Humulin N, R, RU 500 - Drug Monograph

Introduction

Humulin N, R, and RU 500 are recombinant human insulin preparations manufactured by Eli Lilly and Company. These products represent important therapeutic options in diabetes management. Humulin R (Regular insulin) is a short-acting insulin, Humulin N (NPH insulin) is an intermediate-acting insulin, and Humulin R U-500 is a concentrated regular insulin formulation containing 500 units/mL for patients with significant insulin resistance.

Mechanism of Action

Insulin regulates glucose metabolism by binding to insulin receptors on target cells, primarily in liver, muscle, and adipose tissue. This binding activates intracellular signaling pathways that promote glucose uptake, glycogen synthesis, lipogenesis, and protein synthesis while inhibiting gluconeogenesis, glycogenolysis, lipolysis, and proteolysis. Humulin R has an onset of 30-60 minutes, peak of 2-3 hours, and duration of 5-8 hours. Humulin N has an onset of 2-4 hours, peak of 4-10 hours, and duration of 10-16 hours. Humulin R U-500 has a delayed onset and prolonged duration compared to regular U-100 insulin.

Indications

• Treatment of type 1 diabetes mellitus
• Treatment of type 2 diabetes mellitus when glycemic control cannot be achieved with oral agents alone
• Gestational diabetes management when needed
• Hyperglycemic emergencies (DKA/HHS) - primarily using regular insulin
• Perioperative glycemic control
• Humulin R U-500 is specifically indicated for the treatment of diabetic patients with marked insulin resistance requiring more than 200 units of insulin daily

Dosage and Administration

• Typically administered 15-30 minutes before meals (Regular)
• NPH usually administered once or twice daily
• U-500: Extreme caution required due to high concentration - typically administered 2-3 times daily before meals

• Renal impairment: Reduced insulin requirements may be necessary
• Hepatic impairment: Reduced insulin requirements may be necessary
• Elderly: May require lower doses due to decreased renal function
• Pediatrics: Dosing based on weight and individual response

Pharmacokinetics

Contraindications

• Hypersensitivity to insulin or any product component
• Hypoglycemia
• During hypoglycemic episodes
• U-500: Should not be used in insulin-sensitive patients or those requiring less than 200 units daily

Warnings and Precautions

• Hypokalemia: Insulin may cause intracellular shift of potassium
• Lipodystrophy: May occur at injection sites
• Weight gain
• Fluid retention and heart failure with intensive insulin therapy
• Hypersensitivity reactions (rare)
• U-500 specific: High potential for dosing errors due to concentration - requires special prescription notation and patient education

Drug Interactions

• Oral antidiabetic agents
• ACE inhibitors
• Disopyramide
• Fluoxetine
• Fibrates
• Pentoxifylline
• Salicylates
• Somatostatin analogs
• MAOIs
• Beta-blockers (may mask hypoglycemia symptoms)

• Corticosteroids
• Diuretics
• Sympathomimetics
• Phenothiazines
• Thyroid hormones
• Estrogens
• Progestogens
• Protease inhibitors
• Atypical antipsychotics

• Beta-blockers: May blunt hypoglycemia symptoms
• Alcohol: Potentiates hypoglycemic effect

Adverse Effects

• Hypoglycemia
• Injection site reactions (erythema, swelling, itching)
• Weight gain
• Hypokalemia

• Lipodystrophy
• Peripheral edema
• Allergic reactions

• Anaphylaxis
• Visual changes (transient)
• Sodium retention

Monitoring Parameters

• Blood glucose monitoring (preprandial, postprandial, bedtime)
• HbA1c every 3 months until stable, then every 6 months
• Regular assessment of hypoglycemia awareness
• Injection site examination
• Renal function (serum creatinine)
• Electrolytes (especially potassium)
• Weight trends
• Self-monitoring of blood glucose patterns

Patient Education

• Proper injection technique and rotation of injection sites
• U-500 requires U-500-specific syringes - never use U-100 syringes
• Storage requirements (refrigerate unopened vials/pens, room temperature for in-use products)

• Recognition of symptoms (sweating, tremor, palpitations, hunger)
• Treatment with 15-20g fast-acting carbohydrate
• Glucagon prescription and administration education for severe episodes

• Consistency in meal timing and carbohydrate intake
• Alcohol consumption precautions
• Exercise adjustments
• Sick-day management

• Never share pens or needles
• Proper disposal of sharps
• Carry diabetes identification
• Inform healthcare providers about insulin therapy

References

1. American Diabetes Association. Standards of Medical Care in Diabetes - 2024. Diabetes Care. 2024;47(Suppl 1):S1-S300.

2. Hirsch IB, Juneja R, Beals JM, et al. The Evolution of Insulin and How it Informs Therapy and Treatment Choices. Endocr Rev. 2020;41(5):733-755.

3. FDA Prescribing Information: Humulin R U-100, Humulin N, Humulin R U-500.

4. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine Society. Diabetes Care. 2013;36(5):1384-1395.

5. Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2021;64(12):2609-2652.

6. Lane WS, Weinrib SL, Rappaport JM. U-500 regular insulin: clinical experience and pharmacokinetics in obese, insulin-resistant type 2 diabetic patients. Diabetes Care. 2010;33(2):281-283.