OVERDOSAGE SECTION.

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 may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE CARTON HUMULIN U-500 Vial 20 mL 1ct. NDC 0002-8501-0120 mLHumulin(R) U-500insulin human injection10,000 units per 20 mL 500 units per mLRx only500 units/mLWarning Highly ConcentratedIMPORTANT: Use only with U-500 syringe.For subcutaneous use onlyMultiple-dose vialwww.humulin.comLilly. PACKAGE CARTON HUMULIN U-500 Vial 20 mL 1ct.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. There are no well-controlled studies of use of HUMULIN U-500 in children. Standard precautions as applied to use of HUMULIN U-500 in adults are appropriate for use in children. As in adults, the dosage of HUMULIN U-500 in pediatric patients must be individualized based on metabolic needs and results of frequent monitoring of blood glucose.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere:Hypoglycemia [see Warnings and Precautions (5.4)].Hypokalemia [see Warnings and Precautions (5.6)].The following additional adverse reactions have been identified during post-approval use of HUMULIN U-500. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or to establish causal relationship to drug exposure.. Hypoglycemia [see Warnings and Precautions (5.4)].. Hypokalemia [see Warnings and Precautions (5.6)].. Adverse reactions associated with HUMULIN 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.. HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMULIN U-500.. Allergic ReactionsSevere, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including HUMULIN U-500 and may be life threatening.. LipodystrophyLong-term use of insulin, including HUMULIN 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 AmyloidosisLocalized 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 sudden change to an unaffected injection site.. Injection Site ReactionsPatients taking HUMULIN U-500 may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass.. Weight GainWeight gain can occur with insulin therapy, including HUMULIN U-500, and has been attributed to the anabolic effects of insulin.. Peripheral EdemaInsulin, including HUMULIN U-500, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.. ImmunogenicityAs 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 U-500 is unknown.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and fertility studies were not performed with HUMULIN U-500 in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN U-500. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.. 12.2 Pharmacodynamics. In euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m2), single doses of HUMULIN U-500 at 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in mean time of onset of action of less than 15 minutes at both doses and mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation.Figure should be considered representative example since the time course of action of insulin may vary in different individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.3)].Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of 100 Dose of HUMULIN U-500 in Healthy Obese Subjects. Figure 1. 12.3 Pharmacokinetics. Absorption -- In euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between hours (50 unit dose) and hours (100 unit dose) with range of 0.5-8 hours.. Metabolism -- The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.. Elimination -- Mean apparent half-life after subcutaneous administration of single doses of 50 units and 100 units to healthy obese subjects (N>=21) was approximately 4.5 hours (range=1.9-10 hours) for HUMULIN U-500.Figure 2: Mean Serum Insulin Concentrations Versus Time After Subcutaneous Injection of 100 Dose of HUMULIN U-500 Healthy Obese Subjects. Figure 2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. HUMULIN U-500 is contraindicated:During episodes of hypoglycemiaIn patients who are hypersensitive to HUMULIN U-500 or any of its excipients.. During episodes of hypoglycemia. In patients who are hypersensitive to HUMULIN U-500 or any of its excipients.. Do not use during episodes of hypoglycemia. (4)Do not use in patients with hypersensitivity to HUMULIN U-500 or any of its excipients. (4). Do not use during episodes of hypoglycemia. (4). Do not use in patients with hypersensitivity to HUMULIN U-500 or any of its excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. HUMULIN U-500 (insulin human injection) is human insulin solution used to lower blood glucose. Human insulin is produced by recombinant DNA technology utilizing non-pathogenic laboratory strain of Escherichia coli. HUMULIN has the empirical formula C257H383N65O77S6 with molecular weight of 5808.HUMULIN U-500 is sterile, aqueous, and colorless solution. HUMULIN U-500 contains 500 units of insulin in each milliliter. Each milliliter of HUMULIN U-500 also contains glycerin 16 mg, metacresol 2.5 mg, zinc oxide to supplement the endogenous zinc to obtain total zinc content of 0.017 mg/100 units, and Water for Injection. Sodium hydroxide and hydrochloric acid may be added during manufacture to adjust the pH.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adhere to administration instructions to reduce the risk of dosing errors. (2.1, 2.3, 2.4, 5.1)HUMULIN U-500 is available as 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 U-500 based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.2)Administer HUMULIN U-500 subcutaneously two or three times daily 30 minutes before 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 U-500 with other insulins. (2.1)Do NOT administer HUMULIN U-500 intravenously or intramuscularly. (2.1)Do NOT perform dose conversion when using the HUMULIN U-500 KwikPen. The dose window of the HUMULIN U-500 KwikPen shows the number of units of HUMULIN U-500 to be injected. (2.3)Do NOT transfer HUMULIN U-500 from the HUMULIN U-500 KwikPen into any syringe. (2.3)Do NOT perform dose conversion when using U-500 insulin syringe. Use only U-500 insulin syringe with the HUMULIN U-500 vial. (2.4). Adhere to administration instructions to reduce the risk of dosing errors. (2.1, 2.3, 2.4, 5.1). HUMULIN U-500 is available as 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 U-500 based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.2). Administer HUMULIN U-500 subcutaneously two or three times daily 30 minutes before 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 U-500 with other insulins. (2.1). Do NOT administer HUMULIN U-500 intravenously or intramuscularly. (2.1). Do NOT perform dose conversion when using the HUMULIN U-500 KwikPen. The dose window of the HUMULIN U-500 KwikPen shows the number of units of HUMULIN U-500 to be injected. (2.3). Do NOT transfer HUMULIN U-500 from the HUMULIN U-500 KwikPen into any syringe. (2.3). Do NOT perform dose conversion when using U-500 insulin syringe. Use only U-500 insulin syringe with the HUMULIN U-500 vial. (2.4). 2.1 Important Administration Instructions. Prescribe HUMULIN U-500 ONLY to patients who require more than 200 units of insulin per day.HUMULIN U-500 is available as 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 U-500 insulin syringe and on how to correctly draw the prescribed dose of HUMULIN 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 U-500 with their syringe [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Train patients on proper use and injection technique before initiating HUMULIN U-500. Training reduces the risk of administration errors such as needle sticks and dosing errors.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 U-500 visually for particulate matter and discoloration. Only use HUMULIN U-500 if the solution appears clear and colorless.Instruct patients to inject HUMULIN 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 patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.3)].Use HUMULIN U-500 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.DO NOT administer HUMULIN U-500 intravenously or intramuscularly.DO NOT dilute or mix HUMULIN U-500 with any other insulin products or solutions.. Prescribe HUMULIN U-500 ONLY to patients who require more than 200 units of insulin per day.. HUMULIN U-500 is available as 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 U-500 insulin syringe and on how to correctly draw the prescribed dose of HUMULIN 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 U-500 with their syringe [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Train patients on proper use and injection technique before initiating HUMULIN U-500. Training reduces the risk of administration errors such as needle sticks and dosing errors.. 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 U-500 visually for particulate matter and discoloration. Only use HUMULIN U-500 if the solution appears clear and colorless.. Instruct patients to inject HUMULIN 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 patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.3)].. Use HUMULIN U-500 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.. DO NOT administer HUMULIN U-500 intravenously or intramuscularly.. DO NOT dilute or mix HUMULIN U-500 with any other insulin products or solutions.. 2.2 Dosing Instructions. Instruct patients to inject HUMULIN U-500 subcutaneously usually two or three times daily approximately 30 minutes before meals.Individualize and titrate the dosage of HUMULIN U-500 based on the patients 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)].. Instruct patients to inject HUMULIN U-500 subcutaneously usually two or three times daily approximately 30 minutes before meals.. Individualize and titrate the dosage of HUMULIN U-500 based on the patients 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 U-500 Using the HUMULIN U-500 Disposable Prefilled KwikPen Device. The HUMULIN U-500 KwikPen dials in unit increments.DO NOT perform dose conversion when using the HUMULIN U-500 KwikPen. The dose window of the HUMULIN U-500 KwikPen shows the number of units of HUMULIN U-500 to be injected and NO dose conversion is required.DO NOT transfer HUMULIN U-500 from the HUMULIN U-500 KwikPen into any syringe for administration as overdose and severe hypoglycemia can occur [see Warnings and Precautions (5.4)]. The HUMULIN U-500 KwikPen is for single patient use only [see Warnings and Precautions (5.2)]. The HUMULIN U-500 KwikPen dials in unit increments.. DO NOT perform dose conversion when using the HUMULIN U-500 KwikPen. The dose window of the HUMULIN U-500 KwikPen shows the number of units of HUMULIN U-500 to be injected and NO dose conversion is required.. DO NOT transfer HUMULIN U-500 from the HUMULIN U-500 KwikPen into any syringe for administration as overdose and severe hypoglycemia can occur [see Warnings and Precautions (5.4)]. The HUMULIN U-500 KwikPen is for single patient use only [see Warnings and Precautions (5.2)]. 2.4 Delivery of HUMULIN U-500 Using the Vial Presentation and the U-500 Insulin Syringe. DO NOT perform dose conversion when using U-500 insulin syringe. The markings on the U-500 insulin syringe show the number of units of HUMULIN U-500 to be injected. Each marking on the syringe represents units of insulin.Prescribe patients U-500 insulin syringe to administer HUMULIN U-500 from the vial to avoid administration errors. DO NOT use any other type of syringe [see Warnings and Precautions (5.1)].. DO NOT perform dose conversion when using U-500 insulin syringe. The markings on the U-500 insulin syringe show the number of units of HUMULIN U-500 to be injected. Each marking on the syringe represents units of insulin.. Prescribe patients U-500 insulin syringe to administer HUMULIN U-500 from the vial to avoid administration errors. DO NOT use any other type of syringe [see Warnings and Precautions (5.1)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. HUMULIN U-500 (500 units per mL) injection is available in clear, colorless solution as:3 mL single-patient-use HUMULIN U-500 KwikPen (containing 1,500 units of insulin)20 mL multiple-dose vial (containing 10,000 units of insulin). mL single-patient-use HUMULIN U-500 KwikPen (containing 1,500 units of insulin). 20 mL multiple-dose vial (containing 10,000 units of insulin). HUMULIN U-500 (500 units per mL) injection is available as: (3)3 mL single-patient-use HUMULIN(R) U-500 KwikPen(R) (containing 1,500 units of insulin)20 mL multiple-dose vial (containing 10,000 units of insulin). mL single-patient-use HUMULIN(R) U-500 KwikPen(R) (containing 1,500 units of insulin). 20 mL multiple-dose vial (containing 10,000 units of insulin).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Certain drugs may affect glucose metabolism and may necessitate insulin dose adjustment. (7.1, 7.2, 7.3)The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine). (7.3, 7.4). Certain drugs may affect glucose metabolism and may necessitate insulin dose adjustment. (7.1, 7.2, 7.3). The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine). (7.3, 7.4). 7.1 Drugs That May Increase the Risk of Hypoglycemia. The risk of hypoglycemia associated with HUMULIN U-500 use may be increased with antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN U-500 is co-administered with these drugs.. 7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN U-500. The glucose lowering effect of HUMULIN U-500 may be decreased when co-administered with 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. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN U-500 is co-administered with these drugs.. 7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN U-500. The glucose lowering effect of HUMULIN U-500 may be increased or decreased when co-administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN U-500 is co-administered with these drugs.. 7.4 Drugs That May Affect Signs and Symptoms of Hypoglycemia. The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)] may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are co-administered with HUMULIN U-500.

GERIATRIC USE SECTION.

8.5 Geriatric Use. The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN U-500 has not been studied. Caution should be exercised when HUMULIN U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. HUMULIN U-500 (500 units per mL) injection is available in clear, colorless solution as:2 3 mL single-patient-use HUMULIN U-500 KwikPenNDC 0002-8824-2720 mL multiple-dose vialNDC 0002-8501-01The HUMULIN U-500 KwikPen dials in unit increments.. 16.2 Storage and Handling. Dispense in the original sealed carton with the enclosed Instructions for Use.Protect from heat and light. Do not freeze. Do not use HUMULIN U-500 after the expiration date printed on the label or if it has been frozen. Do not shake the vial.. Not In Use (Unopened) HUMULIN U-500 KwikPen. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the pen must be discarded after 28 days.. In-Use (Opened) HUMULIN U-500 KwikPen. RefrigeratedDo NOT store in refrigerator.. Room TemperatureStore at room temperature, below 86F (30C) and the pen must be discarded after 28 days, even if the pen still contains HUMULIN U-500. See storage table below:. Not In Use (Unopened) HUMULIN U-500 Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 40 days.. In-Use (Opened) HUMULIN U-500 Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen. Vials must be used within 40 days or be discarded, even if they still contain HUMULIN U-500.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 40 days, even if the vial still contains HUMULIN U-500. See storage table below:Not In-Use (Unopened) RefrigeratedIn-Use (Opened)3 mL single-patient-use HUMULIN U-500 KwikPenUntil expiration date28 days, room temperature. Do not refrigerate. 20 mL multiple-dose vialUntil expiration date40 days, refrigerated or room temperature.

IMMUNOGENICITY.

ImmunogenicityAs 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 U-500 is unknown.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling.Patients should be counseled that HUMULIN U-500 is 5-times concentrated insulin product. Extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia. Accidental mix-ups between HUMULIN U-500 and other insulins have been reported. To avoid medication errors between HUMULIN U-500 and other insulins, patients should be instructed to always check the insulin label before each injection [see Warnings and Precautions (5.1)].If using the HUMULIN U-500 KwikPen, patients should be counseled to dial and dose the prescribed number of units of insulin (no dose conversion is required) [see Dosage and Administration (2.3)].When using HUMULIN U-500 from vial, patients should be counseled to use only U-500 insulin syringe and be informed that no dose conversion is required [see Dosage and Administration (2.4)].Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN U-500 therapy. Patients must be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision. Refer patients to the HUMULIN U-500 Patient Information Leaflet for additional information [see Warnings and Precautions (5)].Inspect HUMULIN U-500 visually for particulate matter and discoloration. Only use HUMULIN U-500 if the solution appears clear and colorless.Do not dilute or mix HUMULIN U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].Literature Revised: November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USACopyright (C) 1997, 2019, Eli Lilly and Company. All rights reserved.LINR500-0008-USPI-20191115.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use Humulin(R) U-500 insulin human injection (500 units/mL, 20 mL multiple-dose vial)Please read these instructions before use.WarningsFor your safety, always inject Humulin(R) U 500 insulin with U 500 syringe. If you use another kind of syringe, you may get dangerous overdose.U-500 syringe for single injection onlyThe U-500 syringe has green U-500 symbol and green Needle Shield on the syringe.Important InformationHumulin U-500 is concentrated insulin.Know your dose. Your health care provider will tell you the number of insulin units that you should take.Always inject Humulin U-500 insulin with U-500 syringe. Other syringes will not measure your dose correctly.If you use the wrong syringe, you can give yourself severe overdose. This can cause very low blood sugar, which may put your life in danger. For example, using U-100 syringe can give you 5 times overdose.If you do not have U-500 syringe, you should contact your health care provider or pharmacist.Additional Safety InformationEach line on the U-500 syringe measures units of U-500 insulin.You can give from to 250 units in one injection.If your dose is more than 250 units, you will need to give more than injection.Make sure you know how to draw up your dose with U-500 syringe. If you need help, call your health care provider.Do not reuse your U-500 syringe.Do not share your U-500 syringes with other people. You may give other people serious infection or get serious infection from them.Do not mix Humulin U-500 with other insulins in the same syringe.You can get more instructions by calling Lilly at 1-800-LillyRx (1-800-545-5979).SuppliesHumulin U-500 multiple-dose vialU-500 Syringe (BD [Becton, Dickinson and Company] syringes recommended) alcohol swabs1 sharps container Before You StartCheck your vial. Make sure it says Humulin U-500.Check the expiration date on the vial. Do not use it if it is expired. Throw away the opened vial after 40 days, even if there is still insulin left in the vial.See if the insulin in the vial is clear. Do not use if it is thick, cloudy, or colored or has solid particles.Make sure you have new U-500 Syringe. Check for the green U-500 symbol and green Needle Shield.Check your supply. Make sure you have enough Humulin U-500 insulin and U-500 syringes for several injections. Always reorder before you run out.Check with your health care provider if you have any questions.Use only U-500 syringe to inject Humulin U-500 insulinPrepareWash your hands with soap and water.Always use new syringe for each injection to help prevent infections and blocked needles.Step 1:Find the line on the U-500 syringe that matches your prescribed dose. This is your Dose Line.Each line is units.(Example: Arrow shows Dose Line at 85 units)Step 2:If you are using new vial, pull off the plastic Protective Cap.Do not remove the Rubber Stopper.Step 3:Wipe the Rubber Stopper with an alcohol swab.Step 4:Hold the syringe with the Needle pointing up. Pull down on the Plunger Rod until the Plunger Tip reaches your Dose Line.(Example Dose: 85 units shown)Step 5:Push the Needle through the Rubber Stopper of the vial.Step 6:Push the Plunger all the way in. This puts air into the vial.Step 7:Turn the vial and syringe upside down and slowly pull the Plunger down until the Plunger Tip is past your Dose Line.(Example Dose: 85 units Plunger is shown at 100 units)If there are air bubbles, tap the syringe gently few times. This lets the air bubbles rise to the top.Step 8:Slowly push the Plunger up until the Plunger Tip reaches your Dose Line.Check the syringe to make sure that you have the right dose.(Example Dose: 85 units shown)Step 9:Pull the syringe out of the vials Rubber Stopper.InjectInject your insulin exactly as your healthcare provider has shown you.Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.Step 10:Choose your injection site.Humulin U-500 is injected under the skin (subcutaneously). You may inject into your stomach area, buttocks, upper legs, or upper arms.Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose.Step 11:Insert the Needle into your skin.Step 12:Push down on the Plunger to inject your dose.Then keep the Needle in your skin for at least seconds, to make sure you have injected all of your dose.Step 13:Pull the Needle out of your skin.You may see blood after you take the Needle out of your skin. This is normal. Press the injection site lightly with piece of gauze or an alcohol swab. Do not rub the area.Do not put the Needle Shield back on the Needle, because you may get needle stick injury.Disposal of used syringesPut your used syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) syringes in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak-resistant, and-properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Storage and HandlingKeep away from heat and out of direct light.Do not shake the vial.Unopened vials:Store unopened vials in the refrigerator.Do not freeze Humulin U-500. If it has been frozen, do not use it.If unopened vials have been stored in the refrigerator, you may use them until the expiration date.After the vial has been opened:Store opened vials in the refrigerator or at room temperature (less than 86F [30C]) for up to 40 days.Throw away the opened vial after 40 days, even if there is still insulin left in the vial.General InformationAlways use U-500 syringe to inject Humulin U-500 insulin.Never use other syringes. The lines and numbers on other syringes will not measure your dose correctly.You can give yourself the wrong dose if you use any other syringe, such as U-100, tuberculin or allergy syringe.For example, U-100 syringe is made to measure U-100 insulin. If you use U-100 Syringe for your U-500 dose, you can give yourself 5 times overdose. Do not make any changes to your dose or the type of insulin you use unless you are told to do so by your health care provider.Keep your vials and syringes out of the sight and reach of children.Frequently Asked QuestionsWhy do need to use U-500 syringe Humulin U-500 insulin and U-500 syringe work together to help you inject the correct dose. Using any other syringe may result in dosing mistakes. This may put your life in danger.Do have to convert my Humulin U-500 insulin dose when use the U-500 syringe No, you do not have to convert your dose. Your health care provider should tell you how much Humulin U-500 insulin to take in units and when to take it. Your health care provider should show you how to draw up your dose using the U-500 syringe.What should do if run out of U-500 syringes If you run out of U-500 syringes, do not use any other syringe to inject Humulin U-500 insulin. Call your health care provider or pharmacist for help. You may also call Lilly at 1-800-Lilly-Rx (1-800-545-5979).Where to get more information and helpIf you have any questions about Humulin U-500 insulin or U-500 syringes, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979).You can also call your health care provider or pharmacist.For more information on Humulin U-500 insulin, go to www.humulin.com Scan this code to launch the humulin.com websiteThese Instructions for Use have been approved by the U.S. Food and Drug Administration.Humulin(R) is trademark of Eli Lilly and Company.Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USACopyright (C) 1996, 2019, Eli Lilly and Company. All rights reserved.Literature issued: November 2019LINR500VL-0003-IFU-20191115. For your safety, always inject Humulin(R) U 500 insulin with U 500 syringe. If you use another kind of syringe, you may get dangerous overdose.. Humulin U-500 is concentrated insulin.. Know your dose. Your health care provider will tell you the number of insulin units that you should take.. Always inject Humulin U-500 insulin with U-500 syringe. Other syringes will not measure your dose correctly.. If you use the wrong syringe, you can give yourself severe overdose. This can cause very low blood sugar, which may put your life in danger. For example, using U-100 syringe can give you 5 times overdose.. If you do not have U-500 syringe, you should contact your health care provider or pharmacist.. Each line on the U-500 syringe measures units of U-500 insulin.. You can give from to 250 units in one injection.. If your dose is more than 250 units, you will need to give more than injection.. Make sure you know how to draw up your dose with U-500 syringe. If you need help, call your health care provider.. Do not reuse your U-500 syringe.. Do not share your U-500 syringes with other people. You may give other people serious infection or get serious infection from them.. Do not mix Humulin U-500 with other insulins in the same syringe.. You can get more instructions by calling Lilly at 1-800-LillyRx (1-800-545-5979).. Humulin U-500 multiple-dose vial. U-500 Syringe (BD [Becton, Dickinson and Company] syringes recommended) 2 alcohol swabs. sharps container Check your vial. Make sure it says Humulin U-500.. Check the expiration date on the vial. Do not use it if it is expired. Throw away the opened vial after 40 days, even if there is still insulin left in the vial.. See if the insulin in the vial is clear. Do not use if it is thick, cloudy, or colored or has solid particles.. Make sure you have new U-500 Syringe. Check for the green U-500 symbol and green Needle Shield.. Check your supply. Make sure you have enough Humulin U-500 insulin and U-500 syringes for several injections. Always reorder before you run out.. Check with your health care provider if you have any questions.. Wash your hands with soap and water.. Always use new syringe for each injection to help prevent infections and blocked needles.. Inject your insulin exactly as your healthcare provider has shown you.. Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. You may see blood after you take the Needle out of your skin. This is normal. Press the injection site lightly with piece of gauze or an alcohol swab. Do not rub the area.. Do not put the Needle Shield back on the Needle, because you may get needle stick injury.. Put your used syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) syringes in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak-resistant, and-properly labeled to warn of hazardous waste inside the container. -made of heavy-duty plastic,. -can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. -upright and stable during use,. -leak-resistant, and. -properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Keep away from heat and out of direct light.. Do not shake the vial.. Store unopened vials in the refrigerator.. Do not freeze Humulin U-500. If it has been frozen, do not use it.. If unopened vials have been stored in the refrigerator, you may use them until the expiration date.. Store opened vials in the refrigerator or at room temperature (less than 86F [30C]) for up to 40 days.. Throw away the opened vial after 40 days, even if there is still insulin left in the vial.. Always use U-500 syringe to inject Humulin U-500 insulin.. Never use other syringes. The lines and numbers on other syringes will not measure your dose correctly.. You can give yourself the wrong dose if you use any other syringe, such as U-100, tuberculin or allergy syringe.For example, U-100 syringe is made to measure U-100 insulin. If you use U-100 Syringe for your U-500 dose, you can give yourself 5 times overdose. Do not make any changes to your dose or the type of insulin you use unless you are told to do so by your health care provider.. Keep your vials and syringes out of the sight and reach of children.. Why do need to use U-500 syringe Humulin U-500 insulin and U-500 syringe work together to help you inject the correct dose. Using any other syringe may result in dosing mistakes. This may put your life in danger.. Do have to convert my Humulin U-500 insulin dose when use the U-500 syringe No, you do not have to convert your dose. Your health care provider should tell you how much Humulin U-500 insulin to take in units and when to take it. Your health care provider should show you how to draw up your dose using the U-500 syringe.. What should do if run out of U-500 syringes If you run out of U-500 syringes, do not use any other syringe to inject Humulin U-500 insulin. Call your health care provider or pharmacist for help. You may also call Lilly at 1-800-Lilly-Rx (1-800-545-5979).. If you have any questions about Humulin U-500 insulin or U-500 syringes, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979).. You can also call your health care provider or pharmacist.. For more information on Humulin U-500 insulin, go to www.humulin.com Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryAvailable data from published literature suggests that exogenous human insulin products, including HUMULIN R, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for HUMULIN and any potential adverse effects on the breastfed child from HUMULIN or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN U-500. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and fertility studies were not performed with HUMULIN U-500 in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m2), single doses of HUMULIN U-500 at 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in mean time of onset of action of less than 15 minutes at both doses and mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation.Figure should be considered representative example since the time course of action of insulin may vary in different individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.3)].Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of 100 Dose of HUMULIN U-500 in Healthy Obese Subjects. Figure 1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption -- In euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between hours (50 unit dose) and hours (100 unit dose) with range of 0.5-8 hours.. Metabolism -- The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.. Elimination -- Mean apparent half-life after subcutaneous administration of single doses of 50 units and 100 units to healthy obese subjects (N>=21) was approximately 4.5 hours (range=1.9-10 hours) for HUMULIN U-500.Figure 2: Mean Serum Insulin Concentrations Versus Time After Subcutaneous Injection of 100 Dose of HUMULIN U-500 Healthy Obese Subjects. Figure 2.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable 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 HbA1c >7% and has been reported to be as high as 20-25% in women with 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 riskPoorly 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 DataWhile 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1)11/2019Warnings and Precautions (5.3)11/2019.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: November 2019LINR500-0005-PPI-20191115Patient InformationHumulin(R) (HU-mu-lin) U-500 insulin human injection (500 units per mL) Do not share your Humulin U-500 KwikPen or U-500 insulin syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.What is Humulin U-500Humulin U-500 is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus who need more than 200 units of insulin in day.Humulin U-500 contains times as much insulin (500 units/mL) in mL as standard insulin (100 units/mL).It is not known if Humulin U-500 is safe and effective when used in combination with other insulins.It is not known if Humulin U-500 is safe and effective when given by continuous subcutaneous infusion.It is not known if Humulin U-500 is safe and effective in children.Who should not take Humulin U-500Do not take Humulin U-500 if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to human insulin or any of the ingredients in Humulin U-500. See the end of this Patient Information leaflet for complete list of ingredients in Humulin U-500.What should tell my healthcare provider before using Humulin U-500Before using Humulin U-500, tell your healthcare provider about all your medical conditions including, if you:have liver or kidney problems.take other medicines, especially ones called TZDs (thiazolidinediones).have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Humulin U-500.are pregnant, planning to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.are breast-feeding or plan to breastfeed. Humulin U-500 may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using HUMULIN U-500.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements. Before you start using Humulin U-500, talk to your healthcare provider about low blood sugar and how to manage it. How should use Humulin U-500Read the detailed Instructions for Use that come with your Humulin U-500.Use Humulin U-500 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Humulin U-500 to use and when to use it.Know the dose of Humulin U-500 you use. Do not change the dose of Humulin U-500 you use unless your healthcare provider tells you to.Check your insulin label each time you give your injection to make sure you are using the correct insulin.When using the Humulin U-500 KwikPen: The Humulin U-500 KwikPen is specially made to dial and deliver doses of Humulin U-500 insulin. Do not use any syringe to remove Humulin U-500 from your Humulin U-500 KwikPen. The markings on certain syringes will not measure your dose correctly. severe overdose can happen, causing low blood sugar, which may put your life in danger.When using the Humulin U-500 vial: There is special U-500 insulin syringe to measure Humulin U-500. Use only U-500 insulin syringe to draw up and inject your Humulin U-500. If you do not use the right syringe type, you may take the wrong dose of Humulin U-500. This can cause you to have too low blood sugar (hypoglycemia) or too high blood sugar (hyperglycemia). Your healthcare provider should show you how to draw up Humulin U-500.Use Humulin U-500 30 minutes before eating meal.Inject Humulin U-500 under the skin (subcutaneously) of your upper legs (thighs), upper arms, buttocks or stomach area (abdomen). Do not use Humulin U-500 in an insulin pump or inject Humulin U-500 into your vein (intravenously) or your muscle (intramuscularly).Do not mix Humulin U-500 in the KwikPen or vial with any other type of insulin or liquid medicine.Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.-Do not use the exact same spot for each injection.-Do not inject where the skin has pits, is thickened, or has lumps.-Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. Keep Humulin U-500 and all medicines out of reach of children.Your dose of Humulin U-500 may need to change because of:o change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.What should avoid while using Humulin U-500While using Humulin U-500 do not: drive or operate heavy machinery, until you know how Humulin U-500 affects you.drink alcohol or use over-the-counter medicines that contain alcohol. What are the possible side effects of Humulin U-500Humulin U-500 may cause serious side effects that can lead to death, including:low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:-dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.-your healthcare provider may prescribe glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth. severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:-a rash over your whole body, have trouble breathing, fast heartbeat, or sweating.low potassium in your blood (hypokalemia).heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with Humulin U-500 may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure, it may get worse while you take TZDs with Humulin U-500. Your healthcare provider should monitor you closely while you are taking TZDs with Humulin U-500. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:-shortness of breath, swelling of your ankles or feet, sudden weight gain Treatment with TZDs and Humulin U-500 may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have: severe hypoglycemia needing hospitalization or emergency room care, and be sure to tell the hospital staff the units of Humulin U-500 that your healthcare provider has prescribed for you.trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. The most common side effects of Humulin U-500 include:low blood sugar (hypoglycemia), allergic reactions including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy), itching, and rash.These are not all of the possible side effects of Humulin U-500. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General Information about the safe and effective use of Humulin U-500Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Humulin U-500 for condition for which it was not prescribed. Do not give Humulin U-500 to other people, even if they have the same symptoms you have. It may harm them.This Patient Information leaflet summarizes the most important information about Humulin U-500. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Humulin U-500 that is written for healthcare professionals. For more information go to www.humulin.com or call 1-800-545-5979.What are the ingredients in Humulin U-500Active ingredient: human insulin Inactive ingredients: glycerin, metacresol, zinc oxide, water for injection, sodium hydroxide and hydrochloric acid Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA For more information about Humulin U-500 go to www.humulin.com. Copyright (C) 2015, 2019, Eli Lilly and Company. All rights reserved.. Humulin U-500 is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus who need more than 200 units of insulin in day.. Humulin U-500 contains times as much insulin (500 units/mL) in mL as standard insulin (100 units/mL).. It is not known if Humulin U-500 is safe and effective when used in combination with other insulins.. It is not known if Humulin U-500 is safe and effective when given by continuous subcutaneous infusion.. It is not known if Humulin U-500 is safe and effective in children.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to human insulin or any of the ingredients in Humulin U-500. See the end of this Patient Information leaflet for complete list of ingredients in Humulin U-500.. have liver or kidney problems.. take other medicines, especially ones called TZDs (thiazolidinediones).. have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Humulin U-500.. are pregnant, planning to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.. are breast-feeding or plan to breastfeed. Humulin U-500 may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using HUMULIN U-500.. Read the detailed Instructions for Use that come with your Humulin U-500.. Use Humulin U-500 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Humulin U-500 to use and when to use it.. Know the dose of Humulin U-500 you use. Do not change the dose of Humulin U-500 you use unless your healthcare provider tells you to.. Check your insulin label each time you give your injection to make sure you are using the correct insulin.. When using the Humulin U-500 KwikPen: The Humulin U-500 KwikPen is specially made to dial and deliver doses of Humulin U-500 insulin. Do not use any syringe to remove Humulin U-500 from your Humulin U-500 KwikPen. The markings on certain syringes will not measure your dose correctly. severe overdose can happen, causing low blood sugar, which may put your life in danger.. When using the Humulin U-500 vial: There is special U-500 insulin syringe to measure Humulin U-500. Use only U-500 insulin syringe to draw up and inject your Humulin U-500. If you do not use the right syringe type, you may take the wrong dose of Humulin U-500. This can cause you to have too low blood sugar (hypoglycemia) or too high blood sugar (hyperglycemia). Your healthcare provider should show you how to draw up Humulin U-500.. Use Humulin U-500 30 minutes before eating meal.. Inject Humulin U-500 under the skin (subcutaneously) of your upper legs (thighs), upper arms, buttocks or stomach area (abdomen). Do not use Humulin U-500 in an insulin pump or inject Humulin U-500 into your vein (intravenously) or your muscle (intramuscularly).. Do not mix Humulin U-500 in the KwikPen or vial with any other type of insulin or liquid medicine.. Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.-Do not use the exact same spot for each injection.-Do not inject where the skin has pits, is thickened, or has lumps.-Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. -Do not use the exact same spot for each injection.. -Do not inject where the skin has pits, is thickened, or has lumps.. -Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. drive or operate heavy machinery, until you know how Humulin U-500 affects you.. drink alcohol or use over-the-counter medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:-dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.-your healthcare provider may prescribe glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth. -dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.. -your healthcare provider may prescribe glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth.. severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:-a rash over your whole body, have trouble breathing, fast heartbeat, or sweating.. -a rash over your whole body, have trouble breathing, fast heartbeat, or sweating.. low potassium in your blood (hypokalemia).. heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with Humulin U-500 may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure, it may get worse while you take TZDs with Humulin U-500. Your healthcare provider should monitor you closely while you are taking TZDs with Humulin U-500. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:-shortness of breath, swelling of your ankles or feet, sudden weight gain -shortness of breath, swelling of your ankles or feet, sudden weight gain. severe hypoglycemia needing hospitalization or emergency room care, and be sure to tell the hospital staff the units of Humulin U-500 that your healthcare provider has prescribed for you.. trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. low blood sugar (hypoglycemia), allergic reactions including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy), itching, and rash.

SPL UNCLASSIFIED SECTION.

1.1 Limitation of Use. The safety and efficacy of HUMULIN U-500 used in combination with other insulins has not been determined.The safety and efficacy of HUMULIN U-500 delivered by continuous subcutaneous infusion has not been determined.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Dispense in the original sealed carton with the enclosed Instructions for Use.Protect from heat and light. Do not freeze. Do not use HUMULIN U-500 after the expiration date printed on the label or if it has been frozen. Do not shake the vial.. Not In Use (Unopened) HUMULIN U-500 KwikPen. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the pen must be discarded after 28 days.. In-Use (Opened) HUMULIN U-500 KwikPen. RefrigeratedDo NOT store in refrigerator.. Room TemperatureStore at room temperature, below 86F (30C) and the pen must be discarded after 28 days, even if the pen still contains HUMULIN U-500. See storage table below:. Not In Use (Unopened) HUMULIN U-500 Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 40 days.. In-Use (Opened) HUMULIN U-500 Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen. Vials must be used within 40 days or be discarded, even if they still contain HUMULIN U-500.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 40 days, even if the vial still contains HUMULIN U-500. See storage table below:Not In-Use (Unopened) RefrigeratedIn-Use (Opened)3 mL single-patient-use HUMULIN U-500 KwikPenUntil expiration date28 days, room temperature. Do not refrigerate. 20 mL multiple-dose vialUntil expiration date40 days, refrigerated or room temperature.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable 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 HbA1c >7% and has been reported to be as high as 20-25% in women with 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 riskPoorly 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 DataWhile 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.. 8.2 Lactation. Risk SummaryAvailable data from published literature suggests that exogenous human insulin products, including HUMULIN R, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for HUMULIN and any potential adverse effects on the breastfed child from HUMULIN or from the underlying maternal condition.. 8.4 Pediatric Use. There are no well-controlled studies of use of HUMULIN U-500 in children. Standard precautions as applied to use of HUMULIN U-500 in adults are appropriate for use in children. As in adults, the dosage of HUMULIN U-500 in pediatric patients must be individualized based on metabolic needs and results of frequent monitoring of blood glucose.. 8.5 Geriatric Use. The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN U-500 has not been studied. Caution should be exercised when HUMULIN U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.. 8.6 Renal Impairment. Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.. 8.7 Hepatic Impairment. Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with Vial Presentation: Can be life-threatening. Overdose has occurred as 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 HUMULIN 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 patients 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 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). Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with Vial Presentation: Can be life-threatening. Overdose has occurred as 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 HUMULIN 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 patients 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 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 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 ErrorsInstruct patients to always inspect insulin vials to confirm that the correct insulin is dispensed including the correct insulin brand and concentration.The HUMULIN U-500 vial, which contains 20 mL, has band of aqua coloring, 500 units/mL concentration statement consisting of white lettering on green rectangular background, and green U-500 statement prominently displayed next to the trade name. Additionally, the vial has green flip top and red warning on the front panel describing the highly concentrated dose and statement advising use with only U-500 insulin syringes.. Prescribing ErrorsDosing errors have occurred when the HUMULIN U-500 dose was administered with syringes other than U-500 insulin syringe. Patients should be prescribed U-500 syringes for use with the HUMULIN U-500 vials. The prescribed dose of HUMULIN U-500 should always be expressed in units of insulin [see Dosage and Administration (2.4)].. Administration ErrorsInstruct patients to always check the insulin label before each injection.Use only U-500 insulin syringe with HUMULIN U-500 to avoid administration errors. Do not use any other type of syringe to administer Humulin 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 U-500 prescribed, in the event of future hospitalization or visit to the emergency department.. 5.2 Never Share HUMULIN U-500 KwikPen or U-500 Insulin Syringe Between Patients. HUMULIN U-500 KwikPens should never be shared between patients, even if the needle is changed. Patients using HUMULIN U-500 vials should never share needles or U-500 insulin syringes with another person. Sharing poses 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 predispose to hypoglycemia [see Warnings and Precautions (5.4)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)].Make any changes to patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type diabetes, adjustments in concomitant oral anti-diabetic treatment may be needed.. 5.4 Hypoglycemia. Hypoglycemia is the most common adverse reaction associated with insulin, including HUMULIN U-500. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of HUMULIN U-500. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving, or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7.3, 7.4)], or in patients who experience recurrent hypoglycemia.. Risk Factors for HypoglycemiaThe timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulin preparations, the glucose lowering effect time course of HUMULIN U-500 may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7.1, 7.2, 7.3, 7.4)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].. Risk Mitigation Strategies for HypoglycemiaPatients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. To minimize the risk of hypoglycemia do not administer HUMULIN U-500 intravenously, intramuscularly or in an insulin pump or dilute or mix HUMULIN U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].. 5.5 Hypersensitivity and Allergic Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMULIN U-500 [see Adverse Reactions (6)]. If hypersensitivity reactions occur, discontinue HUMULIN U-500; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)].. 5.6 Hypokalemia. All insulin products, including HUMULIN U-500, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).. 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists. Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including HUMULIN U-500, and PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.