Apidra
(insulin glulisine, human)Dosage & Administration
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Apidra Prescribing Information
APIDRA is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.
Important Administration Instructions
- Always check insulin label before administration [see Warnings and Precautions (5.4)].
- Inspect visually for particulate matter and discoloration. Only use APIDRA if the solution appears clear and colorless.
- Use APIDRA SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
Route of Administration Instructions
Subcutaneous Injection
- Inject APIDRA subcutaneously within 15 minutes before a meal or within 20 minutes after starting a meal into the abdominal wall, thigh, or upper arm.
- Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2), Adverse Reactions (6)].
- APIDRA given by subcutaneous injection should generally be used in regimens with an intermediate or long-acting insulin.
- The APIDRA SoloStar prefilled pen dials in 1-unit increments.
- Do not mix APIDRA for subcutaneous injection with insulins other than NPH insulin. If APIDRA is mixed with NPH insulin, draw APIDRA into the syringe first and inject immediately after mixing.
Continuous Subcutaneous Infusion (Insulin Pump)
- Refer to the continuous subcutaneous insulin infusion pump user manual to see if APIDRA can be used with the insulin pump. Use APIDRA in accordance with the insulin pump system's instructions for use.
- Administer APIDRA by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. [see Warnings and Precautions (5.2), Adverse Reactions (6)].
- Train patients using continuous subcutaneous insulin infusion pump therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions (5.8)].
- During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].
- Change APIDRA in the reservoir at least every 48 hours or according to the pump user manual, whichever is shorter.
- Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
- Do not dilute or mix APIDRA when administering by continuous subcutaneous infusion.
- Do not expose APIDRA in the pump reservoir to temperatures greater than 98.6°F (37°C).
Intravenous Administration
- Administer APIDRA intravenously only under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.5)].
- Dilute APIDRA to concentrations from 0.05 unit/mL to 1 unit/mL insulin glulisine in infusion systems using polyvinyl chloride (PVC) infusion bags.
- Diluted APIDRA is stable at room temperature for 48 hours only in normal saline solution (0.9% Sodium Chloride Injection, USP) [see How Supplied/Storage and Handling (16.2)].
- APIDRA is not compatible with Dextrose solution and Ringers solution.
Dosage Information
- Individualize and adjust the dosage of APIDRA based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.
- Dose adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function, or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7), Use in Specific Populations (8.6, 8.7)].
Injection: 100 units per mL (U-100), a clear and colorless solution available as:
- 10 mL multiple-dose vial
- 3 mL single-patient-use APIDRA SoloStar prefilled pen
Pregnancy
Risk Summary
Available pharmacovigilance data have not established an association with insulin glulisine use during pregnancy and major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies have been conducted 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/day (2 times the average human dose, based on body surface area comparison) and to rabbits during organogenesis at subcutaneous doses up to 1.5 units/kg/day (0.5 times the average human dose, based on body surface area comparison). The effects did not differ from those observed with subcutaneous regular human insulin (see Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.
Clinical Considerations
Disease-associated maternal and/or embryo-fetal risk
Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity.
Data
Animal data
Insulin glulisine was given to pregnant female rabbits during gestation at doses up to 1.5 units/kg/day, resulting in an exposure 0.5 times the average human dose, based on body surface area. Adverse effects on embryo-fetal development, including postimplantation loss and skeletal defects, were observed at dose levels that caused maternal hypoglycemia and mortality.
Insulin glulisine given to pregnant female rats during gestation at doses up to 10 units/kg/day, resulting in an exposure 2 times the average human dose based on body surface area, resulted in maternal toxicity indicative of hypoglycemia but did not adversely affect embryo-fetal development. Postnatal development was not adversely affected following administration of insulin glulisine to pregnant female rats during gestation and throughout lactation at doses up to 8 units/kg/day.
The effects of insulin glulisine did not differ from those observed with regular human insulin used as a comparator in the same studies and administered at the same doses.
Lactation
Risk Summary
Available data from published literature suggest that human insulin products, including APIDRA, are transferred into human milk. There are no adverse reactions reported in the breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including APIDRA, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for APIDRA and any potential adverse effects on the breastfed infant from APIDRA or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of APIDRA to improve glycemic control have been established in pediatric patients. Use of APIDRA for this indication is supported by evidence from an active-controlled non-inferiority study in pediatric patients 4 years of age and older with type 1 diabetes mellitus treated with APIDRA (n=271) and from studies in adults with diabetes mellitus [see Clinical Pharmacology (12.3), and Clinical Studies (14)].
In the clinical trials, pediatric patients with type 1 diabetes mellitus had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes mellitus [see Adverse Reactions (6.1)].
Geriatric Use
In clinical trials, APIDRA was administered to 147 patients ≥65 years of age and 27 patients ≥75 years of age. The majority of this small subset of geriatric 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. In geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].
Renal Impairment
Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
Hepatic Impairment
Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
APIDRA is contraindicated:
- during episodes of hypoglycemia
- in patients with known hypersensitivity to insulin glulisine or to any of the excipients in APIDRA; systemic allergic reactions have occurred with APIDRA [see Adverse Reactions (6.1)].
Never Share an APIDRA SoloStar Pen or Syringe or Needle between Patients
APIDRA SoloStar pens must never be shared between patients, even if the needle is changed. Patients using APIDRA vials must never reuse or share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in an insulin regimen (e.g., insulin, insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)].
Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments in concomitant oral antidiabetic treatment may be needed.
Hypoglycemia
Hypoglycemia is the most common adverse reaction of all insulins, including APIDRA [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). APIDRA, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications (4)].
Hypoglycemia can happen suddenly, and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulins, the glucose lowering effect time course of APIDRA may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)].
Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
Hypoglycemia Due to Medication Errors
Accidental mix-ups between insulin products have been reported. To avoid medication errors between APIDRA and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions (6.3)].
Hypokalemia
All insulins, 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).
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including APIDRA [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, discontinue APIDRA; treat per standard of care and monitor until symptoms and signs resolve. APIDRA is contraindicated in patients who have had a hypersensitivity reaction to insulin glulisine or any of its excipients.
Fluid Retention and Heart Failure with Concomitant Use of PPAR-Gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, 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.
Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction
Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. 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 How Supplied/Storage and Handling (16.2)].