Insulin lispro

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

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important administration instructions. ( 2.1 , 2.2 , 2.3 , 2.4 ) Subcutaneous Injection ( 2.2 ): Administer Insulin Lispro 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 Insulin Lispro 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. Intravenous Infusion ( 2.2 ): Administer Insulin Lispro by intravenous infusion ONLY after dilution and under medical supervision. The dosage of Insulin Lispro 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 Insulin Lispro prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. ( 2.1 , 2.3 ) 2.1 Important Administration Instructions Always check insulin labels before administration. This product is HUMALOG (insulin lispro) [see Warnings and Precautions ( 5.4 )] . Inspect Insulin Lispro visually before use. It should appear clear and colorless. Do not use Insulin Lispro if particulate matter or coloration is seen. Use Insulin Lispro prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do NOT mix Insulin Lispro with other insulins when using a continuous subcutaneous infusion pump. Do NOT perform dose conversion when using any Insulin Lispro 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 Administer the dose of Insulin Lispro 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 )] . Insulin Lispro administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. The Insulin Lispro KwikPen dials in 1 unit increments and delivers a maximum dose of 60 units per injection. The Insulin Lispro Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection. Subcutaneous Injection: Diluted Insulin Lispro Insulin Lispro may be diluted with Sterile Diluent for Insulin Lispro for subcutaneous injection ONLY under medical supervision. Dilute one part Insulin Lispro to: Nine parts diluent to yield a concentration one-tenth that of Insulin Lispro (equivalent to U-10). One part diluent to yield a concentration one-half that of Insulin Lispro (equivalent to U-50). Diluted Insulin Lispro 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 86°F (30°C). Continuous Subcutaneous Infusion (Insulin Pump) This Insulin Lispro product can be used with continuous subcutaneous insulin infusion pumps labeled for use with Humalog (insul …

3 DOSAGE FORMS AND STRENGTHS Injection: 100 units/mL (U-100) clear and colorless solution available as: 10 mL multiple-dose vial 3 mL single-patient-use KwikPen prefilled pen 3 mL single-patient-use Junior KwikPen prefilled pen Injection: 100 units/mL (U-100) is available as: ( 3 ) 10 mL multiple-dose vial 3 mL single-patient-use KwikPen ® prefilled pen 3 mL single-patient-use Junior KwikPen ® prefilled pen

4 CONTRAINDICATIONS Insulin Lispro 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 Insulin Lispro [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 Insulin Lispro. ( 4 )

6 ADVERSE REACTIONS 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 Insulin Lispro 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 Insulin Lispro 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 Insulin Lispro (%) (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 Insulin Lispro (%) (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 Insulin Lispro. Lipodystrophy Long-term use of insulin, including Insulin Lispro, 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 Insulin Lispro, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema Insulins, including Insulin Lispro, 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) 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 Insulin Lispro and regular human insulin treated patients ( see Table 3 ). Table 3: Catheter Occlusions and Infusion Site Reactions Insulin Lispro (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 (2 …

7 DRUG INTERACTIONS The table below includes clinically significant drug interactions with Insulin Lispro. 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 Insulin Lispro is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of Insulin Lispro 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 Insulin Lispro is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Lispro 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 Insulin Lispro 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 Insulin Lispro 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 ).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations) . Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day (see Data) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups. Animal Data In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/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 0.2 times the human subcutaneous dose of 1 unit insulin lispro/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. 8.2 Lactation Risk Summary Available data from published literature suggests that exogenous human insulin products, including insulin lispro, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including insulin lispro, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for insulin, any potential adverse effects on the breastfed child from Insulin Lispro or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Insulin Lispro to improve glycemic control have been established in …

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.

11 DESCRIPTION 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: Insulin Lispro injection is a sterile, clear, and colorless solution for subcutaneous or intravenous use. Each mL of Insulin Lispro 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. Insulin Lispro 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

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 a glucagon product for emergency use 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Insulin Lispro injection is a clear and colorless solution available as: Insulin Lispro Total Volume Concentration NDC Number Package Size U-100 multiple-dose vial 10 mL 100 units/mL 0002-7737-01 1 vial U-100 single-patient-use KwikPen 3 mL 100 units/mL 0002-8222-59 5 pens U-100 single-patient-use Junior KwikPen 3 mL 100 units/mL 0002-7752-05 5 pens The KwikPen dials in 1-unit increments. The Junior KwikPen dials in 0.5-unit increments. Each Insulin Lispro prefilled pen is for single-patient-use only. Insulin Lispro prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin Lispro vials must never share needles or syringes with another person. 16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Protect from direct heat and light. Do not freeze and do not use if it has been frozen. See table below for storage information: * When stored at room temperature, Insulin Lispro can only be used for a total of 28 days, including both not in-use (unopened) and in-use (opened) storage time. Not In-Use (Unopened) Room Temperature (Up to 86°F [30°C]) Not In-Use (Unopened) Refrigerated (36° to 46°F [2° to 8°C]) In-Use (Opened) (see temperature below*) 10 mL multiple-dose vial 28 days Until expiration date 28 days Refrigerated or room temperature. 3 mL single-patient-use Insulin Lispro KwikPen 28 days Until expiration date 28 days Room temperature only (Do not refrigerate) 3 mL single-patient-use Insulin Lispro Junior KwikPen 28 days Until expiration date 28 days Room temperature only (Do not refrigerate) Use in an External Insulin Pump — Change the Insulin Lispro in the reservoir at least every 7 days, or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 98.6°F (37°C). Storage of Diluted Insulin Lispro for Subcutaneous Injection — Diluted Insulin Lispro for subcutaneous injection may be stored for 28 days when refrigerated at 41°F (5°C) and 14 days at room temperature up to 86°F (30°C) [see Dosage and Administration ( 2.2 )] . Do not dilute Insulin Lispro used in an external insulin pump. Storage of Intravenous Infusion Preparations with Insulin Lispro Intravenous infusion bags prepared with Insulin Lispro maybe stored for 48 hours when refrigerated at 36° to 46°F (2° to 8°C). The prepared intravenous bags may then be used at room temperature for up to an additional 48 hours [see Dosage and Administration ( 2.2 )] .

16.1 How Supplied Insulin Lispro injection is a clear and colorless solution available as: Insulin Lispro Total Volume Concentration NDC Number Package Size U-100 multiple-dose vial 10 mL 100 units/mL 0002-7737-01 1 vial U-100 single-patient-use KwikPen 3 mL 100 units/mL 0002-8222-59 5 pens U-100 single-patient-use Junior KwikPen 3 mL 100 units/mL 0002-7752-05 5 pens The KwikPen dials in 1-unit increments. The Junior KwikPen dials in 0.5-unit increments. Each Insulin Lispro prefilled pen is for single-patient-use only. Insulin Lispro prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin Lispro vials must never share needles or syringes with another person.