Prescription Drugs

CLINICAL PHARMACOLOGY 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. Pharmacodynamics HUMALOG has been shown to be equipotent to human insulin on a 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 a more rapid onset of action and a 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 1 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]. Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetesa. a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin. Intravenous Administration Of HUMALOG U-100 The glucose lowering effect of intravenously administered HUMALOG was tested in 21 patients with type 1 diabetes. For the study, the patients’ usual doses of insulin were held and blood glucose concentrations were allowed to reach a stable range of 200 to 260 mg/dL during a one to three hours run-in phase. The run-in phase was followed by a 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-100 Time from Start of Infusion (minutes) Mean Blood Glucose (mg/dL) Intravenousa 0 224 ± 16 30 205 ± 21 60 195 ± 20 120 165 ± 26 180 140 ± 26 240 123 ± 20 300 120 ± 27 360 122 ± 25 a Results shown as mean ± SD The pharmacodynamics of a single 20 unit dose of HUMALOG U-200 administered subcutaneously were compared to the pharmacodynamics of a single 20 unit dose of HUMALOG U-100 administered subcutaneously in a 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 g and 126 g 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 h (0.5 h – 6.3 h) and 2.4 h (0.5 h – 4.7 h) for HUMALOG U-200 and HUMALOG U-100, respectively. 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 1 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 a High Carbohydrate Meal in 10 Patients with Type 1 Diabetesa. a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin. HUMALOG U-100 was absorbed at a 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 a study in healthy subjects demonstrated that HUMALOG U-200 is bioequivalent to HUMALOG U-100 following administration of a 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. 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 a 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 a 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 Populations The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMALOG have not been studied. Renal Impairment Type 2 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 2 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. Animal Toxicology And/Or Pharmacology In standard biological assays in fasted rabbits, 0.2 unit/kg of insulin lispro injected subcutaneously had the same glucose-lowering effect and had a more rapid onset of action as 0.2 unit/kg of regular human insulin. Clinical Studies The safety and efficacy of HUMALOG U-100 were studied in children, adolescent, and adult patients with type 1 diabetes (n=789) and adult patients with type 2 diabetes (n=722). Type 1 Diabetes – Adults And Adolescents A 12-month, randomized, parallel, open-label, active-controlled study was conducted in patients with type 1 diabetes to assess the safety and efficacy of HUMALOG (n=81) compared with Humulin® R [REGULAR insulin human injection, USP (rDNA origin)] (n=86). HUMALOG was administered by subcutaneous injection immediately prior to meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® U [ULTRALENTE® human insulin (rDNA origin) extended zinc suspension] was administered once or twice daily as the basal insulin. There was a 2-to 4-week run-in period with Humulin R and Humulin U 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 1 Diabetes Mellitus – Adults and Adolescents Treatment Duration Treatment in Combination with: 12 months Humulin U HUMALOG Humulin R N 81 86 Baseline HbA1c (%)a 8.2 ± 1.4 8.3 ± 1.7 Change from baseline HbA1c (%)a -0.1 ± 0.9 0.1 ± 1.1 Treatment Difference in HbA1c Mean (95% confidence interval) 0.4 (0.0, 0.8) Baseline short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1 End-of-Study short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1 Change from baseline short-acting insulin dose (units/kg/day) 0.0 ± 0.1 0.0 ± 0.1 Baseline Body weight (kg) 72 ± 12.7 71 ± 11.3 Weight change from baseline (kg) 1.4 ± 3.6 1.0 ± 2.6 Patients with severe hypoglycemia (n, %)b 14 (17%) 18 (21%) a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat. Type 2 Diabetes – Adults A 6-month randomized, crossover, open-label, active-controlled study was conducted in insulin-treated patients with type 2 diabetes (n=722) to assess the safety and efficacy of HUMALOG for 3 months followed by Humulin R for 3 months or the reverse sequence. HUMALOG was administered by subcutaneous injection immediately before meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® N [NPH human insulin (rDNA origin) isophane suspension] or Humulin U was administered once or twice daily as the basal insulin. All patients participated in a 2-to 4week run-in period with Humulin R and Humulin N 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 N (84%) compared with Humulin U (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 2 Diabetes Mellitus — Adults End point Baseline HUMALOG + Basal Humulin R + Basal HbA1c (%)a 8.9 ± 1.7 8.2 ± 1.3 8.2 ± 1.4 Change from baseline HbA1c (%)a — -0.7 ± 1.4 -0.7 ± 1.3 Short-acting insulin dose (units/kg/day)a 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.2 Change from baseline short-acting insulin dose (units/kg/day)a — 0.0 ± 0.1 0.0 ± 0.1 Body weight (kg)a 80 ± 15 81 ± 15 81 ± 15 Weight change from baseline — 0.8 ± 2.7 0.9 ± 2.6 Patients with severe hypoglycemia (n, %)b — 15 (2%) 16 (2%) a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat. Type 1 Diabetes – Pediatric And Adolescents An 8-month, crossover study of adolescents with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: HUMALOG or Humulin R, both administered with Humulin N (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 a comparable incidence of hypoglycemia. In a 9-month, crossover study of prepubescent children (n=60) with type 1 diabetes, aged 3 to 11 years, HUMALOG administered immediately before meals, HUMALOG administered immediately after meals and Humulin R 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 1 Diabetes End point Baseline HUMALOG + NPH Humulin R + NPH HbA1c (%)a 8.6 ± 1.5 8.7 ± 1.5 8.7 ± 1.6 Change from baseline HbA1c (%)a — 0.1 ± 1.1 0.1 ± 1.3 Short-acting insulin dose (units/kg/day)a 0.5 ± 0.2 0.5 ± 0.2 0.5 ± 0.2 Change from baseline short-acting insulin dose (units/kg/day)a — 0.01 ± 0.1 -0.01 ± 0.1 Body weight (kg)a 59.1 ± 13.1 61.1 ± 12.7 61.4 ± 12.9 Weight change from baselinea — 2.0 ± 3.1 2.3 ± 3.0 Patients with severe hypoglycemia (n, %)b — 5 (1.1%) 5 (1.1%) Diabetic ketoacidosis (n, %) — 11 (2.4%) 9 (1.9%) a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia that required glucagon or glucose injection or resulted in coma. Type 1 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 1 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. Type 1 Diabetes – Pediatric Continuous Subcutaneous Insulin Infusion A randomized, 16-week, open-label, parallel design, study of children and adolescents with type 1 diabetes (n=298) aged 4 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 1 Diabetes (16 weeks; n=298) HUMALOG Aspart N 100 198 Baseline HbA1c (%)a 8.2 ± 0.8 8.0 ± 0.9 Change from baseline HbA1c (%) -0.1 ± 0.7 -0.1 ± 0.8 Treatment Difference in HbA1c Mean (95% confidence interval) 0.1 (-0.3, 0.1) Baseline short-acting insulin dose (units/kg/day)a 0.9 ± 0.3 0.9 ± 0.3 End-of-Study short-acting insulin dose (units/kg/day)a 0.9 ± 0.2 0.9 ± 0.2 Patients with severe hypoglycemia (n, %)b 8 (8%) 19 (10%) Diabetic ketoacidosis (n, %) 0 (0) 1 (0.5%) Baseline body weight (kg)a 55.5 ± 19.0 54.1 ± 19.7 Weight Change from baseline (kg)a 1.6 ± 2.1 1.8 ± 2.1 a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.

CLINICAL PHARMACOLOGY Antidiabetic Activity The primary activity of insulin, including Humalog Mix50/50, is the regulation of glucose metabolism. In addition, all insulins have several anabolic and anti-catabolic actions on many tissues in the body. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly, promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis, and promotes the conversion of excess glucose into fat. Insulin lispro, the rapid-acting component of Humalog Mix50/50, has been shown to be equipotent to Regular human insulin on a molar basis. One unit of Humalog® has the same glucose-lowering effect as one unit of Regular human insulin, but its effect is more rapid and of shorter duration. Pharmacokinetics Absorption Studies in nondiabetic subjects and patients with type 1 (insulin-dependent) diabetes demonstrated that Humalog, the rapid-acting component of Humalog Mix50/50, is absorbed faster than Regular human insulin (U-100). In nondiabetic subjects given subcutaneous doses of Humalog ranging from 0.1 to 0.4 U/kg, peak serum concentrations were observed 30 to 90 minutes after dosing. When nondiabetic subjects received equivalent doses of Regular human insulin, peak insulin concentrations occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes. Figure 1: Serum Immunoreactive Insulin (IRI) Concentrations, After Subcutaneous Injection of Humalog Mix50/50 or Humulin 50/50 in Healthy Nondiabetic Subjects. Humalog Mix50/50 has two phases of absorption. The early phase represents insulin lispro and its distinct characteristics of rapid onset. The late phase represents the prolonged action of insulin lispro protamine suspension. In 30 healthy nondiabetic subjects given subcutaneous doses (0.3 U/kg) of Humalog Mix50/50, peak serum concentrations were observed 45 minutes to 13.5 hours (median, 60 minutes) after dosing (see Figure 1). In patients with type 1 diabetes, peak serum concentrations were observed 45 minutes to 120 minutes (median, 60 minutes) after dosing. The rapid absorption characteristics of Humalog are maintained with Humalog Mix50/50 (see Figure 1). Direct comparison of Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross-study comparison shown in Figure 1 suggests that Humalog Mix50/50 has a more rapid absorption than Humulin 50/50. Distribution Radiolabeled distribution studies of Humalog Mix50/50 have not been conducted. However, the volume of distribution following injection of Humalog is identical to that of Regular human insulin, with a range of 0.26 to 0.36 L/kg. Metabolism Human metabolism studies of Humalog Mix50/50 have not been conducted. Studies in animals indicate that the metabolism of Humalog, the rapid-acting component of Humalog Mix50/50, is identical to that of Regular human insulin. Elimination Humalog Mix50/50 has two absorption phases, a rapid and a prolonged phase, representative of the insulin lispro and insulin lispro protamine suspension components of the mixture. As with other intermediate-acting insulins, a meaningful terminal phase half-life cannot be calculated after administration of Humalog Mix50/50 because of the prolonged insulin lispro protamine suspension absorption. Pharmacodynamics Studies in nondiabetic subjects and patients with diabetes demonstrated that Humalog has a more rapid onset of glucose-lowering activity, an earlier peak for glucose-lowering, and a shorter duration of glucose-lowering activity than Regular human insulin. The early onset of activity of Humalog Mix50/50 is directly related to the rapid absorption of Humalog. The time course of action of insulin and insulin analogs, such as Humalog (and hence Humalog Mix50/50), may vary considerably in different individuals or within the same individual. The parameters of Humalog Mix50/50 activity (time of onset, peak time, and duration) as presented in Figures 2 and 3 should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables (see General under PRECAUTIONS). In a glucose clamp study performed in 30 nondiabetic subjects, the onset of action and glucose-lowering activity of Humalog, Humalog Mix50/50, Humalog® Mix75/25™, and insulin lisproprotamine suspension (NPL component) were compared (see Figure 2). Graphs of mean glucoseinfusion rate versus time showed a distinct insulin activity profile for each formulation. The rapid onset of glucose-lowering activity characteristic of Humalog was maintained in Humalog Mix50/50. Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross-study comparison shown on Figure 3 suggests that Humalog Mix50/50 has a duration of activity that is similar to Humulin 50/50. Figure 2: Glucose Infusion Rates (A Measure of Insulin Activity) After Injection of Humalog, Humalog Mix50/50, Humalog Mix75/25, or Insulin Lispro Protamine Suspension (NPL Component) in 30 Nondiabetic Subjects. Figure 3: Insulin Activity After Subcutaneous Injection of Humalog Mix50/50 and Humulin 50/50 in Nondiabetic Subjects. Figures 2 and 3 represent insulin activity profiles as measured by glucose clamp studies in healthy nondiabetic subjects. Figure 2 shows the time activity profiles of Humalog, Humalog Mix75/25, Humalog Mix50/50, and insulin lispro protamine suspension (NPL component). Figure 3 is a comparison of the time activity profiles of Humalog Mix50/50 (see Figure 3a) andof Humulin 50/50 (see Figure 3b) from two different studies. Special Populations Age and Gender — Information on the effect of age on the pharmacokinetics of Humalog Mix50/50 is unavailable. Pharmacokinetic and pharmacodynamic comparisons between men and women administered Humalog Mix50/50 showed no gender differences. In large Humalog clinical trials, sub-group analysis based on age and gender demonstrated that differences between Humalog and Regular human insulin in postprandial glucose parameters are maintained across sub-groups. Smoking — The effect of smoking on the pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied. Pregnancy — The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied. Obesity — The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied. In large clinical trials, which included patients with Body Mass Index up to and including 35 kg/m2, no consistent differences were observed between Humalog and Humulin® R with respect to postprandialglucose parameters. Renal Impairment — The effect of renal impairment on the pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied. In a study of 25 patients with type 2 diabetes and a wide range of renal function, the pharmacokinetic differences between Humalog and Regular human insulin were generally maintained. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Careful glucose monitoring and dose reductions of insulin, including Humalog Mix50/50, may be necessary in patients with renal dysfunction. Hepatic Impairment — Some studies with human insulin have shown increased circulating levels of insulin in patients with hepatic failure. The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied. However, in a study of 22 patients with type 2 diabetes, impaired hepatic function did not affect the subcutaneous absorption or general disposition of Humalog when compared with patients withno history of hepatic dysfunction. In that study, Humalog maintained its more rapid absorptionand elimination when compared with Regular human insulin. Careful glucose monitoring and dose adjustments of insulin, incl uding Humalog Mix50/50, may b e necessary in patients with hepatic dysfunction.

Find Lowest Prices on HUMALOG (insulin lispro) Injection DESCRIPTION HUMALOG® (insulin lispro injection) is a rapid-acting human insulin analog used to lower blood glucose. Insulin lispro is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. Insulin lispro differs from human insulin in that the amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline. Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula C257H383N65O77S6 and a molecular weight of 5808, both identical to that of human insulin. HUMALOG has the following primary structure: HUMALOG is a sterile, aqueous, clear, and colorless solution. Each milliliter of HUMALOG U-100 contains insulin lispro 100 units, 16 mg glycerin, 1.88 mg dibasic sodium phosphate, 3.15 mg Metacresol, zinc oxide content adjusted to provide 0.0197 mg zinc ion, trace amounts of phenol, and Water for Injection. Insulin lispro has a pH of 7.0 to 7.8. The pH is adjusted by addition of aqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%. Each milliliter of HUMALOG U-200 contains insulin lispro 200 units, 16 mg glycerin, 5 mg tromethamine, 3.15 mg Metacresol, zinc oxide content adjusted to provide 0.046 mg zinc ion, trace amounts of phenol, and Water for Injection. Insulin lispro has a pH of 7.0 to 7.8. The pH is adjusted by addition of aqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%.

Find Lowest Prices on HUMALOG® Mix50/50™ 50% Insulin Lispro Protamine Suspension and 50% Insulin Lispro Injection (Rdna Origin) 100 Units Per Ml (U-100) DESCRIPTION Humalog® Mix50/50™ [50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin)] is a mixture of insulin lispro solution, a rapid-acting blood glucose-lowering agent and insulin lispro protamine suspension, an intermediate-acting blood glucose-lowering agent. Chemically, insulin lispro is Lys(B28), Pro(B29) human insulin analog, created when the amino acids at positions 28 and 29 on the insulin B-chain are reversed. Insulin lispro is synthesized in a special non-pathogenic laboratory strain of Escherichia coli bacteria that has been genetically altered to produce insulin lispro. Insulin lispro protamine suspension (NPL component) is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation. Insulin lispro has the following primary structure: Insulin lispro has the empirical formula C257H383N65O77S6 and a molecular weight of 5808, both identical to that of human insulin. Humalog Mix50/50 vials and Pens contain a sterile suspension of insulin lispro protamine suspension mixed with soluble insulin lispro for use as an injection. Each milliliter of Humalog Mix50/50 injection contains insulin lispro 100 units, 0.19 mg protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 2.20 mg Metacresol, zinc oxide content adjusted to provide 0.0305 mg zinc ion, 0.89 mg phenol, and Water for Injection. Humalog Mix50/50 has a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% may have been added to adjust pH.

INDICATIONS HUMALOG is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. DOSAGE AND ADMINISTRATION Important Administration Instructions Always check insulin labels before administration [see WARNINGS AND PRECAUTIONS]. Inspect HUMALOG visually before use. It should appear clear and colorless. Do not use HUMALOG if particulate matter or coloration is seen. Do NOT mix HUMALOG U-100 with other insulins when administering using a continuous subcutaneous infusion pump. Do NOT transfer HUMALOG U-200 from the KwikPen to a syringe for administration [see WARNINGS AND PRECAUTIONS]. Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 KwikPens. The dose window shows the number of insulin units to be delivered and no conversion is needed. Humalog U-100 and U-200 KwikPens are designed to dial doses in increments of 1 unit. Humalog Junior KwikPen is designed to dial doses in 0.5 (1/2) unit increments. Do NOT mix HUMALOG U-200 with any other insulins. Do NOT administer HUMALOG U-200 using a continuous subcutaneous infusion pump (i.e., insulin pump). Do NOT administer HUMALOG U-200 intravenously. Route Of Administration Subcutaneous Injection: HUMALOG U-100 Or U-200 Administer the dose of HUMALOG U-100 or HUMALOG U-200 within fifteen minutes before a meal or immediately after a meal by injection into the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. To reduce the risk of lipodystrophy, rotate the injection site within the same region from one injection to the next [see ADVERSE REACTIONS]. HUMALOG administered by subcutaneous injection should generally be used in regimens with an intermediate-or long-acting insulin. Continuous Subcutaneous Infusion (Insulin Pump): HUMALOG U-100 ONLY Do NOT administer HUMALOG U-200 using a continuous subcutaneous infusion pump. Administer HUMALOG U-100 by continuous subcutaneous infusion into the subcutaneous tissue of the abdominal wall. Rotate infusion sites within the same region to reduce the risk of lipodystrophy [see ADVERSE REACTIONS]. 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 7 days. Change the infusion sets and the infusion set insertion site at least every 3 days. Do NOT expose HUMALOG U-100 in the pump reservoir to temperatures greater than 98.6°F (37°C). Use HUMALOG U-100 in pump systems suitable for insulin infusion [see PATIENT INFORMATION]. Intravenous Administration: HUMALOG U-100 ONLY 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. 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 and HOW SUPPLIED]. Dosage Information Individualize and adjust the dosage of HUMALOG based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 KwikPens. The dose window shows the number of insulin units to be delivered and no conversion is needed. Dosage Adjustment Due To Drug Interactions Dosage adjustment may be needed when HUMALOG is coadministered with certain drugs [see DRUG INTERACTIONS]. Dosage adjustment may be needed when switching from another insulin to HUMALOG [see WARNINGS AND PRECAUTIONS]. Instructions for Mixing with Other Insulins HUMALOG U-100 subcutaneous injection route 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. HUMALOG U-100 continuous subcutaneous infusion route (Insulin Pump) Do NOT mix HUMALOG U-100 with any other insulin. HUMALOG U-200 subcutaneous injection route Do NOT mix with any other insulin. HOW SUPPLIED Dosage Forms And Strengths HUMALOG 100 units per mL (U-100) is available as: 10 mL vials 3 mL Humalog KwikPen (prefilled) 3 mL Humalog Junior KwikPen (prefilled) 3 mL cartridges HUMALOG 200 units per mL (U-200) is available as: 3 mL Humalog KwikPen (prefilled) Storage And Handling HUMALOG is available as: HUMALOG Total Volume Concentration Total Units Available in Presentation NDC Number Max Dose per Injection Dose Increment Package Size U-100 vial 10 mL 100 units/mL 1000 units 0002-7510-01 n/a n/a 1 vial U-100 cartridge1 3 mL 100 units/mL 300 units 0002-7516-59 n/a n/a 5 cartridges U-100 KwikPen 3 mL 100 units/mL 300 units 0002-8799-59 60 units 1 unit 5 pens U-100 Junior KwikPen 3 mL 100 units/mL 300 units 0002-7714-59 30 units 0.5 units 5 pens U-200 KwikPen 3 mL 200 units/mL 600 units 0002-7712-27 60 units 1 unit 5 pens Each prefilled KwikPen, cartridge, and reusable pen compatible with Lilly 3 mL cartridges is for use by a single patient. HUMALOG KwikPens, cartridges, and reusable pens compatible with Lilly 3 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. Do not use after the expiration date. Unopened HUMALOG should be stored in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use HUMALOG if it has been frozen. In-use HUMALOG vials, cartridges, and HUMALOG KwikPen should be stored at room temperature, below 86°F (30°C) 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 86°F [30°C]) Not In-Use (Unopened) Refrigerated In-Use (Opened) Room Temperature, (Below 86°F [30°C]) HUMALOG U-100 10 mL vial 28 days Until expiration date 28 days, refrigerated/room temperature. 3 mL cartridge 28 days Until expiration date 28 days, Do not refrigerate. 3 mL Humalog KwikPen (prefilled) 28 days Until expiration date 28 days, Do not refrigerate. 3 mL Humalog Junior KwikPen (prefilled) 28 days Until expiration date 28 days, Do not refrigerate. HUMALOG U-200 3 mL Humalog KwikPen (prefilled) 28 days Until expiration date 28 days, Do not refrigerate. Use In An External Insulin Pump Change the HUMALOG U-100 in the reservoir at least every 7 days, change the infusion sets and the infusion set insertion site at least every 3 days or after exposure to temperatures that exceed 98.6°F (37°C). A HUMALOG 3 mL cartridge used in the D-Tron pumps should be discarded after 7 days, even if it still contains HUMALOG. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion set insertion site should be selected at least every 3 days. Diluted HUMALOG U-100 For Subcutaneous Injection Diluted HUMALOG may remain in patient use for 28 days when stored at 41°F (5°C) and for 14 days when stored at 86°F (30°C). Do not dilute HUMALOG contained in a cartridge or HUMALOG used in an external insulin pump. 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 a concentration one-tenth that of HUMALOG (equivalent to U-10). Diluting one part HUMALOG to one part diluent will yield a concentration one-half that of HUMALOG (equivalent to U-50). Admixture For Intravenous Administration Infusion bags prepared with HUMALOG U-100 are stable when stored in a refrigerator (2° to 8°C [36° to 46°F]) for 48 hours and then may be used at room temperature for up to an additional 48 hours [see DOSAGE AND ADMINISTRATION]. Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA. Revised: June 2017

INDICATIONS Humalog Mix50/50, a mixture of 50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin), is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Based on cross-study comparisons of the pharmacodynamics of Humalog Mix50/50 and Humulin 50/50, it is likely that Humalog Mix50/50 has a more rapid onset of glucose-lowering activity compared with Humulin 50/50 while having a similar duration of action. This profile is achieved by combining the rapid onset of Humalog with the intermediate action of insulin lispro protamine suspension. DOSAGE AND ADMINISTRATION Table 1*: Summary of Pharmacodynamic Properties of Insulin Products (Pooled Cross-Study Comparison) Insulin Products Dose, U/kg Time of Peak Activity, Hours After Dosing Percent of Total Activity Occurring inthe First 4 Hours Humalog 0.3 2.4 (0.8 - 4.3) 70% (49 - 89%) Humulin R 0.32 (0.26 - 0.37) 4.4 (4.0 - 5.5) 54% (38 - 65%) Humalog Mix75/25 0.3 2.6 (1.0 - 6.5) 35% (21 - 56%) Humulin 70/30 0.3 4.4 (1.5 - 16) 32% (14 - 60%) Humalog Mix50/50 0.3 2.3 (0.8 - 4.8) 45% (27 - 69%) Humulin 50/50 0.3 3.3 (2.0 - 5.5) 44% (21 - 60%) NPH 0.32 (0.27 - 0.40) 5.5 (3.5 - 9.5) 14% (3.0 - 48%) NPL component 0.3 5.8 (1.3 - 18.3) 22% (6.3 - 40%) * The information supplied in Table 1 indicates when peak insulin activity can be expected and the percent of the total insulin activity occurring during the first 4 hours. The information was derived from 3 separate glucose clamp studies in nondiabetic subjects. Values represent means, with ranges provided in parentheses. Humalog Mix50/50 is intended only for subcutaneous administration. Humalog Mix50/50 should not be administered intravenously. Dosage regimens of Humalog Mix50/50 will vary among patients and should be determined by the healthcare provider familiar with the patient's metabolic needs, eating habits, and other lifestyle variables. Humalog has been shown to be equipotent to Regular human insulin on a molar basis. One unit of Humalog has the same glucose-lowering effect as one unit of Regular human insulin, but its effect is more rapid and of shorter duration. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate of insulin lispro from subcutaneous tissue. Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross-study comparison shown in Figure 3 suggests that Humalog Mix50/50 has a duration of activity that is similar to Humulin 50/50. 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. As with all insulin preparations, the time course of action of Humalog Mix50/50 may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog Mix50/50 should be inspected visually before use. Humalog Mix50/50 should be used only if it appears uniformly cloudy after mixing. Humalog Mix50/50 should not be used after its expiration date. HOW SUPPLIED Humalog Mix50/50 [50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin)] is available in the following package sizes: each presentation containing 100 units insulin lispro per mL (U-100). 10 mL vials NDC 0002-7512-01 (VL-7512) 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002-8793-59 (HP-8793) 5 x 3 mL prefilled insulin delivery devices (KwikPen™) NDC 0002-8798-59 (HP-8798) Storage Humalog Mix50/50 should be stored in a refrigerator [2° to 8°C (36° to 46°F)], but not in the freezer. Do not use Humalog Mix50/50 if it has been frozen. Unrefrigerated [below 30°C (86°F)] vials must be used within 28 days or be discarded, even if they still contain Humalog Mix50/50. Unrefrigerated [below 30°C (86°F)] Pens, and KwikPens must be used within 10 days or be discarded, even if they still contain Humalog Mix50/50. Protect from direct heat and light. See table below: Not In-Use (Unopened) Room Temperature [Below30°C (86°F)] Not In-Use (Unopened) Refrigerated In-Use (Opened) Room Temperature [Below30°C (86°F)] 10 mL Vial 28 days Until expiration date 28 days,refrigerated/room temperature. 3 mL Pen and KwikPen (prefilled) 10 days Until expiration date 10 days. Do not refrigerate. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. www.humalog.com.

PATIENT INFORMATION HUMALOG® (HU-ma-log) (insulin lispro injection, USP [rDNA origin]) For Injection What is HUMALOG? HUMALOG is a 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 3 years of age or when used to treat children with type 2 diabetes mellitus. Who should not use HUMALOG? Do not use HUMALOG if you: are having an episode of low blood sugar (hypoglycemia). have an allergy to HUMALOG or any of the ingredients in HUMALOG. Before using HUMALOG, tell your healthcare provider about all of your medicalconditions, including if you: have kidney or liver problems. take any other medicines, especially ones commonly 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. have any other medical conditions. Some medical conditions can affect your insulin needs and your dose of HUMALOG. are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant. You and your healthcare provider should decide about the best way to manage your diabetes while you are pregnant. are breastfeeding or plan to breastfeed. It is not known if HUMALOG passes into your breast milk. You and your healthcare provider should decide if you will use HUMALOG while you breastfeed. Tell your healthcare provider about all the medicines you take, including prescription or overthe-counter medicines, vitamins, or herbal supplements. Before you start using HUMALOG, talk to your healthcare provider about low blood sugar and how to manage it. How should I use HUMALOG? Read the Instructions for Use that come with your HUMALOG. Do not share your Humalog KwikPen, cartridges, reusable pen compatible with Lilly 3 mL cartridges, or syringes with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them. Use HUMALOG exactly as your healthcare provider tells you to. HUMALOG starts acting fast, so inject it up to 15 minutes before or right after you eat a meal. Know the type and strength of insulin you use. Do not change the type of insulin you use 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 a different type of insulin. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar level. What should I avoid while using HUMALOG? While using HUMALOG do not: Drive or operate heavy machinery, until you know how HUMALOG affects you. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. What are the possible side effects of HUMALOG? HUMALOG may cause serious side effects, including: low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, hunger, anxiety, irritability, or mood changes. Your HUMALOG dose may need to change because of a: change in level of physical activity or exercise, weight gain or loss, change in diet, illness. serious allergic reactions (whole body allergic reaction). Get medical help right away,if you have any of these symptoms of an allergic reaction: a rash over your whole body, trouble breathing, a 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. Treatment with TZDs and HUMALOG may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. The most common side effects of HUMALOG include: low blood sugar (hypoglycemia), reactions at the injection site, skin thickening or pits at the injection site (lipodystrophy), itching (pruritis), rash. These 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 1800-FDA-1088. General information about the safe and effective use of HUMALOG. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about HUMALOG that is written for health professionals. Do not use HUMALOG for a condition for which it was not prescribed. Do not give or share HUMALOG with other people, even if they also have diabetes. It may harm them. What are the ingredients in HUMALOG? Active ingredient: insulin lispro Inactive ingredients: glycerin, dibasic sodium phosphate, metacresol, zinc oxide (zinc ion), trace amounts of phenol and water for injection Instructions for Use HUMALOG KwikPen® insulin lispro injection (rDNA origin) 100 units/mL, 3 mL pen Read the Instructions for Use before you start taking HUMALOG® and each time you get another KwikPen®. 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 HUMALOG KwikPen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them. HUMALOG KwikPen (“Pen”) is a disposable prefilled pen containing 300 units of HUMALOG. You can give yourself more than 1 dose from the Pen. Each turn (click) of the Dose Knob dials 1 unit of insulin. You can give from 1 to 60 units in a single injection. If your dose is more than60 units, you will need to give yourself more than 1 injection. The Plunger only moves a little with each injection, and you may not notice that it moves. The Plunger will only reach the end of the cartridge when you have used all 300 units in the Pen. This Pen is not recommended for use by the blind or visually impaired without the help ofsomeone trained to use the Pen. How to recognize your HUMALOG KwikPen Pen color: Dark blue Dose Knob: Dark blue Labels: White label with burgundy stripe Supplies you will need to give your injection HUMALOG KwikPen KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles recommended) Alcohol swab Gauze Preparing your Pen Wash your hands with soap and water. Check your Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. Do not use your Pen past the expiration date printed on the Label or for more than 28 days after you first start using the Pen. Always use a 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 otherpeople a serious infection or get a serious infection from them. Step 1: Pull the Pen Cap straight off. Do not remove the Pen Label. Wipe the Rubber Seal with an alcohol swab. Step 2: Check the liquid in the Pen. HUMALOG should look clear and colorless. Do not use if it is cloudy, colored, or has particles or clumps in it. Step 3: Select a new Needle. Pull off the Paper Tab from the Outer Needle Shield. Step 4: Push the capped Needle straight onto the Pen and twist the Needle on until it is tight. Step 5: Pull off the Outer Needle Shield. Do not throw it away. Pull off the Inner Needle Shield and throw it away. Priming your Pen Prime before each injection. Priming your Pen means removing the air from the Needle and Cartridge that may collect during normal use and ensures that the Pen is working correctly. If you do not prime before each injection, you may get too much or too little insulin. Step 6: To prime your Pen, turn the Dose Knob to select 2 units. Step 7: Hold your Pen with the Needle pointing up. Tap the Cartridge Holder gently to collect air bubbles at the top. Step 8: Continue holding your Pen with Needle pointing up. Push the Dose Knob in until it stops, and “0” is seen in the Dose Window. Hold the Dose Knob in and count to 5 slowly. You should see insulin at the tip of the Needle. If you do not see insulin, repeat priming steps 6 to 8, no more than 4 times. If you still do not see insulin, change the Needle and repeat priming steps 6 to 8. Small air bubbles are normal and will not affect your dose. Selecting your dose You can give from 1 to 60 units in a single injection. If your dose is more than 60 units, you will need to give more than 1 injection. If you need help with dividing up your dose the right way, ask your healthcare provider. Use a new Needle for each injection and repeat the priming step. Step 9: Turn the Dose Knob to select the number of units you need to inject. The Dose Indicator should line up with your dose. The Pen dials 1 unit at a time. The Dose Knob clicks as you turn it. Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin. The dose can be corrected by turning the Dose Knob in either direction until the correct dose lines up with the Dose Indicator. The even numbers (for example, 12) are printed on the dial. The odd numbers, (for example, 25) after the number 1, are shown as full lines. Always check the number in the Dose Window to make sure you have dialed the correct dose. The Pen will not let you dial more than the number of units left in the Pen. If you need to inject more than the number of units left in the Pen, you may either: Inject the amount left in your Pen and then use a new Pen to give the rest of your dose, or get a new Pen and inject the full dose. It is normal to see a small amount of insulin left in the Pen that you can not inject. Giving your injection Inject your insulin as your healthcare provider has shown you. Change (rotate) your injection site for each injection. Do not try to change your dose while injecting. Step 10: Choose your injection site. HUMALOG is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose. Step 11: Insert the Needle into your skin. Push the Dose Knob all the way in. Continue to hold the Dose Knob in and slowly count to 5 before removing the Needle. Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob. Step 12: Pull the Needle out of your skin. A drop of insulin at the Needle tip is normal. It will not affect your dose. Check the number in the Dose Window. If you see “0” in the Dose Window, you have received the full amount you dialed. If you do not see “0” in the Dose Window, do not redial. Insert the Needle into your skin and finish your injection. If you still do not think you received the full amount you dialed for your injection, do not start over or repeat the injection. Monitor your blood glucose as instructed by your healthcare provider. If you normally need to give 2 injections for your full dose, be sure to give your second injection. The Plunger only moves a little with each injection, and you may not notice that it moves. If you see blood after you take the Needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. After your injection Step 13: Carefully replace the Outer Needle Shield. Step 14: Unscrew the capped Needle and throw it away (see Disposing of Pens and Needles section). Do not store the Pen with the Needle attached to prevent leaking, blocking the Needle, and air from entering the Pen. Step 15: Replace the Pen Cap by lining up the Cap Clip with the Dose Indicator and pushing straight on. Disposing of Pens and Needles Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, -can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, -upright and stable during use, eak-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 FDA’s 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. The used Pen may be discarded in your household trash after you have removed the needle. Storing your Pen Unused Pens Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze your insulin. Do not use if it has been frozen. Unused Pens may be used until the expiration date printed on the Label, if the Pen has been kept in the refrigerator. In-use Pen Store the Pen you are currently using at room temperature [up to 86°F (30°C)]. Keep away from heat and light. Throw away the HUMALOG Pen you are using after 28 days, even if it still has insulin left in it. General information about the safe and effective use of your Pen Keep your Pen and needles out of the reach of children. Do not use your Pen if any part looks broken or damaged. Always carry an extra Pen in case yours is lost or damaged. Troubleshooting If you can not remove the Pen Cap, gently twist the cap back and forth, and then pull the cap straight off. If the Dose Knob is hard to push: Pushing the Dose Knob more slowly will make it easier to inject. Your Needle may be blocked. Put on a new Needle and prime the Pen. You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen. If you have any questions or problems with your HUMALOG KwikPen, contact Lilly at 1-800LillyRx (1-800-545-5979) or call your healthcare provider for help. For more information on HUMALOG KwikPen and insulin, go to www.humalog.com. Instructions for Use HUMALOG® (HU-ma-log) (insulin lispro injection, USP [rDNA origin]) 10mL Vial (100 Units/mL, U-100) Read the Instructions for Use before you start taking HUMALOG and each time you get a new HUMALOG 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 syringes with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them. Supplies needed to give your injection a HUMALOG vial a U-100 insulin syringe and needle 2 alcohol swabs 1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions. Preparing your HUMALOG dose 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 1 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 a new syringe or needle for each injection to help ensure sterility and prevent blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people a serious infection or get a serious infection fromthem. Step 1: If you are using a 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: Hold the syringe with the needle pointing up. Pull down on the Plunger until the tip of the Plunger 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 tip is a 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 a few times to let any air bubbles rise to the top. Step 7: Slowly push the Plunger up until the 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 vial’s Rubber Stopper. 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 a syringe Inject your insulin exactly as your healthcare provider has shown you. HUMALOG starts acting fast, so give your injection within 15 minutes before or right after you eat a meal. Change (rotate) your injection site for each injection. 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 5 seconds to make sure you have injected all of your insulin dose. Step 12: Pull the needle out of your skin. You may see a drop of insulin at the needle tip. This is normal and does not affect the dose you just received. If you see blood after you take the needle out of your skin, press the injection site with a piece of gauze or an alcohol swab. Do not rub the area. Do not recap the needle. Recapping the needle can lead to a needle stick injury. Giving your HUMALOG using an insulin pump Change your insertion site every 3 days. Change the insulin in the reservoir at least every 7 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 syringes Put your used needles and syringes in a 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 a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a 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 FDA’s 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 I store HUMALOG? All unopened HUMALOG vials: Store all unopened vials in the refrigerator. Do not freeze. Do not use if it 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 HUMALOG vials have been opened: Store opened vials in the refrigerator or at room temperature below 86°F (30°C) 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. General information about the safe and effective use of HUMALOG Keep HUMALOG vials, syringes, needles, and all medicines out of the reach of children. Always use a new syringe or needle for each injection. Do not reuse or share your syringes or needles with other people. You may give other people a serious infection or get a serious infection from them. If you have any questions or problems with your HUMALOG, contact Lilly at 1-800-Lilly-Rx (1800-545-5979) or call your healthcare provider for help. For more information on HUMALOG and insulin, go to www.humalog.com. Instructions for Use HUMALOG® Junior KwikPen® insulin lispro injection 100 units/mL, 3 mL pen Read the Instructions for Use before you start taking HUMALOG and each time you get another HUMALOG® Junior KwikPen®. 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 HUMALOG Junior KwikPen with other people, even if the needle has been changed.You may give other people a serious infection or get a serious infection from them. HUMALOG Junior KwikPen (“Pen”) is a disposable prefilled pen containing 300 units of HUMALOG. You can give yourself more than 1 dose from the Pen. Each turn of the Dose Knob dials 0.5 (½) unit of insulin. You can give from 0.5 (½) to 30 units in a single injection. If your dose is more than 30 units, you will need to give yourself more than 1 injection. The Plunger only moves a little with each injection, and you may not notice that it moves. The Plunger will only reach the end of the cartridge when you have used all 300 units in the Pen. This Pen is not recommended for use by the blind or visually impaired without the help of someone trained to use the Pen. HUMALOG Junior KwikPen Parts How to recognize your HUMALOG Junior KwikPen: Pen color: Blue Dose Knob: Blue, with raised ridges on end and side Label: White with an orange color bar and orange-to-yellow color band Supplies needed to give your injection: HUMALOG Junior KwikPen KwikPen compatible Needle (BD [Becton, Dickinson and Company] Pen Needles recommended) Alcohol swab Gauze Preparing your Pen Wash your hands with soap and water. Check the Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. Do not use your Pen past the expiration date printed on the Label or for more than 28 days after you first start using the Pen. Always use a new needle for each injection to help prevent infections and blocked needles. Do notreuse or share your needles with other people. You may give other people a serious infection or geta serious infection from them. Step 1: Pull the Pen Cap straight off. Do not remove the Pen Label. Wipe the Rubber Seal with an alcohol swab. Step 2: Check the liquid in the Pen. HUMALOG should look clear and colorless. Do not use if it is cloudy, colored, or has particles or clumps in it. Step 3: Select a new Needle. Pull off the Paper Tab from the Outer Needle Shield. Step 4: Push the capped Needle straight onto the Pen and twist the Needle on until it is tight. Step 5: Pull off the Outer Needle Shield. Do not throw it away. Pull off the Inner Needle Shield and throw it away. Priming your Pen Prime before each injection. Priming your Pen means removing the air from the Needle and Cartridge that may collect during normal use and ensures that the Pen is working correctly. If you do not prime before each injection, you may get too much or too little insulin. Step 6: To prime your Pen, turn the Dose Knob to select 2 units. Step 7: Hold your Pen with the Needle pointing up. Tap the Cartridge Holder gently to collect air bubbles at the top. Step 8: Continue holding your Pen with the Needle pointing up. Push the Dose Knob in until it stops, and “0” is seen in the Dose Window. Hold the Dose Knob in and count to 5 slowly. You should see insulin at the tip of the Needle. If you do not see insulin, repeat the priming steps 6 to 8, but not more than 4 times. If you still do not see insulin, change the Needle and repeat the priming steps 6 to 8. Small air bubbles are normal and will not affect your dose. Selecting your dose You can give from 0.5 (½) to 30 units in a single injection. If your dose is more than 30 units, you will need to give more than 1 injection. If you need help with dividing up your dose the right way, ask your healthcare provider. You must use a new Needle for each injection and repeat the priming step. Step 9: Turn the Dose Knob to select the number of units you need to inject. The Dose Indicator should line up with your dose. The Pen dials 0.5 (½) unit at a time. The Dose Knob clicks as you turn it. Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin. The dose can be corrected by turning the Dose Knob in either direction until the correct dose lines up with the Dose Indicator. The whole unit numbers (for example, 4) are printed on the dial. The half units are shown as lines between the whole unit numbers. Always check the number in the Dose Window to make sure you have dialed the correct dose. The Pen will not let you dial more than the number of units left in the Pen. If you need to inject more than the number of units left in the Pen, you may either: inject the amount left in your Pen and then use a new Pen to give the rest of your dose, or get a new Pen and inject the full dose. It is normal to see a small amount of insulin left in the Pen that you can not inject. Giving your injection Inject your insulin as your healthcare provider has shown you. Change (rotate) your injection site for each injection. Do not try to change your dose while injecting. Step 10: Choose your injection site. HUMALOG is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose. Step 11: Insert the Needle into your skin. Push the Dose Knob all the way in. Continue to hold the Dose Knob in and slowly count to 5 before removing the Needle. Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob. Step 12: Pull the Needle out of your skin. A drop of insulin at the Needle tip is normal. It will not affect your dose. Check the number in the Dose Window If you see “0” in the Dose window, you have received the full amount you dialed. If you do not see “0” in the Dose window, do not redial. Insert the Needle into your skin and finish your injection. If you still do not think you received the full amount you dialed for your injection, do not start over or repeat that injection. Monitor your blood glucose as instructed by your healthcare provider. If you normally need to give 2 injections for your full dose, be sure to give your second injection. The Plunger only moves a little with each injection and you may not notice that it moves. If you see blood after you take the Needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. After your injection Step 13: Carefully replace the Outer Needle Shield. Step 14: Unscrew the capped Needle and throw it away (see Disposing of Pens and Needles section). Do not store the Pen with the Needle attached to prevent leaking, blocking the Needle, and air from entering the Pen. Step 15: Replace the Pen Cap by lining up the Cap Clip with the Dose Indicator and pushing straight on. Disposing of Pens and Needles Put your used Needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a 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. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s 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 the container. The used Pen may be discarded in your household trash after you have removed the needle. Storing your Pen Unused Pens Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze your insulin. Do not use if it has been frozen. Unused Pens may be used until the expiration date printed on the Label, if the Pen has been kept in the refrigerator. In-use Pen Store the Pen you are currently using at room temperature [up to 86°F (30°C)]. Keep away from heat and light. Throw away the HUMALOG Pen you are using after 28 days, even if it still has insulin left in it. General information about the safe and effective use of your Pen Keep your Pen and Needles out of the sight and reach of children. Do not use your Pen if any part looks broken or damaged. Always carry an extra Pen in case yours is lost or damaged. Troubleshooting If you can not remove the Pen Cap, gently twist the cap back and forth, and then pull the cap straight off. If the Dose Knob is hard to push: Pushing the Dose Knob more slowly will make it easier to inject. Your Needle may be blocked. Put on a new Needle and prime the Pen. You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen. If you have any questions or problems with your HUMALOG Junior KwikPen, contact Lilly at 1-800-LillyRx (1800-545-5979) or call your healthcare provider for help. For more information on HUMALOG Junior KwikPen and insulin, go to www.humalog.com.

PATIENT INFORMATION Humalog® (HU-ma-log) Mix50/50™ 50% insulin lispro protamine Suspension and 50% insulin lispro Injection (rDNA origin) Important: Know your insulin. Do not change the type of insulin you use unless told to do so by your healthcare provider. Your insulin dose and the time you take your dose can change with different types of insulin. Make sure you have the right type and strength of insulin prescribed for you. Read the Patient Information that comes with Humalog Mix50/50 before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your diabetes or treatment. Make sure that you know how to manage your diabetes. Ask your healthcare provider if you have questions about managing your diabetes. What is Humalog Mix50/50? Humalog Mix50/50 is a mixture of fast-acting and longer-acting man-made insulins. Humalog Mix50/50 is used to control high blood sugar (glucose) in people with diabetes. Humalog Mix50/50 comes in: 10 mL vials (bottles) for use with a syringe Prefilled pens Who should not take Humalog Mix50/50? Do not take Humalog Mix50/50 if: your blood sugar is too low (hypoglycemia). After treating your low blood sugar, follow your healthcare provider's instructions on the use of Humalog Mix50/50. you are allergic to anything in Humalog Mix50/50. See the end of this leaflet for a complete list of ingredients in Humalog Mix50/50. What should I tell my healthcare provider before taking Humalog Mix50/50? Before you use Humalog Mix50/50, tell your healthcare provider if you: have liver or kidney problems or any other medical conditions. Medical conditions can affect your insulin needs and your dose of Humalog Mix50/50. take any other medicines, especially ones commonly 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 Mix50/50. are pregnant or breastfeeding. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant or breastfeeding. Humalog Mix50/50 has not been studied in pregnant or nursing women. take other medicines, including prescription and non-prescription medicines, vitamins and herbal supplements. Many medicines can affect your blood sugar levels and insulin needs. Your Humalog Mix50/50 dose may need to change if you take other medicines. Know the medicines you take. Keep a list of your medicines with you to show to all of your healthcare providers. How should I use Humalog Mix50/50? Talk to your healthcare provider if you have any questions. Your healthcare provider will tell you the right syringes to use with Humalog Mix50/50 vials. Your healthcare provider should show you how to inject Humalog Mix50/50 before you start using it. Read the User Manual that comes with your Humalog Mix50/50 prefilled pen. Use Humalog Mix50/50 exactly as prescribed by your healthcare provider. Humalog Mix50/50 starts working faster than other insulins that contain regular human insulin. Inject Humalog Mix50/50 fifteen minutes or less before a meal. If you do not plan to eat within 15 minutes, delay the injection until the correct time (15 minutes before eating). Check your blood sugar levels as told by your healthcare provider. Mix Humalog Mix50/50 well before each use. For Humalog Mix50/50 in a vial, carefully shake or rotate the vial until completely mixed. For prefilled pens, carefully follow the User Manual for instructions on mixing the pen. Humalog Mix50/50 should be cloudy or milky after mixing well. Look at your Humalog Mix50/50 before each injection. If it is not evenly mixed or has solid particles or clumps in it, do not use. Return it to your pharmacy for new Humalog Mix50/50. Inject your dose of Humalog Mix50/50 under the skin of your stomach area, upper arm, upper leg, or buttocks. Never inject Humalog Mix50/50 into a muscle or vein. Change (rotate) your injection site with each dose. Your insulin needs may change because of: illness stress other medicines you take changes in eating physical activity changes Follow your healthcare provider's instructions to make changes in your insulin dose. Never mix Humalog Mix50/50 in the same syringe with other insulin products. Never use Humalog Mix50/50 in an insulin pump. Always carry a quick source of sugar to treat low blood sugar, such as glucose tablets, hard candy, or juice. What are the possible side effects of Humalog Mix50/50? Low Blood Sugar (Hypoglycemia). Symptoms of low blood sugar include: hunger dizziness feeling shaky or shakiness lightheadedness sweating irritability headache fast heartbeat confusion Low blood sugar symptoms can happen suddenly. Symptoms of low blood sugar may be different for each person and may change from time to time. Severe low blood sugar can cause seizures and death. Low blood sugar may affect your ability to drive a car or use mechanical equipment, risking injury to yourself or others. Know your symptoms of low blood sugar. Low blood sugar can be treated by drinking juice or regular soda or eating glucose tablets, sugar, or hard candy. Follow your healthcare provider's instructions for treating low blood sugar. Talk to your healthcare provider if low blood sugar is a problem for you. Serious allergic reactions (whole body allergic reaction). Severe, life-threatening allergic reactions can happen with insulin. Get medical help right away if you develop a rash over your whole body, have trouble breathing, wheezing, a fast heartbeat, or sweating. Reactions at the injection site (local allergic reaction). You may get redness, swelling, and itching at the injection site. If you keep having injection site reactions or they are serious, you need to call your healthcare provider. Do not inject insulin into a skin area that is red, swollen, or itchy. Skin thickens or pits at the injection site (lipodystrophy). This can happen if you don't change (rotate) your injection sites enough. Humalog Mix50/50 may cause serious side effects, including swelling of your hands and feet heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with Humalog Mix50/50 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 Mix50/50. Your healthcare provider should monitor you closely while you are taking TZDs with Humalog Mix50/50. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: shortness of breath swelling of your ankles or feet sudden weight gain Treatment with TZDs and Humalog Mix50/50 may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure.These are not all the side effects from Humalog Mix50/50. Ask your healthcare provider or pharmacist for more information. How should I store Humalog Mix50/50? Store all unopened (unused) Humalog Mix50/50 in the original carton in a refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze. Do not use Humalog Mix50/50 that has been frozen. Do not use after the expiration date printed on the carton and label. Protect Humalog Mix50/50 from extreme heat, cold or light. After starting use (open): Vials: Keep in the refrigerator or at room temperature below 86°F (30°C) for up to 28 days. Keep open vials away from direct heat or light. Throw away an opened vial 28 days after first use, even if there is insulin left in the vial. Prefilled Pens: Do not store a prefilled pen that you are using in the refrigerator. Keep at room temperature below 86°F (30°C) for up to 10 days. Throw away a prefilled pen 10days after first use, even if there is insulin left in the pen. General information about Humalog Mix50/50 Use Humalog Mix50/50 only to treat your diabetes. Do not share it with anyone else, even if they also have diabetes. It may harm them. This leaflet summarized the most important information about Humalog Mix50/50. If you would like more information about Humalog Mix50/50 or diabetes, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Humalog Mix50/50 that is written for healthcare providers. For questions you may call 1-800-LillyRx (1-800-545-5979) or visit www.humalog.com. What are the ingredients in Humalog Mix50/50? Active ingredients: insulin lispro protamine suspension and insulin lispro. Inactive ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol, zinc oxide (zinc ion), phenol and water for injection. Instructions for Use HUMALOG® Mix50/50™ KwikPen™ 50% insulin lispro protamine suspension and 50% insulin lispro injection (rDNA origin) Read the Instructions for Use before you start taking HUMALOG Mix50/50 and each time you get a refill. 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. HUMALOG® Mix50/50™ KwikPen™ (“Pen”) is a disposable pen containing 3 mL (300 units) of U-100 HUMALOG® Mix50/50™ [50% insulin lispro protamine suspension and 50% insulin lispro injection (rDNA origin)] insulin. You can inject from 1 to 60 units in a single injection. Do not share your HUMALOG Mix50/50 KwikPen or needles with anyone else. You may give an infection to them or get an infection from them. This Pen is not recommended for use by the blind or visually impaired without the assistance of a person trained in the proper use of the product. Supplies you will need to give your HUMALOG Mix50/50 injection: HUMALOG Mix50/50 KwikPen HUMALOG Mix50/50 KwikPen compatible needle (Becton, Dickinson and Company Pen Needles recommended) Alcohol swab Preparing HUMALOG Mix50/50 KwikPen: Wash your hands with soap and water. Check the HUMALOG Mix50/50 KwikPen Label to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. Do not use HUMALOG Mix50/50 past the expiration date printed on the Label. Always use a new needle for each injection to help ensure sterility and prevent blocked needles. Step 1: Pull the Pen Cap straight off. Wipe the Rubber Seal with an alcohol swab. Do not twist the cap. Do not remove the KwikPen Label. Step2: Gently roll the Pen ten times. Invert the Pen ten times. HUMALOG Mix50/50 should look white and cloudy after mixing. Do not use if it looks clear or contains any lumps or particles. Step 3: Pull off the Paper Tab from Outer Needle Shield. Step 4: Push the capped Needle straight onto the Pen and turn the Needle forward until it is tight. Step 5: Pull off the Outer Needle Shield. Do not throw it away. Pull off the Inner Needle Shield and throw it away. Priming your HUMALOG Mix50/50 KwikPen: Prime before each injection. Priming ensures the Pen is ready to dose and removes air that may collect in the cartridge during normal use. If you do not prime before each injection, you may get too much or too little insulin. Step 6 : Turn the Dose Knob to select 2 units. Step 7: Hold your Pen with the Needle pointing up. Tap the Cartridge Holder gently to collect air bubbles at the top. Step 8: Hold your Pen with Needle pointing up. Push the Dose Knob in until it stops, and “0” is seen in the Dose Window. Hold the Dose Knob in and count to 5 slowly. A stream of insulin should be seen from the needle. If you do not see a stream of insulin, repeat steps 6 to 8, no more than 4 times. If you still do not see a stream of insulin, change the needle and repeat steps 6 to 8. Selecting your dose: Step 9: Turn the Dose Knob to select the number of units you need to inject. The Dose Indicator should line up with your dose. The dose can be corrected by turning the Dose Knob in either direction until the correct dose lines up with the Dose Indicator. The even numbers are printed on the dial. The odd numbers, after the number 1, are shown as full lines. The HUMALOG Mix50/50 KwikPen will not let you dial more than the number of units left in the Pen. If your dose is more than the number of units left in the Pen, you may either: inject the amount left in your Pen and then use a new Pen to give the rest of your dose, or get a new Pen and inject the full dose. The Pen is designed to deliver a total of 300 units of insulin. The cartridge contains an additional small amount of insulin that can't be delivered. Giving your HUMALOG Mix50/50 injection: Inject your HUMALOG Mix50/50 as your healthcare provider has shown you. Change (rotate) your injection site for each injection. Do not try to change your dose while injecting HUMALOG Mix50/50. Step 10: Choose your injection site. HUMALOG Mix50/50 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe the skin with an alcohol swab, and let the injection site dry before you inject your dose. Step 11: Insert the Needle into your skin. Step 12: Put your thumb on the Dose Knob and push the Dose Knob in until it stops. Hold the Dose Knob in and slowly count to 5. Step 13: Pull the Needle out of your skin. You should see “0” in the Dose Window. If you do not see “0” in the Dose Window, you did not receive your full dose. If you see blood after you take the Needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. A drop of insulin at the needle tip is normal. It will not affect your dose. If you do not think you received your full dose, do not take another dose. Call Lilly or your healthcare provider for assistance. Step 14: Carefully replace the Outer Needle Shield. Step 15: Unscrew the capped Needle and throw it away. Do not store the Pen with the Needle attached to prevent leaking, blocking of the Needle, and air from entering the Pen. Step 16: Replace the Pen Cap by lining up the Cap Clip with the Dose Indicator and pushing straight on. After your injection: Put your used needles and pens in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and pens in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a 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 pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal How should I store my HUMALOG Mix50/50 KwikPen? Store unused HUMALOG Mix50/50 Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). The Pen you are currently using can be stored out of the refrigerator below 86°F (30°C). Do not freeze HUMALOG Mix50/50. Do not use HUMALOG Mix50/50 if it has been frozen. Unused HUMALOG Mix50/50 Pens may be used until the expiration date printed on the Label, if kept in the refrigerator. The HUMALOG Mix50/50 Pen you are using should be thrown away after 10 days, even if it still has insulin left in it. Keep HUMALOG Mix50/50 away from heat and out of the light. General information about the safe and effective use of HUMALOG Mix50/50 KwikPen Keep HUMALOG Mix50/50 KwikPen and needles out of the reach of children. Do not use your Pen if any part looks broken or damaged. Always carry an extra Pen in case yours is lost or damaged. If you can not remove the Pen Cap, gently twist the Pen Cap back and forth, and then pull the Pen Cap straight off. If it is hard to push the Dose Knob or the Pen is not working the right way: Your Needle may be blocked. Put on a new Needle and prime the Pen. You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new one. It may help to push the Dose Knob more slowly during your injection. Use the space below to keep track of how long you should use each HUMALOG Mix50/50 KwikPen. Write down the date you start using your HUMALOG Mix50/50 KwikPen. Count forward 10 days. Write down the date you should throw it away. Example: Pen 1 - First used on [Date] _______ + 10 days = Throw out on [Date] ______ Pen 1 - First used on [Date] _______ Throw out on [Date] ________ Pen 2 - First used on [Date] _______ Throw out on [Date] ________ Pen 3 - First used on [Date] _______ Throw out on [Date] ________ Pen 4 - First used on [Date] _______ Throw out on [Date] ________ Pen 5 - First used on [Date] _______ Throw out on [Date] ________ If you have any questions or problems with your HUMALOG Mix50/50 KwikPen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more information on HUMALOG Mix50/50 KwikPen and insulin, go to www.humalog.com. These Instructions for Use have been approved by the U.S. Food and Drug Administration.

OVERDOSE Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. CONTRAINDICATIONS Humalog Mix50/50 is contraindicated during episodes of hypoglycemia and in patients sensitive to insulin lispro or any of the excipients contained in the formulation.

SIDE EFFECTS Observed With HUMALOG U-100 The following adverse reactions are discussed elsewhere: Hypoglycemia [see WARNINGS AND PRECAUTIONS]. Hypokalemia [see WARNINGS AND PRECAUTIONS]. 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 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus (adverse events with frequency ≥5%) Events, n (%) Lispro Regular human insulin (n=81) (n=86) Flu syndrome 28 (34.6) 28 (32.6) Pharyngitis 27 (33.3) 29 (33.7) Rhinitis 20 (24.7) 25 (29.1) Headache 24 (29.6) 19 (22.1) Pain 16 (19.8) 14 (16.3) Cough increased 14 (17.3) 15 (17.4) Infection 11 (13.6) 18 (20.9) Nausea 5 (6.2) 13 (15.1) Accidental injury 7 (8.6) 10 (11.6) Surgical procedure 5 (6.2) 12 (14.0) Fever 5 (6.2) 10 (11.6) Abdominal pain 6 (7.4) 7 (8.1) Asthenia 6 (7.4) 7 (8.1) Bronchitis 6 (7.4) 6 (7.0) Diarrhea 7 (8.6) 5 (5.8) Dysmenorrhea 5 (6.2) 6 (7.0) Myalgia 6 (7.4) 5 (5.8) Urinary tract infection 5 (6.2) 4 (4.7) Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus (adverse events with frequency ≥5%) Events, n (%) Lispro(n=714) Regular human insulin(n=709) Headache 63 (11.6) 66 (9.3) Pain 77 (10.8) 71 (10.0) Infection 72 (10.1) 54 (7.6) Pharyngitis 47 (6.6) 58 (8.2) Rhinitis 58 (8.1) 47 (6.6) Flu syndrome 44 (6.2) 58 (8.2) Surgical procedure 53 (7.4) 48 (6.8) Insulin Initiation And Intensification Of Glucose Control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy Long-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]. Weight Gain Weight gain can occur with insulin therapy, including HUMALOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema Insulin, 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-100 In a 12-week, randomized, crossover study in adult patients with type 1 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 Reactions HUMALOG U-100 (n=38) Regular human insulin (n=39) Catheter occlusions/month 0.09 0.10 Infusion site reactions 2.6% (1/38) 2.6% (1/39) In a randomized, 16-week, open-label, parallel design study of children and adolescents with type 1 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 a few days to a 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 a 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]. Antibody Production In large clinical trials with patients with type 1 (n=509) and type 2 (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. Postmarketing Experience HUMALOG U-100 The following additional adverse reactions have been identified during post-approval use of HUMALOG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors in which other insulins have been accidentally substituted for HUMALOG have been identified during postapproval use [see PATIENT INFORMATION]. DRUG INTERACTIONS Drugs That May Increase The Risk Of Hypoglycemia The risk of hypoglycemia associated with HUMALOG use may be increased when co-administered with antidiabetic agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, pramlintide, disopyramide, fibrates, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide). Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs That May Decrease The Blood Glucose Lowering Effect Of HUMALOG The glucose lowering effect of HUMALOG may be decreased when co-administered with corticosteroids, isoniazid, niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs That May Increase Or Decrease The Blood Glucose Lowering Effect Of HUMALOG The glucose lowering effect of HUMALOG may be increased or decreased with co-administered with beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs That May Blunt Signs And Symptoms Of Hypoglycemia The signs and symptoms of hypoglycemia [see WARNINGS AND PRECAUTIONS] may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are co-administered with HUMALOG.

SIDE EFFECTS Clinical studies comparing Humalog Mix50/50 with human insulin mixtures did not demonstrate a difference in frequency of adverse events between the two treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole — allergic reactions (see PRECAUTIONS). Skin and Appendages — injection site reaction, lipodystrophy, pruritus, rash. Other — hypoglycemia (see WARNINGS and PRECAUTIONS). DRUG INTERACTIONS Insulin requirements may be increased by medications with hyperglycemic activity such as corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy. Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzymeinhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Never Share A HUMALOG KwikPen, Cartridge, Reusable Pen Compatible With Lilly 3 mL Cartridges1, Or Syringe Between Patients HUMALOG KwikPens, cartridges, and reusable pens compatible with Lilly 3 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 a risk for transmission of blood-borne pathogens. Hyper-Or Hypoglycemia With Changes In Insulin Regimen Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Hypoglycemia] or hyperglycemia. These changes should be made cautiously and under close medical supervision and the frequency of blood glucose monitoring should be increased. 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], or in patients who experience recurrent hypoglycemia. Risk Factors For Hypoglycemia The 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]. 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]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use In Specific Populations]. Risk Mitigation Strategies For Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 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 a 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 and Hypoglycemia]. 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]. HUMALOG is contraindicated in patients who have had hypersensitivity reactions to HUMALOG or any of its excipients [see CONTRAINDICATIONS]. Hypokalemia All insulin products, including HUMALOG, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. 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). 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 a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. 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 and PATIENT INFORMATION]. Patient Counseling Infprmation Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Never Share A HUMALOG KwikPen, Cartridge, Reusable Pen Compatible With Lilly 3 mL Cartridges, Or Syringe Between Patients Advise patients that they must never share a HUMALOG KwikPen, cartridge, or reusable pen compatible with Lilly 3 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 a risk for transmission of blood-borne pathogens. Hypoglycemia Instruct 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 a 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]. Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with HUMALOG. Inform patients on the symptoms of hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]. Medication Errors Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products. Inform patients that HUMALOG U-200 contains 2 times as much insulin in 1 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 a 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-200 Instruct patients to NOT mix HUMALOG U-200 with any other insulin. Women Of Reproductive Potential Advise females of reproductive potential with diabetes to inform their doctor if they are pregnant or are contemplating pregnancy [see Use In Specific Populations]. Instructions For Patients Using Continuous Subcutaneous Insulin Pumps Patients 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® H-Tron® plus V100, D-Tron® and D-Tronplus® with Disetronic Rapid infusion sets2 MiniMed® Models 506, 507 and 508 and Polyfin® 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 a 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 7 days; infusion sets and infusion set insertion sites should be changed at least every 3 days. Insulin exposed to temperatures higher than 98.6°F (37°C) 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 a 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 a 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 and HOW SUPPLIED]. 1 3 mL cartridge is for use in Eli Lilly and Company’s HumaPen® Luxura® HD insulin delivery device, and Disetronic DTRON ® and D-TRON® Plus pumps. 2 Disetronic®, H-Tron®, D-Tron®, and D-Tronplus® are registered trademarks of Roche Diagnostics GmbH. 3 MiniMed® and Polyfin® are registered trademarks of MiniMed, Inc. Other product and company names may be the trademarks of their respective owners. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Standard 2-year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose. Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays. Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.16, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose. Use In Specific Populations Pregnancy Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. In patients with diabetes or gestational diabetes insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they become pregnant while taking HUMALOG. Although there are limited clinical studies of the use of HUMALOG in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area, respectively) from 2 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 0.24 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose. Nursing Mothers It is unknown whether insulin lispro is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when HUMALOG is administered to a nursing woman. Use of HUMALOG is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses. Pediatric Use HUMALOG is approved for use in children for subcutaneous daily injections [see Clinical Studies]. 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 3 years of age. HUMALOG has not been studied in pediatric patients with type 2 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. 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 2 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. 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]. 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].

WARNINGS Humalog differs from Regular human insulin by its rapid onset of action as well as a shorter duration of activity. Therefore, the dose of Humalog Mix50/50 should be given within 15 minutes before a meal. Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog Mix50/50. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patientswith diabetes. Any change of insulin should be made cautiously and only under medical supervision.Changes in insulin strength, manufacturer, type (e.g., Regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage. 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 combinationwith insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Humalog Mix50/50, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to currentstandards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. PRECAUTIONS General Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog Mix50/50 and otherinsulins, care should be taken in patients in whom such potential side effects might be clinicallyrelevant (e.g., patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins. As with all insulin preparations, the time course of Humalog Mix50/ 50 action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress. Hypoglycemia As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog Mix50/50. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control. Renal Impairment As with other insulins, the requirements for Humalog Mix50/50 may be reduced in patients with renal impairment. Hepatic Impairment Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog Mix50/50, may be necessary. Allergy Local Allergy — As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. Antibody Production — In clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both human insulin mixtures and insulin lispro mixtures treatment groups. Information for Patients Patients should be informed of the potential risks and advantages of Humalog Mix50/50 and alternative therapies. Patients should not mix Humalog Mix50/50 with any other insulin. They should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1c testing, recognition and management of hypo- and hyperglycemia, and periodic assessment for diabetes complications. Patients should be advised to inform their physician if they are pregnant or intend to become pregnant. Refer patients to the PATIENT INFORMATION leaflet for information on normal appearance, timing of dosing (within 15 minutes before a meal), storing, and common adverse effects. For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should readthe Patient Information leaflet that accompanies the drug product and the User Manual thataccompanies the delivery device and re-read them each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others. Laboratory Tests As with all insulins, the therapeutic response to Humalog Mix50/50 should be monitored by periodic blood glucose tests. Periodic measurement of hemogjlobin A1c is recommended for the monitoring of long-term glycemic control. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Humalog, Humalog Mix75/25, or Humalog Mix50/50. Insulin lispro was not mutagenic in a battery of in vitro and in vivo genetic toxicity assays (bacterial mutation tests, unscheduled DNA synthesis, mouse lymphoma assay, chromosomal aberration tests, and a micronucleus test). There is no evidence from animal studies of impairment of fertility induced by insulin lispro. Pregnancy Teratogenic Effects - Pregnancy Category B Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to insulin lispro. There are, however, no adequate and well-controlled studies with Humalog, Humalog Mix75/25, or Humalog Mix50/50 in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is unknown whether insulin lispro is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog Mix50/50 is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog Mix50/50 dose, meal plan, or both. Pediatric Use Safety and effectiveness of Humalog Mix50/50 in patients less than 18 years of age have not been established. Geriatric Use Clinical studies of Humalog Mix50/50 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should take into consideration the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population.