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Insulin Human (Monograph)

Brand names: HumuLIN N, HumuLIN R, NovoLIN N, NovoLIN R
Drug class: Short-acting Insulins

Introduction

Antidiabetic agent; a biosynthetic protein that is structurally identical to endogenous insulin secreted by the beta cells of the human pancreas.1 2 3 5 6 38 53 65 71 75 76 Commercially available as short-acting or intermediate-acting insulins.1 2 3 5 6 38 53 65 71 75 76

Uses for Insulin Human

Diabetes Mellitus

Replacement therapy for the management of diabetes mellitus.5 6 7 8 12 113 Human insulin manufactured using recombinant DNA technology has replaced insulins of animal origin (no longer commercially available in the US).103

Insulin is required in all patients with type 1 diabetes mellitus, and mandatory in the treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic states.iii

Also used in patients with type 2 diabetes mellitus when weight reduction, proper dietary regulation, and/or oral antidiabetic agents have failed to maintain satisfactory glycemic control in both the fasting and postprandial state.z aa ee eee

Diet should be emphasized as the primary form of treatment when initiating therapy for patients with type 2 diabetes mellitus who do not have severe symptoms;ggg hhh caloric restriction and weight reduction are essential in obese patients.ggg

The American Diabetes Association (ADA) and many clinicians recommend the use of physiologically based, intensive insulin regimens (i.e., 3 or more insulin injections daily with dosage adjusted according to the results of multiple daily blood glucose determinations [e.g., at least 4 times daily], dietary intake, and anticipated exercise) in most type 1 and type 2 diabetic patients who are able to understand and carry out the treatment regimen, are not at increased risk for hypoglycemic episodes, and do not have other characteristics that increase risk or decrease benefit (e.g., advanced age, end-stage renal failure, advanced cardiovascular or cerebrovascular disease, other coexisting diseases that shorten life expectancy).v eee

Goals of insulin therapy in all patients generally should include maintenance of blood glucose as close as possible to euglycemia without undue risk of hypoglycemia; avoidance of symptoms attributable to hyperglycemia, glycosuria, or ketonuria; and maintenance of ideal body weight and of normal growth and development in children.bb hh

Diabetic Ketoacidosis or Hyperosmolar Hyperglycemic States

Used in the emergency treatment of diabetic ketoacidosis or hyperosmolar hyperglycemic states when rapid control of hyperglycemia is required.5 6 7 8 12 113 Regular insulin (e.g., insulin human [regular], insulin [regular]) is the insulin of choice in the treatment of such emergency conditions because of its relatively rapid onset of action and because it can be administered IV.113

Critical Illness

Has been used to reduce morbidity and mortality in patients with critical illness† [off-label] requiring intensive care.

Gestational Diabetes Mellitus

The ADA states that human insulin is preferred for use in pregnant women or women considering pregnancy.103 The ADA recommends that insulin therapy (using insulin human) be considered in patients with gestational diabetes who, despite dietary management, have fasting plasma glucose concentrations exceeding 105 mg/dL or 2-hour postprandial plasma glucose concentrations exceeding 130 mg/dL.

Insulin Human Dosage and Administration

General

Transferring from Therapy with Other Insulins

Administration

Insulin human (regular) and isophane insulin human suspension usually are administered sub-Q.12 54 55 71 75 82 84 88

Also may administer insulin human (regular) IM† [off-label] or IV under medical supervision with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia or hypokalemia.125 Insulin human (regular) is the only form of insulin human that may be administered IV.54 55

Do not administer isophane insulin human suspension IV.54 55

Sub-Q Administration

Administer insulin human (regular) injection and isophane insulin human suspension usually by sub-Q injection.12 55 71 75 82 84 88

Avoid excessive agitation of the vial prior to withdrawing the insulin human regular dose since loss of potency, clumping, frosting, or precipitation may occur.67 101

Since suspensions contain insulin in the precipitate, gently agitate the vial to assure a homogeneous mixture for accurate measurement of each dose.6 8 75 84 92 93 Slowly rotate and invert or carefully shake the vial several times before withdrawal of each dose.6 8 75 84 Avoid vigorous shaking since frothing may interfere with correct measurement of a dose.6 8

Administer into the thighs, upper arms, buttocks, or abdomen using a 25- to 28-gauge needle, one-half to five-eighths inch in length.e g h j

Most individuals should grasp a fold of skin lightly with the fingers at least 3 inches apart and insert the needle at a 90° angle; thin individuals or children may need to pinch the skin and inject at a 45° angle to avoid IM injection, especially in the thigh area.s

Routine aspiration to check for inadvertent intravascular injection generally is not necessary.s

Inject over a period of 2–4 seconds.g h j Slow sub-Q injection of insulin suspensions may result in clogging of the tip of the needle.6 8

Press injection site lightly for a few seconds after the needle is withdrawn; do not rub.e g h j

Rotate sites so that any one site is not injected more than once every 1–2 weeks.eee

IV Administration

Dilution

For IV infusion, usually dilute insulin human (regular) injection to a concentration of 0.05–1 unit/mL in 0.9% sodium chloride or 5 or 10% dextrose injection with 40 mEq/L of potassium chloride in polypropylene infusion bags.54 55 125

Standardize 4 Safety

Standardized concentrations for insulin (regular) have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care.249 250 Because recommendations from the S4S panels may differ from the manufacturer’s prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label.249 250 For additional information on S4S (including updates that may be available), see [Web]249 250 .

DKA protocols may require units/kg/hour

Table 1: Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Insulin (Regular)249250

Patient Population

Concentration Standards

Dosing Units

Adults

1 unit/mL

units/hour

Pediatric patients (<50 kg)

0.2 units/mL

units/kg/hour

1 unit/mL

Dosage

Dosage must be individualized.o

Patients receiving insulin should be monitored with regular laboratory evaluations, including blood glucose determinations and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations, to determine the minimum effective dosage of insulin when used alone, with other insulins, or in combination with an oral antidiabetic agent.t ii

Pediatric Patients

Diabetes Mellitus
Sub-Q

Children with newly diagnosed type 1 diabetes mellitus initially require total daily insulin dosage of 0.5–1 units/kg; requirement may be much lower during partial remission period.125 mmm May need substantially higher daily dosage in severe insulin resistance (e.g., puberty, obesity).125

In patients with type 2 diabetes mellitus, initial total daily dosage ranges from 0.2–0.4 units/kg.125

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic States
IV

In children and adolescents <20 years of age, the ADA recommends initially an IV infusion of regular insulin at a rate of 0.1 units/kg per hour.113 An initial direct IV injection of regular insulin is not recommended in such patients.113

IM† [off-label], then Sub-Q

If IV access is unavailable, regular insulin may be given IM in an initial dose of 0.1 units/kg, followed by 0.1 units/kg per hour sub-Q or IM until acidosis is resolved (i.e., venous pH >7.3, serum bicarbonate concentration >15 mEq/L).113

Dosage Following Resolution of Diabetic Ketoacidosis
IV, then Sub-Q

Upon resolution of ketoacidosis or the hyperosmolar state, the regular insulin IV infusion rate should be decreased to 0.05 units/kg per hour until sub-Q replacement insulin therapy is initiated.113

Initiate replacement therapy at an insulin dosage of 0.5–1 units/kg daily given sub-Q in divided doses ((2/3) of the daily dosage in the morning [(1/3) as short-acting insulin, (2/3) as intermediate-acting insulin] and (1/3) in the evening [½ as short-acting insulin, ½ as intermediate-acting insulin]).113 In pediatric patients with newly diagnosed diabetes mellitus, may administer 0.1–0.25 units/kg of regular insulin every 6–8 hours during the first 24 hours to determine insulin requirements.113

Adults

Diabetes Mellitus
Sub-Q

Initial total daily insulin dosages in adults with type 1 diabetes mellitus range from 0.2–1 units/kg.v ee ff eee lll mmm May need substantially higher daily dosage in severe insulin resistance (e.g., obesity).125

In patients with type 2 diabetes mellitus, initial total daily dosage ranges from 0.2–0.4 units/kg.125

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic States
Mild Diabetic Ketoacidosis
IV, then Sub-Q or IM† [off-label]

For the treatment of mild diabetic ketoacidosis (plasma glucose >250 mg/dL with an arterial pH of 7.25–7.3 and serum bicarbonate of 15–18 mEq/L), the ADA recommends a loading dose of 0.4–0.6 units/kg of regular insulin administered in 2 doses, with 50% given by direct IV injection and 50% by sub-Q or IM injection.113 After the loading dose, administer 0.1 units/kg per hour of regular insulin sub-Q or IM.113

Moderate to Severe Diabetic Ketoacidosis
IV

For the treatment of moderate to severe diabetic ketoacidosis (plasma glucose >250 mg/dL with arterial pH ≤7–7.24 and serum bicarbonate ≤10–15 mEq/L) or hyperosmolar hyperglycemia in adults, the ADA recommends a loading dose of 0.15 units/kg of regular insulin by direct IV injection, followed by continuous IV infusion of 0.1 units/kg per hour.113

If plasma glucose concentrations do not fall by 50 mg/dL within the first hour of insulin therapy, insulin infusion rate may be doubled every hour, provided the patient is adequately hydrated, until plasma glucose decreases steadily by 50–75 mg/dL per hour.113

When a plasma glucose concentration of 250 or 300 mg/dL is achieved in patients with diabetic ketoacidosis or hyperosmolar hyperglycemia, respectively, may decrease the insulin infusion rate to 0.05–0.1 units/kg per hour.113 May need to adjust the rate of insulin administration or the concentration of dextrose to maintain glucose concentration until resolution of diabetic ketoacidosis (i.e., serum glucose <200 mg/dL, venous pH >7.3, serum bicarbonate ≥18 mEq/L) or hyperosmolar hyperglycemia (i.e., patient mentally alert, serum osmolality of ≤315 mOsm/kg).b

Dosage Following Resolution of Diabetic Ketoacidosis
IV, then Sub-Q

Upon resolution of diabetic ketoacidosis (i.e., plasma glucose <200 mg/dL, venous pH >7.3, serum bicarbonate ≥18 mEq/L) or hyperosmolar hyperglycemia in patients who are unable to eat, continue IV insulin and fluid replacement; may give sub-Q regular insulin as needed every 4 hours.113 May give regular insulin sub-Q in 5-unit increments for every 50-mg/dL increase in blood glucose concentrations above 150 mg/dL, to a dose of up to 20 units of regular insulin for a blood glucose of ≥300 mg/dL.113

When the patient is able to eat, initiate a multiple-dose, sub-Q insulin regimen consisting of a short- or rapid-acting insulin and an intermediate- or long-acting insulin.113 Continue regular insulin IV for 1–2 hours after initiation of the sub-Q insulin regimen to ensure adequate plasma insulin concentrations during the transition.113 Abrupt discontinuance of IV insulin with the institution of delayed-onset sub-Q insulin may lead to worsened glycemic control.113 Patients with known diabetes mellitus may reinstitute the insulin regimen they were receiving before the onset of hyperglycemic crises, and the regimen may be adjusted further as needed for adequate glycemic control.113

Patients with newly diagnosed diabetes mellitus should receive a total daily insulin dosage of 0.5–1 units/kg as part of a multiple-dose regimen of insulin, until an optimal dosage is established.113 May manage some patients with newly diagnosed type 2 diabetes mellitus with diet therapy and oral antidiabetic agents following resolution of hyperglycemic crises.113

Cautions for Insulin Human

Warnings/Precautions

Warnings

Hypoglycemia

Care should be taken in patients who are most at risk for the development of these effects, including patients who are fasting or those with defective counterregulatory responses (e.g., patients with autonomic neuropathy, adrenal or pituitary insufficiency, those receiving β-adrenergic blocking agents).v z ee ff r ss bbb .

Reduce the potential for late postprandial hypoglycemia by altering the timing, frequency, and content of meals; altering exercise patterns; frequently monitoring blood glucose concentrations; adjusting insulin dosage; and/or switching to a more rapid-acting insulin (i.e., insulin lispro).v x y aa ff gg hh jj kk mm nn qq uu vv ww xx eee

Use intensive insulin therapy with caution in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes.v cc ee hh tt ccc Higher target blood glucose concentrations (e.g., fasting blood glucose concentrations of 140 mg/dL and 2-hour postprandial concentrations of 200–250 mg/dL) are advisable in these patients.v ee ff

Exercise extreme caution when concentrated (U-500) insulin human (regular) injection is used in patients with marked insulin resistance (i.e., daily insulin requirements >200 units).o Inadvertent overdosage may result in irreversible insulin shock.o Serious consequences may result if this concentrated injection is used without constant medical supervision.o

Sensitivity Reactions

Local reactions (e.g., pain at injection site, erythema, pruritus, swelling) reported.c Warming refrigerated insulin to room temperature prior to use will limit local irritation at the injection site.67 101

Generalized hypersensitivity reactions (e.g., rash, shortness of breath, wheezing, hypotension, tachycardia, diaphoresis) reported less frequently, but may be life-threatening.c The incidence of allergic reactions may have decreased with the availability of more purified insulin (e.g., insulin human, insulin lispro).z aa ff

Insulin Resistance

Chronic insulin resistance resulting from immunity has been decreased by changing to a purified insulin preparation (e.g., insulin human).qq zz aaa

General Precautions

Lipodystrophy

Atrophy or hypertrophy of subcutaneous fat tissue may occur at sites of frequent insulin injections.c Rotate injection site to reduce or prevent these effects.d

Hypokalemia

Care should be taken in patients who are most at risk for the development of hypokalemia, such as those who are receiving potassium-lowering drugs.t ff

Since diabetic ketoacidosis often is associated with hypokalemia, the possibility of potassium imbalance should be evaluated and, if present, corrected before administration of insulin as long as adequate renal function is assured.

Concurrent Illness

Illness, particularly nausea and vomiting, and changes in eating patterns may alter insulin requirements.c

Use of Fixed Combinations

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category B.

Most clinicians recommend initiation of intensive insulin therapy (3 or more insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) prior to conception in diabetic patients who are well controlled on oral hypoglycemic agents and who are considering pregnancy.aa eee

Geriatric Use

The safety of an intensive insulin regimen (3 or more insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) in geriatric patients has been questioned.ff hh ii oo ddd eee Increased incidence of hypoglycemia associated with intensive insulin therapy may increase the probability of strokes and heart attacks in such patients.ff hh ii oo ddd eee

Hypoglycemic reactions in geriatric diabetic patients may mimic a cerebrovascular accident.d An increased incidence of macrovascular disease in geriatric patients with type 2 diabetes mellitus may make such patients more vulnerable to serious consequences of hypoglycemiahh (e.g., fainting, seizures, falls, stroke, silent ischemia, MI, sudden death).hh

Common Adverse Effects

Hypoglycemia.s t ff pp

Drug Interactions

Specific Drugs

Insulin Human Pharmacokinetics

Absorption

Bioavailability

Because of its protein nature, insulin is destroyed in the GI tract and usually is administered parenterally.e

Following sub-Q injection, insulin human (regular) appears to be absorbed more rapidly than purified pork insulin (regular) (no longer commercially available in the US).17 24 28 29 30 42

Following IM or IV administration, serum insulin concentrations are similar for insulin human (regular) and purified pork insulin (regular) (no longer commercially available in the US).17 18 19 31 32 43

Onset and Duration of Action of Human Insulins

In patients with diabetes mellitus, insulin human appears to have a slightly faster onset and shorter duration of action than purified pork insulin (no longer commercially available in the US).58

Distribution

Extent

Rapidly distributed throughout extracellular fluids.e

Elimination

Metabolism

Rapidly metabolized mainly in the liver and to a lesser extent in the kidneys and muscle tissue.e

Elimination Route

Excreted in the urine principally as metabolites.e

Half-life

Insulin has a plasma half-life of a few minutes in healthy individuals.e The biologic half-life may be prolonged in diabetic patients, probably as a result of binding of the hormone to antibodies.w eee

Special Populations

In patients with renal impairment, the biologic half-life may be prolonged as a result of altered degradation/decreased clearance.w eee

Stability

Storage

Parenteral

Solution for Injection

With unopened vials or cartridges of insulin human injections than have not been placed in a delivery device, store at 2–8°C; do not freeze.5 7 53 64 67 71 82 89 93 100 101 c j Vials in use, store below 30°C; protect from excessive heat or cold and light.67 c

Discard insulin human (regular) injection exhibiting discoloration, turbidity, or unusual viscosity,5 7 71 82 88 89 since these changes indicate deterioration or contamination.5 7 101

Suspension for Injection

With unopened vials, pens, prefilled syringes, or cartridges containing isophane insulin human suspensions, 2–8°C in the original container; do not freeze.6 8 53 64 65 80 84 92 93 100 101 f g h i k l m p q With vials in use, below 30°C; protect from heat and light.80 g h i k l m r Freezing will cause isophane insulin human to resuspend improperly, preventing accurate measurement of a dose.54 55 In addition, agglomeration of particles may occur, altering absorption from the injection site.54 55

Preparations of insulin isophane suspension available with a delivery device (e.g., Humulin N pen) are stable below 30°C for 14 days.67 m Protect from excessive heatf m or coldf and light.f m

Combination preparations of insulin human and isophane insulin human suspension available with a delivery device (Humulin 70/30 pen) are stable below 30°C for 10 days.67 p Should discard unrefrigerated insulin after 10 days.p Protect from excessive heat and light.p

Should discard isophane insulin human if the suspension is clear, if it remains clear after the vial is rotated, if the precipitate has become clumped or granular in appearance, or if solid particles have adhered to the wall of the vial.6 8 64 65 75 76 80 83 84 90 92 93 101

Actions

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Insulin Human (Regular) (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

100 units/mL

HumuLIN R

Lilly

NovoLIN R

Novo Nordisk

500 units/mL

HumuLIN R (concentrated U-500)

Lilly
Isophane Insulin Human (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Suspension, sterile

100 units/mL

HumuLIN N

Lilly

HumuLIN N Pen (available as prefilled cartridge preassembled into pen)

Lilly

NovoLIN N

Novo Nordisk
Insulin Human Combinations (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Suspension, sterile

Insulin Human (Regular) 30 units/mL with Isophane Insulin Human 70 units/mL

HumuLIN 70/30

Lilly

HumuLIN 70/30 Pen (available as cartridge pressambled into pen)

Lilly

NovoLIN 70/30

Novo Nordisk

AHFS DI Essentials™. © Copyright 2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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