Novolin

1 INDICATIONS AND USAGE NOVOLIN 70/30 is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. Limitations of Use: In NOVOLIN 70/30, the proportions of short-acting and intermediate-acting insulins are fixed and do not allow for basal versus prandial dose adjustments. NOVOLIN 70/30 is a mixture of human insulin isophane, an intermediate-acting human insulin, and human insulin, a short-acting human insulin, indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. ( 1 )

2 DOSAGE AND ADMINISTRATION • See Full Prescribing Information for important administration instructions. ( 2.1 ) • Inject subcutaneously in abdominal wall, thigh, upper arm, or buttocks and rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 ) • Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.2 ) • Administer NOVOLIN N once or twice daily. ( 2.2 ) • In patients with type 1 diabetes, NOVOLIN N should generally be used in regimens that include a short-acting insulin. ( 2.2 ) • NOVOLIN N can be mixed with NOVOLIN R. ( 2.4 ) 2.1 Important Administration Instructions • Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )]. • NOVOLIN N is a suspension that must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature. • To resuspend vial, roll the vial gently in your hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately. • To resuspend FlexPen, gently move the pen up and down 20 times so the glass ball moves from one end of the cartridge to the other until the suspension appears uniformly white and cloudy. Inject immediately. • Inspect NOVOLIN N visually before use. Do not use NOVOLIN N if discoloration or particulate matter is seen. • Administer NOVOLIN N by subcutaneous injection in the abdominal wall, thigh, upper arm, or buttocks. • Rotate the injection site 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 ), Adverse Reactions ( 6 )] . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . • Do not administer NOVOLIN N intravenously and do not use in an insulin infusion pump. 2.2 Dosage Information • Individualize and adjust the dosage of NOVOLIN N based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. • Administer NOVOLIN N once or twice daily. • In patients with type 1 diabetes, NOVOLIN N should generally be used in regimens that include a short-acting insulin. • 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 )]. • Dosage adjustment may be needed when switching from another insulin to NOVOLIN N [see Warnings and Precautions ( 5.2 )]. 2.3 Dosage Adjustment due to Drug Interactions • Dosage adjustment may be needed when NOVOLIN N is co-administered with certain drugs [see Drug Interactions ( 7 )] . 2.4 Instructions for Mixing with Other Insulins • NOVOLIN N can be mixed in the same syringe with NOVOLIN R. • When mixing, the NOVOLIN R should be drawn into the syringe first, followed by the NOVOLIN N. The mixture should be injected immediately after mixing.

3 DOSAGE FORMS AND STRENGTHS Injectable suspension: 70% insulin isophane human and 30% insulin human, 100 units/mL (U-100), white and cloudy suspension available as: • 10 mL multiple-dose vial • 3 mL single-patient-use NOVOLIN 70/30 FlexPen prefilled pen Injectable suspension: 100 units/mL (U-100) available as: • 10 mL multiple-dose vial ( 3 ) • 3 mL single-patient-use NOVOLIN 70/30 FlexPen prefilled pen ( 3 )

4 CONTRAINDICATIONS NOVOLIN 70/30 is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . • In patients who have had hypersensitivity reactions to NOVOLIN 70/30 or any of its excipients [see Warnings and Precautions ( 5.5 )] . • During episodes of hypoglycemia ( 4 ) • Hypersensitivity to NOVOLIN 70/30 or any of its excipients ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • 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 from Clinical Studies or Postmarketing Reports The following additional adverse reactions have been identified during clinical studies or from postmarketing reports with use of NOVOLIN 70/30. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. 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. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy. Hypersensitivity reactions Severe, life-threatening, generalized allergy, including anaphylaxis. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in NOVOLIN 70/30. Hypokalemia NOVOLIN 70/30 can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection site reactions NOVOLIN 70/30 can cause local injection site reactions including redness, swelling, or itching at the site of injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation. Localized reactions and generalized myalgias have been reported with the use of metacresol, which is an excipient in NOVOLIN 70/30. Lipodystrophy Administration of insulin subcutaneously, including NOVOLIN 70/30, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration ( 2.1 )] in some patients. Localized Cutaneous Amyloidosis Localized cutaneous amyloidosis at the injection site has occurred. 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. Medication Errors Medication errors in which other insulins have been accidentally substituted for NOVOLIN 70/30 have been identified during postapproval use. Peripheral edema Insulins, including NOVOLIN 70/30, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Weight gain Weight gain can occur with insulins, including NOVOLIN 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with NOVOLIN 70/30 is unknown. Adverse reactions observed with NOVOLIN 70/30 include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain and edema. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Table 1: Clinically Significant Drug Interactions with NOVOLIN 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 NOVOLIN 70/30 is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLIN 70/30 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 NOVOLIN 70/30 is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLIN 70/30 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 NOVOLIN 70/30 is co-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 NOVOLIN 70/30 is co-administered with these drugs. • Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 ) • Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage 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). Animal reproduction studies were not performed. 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, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human Data While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations including lack of blinding, unclear methods of randomization, and small sample size. 8.2 Lactation Risk Summary Available data from published literature suggests that exogenous human insulin products, including NOVOLIN 70/30, are transferred into human milk. There are no adverse reactions reported in the breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including NOVOLIN 70/30, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOVOLIN 70/30, and any potential adverse effects on the breastfed infant from NOVOLIN 70/30, or from the underlying maternal condition. 8.4 Pediatric Use NOVOLIN 70/30 is indicated to improve glycemic control in pediatric patients with diabetes mellitus. The dosage of NOVOLIN 70/30 must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose to reduce the risk of hypoglycemia [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.3 )]. 8.5 Geriatric Use The effect of age on the pharmacokinetics and pharmacodynamics of NOVOLIN 70/30 has not been studied. Elderly patients using insulin, including NOVOLIN 70/30, may be at increased risk of hypoglycemia due to co-morbid disease [see Warnings and Precautions ( 5.3 )]. 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics and pharmacodynamics of NOVOLIN 70/30 has not been studied. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent NOVOLIN 70/30 dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions ( 5.3 )] . 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of NOVOLIN 70/30 has not been studied. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent NOVOLIN 70/30 dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions ( 5.3 )] .

12.1 Mechanism of Action The primary activity of insulin, including NOVOLIN 70/30, is the regulation of glucose metabolism. Insulins 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 human is produced by recombinant DNA technology, utilizing Saccharomyces cerevisiae (baker’s yeast) as the production organism. The amino acid sequence of insulin human is identical to human insulin and has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5808 Da. NOVOLIN 70/30 (insulin isophane human and insulin human) injectable suspension is a mixture of 70% of insulin isophane human, an intermediate-acting insulin, and 30% of insulin human, a short-acting insulin. NOVOLIN 70/30 is a suspension of crystals produced from combining insulin human and protamine sulfate under appropriate conditions for crystal formation and mixing with insulin human injection. Figure 1: Structural formula of human insulin NOVOLIN 70/30 is a sterile, white and cloudy injectable suspension that contains insulin isophane human suspension (NPH) and insulin human injection (regular) for subcutaneous use. Each milliliter of NOVOLIN 70/30 contains 100 units of insulin human, dibasic sodium phosphate (1.9 mg), glycerin (16 mg), metacresol (1.5 mg), phenol (0.65 mg), protamine sulfate (approximately 0.25 mg), zinc (20.5 mcg/mL for the vial or 30.1 mcg for the FlexPen), and Water for Injection. Hydrochloric acid 2N and sodium hydroxide 2N may be added during manufacture to adjust the pH. The pH is 7.1-7.5. Structural formula of human insulin

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia. 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 can be treated with intramuscular or subcutaneous glucagon or intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately [see Warnings and Precautions ( 5.3 , 5.6 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NOVOLIN 70/30 injectable suspension is 70% insulin isophane human and 30% insulin human, 100 units/mL (U-100), a white and cloudy suspension available as: 10 mL multiple-dose vial NDC 0169-1837-11 ReliOn ® brand NDC 0169-1837-02 3 mL single-patient-use FlexPen NDC 0169-3007-15 ReliOn ® brand NDC 0169-3007-25 The NOVOLIN 70/30 FlexPen dials in 1-unit increments. 16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Do not expose NOVOLIN 70/30 vials and NOVOLIN 70/30 FlexPen to excessive heat or light. Do not freeze. Do not use after the expiration date. NOVOLIN 70/30 FlexPen must never be shared between patients, even if the needle is changed. Always remove and discard the needle after each injection from the NOVOLIN 70/30 FlexPen and store without a needle attached. Patients using NOVOLIN 70/30 vials, must never share needles or syringes with another person. Always use a new disposable syringe or needle for each injection to prevent contamination. Table 2: Storage Conditions and Expiration Dates for NOVOLIN 70/30 Not In-use (Unopened) Refrigerated (36°F - 46°F [2°C - 8°C]) Not In-use (Unopened) Room Temperature (see temperature below) In-use (Opened) Room Temperature (see temperature below) 10 mL multiple-dose vial Until expiration date 42 days up to 77°F (25°C) 42 days up to 77°F (25° C) (Do not refrigerate) 3 mL single-patient-use FlexPen Until expiration date 28 days up to 86°F (30°C) 28 days up to 86°F (30°C) (Do not refrigerate)