Insulin Aspart Injection

1 INDICATIONS AND USAGE FIASP is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. • FIASP is a rapid-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus ( 1 ).

2 DOSAGE AND ADMINISTRATION • Individualize and adjust the dosage of FIASP based on route of administration, individual’s metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.3 ). • 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 ). • Subcutaneous injection ( 2.2 ): o Inject at the start of a meal or within 20 minutes after starting a meal into the abdomen, upper arm, or thigh. o Rotate injection sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. o Should generally be used in regimens with an intermediate- or long-acting insulin. • Continuous Subcutaneous Infusion (Insulin Pump) ( 2.2 ): o Refer to the insulin infusion pump user manual to see if FIASP can be used. Use in accordance with the insulin pumps’ instructions for use. o 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. • Intravenous Infusion: Administer only under medical supervision after diluting to concentrations from 0.5 to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags ( 2.2 ). 2.1 Important Preparation and Administration Instructions • Always check insulin label before administration [see Warnings and Precautions ( 5.4 ) ] . • Inspect FIASP visually before use. It should appear clear and colorless. Do not use FIASP if particulate matter or coloration is seen. • Use FIASP FlexTouch pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. • Use PenFill cartridges with caution in patients with visual impairment. • Do not mix FIASP with any other insulin. 2.2 Route of Administration Instructions Subcutaneous Injection: • Inject FIASP at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, or thigh. • 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 Adverse Reactions ( 6.1 , 6.2 )]. • FIASP given by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin. • Instruct patients on basal-bolus treatment who forget a mealtime dose to monitor their blood glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal. • The FIASP FlexTouch pen dials in 1 unit increments. Continuous Subcutaneous Infusion (Insulin Pump): • Refer to the continuous subcutaneous insulin infusion pump user manual to see if FIASP or FIASP PumpCart can be used with the insulin pump. Use FIASP and FIASP PumpCart in accordance with the insulin pump system’s instructions for use. • Administer FIASP 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. Do not infuse into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) Adverse Reactions ( 6.1 )]. • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions ( 5.8 )]. • Change FIASP in the pump reservoir at least every 6 days or replace the PumpCart cartridge at least every 4 days, or according to the pump user manual, whichever is shorter. Follow the FIASP-specific information for in-use time because FIASP-specific information may differ from general insulin pump user manual instructions. • Change the infusion sets and the infusion set insertion site according to the manufacturers user manual. • Do not mix with other insulins or diluents in the insulin pump. • Do not expose FIASP in the pump reservoir to temperatures greater than 37°C (98.6°F). Intravenous Administration: • Administer FIASP 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 FIASP to concentrations from 0.5 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags. • FIASP is stable at room temperature at 20°C to 25°C (68°F to 77°F) for 24 hours in 0.9% sodium chloride or 5% dextrose infusion fluids. 2.3 Dosage Recommendations • Individualize the dosage of FIASP based on the route of administration, patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal. • If converting from another mealtime insulin to FIASP, the initial change can be done on a unit-to-unit basis. • 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 ) and Drug Interactions ( 7 ), and Use in Specific Populations ( 8.6 , 8.7 )] . • Closely monitor blood glucose when converting insulins used in insulin pumps as individualization of insulin pump parameters may be necessary to minimize the risk of hypoglycemia and hyperglycemia [see Warnings and Precautions ( 5.2 , 5.3 ) and Adverse Reactions ( 6.1 )] • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. • Dosage adjustment may be needed when FIASP is co-administered with certain drugs [see Drug Interactions ( 7 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypokalemia [see Warnings and Precautions ( 5.5 )] • Hypersensitivity and allergic reactions [see Warnings and Precautions ( 5.6 )] Adverse reactions observed with FIASP include: hypoglycemia, allergic reactions, hypersensitivity, injection/infusion site reactions, lipodystrophy, and weight gain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates actually observed in clinical practice. The data in Table 1 reflect the exposure of 763 adult patients with type 1 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 25 weeks [see Clinical Studies ( 14.2 )] . The mean age was 44.4 years and the mean duration of diabetes was 19.9 years. 59% were male, 93% were White, and 2% were Black or African American; and 7% were Hispanic or Latino. The mean BMI was 26.7 kg/m 2 and the mean HbA 1c at baseline was 7.6%. The data in Table 2 reflect the exposure of 341 adult patients with type 2 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 24 weeks [see Clinical Studies ( 14 )] . The mean age was 59.6 years and the mean duration of diabetes was 13.2 years. 47% were male, 80% were White, and 6% were Black or African American; and 8% were Hispanic or Latino. The mean BMI was 31.5 kg/m 2 and the mean HbA 1c at baseline was 8.0%. The data in Table 3 reflect the exposure of 519 pediatric patients with type 1 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 26 weeks [see Clinical Studies ( 14.3 )] . The mean age was 11.7 years and the mean duration of diabetes mellitus was 4.4 years. 54% were male, 81% were White, 16% were Asian and 2% were Black or African American. The mean BMI was 19.7 kg/m 2 and the mean HbA 1c at baseline was 7.6%. Common adverse reactions, excluding hypoglycemia, were defined as events occurring in ≥5% and occurring at the same rate or greater for FIASP-treated patients than comparator-treated patients. Table 1. Adverse Reactions (%*) in Adult Patients with Type 1 Diabetes Mellitus Mealtime FIASP + Insulin detemir (N=386) Postmeal FIASP + Insulin detemir (N=377) Nasopharyngitis 20.2 23.9 Upper respiratory tract infection 9.1 7.4 Nausea 4.9 5.0 Diarrhea 5.4 3.2 Back pain 5.2 4.0 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Table 2. Adverse Reactions (%*) in Adult Patients with Type 2 Diabetes Mellitus FIASP + Insulin glargine (N=341) Urinary tract infection 5.9 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Table 3: Adverse Reactions (%*) in Pediatric Patients with Type 1 Diabetes Mellitus Mealtime FIASP + Insulin degludec (N=261) Postmeal FIASP + Insulin degludec (N=258) Viral upper respiratory tract infection Upper respiratory tract infection Influenza Rhinitis Headache Pyrexia Vomiting 23.0 8.4 7.7 3.8 6.1 8.4 3.4 20.5 12.4 5.8 6.2 10.1 6.2 8.1 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including FIASP. 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 FIASP 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. Incidence rates for severe hypoglycemia in adults with type 1 and type 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus treated with FIASP in clinical trials are shown in Table 4 [see Clinical Studies ( 14 )] . Table 4. Proportion (%) of Patients with Type 1 Diabetes and Type 2 Diabetes Mellitus Experiencing at Least One Episode of Severe Hypoglycemia in Adult and Pediatric Clinical Trials Study A (Type 1) Adults Study B (Type 2) Adults Study E (Type 1) Pediatric Study D (Type 1 CSII) Mealtime FIASP + Insulin detemir (N=386) Postmeal FIASP + Insulin detemir (N=377) FIASP + Insulin glargine (N=341) Mealtime FIASP + Insulin degludec (N=261) Postmeal FIASP + Insulin degludec (N=258) FIASP (N=236) Severe hypoglycemia* 6.7 8.0 3.2 1.1 3.1 4.7 *Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions Blood glucose confirmed hypoglycemia was defined as a self-measured glucose calibrated to plasma of less than 56 mg/dL. In Study D, adult patients with type 1 diabetes mellitus treated with FIASP in a pump reported a higher rate of blood glucose confirmed hypoglycemic episodes within the first hour after a meal compared to patients treated with NovoLog [see Clinical Trials ( 14.5 )] . In Study E, pediatric patients with type 1 diabetes mellitus treated with mealtime and postmeal FIASP reported a higher rate of blood glucose confirmed hypoglycemic episodes compared to patients treated with NovoLog; the imbalance was greater during the nocturnal period [see Use in Specific Populations ( 8.4 ), Clinical Trials ( 14.3 )]. Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including FIASP, and may be life threatening. In the clinical program, generalized hypersensitivity reactions (manifested by generalized skin rash and facial edema) were reported in 0.4% of adult patients treated with FIASP. Allergic skin manifestations reported with FIASP in 1.7% of adult patients from the clinical program include eczema, rash, rash pruritic, urticaria and dermatitis. In Study D, allergic reactions were reported in 4.2% of adult patients with type 1 diabetes mellitus treated with FIASP. In Study E, allergic reactions were reported in 4% of pediatric patients with type 1 diabetes mellitus treated with FIASP. Lipodystrophy Administration of insulin, including FIASP, has resulted in lipohypertrophy (enlargement or thickening of tissue) and lipoatrophy (depression in the skin). In the clinical program, lipodystrophy was reported in 0.4% of adult patients and 2.1% of pediatric patients treated with FIASP [see Dosage and Administration ( 2.2 )] . Injection/Infusion Site Reactions As with other insulin therapy, patients may experience rash, redness, inflammation, pain, bruising or itching at the site of FIASP injection or infusion. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of FIASP. In the clinical program, injection site reactions occurred in 1.6% of adult patients treated with FIASP. In Study A, adult patients with type 1 diabetes mellitus treated with FIASP reported 2.2% injection site reactions. In Study D, infusion site reactions were reported in 10.2% of adult patients with type 1 diabetes mellitus treated with FIASP. In Study E, injection site reactions were reported in 4.2% of pediatric patients with type 1 diabetes mellitus treated with FIASP. Weight Gain Weight gain can occur with insulin therapy, including FIASP, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. In Study A, adult patients with type 1 diabetes mellitus treated with FIASP gained an average of 0.7 kg and in Study B, adult patients with type 2 diabetes mellitus treated with FIASP gained an average of 2.7 kg. Peripheral Edema Insulin, including FIASP, may cause sodium retention and edema, particularly if previous poor metabolic control is improved by intensified insulin therapy. In the clinical program, peripheral edema occurred in 0.8% of adult patients treated with FIASP. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of insulin aspart. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

12.3 Pharmacokinetics Absorption Pharmacokinetic results from a euglycemic clamp study in adult patients with type 1 diabetes mellitus (N=51) showed that insulin aspart appeared in the circulation ~2.5 minutes after administration of FIASP (Figure 3). Time to maximum insulin concentrations was achieved ~63 minutes after administration of FIASP. Figure 3. Mean Insulin Aspart Serum Concentration Profile in Adult Subjects with Type 1 Diabetes Mellitus (N=51) following a single 0.2 unit/kg dose (subcutaneous) of FIASP Total insulin exposure and maximum insulin concentration increase proportionally with increasing subcutaneous dose of FIASP within the therapeutic dose range. Distribution Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin. Elimination The apparent terminal half-life after subcutaneous administration of FIASP is about 1.1 hours. Specific Populations Age, gender, BMI, and race did not meaningfully affect the pharmacokinetics and pharmacodynamics of FIASP. Patients with Renal and Hepatic Impairment Based on studies conducted with insulin aspart, renal and hepatic impairment is not known to impact the pharmacokinetics of insulin aspart. Figure 3