ustment 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 )

ersensitivity 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 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 a 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 a patient's 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 2 diabetes, adjustments in concomitant oral anti-diabetic treatment may be needed. 5.4 hypoglycemia hypoglycemia is the most common adverse reaction associated with insulins, including humulin r 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 r u-500. hypoglycemia can impair concentration ability and reaction time; this may place the patient 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 patient and change over time in the same patient. symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, 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 hypoglycemia the 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 r 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 concomitant drugs [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 hypoglycemia patients 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 r u-500 intravenously or in an insulin pump or dilute or mix humulin r u-500 with any other insulin products or solutions [see dosage and administration ( 2.1 )] . 5.5 hypersensitivity reactions severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including humulin r u-500. if hypersensitivity reactions occur, discontinue humulin r u-500; treat per standard of care and monitor until symptoms and signs resolve [see adverse reactions ( 6 )] . 5.6 hypokalemia all insulins, including humulin r u-500, cause a 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, when used in combination with insulin. fluid retention may lead to or exacerbate heart failure. patients treated with insulin, including humulin r u-500, and a 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.

ot 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 humulin r u-500 kwikpen shows the number of units of humulin r u-500 to be injected and no dose conversion is required . do not transfer humulin r u-500 from the humulin r u-500 kwikpen into any syringe for administration as overdose and severe hypoglycemia can occur [see warnings and precautions ( 5.4 )]. 2.4 delivery of humulin r u-500 using the vial presentation and the u-500 insulin syringe do not perform dose conversion when using a u-500 insulin syringe. the markings on the u-500 insulin syringe show the number of units of humulin r u-500 to be injected. each marking on the syringe represents 5 units of insulin. prescribe patients a u-500 insulin syringe to administer humulin r u-500 from the vial to avoid administration errors. do not use any other type of syringe [see warnings and precautions ( 5.1 )] .

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.

ustment 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 )

es 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. 8.2 lactation risk summary available data from published literature suggests that exogenous human insulin products, including humulin r u-500, 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 r u-500 on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for humulin r u-500 and any potential adverse effects on the breastfed child from humulin r u-500 or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of humulin r u-500 in pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day to improve glycemic control have been established. use of humulin r u-500 for this indication is supported by evidence from studies with other insulin human in pediatric patients with type 1 diabetes mellitus and from studies in adults with diabetes mellitus. standard precautions as applied to use of humulin r u-500 in adults are appropriate for use in pediatric patients. 8.5 geriatric use the effect of age on the pharmacokinetics and pharmacodynamics of humulin r u-500 has not been studied. caution should be exercised when humulin r 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.

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.

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 a 100 u dose of humulin r u-500 in healthy obese subjects figure 1 12.3 pharmacokinetics absorption — in a euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between 4 hours (50 unit dose) and 8 hours (100 unit dose) with a 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 r u-500. figure 2: mean serum insulin concentrations versus time after subcutaneous injection of a 100 u dose of humulin r u-500 healthy obese subjects figure 2

oom temperature (up to 86°f [30°c]) refrigerated (36° to 46°f [2° to 8°c]) room temperature (up to 86°f [30°c]) refrigerated (36° to 46°f [2° to 8°c]) 20 ml multiple-dose vial a 40 days until expiration date 40 days 40 days 3 ml single-patient-use humulin r u-500 kwikpen b 28 days until expiration date 28 days do not refrigerate.

ould be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of humulin r 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 r u-500 patient information leaflet for additional information [see warnings and precautions ( 5 )] . do not dilute or mix humulin r u-500 with any other insulin products or solutions [see dosage and administration ( 2.1 )] . literature revised: june 2022 manufactured by: eli lilly and company, indianapolis, in 46285, usa us license number 1891 copyright © 1997, 2022, eli lilly and company. all rights reserved. linr500-0009-uspi-20220627

in r u-500? do not take humulin r 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 r u-500. see the end of this patient information leaflet for a complete list of ingredients in humulin r u-500. what should i tell my healthcare provider before using humulin r u-500? before using humulin r 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 r 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 r u-500 may pass into your breast milk. talk with your healthcare provider about the best way to feed your baby while using humulin r 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 r u-500, talk to your healthcare provider about low blood sugar and how to manage it. how should i use humulin r u-500? read the detailed instructions for use that come with your humulin r u-500. use humulin r u-500 exactly as your healthcare provider tells you to. your healthcare provider should tell you how much humulin r u-500 to use and when to use it. know the dose of humulin r u-500 you use. do not change the dose of humulin r 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 r u-500 kwikpen: the humulin r u-500 kwikpen is specially made to dial and deliver doses of humulin r u-500 insulin. do not use any syringe to remove humulin r u-500 from your humulin r u-500 kwikpen. the markings on certain syringes will not measure your dose correctly. a severe overdose can happen, causing low blood sugar, which may put your life in danger. when using the humulin r u-500 vial: there is a special u-500 insulin syringe to measure humulin r u-500. use only a u-500 insulin syringe to draw up and inject your humulin r u-500. if you do not use the right syringe type, you may take the wrong dose of humulin r 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 r u-500. use humulin r u-500 30 minutes before eating a meal. inject humulin r u-500 under the skin (subcutaneously) of your upper legs (thighs), upper arms, buttocks or stomach area (abdomen). do not use humulin r u-500 in an insulin pump or inject humulin r u-500 into your vein (intravenously). do not mix humulin r 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 r u-500 and all medicines out of reach of children. your dose of humulin r u-500 may need to change because of: • 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 i avoid while using humulin r u-500? while using humulin r u-500 do not: drive or operate heavy machinery, until you know how humulin r u-500 affects you. drink alcohol or use over-the-counter medicines that contain alcohol. what are the possible side effects of humulin r u-500? humulin r 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 a glucagon product for emergency use 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 a severe allergic reaction: - a rash over your whole body, have trouble breathing, a fast heartbeat, or sweating. low potassium in your blood (hypokalemia). heart failure. taking certain diabetes pills called thiazolidinediones or “tzds” with humulin r 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 r u-500. your healthcare provider should monitor you closely while you are taking tzds with humulin r 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 r 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 r 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 r 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 r 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 r u-500 medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use humulin r u-500 for a condition for which it was not prescribed. do not give humulin r 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 r 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 r 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 r u-500? active ingredient: insulin human inactive ingredients: glycerin, metacresol, zinc oxide, and water for injection as inactive ingredients. sodium hydroxide and hydrochloric acid may be added to adjust the ph. manufactured by: eli lilly and company, indianapolis, in 46285, usa us license number 1891 for more information about humulin r u-500 go to www.humulin.com. copyright © 2015, 2022, eli lilly and company. all rights reserved.