nursing, Abuse - Insulin glulisine
Apidra Warnings, Precautions, Pregnancy, Nursing, Abuse - Insulin glulisine
WARNINGS
APIDRA differs from regular human insulin by its rapid onset
of action and shorter duration of action. When used as a meal time insulin,
the dose of APIDRA should be given within 15 minutes before or immediately after
a meal.
Because of the short duration of action of APIDRA, patients
with diabetes also require a longer-acting insulin or insulin infusion pump
therapy to maintain adequate glucose control.
Any change of insulin should be made cautiously and only under
medical supervision. Changes in insulin strength, manufacturer, type (e.g.,
regular, NPH, analogs), or species (animal, human) may result in the need for
a change in dosage. Concomitant oral antidiabetic treatment may need to be adjusted.
Glucose monitoring is recommended for all patients with diabetes.
Hypoglycemia is the most common adverse effect of insulin therapy,
including APIDRA. The timing of hypoglycemia may differ among various insulin
formulations.
Insulin Pumps: When used in an external insulin pump
for subcutaneous infusion, APIDRA should not be diluted or mixed with
any other insulin. Physicians and patients should carefully evaluate information
on pump use in the APIDRA prescribing information, Patient Information
Leaflet, and the pump manufacturer’s manual. APIDRA-specific information
should be followed for in-use time, frequency of changing infusion sets,
or other details specific to APIDRA usage, because APIDRA-specific information
may differ from general pump manual instructions. Pump or infusion set
malfunctions or insulin degradation can lead to hyperglycemia and ketosis
in a short time. This is especially pertinent for rapid-acting insulin
analogs that are more rapidly absorbed through skin and have a shorter
duration of action. Prompt identification and correction of the cause
of hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous
injection may be required. (See PRECAUTIONS,
Usage in Pumps, Information for
Patients, Mixing of Insulins, DOSAGE
AND ADMINISTRATION, and RECOMMENDED
STORAGE.)
PRECAUTIONS
General
As with all insulin preparations, the time course of APIDRA
action may vary in different individuals or at different times in the same individual
and is dependent on site of injection, blood supply, temperature, and physical
activity.
Adjustment of dosage of any insulin may be necessary if patients
change their physical activity or their usual meal plan.
Insulin requirements may be altered during intercurrent conditions
such as illness, emotional disturbances, or stress.
Hypoglycemia
As with all insulin preparations, hypoglycemic reactions may
be associated with the administration of APIDRA. Rapid changes in serum glucose
levels may induce symptoms similar to hypoglycemia in persons with diabetes,
regardless of the glucose value. Early warning symptoms of hypoglycemia
may be different or less pronounced under certain conditions, such as long duration
of diabetes, diabetic nerve disease, use of medications such as beta-blockers,
or intensified diabetes control. (See PRECAUTIONS,
Drug Interactions.) Such situations may result
in severe hypoglycemia (and, possibly, loss of consciousness) prior to patients’
awareness of hypoglycemia.
Renal Impairment
The requirements for APIDRA may be reduced in patients with
renal impairment. (See CLINICAL PHARMACOLOGY,
Special Populations.)
Hepatic Impairment
Studies have not been performed in patients with hepatic impairment.
APIDRA requirements may be diminished due to reduced capacity for gluconeogenesis
and reduced insulin metabolism, similar to observations found with other insulins.
(See CLINICAL PHARMACOLOGY, Special Populations.)
Allergy
Local Allergy
As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of injection. These minor reactions usually
resolve in a few days to a few weeks. In some instances, these reactions may
be related to factors other than insulin, such as irritants in a skin cleansing
agent or poor injection technique.
Systemic Allergy
Less common, but potentially more serious, is generalized allergy
to insulin, which may cause rash (including pruritus) over the whole body, shortness
of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating.
Severe cases of generalized allergy, including anaphylactic reactions, may be
life threatening.
In controlled clinical trials up to 12 months, potential systemic
allergic reactions were reported in 79 of 1833 patients (4.3%) who received
APIDRA and 58 of 1524 patients (3.8%) who received the comparator short-acting
insulins. During these trials treatment with APIDRA was permanently discontinued
in 1 of 1833 patients due to a potential systemic allergic reaction.
Localized reactions and generalized myalgias have been reported
with the use of cresol as an injectable excipient.
As with any insulin therapy, lipodystrophy may occur at the
injection site and delay insulin absorption.
Antibody Production
In a study in patients with type 1 diabetes (n=333), the concentrations
of insulin antibodies that react with both human insulin and insulin glulisine
(cross-reactive insulin antibodies) remained near baseline during the first
6 months of the study in the patients treated with APIDRA. A decrease in antibody
concentration was observed during the following 6 months of the study. In a
study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive
insulin antibody concentration was observed in the patients treated with APIDRA
and in the patients treated with human insulin during the first 9 months of
the study. Thereafter the concentration of antibodies decreased in the APIDRA
patients and remained stable in the human insulin patients. There was no correlation
between cross-reactive insulin antibody concentration and changes in HbA1c,
insulin doses, or incidences of hypoglycemia.
Usage in Pumps
APIDRA has been studied in the following pumps and infusion
sets: Disetronic® H-Tron® plus V100 and D-Tron® with Disetronic
catheters (Rapid™, Rapid C™, Rapid D™, and Tender™);
MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate
QR™, and Quick-set™)‡. Based on in vitro studies
which have shown loss of m-cresol, and insulin degradation, APIDRA should not
be used beyond 48 hours at 98.6°F (37°C)
in infusion sets and reservoirs. APIDRA in clinical use should not be exposed
to temperatures greater than 98.6°F
(37°C). APIDRA should not be mixed
with other insulins or with a diluent when used in the pump. (See WARNINGS,
PRECAUTIONS, Information
for Patients, Mixing of Insulins, DOSAGE
AND ADMINISTRATION, and RECOMMENDED
STORAGE.)
INFORMATION FOR PATIENTS
For all patients
Patients should be instructed on self-management procedures
including glucose monitoring, proper injection technique, and hypoglycemia and
hyperglycemia management. Patients must be instructed on handling of special
situations such as intercurrent conditions (illness, stress, or emotional disturbances),
an inadequate or skipped insulin dose, inadvertent administration of an increased
insulin dose, inadequate food intake, or skipped meals. Refer patients to the
APIDRA Patient Information Leaflet for additional information.
Women with diabetes should be advised to inform their doctor
if they are pregnant or are contemplating pregnancy.
For patients using pumps
Patients using external pump infusion therapy should be trained
appropriately. APIDRA has been studied in the following pumps and infusion sets:
Disetronic H-Tron plus V100 and D-Tron with Disetronic catheters (Rapid, Rapid
C, Rapid D, and Tender); MiniMed Models 506, 507, 507c and 508 with MiniMed
catheters (Sof-set Ultimate QR, and Quick-set).
To minimize insulin degradation, infusion set occlusion,
and loss of the preservative (m-cresol), the infusion sets (reservoir, tubing,
and catheter) and the APIDRA in the reservoir should be replaced every 48 hours
or less and a new infusion site should be selected. The temperature of the
insulin may exceed ambient temperature when the pump housing, cover, tubing
or sport case is exposed to sunlight or radiant heat. Insulin exposed to
temperatures higher than 98.6°F
(37°C) should be discarded.
Infusion sites that are erythematous, pruritic, or thickened should be reported
to the healthcare professional, and a new site selected because continued infusion
may increase the skin reaction and/or alter the absorption of APIDRA.
Pump or infusion set malfunctions or insulin degradation can
lead to hyperglycemia and ketosis in a short time. This is especially pertinent
for rapid-acting insulin analogs that are more rapidly absorbed through skin
and have a shorter duration of action. Prompt identification and correction
of the cause of hyperglycemia or ketosis is necessary. Problems include pump
malfunction, infusion set occlusion, leakage, disconnection or kinking, and
degraded insulin. Less commonly, hypoglycemia from pump malfunction may occur.
If these problems cannot be promptly corrected, patients should resume therapy
with subcutaneous insulin injection and contact their healthcare professional.
(See WARNINGS,
PRECAUTIONS, Usage in Pumps, Mixing of Insulins,
DOSAGE AND
ADMINISTRATION, and RECOMMENDED STORAGE.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not
been performed. In Sprague Dawley rats, a 12-month repeat dose toxicity study
was conducted with insulin glulisine at subcutaneous doses of 2.5, 5, 20 or
50 IU/kg twice daily (dose resulting in an exposure 1, 2, 8, and 20 times the
average human dose, based on body surface area comparison).
There was a non-dose dependent higher incidence of mammary
gland tumors in female rats administered insulin glulisine compared to untreated
controls. The incidence of mammary tumors for insulin glulisine and regular
human insulin was similar. The relevance of these findings to humans is not
known. Insulin glulisine was not mutagenic in the following tests: Ames test,
in vitro mammalian chromosome aberration test in V79 Chinese hamster
cells, and in vivo mammalian erythrocyte micronucleus test in rats. In
fertility studies in male and female rats at subcutaneous doses up to 10 IU/kg
once daily (dose resulting in an exposure 2 times the average human dose, based
on body surface area comparison), no clear adverse effects on male and female
fertility, or general reproductive performance of animals were observed.
Pregnancy - Teratogenic Effects - Pregnancy Category C
Reproduction and teratology studies have been performed with
insulin glulisine in rats and rabbits using regular human insulin as a comparator.
The drug was given to female rats throughout pregnancy at subcutaneous doses
up to 10 IU/kg once daily (dose resulting in an exposure 2 times the average
human dose, based on body surface area comparison). Insulin glulisine did not
have any remarkable toxic effects on the embryo-fetal development in rats.
The drug was given to female rabbits throughout pregnancy at
subcutaneous doses up to 1.5 IU/kg/day (dose resulting in an exposure 0.5 times
the average human dose, based on body surface area comparison). Adverse effects
on embryo-fetal development were only seen at maternal toxic dose levels inducing
hypoglycemia. Increased incidence of post-implantation losses and skeletal defects
were observed at a dose level of 1.5 IU/kg once daily (dose resulting in an
exposure 0.5 times the average human dose, based on body surface area comparison)
that also caused mortality in dams. A slight increased incidence of post-implantation
losses was seen at the next lower dose level of 0.5 IU/kg once daily (dose resulting
in an exposure 0.2 times the average human dose, based on body surface area
comparison) which was also associated with severe hypoglycemia but there were
no defects at that dose. No effects were observed in rabbits at a dose of 0.25
IU/kg once daily (dose resulting in an exposure 0.1 times the average human
dose, based on body surface area comparison). The effects of insulin glulisine
did not differ from those observed with subcutaneous regular human insulin at
the same doses and were attributed to secondary effects of maternal hypoglycemia.
There are no well-controlled clinical studies of the use of
insulin glulisine in pregnant women. Because animal reproduction studies are
not always predictive of human response, this drug should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus. It
is essential for patients with diabetes or a history of gestational diabetes
to maintain good metabolic control before conception and throughout pregnancy.
Insulin requirements may decrease during the first trimester, generally increase
during the second and third trimesters, and rapidly decline after delivery.
Careful monitoring of glucose control is essential in such patients.
Nursing Mothers
It is unknown whether insulin glulisine is excreted in human
milk. Many drugs, including human insulin, are excreted in human milk. For this
reason, caution should be exercised when APIDRA is administered to a nursing
woman. Patients with diabetes who are lactating may require adjustments in APIDRA
dose, meal plan, or both.
Pediatric Use
Safety and effectiveness of APIDRA in pediatric patients have
not been established.
Geriatric Use
In Phase III clinical trials (n=2408), APIDRA was administered
to 147 patients =65 years of age and 27 patients >75 years of age.
The majority of these were patients with type 2 diabetes. The change in A1C
values and hypoglycemia frequencies did not differ by age, but greater sensitivity
of some older individuals cannot be ruled out.
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