Humulin R U-500

1 INDICATIONS AND USAGE HUMULIN R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day. HUMULIN ® R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day. ( 1 ) Limitation of Use: The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined. The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined. ( 1.1 ) 1.1 Limitation of Use The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined. The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined.

2 DOSAGE AND ADMINISTRATION Adhere to administration instructions to reduce the risk of dosing errors. ( 2.1 , 2.3 , 2.4 , 5.1 ) HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors. ( 2.1 ) Individualize dose of HUMULIN R U-500 based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.2 ) Administer HUMULIN R U-500 subcutaneously two or three times daily 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. ( 2.1 , 2.2 ) Do NOT mix HUMULIN R U-500 with other insulins. ( 2.1 ) Do NOT administer HUMULIN R U-500 intravenously ( 2.1 ) Do NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected. ( 2.3 ) Do NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe. ( 2.3 ) Do NOT perform dose conversion when using a U-500 insulin syringe. Use only a U-500 insulin syringe with the HUMULIN R U-500 vial. ( 2.4 ) 2.1 Important Administration Instructions Prescribe HUMULIN R U-500 ONLY to patients who require more than 200 units of insulin per day. HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors. Instruct patients using the vial presentation to use only a U-500 insulin syringe and on how to correctly draw the prescribed dose of HUMULIN R U-500 into the U-500 insulin syringe. Confirm that the patient has understood these instructions and can correctly draw the prescribed dose of HUMULIN R U-500 with their syringe [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )] . Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions ( 5.1 )] . Inspect HUMULIN R U-500 visually for particulate matter and discoloration. Only use HUMULIN R U-500 if the solution appears clear and colorless. Instruct patients to inject HUMULIN R U-500 subcutaneously 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 ( 5.3 ) and Adverse Reactions ( 6 )] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.3 )] . Use HUMULIN R U-500 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. DO NOT administer HUMULIN R U-500 intravenously. DO NOT dilute or mix HUMULIN R U-500 with any other insulin products or solutions. 2.2 Dosing Instructions Instruct patients to inject HUMULIN R U-500 subcutaneously usually two or three times daily approximately 30 minutes before meals. Individualize and titrate the dosage of HUMULIN R U-500 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, changes in medications or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions ( 5.3 )] . 2.3 Delivery of HUMULIN R U-500 Using the HUMULIN R U-500 Disposable Prefilled KwikPen Device The HUMULIN R U-500 KwikPen dials in 5 unit increments and delivers a maximum dose of 300 units per injection. DO NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the…

5 WARNINGS AND PRECAUTIONS Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with Vial Presentation: Can be life-threatening. Overdose has occurred as a result of dispensing, prescribing or administration errors. Attention to details at all levels is required to prevent these errors. ( 2.1 , 2.3 , 2.4 , 5.1 ) Never share a HUMULIN R U-500 KwikPen or U-500 insulin syringe between patients, even if the needle is changed. ( 5.2 ) Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.3 ) Hypoglycemia: May be life-threatening. Increase monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. ( 5.4 ) Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMULIN R U-500, monitor, and treat if indicated. ( 5.5 ) Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ( 5.6 ) Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.7 ) 5.1 Hyperglycemia, Hypoglycemia or Death Due to Dosing Errors with the Vial Presentation Medication errors associated with the HUMULIN R U-500 vial presentation resulting in patients experiencing hyperglycemia, hypoglycemia or death have been reported. The majority of errors occurred due to errors in dispensing, prescribing or administration. Attention to details at all levels may prevent these errors. Dispensing Errors Instruct patients to always inspect insulin vials to confirm that the correct insulin is dispensed including the correct insulin brand and concentration. The HUMULIN R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement consisting of white lettering on a green rectangular background, and a green “U-500” statement prominently displayed next to the trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and a statement advising use with only U-500 insulin syringes. Prescribing Errors Dosing errors have occurred when the HUMULIN R U-500 dose was administered with syringes other than a U-500 insulin syringe. Patients should be prescribed U-500 syringes for use with the HUMULIN R U-500 vials. The prescribed dose of HUMULIN R U-500 should always be expressed in units of insulin [see Dosage and Administration ( 2.4 )] . Administration Errors Instruct patients to always check the insulin label before each injection. Use only a U-500 insulin syringe with HUMULIN R U-500 to avoid administration errors. Do not use any other type of syringe to administer Humulin R U-500. Adhere to administration instructions [see Dosage and Administration ( 2.1 , 2.4 )] . Instruct the patient to inform hospital or emergency department staff of the dose of HUMULIN R U-500 prescribed, in the event of a future hospitalization or visit to the emergency department. 5.2 Never Share a HUMULIN R U-500 KwikPen or U-500 Insulin Syringe Between Patients HUMULIN R U-500 KwikPens should never be shared between patients, even if the needle is changed. Patients using HUMULIN R U-500 vials should never share needles or U-500 insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.3 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and pre…

4 CONTRAINDICATIONS HUMULIN R U-500 is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions ( 5.4 )] In patients who are hypersensitive to HUMULIN R U-500 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 U-500 or any of its excipients. ( 4 )

7 DRUG INTERACTIONS Table 1: Clinically Significant Drug Interactions with HUMULIN R U-500 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 U-500 is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN R U 500 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 U-500 is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN R U 500 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 U-500 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 U-500 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 )

8.1 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 HbA1c >7% and has been reported to be as high as 20-25% in women with a HbA1c >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 over decades 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 or randomization, and small sample size.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.4 )] . Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] . Hypokalemia [see Warnings and Precautions ( 5.6 )] . The following additional adverse reactions have been identified during post-approval use of HUMULIN R U-500. Because 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 HUMULIN R U-500 include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, 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. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMULIN R U-500. Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, hypotension, and shock may occur with insulins, including HUMULIN R U-500 and may be life threatening. Lipodystrophy Long-term use of insulin, including HUMULIN R U-500, 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. Rotate insulin injections sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration ( 2.1 )] . 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. Injection Site Reactions Patients taking HUMULIN R U-500 may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. Weight Gain Weight gain can occur with insulins, including HUMULIN R U-500, and has been attributed to the anabolic effects of insulin. Peripheral Edema Insulins, including HUMULIN R U-500, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The presence of antibodies that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper- or hypoglycemia. The incidence of antibody formation with HUMULIN R U-500 is unknown.