Novolin

1 INDICATIONS AND USAGE NOVOLIN R is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. NOVOLIN R is 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 ) • Subcutaneous injection: inject subcutaneously 30 minutes before a meal into the abdominal area, buttocks, thigh or the upper arm. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.2 ) • Intravenous use: administer intravenously ONLY under medical supervision at concentrations from 0.05 unit/mL to 1 unit/mL in infusion systems using polypropylene infusion bags. ( 2.2 ) • Individualize dose based on route of administration, metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.3 ) • NOVOLIN R given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. ( 2.3 ) • Can be mixed with NOVOLIN N. ( 2.5 ) 2.1 Important Administration Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )]. • Inspect NOVOLIN R visually before use. It should appear clear and colorless. Do not use NOVOLIN R if particulate matter or coloration is seen. • Use of NOVOLIN R in insulin pumps is not recommended because of the risk of precipitation. 2.2 Route of Administration Subcutaneous Administration • Inject NOVOLIN R subcutaneously approximately 30 minutes prior to the start of a meal into the abdominal area, buttocks, thigh, or the 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 ), Adverse Reactions ( 6 )]. Intravenous Administration • Administer NOVOLIN R intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to reduce the risk of hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 ) and How Supplied/Storage and Handling ( 16.2 )] . • Dilute NOVOLIN R to concentrations from 0.05 unit/mL to 1 unit/mL insulin in infusion systems using polypropylene infusion bags. NOVOLIN R is stable in infusion fluids such as 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L potassium chloride. Intravenous infusion bags are stable at room temperature for 24 hours. 2.3 Dosage Information • Individualize and adjust the dosage of NOVOLIN R based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. • NOVOLIN R given by subcutaneous injection should generally be used in regimens that include an intermediate or long-acting insulin . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)] . • 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 [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 R [see Warnings and Precautions ( 5.2 )]. 2.4 Dosage Adjustment due to Drug Interactions • Dosage adjustment may be needed when NOVOLIN R is co-administered with certain drugs [see Drug Interactions ( 7 )] . 2.5 Instructions for Mixing with Other Insulins for Subcutaneous Injection • NOVOLIN R can be mixed with NOVOLIN N. • When mixing, the NOVOLIN R should be drawn into the syringe first and the mixture should be injected immediately after mixing.

3 DOSAGE FORMS AND STRENGTHS Injection: 100 units/mL (U-100), a clear and colorless solution available as: • 10 mL multiple-dose vial • 3 mL single-patient-use NOVOLIN R FlexPen prefilled pen Injection: 100 units/mL (U-100) is available as: • 10 mL multiple-dose vial ( 3 ) • 3 mL single-patient-use NOVOLIN R FlexPen prefilled pen ( 3 )

4 CONTRAINDICATIONS NOVOLIN R is contraindicated: • During episodes of hypoglycemia • In patients with hypersensitivity to NOVOLIN R or any of its excipients • During episodes of hypoglycemia ( 4 ) • Hypersensitivity to NOVOLIN R 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 R. 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 R. Hypokalemia NOVOLIN R can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection site reactions NOVOLIN R 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 R. Lipodystrophy Administration of insulin subcutaneously, including NOVOLIN R, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.2)] 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 R have been identified during postapproval use. Peripheral edema Insulins, including NOVOLIN R, 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 R, 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. Increases in titers of anti-insulin antibodies that react with human insulin have been observed in patients treated with NOVOLIN R. Adverse reactions observed with NOVOLIN R 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 R 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 R is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLIN R 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 R is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLIN R 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 R 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 R 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 suggest that exogenous human insulin products, including NOVOLIN R, 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 R, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOVOLIN R and any potential adverse effects on the breastfed infant from NOVOLIN R or from the underlying maternal condition. 8.4 Pediatric Use NOVOLIN R is indicated to improve glycemic control in pediatric patients with diabetes mellitus. The dosage of NOVOLIN R 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 ( 2.3 ) and Warnings and Precautions ( 5.3 )] . 8.5 Geriatric Use In clinical trials 18 of 1285 patients (1.4%) with type 1 diabetes and 151 of 635 patients (24%) with type 2 diabetes treated with NOVOLIN R were ≥65 years of age. Therefore, conclusions are limited regarding the efficacy and safety of NOVOLIN R in patients ≥65 years of age. The effect of age on the pharmacokinetics and pharmacodynamics of NOVOLIN R has not been studied. Elderly patients using NOVOLIN R, 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 R has not been studied. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent NOVOLIN R 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 R has not been studied. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent NOVOLIN R 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 R 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 a short-acting human insulin produced by recombinant DNA technology, utilizing Saccharomyces cerevisiae (baker’s yeast) as the production organism and has the empirical formula C 257 H 383 N 65 O 77 S 6 with a molecular weight of 5808 Da. Figure 1: Structural formula of NOVOLIN R NOVOLIN R (insulin human) injection is a sterile, clear and colorless solution for subcutaneous or intravenous use. Each mililiter of NOVOLIN R contains 100 units of insulin human, and glycerin (16 mg), metacresol (3 mg), zinc (approximately 21 mcg/mL) and Water for Injection. Hydrochloric acid 2N and sodium hydroxide 2N may be added during manufacture to adjust pH. The pH is 7.0 to 7.8. Structural formula of Novolin R

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and, particularly when given intravenously, 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 R (insulin human) injection is 100 units/mL (U-100), a clear and colorless solution available as: 10 mL multiple-dose vial NDC 0169-1833-11 ReliOn ® brand NDC 0169-1833-02 3 mL single-patient-use FlexPen NDC 0169-3003-15 ReliOn ® brand NDC 0169-3003-25 The NOVOLIN R 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 freeze. • Do not use if it has been frozen. • Do not use after the expiration date. • Do not expose to excessive heat or light. NOVOLIN R 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 R FlexPen and store without a needle attached. Patients using NOVOLIN R 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 R 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) Intravenous infusion bags prepared as indicated [see Dosage and Administration ( 2.2 )] are stable at room temperature for 24 hours.