HUMULIN 70/30

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.

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 )

Only administer subcutaneously (in abdominal wall, thigh, upper arm, or buttocks). ( 2.1 ) Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 ) Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.2 ) See Full Prescribing Information for dosage adjustments due to drug interactions and patients with renal and hepatic impairment. ( 2.2 ) Administer approximately 30-45 minutes before a meal. ( 2.2 ) 2.1 Important Administration Instructions Inspect HUMULIN 70/30 visually before use. It should not contain particulate matter and should appear uniformly cloudy after mixing. Do not use HUMULIN 70/30 if particulate matter is seen. Administer HUMULIN 70/30 subcutaneously into 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 )] . The HUMULIN 70/30 KwikPen dials in 1 unit increments. Use HUMULIN 70/30 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do not administer HUMULIN 70/30 intravenously and do not use in an insulin infusion pump. Do not mix HUMULIN 70/30 with any other insulins or diluents. 2.2 Dosage Information Inject HUMULIN 70/30 subcutaneously approximately 30-45 minutes before a meal. The proportion of rapid acting and long acting insulin is fixed in a premixed insulin such as HUMULIN 70/30. Independent adjustment of the basal or prandial dose is not possible when using a premixed insulin. Individualize and adjust the dosage of HUMULIN 70/30 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 )] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . HUMULIN 70/30 dose requirements may change with changes in level of physical activity, meal patterns (i.e., macronutrient content or timing of food intake), during major illness, or with some coadministered drugs [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.6 , 8.7 )] .

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 )

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.

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 )

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 3 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.