Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPen

1 INDICATIONS AND USAGE Insulin Lispro Protamine and Insulin Lispro Mix75/25 is indicated to improve glycemic control in adults with diabetes mellitus. Insulin Lispro Protamine and Insulin Lispro Mix75/25™ 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 Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 intravenously or by a continuous subcutaneous insulin infusion pump. ( 2.1 ) Insulin Lispro Protamine and Insulin Lispro 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. This product is HUMALOG Mix75/25 [see Warnings and Precautions ( 5.4 )] . Insulin Lispro Protamine and Insulin Lispro Mix75/25 is a suspension that must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature. To resuspend 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 visually before use. Do not use if discoloration or particulate matter is seen. Administration Instructions After resuspension, immediately administer Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen dials in 1 unit increments. Use Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do not administer Insulin Lispro Protamine and Insulin Lispro Mix75/25 intravenously or by a continuous subcutaneous insulin infusion pump. Do not mix Insulin Lispro Protamine and Insulin Lispro Mix75/25 with any other insulins or diluents. 2.2 Dosage Recommendations Individualize and adjust the dosage of Insulin Lispro Protamine and Insulin Lispro Mix75/25 based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. Inject Insulin Lispro Protamine and Insulin Lispro Mix75/25 subcutaneously within 15 minutes before a meal. Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25, a different dosage of Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 is used concomitantly with certain drugs [see Drug Interactions ( 7 )] .

4 CONTRAINDICATIONS Insulin Lispro Protamine and Insulin Lispro Mix75/25 is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] in patients who have had hypersensitivity reactions to Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 or any of its excipients. ( 4 )

5 WARNINGS AND PRECAUTIONS Never share an Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen between patients, even if the needle is changed. ( 5.1 ) Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.2 ) Hypoglycemia: May be life-threatening. Increase frequency of blood glucose monitoring with changes to insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. ( 5.3 ) Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. ( 5.4 ) Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin Lispro Protamine and Insulin Lispro Mix75/25, monitor and treat if indicated. ( 5.5 ) Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 5.6 ) Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reductions or discontinuation if heart failure occurs. ( 5.7 ) 5.1 Never Share an Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen Between Patients Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPens must never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6 )] . Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with all insulins, including Insulin Lispro Protamine and Insulin Lispro Mix75/25. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly, and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )] , or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 insulin products have been reported. To avoid medication errors between Insulin Lispro Protamine and Insulin Lispro Mix75/25 and other insulins, instruct patients to always check the insulin label before each injection. 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including Insulin Lispro Protamine and Insulin Lispro Mix75/25. If hypersensitivity reactions occur, discontinue Insulin Lispro Protamine and Insulin Lispro Mix75/25; treat per standard of care and monitor until symptoms and signs resolve. Insulin Lispro Protamine and Insulin Lispro Mix75/25 is contraindicated in patients who have had hypersensitivity reactions to Insulin Lispro Protamine and Insulin Lispro Mix75/25 or any of its excipients [see Contraindications ( 4 )] . 5.6 Hypokalemia All insulins, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25, 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.

7 DRUG INTERACTIONS Table 1 below presents clinically significant drug interactions with Insulin Lispro Protamine and Insulin Lispro Mix75/25. Table 1: Clinically Significant Drug Interactions with Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro 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 Insulin Lispro Protamine and Insulin Lispro 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 )

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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25. 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25. Hypokalemia Insulin Lispro Protamine and Insulin Lispro Mix75/25 can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection site reactions Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25. Lipodystrophy Administration of insulin subcutaneously, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 have been identified during postapproval use. Peripheral Edema Insulins, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25, 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 is unknown.

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 Insulin Lispro Protamine and Insulin Lispro Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of Insulin Lispro Protamine and Insulin Lispro 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.