SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: November 2019Patient InformationHUMALOG(R)(HU-ma-log)insulin lispro injectionU-100 (100 units per mL)for subcutaneous or intravenous useDo not share your Humalog prefilled pens, cartridges, reusable pen compatible with Lilly mL cartridges, needles, or 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 HUMALOGHUMALOG is man-made fast-acting insulin used to control high blood sugar in adults and children with diabetes mellitus.It is not known if HUMALOG is safe and effective in children younger than years of age or when used to treat children with type diabetes mellitus.Who should not take HUMALOGDo not take HUMALOG if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to HUMALOG or any of the ingredients in HUMALOG. See the end of this Patient Information leaflet for complete list of ingredients in HUMALOG.What should tell my healthcare provider before taking HUMALOGBefore taking HUMALOG, tell your healthcare provider about all of your medical conditions, including if you:have kidney or liver problems.take any 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 HUMALOG.are pregnant or plan 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 breastfeeding or plan to breastfeed. Talk with your healthcare provider about the best way to feed your baby while taking HUMALOG. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Before you start taking HUMALOG, talk to your healthcare provider about low blood sugar and how to manage it. How should take HUMALOGRead the Instructions for Use that comes with your HUMALOG.Take HUMALOG exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much HUMALOG to take and when to take it.HUMALOG starts acting fast. Inject HUMALOG within 15 minutes before or right after you eat meal.Know the type, strength and amount of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.Check your insulin label each time you give your injection to make sure you are taking the correct insulin.Inject HUMALOG under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms, or by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump.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. Always use new needle for each injection to help prevent infections and blocked needles. Do not reuse or share your needles with other people. You may give other people serious infection or get serious infection from them.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 HUMALOG and all medicines out of the reach of children.Your dose of HUMALOG may need to change because of a:change in 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 taking HUMALOGWhile taking HUMALOG do not:drive or operate heavy machinery, until you know how HUMALOG affects you.drink alcohol or take prescription or over-the-counter medicines that contain alcohol.What are the possible side effects of HUMALOGHUMALOG 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 light-headednesssweatingconfusionheadacheblurred visionslurred speechshakinessfast heartbeatanxiety, irritability or mood changeshungerYour healthcare provider may prescribe glucagon emergency kit so that someone else can give you glucagon if your blood sugar becomes too low (severe hypoglycemia) and you are unable to take sugar by mouth. serious allergic reactions (whole body allergic reaction). Get medical help right away, if you have any of these signs or symptoms of severe allergic reaction:a rash over your whole bodytrouble breathinga fast heartbeatsweatingfeel faintlow potassium in your blood (hypokalemia).heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with HUMALOG 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 HUMALOG. Your healthcare provider should monitor you closely while you are taking TZDs with HUMALOG. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breathswelling of your ankles or feetsudden weight gainTreatment with TZDs and HUMALOG 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: trouble breathingshortness of breathfast heartbeatswelling of your face, tongue, or throatsweatingextreme drowsinessdizzinessconfusionThe most common side effects of HUMALOG include:low blood sugar (hypoglycemia)reactions at your injection siteskin thickening or pits at the injection site (lipodystrophy)weight gainswelling in your hands or feetitchingrashThese are not all the possible side effects of HUMALOG. 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 HUMALOG.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not take HUMALOG for condition for which it was not prescribed. Do not give HUMALOG to other people, even if they have the same symptoms that you have. It may harm them.This Patient Information leaflet summarizes the most important information about HUMALOG. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about HUMALOG that is written for health professionals.What are the ingredients in HUMALOGActive ingredient: insulin lispro Inactive ingredients: dibasic sodium phosphate, glycerin, metacresol, zinc oxide (zinc ion), trace amounts of phenol and Water for Injection, USP.Humalog(R) is registered 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.For more information, go to www.humalog.com or call 1-800-545-5979.LOG-0006-PPI-20191115. HUMALOG is man-made fast-acting insulin used to control high blood sugar in adults and children with diabetes mellitus.. It is not known if HUMALOG is safe and effective in children younger than years of age or when used to treat children with type diabetes mellitus.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to HUMALOG or any of the ingredients in HUMALOG. See the end of this Patient Information leaflet for complete list of ingredients in HUMALOG.. have kidney or liver problems.. take any 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 HUMALOG.. are pregnant or plan 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 breastfeeding or plan to breastfeed. Talk with your healthcare provider about the best way to feed your baby while taking HUMALOG. Read the Instructions for Use that comes with your HUMALOG.. Take HUMALOG exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much HUMALOG to take and when to take it.. HUMALOG starts acting fast. Inject HUMALOG within 15 minutes before or right after you eat meal.. Know the type, strength and amount of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.. Check your insulin label each time you give your injection to make sure you are taking the correct insulin.. Inject HUMALOG under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms, or by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump.. 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.. Always use new needle for each injection to help prevent infections and blocked needles. Do not reuse or share your needles with other people. You may give other people serious infection or get serious infection from them.. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. change in physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.. drive or operate heavy machinery, until you know how HUMALOG affects you.. drink alcohol or take prescription or over-the-counter medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include: dizziness or light-headedness. sweating. confusion. headache. blurred vision. slurred speech. shakiness. fast heartbeat. anxiety, irritability or mood changes. hunger. serious allergic reactions (whole body allergic reaction). Get medical help right away, if you have any of these signs or symptoms of severe allergic reaction:. rash over your whole body. trouble breathing. fast heartbeat. sweating. feel faint. low potassium in your blood (hypokalemia).. heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with HUMALOG 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 HUMALOG. Your healthcare provider should monitor you closely while you are taking TZDs with HUMALOG. 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. trouble breathing. shortness of breath. fast heartbeat. swelling of your face, tongue, or throat. sweating. extreme drowsiness. dizziness. confusion. low blood sugar (hypoglycemia). reactions at your injection site. skin thickening or pits at the injection site (lipodystrophy). weight gain. swelling in your hands or feet. itching. rash.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adverse reactions associated with HUMALOG include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash. (6.1)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.. Observed with HUMALOG U-100The following adverse reactions are discussed elsewhere:Hypoglycemia [see Warnings and Precautions (5.3)].Hypokalemia [see Warnings and Precautions (5.6)].. Hypoglycemia [see Warnings and Precautions (5.3)].. Hypokalemia [see Warnings and Precautions (5.6)].. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.The frequencies of Treatment-Emergent Adverse Events during HUMALOG clinical trials in patients with type diabetes mellitus and type diabetes mellitus are listed in the tables below.Table 1: Treatment-Emergent Adverse Events in Patients with Type Diabetes Mellitus (adverse events with frequency >=5%)Events, (%)Lispro(n=81)Regular human insulin(n=86)Flu syndrome28 (34.6)28 (32.6)Pharyngitis27 (33.3)29 (33.7)Rhinitis20 (24.7)25 (29.1)Headache24 (29.6)19 (22.1)Pain16 (19.8)14 (16.3)Cough increased14 (17.3)15 (17.4)Infection11 (13.6)18 (20.9)Nausea5 (6.2)13 (15.1)Accidental injury7 (8.6)10 (11.6)Surgical procedure5 (6.2)12 (14.0)Fever5 (6.2)10 (11.6)Abdominal pain6 (7.4)7 (8.1)Asthenia6 (7.4)7 (8.1)Bronchitis6 (7.4)6 (7.0)Diarrhea7 (8.6)5 (5.8)Dysmenorrhea5 (6.2)6 (7.0)Myalgia6 (7.4)5 (5.8)Urinary tract infection5 (6.2)4 (4.7)Table 2: Treatment-Emergent Adverse Events in Patients with Type Diabetes Mellitus (adverse events with frequency >=5%)Events, (%)Lispro(n=714)Regular human insulin(n=709)Headache83 (11.6)66 (9.3)Pain77 (10.8)71 (10.0)Infection72 (10.1)54 (7.6)Pharyngitis47 (6.6)58 (8.2)Rhinitis58 (8.1)47 (6.6)Flu syndrome44 (6.2)58 (8.2)Surgical procedure53 (7.4)48 (6.8). Insulin initiation and intensification of glucose controlIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.. LipodystrophyLong-term use of insulin, including HUMALOG, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.2)].. Weight gainWeight gain can occur with insulin therapy, including HUMALOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.. Peripheral EdemaInsulin, including HUMALOG, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.. Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) -- HUMALOG U-100In 12-week, randomized, crossover study in adult patients with type diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for HUMALOG U-100 and regular human insulin treated patients (see Table 3).Table 3: Catheter Occlusions and Infusion Site ReactionsHUMALOG U-100(n=38)Regular human insulin(n=39)Catheter occlusions/month0.090.10Infusion site reactions2.6% (1/38)2.6% (1/39)In randomized, 16-week, open-label, parallel design study of children and adolescents with type diabetes, adverse event reports related to infusion-site reactions were similar for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site adverse events were infusion site erythema and infusion site reaction.. Allergic Reactions. Local Allergy -- As with any insulin therapy, patients taking HUMALOG may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in few days to few weeks, but in some occasions, may require discontinuation of HUMALOG. In some instances, these reactions may be related to factors other than insulin, such as irritants in skin cleansing agent or poor injection technique.. Systemic Allergy -- Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including HUMALOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving HUMALOG (n=2944).Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in HUMALOG [see Contraindications (4)].. Antibody ProductionIn large clinical trials with patients with type (n=509) and type (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and HUMALOG (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study. These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types.. 6.2 Postmarketing Experience. HUMALOG U-100The following additional adverse reactions have been identified during post-approval use of HUMALOG. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Medication errors in which other insulins have been accidentally substituted for HUMALOG have been identified during post-approval use [see Patient Counseling Information (17)].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 sudden change to an unaffected injection site.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro. 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. HUMALOG has been shown to be equipotent to human insulin on molar basis. One unit of HUMALOG has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that HUMALOG has more rapid onset of action and shorter duration of activity than regular human insulin when given subcutaneously.The time course of action of insulin and insulin analogs, such as HUMALOG, may vary considerably in different individuals or within the same individual. The parameters of HUMALOG activity (time of onset, peak time, and duration) as designated in Figure should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.2)].Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before High Carbohydrate Meal in 10 Patients with Type Diabetesa.a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.. Figure 1. Intravenous Administration of HUMALOG U-100 -- The glucose lowering effect of intravenously administered HUMALOG was tested in 21 patients with type diabetes. For the study, the patients usual doses of insulin were held and blood glucose concentrations were allowed to reach stable range of 200 to 260 mg/dL during one to three hours run-in phase. The run-in phase was followed by 6-hour assessment phase. During the assessment phase, patients received intravenous HUMALOG at an initial infusion rate of 0.5 units/hour. The infusion rate of HUMALOG could be adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL.The mean blood glucose levels during the assessment phase for patients on HUMALOG therapy are summarized below in Table 4. All patients achieved the targeted glucose range at some point during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 17 of 20 patients treated with HUMALOG. The average time (+-SE) required to attain near normoglycemia was 129 +- 14 minutes for HUMALOG.Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of HUMALOG U-100a Results shown as mean +- SDTime from Start of Infusion (minutes)Mean Blood Glucose (mg/dL) Intravenousa 0224 +- 1630205 +- 2160195 +- 20120165 +- 26180140 +- 26240123 +- 20300120 +- 27360122 +- 25The pharmacodynamics of single 20 unit dose of HUMALOG U-200 administered subcutaneously were compared to the pharmacodynamics of single 20 unit dose of HUMALOG U-100 administered subcutaneously in euglycemic clamp study enrolling healthy subjects. In this study, the overall, maximum, and time to maximum glucose lowering effect were similar between HUMALOG U-200 and HUMALOG U-100. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) were 125 and 126 for HUMALOG U-200 and HUMALOG U-100, respectively. The maximum glucose infusion rate was 534 mg/min and 559 mg/min and the corresponding median time (min, max) to maximum effect were 2.8 (0.5 - 6.3 h) and 2.4 (0.5 - 4.7 h) for HUMALOG U-200 and HUMALOG U-100, respectively.. 12.3 Pharmacokinetics. Absorption and Bioavailability -- Studies in healthy volunteers and patients with diabetes demonstrated that HUMALOG is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of HUMALOG ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type diabetes (see Figure 2).Figure 2: Serum HUMALOG and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before High Carbohydrate Meal in 10 Patients with Type Diabetesa.a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.HUMALOG U-100 was absorbed at consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After HUMALOG was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of HUMALOG is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.The results of study in healthy subjects demonstrated that HUMALOG U-200 is bioequivalent to HUMALOG U-100 following administration of single 20 unit dose.The mean observed area under the serum insulin concentration-time curve from time zero to infinity was 2360 pmol hr/L and 2390 pmol hr/L for HUMALOG U-200 and HUMALOG U-100, respectively. The corresponding mean peak serum insulin concentration was 795 pmol/L and 909 pmol/L for HUMALOG U-200 and HUMALOG U-100, respectively. The median time to maximum concentration was 1.0 hour for both formulations.. Figure 2. Distribution -- When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of HUMALOG appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively).. Metabolism -- Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of HUMALOG is identical to that of regular human insulin.. Elimination -- After subcutaneous administration of HUMALOG, the t1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, HUMALOG and regular human insulin demonstrated similar dose-dependent clearance, with mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). Accordingly, HUMALOG demonstrated mean t1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses.. Specific PopulationsThe effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMALOG have not been studied.. Renal Impairment -- Type diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and HUMALOG. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including HUMALOG, may be necessary in patients with renal dysfunction.. Hepatic Impairment -- Type diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of HUMALOG as compared to patients with no hepatic dysfunction. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including HUMALOG, may be necessary in patients with hepatic dysfunction.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of HUMALOG U-100 were studied in children, adolescent, and adult patients with type diabetes (n=789) and adult patients with type diabetes (n=722).. 14.1 Type Diabetes Adults and Adolescents. 12-month, randomized, parallel, open-label, active-controlled study was conducted in patients with type diabetes to assess the safety and efficacy of HUMALOG (n=81) compared with Humulin(R) [insulin human injection (100 units per mL)] (n=86). HUMALOG was administered by subcutaneous injection immediately prior to meals and Humulin was administered 30 to 45 minutes before meals. Humulin(R) [ULTRALENTE(R) human insulin (rDNA origin) extended zinc suspension] was administered once or twice daily as the basal insulin. There was 2- to 4-week run-in period with Humulin and Humulin before randomization. Most patients were Caucasian (97%). Forty-seven percent of the patients were male. The mean age was 31 years (range 12 to 70 years). Glycemic control, the total daily doses of HUMALOG and Humulin R, and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar in the two treatment groups. There were no episodes of diabetic ketoacidosis in either treatment group.Table 5: Type Diabetes Mellitus Adults and Adolescentsa Values are Mean +- SDb Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat.Treatment DurationTreatment in Combination with:12 monthsHumulin UHUMALOGHumulin RN8186Baseline HbA1c (%)a 8.2 +- 1.48.3 +- 1.7Change from baseline HbA1c (%)a -0.1 +- 0.90.1 +- 1.1Treatment Difference in HbA1c Mean (95% confidence interval)0.4 (0.0, 0.8)Baseline short-acting insulin dose (units/kg/day)0.3 +- 0.10.3 +- 0.1End-of-Study short-acting insulin dose (units/kg/day)0.3 +- 0.10.3 +- 0.1Change from baseline short-acting insulin dose (units/kg/day)0.0 +- 0.10.0 +- 0.1Baseline Body weight (kg)72 +- 12.771 +- 11.3Weight change from baseline (kg)1.4 +- 3.61.0 +- 2.6Patients with severe hypoglycemia (n, %)b 14 (17%)18 (21%). 14.2 Type Diabetes Adults. 6-month randomized, crossover, open-label, active-controlled study was conducted in insulin-treated patients with type diabetes (n=722) to assess the safety and efficacy of HUMALOG for months followed by Humulin for months or the reverse sequence. HUMALOG was administered by subcutaneous injection immediately before meals and Humulin was administered 30 to 45 minutes before meals. Humulin(R) [NPH human insulin (rDNA origin) isophane suspension] or Humulin was administered once or twice daily as the basal insulin. All patients participated in 2- to 4-week run-in period with Humulin and Humulin or Humulin U. Most of the patients were Caucasian (88%), and the numbers of men and women in each group were approximately equal. The mean age was 58.6 years (range 23.8 to 85 years). The average body mass index (BMI) was 28.2 kg/m2. During the study, the majority of patients used Humulin (84%) compared with Humulin (16%) as their basal insulin. The reductions from baseline in HbA1c and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar between the two treatments from the combined groups (see Table 6).Table 6: Type Diabetes Mellitus -- Adultsa Values are Mean +- SDb Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat.End pointBaselineHUMALOG+BasalHumulin R+BasalHbA1c (%)a 8.9 +- 1.78.2 +- 1.38.2 +- 1.4Change from baseline HbA1c (%)a ---0.7 +- 1.4-0.7 +- 1.3Short-acting insulin dose (units/kg/day)a 0.3 +- 0.20.3 +- 0.20.3 +- 0.2Change from baseline short-acting insulin dose (units/kg/day)a --0.0 +- 0.10.0 +- 0.1Body weight (kg)a 80 +- 1581 +- 1581 +- 15Weight change from baseline--0.8 +- 2.70.9 +- 2.6Patients with severe hypoglycemia (n, %)b --15 (2%)16 (2%). 14.3 Type Diabetes Pediatric and Adolescents. An 8-month, crossover study of adolescents with type diabetes (n=463), aged to 19 years, compared two subcutaneous multiple-dose treatment regimens: HUMALOG or Humulin R, both administered with Humulin (NPH human insulin) as the basal insulin. HUMALOG achieved glycemic control comparable to Humulin R, as measured by HbA1c (see Table 7), and both treatment groups had comparable incidence of hypoglycemia. In 9-month, crossover study of prepubescent children (n=60) with type diabetes, aged to 11 years, HUMALOG administered immediately before meals, HUMALOG administered immediately after meals and Humulin administered 30 minutes before meals resulted in similar glycemic control, as measured by HbA1c, and incidence of hypoglycemia, regardless of treatment group.Table 7: Pediatric Subcutaneous Administration of HUMALOG in Type Diabetesa Values are Mean +- SDb Severe hypoglycemia refers to hypoglycemia that required glucagon or glucose injection or resulted in coma.End pointBaselineHUMALOG+NPHHumulin R+NPHHbA1c (%)a 8.6 +- 1.58.7 +- 1.58.7 +- 1.6Change from baseline HbA1c (%)a --0.1 +- 1.10.1 +- 1.3Short-acting insulin dose (units/kg/day)a 0.5 +- 0.20.5 +- 0.20.5 +- 0.2Change from baseline short-acting insulin dose (units/kg/day)a --0.01 +- 0.1-0.01 +- 0.1Body weight (kg)a 59.1 +- 13.161.1 +- 12.761.4 +- 12.9Weight change from baseline (kg)a --2.0 +- 3.12.3 +- 3.0Patients with severe hypoglycemia (n, %)b --5 (1.1%)5 (1.1%)Diabetic ketoacidosis (n, %)--11 (2.4%)9 (1.9%). 14.4 Type Diabetes Adults Continuous Subcutaneous Insulin Infusion. To evaluate the administration of HUMALOG U-100 via external insulin pumps, two open-label, crossover design studies were performed in patients with type diabetes. One study involved 39 patients, ages 19 to 58 years, treated for 24 weeks with HUMALOG or regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.8% to 7.2% in the HUMALOG-treated patients and from 7.8% to 7.5% in the regular human insulin-treated patients. Another study involved 60 patients (mean age 39, range 15 to 58 years) treated for 24 weeks with either HUMALOG or buffered regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.7% to 7.4% in the HUMALOG-treated patients and remained unchanged from 7.7% in the buffered regular human insulin-treated patients. Rates of hypoglycemia were comparable between treatment groups in both studies.. 14.5 Type Diabetes Pediatric Continuous Subcutaneous Insulin Infusion. randomized, 16-week, open-label, parallel design, study of children and adolescents with type diabetes (n=298) aged to 18 years compared two subcutaneous infusion regimens administered via an external insulin pump: insulin aspart (n=198) or HUMALOG U-100 (n=100). These two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of hypoglycemia after 16 weeks of treatment (see Table 8). Infusion site reactions were similar between groups.Table 8: Pediatric Insulin Pump Study in Type Diabetes (16 weeks; n=298)a Values are Mean +- SDb Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.HUMALOGAspartN100198Baseline HbA1c (%)a 8.2 +- 0.88.0 +- 0.9Change from Baseline HbA1c (%)-0.1 +- 0.7-0.1 +- 0.8Treatment Difference in HbA1c, Mean (95% confidence interval)0.1 (-0.3, 0.1)Baseline insulin dose (units/kg/24 hours)a 0.9 +- 0.30.9 +- 0.3End-of-Study insulin dose (units/kg/24 hours)a 0.9 +- 0.20.9 +- 0.2Patients with severe hypoglycemia (n, %)b (8%)19 (10%)Diabetic ketoacidosis (n, %)0 (0)1 (0.5%)Baseline body weight (kg)a 55.5 +- 19.054.1 +- 19.7Weight Change from baseline (kg)a 1.6 +- 2.11.8 +- 2.1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.The frequencies of Treatment-Emergent Adverse Events during HUMALOG clinical trials in patients with type diabetes mellitus and type diabetes mellitus are listed in the tables below.Table 1: Treatment-Emergent Adverse Events in Patients with Type Diabetes Mellitus (adverse events with frequency >=5%)Events, (%)Lispro(n=81)Regular human insulin(n=86)Flu syndrome28 (34.6)28 (32.6)Pharyngitis27 (33.3)29 (33.7)Rhinitis20 (24.7)25 (29.1)Headache24 (29.6)19 (22.1)Pain16 (19.8)14 (16.3)Cough increased14 (17.3)15 (17.4)Infection11 (13.6)18 (20.9)Nausea5 (6.2)13 (15.1)Accidental injury7 (8.6)10 (11.6)Surgical procedure5 (6.2)12 (14.0)Fever5 (6.2)10 (11.6)Abdominal pain6 (7.4)7 (8.1)Asthenia6 (7.4)7 (8.1)Bronchitis6 (7.4)6 (7.0)Diarrhea7 (8.6)5 (5.8)Dysmenorrhea5 (6.2)6 (7.0)Myalgia6 (7.4)5 (5.8)Urinary tract infection5 (6.2)4 (4.7)Table 2: Treatment-Emergent Adverse Events in Patients with Type Diabetes Mellitus (adverse events with frequency >=5%)Events, (%)Lispro(n=714)Regular human insulin(n=709)Headache83 (11.6)66 (9.3)Pain77 (10.8)71 (10.0)Infection72 (10.1)54 (7.6)Pharyngitis47 (6.6)58 (8.2)Rhinitis58 (8.1)47 (6.6)Flu syndrome44 (6.2)58 (8.2)Surgical procedure53 (7.4)48 (6.8). Insulin initiation and intensification of glucose controlIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.. LipodystrophyLong-term use of insulin, including HUMALOG, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.2)].. Weight gainWeight gain can occur with insulin therapy, including HUMALOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.. Peripheral EdemaInsulin, including HUMALOG, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.. Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) -- HUMALOG U-100In 12-week, randomized, crossover study in adult patients with type diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for HUMALOG U-100 and regular human insulin treated patients (see Table 3).Table 3: Catheter Occlusions and Infusion Site ReactionsHUMALOG U-100(n=38)Regular human insulin(n=39)Catheter occlusions/month0.090.10Infusion site reactions2.6% (1/38)2.6% (1/39)In randomized, 16-week, open-label, parallel design study of children and adolescents with type diabetes, adverse event reports related to infusion-site reactions were similar for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site adverse events were infusion site erythema and infusion site reaction.. Allergic Reactions. Local Allergy -- As with any insulin therapy, patients taking HUMALOG may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in few days to few weeks, but in some occasions, may require discontinuation of HUMALOG. In some instances, these reactions may be related to factors other than insulin, such as irritants in skin cleansing agent or poor injection technique.. Systemic Allergy -- Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including HUMALOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving HUMALOG (n=2944).Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in HUMALOG [see Contraindications (4)].. Antibody ProductionIn large clinical trials with patients with type (n=509) and type (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and HUMALOG (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study. These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. See Full Prescribing Information for important administration instructions. (2.1, 2.2, 2.3, 2.4)Subcutaneous injection (2.2):Administer HUMALOG(R) U-100 or U-200 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks within 15 minutes before meal or immediately after meal.Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Continuous subcutaneous infusion (Insulin Pump) (2.2):Administer HUMALOG U-100 by continuous subcutaneous infusion using an insulin pump in region recommended in the instructions from the pump manufacturer.Rotate infusion sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.DO NOT administer HUMALOG U-200 by continuous subcutaneous infusion. Intravenous Infusion (2.2):Administer HUMALOG U-100 by intravenous infusion ONLY after dilution and under medical supervision. DO NOT administer HUMALOG U-200 by intravenous infusion. The dosage of HUMALOG must be individualized based on the route of administration and the individuals metabolic needs, blood glucose monitoring results and glycemic control goal. (2.3)Do not perform dose conversion when using the HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. (2.1, 2.3)Do not mix HUMALOG U-200 with any other insulin. (2.4). See Full Prescribing Information for important administration instructions. (2.1, 2.2, 2.3, 2.4). Subcutaneous injection (2.2):Administer HUMALOG(R) U-100 or U-200 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks within 15 minutes before meal or immediately after meal.Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Administer HUMALOG(R) U-100 or U-200 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks within 15 minutes before meal or immediately after meal.. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.. Continuous subcutaneous infusion (Insulin Pump) (2.2):Administer HUMALOG U-100 by continuous subcutaneous infusion using an insulin pump in region recommended in the instructions from the pump manufacturer.Rotate infusion sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.DO NOT administer HUMALOG U-200 by continuous subcutaneous infusion. Administer HUMALOG U-100 by continuous subcutaneous infusion using an insulin pump in region recommended in the instructions from the pump manufacturer.. Rotate infusion sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.. DO NOT administer HUMALOG U-200 by continuous subcutaneous infusion.. Intravenous Infusion (2.2):Administer HUMALOG U-100 by intravenous infusion ONLY after dilution and under medical supervision. DO NOT administer HUMALOG U-200 by intravenous infusion. Administer HUMALOG U-100 by intravenous infusion ONLY after dilution and under medical supervision. DO NOT administer HUMALOG U-200 by intravenous infusion.. The dosage of HUMALOG must be individualized based on the route of administration and the individuals metabolic needs, blood glucose monitoring results and glycemic control goal. (2.3). Do not perform dose conversion when using the HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. (2.1, 2.3). Do not mix HUMALOG U-200 with any other insulin. (2.4). 2.1 Important Administration Instructions. Always check insulin labels before administration [see Warnings and Precautions (5.4)]. Inspect HUMALOG visually before use. It should appear clear and colorless. Do not use HUMALOG if particulate matter or coloration is seen.Use HUMALOG prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.Do NOT mix HUMALOG U-100 with other insulins when administering using continuous subcutaneous infusion pump.Do NOT transfer HUMALOG U-200 from the prefilled pen to syringe for administration [see Warnings and Precautions (5.4)]. Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. Do NOT mix HUMALOG U-200 with any other insulins.Do NOT administer HUMALOG U-200 using continuous subcutaneous infusion pump (i.e., insulin pump).Do NOT administer HUMALOG U-200 intravenously.. Always check insulin labels before administration [see Warnings and Precautions (5.4)]. Inspect HUMALOG visually before use. It should appear clear and colorless. Do not use HUMALOG if particulate matter or coloration is seen.. Use HUMALOG prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.. Do NOT mix HUMALOG U-100 with other insulins when administering using continuous subcutaneous infusion pump.. Do NOT transfer HUMALOG U-200 from the prefilled pen to syringe for administration [see Warnings and Precautions (5.4)]. Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. Do NOT mix HUMALOG U-200 with any other insulins.. Do NOT administer HUMALOG U-200 using continuous subcutaneous infusion pump (i.e., insulin pump).. Do NOT administer HUMALOG U-200 intravenously.. 2.2 Route of Administration. Subcutaneous Injection: HUMALOG U-100 or U-200Administer the dose of HUMALOG U-100 or HUMALOG U-200 within fifteen minutes before meal or immediately after meal by injection into the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. To reduce the risk of lipodystrophy and localized cutaneous amyloidosis, rotate the injection site within the same region from one injection to the next. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].HUMALOG administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.The HUMALOG U-100 KwikPen, HUMALOG U-100 Tempo Pen and HUMALOG U-200 KwikPen each dial in unit increments and delivers maximum dose of 60 units per injection.The HUMALOG U-100 Junior KwikPen dials in 0.5 unit increments and delivers maximum does of 30 units per injection.. Administer the dose of HUMALOG U-100 or HUMALOG U-200 within fifteen minutes before meal or immediately after meal by injection into the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. To reduce the risk of lipodystrophy and localized cutaneous amyloidosis, rotate the injection site within the same region from one injection to the next. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].. During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].. HUMALOG administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.. The HUMALOG U-100 KwikPen, HUMALOG U-100 Tempo Pen and HUMALOG U-200 KwikPen each dial in unit increments and delivers maximum dose of 60 units per injection.. The HUMALOG U-100 Junior KwikPen dials in 0.5 unit increments and delivers maximum does of 30 units per injection.. Continuous Subcutaneous Infusion (Insulin Pump): HUMALOG U-100 ONLYDo NOT administer HUMALOG U-200 using continuous subcutaneous infusion pump.Administer HUMALOG U-100 by continuous subcutaneous infusion in region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].Follow healthcare professional recommendations when setting basal and meal time infusion rate.Do NOT dilute or mix HUMALOG U-100 when administering by continuous subcutaneous infusion.Change HUMALOG U-100 in the pump reservoir at least every days.Change the infusion sets and the infusion set insertion site at least every days.Do NOT expose HUMALOG U-100 in the pump reservoir to temperatures greater than 98.6F (37C).Use HUMALOG U-100 in pump systems suitable for insulin infusion [see Patient Counseling Information (17)].. Do NOT administer HUMALOG U-200 using continuous subcutaneous infusion pump.. Administer HUMALOG U-100 by continuous subcutaneous infusion in region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].. During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].. Follow healthcare professional recommendations when setting basal and meal time infusion rate.. Do NOT dilute or mix HUMALOG U-100 when administering by continuous subcutaneous infusion.. Change HUMALOG U-100 in the pump reservoir at least every days.. Change the infusion sets and the infusion set insertion site at least every days.. Do NOT expose HUMALOG U-100 in the pump reservoir to temperatures greater than 98.6F (37C).. Use HUMALOG U-100 in pump systems suitable for insulin infusion [see Patient Counseling Information (17)].. Intravenous Administration: HUMALOG U-100 ONLYDo NOT administer HUMALOG U-200 intravenously.Dilute HUMALOG U-100 to concentrations from 0.1 unit/mL to 1.0 unit/mL using 0.9% Sodium Chloride Injection, USP.Administer HUMALOG U-100 intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6) and How Supplied/Storage and Handling (16.4)].. Do NOT administer HUMALOG U-200 intravenously.. Dilute HUMALOG U-100 to concentrations from 0.1 unit/mL to 1.0 unit/mL using 0.9% Sodium Chloride Injection, USP.. Administer HUMALOG U-100 intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6) and How Supplied/Storage and Handling (16.4)].. 2.3 Dosage Information. Individualize and adjust the dosage of HUMALOG based on route of administration, the individuals 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 or during acute illness [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.6, 8.7)].Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed.. Individualize and adjust the dosage of HUMALOG based on route of administration, the individuals 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 or during acute illness [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.6, 8.7)].. Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed.. 2.4 Dosage Adjustment Due to Drug Interactions. Dosage adjustment may be needed when HUMALOG is coadministered with certain drugs [see Drug Interactions (7)].Dosage adjustment may be needed when switching from another insulin to HUMALOG [see Warnings and Precautions (5.2)].Instructions for Mixing with Other InsulinsHUMALOG U-100 subcutaneous injection routeHUMALOG U-100 may be mixed with NPH insulin preparations ONLY.If HUMALOG U-100 is mixed with NPH insulin, HUMALOG U-100 should be drawn into the syringe first. Injection should occur immediately after mixing.HUMALOG U-100 continuous subcutaneous infusion route (Insulin Pump)Do NOT mix HUMALOG U-100 with any other insulin.HUMALOG U-200 subcutaneous injection routeDo NOT mix with any other insulin.. Dosage adjustment may be needed when HUMALOG is coadministered with certain drugs [see Drug Interactions (7)].. Dosage adjustment may be needed when switching from another insulin to HUMALOG [see Warnings and Precautions (5.2)].. Instructions for Mixing with Other Insulins. HUMALOG U-100 may be mixed with NPH insulin preparations ONLY.. If HUMALOG U-100 is mixed with NPH insulin, HUMALOG U-100 should be drawn into the syringe first. Injection should occur immediately after mixing.. Do NOT mix HUMALOG U-100 with any other insulin.. Do NOT mix with any other insulin.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. HUMALOG (insulin lispro injection) is clear and colorless solution available as:a Tempo Pen contains component that allows for data connectivity when used with compatible transmitter.HUMALOGTotal VolumeConcentrationTotal Units Available in PresentationNDC NumberPackage SizeU-100 multiple-dose vial10 mL100 units/mL1000 units0002-7510-011 vialU-100 multiple-dose vial3 mL100 units/mL300 units0002-7510-171 vialU-100 single-patient-use cartridge1 mL100 units/mL300 units0002-7516-595 cartridgesU-100 single-patient-use KwikPen3 mL100 units/mL300 units0002-8799-595 pensU-100 single-patient-use Tempo Pena mL100 units/mL300 units0002-8213-055 pensU-100 single-patient-use Junior KwikPen3 mL100 units/mL300 units0002-7714-595 pensU-200 single-patient-use KwikPen3 mL200 units/mL600 units0002-7712-272 pensThe U-100 KwikPen, U-100 Tempo Pen, and U-200 KwikPen dial in unit increments. The U-100 Junior KwikPen dials in 0.5 unit increments.Each prefilled pen, cartridge, and reusable pen compatible with Lilly mL cartridges is for single-patient-use only. HUMALOG prefilled pens, cartridges, and reusable pens compatible with Lilly mL cartridges must never be shared between patients, even if the needle is changed. Patients using HUMALOG vials must never share needles or syringes with another person.. 16.2 Storage and Handling. Dispense in the original sealed carton with the enclosed Instructions for Use.Do not use after the expiration date.Unopened HUMALOG should be stored in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use HUMALOG if it has been frozen. In-use HUMALOG vials, cartridges, and HUMALOG prefilled pens should be stored at room temperature, below 86F (30C) and must be used within 28 days or be discarded, even if they still contain HUMALOG. Protect from direct heat and light. See table below:Not In-Use (Unopened) Room Temperature (Below 86F [30C])Not In-Use (Unopened) RefrigeratedIn-Use (Opened) Room Temperature, (Below 86F [30C])HUMALOG U-10010 mL multiple-dose vial28 daysUntil expiration date28 days, refrigerated/room temperature.3 mL multiple-dose vial28 daysUntil expiration date28 days, refrigerated/room temperature.3 mL single-patient-use cartridge28 daysUntil expiration date28 days, Do not refrigerate.3 mL single-patient-use Humalog KwikPen28 daysUntil expiration date28 days, Do not refrigerate.3 mL single-patient-use Humalog Tempo Pen28 daysUntil expiration date28 days, Do not refrigerate.3 mL single-patient-use Humalog Junior KwikPen28 daysUntil expiration date28 days, Do not refrigerate.HUMALOG U-2003 mL single-patient use Humalog KwikPen28 daysUntil expiration date28 days, Do not refrigerate.. Use in an External Insulin Pump -- Change the HUMALOG U-100 in the reservoir at least every days, change the infusion sets and the infusion set insertion site at least every days or after exposure to temperatures that exceed 98.6F (37C). HUMALOG mL cartridge used in the D-Tron pumps should be discarded after days, even if it still contains HUMALOG. However, as with other external insulin pumps, the infusion set should be replaced and new infusion set insertion site should be selected at least every days.. Diluted HUMALOG U-100 for Subcutaneous Injection -- Diluted HUMALOG may remain in patient use for 28 days when stored at 41F (5C) and for 14 days when stored at 86F (30C). Do not dilute HUMALOG contained in cartridge or HUMALOG used in an external insulin pump.. 16.3 Preparation and Handling. Diluted HUMALOG U-100 for Subcutaneous Injection -- HUMALOG may be diluted with Sterile Diluent for HUMALOG for subcutaneous injection. Diluting one part HUMALOG to nine parts diluent will yield concentration one-tenth that of HUMALOG (equivalent to U-10). Diluting one part HUMALOG to one part diluent will yield concentration one-half that of HUMALOG (equivalent to U-50).. 16.4 Admixture for Intravenous Administration. Infusion bags prepared with HUMALOG U-100 are stable when stored in refrigerator (2 to 8C [36 to 46F]) for 48 hours and then may be used at room temperature for up to an additional 48 hours [see Dosage and Administration (2.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Never Share HUMALOG Prefilled Pen, Cartridge, Reusable Pen Compatible with Lilly mL Cartridges, or Syringe Between PatientsAdvise patients that they must never share HUMALOG prefilled pen, cartridge, or reusable pen compatible with Lilly mL cartridges with another person, even if the needle is changed. Advise patients using HUMALOG vials not to share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].. Hyperglycemia or HypoglycemiaInstruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMALOG therapy. Instruct patients 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. Instruct patients on the management of hypoglycemia.Inform patients that their ability to concentrate and react may be impaired as result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)].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 [see Warnings and Precautions (5.2)].. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions have occurred with HUMALOG. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].. Medication ErrorsInstruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products.Inform patients that HUMALOG U-200 contains times as much insulin in mL as HUMALOG U-100.Inform patients that the HUMALOG U-200 KwikPen dose window shows the number of units of HUMALOG U-200 to be injected and that no dose conversion is required.Instruct patients to NOT transfer HUMALOG U-200 from the HUMALOG KwikPen to syringe. The markings on the syringe will not measure the dose correctly and this can result in overdosage and severe hypoglycemia.. Administration Instruction for HUMALOG U-200Instruct patients to NOT mix HUMALOG U-200 with any other insulin.. Instructions For Patients Using Continuous Subcutaneous Insulin PumpsPatients using external pump infusion therapy should be trained appropriately.The following insulin pumps have been tested in HUMALOG clinical trials conducted by Eli Lilly and Company.Disetronic(R) H-Tron(R) plus V100, D-Tron(R) and D-Tronplus(R) with Disetronic Rapid infusion sets2 MiniMed(R) Models 506, 507 and 508 and Polyfin(R) infusion sets3 HUMALOG is recommended for use in pump systems suitable for insulin infusion such as MiniMed, Disetronic, and other equivalent pumps. Before using HUMALOG in pump system, read the pump label to make sure the pump is indicated for continuous delivery of fast-acting insulin. HUMALOG is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump. Please see recommended reservoir and infusion sets in the pump manual. Do not use HUMALOG U-200 in an external insulin pump.To avoid insulin degradation, infusion set occlusion, and loss of the preservative (metacresol), insulin in the reservoir should be replaced at least every days; infusion sets and infusion set insertion sites should be changed at least every days.Insulin exposed to temperatures higher than 98.6F (37C) should be discarded. The temperature of the insulin may exceed ambient temperature when the pump housing, cover, tubing or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous, pruritic, or thickened should be reported to the healthcare professional, and new site selected because continued infusion may increase the skin reaction or alter the absorption of HUMALOG.Pump or infusion set malfunctions or insulin degradation can lead to rapid hyperglycemia and ketosis. This is especially pertinent for rapid acting insulin analogs that are more rapidly absorbed through skin and have shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump malfunction may occur. If these problems cannot be promptly corrected, patients should resume therapy with subcutaneous insulin injection and contact their healthcare professionals [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16.2)].1 mL cartridge is for use in Eli Lilly and Companys HumaPen(R) Luxura(R) HD insulin delivery device, and Disetronic D-TRON(R) and D-TRON(R) Plus pumps. Humalog(R), Humalog KwikPen(R), Humalog Tempo Pen(TM) ,Humalog(R) Junior KwikPen(R), HumaPen(R), HumaPen(R) Luxura(R) and HumaPen(R) Luxura(R) HD are trademarks of Eli Lilly and Company.2 Disetronic(R), H-Tron(R), D-Tron(R), and D-Tronplus(R) are registered trademarks of Roche Diagnostics GmbH.3 MiniMed(R) and Polyfin(R) are registered trademarks of MiniMed, Inc.Other product and company names may be the trademarks of their respective owners.Literature revised November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USAwww.humalog.comCopyright (C) 1996, 2019, Eli Lilly and Company. All rights reserved.LOG-0009-USPI-20191115. Disetronic(R) H-Tron(R) plus V100, D-Tron(R) and D-Tronplus(R) with Disetronic Rapid infusion sets2 MiniMed(R) Models 506, 507 and 508 and Polyfin(R) infusion sets3.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseHUMALOG(R)(HU-ma-log) (insulin lispro injection)Read this Instructions for Use before you start taking HUMALOG and each time you get new vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.Do not share your needles or syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.Supplies needed to give your injectiona multiple-dose HUMALOG viala U-100 insulin syringe and needle2 alcohol swabsgauze1 sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.VialSyringePreparing your HUMALOG doseWash your hands with soap and water.Check the HUMALOG label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.HUMALOG should look clear and colorless. Do not use HUMALOG if it is thick, cloudy, or colored, or if you see lumps or particles in it.Do not use HUMALOG past the expiration date printed on the label or 28 days after you first use it.Always use new syringe and needle for each injection to prevent infections and blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.Step 1:If you are using new vial, pull off the plastic Protective Cap, but do not remove the Rubber Stopper.Step 2:Wipe the Rubber Stopper with an alcohol swab.Step 3:Remove the Needle Shield from the syringe by pulling the Needle Shield straight off. Hold the syringe with the needle pointing up. Pull down on the Plunger until the Plunger Tip reaches the line for the number of units for your prescribed dose.(Example Dose: 20 units shown)Step 4:Push the needle through the Rubber Stopper of the vial.Step 5:Push the Plunger all the way in. This puts air into the vial.Step 6:Turn the vial and syringe upside down and slowly pull the Plunger down until the Plunger Tip is few units past the line for your prescribed dose.(Example Dose: 20 units Plunger is shown at 24 units)If there are air bubbles, tap the syringe gently few times to let any air bubbles rise to the top.Step 7:Slowly push the Plunger up until the Plunger Tip reaches the line for your prescribed dose.Check the syringe to make sure that you have the right dose.(Example Dose: 20 units shown)Step 8:Pull the syringe out of the Rubber Stopper of the vial.If you use HUMALOG with NPH insulin:NPH insulin is the only type of insulin that can be mixed with HUMALOG. Do not mix HUMALOG with any other type of insulin.HUMALOG should be drawn up into the syringe first, before you draw up your NPH insulin. Talk to your healthcare provider if you are not sure about the right way to mix HUMALOG and NPH insulin.Give your injection right away.Giving your HUMALOG Injection with syringeInject your insulin exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting.HUMALOG starts acting fast, so give your injection within 15 minutes before or right after you eat meal.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 9:Choose your injection site.HUMALOG is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms.Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose.Step 10:Insert the needle into your skin.Step 11:Push down on the Plunger to inject your dose.The needle should stay in your skin for at least seconds to make sure you have injected all of your insulin dose.Step 12:Pull the needle out of your skin.If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.Do not recap the needle. Recapping the needle can lead to needle stick injury.Giving your HUMALOG using an insulin pumpHUMALOG should be given into an area of your body recommended in the instructions that come with your insulin pump.Change (rotate) your insertion site every days.Change (rotate) your insertion sites within the area you choose for each insertion to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the insertion sites. Do not insert into the exact same spot for each insertion. Do not insert where the skin has pits, is thickened, or has lumps. Do not insert where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.Change the insulin in the reservoir at least every days, even if you have not used all of the insulin.Do not dilute or mix HUMALOG with any other type of insulin in your insulin pump.See your insulin pump manual for instructions or talk to your healthcare provider.Disposing of used needles and syringesPut your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and 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.How should store HUMALOGAll unopened vials:Store all unopened vials in the refrigerator at 36F to 46F (2C to 8C).Do not freeze. Do not use if HUMALOG has been frozen.Keep away from heat and out of direct light.Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.Unopened vials should be thrown away after 28 days, if they are stored at room temperature.After vials have been opened:Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 28 days.Keep vials away from heat and out of direct light.Throw away all opened vials after 28 days of use, even if there is insulin left in the vial.Keep HUMALOG vials, syringes, needles and all medicines out of the reach of children.If you have any questions or problems with your HUMALOG, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more information on HUMALOG and insulin, go to www.humalog.com.Scan this code to launch the humalog.com websiteThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Humalog(R) is registered trademark of Eli Lilly and Company.Revised: November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USACopyright (C) 1996, 2019, Eli Lilly and Company. All rights reserved.LOGVL-0008-IFU-20191125. multiple-dose HUMALOG vial. U-100 insulin syringe and needle. alcohol swabs. gauze. sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.. Wash your hands with soap and water.. Check the HUMALOG label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.. HUMALOG should look clear and colorless. Do not use HUMALOG if it is thick, cloudy, or colored, or if you see lumps or particles in it.. Do not use HUMALOG past the expiration date printed on the label or 28 days after you first use it.. Always use new syringe and needle for each injection to prevent infections and blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. NPH insulin is the only type of insulin that can be mixed with HUMALOG. Do not mix HUMALOG with any other type of insulin.. HUMALOG should be drawn up into the syringe first, before you draw up your NPH insulin. Talk to your healthcare provider if you are not sure about the right way to mix HUMALOG and NPH insulin.. Give your injection right away.. Inject your insulin exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting.. HUMALOG starts acting fast, so give your injection within 15 minutes before or right after you eat meal.. 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.. If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.. Do not recap the needle. Recapping the needle can lead to needle stick injury.. HUMALOG should be given into an area of your body recommended in the instructions that come with your insulin pump.. Change (rotate) your insertion site every days.. Change (rotate) your insertion sites within the area you choose for each insertion to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the insertion sites. Do not insert into the exact same spot for each insertion. Do not insert where the skin has pits, is thickened, or has lumps. Do not insert where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. Change the insulin in the reservoir at least every days, even if you have not used all of the insulin.. Do not dilute or mix HUMALOG with any other type of insulin in your insulin pump.. See your insulin pump manual for instructions or talk to your healthcare provider.. Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and 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.. Store all unopened vials in the refrigerator at 36F to 46F (2C to 8C).. Do not freeze. Do not use if HUMALOG has been frozen.. Keep away from heat and out of direct light.. Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.. Unopened vials should be thrown away after 28 days, if they are stored at room temperature.. Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 28 days.. Keep vials away from heat and out of direct light.. Throw away all opened vials after 28 days of use, even if there is insulin left in the vial.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatrics: Not studied in children with type diabetes or in children with type diabetes <3 years of age. (8.4). 8.1 Pregnancy. Risk SummaryThe limited available data with HUMALOG in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of 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).Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at dose approximately times the human subcutaneous dose of unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of unit/kg/day (see Data).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 DataPublished data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups.. Animal DataIn combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) from weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.. 8.2 Lactation. Risk SummaryThere are no data on the presence of HUMALOG in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin was present in human milk. However, there is insufficient information to determine the effects of HUMALOG on the breastfed infant and no available information on the effects of HUMALOG on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for insulin, any potential adverse effects on the breastfed child from HUMALOG or from the underlying maternal condition.. 8.4 Pediatric Use. HUMALOG is approved for use in children for subcutaneous daily injections [see Clinical Studies (14)]. Only the U-100 formulation of HUMALOG is approved for use in children by continuous subcutaneous infusion in insulin pumps. HUMALOG has not been studied in pediatric patients younger than years of age. HUMALOG has not been studied in pediatric patients with type diabetes.As in adults, the dosage of HUMALOG must be individualized in pediatric patients based on metabolic needs and results of frequent monitoring of blood glucose.. 8.5 Geriatric Use. Of the total number of subjects (n=2834) in eight clinical studies of HUMALOG, twelve percent (n=338) were 65 years of age or over. The majority of these had type diabetes. HbA1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of HUMALOG action have not been performed.. 8.6 Renal Impairment. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share HUMALOG prefilled pen, cartridge, reusable pen compatible with Lilly mL cartridges, or syringe between patients, even if the needle is changed. (5.1)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. (5.2)Hypoglycemia: May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (5.3, 7, 8.6, 8.7)Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. Do not transfer HUMALOG U-200 from the HUMALOG KwikPen to syringe as overdosage and severe hypoglycemia can result. (5.4)Hypersensitivity Reactions: May be life-threatening. Discontinue HUMALOG, monitor and treat if indicated. (5.5)Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of 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 and Ketoacidosis Due to Insulin Pump Device Malfunction: Monitor glucose and administer HUMALOG U-100 by subcutaneous injection if pump malfunction occurs. (5.8). Never share HUMALOG prefilled pen, cartridge, reusable pen compatible with Lilly mL cartridges, or syringe between patients, even if the needle is changed. (5.1). 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. (5.2). Hypoglycemia: May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (5.3, 7, 8.6, 8.7). Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. Do not transfer HUMALOG U-200 from the HUMALOG KwikPen to syringe as overdosage and severe hypoglycemia can result. (5.4). Hypersensitivity Reactions: May be life-threatening. Discontinue HUMALOG, monitor and treat if indicated. (5.5). Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of 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 and Ketoacidosis Due to Insulin Pump Device Malfunction: Monitor glucose and administer HUMALOG U-100 by subcutaneous injection if pump malfunction occurs. (5.8). 5.1 Never Share HUMALOG Prefilled Pen, Cartridge, Reusable Pen Compatible with Lilly mL Cartridges1, or Syringe Between Patients. HUMALOG prefilled pens, cartridges, and reusable pens compatible with Lilly mL cartridges must never be shared between patients, even if the needle is changed. Patients using HUMALOG vials must never share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. 5.2 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 (5.3)] 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, dosage adjustments of concomitant antidiabetic products may be needed.. 5.3 Hypoglycemia. Hypoglycemia is the most common adverse reaction associated with insulins, including HUMALOG. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. 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)], or in patients who experience recurrent hypoglycemia.. Risk Factors for HypoglycemiaThe risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of HUMALOG 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 [see Clinical Pharmacology (12.2)]. 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)]. 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.. 5.4 Hypoglycemia Due to Medication Errors. Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors between HUMALOG and other insulins, instruct patients to always check the insulin label before each injection.Do not transfer HUMALOG U-200 from the HUMALOG KwikPen to syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia [see Dosage and Administration (2.1) and Warnings and Precautions (5.3)].. 5.5 Hypersensitivity Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMALOG. If hypersensitivity reactions occur, discontinue HUMALOG; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1)]. HUMALOG is contraindicated in patients who have had hypersensitivity reactions to HUMALOG or any of its excipients [see Contraindications (4)].. 5.6 Hypokalemia. All insulin products, including HUMALOG, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (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 HUMALOG, 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.. 5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction. Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with HUMALOG may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see How Supplied/Storage and Handling (16.2) and Patient Counseling Information (17)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. HUMALOG has been shown to be equipotent to human insulin on molar basis. One unit of HUMALOG has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that HUMALOG has more rapid onset of action and shorter duration of activity than regular human insulin when given subcutaneously.The time course of action of insulin and insulin analogs, such as HUMALOG, may vary considerably in different individuals or within the same individual. The parameters of HUMALOG activity (time of onset, peak time, and duration) as designated in Figure should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.2)].Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before High Carbohydrate Meal in 10 Patients with Type Diabetesa.a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.. Figure 1. Intravenous Administration of HUMALOG U-100 -- The glucose lowering effect of intravenously administered HUMALOG was tested in 21 patients with type diabetes. For the study, the patients usual doses of insulin were held and blood glucose concentrations were allowed to reach stable range of 200 to 260 mg/dL during one to three hours run-in phase. The run-in phase was followed by 6-hour assessment phase. During the assessment phase, patients received intravenous HUMALOG at an initial infusion rate of 0.5 units/hour. The infusion rate of HUMALOG could be adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL.The mean blood glucose levels during the assessment phase for patients on HUMALOG therapy are summarized below in Table 4. All patients achieved the targeted glucose range at some point during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 17 of 20 patients treated with HUMALOG. The average time (+-SE) required to attain near normoglycemia was 129 +- 14 minutes for HUMALOG.Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of HUMALOG U-100a Results shown as mean +- SDTime from Start of Infusion (minutes)Mean Blood Glucose (mg/dL) Intravenousa 0224 +- 1630205 +- 2160195 +- 20120165 +- 26180140 +- 26240123 +- 20300120 +- 27360122 +- 25The pharmacodynamics of single 20 unit dose of HUMALOG U-200 administered subcutaneously were compared to the pharmacodynamics of single 20 unit dose of HUMALOG U-100 administered subcutaneously in euglycemic clamp study enrolling healthy subjects. In this study, the overall, maximum, and time to maximum glucose lowering effect were similar between HUMALOG U-200 and HUMALOG U-100. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) were 125 and 126 for HUMALOG U-200 and HUMALOG U-100, respectively. The maximum glucose infusion rate was 534 mg/min and 559 mg/min and the corresponding median time (min, max) to maximum effect were 2.8 (0.5 - 6.3 h) and 2.4 (0.5 - 4.7 h) for HUMALOG U-200 and HUMALOG U-100, respectively.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and Bioavailability -- Studies in healthy volunteers and patients with diabetes demonstrated that HUMALOG is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of HUMALOG ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type diabetes (see Figure 2).Figure 2: Serum HUMALOG and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before High Carbohydrate Meal in 10 Patients with Type Diabetesa.a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.HUMALOG U-100 was absorbed at consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After HUMALOG was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of HUMALOG is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.The results of study in healthy subjects demonstrated that HUMALOG U-200 is bioequivalent to HUMALOG U-100 following administration of single 20 unit dose.The mean observed area under the serum insulin concentration-time curve from time zero to infinity was 2360 pmol hr/L and 2390 pmol hr/L for HUMALOG U-200 and HUMALOG U-100, respectively. The corresponding mean peak serum insulin concentration was 795 pmol/L and 909 pmol/L for HUMALOG U-200 and HUMALOG U-100, respectively. The median time to maximum concentration was 1.0 hour for both formulations.. Figure 2. Distribution -- When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of HUMALOG appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively).. Metabolism -- Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of HUMALOG is identical to that of regular human insulin.. Elimination -- After subcutaneous administration of HUMALOG, the t1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, HUMALOG and regular human insulin demonstrated similar dose-dependent clearance, with mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). Accordingly, HUMALOG demonstrated mean t1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses.. Specific PopulationsThe effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMALOG have not been studied.. Renal Impairment -- Type diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and HUMALOG. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including HUMALOG, may be necessary in patients with renal dysfunction.. Hepatic Impairment -- Type diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of HUMALOG as compared to patients with no hepatic dysfunction. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including HUMALOG, may be necessary in patients with hepatic dysfunction.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited available data with HUMALOG in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of 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).Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at dose approximately times the human subcutaneous dose of unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of unit/kg/day (see Data).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 DataPublished data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups.. Animal DataIn combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) from weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.