INSULIN LISPRO PROTAMINE AND INSULIN LISPRO INJECTABLE SUSPENSION MIX75/25 KWIKPEN

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. Insulin Lispro Protamine and Insulin Lispro Mix75/25 is a mixture of 75% insulin lispro protamine, an intermediate-acting human insulin analog, and 25% 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: Insulin Lispro Protamine and Insulin Lispro Mix75/25 injectable suspension is a white and cloudy, sterile suspension for subcutaneous use. Each mL of Insulin Lispro Protamine and Insulin Lispro Mix75/25 contains 100 units of insulin lispro; dibasic sodium phosphate (2.0 mg), glycerin (16 mg), metacresol (1.76 mg), phenol (0.715 mg), protamine sulfate (0.28 mg), zinc oxide content adjusted to provide zinc ion (0.025 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

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.

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 )] .

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 )

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.

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 )

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: 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) 3 mL single-patient-use KwikPen Until expiration date 10 days 10 days Room temperature only (Do not refrigerate)