Included as part of the PRECAUTIONS section.
Dosage Adjustment And Monitoring
Glucose monitoring is essential for patients receiving
insulin therapy. Changes to an insulin regimen should be made cautiously and
only under medical supervision. Changes in insulin strength, manufacturer,
type, or method of administration may result in the need for a change in
insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.
As with all insulin preparations, the time course of
action for APIDRA may vary in different individuals or at different times in
the same individual and is dependent on many conditions, including the site of
injection, local blood supply, or local temperature. Patients who change their
level of physical activity or meal plan may require adjustment of insulin
Hypoglycemia is the most common adverse reaction of
insulin therapy, including APIDRA. The risk of hypoglycemia increases with
tighter glycemic control. Patients must be educated to recognize and manage
hypoglycemia. Severe hypoglycemia may lead to unconsciousness and/or
convulsions and may result in temporary or permanent impairment of brain
function or death. Severe hypoglycemia requiring the assistance of another
person and/or parenteral glucose infusion or glucagon administration has been
observed in clinical trials with insulin, including trials with APIDRA.
The timing of hypoglycemia usually reflects the
time-action profile of the administered insulin formulations. Other factors
such as changes in food intake (e.g., amount of food or timing of meals),
injection site, exercise, and concomitant medications may also alter the risk
of hypoglycemia [See DRUG INTERACTIONS].
As with all insulins, use caution in patients with
hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia
(e.g., the pediatric population and patients who fast or have erratic food
intake). The patient's ability to concentrate and react may be impaired as a
result of hypoglycemia. This may present a risk in situations where these
abilities are especially important, such as driving or operating other
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 longstanding diabetes, diabetic
nerve disease, use of medications such as beta-blockers [See DRUG
INTERACTIONS], or intensified diabetes control. These situations may result
in severe hypoglycemia (and, possibly, loss of consciousness) prior to the
patient's awareness of hypoglycemia.
Intravenously administered insulin has a more rapid onset
of action than subcutaneously administered insulin, requiring closer monitoring
Hypersensitivity And Allergic Reactions
Severe, life-threatening, generalized allergy, including
anaphylaxis, can occur with insulin products, including APIDRA [See ADVERSE
All insulin products, including APIDRA, cause a shift in
potassium from the extracellular to intracellular space, possibly leading to
hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular
arrhythmia, and death. Use caution in patients who may be at risk for
hypokalemia (e.g., patients using potassium-lowering medications, patients
taking medications sensitive to serum potassium concentrations). Monitor
glucose and potassium frequently when APIDRA is administered intravenously.
Renal Or Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction
may be required in patients with renal or hepatic impairment [See CLINICAL
Mixing Of Insulins
APIDRA for subcutaneous injection should not be mixed
with insulin preparations other than NPH insulin. If APIDRA is mixed with NPH
insulin, APIDRA should be drawn into the syringe first. Injection should occur
immediately after mixing.
Do not mix APIDRA with other insulins for intravenous
administration or for use in a continuous subcutaneous infusion pump.
APIDRA for intravenous administration should not be
diluted with solutions other than 0.9% sodium chloride (normal saline). The
efficacy and safety of mixing APIDRA with diluents or other insulins for use in
external subcutaneous infusion pumps have not been established.
Subcutaneous Insulin Infusion pumps
When used in an external insulin pump for subcutaneous
infusion, APIDRA should not be diluted or mixed with any other insulin. APIDRA
in the reservoir must be changed at least every 48 hours. APIDRA should not be
exposed to temperatures greater than 98.6°F (37°C).
Malfunction of the insulin pump or infusion set or
handling errors or insulin degradation can rapidly lead to hyperglycemia,
ketosis and diabetic ketoacidosis. Prompt identification and correction of the
cause of hyperglycemia or ketosis or diabetic ketoacidosis is necessary.
Interim subcutaneous injections with APIDRA may be required. Patients using
continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available. [See
DOSAGE AND ADMINISTRATION, HOW SUPPLIED/Storage and Handling,
and PATIENT INFORMATION].
When APIDRA is administered intravenously, glucose and
potassium levels must be closely monitored to avoid potentially fatal
hypoglycemia and hypokalemia.
Do not mix APIDRA with other insulins for intravenous
administration. APIDRA may be diluted only in normal saline solution.
Some medications may alter insulin requirements and the
risk for hypoglycemia or hyperglycemia [See DRUG INTERACTIONS].
Fluid Retention And Heart Failure With Concomitant Use Of
Thiazolidinediones (TZDs), which are peroxisome
proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related
fluid retention, particularly when used in combination with insulin. Fluid
retention may lead to or exacerbate heart failure. Patients treated with
insulin, including APIDRA and a PPAR-gamma agonist should be observed for signs
and symptoms of heart failure. If heart failure develops, it should be managed
according to current standards of care, and discontinuation or dose reduction
of the PPAR-gamma agonist must be considered.
Patient Counseling Information
See FDA-approved patient labeling.
Instructions For All Patients
Patients should be instructed on self-management
procedures including glucose monitoring, proper injection technique, and
management of hypoglycemia and hyperglycemia. 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, and 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.
Accidental mix-ups between APIDRA and other insulins,
particularly long-acting insulins, have been reported. To avoid medication
errors between APIDRA and other insulins, patients should be instructed to
always check the insulin label before each injection.
For Patients Using Continuous Subcutaneous Insulin Pumps
Patients using external pump infusion therapy should be
The following insulin pumps† have been used in
APIDRA clinical trials conducted by sanofiaventis, the manufacturer of APIDRA:
- 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™).
Before using a different insulin pump with APIDRA, read
the pump label to make sure the pump has been evaluated with APIDRA.
To minimize insulin degradation, infusion set occlusion,
and loss of the preservative (metacresol), the infusion sets (reservoir,
tubing, and catheter) and the APIDRA in the reservoir must be replaced at least
every 48 hours 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 or alter the absorption of APIDRA.
Pump or infusion set malfunctions or handling errors or
insulin degradation can lead to rapid hyperglycemia, and ketosis and diabetic
ketoacidosis. 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 or diabetic ketoacidosis is necessary. Problems include pump
malfunction, infusion set occlusion, leakage, disconnection or kinking,
handling errors 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. Patients administering APIDRA by continuous
subcutaneous infusion must have an alternative insulin delivery system in case
of pump system failure. [See DOSAGE AND ADMINISTRATION, WARNINGS AND
PRECAUTIONS, and HOW SUPPLIED/Storage and Handling].
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 Units/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 Units/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.
Use In Specific Populations
Pregnancy Category C
Reproduction and teratology studies have been performed
with insulin glulisine in rats and rabbits using regular human insulin as a
comparator. Insulin glulisine was given to female rats throughout pregnancy at
subcutaneous doses up to 10 Units/kg once daily (dose resulting in an exposure
2 times the average human dose, based on body surface area comparison) and did
not have any remarkable toxic effects on embryo-fetal development.
Insulin glulisine was given to female rabbits throughout
pregnancy at subcutaneous doses up to 1.5 Units/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 Units/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 Units/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
Units/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
There are no well-controlled clinical studies of the use
of APIDRA 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 these patients.
It is unknown whether insulin glulisine is excreted in
human milk. Because many drugs are excreted in human milk, caution should be
exercised when APIDRA is administered to a nursing woman. Use of APIDRA is
compatible with breastfeeding, but women with diabetes who are lactating may
require adjustments of their insulin doses.
The safety and effectiveness of subcutaneous injections
of APIDRA have been established in pediatric patients (age 4 to 17 years) with
type 1 diabetes [See Clinical Studies]. APIDRA has not been studied in
pediatric patients with type 1 diabetes younger than 4 years of age and in
pediatric patients with type 2 diabetes.
As in adults, the dosage of APIDRA must be individualized
in pediatric patients based on metabolic needs and frequent monitoring of blood
In clinical trials (n=2408), APIDRA was administered to
147 patients ≥ 65 years of age and 27 patients ≥ 75 years of age. The
majority of this small subset of elderly patients had type 2 diabetes. The
change in HbA1c values and hypoglycemia frequencies did not differ by age.
Nevertheless, caution should be exercised when APIDRA is administered to