Insulin Aspart

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 ).

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.

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.

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