Human insulin: uses, appearance and warnings

HUMULIN R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day. HUMULIN ® R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day. ( 1 ) Limitation of Use: The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined. The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined. ( 1.1 ) 1.1 Limitation of Use The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined. The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined.

Injection: 500 units/mL (U-500) clear, colorless solution available as: 3 mL single-patient-use HUMULIN R U-500 KwikPen prefilled pen (containing 1,500 units of insulin) Injection: 500 units/mL (U-500) available as: ( 3 ) 3 mL single-patient-use HUMULIN ® R U-500 KwikPen ® prefilled pen (containing 1,500 units of insulin)

16.1 How Supplied HUMULIN R U-500 (500 units/mL) injection is available in a clear, colorless solution as: 2 x 3 mL single-patient-use HUMULIN R U-500 KwikPen NDC 0002-8824-27 The HUMULIN R U-500 KwikPen dials in 5 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. Do not shake the vial. See Table 2 below for storage conditions. Table 2: Storage Conditions for HUMULIN R U-500 Pens a When stored at room temperature, HUMULIN R U-500 KwikPen can only be used for a total of 28 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]) 3 mL single-patient-use HUMULIN R U-500 KwikPen a 28 days Until expiration date 28 days Do not refrigerate. 16.1 How Supplied HUMULIN R U-500 (500 units/mL) injection is available in a clear, colorless solution as: 2 x 3 mL single-patient-use HUMULIN R U-500 KwikPen NDC 0002-8824-27 The HUMULIN R U-500 KwikPen dials in 5 unit increments.

HUMULIN R U-500 is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] In patients who are hypersensitive to HUMULIN R U-500 or any of its excipients [see Warnings and Precautions ( 5.4 )] Do not use during episodes of hypoglycemia. ( 4 ) Do not use in patients with hypersensitivity to HUMULIN R U-500 or any of its excipients. ( 4 )

Never share a HUMULIN R U-500 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 monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. ( 5.3 ) Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMULIN R U-500, monitor, and treat if indicated. ( 5.4 ) Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for 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 R U-500 KwikPen Between Patients HUMULIN R U-500 KwikPens should 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, adjustments in concomitant oral anti-diabetic treatment may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN R U-500. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of HUMULIN R U-500. Hypoglycemia can impair concentration ability and reaction time; this may place the patient 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 patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, 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 timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulin preparations, the glucose lowering effect time course of HUMULIN R U-500 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. 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 concomitant drugs [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. To minimize the risk of hypoglycemia do not administer HUMULIN R U-500 intravenously or in an insulin pump or dilute or mix HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration ( 2.1 )] . 5.4 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including HUMULIN R U-500. If hypersensitivity reactions occur, discontinue HUMULIN R U-500; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions ( 6 )] . 5.5 Hypokalemia All insulins, including HUMULIN R U-500, 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. Use caution in patients who may be at risk for hypokalemia (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, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. …

The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] . Hypokalemia [see Warnings and Precautions ( 5.5 )] . The following additional adverse reactions have been identified during post-approval use of HUMULIN R U-500. 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 associated with HUMULIN R U-500 include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, 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. …

Table 1: Clinically Significant Drug Interactions with HUMULIN R U-500 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 R U-500 is co-administered with these drugs. …