WARNINGS AND PRECAUTIONS
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 dosages.
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 (7) ].
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 machinery.
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 (7) ], 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 for hypoglycemia.
Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including APIDRA [See Adverse reactions].
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 Pharmacology].
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 should 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 insulin degradation can rapidly lead to hyperglycemia and ketosis. Prompt identification and correction of the cause of hyperglycemia or ketosis 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 in case of pump failure. [See Dosage and Administration, How Supplied/Storage and Handling, and Patient Counseling 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 (7) ].
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 hypoglycemia.
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 glucose.
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 geriatric patients.