NOVOLOG

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere: • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] • Hypokalemia [see Warnings and Precautions ( 5.6 )] Adverse reactions observed with NOVOLOG include: hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus ( 6 ). 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 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 NOVOLOG was evaluated in two treat-to-target trials of 6 months duration, conducted in patients 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 NOVOLOG in one clinical trial with a mean exposure duration to NOVOLOG of 24 weeks. The mean age was 39 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 NOVOLOG in one clinical trial with a mean exposure duration to NOVOLOG of 24 weeks. The mean age was 57 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 that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse events that occurred at the same rate or greater for NOVOLOG-treated patients than in comparator-treated patients 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 that occurred in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients treated with NOVOLOG and at the same rate or greater on NOVOLOG than on comparator NOVOLOG + 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 that occurred in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients treated with NOVOLOG and at the same rate or greater on NOVOLOG than on comparator NOVOLOG + 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 NOVOLOG . 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 NOVOLOG 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 with type 1 diabetes mellitus who received subcutaneous NOVOLOG was 17% at 24 weeks and 6% at 24 weeks, respectively [see Clinical Studies (14) ] . • Adult patients with type 2 diabetes mellitus who received subcutaneous NOVOLOG was 10% at 24 weeks. • Adult and pediatric patients with type 1 diabetes mellitus, who received NOVOLOG 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 NOVOLOG via continuous subcutaneous insulin infusion by external pump at 16 weeks. Allergic Reactions Some patients taking insulin, including NOVOLOG 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 . Adverse Reactions Associated with 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 NOVOLOG, 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 Insulins, including NOVOLOG, 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 insulins, including NOVOLOG, 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 NOVOLOG 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 NOVOLOG 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 NOVOLOG 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 NOVOLOG, 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 NOVOLOG. 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 NOVOLOG. 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 NOVOLOG is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] • In patients with hypersensitivity to NOVOLOG or one of its excipients, [see Warnings and Precautions ( 5.5 )] • During episodes of hypoglycemia ( 4 ). • Hypersensitivity to NOVOLOG or one of its excipients.

11 DESCRIPTION Insulin aspart is a rapid-acting human insulin analog 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 Da. Figure 1. Structural formula of insulin aspart. NOVOLOG (insulin aspart) injection is a sterile, clear, and colorless solution for subcutaneous or intravenous use. Each mL contains 100 units of insulin aspart and the inactive ingredients: disodium hydrogen phosphate dihydrate (1.25 mg), glycerin (16.0 mg), metacresol (1.72 mg), phenol (1.50 mg), sodium chloride (0.58 mg), zinc (19.6 mcg), and Water for Injection, USP. NOVOLOG has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH. Fig. 1 - Structural Formula of Insulin Aspart

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important preparation, 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 Refer to the insulin infusion pump user manual to see if NOVOLOG can be used. Use in accordance with the insulin pump instructions for use. 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 Do not mix with other insulins or diluents in the pump. • Intravenous Administration ( 2.2 ) : o Dilute NOVOLOG to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags. o NOVOLOG is stable in infusion fluids such as 0.9% Sodium Chloride Injection, USP. • Individualize and adjust the dosage of NOVOLOG 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 Preparation and Administration Instructions • Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . • Inspect NOVOLOG visually before use. It should appear clear and colorless. Do not use NOVOLOG if particulate matter or coloration is seen. • In patients with visual impairment, use: o NOVOLOG FlexPen and NOVOLOG FlexTouch with caution in those who may rely on audible clicks to dial their dose. o PenFill cartridges with caution. • Do not mix NOVOLOG with other insulins when administering using a continuous subcutaneous infusion pump. 2.2 Preparation and Administration Instructions for the Approved Routes of Administration Subcutaneous Injection • Inject NOVOLOG 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 )]. • Dial the NOVOLOG FlexPen and FlexTouch in 1-unit increments. • Generally use NOVOLOG (administered by subcutaneous injection) in regimens with an intermediate- or long-acting insulin. • May dilute NOVOLOG with Insulin Diluting Medium for NOVOLOG for subcutaneous injection. Diluting one part NOVOLOG to: o Nine parts diluent will yield a concentration one-tenth that of NOVOLOG (equivalent to U-10). o One part diluent will yield a concentration one-half that of NOVOLOG (equivalent to U-50). Continuous Subcutaneous Infusion (Insulin Pump) • Can use this NOVOLOG product with the continuous subcutaneous insulin infusion pumps labeled for use with NOVOLOG (insulin aspart). Refer to the insulin pump user manual to see if NOVOLOG can be used. Use NOVOLOG in accordance with the insulin pump system’s instructions for use. • Train patients using continuous subcutaneous insulin infusion pump therapy to administer insulin by injection and have alternate insulin therapy available in case of pump failure. • Administer NOVOLOG 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 )]. • Instruct patients to follow healthcare provider recommendations when setting basal and meal time infusion rate. • Change the NOVOLOG in the reservoir at least every 7 days or according to the pump user manual, whichever is shorter. Follow the NOVOLOG-specific information for in-use time because NOVOLOG-specific information may differ from general pump manual instructions. • Change the infusion set and the infusion set insertion site according to the manufacturer’s user manual. • Do not dilute or mix NOVOLOG when administering by continuous subcutaneous infusion. • Do not expose NOVOLOG in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration • Dilute NOVOLOG to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags. NOVOLOG is stable in infusion fluids such as 0.9% Sodium Chloride Injection, USP. • Administer NOVOLOG 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 Recommendations • Individualize the dosage of NOVOLOG based on the route of administration, the patient’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 )] . • When switching from another insulin to NOVOLOG, a different dosage of NOVOLOG may be needed [see Warnings and Precautions ( 5.2 )] . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. 2.4 Dosage Modifications for Drug Interactions Dosage modification may be needed when NOVOLOG is used concomitantly with certain drugs [see Drug Interactions ( 7 )] . 2.5 Instructions for Mixing NOVOLOG with Other Insulins The table below includes instructions regarding mixing NOVOLOG with other insulins. Subcutaneous injection route • NOVOLOG may only be mixed with NPH insulin preparations. • If NOVOLOG is mixed with NPH insulin, withdraw NOVOLOG into the syringe first and inject immediately after mixing. Continuous subcutaneous infusion route (Insulin Pump) Do not mix NOVOLOG with any other insulin.

1 INDICATIONS AND USAGE NOVOLOG is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. NOVOLOG is rapid acting human insulin analog indicated to improve glycemic control in adults and pediatric patients 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 The table below presents clinically significant drug interactions with NOVOLOG. 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 analog (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG is concomitantly administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of NOVOLOG 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 NOVOLOG is concomitantly administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG 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 NOVOLOG is concomitantly 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 NOVOLOG is concomitantly 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, 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 NOVOLOG 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 Pharmacodynamics of NOVOLOG After Subcutaneous Administration The pharmacodynamic profile of NOVOLOG given subcutaneously in 22 patients with type 1 diabetes is shown in Figure 2. The maximum glucose-lowering effect of NOVOLOG occurred between 1 and 3 hours after subcutaneous injection (0.15 units/kg). The duration of action for NOVOLOG is 3 to 5 hours. The time course of action of insulin and insulin analogs such as NOVOLOG may vary considerably in different individuals or within the same individual. The parameters of NOVOLOG 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 NOVOLOG (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes. Pharmacodynamics of NOVOLOG After Intravenous Administration A double-blind, randomized, two-way crossover study in 16 patients with type 1 diabetes demonstrated that intravenous infusion of NOVOLOG resulted in a blood glucose profile that was similar to that after intravenous infusion with regular human insulin. NOVOLOG 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 NOVOLOG (hatched curve) and regular human insulin (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction. Figure 2 Fig. 3 - Pharmacodynamics Graph - Time of Autonomic Reaction 12.3 Pharmacokinetics Pharmacokinetics of subcutaneous administration of NOVOLOG is presented below. 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 NOVOLOG in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively. The relative bioavailability of NOVOLOG (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, NOVOLOG 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 NOVOLOG (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 NOVOLOG 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 NOVOLOG group and 1.2 L/h/kg for the regular human insulin group. After subcutaneous administration in normal male volunteers (n=24), NOVOLOG was eliminated with an average apparent half-life of 81 minutes. Specific Populations Pediatric Patients - The pharmacokinetic and pharmacodynamic properties of NOVOLOG and regular human insulin were evaluated in a single dose study in 18 pediatric patients with type 1 diabetes in 2 age groups: 6-12 years, n=9 and 13-17 years (Tanner grade ≥ 2), n=9. The relative differences in pharmacokinetics and pharmacodynamics in the pediatric patients with type 1 diabetes in both age groups between NOVOLOG and regular human insulin were similar to those in healthy adult subjects and adults with type 1 diabetes. Geriatric Patients : The pharmacokinetic and pharmacodynamic properties of NOVOLOG 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 NOVOLOG and regular human insulin were similar to those in younger adults. Male and Female Patients : In healthy volunteers given a single subcutaneous dose of NOVOLOG 0.06 units/kg, no difference in insulin aspart levels was seen between males and females based on comparison of AUC (0-10h) or C max . Obese Patients : A single subcutaneous dose of 0.1 units/kg NOVOLOG 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 NOVOLOG 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 NOVOLOG was reduced by 28% in patients with BMI >32 kg/m 2 compared to patients with BMI <23 kg/m 2 . Patients with Renal Impairment : A single subcutaneous dose of 0.08 units/kg NOVOLOG 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 NOVOLOG. Patients with Hepatic Impairment : A single subcutaneous dose of 0.06 units/kg NOVOLOG 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 NOVOLOG pharmacokinetic parameter. Figure 4

12.1 Mechanism of Action The primary activity of insulin, including NOVOLOG 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 Pharmacodynamics of NOVOLOG After Subcutaneous Administration The pharmacodynamic profile of NOVOLOG given subcutaneously in 22 patients with type 1 diabetes is shown in Figure 2. The maximum glucose-lowering effect of NOVOLOG occurred between 1 and 3 hours after subcutaneous injection (0.15 units/kg). The duration of action for NOVOLOG is 3 to 5 hours. The time course of action of insulin and insulin analogs such as NOVOLOG may vary considerably in different individuals or within the same individual. The parameters of NOVOLOG 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 NOVOLOG (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes. Pharmacodynamics of NOVOLOG After Intravenous Administration A double-blind, randomized, two-way crossover study in 16 patients with type 1 diabetes demonstrated that intravenous infusion of NOVOLOG resulted in a blood glucose profile that was similar to that after intravenous infusion with regular human insulin. NOVOLOG 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 NOVOLOG (hatched curve) and regular human insulin (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction. Figure 2 Fig. 3 - Pharmacodynamics Graph - Time of Autonomic Reaction

12.3 Pharmacokinetics Pharmacokinetics of subcutaneous administration of NOVOLOG is presented below. 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 NOVOLOG in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively. The relative bioavailability of NOVOLOG (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, NOVOLOG 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 NOVOLOG (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 NOVOLOG 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 NOVOLOG group and 1.2 L/h/kg for the regular human insulin group. After subcutaneous administration in normal male volunteers (n=24), NOVOLOG was eliminated with an average apparent half-life of 81 minutes. Specific Populations Pediatric Patients - The pharmacokinetic and pharmacodynamic properties of NOVOLOG and regular human insulin were evaluated in a single dose study in 18 pediatric patients with type 1 diabetes in 2 age groups: 6-12 years, n=9 and 13-17 years (Tanner grade ≥ 2), n=9. The relative differences in pharmacokinetics and pharmacodynamics in the pediatric patients with type 1 diabetes in both age groups between NOVOLOG and regular human insulin were similar to those in healthy adult subjects and adults with type 1 diabetes. Geriatric Patients : The pharmacokinetic and pharmacodynamic properties of NOVOLOG 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 NOVOLOG and regular human insulin were similar to those in younger adults. Male and Female Patients : In healthy volunteers given a single subcutaneous dose of NOVOLOG 0.06 units/kg, no difference in insulin aspart levels was seen between males and females based on comparison of AUC (0-10h) or C max . Obese Patients : A single subcutaneous dose of 0.1 units/kg NOVOLOG 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 NOVOLOG 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 NOVOLOG was reduced by 28% in patients with BMI >32 kg/m 2 compared to patients with BMI <23 kg/m 2 . Patients with Renal Impairment : A single subcutaneous dose of 0.08 units/kg NOVOLOG 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 NOVOLOG. Patients with Hepatic Impairment : A single subcutaneous dose of 0.06 units/kg NOVOLOG 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 NOVOLOG pharmacokinetic parameter. Figure 4

20230228

32

3 DOSAGE FORMS AND STRENGTHS Injection: 100 units/mL (U-100) is a clear and colorless solution available as: • 10 mL multiple-dose vial • 3 mL single-patient-use PenFill prefilled cartridge for the 3 mL PenFill cartridge delivery device with NovoFine ® disposable needles • 3 mL single-patient-use FlexPen prefilled pen • 3 mL single-patient-use FlexTouch prefilled pen Injection: 100 units/mL (U-100) of insulin aspart available as: • 10 mL multiple-dose vial ( 3 ) • 3 mL single-patient-use PenFill prefilled cartridge for the 3 mL PenFill cartridge delivery device with NovoFine ® disposable needles ( 3 ) • 3 mL single-patient-use FlexPen ® prefilled pen ( 3 ) • 3 mL single-patient-use FlexTouch ® prefilled pen ( 3 )

NOVOLOG insulin aspart INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, DIHYDRATE GLYCERIN HYDROCHLORIC ACID METACRESOL PHENOL SODIUM CHLORIDE SODIUM HYDROXIDE ZINC NOVOLOG insulin aspart INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, DIHYDRATE GLYCERIN HYDROCHLORIC ACID METACRESOL PHENOL SODIUM CHLORIDE SODIUM HYDROXIDE ZINC NOVOLOG insulin aspart INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, DIHYDRATE GLYCERIN HYDROCHLORIC ACID METACRESOL PHENOL SODIUM CHLORIDE SODIUM HYDROXIDE ZINC NOVOLOG insulin aspart INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, DIHYDRATE GLYCERIN HYDROCHLORIC ACID METACRESOL PHENOL SODIUM CHLORIDE SODIUM HYDROXIDE ZINC Insulin Diluting Medium for NovoLog water injection WATER WATER GLYCERIN SODIUM PHOSPHATE, DIBASIC, DIHYDRATE METACRESOL PHENOL SODIUM HYDROXIDE HYDROCHLORIC ACID NOVOLOG insulin aspart INSULIN ASPART INSULIN ASPART SODIUM PHOSPHATE, DIBASIC, DIHYDRATE GLYCERIN HYDROCHLORIC ACID METACRESOL PHENOL SODIUM CHLORIDE SODIUM HYDROXIDE ZINC NOVOLOG 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 NOVOLOG 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 NOVOLOG. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG 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, NOVOLOG increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is unknown. NOVOLOG 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 NOVOLOG. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG 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, NOVOLOG increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is unknown. NOVOLOG 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 NOVOLOG has the same glucose-lowering effect as one unit of regular human insulin.

BLA020986

NOVOLOG

insulin aspart

0169-2101

HUMAN PRESCRIPTION DRUG

INTRAVENOUS,SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL - 10 mL NovoLog Vial NovoLog ® NDC 0169-7501-11 (insulin aspart) injection List 750111 100 units/mL (U-100) For intravenous or subcutaneous use. Rx only Use only with a U-100 syringe. 10 mL multiple-dose vial NovoLog Vial (NN) Carton - 8-0902-31-305-9

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Never Share a NOVOLOG FlexPen or a NOVOLOG FlexTouch, PenFill Cartridge or PenFill Cartridge Device between Patients Advise patients that they must never share NOVOLOG FlexPen, NOVOLOG FlexTouch, 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 NOVOLOG 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 NOVOLOG 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 NOVOLOG. Inform patients of the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] . 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. • This NOVOLOG product can be used with continuous subcutaneous insulin infusion pumps labeled for use with NOVOLOG (insulin aspart) - refer to the insulin pump user manual to see if NOVOLOG can be used. See recommended infusion sets in the insulin pump user manual. • Instruct patients to replace insulin in the reservoir at least every 7 days or according to the user manual, whichever is shorter; infusion sets and infusion set insertion sites should be changed according to the manufacturer’s 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 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 )] . Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License Number 1261 Version: 30 Novo Nordisk ® , NOVOLOG ® , PenFill ® , Novolin ® , FlexPen ® , FlexTouch ® , NovoFine ® , and NovoTwist ® are registered trademarks of Novo Nordisk A/S. ReliOn ® is a registered trademark of Walmart Inc. and is used under license by Novo Nordisk Inc. Patent Information: http://novonordisk-us.com/products/product-patents.html © 2023 Novo Nordisk For additional information about NOVOLOG contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-800-727-6500 (Se Habla español) www.novonordisk-us.com

14 CLINICAL STUDIES 14.1 Overview of Clinical Studies The safety and effectiveness of subcutaneous NOVOLOG were 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 NOVOLOG administered by continuous subcutaneous insulin infusion (CSII) by external pump were compared to buffered regular human insulin (administered by CSII), to lispro (administered by CSII) and compared to NOVOLOG 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 with Subcutaneous 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 NOVOLOG 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 39 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 . NOVOLOG 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 (NOVOLOG plus NPH insulin vs. regular human insulin plus NPH insulin) NOVOLOG + 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 NOVOLOG 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 pediatric patients with type 1 diabetes (n = 283), aged 6 to 18 years, compared two subcutaneous multiple-dose treatment regimens: NOVOLOG (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 NOVOLOG and regular human insulin have also been compared in pediatric patients with type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA 1c . Table 4. Pediatric Subcutaneous Administration of NOVOLOG in Type 1 Diabetes (24 weeks; n=283) NOVOLOG + 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 with Subcutaneous 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 NOVOLOG 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 . NOVOLOG 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 NOVOLOG Administration in Type 2 Diabetes (6 months; n=176) NOVOLOG + 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 NOVOLOG 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) NOVOLOG (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 pediatric patients with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens administered via an external insulin pump: NOVOLOG (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) NOVOLOG (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 NOVOLOG injection in conjunction with NPH injections to NOVOLOG 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) NOVOLOG pump (n=66) NOVOLOG + 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 NOVOLOG 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 NOVOLOG, as compared to regular human insulin, did not differ by age.

8.4 Pediatric Use The safety and effectiveness of NOVOLOG to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of NOVOLOG for this indication is supported by evidence from an adequate and well-controlled study in 283 pediatric patients with type 1 diabetes mellitus aged 6 to 18 years and from studies in adults with diabetes mellitus [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )] .

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] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a periconceptional HbA 1c >7% and has been reported to be as high as 20 to 25% in women with a periconceptional HbA 1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. 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 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] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a periconceptional HbA 1c >7% and has been reported to be as high as 20 to 25% in women with a periconceptional HbA 1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. 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 NOVOLOG 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 NOVOLOG, and any potential adverse effects on the breastfed infant from NOVOLOG, or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of NOVOLOG to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of NOVOLOG for this indication is supported by evidence from an adequate and well-controlled study in 283 pediatric patients with type 1 diabetes mellitus aged 6 to 18 years and from studies in adults with diabetes mellitus [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )] . 8.5 Geriatric Use Of the total number of patients (n=1,375) treated with NOVOLOG 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 NOVOLOG, 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 NOVOLOG 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 NOVOLOG 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 NOVOLOG (insulin aspart) injection 100 units/mL (U-100) is available as a clear and colorless solution in: One 10 mL multiple-dose vial per carton NDC 0169-7501-11 ReliOn ® brand NDC 0169-2100-11 Five 3 mL single-patient-use FlexPen prefilled pens per carton NDC 0169-6339-10 ReliOn ® brand NDC 0169-2101-25 Five 3 mL single-patient-use PenFill prefilled cartridges* per carton NDC 0169-3303-12 Five 3 mL single-patient-use FlexTouch prefilled pens per carton NDC 0169-6338-10 *NOVOLOG PenFill cartridges are designed for use with compatible insulin delivery devices with NovoFine disposable needles. FlexPen and FlexTouch can be used with NovoFine or NovoTwist disposable needles. The NOVOLOG FlexPen and FlexTouch dial in 1-unit increments. 16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused NOVOLOG in a refrigerator between 2°C to 8°C (36°F to 46°F). Do not freeze NOVOLOG and do not use NOVOLOG if it has been frozen. Do not expose NOVOLOG to excessive heat or light. Do not withdraw NOVOLOG into a syringe and store for later use. Always remove and discard the needle after each injection from the NOVOLOG FlexPen or NOVOLOG FlexTouch and store without a needle attached. The storage conditions are summarized in the following table: Table 9. Storage Conditions for vial, PenFill cartridges, NOVOLOG FlexPen, and NOVOLOG FlexTouch NOVOLOG presentation Not in-use (unopened) Room Temperature (up to 30°C [86°F]) Not in-use (unopened) Refrigerated (2°C to 8°C [36°F to 46°F]) In-use (opened) Room Temperature (up to 30°C [86°F]) 10 mL multiple-dose vial 28 days Until expiration date 28 days* (refrigerated/room temperature) 3 mL single-patient-use PenFill cartridges 28 days Until expiration date 28 days (Do not refrigerate) 3 mL single-patient-use FlexPen 28 days Until expiration date 28 days (Do not refrigerate) 3 mL single-patient-use FlexTouch 28 days Until expiration date 28 days (Do not refrigerate) *For insulin pump use, the total in-use time is 19 days, including 7 days pump in-use time. Storage in External Insulin Pump: Change the NOVOLOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 37°C (98.6°F). Storage of Diluted NOVOLOG NOVOLOG diluted with Insulin Diluting Medium for NOVOLOG to a concentration equivalent to U-10 or equivalent to U-50 prepared as indicated under Dosage and Administration (2.2) may remain in patient use at temperatures up to 30°C (86°F) for 28 days. Storage of NOVOLOG in Intravenous Infusion Fluids Infusion bags prepared as indicated under Dosage and Administration (2.2) are stable at room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the infusion.

16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused NOVOLOG in a refrigerator between 2°C to 8°C (36°F to 46°F). Do not freeze NOVOLOG and do not use NOVOLOG if it has been frozen. Do not expose NOVOLOG to excessive heat or light. Do not withdraw NOVOLOG into a syringe and store for later use. Always remove and discard the needle after each injection from the NOVOLOG FlexPen or NOVOLOG FlexTouch and store without a needle attached. The storage conditions are summarized in the following table: Table 9. Storage Conditions for vial, PenFill cartridges, NOVOLOG FlexPen, and NOVOLOG FlexTouch NOVOLOG presentation Not in-use (unopened) Room Temperature (up to 30°C [86°F]) Not in-use (unopened) Refrigerated (2°C to 8°C [36°F to 46°F]) In-use (opened) Room Temperature (up to 30°C [86°F]) 10 mL multiple-dose vial 28 days Until expiration date 28 days* (refrigerated/room temperature) 3 mL single-patient-use PenFill cartridges 28 days Until expiration date 28 days (Do not refrigerate) 3 mL single-patient-use FlexPen 28 days Until expiration date 28 days (Do not refrigerate) 3 mL single-patient-use FlexTouch 28 days Until expiration date 28 days (Do not refrigerate) *For insulin pump use, the total in-use time is 19 days, including 7 days pump in-use time. Storage in External Insulin Pump: Change the NOVOLOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 37°C (98.6°F). Storage of Diluted NOVOLOG NOVOLOG diluted with Insulin Diluting Medium for NOVOLOG to a concentration equivalent to U-10 or equivalent to U-50 prepared as indicated under Dosage and Administration (2.2) may remain in patient use at temperatures up to 30°C (86°F) for 28 days. Storage of NOVOLOG in Intravenous Infusion Fluids Infusion bags prepared as indicated under Dosage and Administration (2.2) are stable at room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the infusion.