Humulin

1 INDICATIONS AND USAGE HUMULIN 70/30 is a fixed ratio insulin formulation indicated to improve glycemic control in adults with diabetes mellitus. HUMULIN ® 70/30 is a mixture of insulin isophane human, an intermediate-acting human insulin, and insulin human, a short-acting insulin human, indicated to improve glycemic control in adults with diabetes mellitus. ( 1 )

2 DOSAGE AND ADMINISTRATION Only administer subcutaneously (in abdominal wall, thigh, upper arm, or buttocks). ( 2.2 ) Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.2 ) Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.3 ) See Full Prescribing Information for dosage adjustments due to drug interactions and patients with renal and hepatic impairment. ( 2.3 , 2.4 ) May use with a meal-time insulin if indicated. ( 2.4 ) 2.1 Important Administration Instructions Inspect HUMULIN N visually before use. It should not contain particulate matter and should appear uniformly cloudy after mixing. Do not use HUMULIN N if particulate matter is seen. Use HUMULIN N KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. 2.2 Route of Administration HUMULIN N should only be administered subcutaneously. Administer in the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. Rotate injection sites 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 )] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . The HUMULIN N KwikPen dials in 1 unit increments. Do not administer HUMULIN N intravenously and do not use HUMULIN N in an insulin infusion pump. 2.3 Dosage Information Individualize and adjust the dosage of HUMULIN N based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. 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 )] . 2.4 Dosage Adjustment due to Drug Interactions Dosage adjustment may be needed when HUMULIN N is coadministered with certain drugs [see Drug Interactions ( 7 )]. Dosage adjustment may be needed when changing from another insulin to HUMULIN N [see Warnings and Precautions ( 5.2 )] . Instructions for Mixing with Other Insulins HUMULIN N may be used with a prandial insulin if indicated. HUMULIN N may be mixed with HUMULIN R or HUMALOG before injection. If HUMULIN N is mixed with HUMULIN R, HUMULIN R should be drawn into the syringe first. Injection should occur immediately after mixing. If HUMULIN N is mixed with HUMALOG, HUMALOG should be drawn into the syringe first. Injection should occur immediately after mixing.

3 DOSAGE FORMS AND STRENGTHS Injectable suspension: 70% insulin isophane human and 30% insulin human, 100 units/mL (U-100), white and cloudy suspension available as: 10 mL multiple-dose vial 3 mL single-patient-use HUMULIN 70/30 KwikPen prefilled pen Injectable suspension 100 units/mL (U-100) available as: 10 mL multiple-dose vial ( 3 ) 3 mL single-patient-use HUMULIN ® 70/30 KwikPen ® prefilled pen ( 3 )

4 CONTRAINDICATIONS HUMULIN 70/30 is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )], and In patients who have had hypersensitivity reactions to HUMULIN 70/30 or any of its excipients [see Warnings and Precautions ( 5.5 )] . During episodes of hypoglycemia. ( 4 ) In patients with hypersensitivity to HUMULIN 70/30 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 )] . The following additional adverse reactions have been identified during post-approval use of HUMULIN 70/30. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Adverse reactions observed with insulin therapy include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight gain, and edema. ( 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. Allergic Reactions Some patients taking HUMULIN 70/30 have experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and Precautions ( 5.5 )] . Peripheral Edema Some patients taking HUMULIN 70/30 have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy Administration of insulin subcutaneously, including HUMULIN 70/30, 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. Weight gain Weight gain has occurred with insulins, including HUMULIN 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. Immunogenicity Development of antibodies that react with human insulin have been observed with all insulins, including HUMULIN 70/30.

7 DRUG INTERACTIONS Table 1: Clinically Significant Drug Interactions with HUMULIN 70/30 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 HUMULIN 70/30 is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30 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 HUMULIN 70/30 is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30 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 HUMULIN 70/30 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 HUMULIN 70/30 is co-administered with these drugs. Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 ) Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published studies over decades have not established an association with human insulin use during pregnancy and 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). Animal reproduction studies were not performed. 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 While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size. 8.2 Lactation Risk Summary Available data from published literature suggests that exogenous human insulin products, including HUMULIN 70/30, 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 HUMULIN 70/30 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HUMULIN 70/30 and any potential adverse effects on the breastfed child from HUMULIN 70/30 or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of HUMULIN 70/30 in pediatric patients have not been established. 8.5 Geriatric Use The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied [see Clinical Pharmacology ( 12.3 )] . Patients with advanced age using any insulin, including HUMULIN 70/30, may be at increased risk of hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions ( 5.3 )] . 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied [see Clinical Pharmacology ( 12.3 )] . Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied [see Clinical Pharmacology ( 12.3 )] . Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring.

12.1 Mechanism of Action HUMULIN 70/30 lowers 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 human is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. The amino acid sequence of insulin human is identical to human insulin and has the empirical formula C 257 H 383 N 65 O 77 S 6 with a molecular weight of 5.808 kDa. HUMULIN 70/30 (insulin isophane human and insulin human) injectable suspension is a mixture of 70% insulin isophane human suspension, an intermediate-acting insulin, and 30% insulin human injection, a short-acting insulin. HUMULIN 70/30 is a suspension of crystals produced from combining insulin human and protamine sulfate under appropriate conditions for crystal formation and mixing with insulin human injection. HUMULIN 70/30 is a sterile, white and cloudy suspension that contains insulin isophane human suspension (NPH) and insulin human injection (regular) for subcutaneous use. Each milliliter of HUMULIN 70/30 contains 100 units of insulin human, dibasic sodium phosphate (3.78 mg), glycerin (16 mg), metacresol (1.6 mg), phenol (0.65 mg), protamine sulfate (0.24 mg), zinc oxide content adjusted to provide 0.025 mg zinc ion, and Water for Injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 )] . Mild episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or physical activity level 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 HUMULIN 70/30 (insulin isophane human and insulin human) injectable suspension is 70% insulin isophane human and 30% insulin human, 100 units/mL (U-100), a white and cloudy suspension available as: 10 mL multiple-dose vial NDC 0002-8715-01 (HI-710) 5 x 3 mL single-patient-use HUMULIN 70/30 KwikPen NDC 0002-8803-59 (HP-8803) Each prefilled HUMULIN 70/30 KwikPen is for use by a single patient. HUMULIN 70/30 KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMULIN 70/30 vials must never share needles or syringes with another person. The HUMULIN 70/30 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 heat and light. Do not freeze. Do not use if it has been frozen. See Table 2 below for storage conditions. Table 2: Storage Conditions for HUMULIN 70/30 Vials and Pens a When stored at room temperature, HUMULIN 70/30 vial can only be used for a total of 31 days including both not in-use (unopened) and in-use (opened) storage time. b When stored at room temperature, HUMULIN 70/30 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) In-use (Opened) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) 10 mL multiple-dose vial a 31 days Until expiration date 31 days 31 days 3 mL single-patient-use HUMULIN 70/30 KwikPen b 10 days Until expiration date 10 days Do not refrigerate.

16.1 How Supplied HUMULIN 70/30 (insulin isophane human and insulin human) injectable suspension is 70% insulin isophane human and 30% insulin human, 100 units/mL (U-100), a white and cloudy suspension available as: 10 mL multiple-dose vial NDC 0002-8715-01 (HI-710) 5 x 3 mL single-patient-use HUMULIN 70/30 KwikPen NDC 0002-8803-59 (HP-8803) Each prefilled HUMULIN 70/30 KwikPen is for use by a single patient. HUMULIN 70/30 KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMULIN 70/30 vials must never share needles or syringes with another person. The HUMULIN 70/30 KwikPen dials in 1 unit increments.