Humalog

1 INDICATIONS AND USAGE HUMALOG Mix75/25 is indicated to improve glycemic control in adults with diabetes mellitus. HUMALOG ® Mix75/25TM is a mixture of insulin lispro protamine, an intermediate-acting human insulin analog, and insulin lispro, a rapid-acting human insulin analog indicated to improve glycemic control in adults with diabetes mellitus. ( 1 ) Limitations of Use: The proportions of rapid-acting and intermediate-acting insulins are fixed and do not allow for basal versus prandial dose adjustments. ( 1 ) Limitations of Use : The proportions of rapid-acting and intermediate-acting insulins in HUMALOG Mix75/25 are fixed and do not allow for basal versus prandial dose adjustments.

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important preparation and administration instructions. ( 2.1 ) Inject HUMALOG Mix75/25 subcutaneously (within 15 minutes before a meal) in abdominal wall, thigh, upper arm, or buttocks and rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 , 2.2 ) Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.2 ) Do not administer HUMALOG Mix75/25 intravenously or by a continuous subcutaneous insulin infusion pump. ( 2.1 ) HUMALOG Mix75/25 is typically dosed twice daily (with each dose intended to cover 2 meals or a meal and a snack). ( 2.2 ) 2.1 Important Preparation and Administration Instructions Preparation Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . HUMALOG Mix75/25 is a suspension that must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature. To resuspend the: vial, carefully invert the vial at least 10 times until the suspension appears uniformly white and cloudy. KwikPen, gently roll the KwikPen at least 10 times and then carefully invert the KwikPen at least 10 times until the suspension appears uniformly white and cloudy. Inspect HUMALOG Mix75/25 visually before use. Do not use if discoloration or particulate matter is seen. Administration Instructions After resuspension, immediately administer HUMALOG Mix75/25 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks. Rotate the injection site within the same region from one injection to the next 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 )] . The HUMALOG Mix75/25 KwikPen dials in 1 unit increments. Use HUMALOG Mix75/25 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do not administer HUMALOG Mix75/25 intravenously or by a continuous subcutaneous insulin infusion pump. Do not mix HUMALOG Mix75/25 with any other insulins or diluents. 2.2 Dosage Recommendations Individualize and adjust the dosage of HUMALOG Mix75/25 based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. Inject HUMALOG Mix75/25 subcutaneously within 15 minutes before a meal. HUMALOG Mix75/25 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack). Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions ( 5.2 , 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )] . When switching from another insulin to HUMALOG Mix75/25 a different dosage of HUMALOG Mix75/25 may be needed. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . 2.3 Dosage Modifications for Drug Interactions Dosage modification may be needed when HUMALOG Mix75/25 is used concomitantly with certain drugs [see Drug Interactions ( 7 )] .

3 DOSAGE FORMS AND STRENGTHS Injectable suspension: 100 units/mL (U-100) of HUMALOG Mix75/25, 75% insulin lispro protamine and 25% insulin lispro, is a white and cloudy suspension available as: 10 mL multiple-dose vial 3 mL single-patient-use KwikPen prefilled pen Injectable suspension: 100 units/mL (U-100) of HUMALOG Mix75/25, 75% insulin lispro protamine and 25% insulin lispro available as: ( 3 ) 10 mL multiple-dose vial 3 mL single-patient-use KwikPen ® prefilled pen

4 CONTRAINDICATIONS HUMALOG Mix75/25 is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] in patients who have had hypersensitivity reactions to HUMALOG Mix75/25 or to any of its excipients. [see Warnings and Precautions ( 5.5 )] Do not use during episodes of hypoglycemia. ( 4 ) Do not use in patients with hypersensitivity to HUMALOG Mix75/25 or any of its excipients. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: 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 observed with HUMALOG Mix50/50 include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, and rash. ( 6 ) 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. Adverse Reactions from Clinical Studies or Postmarketing Reports The following adverse reactions have been identified during post-marketing use of HUMALOG Mix50/50. Because some of 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. Adverse reactions associated with insulin initiation and glucose control intensification 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. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy. Hypersensitivity reactions Severe, life-threatening, generalized allergy, including anaphylaxis. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in HUMALOG Mix50/50. Hypokalemia HUMALOG Mix50/50 can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection site reactions HUMALOG Mix50/50 can cause local injection site reactions including redness, swelling, or itching at the site of injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation. Localized reactions and generalized myalgias have been reported with the use of meta-cresol, which is an excipient in HUMALOG Mix50/50. Lipodystrophy Administration of insulin subcutaneously, including HUMALOG Mix50/50, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration ( 2.1 )] in some patients. Localized cutaneous amyloidosis 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. Medication Errors Medication errors in which other insulins have been accidentally substituted for HUMALOG Mix50/50 have been identified during postapproval use. Peripheral Edema Insulins, including HUMALOG Mix50/50, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Weight gain Weight gain can occur with insulins, including HUMALOG Mix50/50, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with HUMALOG Mix50/50 is unknown.

7 DRUG INTERACTIONS Table 1 below presents clinically significant drug interactions with HUMALOG Mix75/25. Table 1: Clinically Significant Drug Interactions with HUMALOG Mix75/25 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 Mix75/25 is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of HUMALOG Mix75/25 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 Mix75/25 is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of HUMALOG Mix75/25 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 Mix75/25 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 Mix75/25 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, still birth, 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 Animal reproduction studies have not been performed with HUMALOG Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of HUMALOG Mix75/25). 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 HUMALOG Mix75/25, 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 HUMALOG Mix75/25, 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 e …

12.1 Mechanism of Action The primary activity of insulin, including HUMALOG Mix75/25, is the regulation of glucose metabolism. 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 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. Humalog Mix50/50 (insulin lispro protamine and insulin lispro) injectable suspension is a mixture of 50% insulin lispro protamine, an intermediate-acting human insulin analog, and 50% insulin lispro, a rapid-acting human insulin analog. Insulin lispro protamine suspension is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation. Insulin lispro has the following primary structure: HUMALOG Mix50/50 (insulin lispro protamine and insulin lispro) injectable suspension is a sterile, white and cloudy suspension for subcutaneous use. Each mL of HUMALOG Mix50/50 contains 100 units of insulin lispro; dibasic sodium phosphate (2.0 mg), glycerin (16 mg), metacresol (2.20 mg), phenol (0.89 mg), protamine sulfate (0.19 mg), zinc oxide content adjusted to provide zinc ion (0.0305 mg), and Water for Injection, USP. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid is added during manufacture 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 [see Warnings and Precautions ( 5.3 , 5.6 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied HUMALOG Mix75/25 (insulin lispro protamine and insulin lispro) injectable suspension is a white and cloudy suspension of 100 units/mL (U-100) of 75% insulin lispro protamine and 25% insulin lispro available as: One 10 mL multiple-dose vial NDC 0002-7511-01 Five 3 mL single-patient-use KwikPen prefilled pen NDC 0002-8797-59 HUMALOG Mix75/25 KwikPen must never be shared between patients, even if the needle is changed. Patients using HUMALOG Mix75/25 vials must never share needles or syringes with another person. Always use a new disposable syringe or needle for each injection to prevent contamination. The HUMALOG Mix75/25 KwikPen dials in 1 unit increments. 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 storage table below: a When stored at room temperature, HUMALOG Mix75/25 vial can only be used for a total of 28 days including both not in use (unopened) and in-use (opened) storage time. b When stored at room temperature, HUMALOG Mix75/25 KwikPen can only be used for a total of 10 days including both not in-use (unopened) and in-use (opened) storage time. Not In-Use (Unopened) Refrigerated (36° to 46°F [2° to 8°C]) Not In-Use (Unopened) Room Temperature (up to 86°F [30°C]) In-Use (Opened) (see temperature below) 10 mL multiple-dose vial a Until expiration date 28 days 28 days Refrigerated or room temperature 3 mL single-patient-use KwikPen b prefilled pen Until expiration date 10 days 10 days Room temperature only (Do not refrigerate)

16.1 How Supplied HUMALOG Mix75/25 (insulin lispro protamine and insulin lispro) injectable suspension is a white and cloudy suspension of 100 units/mL (U-100) of 75% insulin lispro protamine and 25% insulin lispro available as: One 10 mL multiple-dose vial NDC 0002-7511-01 Five 3 mL single-patient-use KwikPen prefilled pen NDC 0002-8797-59 HUMALOG Mix75/25 KwikPen must never be shared between patients, even if the needle is changed. Patients using HUMALOG Mix75/25 vials must never share needles or syringes with another person. Always use a new disposable syringe or needle for each injection to prevent contamination. The HUMALOG Mix75/25 KwikPen dials in 1 unit increments.