Apidra
(Insulin Glulisine)Dosage & Administration
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Apidra Prescribing Information
APIDRA is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.
- See Full Prescribing Information for important administration instructions. (,
2.1 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.
)2.2 Route of Administration InstructionsSubcutaneous 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.
- Always check insulin label before administration
- Individualize and adjust the dosage of APIDRA based on route of administration, individual's metabolic needs, blood glucose monitoring results, and glycemic control goal. ()
2.3 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)].
- Dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns, changes in renal or hepatic function or during acute illness. ()
2.3 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)].
- Subcutaneous Injection:()
2.2 Route of Administration InstructionsSubcutaneous 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.
- Inject within 15 minutes before a meal or within 20 minutes after starting a meal into the abdomen, thigh, or upper arm.
- Rotate injection sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis.
- Should generally be used in regimens with an intermediate or long-acting insulin.
- Continuous Subcutaneous Infusion (Insulin Pump):()
2.2 Route of Administration InstructionsSubcutaneous 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.
- Refer to the insulin infusion pump user manual to see if APIDRA can be used. Use in accordance with the insulin pump instructions for use.
- Administer by continuous subcutaneous infusion using an insulin pump 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.
- Do not mix with other insulins or diluents in the pump.
- Intravenous Administration:Administer only under medical supervision after diluting to concentrations from 0.05 to 1 unit/mL APIDRA in 0.9% sodium chloride injection, USP using polyvinyl chloride infusion bags. ()
2.2 Route of Administration InstructionsSubcutaneous 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.
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
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
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.
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.
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.
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.]
6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial and may not reflect the rates actually observed in clinical practice.
The data in Table 1 reflect the exposure of 1591 patients with type 1 diabetes to APIDRA or comparators
[see Clinical Studies (14.1)]. The type 1 diabetes population had the following characteristics: Mean age was 39.74 years. 54.5 % were male, 95.5% were Caucasian, 1.5% were Black or African American.The data in Table 2 reflect the exposure of 1766 patients with type 2 diabetes to APIDRA or comparators
[see Clinical Studies (14.2)]. The type 2 diabetes population had the following characteristics: Mean age was 59.08 years. 51.2% were male, 88.5% were Caucasian, 7.2% were Black or African American.The frequencies of adverse drug reactions during APIDRA clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Adverse Reactions Occurring ≥5% in Pooled Studies of Adults with Type 1 Diabetes APIDRA, %
(n=950)All ComparatorsInsulin lispro, regular human insulin, insulin aspart, %
(n=641)Nasopharyngitis 10.6 12.9 HypoglycemiaOnly severe symptomatic hypoglycemia 6.8 6.7 Upper respiratory tract infection 6.6 5.6 Influenza 4.0 5.0 Table 2: Adverse Reactions Occurring ≥5% in Pooled Studies of Adults with Type 2 Diabetes APIDRA, %
(n=883)Regular Human Insulin, %
(n=883)Upper respiratory tract infection 10.5 7.7 Nasopharyngitis 7.6 8.2 Edema peripheral 7.5 7.8 Influenza 6.2 4.2 Arthralgia 5.9 6.3 Hypertension 3.9 5.3 PediatricsTable 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical study in pediatric patients with type 1 diabetes treated with APIDRA (n=277) or insulin lispro (n=295).
Table 3: Adverse Reactions Occurring ≥5% in Pediatric Patients with Type 1 Diabetes APIDRA, %
(n=277)Insulin Lispro, %
(n=295)Nasopharyngitis 9.0 9.5 Upper respiratory tract infection 8.3 10.8 Headache 6.9 11.2 Hypoglycemic seizure 6.1 4.7 Severe Symptomatic HypoglycemiaHypoglycemia was the most commonly observed adverse reaction in patients treated with insulin, including APIDRA. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for APIDRA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that occur in clinical practice. The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party are presented in Table 4. In the clinical trials, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes (see Table 4)
[see Clinical Studies (14)].Table 4: Severe Symptomatic HypoglycemiaSevere symptomatic hypoglycemia defined as a hypoglycemic event requiring the assistance of another person that met one of the following criteria:
the event was associated with a whole blood referenced blood glucose <36 mg/dL or the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.Type 1 Diabetes
Adults
12 weeks with insulin glargineType 1 Diabetes
Adults
26 weeks with insulin glargineType 2 Diabetes
Adults
26 weeks with NPH human insulinType 1 Diabetes
Pediatrics
26 weeksAPIDRA
Pre mealAPIDRA
Post mealRegular Human InsulinAPIDRAInsulin LisproAPIDRARegular Human InsulinAPIDRAInsulin LisproEvents per month per patient 0.05 0.05 0.13 0.02 0.02 0.00 0.00 0.09 0.08 Percent of patients
(n/total N)8.4%
(24/286)8.4%
(25/296)10.1%
(28/278)4.8%
(16/339)4.0%
(13/333)1.4%
(6/416)1.2%
(5/420)16.2%
(45/277)19.3%
(57/295)Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)In a 12-week randomized study in patients with type 1 diabetes (n=59), the rates of catheter occlusions and infusion site reactions were similar for APIDRA and insulin aspart–treated patients (see Table 5).
Table 5: Catheter Occlusions and Infusion Site Reactions APIDRA
(n=29)Insulin Aspart
(n=30)Catheter occlusions/month 0.08 0.15 Infusion site reactions 10.3% (3/29) 13.3% (4/30) Allergic ReactionsSevere, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including APIDRA. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
In controlled clinical trials up to 12 months duration, 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.
Injection Site ReactionsAs with any insulin, patients taking APIDRA may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks, but on some occasions may require discontinuation of APIDRA. 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.
Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.
LipodystrophyLong-term use of insulin, including APIDRA, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption
[see Dosage and Administration (2.2)].Peripheral EdemaInsulins, including APIDRA, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
Weight GainWeight gain can occur with insulins, including APIDRA, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
- Never sharean APIDRA SoloStar pen between patients, even if the needle is changed. ()
5.1 Never Share an APIDRA SoloStar Pen or Syringe or Needle between PatientsAPIDRA 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:Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ()
5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin RegimenChanges 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:May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, coadministered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. ()
5.3 HypoglycemiaHypoglycemia 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 HypoglycemiaThe 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 HypoglycemiaPatients 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 can occur. Instruct patients to check insulin labels before injection. ()
5.4 Hypoglycemia Due to Medication ErrorsAccidental 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:May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ()
5.5 HypokalemiaAll 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. Discontinue APIDRA, monitor and treat if indicated. ()
5.6 Hypersensitivity ReactionsSevere, 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 Can Occur with Concomitant Use of Thiazolidinediones (TZDs):Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. ()
5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-Gamma AgonistsThiazolidinediones (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:Monitor glucose and administer APIDRA by subcutaneous injection if pump malfunction occurs. ()
5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device MalfunctionMalfunction 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)].