HUMALOG KWIKPEN

Insulin lispro is a rapid-acting human insulin analog 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 H 383 N 65 O 77 S 6 and a molecular weight of 5.808 kDa, both identical to that of human insulin. Insulin lispro has the following primary structure: HUMALOG (insulin lispro) injection is a sterile, clear, and colorless solution for subcutaneous or intravenous use. Each mL of HUMALOG U-100 contains 100 units of insulin lispro, and the inactive ingredients: dibasic sodium phosphate (1.0 mg), glycerin (16 mg), metacresol (3.15 mg), trace amounts of phenol, zinc oxide (content adjusted to provide 0.0197 mg zinc ion), and Water for Injection, USP. Each mL of HUMALOG U-200 contains 200 units of insulin lispro, and the inactive ingredients: glycerin (16 mg), metacresol (3.15 mg), trace amounts of phenol, tromethamine (5 mg), zinc oxide (content adjusted to provide 0.046 mg zinc ion), and Water for Injection, USP. HUMALOG has a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% is added to adjust the pH. Primary Structure

HUMALOG is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. HUMALOG is a rapid acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. ( 1 )

See Full Prescribing Information for important administration instructions. ( 2.1 , 2.2 , 2.3 , 2.4 ) Subcutaneous injection ( 2.2 ): Administer HUMALOG ® U-100 or U-200 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks within 15 minutes before a meal or immediately after a meal. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Continuous subcutaneous infusion (Insulin Pump) ( 2.2 ): Refer to the insulin infusion pump user manual to see if HUMALOG can be used. Use in accordance with the insulin pump instructions for use. Administer HUMALOG U-100 by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. DO NOT administer HUMALOG U-200 by continuous subcutaneous infusion. Intravenous Infusion ( 2.2 ): Administer HUMALOG U-100 by intravenous infusion ONLY after dilution and under medical supervision. DO NOT administer HUMALOG U-200 by intravenous infusion. The dosage of HUMALOG must be individualized based on the route of administration and the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.3 ) Do not perform dose conversion when using the HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. ( 2.1 , 2.3 ) Do not mix HUMALOG U-200 with any other insulin. ( 2.4 ) 2.1 Important Administration Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . Inspect HUMALOG visually before use. It should appear clear and colorless. Do not use HUMALOG if particulate matter or coloration is seen. Use HUMALOG prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do NOT mix HUMALOG U-100 with other insulins when using a continuous subcutaneous infusion pump. Do NOT transfer HUMALOG U-200 from the prefilled pen to a syringe for administration [see Warnings and Precautions ( 5.4 )] . Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. 2.2 Administration Instructions for the Approved Routes 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. Rotate the injection site within the same region from one injection to the next (abdominal wall, thigh, upper arm, or buttocks) to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6 )] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . HUMALOG administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. The HUMALOG U-100 KwikPen, HUMALOG U-100 Tempo Pen and HUMALOG U-200 KwikPen each dial in 1 unit increments and delivers a maximum dose of 60 units per injection. The HUMALOG U-100 Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection. Subcutaneous Injection: Diluted HUMALOG U-100 HUMALOG U-100 may be diluted with Sterile Diluent for HUMALOG for subcutaneous injection ONLY under medical supervision. Dilute one part HUMALOG U-100 to: Nine parts diluent to yield a concentration one-tenth that of HUMALOG U-100 (equivalent to U-10). One part diluent to yield a concentration one-half that of HUMALOG U-100 (equivalent to U-50). Diluted HUMALOG for subcutaneous injection may be stored for 28 days when refrigerated at 41°F (5°C) and for 14 days at room temperature up to 80°F (30°C). Continuous Subcutaneous Infusion (Insulin Pump): HUMALOG U-100 ONLY Do NOT administer HUMALOG U-200 using a continuous subcutaneous infusion pump. Refer to the continuous subcutaneous insulin infusion pump user manual to see if HUMALOG can be used with the insulin pump. Use HUMALOG in accordance with the insulin pump system's instructions for use. Administer HUMALOG U-100 by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6 )] . Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions ( 5.8 )]. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . Change HUMALOG U-100 in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter. Change the infusion set and the infusion set insertion site according to the manufacturer's user manual. Do NOT dilute or mix HUMALOG U-100 when administering by continuous subcutaneous infusion. Do NOT expose HUMALOG U-100 in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration: HUMALOG U-100 ONLY Do NOT administer HUMALOG U-200 intravenously. Administer HUMALOG U-100 intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 )] . Dilute HUMALOG U-100 to concentrations from 0.1 unit/mL to 1.0 unit/mL using 0.9% Sodium Chloride Injection, USP. 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. 2.3 Dosage Recommendations 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. When switching from another insulin to HUMALOG, a different dosage of HUMALOG may be needed [see Warnings and Precautions ( 5.2 )] . Dosage modifications may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions ( 5.2 , 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )] . Do NOT perform dose conversion when using any HUMALOG U-100 or U-200 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. 2.4 Dosage Modifications for Drug Interactions Dosage modification may be needed when HUMALOG is used concomitantly with certain drugs [see Drug Interactions ( 7 )] . 2.5 Instructions for Mixing with Other Insulins The table below includes administration instructions regarding mixing HUMALOG U-100 and HUMALOG U-200 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.

HUMALOG is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . in patients who are hypersensitive to insulin lispro or to any of the excipients in HUMALOG [see Warnings and Precautions ( 5.5 )] . Do not use during episodes of hypoglycemia. ( 4 ) Do not use in patients with hypersensitivity to insulin lispro or any of the excipients in HUMALOG. ( 4 )

The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )]. Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )]. Hypokalemia [see Warnings and Precautions ( 5.6 )] . Adverse reactions associated with HUMALOG include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% of patients treated with insulin lispro or regular human insulin. The frequencies of adverse reactions during HUMALOG clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Adverse Reactions That Occurred in ≥5% in Patients with Type 1 Diabetes Mellitus HUMALOG (%) (n=81) Regular human insulin (%) (n=86) Flu syndrome 34.6 32.6 Pharyngitis 33.3 33.7 Rhinitis 24.7 29.1 Headache 29.6 22.1 Pain 19.8 16.3 Cough increased 17.3 17.4 Infection 13.6 20.9 Nausea 6.2 15.1 Accidental injury 8.6 11.6 Surgical procedure 6.2 14.0 Fever 6.2 11.6 Abdominal pain 7.4 8.1 Asthenia 7.4 8.1 Bronchitis 7.4 7.0 Diarrhea 8.6 5.8 Dysmenorrhea 6.2 7.0 Myalgia 7.4 5.8 Urinary tract infection 6.2 4.7 Table 2: Adverse Reactions That Occurred in ≥5% in Patients with Type 2 Diabetes Mellitus HUMALOG (%) (n=714) Regular human insulin (%) (n=709) Headache 11.6 9.3 Pain 10.8 10.0 Infection 10.1 7.6 Pharyngitis 6.6 8.2 Rhinitis 8.1 6.6 Flu syndrome 6.2 8.2 Surgical procedure 7.4 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. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMALOG. 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 [see Dosage and Administration ( 2.2 )] . Weight gain Weight gain can occur with insulins, including HUMALOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema Insulins, 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 pediatric patients with type 1 diabetes, adverse reactions 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 reactions were infusion site erythema and infusion site reaction. Allergic Reactions Local Allergy — As with any insulin, 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. Systemic Allergy — Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including HUMALOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving HUMALOG (n=2944). Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in HUMALOG [see Contraindications ( 4 )] . Antibody 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. 6.2 Postmarketing Experience 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 post-approval use. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

The table below includes clinically significant drug interactions with HUMALOG. Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics. Intervention: 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 Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: 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 Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine and reserpine. Intervention: Increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics ( 7 ). Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones ( 7 ). Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine ( 7 ). Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine ( 7 ).