Humulin Drug Information

R is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. HUMULIN ® R is a short-acting human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

Important

Administration Instructions Always check the insulin label before administration to confirm the correct insulin product is being used . Inspect HUMULIN R visually before use. It should appear clear and colorless. Do not use HUMULIN R if particulate matter or coloration is seen.

Route of

Administration Subcutaneous Injection Inject HUMULIN R subcutaneously approximately 30 minutes before meals into the thigh, upper arm, abdomen, 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 . HUMULIN R may be diluted with Sterile Diluent for HUMULIN R for subcutaneous injection ONLY under medical supervision.

Dilute one part HUMULIN R to nine parts diluent to yield a concentration one-tenth that of HUMULIN R (equivalent to U-10). Dilute one part HUMULIN R to one part diluent to yield a concentration one-half that of HUMULIN R (equivalent to U-50). Diluted HUMULIN R may be used for 28 days when stored at 41°F (5°C) or for 14 days when stored at 86°F (30°C). Intravenous Administration Administer HUMULIN R intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to reduce the risk of hypoglycemia and hypokalemia . For intravenous use, HUMULIN R should be used at concentrations from 0.1 unit/mL to 1 unit/mL in infusion systems containing 0.9% Sodium Chloride Injection. Intravenous infusion bags prepared with HUMULIN R are stable when stored in a refrigerator (36° to 46°F ) for 48 hours and then may be used at room temperature for up to an additional 48 hours.

Dosing Instructions Individualize and adjust the dosage of

HUMULIN R based on the route of administration, the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal. HUMULIN R given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring . Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (e.g., macronutrient content or timing of food intake), changes in renal or hepatic function, or during acute illness . Dosage adjustment may be needed when changing from another insulin to HUMULIN R .

Dosage Adjustment due to Drug Interactions Dosage adjustment may be needed when

HUMULIN R is co-administered with certain drugs .

Instructions for Mixing with Other Insulins for Subcutaneous Injection Do not mix

HUMULIN R with insulin preparations other than HUMULIN N. To mix HUMULIN R and HUMULIN N, draw HUMULIN R into the syringe first. Inject immediately after mixing.

The following adverse reactions are also discussed elsewhere in the labeling: Hypoglycemia Hypoglycemia Due to Medication Errors Hypersensitivity Hypokalemia Adverse reactions observed with HUMULIN R include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, and rash. 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 additional adverse reactions have been identified during clinical studies or from postmarketing reports with use of HUMULIN R. 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 to 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 allergic reactions may include anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, hypotension, and shock.

Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in HUMULIN R. Hypokalemia HUMULIN R can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection Site Reactions Injection site reactions may include injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. Lipodystrophy Administration of insulin subcutaneously, including HUMULIN R, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) 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 HUMULIN R have been identified during postapproval use. Peripheral Edema Insulins, including HUMULIN R, 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 HUMULIN R, and has been attributed to the anabolic effects of insulin. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with HUMULIN R is unknown.

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

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.

Pediatric Use HUMULIN R is indicated to improve glycemic control in pediatric patients with diabetes mellitus. The dosage of HUMULIN R must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose to reduce the risk of hypoglycemia .

R is contraindicated: during episodes of hypoglycemia in patients with hypersensitivity to HUMULIN R or any of its excipients Do not use during episodes of hypoglycemia. Do not use in patients with hypersensitivity to HUMULIN R or any of its excipients.

Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately .