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

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.

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 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

See Full Prescribing Information for important preparation, administration, and dosage instructions ( 2.1, 2.2, 2.3, 2.4, 2.5 ). • Subcutaneous injection: 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): 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 : 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. • 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

Important Preparation and Administration Instructions • Always check insulin labels before administration . • 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

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 . • 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 . • 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

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 . • When switching from another insulin to NOVOLOG, a different dosage of NOVOLOG may be needed . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring

Dosage Modifications for Drug Interactions Dosage modification may be needed when NOVOLOG is used concomitantly with certain drugs

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.

• Never share a NOVOLOG FlexPen or a NOVOLOG FlexTouch, PenFill cartridge or PenFill cartridge device between patients, even if the needle is changed. • Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. • Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitantly administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairments and hypoglycemia unawareness ( 5. 3). • Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection ( 5. 4). • Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur. Discontinue NOVOLOG, treat, and monitor, if indicated. • Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated ( 5. 6). • Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. • Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction: Monitor glucose and administer NOVOLOG by subcutaneous injection if pump malfunction occurs

Never Share a NOVOLOG FlexPen, NOVOLOG FlexTouch, PenFill Cartridge, or PenFill Cartridge Device between Patients NOVOLOG FlexPen, NOVOLOG FlexTouch, PenFill cartridge, and PenFill cartridge devices should never be shared between patients, even if the needle is changed. Patients using NOVOLOG vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens

Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia . Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed

Hypoglycemia Hypoglycemia is the most common adverse reaction of all insulins, including NOVOLOG. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) , or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of NOVOLOG may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature . Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitantly administered medication [ see Drug Interactions ] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia; increased frequency of blood glucose monitoring is recommended. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia; increased frequency of blood glucose monitoring is recommended

Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products have been reported. To avoid medication errors between NOVOLOG and other insulins, instruct patients to always check the insulin label before each injection

Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including NOVOLOG. If hypersensitivity reactions occur, discontinue NOVOLOG; treat per standard of care and monitor until symptoms and signs resolve . NOVOLOG is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients

Hypokalemia All insulins, including NOVOLOG, can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentration)

Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including NOVOLOG, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered

Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with NOVOLOG may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure .

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. • 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. • Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine. • Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine.