HUMULIN R

Insulin human is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli and has the empirical formula C 257 H 383 N 65 O 77 S 6 with a molecular weight of 5.808 kDa. HUMULIN R (insulin human) injection is a short-acting human insulin for subcutaneous or intravenous use. HUMULIN R is a sterile, aqueous, clear, and colorless solution. HUMULIN R contains 100 units of insulin human in each milliliter. Each milliliter of HUMULIN R also contains glycerin (16 mg), metacresol (2.5 mg), endogenous zinc (approximately 0.015 mg/100 units,) and Water for Injection. Sodium hydroxide and hydrochloric acid may be added during manufacture to adjust the pH. The pH is 7.0 to 7.8.

HUMULIN R is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. HUMULIN ® R is a short-acting human insulin indicated to improve glycemic control in adult 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 thigh, upper arm, abdomen, or buttocks. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.2 ) Intravenous infusion: administer intravenously ONLY under medical supervision at concentrations from 0.1 unit/mL to 1 unit/mL in infusion systems containing 0.9% Sodium Chloride Injection. ( 2.2 ) Individualize dose based on route of administration, metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.3 ) HUMULIN R given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. ( 2.3 ) Do not mix with insulin preparations other than HUMULIN ® N. ( 2.5 ) 2.1 Important Administration Instructions Always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions ( 5.4 )] . Inspect HUMULIN R visually before use. It should appear clear and colorless. Do not use HUMULIN R if particulate matter or coloration is seen. 2.2 Route of Administration Subcutaneous Injection Inject HUMULIN R subcutaneously approximately 30 minutes before meals into the thigh, upper arm, abdomen, or buttocks. 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 )] . HUMULIN R may be diluted with Sterile Diluent for HUMULIN R for subcutaneous injection ONLY under medical supervision. Dilute one part HUMULIN R to nine parts diluent to yield a concentration one-tenth that of HUMULIN R (equivalent to U-10). Dilute one part HUMULIN R to one part diluent to yield a concentration one-half that of HUMULIN R (equivalent to U-50). Diluted HUMULIN R may be used for 28 days when stored at 41°F (5°C) or for 14 days when stored at 86°F (30°C). Intravenous Administration Administer HUMULIN 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 )] . For intravenous use, HUMULIN R should be used at concentrations from 0.1 unit/mL to 1 unit/mL in infusion systems containing 0.9% Sodium Chloride Injection. Intravenous infusion bags prepared with HUMULIN R are stable when stored in a refrigerator (36° to 46°F [2° to 8°C]) for 48 hours and then may be used at room temperature for up to an additional 48 hours. 2.3 Dosing Instructions Individualize and adjust the dosage of HUMULIN R based on the route of administration, the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal. HUMULIN R given by subcutaneous injection should generally be used in regimens with 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 (e.g., 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 ), Use in Specific Populations ( 8.6 , 8.7 )] . Dosage adjustment may be needed when changing from another insulin to HUMULIN R [see Warnings and Precautions ( 5.2 )] . 2.4 Dosage Adjustment due to Drug Interactions Dosage adjustment may be needed when HUMULIN R is co-administered with certain drugs [see Drug Interactions ( 7 )] . 2.5 Instructions for Mixing with Other Insulins for Subcutaneous Injection Do not mix HUMULIN R with insulin preparations other than HUMULIN N. To mix HUMULIN R and HUMULIN N, draw HUMULIN R into the syringe first. Inject immediately after mixing.

HUMULIN R is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] in patients with hypersensitivity to HUMULIN R or any 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 HUMULIN 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 )] Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )] Hypersensitivity [see Warnings and Precautions ( 5.5 )] Hypokalemia [see Warnings and Precautions ( 5.6 )] Adverse reactions observed with HUMULIN R include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 HUMULIN 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 allergic reactions may include anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, hypotension, and shock. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in HUMULIN R. Hypokalemia HUMULIN R can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection Site Reactions Injection site reactions may include injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. Lipodystrophy Administration of insulin subcutaneously, including HUMULIN R, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration ( 2.2 )] . 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 HUMULIN R have been identified during postapproval use. Peripheral Edema Insulins, including HUMULIN 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 HUMULIN R, and has been attributed to the anabolic effects of insulin. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with HUMULIN R is unknown.

Table 1: Clinically Significant Drug Interactions with HUMULIN 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 HUMULIN R is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of HUMULIN 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 HUMULIN R is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN 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 HUMULIN 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 HUMULIN 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 )

16.2 Storage and Handling Protect from heat and light. Do not freeze. Do not use HUMULIN R after the expiration date printed on the label or if it has been frozen. See Table 3 below for storage conditions. Table 3: Storage Conditions HUMULIN R Vials a a When stored at room temperature, HUMULIN R can only be used for a total of 31 days including both not in-use (unopened) and in-use (opened) storage time. Not In-use (Unopened) In-use (Opened) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) 10 mL multiple-dose vial 3 mL multiple-dose vial 31 days Until expiration date 31 days 31 days Storage of Diluted HUMULIN R and Intravenous Infusion Preparations with HUMULIN R Diluted HUMULIN R for subcutaneous injection may be stored for 28 days when refrigerated at 36° to 46°F [2° to 8°C] or for 14 days at room temperature up to 86°F (30°C) [see Dosage and Administration ( 2.2 )]. Intravenous infusion bags prepared with HUMULIN R may be stored for 48 hours when refrigerated at 36° to 46°F [2° to 8°C]. The prepared intravenous infusion bags may then be stored at room temperature for up to an additional 48 hours [see Dosage and Administration ( 2.2 )] .