INSULIN ASPART

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. 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. 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

Insulin Aspart is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. Insulin Aspart is rapid acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus ( 1 ).

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 (insulin aspart) 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 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 Injection, USP. • 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 Preparation and Administration Instructions • Always check insulin labels before administration. This product is NovoLog (insulin aspart) [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. • In patients with visual impairment, use: o Insulin Aspart FlexPen with caution in those who may rely on audible clicks to dial their dose. o PenFill cartridges with caution. • Do not mix Insulin Aspart 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 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 )]. • Dial the Insulin Aspart FlexPen dials in 1-unit increments. • Generally use Insulin Aspart (administered by subcutaneous injection) in regimens with an intermediate- or long-acting insulin. • May dilute this Insulin Aspart product with Insulin Diluting Medium for NovoLog for subcutaneous injection. Diluting one part Insulin Aspart to: o Nine parts diluent will yield a concentration one-tenth that of Insulin Aspart (equivalent to U-10). o One part diluent will yield a concentration one-half that of Insulin Aspart (equivalent to U-50). Continuous Subcutaneous Infusion (Insulin Pump) • Can use this Insulin Aspart 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 Insulin Aspart 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 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)]. • Instruct patients to follow healthcare provider recommendations when setting basal and meal time infusion rate. • Change the Insulin Aspart 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 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 • 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)]. • 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 Injection, USP. 2.3 Dosage Recommendations • Individualize the dosage of Insulin Aspart 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 Insulin Aspart, a different dosage of Insulin Aspart 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 Insulin Aspart is used concomitantly with certain drugs [see Drug Interactions (7)] . 2.5 Instructions for Mixing Insulin Aspart with Other Insulins The table below includes instructions regarding mixing Insulin Aspart with other insulins. Subcutaneous injection route • Insulin Aspart may only be mixed with NPH insulin preparations. • If Insulin Aspart is mixed with NPH insulin, withdraw Insulin Aspart into the syringe first and inject immediately after mixing. Continuous subcutaneous infusion route (Insulin Pump) Do not mix Insulin Aspart with any other insulin.

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.

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 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 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 Insulin Aspart in one clinical trial with a mean exposure duration to Insulin Aspart 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 Insulin Aspart in one clinical trial with a mean exposure duration to Insulin Aspart 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 Insulin Aspart-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 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 that occurred 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 . 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 with type 1 diabetes mellitus who received subcutaneous Insulin Aspart 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 Insulin Aspart was 10% at 24 weeks. • Adult and pediatric patients with type 1 diabetes mellitus, who received 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, 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. 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 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 Insulins, 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 insulins 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. 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.

The table below presents clinically significant drug interactions with Insulin Aspart. 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 Insulin Aspart is concomitantly 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 concomitantly 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 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 Insulin Aspart 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 ).