Insulin Aspart Protamine and Insulin Aspart

1 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) .

2 DOSAGE AND ADMINISTRATION • Inspect visually before use. Appearance should be uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles ( 2.1 ). • Insulin Aspart Protamine and Insulin Aspart Mix 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature ( 2.1 ). • Inject Insulin Aspart Protamine and Insulin Aspart Mix 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm (2.1). • Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation ( 2.1 ). • Rotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis (2.1) . • Do not administer intravenously or use in insulin infusion pumps ( 2.1 ). • Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack) (2.2) . • Individualize dosage based on metabolic needs, blood glucose monitoring results, glycemic control goal ( 2.2 ). • 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 ( 2.2 ). • When switching from another insulin to Insulin Aspart Protamine and Insulin Aspart Mix 70/30, a different dosage of Insulin Aspart Protamine and Insulin Aspart Mix 70/30 may be needed ( 2.2 ). 2.1 Important Preparation and Administration Instructions • Always check insulin labels before administration. This product is NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart) [see Warnings and Precautions ( 5.4 )] . • Inspect Insulin Aspart Protamine and Insulin Aspart Mix 70/30 (referred to as Insulin Aspart Protamine and Insulin Aspart ) visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles. • Insulin Aspart Protamine and Insulin Aspart must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature. • When using the: o Vial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately. o Insulin Aspart Protamine and Insulin Aspart FlexPen, roll Insulin Aspart Protamine and Insulin Aspart FlexPen gently between hands in a horizontal position 10 times. Then, turn Insulin Aspart Protamine and Insulin Aspart FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately. • The Insulin Aspart Protamine and Insulin Aspart FlexPen dials in 1-unit increments. • Use Insulin Aspart Protamine and Insulin Aspart FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. • Inject Insulin Aspart Protamine and Insulin Aspart subcutaneously in the abdominal region, buttocks, thigh, or upper arm. • Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation. • 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 )] . • Do not administer Insulin Aspart Protamine and Insulin Aspart intravenously or use in insulin infusion pumps. • Do not mix Insulin Aspart Protamine and Insulin Aspart with any other insulins. 2.2 Dosage Recommendations • Insulin Aspart Protamine and Insulin Aspart is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack). • Individualize …

3 DOSAGE FORMS AND STRENGTHS Injectable suspension: 100 units/mL (U-100) of Insulin Aspart Protamine and Insulin Aspart Mix 70/30, 70% insulin aspart protamine and 30% insulin aspart, is a white and cloudy suspension available as: • 10 mL multiple-dose vial • 3 mL single-patient-use FlexPen prefilled pen Injectable suspension: 100 units/mL (U-100) of Insulin Aspart Protamine and Insulin Aspart Mix 70/30, 70% insulin aspart protamine and 30% insulin aspart available as: • 10 mL multiple-dose vial ( 3 ) • 3 mL single-patient-use FlexPen prefilled pen ( 3 )

4 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) .

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 insulin therapy 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 Clinical trials are conducted under widely varying designs, therefore, 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 data in: • Table 1 reflects the exposure of 55 patients with type 1 diabetes to Insulin Aspart Protamine and Insulin Aspart Mix 70/30 (referred to as Insulin Aspart Protamine and Insulin Aspart ) with a mean exposure duration of three months. The mean age was 43 years old. Sixty-four percent were male and 100% were White. The mean body mass index (BMI) was 26.1 kg/m 2 . The mean duration of diabetes was 15 years. • Table 2 reflects the exposure of 85 patients with type 2 diabetes to Insulin Aspart Protamine and Insulin Aspart with a mean exposure duration of three months. The mean age was 63 years old. Fifty-four percent were male and 100% were White. The mean body mass index (BMI) was 28.1 kg/m 2 . The mean duration of diabetes was 15 years. Common adverse reactions were defined as events that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse reactions that occurred for Insulin Aspart Protamine and Insulin Aspart-treated patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. The trial was a three-month, open-label trial in patients with type 1 or type 2 diabetes who were treated twice daily (before breakfast and before supper) with Insulin Aspart Protamine and Insulin Aspart. Table 1: Adverse Reactions that Occurred in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients Treated with Insulin Aspart Protamine and Insulin Aspart Insulin Aspart Protamine and Insulin Aspart (n=55) Preferred Term N % Hypoglycemia 38 69 Headache 19 35 Influenza-like symptoms 7 13 Dyspepsia 5 9 Back pain 4 7 Diarrhea 4 7 Pharyngitis 4 7 Rhinitis 3 5 Skeletal pain 3 5 Upper respiratory tract infection 3 5 Table 2: Adverse Reactions that Occurred in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients Treated with Insulin Aspart Protamine and Insulin Aspart Insulin Aspart Protamine and Insulin Aspart (n=85) Preferred Term N % Hypoglycemia 40 47 Upper respiratory tract infection 10 12 Headache 8 9 Diarrhea 7 8 Neuropathy 7 8 Pharyngitis 5 6 Abdominal pain 4 5 Rhinitis 4 5 Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin Aspart Protamine and 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 Protamine and 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 requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with Insulin Aspart Protamine and Insulin Aspart. The incidence of severe hypoglycemia in adult patients receiving subcutaneous I …

7 DRUG INTERACTIONS The table below presents clinically significant drug interactions with Insulin Aspart Protamine and Insulin Aspart Mix 70/30 Table 3: Clinically Significant Drug Interactions with Insulin Aspart Protamine and Insulin Aspart Mix 70/30 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 Protamine and Insulin Aspart is concomitantly administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Aspart Protamine and 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 Protamine and Insulin Aspart is concomitantly administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Aspart Protamine and Insulin Aspart Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. 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 Protamine and 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 Protamine and 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) .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data with Insulin Aspart Protamine and Insulin Aspart Mix 70/30 (referred to as Insulin Aspart Protamine and Insulin Aspart ) in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. 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] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA 1c >7% and has been reported to be as high as 20-25% in women with a HbA 1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 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, still birth, 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 hypogly …

12.1 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.

11 DESCRIPTION Insulin aspart protamine and insulin aspart is a human insulin analog containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. Insulin aspart is 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 O 79 S 6 and a molecular weight of 5825.8 Da. Figure 1. Structural formula of insulin aspart Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is a uniform, white and cloudy, sterile injectable suspension for subcutaneous use. Each mL contains 100 units of insulin aspart and the inactive ingredients: disodium hydrogen phosphate dihydrate (1.25 mg), glycerol (16.0 mg), metacresol (1.72 mg), phenol (1.50 mg), protamine sulfate (0.32 mg), sodium chloride (0.877 mg), zinc (19.6 mcg), and Water for Injection, USP. Insulin Aspart Protamine and Insulin Aspart Mix 70/30 has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH. Molecular chain of insulin aspart.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Insulin Aspart Protamine and Insulin Aspart Mix 70/30 (referred to as Insulin Aspart Protamine and Insulin Aspart ) is a white and cloudy injectable suspension containing 100 units/mL (U-100) of 70% insulin aspart protamine and 30% insulin aspart available as: One 10 mL multiple-dose vial per carton NDC 73070-200-11 Five 3 mL single-patient-use FlexPen prefilled pens per carton NDC 73070-203-15 The Insulin Aspart Protamine and Insulin Aspart FlexPen dials in 1-unit increments. 16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused Insulin Aspart Protamine and Insulin Aspart in a refrigerator between 2°C to 8°C (36°F to 46°F). Do not freeze Insulin Aspart Protamine and Insulin Aspart or use Insulin Aspart Protamine and Insulin Aspart if it has been frozen. Do not expose Insulin Aspart Protamine and Insulin Aspart to excessive heat or light. Always remove the needle after each injection and store Insulin Aspart Protamine and Insulin Aspart FlexPen without a needle attached. The storage conditions are summarized in the following table: Table 7: Storage conditions for Insulin Aspart Protamine and Insulin Aspart Mix 70/30 vial and FlexPen 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 FlexPen 14 days Until expiration date 14 days (Do not refrigerate)