3 ML insulin aspart, human 100 UNT/ML Cartridge [NovoLog]

INDICATIONS AND USAGE Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is a mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in adult patients with diabetes mellitus. Limitations of Use: • Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is not recommended for the treatment of diabetic ketoacidosis. • The proportions of rapid-acting and long-acting insulins in Insulin Aspart Protamine and Insulin Aspart Mix 70/30 are fixed and do not allow for basal versus prandial dose adjustments. Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is a mixture of insulin aspart protamine, an intermediate-acting human insulin analog, and insulin aspart, a rapid-acting human insulin analog, indicated to improve glycemic control in adult patients with diabetes mellitus. Limitations of Use: • Not recommended for the treatment of diabetic ketoacidosis. • The proportions of rapid-acting and long-acting insulins are fixed and do not allow for basal versus prandial dose adjustments (1) .

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 ): Inject 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 risk of lipodystrophy and localized cutaneous amyloidosis. Should generally be used in regimens with an intermediate- or long-acting insulin. Continuous Subcutaneous Infusion (Insulin Pump) ( 2.2 ): 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. Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate the injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not mix with other insulins or diluents in the pump. Intravenous Administration ( 2.2 ) : 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. 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: Insulin Aspart FlexPen with caution in those who may rely on audible clicks to dial their dose. 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: Nine parts diluent will yield a concentration one-tenth that of Insulin Aspart (equivalent to U-10). 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.

WARNINGS AND PRECAUTIONS Never share a Insulin Aspart FlexPen, PenFill cartridge or PenFill cartridge device between patients, even if the needle is changed ( 5.1 ). 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 ( 5.2 ). 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 Insulin Aspart, treat, and monitor, if indicated ( 5.5 ). 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 ( 5.7 ). Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction: Monitor glucose and administer Insulin Aspart by subcutaneous injection if pump malfunction occurs ( 5.8 ). 5.1 Never Share a Insulin Aspart FlexPen, PenFill Cartridge, or PenFill Cartridge Device between Patients Insulin Aspart FlexPen, PenFill cartridge, and PenFill cartridge devices should never be shared between patients, even if the needle is changed. Patients using Insulin Aspart vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 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 [see Warnings and Precautions ( 5.3 )] 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 [see Adverse Reactions ( 6.1 , 6.3 )]. 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. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of all insulins, including Insulin Aspart. 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) [see Drug Interactions ( 7 )] , 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 Insulin Aspart 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 [see Clinical Pharmacology ( 12.2 )] . 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 ( 7 )] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )]. 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. 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products have been reported. To avoid medication errors between this Insulin Aspart product and other insulins, instruct patients to always check the insulin label before each injection. 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including Insulin Aspart. If hypersensitivity reactions occur, discontinue Insulin Aspart; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions ( 6 )]. Insulin Aspart is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients [see Contraindications ( 4 )]. 5.6 Hypokalemia All insulins, including Insulin Aspart, 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). 5.7 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 Insulin Aspart, 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. 5.8 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 Insulin Aspart 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 [see How Supplied/Storage and Handling ( 16.2 ) and Patient Counseling Information ( 17 )] .

CONTRAINDICATIONS Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] • In patients with hypersensitivity to Insulin Aspart Protamine and Insulin Aspart Mix 70/30 or one of its excipients [see Warnings and Precautions ( 5.5 )] • Do not use during episodes of hypoglycemia (4) . • Do not use in patients with hypersensitivity to Insulin Aspart Protamine and Insulin Aspart Mix 70/30 or one of its excipients (4) .

Mechanism of Action The primary activity of insulin, including Insulin Aspart Protamine and Insulin Aspart Mix 70/30 (referred to as Insulin Aspart Protamine and Insulin Aspart ) is the regulation of glucose metabolism. Insulin and its analog 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.