INSULIN ASPART PROTAMINE AND INSULIN ASPART MIX 70/30

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.

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) .

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: Vial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately. 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 the dosage of Insulin Aspart Protamine and Insulin Aspart based on 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 ( 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )]. When switching from another insulin to Insulin Aspart Protamine and Insulin Aspart, a different dosage of Insulin Aspart Protamine and 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 )] . 2.3 Dosage Modifications for Drug Interactions Dosage modification may be needed when Insulin Aspart Protamine and Insulin Aspart is used concomitantly with certain drugs [see Drug Interactions ( 7 )] .

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) .

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 Insulin Aspart Protamine and Insulin Aspart was 16% and 4% for type 1 and type 2 diabetes patients respectively at 12 weeks [see Clinical Studies ( 14 )] . Allergic Reactions Patients have experienced reactions such as erythema, edema or pruritus at the site of Insulin Aspart Protamine and Insulin Aspart injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, have required discontinuation of Insulin Aspart Protamine and Insulin Aspart. 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 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 Long-term use of insulin, including Insulin Aspart Protamine and Insulin Aspart, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.1)] . Weight Gain Weight gain can occur with insulins, including Insulin Aspart Protamine and Insulin Aspart, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. Peripheral Edema Insulins, including Insulin Aspart Protamine and Insulin Aspart, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. 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 Protamine and Insulin Aspart in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In a 3-month study with an extension in adult patients with type 2 diabetes, 100% of patients who received Insulin Aspart Protamine and Insulin Aspart were positive for anti-insulin antibodies (AIA) at least once during the first 12 months of the study including 91.4% that were positive at baseline. A total of 91.4% of patients who received Insulin Aspart Protamine and Insulin Aspart were positive for anti-drug antibodies (ADA) at least once during the first 12 months of the study, including 62.1% that were positive at baseline. In a type 2 diabetes clinical trial of Insulin Aspart Protamine and Insulin Aspart, initial increase in titers of antibodies to insulin followed by a decrease approaching to baseline values was observed in Insulin Aspart Protamine and Insulin Aspart and Novolin 70/30 treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Insulin Aspart Protamine and 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 in which other insulins have been accidentally substituted for Insulin Aspart Protamine and Insulin Aspart have been reported. 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 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) .