FDA label 270de939-e175-41d2-ab62-6409f586bc38

5 WARNINGS 5.2 Changes in Insulin Regimen Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. These changes should be made cautiously and under close medical supervision and the frequency of blood glucose monitoring should be increased. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN N. Severe hypoglycemia can cause seizures, 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 insulin preparations, the glucose lowering effect time course of HUMULIN N 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 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMULIN N. If hypersensitivity reactions occur, discontinue HUMULIN N; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions ( 6 )] . HUMULIN N is contraindicated in patients who have had hypersensitivity reactions to HUMULIN N or any of its excipients [see Contraindications ( 4 )] . 5.5 Hypokalemia All insulin products, including HUMULIN N, 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). 5.6 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 HUMULIN N, 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.

5 WARNINGS AND PRECAUTIONS Never share a HUMULIN N KwikPen or syringe between patients, even if the needle is changed. ( 5.1 ) Changes in Insulin Regimen : Carry out under close medical supervision and increase frequency of blood glucose monitoring. ( 5.2 ) Hypoglycemia : May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. ( 5.3 , 7 , 8.6 , 8.7 ) Hypersensitivity Reactions : May be life-threatening. Discontinue HUMULIN N, monitor and treat if indicated. ( 5.4 ) Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 5.5 ) Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.6 ) 5.1 Never Share a HUMULIN N KwikPen or Syringe Between Patients HUMULIN N KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMULIN N vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypokalemia [see Warnings and Precautions ( 5.5 )] . The following additional adverse reactions have been identified during post-approval use of HUMULIN N. 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 HUMULIN N 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 N 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 ( 5.4 )] . Peripheral Edema Some patients taking HUMULIN N 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 N, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration ( 2.2 )] in some patients. Weight gain Weight gain has occurred with some insulin therapies including HUMULIN N 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 insulin, including HUMULIN N.