Fiasp

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.

4 CONTRAINDICATIONS FIASP is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . • In patients with known hypersensitivity to insulin aspart or any of the excipients in FIASP [see Warnings and Precautions ( 5.6 )] . • During episodes of hypoglycemia ( 4 ). • Hypersensitivity to insulin aspart or any of the excipients in FIASP ( 4 ).

11 DESCRIPTION Insulin aspart is a rapid-acting insulin analog for subcutaneous or intravenous administration. Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae . Insulin aspart has the empirical formula C 256 H 381 N 65 0 79 S 6 and a molecular weight of 5825.8 daltons. FIASP (insulin aspart) injection is an aqueous, sterile, clear and colorless solution. Each mL contains 100 units of insulin aspart and the inactive ingredients: arginine (as L-arginine hydrochloride), USP (3.48 mg); dibasic sodium phosphate, USP (0.42 mg); glycerin, USP (3.3 mg); metacresol, USP (1.72 mg); niacinamide, USP (20.8 mg); phenol, USP (1.50 mg); zinc (as zinc acetate), USP (19.6 mcg) and Water for Injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH to 7.1. Figure 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 )].

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 ).

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.5 )] . Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure or neurologic impairment may be treated with an intramuscular/subcutaneous glucagon product for emergency use or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

7 DRUG INTERACTIONS Table 5 includes clinically significant drug interactions with FIASP. Table 5. Clinically Significant Drug Interactions with FIASP Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose reductions and increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of FIASP Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dose increases and increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of FIASP Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine. Intervention: Increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. • Drugs that Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose ( 7 ). • Drugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine) : Increased frequency of glucose monitoring may be required ( 7 ).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The primary activity of FIASP is the regulation of glucose metabolism. Insulins, including insulin aspart, the active ingredient in FIASP, exert their specific action through binding to insulin receptors. Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis. 12.2 Pharmacodynamics The time course of insulin action (i.e., glucose lowering) may vary considerably in different individuals or within the same individual. The average pharmacodynamic profile (i.e., glucose lowering effect measured as glucose infusion rate (GIR) in a euglycemic clamp study) for subcutaneous administration of 0.1, 0.2, and 0.4 unit/kg of FIASP in 46 patients with Type 1 diabetes mellitus is shown in Figure 2 and key characteristics of the timing of the effect are described in Table 6 below. Table 6. Timing of insulin effect (i.e., mean pharmacodynamic effect) after subcutaneous administration of 0.1, 0.2 and 0.4 unit/kg of FIASP in patients (N=46) with Type 1 Diabetes Mellitus and corresponding to the data shown in Figure 2 Parameter for Insulin Effect FIASP 0.1 unit/kg FIASP 0.2 unit/kg FIASP 0.4 unit/kg Time to first measurable effect ~20 minutes ~17 minutes ~16 minutes Time to peak effect ~91 minutes ~122 minutes ~133 minutes Time for effect to return to baseline ~5 hours ~6 hours ~7 hours Figure 2. Mean insulin effect (i.e., mean pharmacodynamic effect) over time after subcutaneous administration of 0.1, 0.2 and 0.4 unit/kg of FIASP in patients (N=46) with Type 1 Diabetes Mellitus On average, the pharmacodynamic effects of FIASP, measured as area under the glucose infusion rate-time curve (AUC GIR ), was 697 mg/kg, 1406 mg/kg, and 2427 mg/kg following administration of 0.1, 0.2, and 0.4 unit/kg of FIASP. The day-to-day variability in glucose-lowering-effect of FIASP within patients was ~18% for total glucose lowering (AUC GIR, 0-12h ) and ~19% for maximum glucose lowering effect (GIR max ). Figure 2 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 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of FIASP or of other insulin aspart products. In a 26-week study in adult subjects with type 1 diabetes mellitus (Study A) [see Clinical Studies ( 14.2 )], among the 763 subjects who received FIASP, 97% were positive for cross-reacting anti-insulin antibodies (AIA) at least once during the study, including 90% that were positive at baseline. A total of 25% of patients who received FIASP were positive for anti-drug (insulin aspart) antibodies (ADA) at least once during the study, including 17% that were positive at baseline. In a 26-week study in pediatric subjects with type 1 diabetes mellitus (Study E) [see Clinical Studies ( 14.3 )] , among the 519 subjects who received FIASP, 97% were positive for cross-reacting AIA at least once during the study, including 95% that were positive at baseline. A total of 19% of patients who received FIASP were positive for ADA at least once during the study, including 16.0% that were positive at baseline. There was no identified clinically significant effect of ADA on pharmacokinetics, pharmacodynamics, safety, or effectiveness of FIASP.

12.1 Mechanism of Action The primary activity of FIASP is the regulation of glucose metabolism. Insulins, including insulin aspart, the active ingredient in FIASP, exert their specific action through binding to insulin receptors. Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

12.2 Pharmacodynamics The time course of insulin action (i.e., glucose lowering) may vary considerably in different individuals or within the same individual. The average pharmacodynamic profile (i.e., glucose lowering effect measured as glucose infusion rate (GIR) in a euglycemic clamp study) for subcutaneous administration of 0.1, 0.2, and 0.4 unit/kg of FIASP in 46 patients with Type 1 diabetes mellitus is shown in Figure 2 and key characteristics of the timing of the effect are described in Table 6 below. Table 6. Timing of insulin effect (i.e., mean pharmacodynamic effect) after subcutaneous administration of 0.1, 0.2 and 0.4 unit/kg of FIASP in patients (N=46) with Type 1 Diabetes Mellitus and corresponding to the data shown in Figure 2 Parameter for Insulin Effect FIASP 0.1 unit/kg FIASP 0.2 unit/kg FIASP 0.4 unit/kg Time to first measurable effect ~20 minutes ~17 minutes ~16 minutes Time to peak effect ~91 minutes ~122 minutes ~133 minutes Time for effect to return to baseline ~5 hours ~6 hours ~7 hours Figure 2. Mean insulin effect (i.e., mean pharmacodynamic effect) over time after subcutaneous administration of 0.1, 0.2 and 0.4 unit/kg of FIASP in patients (N=46) with Type 1 Diabetes Mellitus On average, the pharmacodynamic effects of FIASP, measured as area under the glucose infusion rate-time curve (AUC GIR ), was 697 mg/kg, 1406 mg/kg, and 2427 mg/kg following administration of 0.1, 0.2, and 0.4 unit/kg of FIASP. The day-to-day variability in glucose-lowering-effect of FIASP within patients was ~18% for total glucose lowering (AUC GIR, 0-12h ) and ~19% for maximum glucose lowering effect (GIR max ). Figure 2

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

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3 DOSAGE FORMS AND STRENGTHS Injection: 100 units of insulin aspart per mL (U-100) is available as a clear and colorless solution in: • 10 mL multiple-dose vial • 3 mL single-patient-use FIASP FlexTouch pen • 3 mL single-patient-use PenFill cartridges for use in a PenFill cartridge delivery device • 1.6 mL single-patient-use PumpCart cartridges for use in a compatible insulin pump. Injection: 100 units/mL (U-100) available as: • 10 mL multiple-dose vial ( 3 ) • 3 mL single-patient-use FIASP FlexTouch ® pen ( 3 ) • 3 mL single-patient-use PenFill ® cartridges for use in a PenFill cartridge device ( 3 ) • 1.6 mL single-patient-use PumpCart ® cartridges for use in a compatible insulin pump ( 3 )

Fiasp insulin aspart injection INSULIN ASPART INSULIN ASPART WATER HYDROCHLORIC ACID SODIUM HYDROXIDE Fiasp insulin aspart injection INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM WATER HYDROCHLORIC ACID SODIUM HYDROXIDE Fiasp insulin aspart injection INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM WATER HYDROCHLORIC ACID SODIUM HYDROXIDE Fiasp insulin aspart INSULIN ASPART INSULIN ASPART WATER HYDROCHLORIC ACID SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with insulin aspart at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 units/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, insulin aspart increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for insulin aspart was not significantly different than for regular human insulin. The relevance of these findings to humans is not known. Insulin aspart was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility studies in male and female rats, at subcutaneous doses up to 200 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with insulin aspart at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 units/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, insulin aspart increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for insulin aspart was not significantly different than for regular human insulin. The relevance of these findings to humans is not known. Insulin aspart was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility studies in male and female rats, at subcutaneous doses up to 200 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.

BLA208751

Fiasp

insulin aspart injection

0169-3201

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL - VIAL NDC 0169-3201-11 List 320111 FIASP ® (insulin apart) injection 100 units/mL (U-100) For subcutaneous or intravenous use Rx only One 10 mL multi-dose vial Fiasp Vial 8-0911-31-301-X

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-Approved Patient Labeling (Patient Information and Instructions for Use). Never Share a FIASP FlexTouch Pen Device, PenFill Cartridge or PenFill Cartridge Device Between Patients Advise patients that they should never share a FIASP FlexTouch pen device, PenFill cartridge or PenFill cartridge devices with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens. Advise patients using FIASP vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions ( 5.1 )] . Hyperglycemia or Hypoglycemia Inform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of FIASP therapy. Instruct patients 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. Instruct patients on the management of hypoglycemia [see Warnings and Precautions ( 5.3 )] . Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery. Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions ( 5.2 )] . Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with FIASP. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.6 )] . Hypoglycemia due to Medication Errors Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products. Patients Using Continuous Subcutaneous Insulin Pumps • Train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories. • Instruct patients to follow healthcare provider recommendations when setting basal and meal time infusion rate. • Refer to the continuous subcutaneous infusion pump user manual to see if FIASP can be used with the pump. See recommended reservoir and infusion sets in the insulin pump user manual. • Instruct patients to 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; infusion sets and infusion set insertion sites should be changed in accordance with the manufacturers’ user manual. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative. • Instruct patients to discard insulin exposed to temperatures higher than 37°C (98.6°F). • Instruct patients to inform physician and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened. • Instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Instruct patients on the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their physician [see Warnings and Precautions ( 5 ) and How Supplied/Storage and Handling ( 16.2 )] . Version: 8 Novo Nordisk ® , FIASP ® , NovoLog ® , FlexTouch ® , PenFill ® and PumpCart ® are registered trademarks of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/products/product-patents.html © 2023 Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, New Jersey 08536 U.S. License 1261 For information about FIASP contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, New Jersey 08536 1-800-727-6500 www.novonordisk-us.com

INSTRUCTIONS FOR USE FIASP (fee’ asp) (insulin aspart) injection 10 mL multiple-dose vial (100 units/mL, U-100) Read this Instructions for Use before you start taking FIASP and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. The vial is not recommended for use by the blind or visually impaired without the assistance of a person trained in the proper use of the product and insulin syringe. Do not reuse or share syringes or needles with other people. You may give other people a serious infection or get a serious infection from them. Supplies you will need to give your FIASP injection: • a 10 mL FIASP vial • a U-100 insulin syringe and needle • 2 alcohol swabs • 1 sharps container for throwing away used needles and syringes. See “Disposing of your used needles and syringes” at the end of these instructions. Preparing your FIASP dose: • Do not roll or shake the FIASP vial. Shaking the FIASP vial right before the dose is drawn into the syringe may cause bubbles or foam. This can cause you to draw up the wrong dose of insulin. • The tamper-resistant cap should not be loose or damaged before the first use. Do not use if the tamper-resistant cap is loose or damaged before using FIASP for the first time. • Wash your hands with soap and water. • Before you start to prepare your injection, check the FIASP label to make sure that you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. • Check that the FIASP vial is not cracked or damaged. Do not use if the FIASP vial is cracked or damaged. • FIASP should look clear and colorless. Do not use FIASP if it is thick, cloudy, or is colored. • Do not use FIASP past the expiration date printed on the label. Step 1: Pull off the tamper-resistant cap (See Figure A). Step 2: Wipe the rubber stopper with an alcohol swab (See Figure B). (Figure A Figure B) Step 3: Hold the syringe with the needle pointing up. Pull down on the plunger until the tip of the plunger reaches the line for the number of units for your prescribed dose (See Figure C). (Figure C) Step 4: Push the needle through the rubber stopper of the FIASP vial (See Figure D). (Figure D) Step 5: Push the plunger all the way in. This puts air into the FIASP vial (See Figure E). (Figure E) Step 6: Turn the FIASP vial and syringe upside down and slowly pull the plunger down until the tip of the plunger is a few units past the line for your dose (See Figure F). If there are air bubbles, tap the syringe gently a few times to let any air bubbles rise to the top (See Figure G). (Figure F) (Figure G) Step 7: Slowly push the plunger up until the tip of the plunger reaches the line for your prescribed FIASP dose (See Figure H). (Figure H) Step 8: Check the syringe to make sure you have the right dose of FIASP. Step 9: Pull the syringe out of the rubber stopper on the vial (See Figure I). (Figure I) Giving your FIASP injection: • Inject your FIASP exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. • You should take your dose of FIASP at the start of a meal or within 20 minutes after starting a meal. • FIASP can be injected under the skin (subcutaneously) of your stomach area, upper legs, or upper arms, infused in an insulin pump into an area of your body recommended in the instructions that come with your insulin pump, or given through a needle in your arm (intravenously) by your healthcare provider. Do not inject FIASP into your muscle. • If you use FIASP in an insulin pump, you should change the infusion sets and the infusion set insertion site according to the pump manufacturers’ user manual. The insulin in the reservoir should be changed at least every 6 days even if you have not used all of the insulin. • If you use FIASP in an insulin pump, see your insulin pump manual for instructions or talk to your healthcare provider. Your healthcare provider should provide recommendations for appropriate basal and meal time infusion rates. • Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. • Do not dilute or mix FIASP with any other type of insulin products or solutions. Step 10: Choose your injection site (thighs, upper arms, or abdomen) and wipe the skin with an alcohol swab (See Figure J). Let the injection site dry before you inject your dose. (Figure J) Step 11: Insert the needle into your skin. Push down on the plunger to inject your dose (See Figure K). Make sure you have injected all the insulin in the syringe. (Figure K) Step 12: Pull the needle out of your skin. After your injection you may see a drop of FIASP at the needle tip. This is normal and does not affect the dose you just received (See Figure L). • If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. (Figure L) After your injection: • Do not recap the needle. Recapping the needle can lead to needle stick injury. Disposing of your used needles and syringes: Put your used insulin needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic; o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out; o upright and stable during use; o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. Do not reuse or share needles or syringes with another person. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. How should I store FIASP? • Do not freeze FIASP. Do not use FIASP if it has been frozen. • Keep FIASP away from excessive heat or light. All unopened vials: • Store unopened FIASP vials in the refrigerator at 36 ° F to 46 ° F (2 ° C to 8 ° C) or at room temperature below 86 ° F (30 ° C). • If unopened vials have been stored in the refrigerator, vials may be used until the expiration date printed on the label. • If unopened vials have been stored at room temperature, vials should be thrown away after 28 days. After vials have been opened: • Opened FIASP vials can be stored in the refrigerator at 36 ° F to 46 ° F (2 ° C to 8 ° C) or at room temperature below 86 ° F (30 ° C). • Throw away all opened FIASP vials after 28 days (including 6 days pump in-use time), even if they still have insulin left in them. General information about the safe and effective use of FIASP • Always use a new syringe and needle for each injection to help ensure sterility and prevent blocked needles. • Do not reuse or share syringes or needles with other people. You may give other people a serious infection or get a serious infection from them. • Keep FIASP vials, syringes, and needles out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-800-727-6500 U.S. License No. 1261 FIASP ® is a registered trademark of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/products/product-patents.html © 2023 Novo Nordisk For information about FIASP ® contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, New Jersey 08536 1-800-727-6500 www.novonordisk-us.com Revised: 06/2023 Fiasp Vial Vial of Fiasp Figure A and B - Pull off cap Figure C - Hold syringe with needle pointing up Figure D - Push needle through stopper. Figure E - Push plunger all the way in. Figure F Pull the plunger down. Figure G - Tap the syringe. Figure H - Slowly push the plunger. Figure I - Pull the syringe out. Figure J - Choose injection site. Figure K - Insert the needle. Figure L - Pull the needle out.

14 CLINICAL STUDIES 14.1 Overview of Clinical Studies The efficacy of FIASP was evaluated in 3 randomized, active-controlled trials of 18 to 26 weeks duration in adults and one randomized, active-controlled, treat-to-target trial of 26 weeks duration in pediatric patients. In total 1,224 adult subjects (N=763 with type 1 diabetes mellitus; N=461 with type 2 diabetes mellitus) and 519 pediatric subjects with type 1 diabetes mellitus were randomized to FIASP. In adult and pediatric patients with type 1 diabetes mellitus, mealtime FIASP and postmeal FIASP led to non-inferior glycemic control compared to mealtime NovoLog, both in combination with basal insulin. In adult patients with type 2 diabetes mellitus, mealtime FIASP provided non-inferior glycemic control compared to mealtime NovoLog, both in combination with metformin. In addition, mealtime FIASP in a basal-bolus regimen with metformin also provided statistically significant improvement in the overall glycemic control compared to basal insulin therapy alone with metformin in adult patients with type 2 diabetes mellitus. In adults with type 1 diabetes mellitus (N=472), FIASP led to non-inferior glycemic control compared to NovoLog when both were administered by continuous subcutaneous insulin infusion (CSII) pump. 14.2 Type 1 Diabetes Mellitus - Adults Study A (NCT01831765): FIASP added to insulin detemir in adult patients with Type 1 Diabetes Mellitus inadequately controlled at baseline. The efficacy of FIASP was evaluated in a 26-week, randomized, active controlled, treat-to-target, multicenter trial in 1,143 adult patients with type 1 diabetes mellitus inadequately controlled at baseline. Patients were randomized to either blinded mealtime FIASP (N=381), blinded mealtime NovoLog (N=380), or open-label postmeal FIASP (N=382), all in combination with once or twice daily insulin detemir. At randomization, patients were switched to FIASP on a unit to unit basis. Mealtime FIASP or NovoLog was injected 0-2 minutes before the meal, and postmeal FIASP was injected 20 minutes after the start of the meal. The mean age of the randomized subjects was 44.4 years and 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 . After 26 weeks of treatment, treatment difference in HbA 1c reduction from baseline between mealtime FIASP compared to mealtime NovoLog, and the treatment difference between postmeal FIASP compared to mealtime NovoLog met the pre-specified non-inferiority margin (0.4%). See Table 7. Insulin doses were similar among study arms at baseline and at the end of the trial. Table 7. Results from Study A: 26-Week Trial of Mealtime FIASP and Postmeal FIASP compared to Mealtime NovoLog Used in Combination with Insulin Detemir in Adults with Type 1 Diabetes Mellitus Mealtime FIASP + insulin detemir Postmeal FIASP + insulin detemir Mealtime NovoLog + insulin detemir Number of subjects randomized (N) 381 382 380 HbA 1c (%) Baseline (mean) 7.6 7.6 7.6 Adjusted mean change from baseline -0.32 -0.13 -0.17 Estimated treatment difference vs. mealtime NovoLog [95% CI]* -0.15 [-0.23;-0.07] 0.04 [-0.04;0.12] Baseline is based on the mean of the observed last available values prior to randomization. * Tested for non-inferiority Estimated treatment difference was calculated using mixed model for repeated measurements (MMRM). 7.6% of subjects on the Mealtime FIASP arm, 7.6% of subjects on the Postmeal FIASP arm, and 5.3% of subjects on the Mealtime NovoLog arm were missing the final HbA 1c assessment. 14.3 Type 1 Diabetes Mellitus - Pediatric Patients Study E (NCT02670915): FIASP added to insulin degludec in pediatric patients with Type 1 Diabetes Mellitus. The efficacy of FIASP was evaluated in a 26-week, randomised, multinational, active controlled, treat-to-target, 3-armed parallel-group trial in 777 pediatric patients with type 1 diabetes mellitus. Patients were randomized to either blinded mealtime FIASP (N=260), blinded mealtime NovoLog (N=258), or open-label postmeal FIASP (N=259), all in combination with once daily insulin degludec. Mealtime FIASP or NovoLog was injected 0-2 minutes before the meal, and postmeal FIASP was injected 20 minutes after the start of the meal. The mean age of the subjects at baseline was 11.7 years (range 2 to 17 years) and the mean duration of diabetes 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 . After 26 weeks of treatment, the treatment difference for change in HbA 1c from baseline between mealtime FIASP compared to mealtime NovoLog, and the treatment difference between postmeal FIASP compared to mealtime NovoLog met the pre-specified non-inferiority margin (0.4%). See Table 8. Insulin doses were similar among study arms at baseline and at the end of the trial. Table 8. Results from Study E: 26-Week Trial of Mealtime FIASP and Postmeal FIASP compared to Mealtime NovoLog Used in Combination with Insulin Degludec in Pediatrics with Type 1 Diabetes Mellitus Mealtime FIASP + insulin degludec Postmeal FIASP + insulin degludec Mealtime NovoLog + insulin degludec Number of subjects randomized (N) 260 259 258 HbA 1c (%) Baseline (mean) 7.57 7.58 7.53 Adjusted mean change from baseline 0.06 0.35 0.22 Estimated treatment difference vs. mealtime NovoLog [95% CI]* -0.17 [-0.30; -0.03] 0.13 [-0.01; 0.26] Baseline is based on the mean of the observed last available values prior to randomization. *Tested for non-inferiority Estimated treatment difference was calculated using ANCOVA. Week 26, change in HbA 1c was missing for 1.5%, 1.9%, and 1.6% of subjects in mealtime FIASP, post-meal FIASP, and NovoLog respectively. Missing values were imputed with a missing at random assumption. 14.4 Type 2 Diabetes Mellitus - Adults Study B (NCT01819129): FIASP added to basal insulin and oral antidiabetics in patients with Type 2 Diabetes Mellitus inadequately controlled at baseline on basal insulin and oral antidiabetics The efficacy of FIASP was evaluated in a 26-week randomized, double-blind, active controlled, treat-to-target, multicenter, multinational, parallel group trial in 689 adult patients with type 2 diabetes mellitus who were inadequately controlled at baseline on basal insulin and oral antidiabetic therapy and had been on these therapies for at least 6 months. Patients were randomized to either mealtime FIASP or to mealtime NovoLog, both in combination with insulin glargine and metformin in a basal-bolus regimen. Mealtime FIASP or mealtime NovoLog was injected 0-2 minutes before the meal. The mean age of the randomized subjects was 59.5 years and the mean duration of diabetes was 12.7 years. 49% were male, 81% were White, and 6% were Black or African American; and 6% were Hispanic or Latino. The mean BMI was 31.2 kg/m 2 . After 26 weeks of treatment, the treatment difference in HbA 1c reduction from baseline between mealtime FIASP and mealtime NovoLog, both in combination with insulin glargine and metformin, met the pre-specified non-inferiority margin (0.4%). See Table 9. Insulin doses were similar among study arms at the end of the trial. Table 9. Results from Study B: 26-Week Trial of Mealtime FIASP Compared to Mealtime NovoLog, Both used in Combination with Insulin Glargine and Metformin, in Adults with Type 2 Diabetes Mellitus Mealtime FIASP +insulin glargine +metformin Mealtime NovoLog +insulin glargine +metformin Number of subjects randomized (N) 345 344 HbA 1c (%) Baseline 8.0 7.9 Adjusted change from baseline -1.38 -1.36 Estimated treatment difference vs. NovoLog [95%CI]* -0.02 [-0.15;0.10] Baseline is based on the mean of the observed last available values prior to randomization. * Tested for non-inferiority Estimated treatment difference was calculated using mixed model for repeated measurements (MMRM). 11.9% of subjects on the Mealtime FIASP arm and 10.2% of subjects on the Mealtime NovoLog arm were missing the final HbA 1c assessment. Study C (NCT01850615): FIASP added to basal insulin and metformin in patients with Type 2 Diabetes Mellitus inadequately controlled at baseline on basal insulin and metformin The efficacy of FIASP was evaluated in an 18-week randomized, open-label, parallel group trial in 236 adult patients with type 2 diabetes mellitus who were inadequately controlled on basal insulin and metformin therapy, either with or without other oral antidiabetic therapy, for at least 3 months. Patients were randomized to either mealtime FIASP in addition to basal insulin and metformin or to continuing basal insulin and metformin therapy without FIASP. The basal insulins used in both treatment arms were insulin glargine, insulin detemir or NPH. All patients were also required to be on ≥1000 mg metformin treatment at baseline. The mean age of the trial population was 57.4 years and the mean duration of diabetes was 11years. 48% were male, 70% were White and 4% were Black or African American; and 37% were Hispanic or Latino. The mean BMI was 30.8 kg/m 2 . After 18 weeks of treatment, addition of FIASP to basal insulin and metformin statistically significantly reduced HbA 1c compared to continuing basal insulin and metformin therapy without addition of FIASP (Table 10). Table 10. Results from Study C: 18-Week Trial of Mealtime FIASP in Adults with Type 2 Diabetes Mellitus Inadequately Controlled at Baseline on Basal Insulin and Metformin FIASP + basal insulin + metformin Basal insulin + metformin Number of subjects randomized (N) 116 120 HbA 1c (%) Baseline 7.9 7.9 Adjusted change from baseline -1.16 -0.22 Estimated treatment difference vs. basal insulin+metformin [95%CI] -0.94 [-1.17; -0.72] * Proportion of patients Achieving HbA 1c < 7% at Trial End 60.3% 18.3% Baseline is based on the mean of the observed last available values prior to randomization. * p<0.0001, 1-sided p-value evaluated at 2.5% level for superiority. Estimated treatment difference was calculated using mixed model for repeated measurements (MMRM). 6.0% of subjects on the mealtime FIASP arm and 3.3% of subjects on the placebo arm were missing the final HbA 1c assessment. 14.5 Type 1 Diabetes Mellitus– Adult Continuous Subcutaneous Insulin Infusion (CSII) Study D (NCT02825251): FIASP in Continuous Subcutaneous Insulin Infusion (CSII) in Adults with Type 1 Diabetes Mellitus The efficacy and safety of FIASP vs. NovoLog in CSII in adult subjects with type 1 diabetes mellitus (N=472) was evaluated in a randomized, multicenter, multinational, active controlled, treat-to-target, parallel group trial with a 4-week run-in and a 16-week treatment period. Meal-time bolus insulin infusion was initiated 0-2 minutes before a meal. The mean age of the randomized subjects was 43 years and the mean duration of diabetes was 24 years. 43% were male. 89% were White, 1% were Black or African American, and 1% were Asian; and 3% were Hispanic or Latino. The mean BMI was 26.3 kg/m 2 . After 16 weeks of treatment, the treatment difference in HbA 1c reduction from baseline between FIASP and NovoLog was 0.10 with 95%CI [0.02, 0.18] (Table 11). Table 11. Results from Study D: 16-Week Trial FIASP in Adults with Type 1 Diabetes FIASP NovoLog Number of subjects randomized (N) 236 236 HbA 1c (%) Baseline 7.5 7.5 Adjusted change from baseline -0.04 -0.14 Estimated treatment difference FIASP vs. NovoLog [95%CI] * 0.10 [0.02; 0.18] Proportion of patients Achieving HbA 1c < 7% at Trial End 20.3% 23.3% Baseline is based on the mean of the observed last available values prior to randomization. * Tested for non-inferiority using a margin of 0.4%. Estimated treatment difference was calculated using ANCOVA. 2.1% of subjects on the FIASP arm and 2.5% of subjects on the NovoLog arm were missing the final HbA 1c assessment. Missing values were imputed using multiple imputation with a mean equal to the baseline value of the corresponding patient.

8.5 Geriatric Use In the three controlled clinical studies, 192 of 1219 (16%) FIASP treated patients with type 1 or type 2 diabetes mellitus were ≥ 65 years of age and 24 of 1219 (2%) were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and younger adult patients. Nevertheless, caution should be exercised when FIASP is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 )] . Pharmacokinetic/pharmacodynamic study to assess the effect of age on the onset of FIASP action has been performed [see Clinical Pharmacology ( 12.3 )] .

8.4 Pediatric Use The safety and effectiveness of FIASP have been established to improve glycemic control in pediatric patients with diabetes mellitus. Use of FIASP for this indication is supported by evidence from an adequate and well-controlled study in 777 pediatric patients with type 1 diabetes mellitus aged 2 to 17 years, and from studies in adults with diabetes mellitus [ see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )]. 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. Monitor blood glucose levels closely in pediatric patients [see Warnings and Precautions ( 5.3 ), Clinical Trial Experience ( 6.1 )].

8.1 Pregnancy Risk Summary There are no available data with FIASP in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal outcomes [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8- times and equal to the human subcutaneous dose of 1.0 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [see Data] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA 1c >7% and has been reported to be as high as 20-25% in women with a HbA 1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart starting during the late 2 nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials. Animal Data Fertility, embryo-fetal and pre-and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 unit/kg/day for rats and equal to the human subcutaneous dose of 1.0 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data with FIASP in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal outcomes [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8- times and equal to the human subcutaneous dose of 1.0 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [see Data] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA 1c >7% and has been reported to be as high as 20-25% in women with a HbA 1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart starting during the late 2 nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials. Animal Data Fertility, embryo-fetal and pre-and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 unit/kg/day for rats and equal to the human subcutaneous dose of 1.0 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia. 8.2 Lactation Risk Summary There are no data on the presence of FIASP in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin, including insulin aspart, was present in human milk. However, there is insufficient information to determine the effects of insulin aspart on the breastfed infant and no available information on the effects of insulin aspart on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for insulin, any potential adverse effects on the breastfed child from FIASP or insulin aspart or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of FIASP have been established to improve glycemic control in pediatric patients with diabetes mellitus. Use of FIASP for this indication is supported by evidence from an adequate and well-controlled study in 777 pediatric patients with type 1 diabetes mellitus aged 2 to 17 years, and from studies in adults with diabetes mellitus [ see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )]. 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. Monitor blood glucose levels closely in pediatric patients [see Warnings and Precautions ( 5.3 ), Clinical Trial Experience ( 6.1 )]. 8.5 Geriatric Use In the three controlled clinical studies, 192 of 1219 (16%) FIASP treated patients with type 1 or type 2 diabetes mellitus were ≥ 65 years of age and 24 of 1219 (2%) were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and younger adult patients. Nevertheless, caution should be exercised when FIASP is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 )] . Pharmacokinetic/pharmacodynamic study to assess the effect of age on the onset of FIASP action has been performed [see Clinical Pharmacology ( 12.3 )] . 8.6 Renal Impairment Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent FIASP dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent FIASP dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied FIASP (insulin aspart) injection 100 units of insulin aspart per mL (U-100) is available as a clear and colorless solution in the following presentations and packaging configurations: Carton of one 10 mL multiple-dose vials NDC 0169-3201-11 Carton of five 3 mL single-patient-use FIASP FlexTouch pens NDC 0169-3204-15 Carton of five 3 mL single-patient-use PenFill cartridges * NDC 0169-3205-15 Carton of five 1.6 mL single-patient-use PumpCart cartridges** NDC 0169-3206-15 The FIASP FlexTouch pen dials in 1 unit increments. * FIASP PenFill cartridges are designed for use with Novo Nordisk insulin delivery devices. ** FIASP PumpCart cartridges are designed for use in compatible pumps only. 16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Unused FIASP vials should be stored between 2° to 8°C (36° to 46°F) in a refrigerator, but not in or near a freezing compartment. FIASP should not be exposed to excessive heat or light and must never be frozen. Do not use FIASP if it has been frozen. FIASP should not be drawn into a syringe and stored for later use. Keep the cap on the pen in order to protect from light. Remove the needle from the FIASP FlexTouch pen after each injection and store without a needle attached. Use a new needle for each injection. Keep unused vials, FIASP FlexTouch, PenFill Cartridges and PumpCart cartridges in the carton so they will stay clean and protected from light. The storage conditions for vials, FIASP FlexTouch pens, 3 mL PenFill cartridges and 1.6 mL PumpCart cartridges are summarized in Table 12: Table 12. Storage Conditions for Vial, FIASP FlexTouch, PenFill Cartridges and PumpCart Cartridges FIASP presentation Not in-use (unopened) In-use (opened) Room Temperature (up to 30°C [86°F]) Refrigerated (2°C to 8°C [36°F to 46°F]) Room Temperature (up to 30°C [86°F]) Refrigerated (2°C to 8°C [36°F to 46°F]) 10 mL multiple-dose vial 28 days Until expiration date 28 days* (up to 30°C [86°F]) 28 days* 3 mL single-patient-use FIASP FlexTouch pen 28 days Until expiration date 28 days (up to 30°C [86°F]) 28 days 3 mL single-patient-use PenFill cartridges 28 days Until expiration date 28 days (up to 30°C [86°F]) Do not refrigerate 1.6 mL single-patient-use PumpCart cartridges 18 days** Until expiration date 4 days** (up to 37°C [98.6°F]) Do not refrigerate *Pump Reservoir: The total in use time is 28 days, including 6 days in the pump reservoir **PumpCart Cartridges: The maximum time at room temperature is 18 days including 4 days in the pump Storage of FIASP in Insulin Pump: • Change FIASP in the pump reservoir at least every 6 days or according to the pump user manual, whichever is shorter. • Replace the FIASP PumpCart cartridge at least every 4 days or according to the pump user manual, whichever is shorter. • Change FIASP to avoid insulin degradation or after exposure to temperatures that exceed 37°C (98.6°F). • The infusion set and infusion set insertion sites should be changed according to the manufacturers’ user manual. Storage of FIASP in Intravenous Infusion Fluids: Infusion bags prepared as indicated under Dosage and Administration ( 2.2 ) are stable at room temperature at 20°C to 25°C (68°F to 77°F) for 24 hours.