Insulin Aspart

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere: • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypersensitivity and allergic reactions [see Warnings and Precautions ( 5.5 )] • Hypokalemia [see Warnings and Precautions ( 5.6 )] Adverse reactions observed with insulin aspart include: hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Pharma, 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 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 safety of insulin aspart was evaluated in two treat-to-target trials of 6 months duration, conducted in subjects with type 1 diabetes or type 2 diabetes [see Clinical Studies ( 14 )]. The data in Table 1 reflect the exposure of 596 patients with type 1 diabetes to insulin aspart in one clinical trial with a mean exposure duration to insulin aspart of 24 weeks. The mean age was 38.9 years. Fifty-one percent were male, 94% were Caucasian, 2% were Black and 4% were other races. The mean body mass index (BMI) was 25.6 kg/m 2 . The mean duration of diabetes was 15.7 years and the mean HbA 1c at baseline was 7.9%. The data in Table 2 reflect the exposure of 91 patients with type 2 diabetes to insulin aspart in one clinical trial with a mean exposure duration to insulin aspart of 24 weeks. The mean age was 56.6 years. Sixty-three percent were male, 76% were Caucasian, 9% were Black and 15% were other races. The mean BMI was 29.7 kg/m 2 . The mean duration of diabetes was 12.7 years and the mean HbA 1c at baseline was 8.1%. Common adverse reactions were defined as events occurring in ≥5%, excluding hypoglycemia, of the population studied. Common adverse events occurring at the same rate or greater for insulin aspart-treated subjects than in comparator-treated subjects during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2, respectively. Table 1: Adverse reactions occurring in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparator insulin aspart + NPH (%) (n= 596) Regular Human Insulin + NPH (%) (n= 286) Headache 12 10 Injury accidental 11 10 Nausea 7 5 Diarrhea 5 3 Table 2: Adverse reactions occurring in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparator insulin aspart + NPH (%) (n= 91) Human Regular Insulin + NPH (%) (n= 91) Hyporeflexia 11 7 Onychomycosis 10 5 Sensory disturbance 9 7 Urinary tract infection 8 7 Chest pain 5 3 Headache 5 3 Skin disorder 5 2 Abdominal pain 5 1 Sinusitis 5 1 Severe hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin aspart [see Warnings and Precautions ( 5.3 )]. 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 insulin aspart with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. Severe hypoglycemia was defined as hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. The incidence of severe hypoglycemia in adult and pediatric patients receiving subcutaneous insulin aspart with type 1 diabetes mellitus was 17% at 24 weeks and 6% at 24 weeks, respectively [see Clinical Studies ( 14 )] . The incidence of severe hypoglycemia in adult patients receiving subcutaneous insulin aspart with type 2 diabetes mellitus was 10% at 24 weeks. The incidence of severe hypoglycemia in adult and pediatric patients with type 1 diabetes mellitus, receiving insulin aspart via continuous subcutaneous insulin infusion by external pump was 2% at 16 weeks and 10% at 16 weeks respectively. No severe hypoglycemic episodes were reported in adult patients with type 2 diabetes mellitus receiving insulin aspart via continuous subcutaneous insulin infusion by external pump at 16 weeks. Allergic Reactions Some patients taking insulin therapy, including insulin aspart have experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and Precautions ( 5.5 )]. Insulin initiation and glucose control intensification Intensification 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. Lipodystrophy Administration of insulin, including insulin aspart, subcutaneously and via subcutaneous insulin infusion by external pump, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration ( 2.2 )]. Peripheral Edema Insulin products, including insulin aspart, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Weight gain Weight gain has occurred with some insulin therapies including insulin aspart and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to insulin aspart in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In a 6-month study with a 6-month extension in adult subjects with type 1 diabetes, 99.8% of patients who received insulin aspart were positive for anti-insulin antibodies (AIA) at least once during the study, including 97.2% that were positive at baseline. A total of 92.1% of patients who received insulin aspart were positive for anti-drug antibodies (ADA) at least once during the study, including 64.6% that were positive at baseline. In a phase 3 type 1 diabetes clinical trial of insulin aspart, initial increase in titers of antibodies to insulin, followed by a decrease to baseline values, was observed in regular human insulin and insulin aspart treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose. 6.3 Post Marketing Experience The following adverse reactions have been identified during post-approval use of insulin aspart. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which other insulins have been accidentally substituted for insulin aspart [see Warnings and Precautions ( 5.4 )] . Localized cutaneous amyloidosis at the injection site has occurred with insulin aspart. 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 Insulin aspart is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] • In patients with hypersensitivity to insulin aspart or one of its excipients, [see Warnings and Precautions ( 5.5 )] • During episodes of hypoglycemia ( 4 ). • Hypersensitivity to insulin aspart or one of its excipients.

11 DESCRIPTION Insulin aspart (injection) is a rapid-acting human insulin analog used to lower blood glucose. 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 (baker's yeast). Insulin aspart has the empirical formula C 256 H 381 N 65 0 79 S 6 and a molecular weight of 5825.8. Figure 1. Structural formula of insulin aspart. Insulin aspart is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart 100 units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL and water for injection. Insulin aspart has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH. Molecular Formula

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important administration and dosage instructions ( 2.1, 2.2, 2.3, 2.4, 2.5 ). • Subcutaneous injection ( 2.2 ): o Inject subcutaneously within 5-10 minutes before a meal into the abdominal area, thigh, buttocks or upper arm. o Rotate injection sites within the same region from one injection to the next to reduce 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 Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. o Rotate the injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. o Change the Insulin aspart in the reservoir at least every 6 days. o Change the infusion set and the infusion set insertion site at least every 3 days. o Do not mix with other insulins or diluents in the pump. • Intravenous Administration ( 2.2 ) : o Dilute insulin aspart to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags. o Insulin aspart is stable in infusion fluids such as 0.9% sodium chloride. • Individualize and adjust the dosage of insulin aspart based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.4 ). • Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness ( 2.4 ). 2.1 Important Administration Instructions • Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . • Inspect insulin aspart visually before use. It should appear clear and colorless. Do not use insulin aspart if particulate matter or coloration is seen. • Use Insulin Aspart FlexPen 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 insulin aspart with other insulins when administering using a continuous subcutaneous infusion pump. 2.2 Route of Administration Subcutaneous Injection • Inject insulin aspart subcutaneously within 5-10 minutes before a meal into the abdominal area, thigh, buttocks 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 ) and Adverse Reactions ( 6.1 , 6.3 )]. • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. • The Insulin Aspart FlexPen dial in 1-unit increments. • Insulin aspart administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. • Insulin aspart may be diluted with Insulin Diluting Medium for NovoLog ® for subcutaneous injection. Diluting one part insulin aspart to nine parts diluent will yield a concentration one-tenth that of insulin aspart (equivalent to U-10). Diluting one part insulin aspart to one part diluent will yield a concentration one-half that of insulin aspart (equivalent to U-50). Continuous Subcutaneous Infusion (Insulin Pump) • Use insulin aspart in pump systems specifically indicated for insulin infusion. • Train patients using continuous subcutaneous insulin fusion pump therapy to administer insulin by injection and have alternate insulin therapy available in case of pump failure. • Administer insulin aspart 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 or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 , 6.3 )]. • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. • Follow healthcare provider recommendations when setting basal and meal time infusion rate. • Change the insulin aspart in the reservoir at least every 6 days. Follow the insulin aspart-specific information for in-use time because insulin aspart-specific information may differ from general pump manual instructions. • Change the infusion set and the infusion set insertion site at least every 3 days. • Do NOT dilute or mix insulin aspart when administering by continuous subcutaneous infusion. • Do NOT expose insulin aspart in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration • Dilute insulin aspart to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags. Insulin aspart is stable in infusion fluids such as 0.9% sodium chloride. • Administer insulin aspart 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 , 5.6 ) and How Supplied/Storage and Handling ( 16.2 )] . 2.3 Dosage Information • Individualize and adjust the dosage of insulin aspart based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. • Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions ( 5.2 , 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )] . • Dosage adjustment may be needed when switching from another insulin to insulin aspart [see Warnings and Precautions ( 5.2 )] . 2.4 Dosage Adjustment Due to Drug Interactions • Dosage adjustment may be needed when insulin aspart is coadministered with certain drugs [see Drug Interactions ( 7 )] . 2.5 Instructions for Mixing with Other Insulins Insulin aspart subcutaneous injection route Insulin aspart may be mixed with NPH insulin preparations ONLY . • If insulin aspart is mixed with NPH insulin, draw insulin aspart into the syringe first and inject immediately after mixing. Insulin aspart continuous subcutaneous infusion route (Insulin Pump) Do NOT mix insulin aspart with any other insulin.

1 INDICATIONS AND USAGE Insulin aspart is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. • Insulin aspart is rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus ( 1 ).

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 )] . 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 intramuscular/subcutaneous glucagon 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 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, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when insulin aspart is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of insulin aspart 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 adjustment and increased frequency of glucose monitoring may be required when insulin aspart is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of insulin aspart Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when insulin aspart 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 insulin aspart is co-administered with these drugs. • Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics ( 7 ). • Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, 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 ( 7 ). • Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine ( 7 ). • Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine ( 7 ).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The primary activity of insulin, including insulin aspart is the regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis. 12.2 Pharmacodynamics Subcutaneous administration The pharmacodynamic profile of insulin aspart given subcutaneously in 22 patients with type 1 diabetes is shown in Figure 2. The maximum glucose-lowering effect of insulin aspart occurred between 1 and 3 hours after subcutaneous injection (0.15 units/kg). The duration of action for insulin aspart is 3 to 5 hours. The time course of action of insulin and insulin analogs such as insulin aspart may vary considerably in different individuals or within the same individual. The parameters of insulin aspart activity (time of onset, peak time and duration) as designated in Figure 2 should be considered only as general guidelines. The rate of insulin absorption and onset of activity is affected by the site of injection, exercise, and other variables [see Warnings and Precautions ( 5.3 )] . Figure 2. Serial mean serum glucose collected up to 6 hours following a single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes. Intravenous administration A double-blind, randomized, two-way crossover study in 16 patients with type 1 diabetes demonstrated that intravenous infusion of insulin aspart resulted in a blood glucose profile that was similar to that after intravenous infusion with regular human insulin. Insulin aspart or human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as the time of autonomic reaction (R) (see Figure 3). Figure 3. Mean blood glucose profiles following intravenous infusion of insulin aspart (hatched curve) and regular human insulin (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction. Figure 1 Figure 3 12.3 Pharmacokinetics Subcutaneous administration Absorption and Bioavailability In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total n=40), the median time to maximum concentration of insulin aspart in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively. The relative bioavailability of insulin aspart (0.15 units/kg) compared to regular human insulin indicates that the two insulins are absorbed to a similar extent. In a clinical trial in patients with type 1 diabetes, insulin aspart and regular human insulin, both administered subcutaneously at a dose of 0.15 units/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L , respectively. Distribution Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin. Figure 4. Serial mean serum free insulin concentration collected up to 6 hours following a single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes. Metabolism and Elimination In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects between 18 and 40 years of age received an intravenous infusion of either insulin aspart or regular human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for the two groups with mean values of 1.2 L/h/kg for the insulin aspart group and 1.2 L/h/kg for the regular human insulin group. After subcutaneous administration in normal male volunteers (n=24), insulin aspart was eliminated with an average apparent half-life of 81 minutes. Specific Populations Pediatrics: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were evaluated in a single dose study in 18 children (6-12 years, n=9) and adolescents (13-17 years [Tanner grade ≥ 2], n=9) with type 1 diabetes. The relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with type 1 diabetes between insulin aspart and regular human insulin were similar to those in healthy adult subjects and adults with type 1 diabetes. Geriatrics: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were investigated in a single dose study in 18 subjects with type 2 diabetes who were ≥ 65 years of age. The relative differences in pharmacokinetics and pharmacodynamics in geriatric patients with type 2 diabetes between insulin aspart and regular human insulin were similar to those in younger adults. Gender: In healthy volunteers given a single subcutaneous dose of insulin aspart 0.06 units/kg, no difference in insulin aspart levels was seen between men and women based on comparison of AUC (0-10h) or C max . Obesity: A single subcutaneous dose of 0.1 units/kg insulin aspart was administered in a study of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m 2 ). The pharmacokinetic parameters, AUC and C max , of insulin aspart were generally unaffected by BMI in the different groups – BMI 19-23 kg/m 2 (N=4); BMI 23-27 kg/m 2 (N=7); BMI 27-32 kg/m 2 (N=6) and BMI >32 kg/m 2 (N=6). Clearance of insulin aspart was reduced by 28% in patients with BMI >32 kg/m 2 compared to patients with BMI <23 kg/m 2 . Renal Impairment: A single subcutaneous dose of 0.08 units/kg insulin aspart was administered in a study to subjects with either normal renal function (N=6) creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment. In this study, there was no apparent effect of creatinine clearance values on AUC and C max of insulin aspart. Hepatic Impairment: A single subcutaneous dose of 0.06 units/kg insulin aspart was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this study, there was no correlation between the degree of hepatic impairment and any insulin aspart pharmacokinetic parameter. Figure 4

12.1 Mechanism of Action The primary activity of insulin, including insulin aspart is the regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

12.2 Pharmacodynamics Subcutaneous administration The pharmacodynamic profile of insulin aspart given subcutaneously in 22 patients with type 1 diabetes is shown in Figure 2. The maximum glucose-lowering effect of insulin aspart occurred between 1 and 3 hours after subcutaneous injection (0.15 units/kg). The duration of action for insulin aspart is 3 to 5 hours. The time course of action of insulin and insulin analogs such as insulin aspart may vary considerably in different individuals or within the same individual. The parameters of insulin aspart activity (time of onset, peak time and duration) as designated in Figure 2 should be considered only as general guidelines. The rate of insulin absorption and onset of activity is affected by the site of injection, exercise, and other variables [see Warnings and Precautions ( 5.3 )] . Figure 2. Serial mean serum glucose collected up to 6 hours following a single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes. Intravenous administration A double-blind, randomized, two-way crossover study in 16 patients with type 1 diabetes demonstrated that intravenous infusion of insulin aspart resulted in a blood glucose profile that was similar to that after intravenous infusion with regular human insulin. Insulin aspart or human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as the time of autonomic reaction (R) (see Figure 3). Figure 3. Mean blood glucose profiles following intravenous infusion of insulin aspart (hatched curve) and regular human insulin (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction. Figure 1 Figure 3

12.3 Pharmacokinetics Subcutaneous administration Absorption and Bioavailability In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total n=40), the median time to maximum concentration of insulin aspart in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively. The relative bioavailability of insulin aspart (0.15 units/kg) compared to regular human insulin indicates that the two insulins are absorbed to a similar extent. In a clinical trial in patients with type 1 diabetes, insulin aspart and regular human insulin, both administered subcutaneously at a dose of 0.15 units/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L , respectively. Distribution Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin. Figure 4. Serial mean serum free insulin concentration collected up to 6 hours following a single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes. Metabolism and Elimination In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects between 18 and 40 years of age received an intravenous infusion of either insulin aspart or regular human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for the two groups with mean values of 1.2 L/h/kg for the insulin aspart group and 1.2 L/h/kg for the regular human insulin group. After subcutaneous administration in normal male volunteers (n=24), insulin aspart was eliminated with an average apparent half-life of 81 minutes. Specific Populations Pediatrics: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were evaluated in a single dose study in 18 children (6-12 years, n=9) and adolescents (13-17 years [Tanner grade ≥ 2], n=9) with type 1 diabetes. The relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with type 1 diabetes between insulin aspart and regular human insulin were similar to those in healthy adult subjects and adults with type 1 diabetes. Geriatrics: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were investigated in a single dose study in 18 subjects with type 2 diabetes who were ≥ 65 years of age. The relative differences in pharmacokinetics and pharmacodynamics in geriatric patients with type 2 diabetes between insulin aspart and regular human insulin were similar to those in younger adults. Gender: In healthy volunteers given a single subcutaneous dose of insulin aspart 0.06 units/kg, no difference in insulin aspart levels was seen between men and women based on comparison of AUC (0-10h) or C max . Obesity: A single subcutaneous dose of 0.1 units/kg insulin aspart was administered in a study of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m 2 ). The pharmacokinetic parameters, AUC and C max , of insulin aspart were generally unaffected by BMI in the different groups – BMI 19-23 kg/m 2 (N=4); BMI 23-27 kg/m 2 (N=7); BMI 27-32 kg/m 2 (N=6) and BMI >32 kg/m 2 (N=6). Clearance of insulin aspart was reduced by 28% in patients with BMI >32 kg/m 2 compared to patients with BMI <23 kg/m 2 . Renal Impairment: A single subcutaneous dose of 0.08 units/kg insulin aspart was administered in a study to subjects with either normal renal function (N=6) creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment. In this study, there was no apparent effect of creatinine clearance values on AUC and C max of insulin aspart. Hepatic Impairment: A single subcutaneous dose of 0.06 units/kg insulin aspart was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this study, there was no correlation between the degree of hepatic impairment and any insulin aspart pharmacokinetic parameter. Figure 4

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7

3 DOSAGE FORMS AND STRENGTHS Insulin aspart 100 units per mL (U-100) is available as a clear and colorless solution for injection in: • 10 mL multiple-dose vial • 3 mL single-patient-use PenFill cartridges for the 3 mL PenFill cartridge delivery device with NovoFine ® disposable needles • 3 mL single-patient-use Insulin Aspart FlexPen Each presentation contains 100 Units of insulin aspart per mL (U-100) • 10 mL multiple-dose vial ( 3 ) • 3 mL single-patient-use PenFill ® cartridges for the 3 mL PenFill cartridge device ( 3 ) • 3 mL single-patient-use Insulin Aspart FlexPen ® ( 3 )

Insulin Aspart insulin aspart INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, DIHYDRATE GLYCERIN HYDROCHLORIC ACID METACRESOL PHENOL SODIUM CHLORIDE SODIUM HYDROXIDE ZINC

13.2 Animal Toxicology and/or Pharmacology In standard biological assays in mice and rabbits, one unit of insulin aspart has the same glucose-lowering effect as one unit of regular human insulin.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin aspart. 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 relevance of these findings to humans is unknown. 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 Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin aspart. 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 relevance of these findings to humans is unknown. 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. 13.2 Animal Toxicology and/or Pharmacology In standard biological assays in mice and rabbits, one unit of insulin aspart has the same glucose-lowering effect as one unit of regular human insulin.

BLA020986

Insulin Aspart

insulin aspart

50090-4956

HUMAN PRESCRIPTION DRUG

INTRAVENOUS,SUBCUTANEOUS

insulin aspart Label Image

Dosage and Administration ( 2.1 )…………….12/2018 Dosage and Administration ( 2.2 ) ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙11/2019 Warnings and Precautions ( 5.2 ) ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙11/2019

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Never Share an Insulin Aspart FlexPen, PenFill Cartridge or PenFill Cartridge Device Between Patients Advise patients that they must never share Insulin Aspart FlexPen, 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 insulin aspart 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 insulin aspart 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 )] . Hypoglycemia with Medication Errors Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions ( 5.3 )] . Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with insulin aspart. Inform patients of the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] . Administration Insulin aspart must only be used if the solution is clear and colorless with no particles visible. Instruct patients that when injecting insulin aspart, they must press and hold down the dose button until the dose counter shows 0 and then keep the needle in the skin and count slowly to 6 as the prescribed dose is not completely delivered until 6 seconds later. If the needle is removed earlier, the full dose may not be delivered (a possible under-dose may occur by as much as 20%). Inform the patient to increase the frequency of checking their blood glucose and that possible additional insulin administration may be necessary. If 0 does not appear in the dose counter after continuously pressing the dose button, the patient may have used a blocked needle. In this case they would not have received any insulin – even though the dose counter has moved from the original dose that was set. Instruct the patient to change the needle as described in Section 5 of the Instructions for Use and repeat all steps in the IFU starting with Section 1: Prepare your pen with a new needle. Make sure the patient selects the full dose needed. Patients Using Continuous Subcutaneous Insulin Pumps • Train patients in both intensive insulin therapy with multiple injections and in the function of their pump and pump accessories. • Instruct patients to replace insulin in the reservoir at least every 6 days; infusion sets and infusion set insertion sites should be changed at least every 3 days. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative. Insulin aspart is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump. Please see recommended reservoir and infusion sets in the pump manual. • 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 of the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. 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 )] . • Instruct patients of 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 )] . Before using an insulin pump with insulin aspart, read the pump label to make sure the pump has been evaluated with insulin aspart. Rx only Date of Issue: 11/2019 Version: 2 Novo Nordisk ® , NovoLog ® , PenFill ® , Novolin ® , FlexPen ® , NovoFine ® , and NovoTwist ® are registered trademarks of Novo Nordisk A/S. Patent Information: http://novonordisk-us.com/patients/products/product-patents.html © 2002-2019 Novo Nordisk Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark Distributed by: Novo Nordisk Pharma, Inc. 1-800-727-6500

14 CLINICAL STUDIES 14.1 Overview of Clinical Studies The safety and effectiveness of subcutaneous insulin aspart was compared to regular human insulin in 596 type 1 diabetes adult, 187 pediatric type 1 diabetes, and 91 adult type 2 diabetes patients using NPH as basal insulin (see Tables 3, 4, 5). The reduction in glycated hemoglobin (HbA 1c ) was similar to regular human insulin. The safety and effectiveness of insulin aspart administered by continuous subcutaneous insulin infusion (CSII) by external pump was compared to buffered regular human insulin (administered by CSII), to lispro (administered by CSII) and compared to insulin aspart injections and NPH injection. Overall, the reduction in HbA 1c was similar to the comparator. 14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes and Subcutaneous Daily Injections Type 1 Diabetes – Adults (see Table 3) Two 24 week, open‑label, active-controlled studies were conducted to compare the safety and efficacy of insulin aspart to regular human insulin injection in adult patients with type 1 diabetes. Because the two study designs and results were similar, data are shown for only one study (see Table 3). The mean age of the trial population was 38.9 years and mean duration of diabetes was 15.7 years. Fifty-one percent were male. Ninety-four percent were Caucasian, 2% were Black and 4% were Other. The mean BMI was approximately 25.6 kg/m 2 . Insulin aspart was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA 1c were comparable for the two treatment regimens in this study (Table 3). Table 3. Type 1 Diabetes Mellitus – Adult (insulin aspart plus NPH insulin vs. regular human insulin plus NPH insulin) insulin aspart + NPH (N=596) Regular Human Insulin+ NPH (N=286) Baseline HbA 1c (%)* 7.9 ±1.1 8.0 ± 1.2 Change from Baseline HbA 1c (%) -0.1 ± 0.8 0.0 ± 0.8 Treatment Difference in HbA 1c , Mean (95% confidence interval) -0.2 (-0.3, -0.1) *Values are Mean ± SD Type 1 Diabetes – Pediatric ( see Table 4) The efficacy of insulin aspart to improve glycemic control in pediatric patients with type 1 diabetes mellitus is based on an adequate and well-controlled trial of regular human insulin in pediatric patients with type 1 diabetes mellitus (Table 4). This 24-week, parallel-group study of children and adolescents with type 1 diabetes (n = 283), aged 6 to 18 years, compared two subcutaneous multiple-dose treatment regimens: insulin aspart (n=187) or regular human insulin (n=96). NPH insulin was administered as the basal insulin. Similar effects on HbA 1c were observed in both treatment groups (Table 4). Subcutaneous administration of insulin aspart and regular human insulin have also been compared in children with type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA 1c . Table 4. Pediatric Subcutaneous Administration of insulin aspart in Type 1 Diabetes (24 weeks; n=283) insulin aspart + NPH (N=187) Regular Human Insulin+ NPH (N=96) Baseline HbA 1c (%)* 8.3 ± 1.2 8.3 ± 1.3 Change from Baseline HbA 1c (%) 0.1± 1.0 0.1± 1.1 Treatment Difference in HbA 1c, Mean (95% confidence interval) -0.2 (-0.5, 0.1) *Values are Mean ± SD 14.3 Clinical Studies in Adults with Type 2 Diabetes and Subcutaneous Daily Injections Type 2 Diabetes - Adults ( see Table 5) One six-month, open-label, active-controlled study was conducted to compare the safety and efficacy of insulin aspart to regular human insulin in patients with type 2 diabetes (Table 5). The mean age of the trial population was 56.6 years and mean duration of diabetes was 12.7 years. Sixty-three percent were male. Seventy-six percent were Caucasian, 9% were Black and 15% were Other. The mean BMI was approximately 29.7 kg/m 2 . Insulin aspart was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA 1c were comparable for the two treatment regimens. Table 5. Subcutaneous insulin aspart Administration in Type 2 Diabetes (6 months; n=176) insulin aspart + NPH (N=90) Regular Human Insulin + NPH (N=86) Baseline HbA 1c (%)* 8.1 ± 1.2 7.8 ± 1.1 Change from Baseline HbA 1c (%) -0.3 ± 1.0 -0.1 ± 0.8 Treatment Difference in HbA 1c, Mean (95% confidence interval) - 0.1 (-0.4, 0.1) *Values are Mean ± SD 14.4 Clinical Studies in Adults and Pediatrics with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion (CSII) by External Pump Type 1 Diabetes – Adult ( see Table 6) Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118]) compared insulin aspart to buffered regular human insulin (Velosulin) in adults with type 1 diabetes receiving a subcutaneous infusion with an external insulin pump. The mean age of the trial population was 42.3 years. Thirty-nine percent were male. Ninety-eight percent were Caucasian and 2% were Black. The two treatment regimens had comparable changes in HbA 1c . Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118) insulin aspart (N=59) Buffered human insulin (N=59) Baseline HbA 1c (%)* 7.3 ± 0.7 7.5 ± 0.8 Change from Baseline HbA 1c (%) 0.0 ± 0.5 0.2 ± 0.6 Treatment Difference in HbA 1c, Mean (95% confidence interval) 0.2 (-0.1, 0.4) *Values are Mean ± SD Type 1 Diabetes – Pediatric ( see Table 7) A randomized, 16-week, open-label, parallel design study of children and adolescents with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens administered via an external insulin pump: insulin aspart (n=198) or insulin lispro (n=100). These two treatments resulted in comparable changes from baseline in HbA 1c (see Table 7). Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298) insulin aspart (N=198) Lispro (N=100) Baseline HbA 1c (%)* 8.0 ± 0.9 8.2 ± 0.8 Change from Baseline HbA 1c (%) -0.1 ± 0.8 -0.1 ± 0.7 Treatment Difference in HbA 1c, Mean (95% confidence interval) -0.1 (-0.3, 0.1) *Values are Mean ± SD 14.5 Clinical Studies in Adults with Type 2 Diabetes Using Continuous Subcutaneous Insulin Infusion (CSII) by External Pump Type 2 Diabetes – Adults ( see Table 8) An open-label, 16-week parallel design trial compared pre-prandial insulin aspart injection in conjunction with NPH injections to insulin aspart administered by continuous subcutaneous infusion in 127 adults with type 2 diabetes. The mean age of the trial population was 55.1 years. Sixty-four percent were male. Eighty percent were Caucasian, 12% were Black and 8% were Other. The mean BMI was approximately 32.2 kg/m 2 . The two treatment groups had similar reductions in HbA 1c (Table 8). Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127) insulin aspart pump (N=66) insulin aspart + NPH (N=61) Baseline HbA 1c (%)* 8.2 ± 1.4 8.0 ± 1.1 Change from Baseline HbA 1c (%) -0.6 ± 1.1 -0.5 ± 0.9 Treatment Difference in HbA 1c, Mean (95% confidence interval) 0.1 (-0.3, 0.4) *Values are Mean ± SD

8.5 Geriatric Use Of the total number of patients (n=1,375) treated with insulin aspart in 3 controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes (18/1285) and the other half had type 2 diabetes (18/90). The HbA 1c response to insulin aspart, as compared to regular human insulin, did not differ by age.

8.4 Pediatric Use Insulin aspart is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump [see Clinical Studies ( 14.1 , 14.2 )] . Insulin aspart has not been studied in pediatric patients younger than 2 years of age. Insulin aspart has not been studied in pediatric patients with type 2 diabetes.

8.1 Pregnancy Risk Summary 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 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 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 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 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 unit/kg/day for rats and equal to the human subcutaneous dose of 1 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

8 USE IN SPECIFIC POPULATIONS • Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <2 years of age (8.4). 8.1 Pregnancy Risk Summary 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 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 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 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 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 unit/kg/day for rats and equal to the human subcutaneous dose of 1 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 insulin aspart 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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for insulin aspart, and any potential adverse effects on the breastfed infant from insulin aspart, or from the underlying maternal condition. 8.4 Pediatric Use Insulin aspart is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump [see Clinical Studies ( 14.1 , 14.2 )] . Insulin aspart has not been studied in pediatric patients younger than 2 years of age. Insulin aspart has not been studied in pediatric patients with type 2 diabetes. 8.5 Geriatric Use Of the total number of patients (n=1,375) treated with insulin aspart in 3 controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes (18/1285) and the other half had type 2 diabetes (18/90). The HbA 1c response to insulin aspart, as compared to regular human insulin, did not differ by age. 8.6 Renal Impairment Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent insulin aspart 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 insulin aspart 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 Product: 50090-4956 NDC: 50090-4956-0 3 mL in a SYRINGE, PLASTIC / 5 in a CARTON