NOVOLIN R

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

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 ).

• 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.

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 )

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.

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 )