APA Paper on Medication Insulin Lispro

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HUMALOG safely and effectively. See full prescribing information for HUMALOG.

HUMALOG (insulin lispro injection) , for subcutaneous or intravenous use Initial U.S. Approval: 1996 --------------------------- RECENT MAJOR CHANGES ------------------------- Dosage and Administration (2.1, 2.2, 2.3, 2.4) 05/2015 Warnings and Precautions Never Share a Humalog KwikPen, Cartridge, Reusable P en Compatible with Lilly 3 mL Cartridges, or Syringe Between Patients (5.1) 02/2015 Hypoglycemia Due to Medication Errors (5.4) 05/2015 ---------------------------- INDICATIONS AND USAGE -------------------------- HUMALOG is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus . (1) ------------------------ DOSAGE AND ADMINISTRATION ---------------------- 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Type 1 Diabetes – Adults and Adoles cents 14.2 Type 2 Diabetes – Adults 14.3 Type 1 Diabetes – Pediatric and Adolescents 14.4 Type 1 Diabetes – Adults Continuous Subcutaneous Insulin Infusion 14.5 Type 1 Diabetes – Pediatric Continuous Subcutaneous Insulin Infusion 16 HOW SUPPLIED/STORAGE AN D HANDLING 16.1 How Supplied 16.2 Storage and Handling 16.3 Preparation and Handling 16.4 Admixture for Intravenous Administration 17 PATIENT COUNSELING INFORMATION 17.1 Never Share a HUMALOG KwikPen, Cartridge, Reusable Pen Compatible with Lilly 3 mL Cartridges, or Syringe Between Patients 17.2 Hypoglycemia 17.3 Hypersensitivity Reactions 17.4 Medication Errors 17.5 Administration Instruction for HUMALOG U- 200 17. 6 Women of Reproductive Potential 17. 7 Instructions For Patients Using Continuous Subcutaneous Insulin Pumps * Sections or subsections omitted from the full prescribing information are not listed . FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE HUMALOG is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • 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 P ump ) • Do NOT mix HUMALOG U -100 with any other insulin . HUMALOG U -200 subcutaneous injection route • Do NOT mix with any other insulin. 3 DOSAGE FORM S AND STRENGTHS HUMALOG 100 units per mL (U -100) is available as: 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 (12.2)] . Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co- administered medication [see Drug Interactions (7)] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)] .

Risk Mitigation Strategies for 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.

5. 4 Hypoglycemia Due to Medication Errors Accidental mix -ups between basal insulin products and other insulins, particularly rapid- acting insulins, have been reported. To avoid medication errors between HUMALOG and other insulins, instruct patients to always check the insulin label before each injection. Do not transfer HUMALOG U -200 from the HUMALOG KwikPen to 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 (2.1) and Warnings and Precautions (5.3) ].

5. 5 Hypersensitivity Reactions Severe, life -threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMALOG. If hypersensitivity reactions occur, discontinue HUMALOG; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1 )]. HUMALOG is contraindicated in patients who have had hyper sensitivity reactions to HUMALOG or any of its excipients [see Contraindications (4)].

5. 6 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 ).

5. 7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator -activated receptor (PPAR) -gamma agonists, can cause dose- related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including HUMALOG, and 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.

5.8 Hyperglycemia and Keto acidosis Due to Insulin Pump Device Malfunction Malfunction of the ins ulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidos is. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with HUMALOG may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see How Supplied/Storage and Handling (16.2 ) and Patient Counseling Information (17.7)].

6 ADVERSE REACTIONS O bserved with HUMALOG U -100 The following adverse reactions are discussed elsewhere:

Events, n (%) Lispro (n=81) Regular human insulin (n=86) Flu syndrome 28 (34.6) 28 (32.6) Reference ID: 4038466 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 (2.2)] .

Weight gain Weight gain can occur with insulin therapy, including HUMALOG, and has been attributed to the anabolic effects of insu lin 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 Reference ID: 4038466 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 wi th any insulin, including HUMALOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving HUMALOG (n=2944). Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in HUMALOG [see Contraindications (4)] .

Antibody P roduction 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 patient s 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 peak ed by 12 months and declined over the remaining years of the study . These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types.

6.2 Postmarketing Experience HUMALOG U -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 Counseling Information (17.4 )].

7 DRUG INTERACTIONS 7.1 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.

7.2 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.

7.3 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 followe d by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co -administered with these drugs.

7.4 Drugs That May Blunt Signs and Symptoms of Hypoglycemia The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)] may be blunted when beta- blockers, clonidine, guanethidine, and reserpine are co- administered with HUMALOG.

8 USE IN SPECIFIC POPULATIONS 8.1 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 trime sters, 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 . Reference ID: 4038466 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 s ubcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.

8.3 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.

8.4 Pediatric Use HUMALOG is approved for use in children for subcutaneous daily injections [see Clinical Studies (14)]. Only the U- 100 formulation of HUMALOG is approved for use in children by continuous subcutaneous infusion in insulin pump s.

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.

8.5 Geriatric Use Of the total number of subjects (n=2834) in eight clinical studies of HUMALOG, twelve percent (n=338) were 65 years of age or over. The majority of these had type 2 diabetes. HbA 1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of HUMALOG action have not been performed.

8.6 Renal Impairment Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12 .3)].

8.7 Hepatic Impairment Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12 .3)].

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

11 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 C 257 H383 N65O77S6 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 Reference ID: 4038466 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%.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro.

Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

12.2 Pharmacodynamics HUMALOG has been shown to be equipotent to human insulin on 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 ( 5.2)]. 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 Diabetes a . 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 2 60 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 target ed 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) Intravenous a 0 224 ± 16 30 205 ± 21 60 195 ± 20 120 165 ± 26 180 140 ± 26 240 123 ± 20 Reference ID: 4038466 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.

12.3 Pharmacokinetics Absorption and Bioavailability — Studies in healthy volunteers and patients with diabetes demonstrated that HUMALOG is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of HUMALOG ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin le vels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes ( see Figure 3). Figure 3: 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 Diabetes a .

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 — W hen 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 t 1/2 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, Reference ID: 4038466 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 t 1/2 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 t 1/2 was 0.79 hours ( 47 minutes) and 1.28 hours (77 min utes ), 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 pharmacokinetic s 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard 2- year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12- month repeat -do se 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.

13.2 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.

14 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 adu lt patients with type 2 diabetes (n=722).

14.1 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 suspe nsion] was administered once or twice daily as the bas al 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 dai ly 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 Humul in R N 81 86 Baseline HbA 1c (%) a 8.2 ± 1.4 8.3 ± 1.7 Change from baseline HbA 1c (%) a -0.1 ± 0.9 0.1 ± 1.1 Treatment Difference in HbA 1c 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 Reference ID: 4038466 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.

14.2 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 4 week 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/m 2. 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 HbA 1c 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 HbA 1c (%) a 8.9 ± 1.7 8.2 ± 1.3 8.2 ± 1.4 Change from baseline HbA 1c (%) 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.

14.3 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 HbA 1c ( see Table 7), and both treatment groups had a comparable incidence of hypoglycemia. In a 9- month, crossover study of prepubescent children (n=60) wit h 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 HbA 1c, 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 HbA 1c (%) a 8.6 ± 1.5 8.7 ± 1.5 8.7 ± 1. 6 Change from baseline HbA 1c (%) 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 baseline (kg) a — 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.

14.4 Type 1 Diabetes – Adults Continuous Subcutaneous Insulin Infusion Reference ID: 4038466 To evaluate the administration of HUMALOG U-100 via external insulin pumps, two open- label, crossover design studies were performed in patient s 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 HbA 1c 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 HbA 1c valu es decreased from 7.7% to 7.4% in the HUMALOG -treated patients and remained unchanged from 7.7% in the buffered regular human insulin- treated patients.

Rates of hypoglycemia were comparable between treatment groups in both studies.

14.5 Type 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 HbA 1c 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 HbA 1c (%) a 8.2 ± 0.8 8.0 ± 0.9 Change from B aseline HbA 1c (%) -0.1 ± 0.7 -0.1 ± 0.8 Treatment Difference in HbA 1c, Mean (95% confidence interval) 0.1 ( -0.3, 0.1) Baseline insulin dose (units/kg/24 hours) a 0.9 ± 0.3 0.9 ± 0.3 End -of-Study insulin dose (units/kg/24 hours) a 0.9 ± 0.2 0.9 ± 0.2 Patients with severe hypoglycemia (n, %) b 8 (8%) 19 (10%) Diabetic k etoacidosis (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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied HUMALOG 100 units per mL (U -100) is available as:

10 mL vials NDC 0002 -7510 -01 (VL -7510) 5 x 3 mL cartridges 1 NDC 0002 -7516 -59 (VL -7516) 5 x 3 mL Humalog KwikPen (prefilled) NDC 0002 -8799 -59 (HP -8799) HUMALOG 200 units per mL (U -200) is available as: 2 x 3 mL Humalog KwikPen (prefilled) NDC 0002 -7712 -27 (HP -7712 ) 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.

16.2 Storage and Handling 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 Te mperature, (Below 86°F [30°C]) HUMALOG U -100 10 mL vial 28 days Until expiration date 28 days, refrigerated/room temperature. Reference ID: 4038466 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. 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 ex ceed 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 da ys 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.

16.3 Preparation and Handling Diluted HUMALOG U-100 for Su bcutaneous 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).

16. 4 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 (2. 2)] .

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

17.1 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.

17.2 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 (5.3)] .

17. 3 Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with HUMALOG. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)] .

17.4 Medication Er rors 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 K wikPen 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.

17. 5 Administration Instruction for HUMALOG U-200 Instruct patients to NOT mix HUMALOG U -200 with any other insulin.

17. 6 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 (8.1)] .

17. 7 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. Reference ID: 4038466 ____________ A 1.0- LOG -0002- USPI-YYYYMMDD Patient Information HUMALOG ® (HU- ma-log) (insulin lispro injection, USP [rDNA origin]) for injection What is HUMALOG? B3- LOG -0001 -PPI -YYYYMMDD 1 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.

H UMALOG 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 than 60 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 P lunger 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. Pen Needle Parts (Needles Not Included) Dose Knob Paper Tab Outer Needle Inner Needle Needle Shield Shield Reference ID: 4038466 2 How to recognize your HUMALOG KwikPen Step 3:

Step 4:

• Push the capped N eedle straight onto the Pen and twist the Needle on until it is tight. Reference ID: 4038466 3 Step 5: Keep Outer Needle Shield Throw Away Inner Needle Shield Priming your Pen Prime before each injection.

Step 7:

• Hold your Pen with the N eedle pointing up.

Tap the C artridge Holder gently to collect air bubbles at the top.

Step 8:

• Continue holding your Pen with N eedle pointing up . Push the Dose Knob in until it stops , and “0” is seen in the Dose W indow.

Hold the D ose Knob in and count to 5 slowly .

You should see insulin at the tip of the N eedle.

- 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. Reference ID: 4038466 4 Selecting your dose Always check the number in the Dose Window to make sure you have dialed the correct dose. (Example: 12 units shown in the Dose Window ) (Example: 25 units shown in the Dose Window) 5 Step 10:

Step 11:

Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob. Reference ID: 4038466 6 Step 12:

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: Do not store the Pen with the Needle attached to prevent leaking, blocking the Needle, and air from entering the Pen. Reference ID: 4038466 7 Step 15:

• Replace the P en Cap by lining up the Cap C lip with the D ose Indicator and pushing straight on.

Disposing of Pens and Needles 8 A3LOGKP -0002- IFU-YYYYMMDD Scan this code to launch www. humalog .com This Instructions for Use has been approved by the U.S. Food and Drug Administration.

HUMALOG ® and HUMALOG KwikPen ® are trademarks of Eli Lilly and Company.

HUMALOG KwikPen meets the current dose accuracy and functional requirements of ISO 11608- 1:2014. Reference ID: 4038466 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 Rubber Stopper (under Cap) Protective Cap Preparing your HUMALOG dose (Example Dose: 20 units shown) xample Dose: 20 units Plunger is shown at 24 units) (E people. You may give other people a serious infection or get a serious infection from them. 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 R ubber S topper with an alcohol swab. Step 3: Hold the syringe with the needle pointing up. Pull down on the P lunger until the tip of the Plunger reaches the line for the number of units for your prescribed dose. Step 4: Push the needle through the R ubber S topper 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. Reference ID: 4038466 (Example Dose: 20 units shown) 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 P lunger up until the tip reaches the line for your prescribed dose. Check the syringe to make sure that you have the right dose. Step 8: Pull the syringe out of the vial’s R ubber S topper . If you use HUMALOG with NPH insulin: Reference ID: 4038466 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 injec tion site with a piece of gauze or an alcohol swab. Do not rub the area. • Do not recap the needle. Recapping t he needle can lead to a needle sti ck injury. Giving your HUMALOG usin g an insulin pump - properly labeled to warn of hazardous waste inside the container. Scan this code to launch the humalog.com website These Instructions for Use have been approved by the U.S. Food and Drug Administration.

Humalog ® is a registered trademarks of Eli Lilly and Company.

Instructions for Use issued: Month DD, YYYY Reference ID: 4038466 A5- LOGVL -0001 -IFU -YYYYMMDD Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 1996, yyyy, Eli Lilly and Company. All rights reserved. Reference ID: 4038466 Patient Information HUMALOG KwikPen ® insulin lispro injection U-200 (200 units per mL) 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.

What is HUMALOG?

• HUMALOG is a rapid- acting man- made insulin used to control high blood sugar in adults and children with diabetes mellitus .

• This HUMALOG Kwi kPen (“Pen”) contains 2 times as much insulin (200U/mL) in 1 mL as standard insulin (100U/mL).

• It is not known if HUMALOG is safe and effective in children less than 3 years of age.

• It is not known if HUMALOG is safe and effective in children with type 2 diabetes. Who should not take HUMALOG?

Do not take HUMALOG if you:

• are having an episode of low blood sugar (hypoglycemia).

• have an allergy to insulin lispro or any of the ingredients in HUMALOG. See the end of this Patient Information leaflet for a complete list of ingredients in HUMALOG. What should I tell my healthcare provider before using HUMALOG?

Before using HUMALOG, tell your healthcare provider about all your medical conditions, including if you:

• have liver or kidney problems • take other medicines, especially ones called TZDs (thiazolidinediones).

• have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with HUMALOG .

• are pregnant, planning to become pregnant, or breastfeeding. It is not known if HUMALOG may harm your unborn or breastfeeding baby.

Tell your healthcare provider about all the medicines you take, including prescription and over -the- counter medicines, vitamins, and 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 KwikPen?

• Read the detailed Instructions for Use that come with your HUMALOG KwikPen.

• Use HUMALOG KwikPen exactly as your healthcare provider tells you to. Yo ur healthcare provider should tell you how much HUMALOG to use and when to use it.

• Know the amount of HUMALOG you use. Do not change the amount of HUMALOG you use unless your healthcare provider tells you to.

• Check your insulin label each time you give your injection to make sure you are using the correct insulin.

• HUMALOG comes in a KwikPen which is a disposable prefilled pen that you must use to give your HUMALOG. The dose window on your pen shows your dose of HUMALOG. Do not make any dose changes unless your healthcare provider tells you to.

• Do not use a syringe to remove HUMALOG from your KwikPen disposable prefilled pen.

• Do not re-use needles. Always use a new needle for each injection. Re- use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of HUMALOG. Using a new needle for each injection also lowers your risk of getting an infection. If your needle is blocked, follow the instructions in the “General information about the safe and effective use of your Pen” section of the Instructions for Use.

• HUMALOG is a rapid- acting insulin. Take HUMALOG within 15 minutes before eating or right after eating a meal.

• Inject HUMALOG under your skin (subcutaneously) . Do not use HUMALOG KwikPen (“Pen”) in an insulin pump or inject HUMALOG KwikPen into your vein (intravenously).

• Change (rotate) your injection site with each dose.

• Do not mix the HUMALOG in the HUMALOG KwikPen with any other type of insulin or liquid medicine.

• Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.

Keep HUMALOG KwikPen and all medicines out of reach of children.

Your dose of HUMALOG may need to change because of a: • change in physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take. What should I avoid while using HUMALOG KwikPen?

While using HUMALOG KwikPen do not:

• drive or operate heavy machinery, until you know how HUMALOG KwikPen affects you • drink alcohol or use over -the -counter medicines that contain alcohol What are the possible side effects of HUMALOG? Reference ID: 4038466 LOG200-A4- 0000-PPI-YYYYMMDD HUMALOG may cause serious side effects that can lead to death, including: • low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:

• dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.

• severe allergic reaction (whole body reaction). Get medical help right away, if you have any of these signs or symptoms of a severe allergic reaction:

• a rash over your whole body, have trouble breathing, a fast heartbeat, or sweating.

• low potassium in your blood (hypokalemia).

• heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) 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.

Get emergency help if you have:

• trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.

The most common side effects of HUMALOG include:

• low blood sugar (hypoglycemia), allergic reactions, including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy), itching, and rash.

These are not all of the possible side effects from HUMALOG. Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1 -800 -FDA -1088 . General Information about the safe and effective use of HUMALOG KwikPen.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use HUMALOG for a condition for which it was not prescribed. Do not give HUMALOG to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about HUMALOG KwikPen. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about HUMALOG that is written for healthcare providers. For more information go to www.humalog.com or call 1-800 -LillyRx (1 -800 -545 -5979). What are the ingredients in HUMALOG U -200?

Active ingredient: insulin lispro.

Inactive ingredient: glycerin, tromethamine, metacresol, zinc oxide (zinc ion), trace amounts of phenol and water for injection.

Humalog ® and Hu malog KwikPen ® are registered trademarks of Eli Lilly and Company.

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA For more information, go to www.humalog.com .

This Patient Information has been approved by the U.S. Food and Drug Administration Reference ID: 4038466 1 Instructions for Use HUMALOG KwikPen ® i nsulin lispro injection 200 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 200 units/mL (“Pen”) is a disposable prefilled pen containing 600 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 than 60 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 600 units in the Pen.

H UMALOG KwikPen is available in 2 strengths, 100 units/mL and 200 units/mL. Inject HUMALOG 200 units/mL only with your Pen. Do not transfer insulin from your Pen to a syringe. Syringes will not measure 200 units/mL insulin correctly. A severe overdose can result, causing very low blood sugar which may put your life in danger.

Thi s Pen is not recommended for use by the blind or visually impaired without the help of someone trained to use the P en. Reference ID: 4038466 2 KwikPen Parts Pen Needle Parts Dose Knob (Needles Not Included) Needle Outer Needle Inner Needle Paper Tab Shield Shield How to recognize your HUMALOG 200 units/mL KwikPen Reference ID: 4038466 3 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:

Step 4:

• Push the capped Needle straight onto the Pen and twist the Needle on until it is tight.

Step 5: Keep Outer Needle Shield Throw Away Inner Needle Shield Priming your Pen Prime before each injection.

Step 7:

• Hold your Pen with the N eedle pointing up. Tap the Cartridge Holder gently to collect air bubbles at the top. Reference ID: 4038466 4 Step 8:

• Continue holding your Pen with N eedle pointing up. Push the D ose Knob in until it stops , and “0 ” is seen in the Dose W indow. Hold the D ose 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 8 times.

- If you still do not see insulin , change the N eedle and repeat priming steps 6 to 8.

S mall air bubbles are normal and will not affect your dose.

Selecting your dose This Pen has been made to deliver the dose that is shown in the Dose Window. Dial your usual dose as instructed by your healthcare provider. (Example: 12 units shown in the Dose Window ) (Example: 25 units shown in the Dose Window ) Reference ID: 4038466 5 Step 11:

Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob. Reference ID: 4038466 6 Step 12:

After your injection Step 13: • Carefully replace the Outer Needle Shield.

Step 14: Do not store the Pen with the Needle attached to prevent leaking, block ing 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 N eedles Reference ID: 4038466 7 S can this code to launch www. humalog.com Reference ID: 4038466 8 A3LOGKP200- 0001-IFU-YYYYMMDD This Instructions for Use has been approved by the U.S. Food and Drug Administration.

HUMALOG ® and HUMALOG KwikPen ® are trademarks of Eli Lilly and Company.

HUMALOG KwikPen meets the current dose accuracy and functional requirements of ISO 11608 -1:2014 . Reference ID: 4038466 ------------------------------------------------------------------------\�--------------------------------- ------------------------------------------------------------------------\�--------------------------------- ---------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

/s/ JEAN-MARC P GUETTIER 01/06/2017 Reference ID: 4038466