Insulin Human (Monograph)

Brand names: Afrezza, HumuLIN N, HumuLIN R, Myxredlin, 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. Commercially available insulin human formulations are classified as short-acting (insulin human [regular]) or intermediate-acting (isophane insulin human).

Uses for Insulin Human

Diabetes Mellitus

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

Commercially available as single entity preparation and also in fixed combination of short- and intermediate-acting insulin.

Concentrated (U-500) insulin human (regular) used in patients with marked insulin resistance (daily requirement >200 units) so that a large dose may be administered in reasonable volume.

Insulin human dry powder for inhalation used in adult patients for management of diabetes mellitus;notrecommended for treatment of diabetic ketoacidosis or in patients who smoke or recently stopped smoking.

Guidelines from the American Diabetes Association (ADA) and other experts generally recommend insulin be considered in type 2 diabetes mellitus in patients with symptoms of hyperglycemia or when the HbA_1c or blood glucose are very high (i.e., HbA^_1c >10% or blood glucose ≥300 mg/dL). Insulin therapy may also be considered in patients on other antidiabetic agents who require additional glycemic control. Insulin, typically as combination of basal, mealtime, and correction, is essential for the treatment of type 1 diabetes and should be tailored to individual patient to meet glycemic goals, prevent diabetic ketoacidosis, and minimize risk of hypoglycemia. When selecting treatment regimen, consider factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences. Weight management should be included as a distinct treatment goal and other healthy lifestyle behaviors should also be considered. In all patients treated with insulin, routine assessment of administration technique is essential to ensure optimized safety and efficacy.

ADA states that insulin human should be used in pregnant women with type 1 diabetes mellitus and is preferred in patients with type 2 diabetes mellitus and gestational diabetes mellitus.

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. 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.

Cardiovascular Disease/Hyperkalemia

IV insulin human (often in combination with glucose to prevent hypoglycemia) used to shift potassium intracellularly in management of hyperkalemic emergencies when urgent reduction in serum potassium levels needed^{† [off-label]}.

β-Adrenergic or Calcium Channel Blocking Agent Overdosage

Resuscitation following cardiac arrest from β-adrenergic or calcium channel blocking agent overdosage should follow standard basic life support (BLS) and advanced cardiac life support (ACLS) algorithms. While no controlled studies have been conducted, available evidence indicates that high-dose insulin euglycemic therapy utilizing IV insulin human (regular) at 1—10 units/kg per hour following a 1 unit/kg loading dose (in combination with glucose) can increase heart rate and improve hemodynamics and can be considered in patients in refractory shock.

Insulin Human Dosage and Administration

General

Pretreatment Screening

• Evaluate all patients with medical history, physical examination, and spirometry (FEV₁) to identify potential underlying lung disease before initiating therapy with insulin human dry powder for inhalation.

Patient Monitoring

• Self-monitoring of blood glucose is essential in prevention and management of hypoglycemia. In patients at higher risk of hypoglycemia and those with reduced symptomatic awareness, increased frequency of blood glucose monitoring is recommended.

• Changes to insulin regimen should be performed under close medical supervision with increased frequency of blood glucose monitoring.

• Monitor potassium levels in patients at risk for hypokalemia (e.g., patients taking potassium-lowering medications or medications sensitive to serum potassium concentrations).

• Observe for signs and symptoms of heart failure in patients taking insulin human and a peroxisome proliferator-activated receptor (PPAR)-γ agonist (i.e., a thiazolidinedione).

• After initiating therapy with insulin human dry powder for inhalation, assess pulmonary function (e.g., spirometry) after first 6 months of therapy and annually thereafter, even in absence of pulmonary symptoms. Consider more frequent monitoring in patients with symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough.

• Patients receiving insulin should be monitored with regular laboratory evaluations, including blood glucose determinations and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations, to determine the minimum effective dosage of insulin when used alone, with other insulins, or in combination with an oral antidiabetic agent.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices, insulin human is a high-alert medication that has a heightened risk of significant patient harm if used in error.

• The ISMP includes HumuLIN (insulin human regular) and NovoLIN (insulin human regular), HumuLIN (insulin human regular) and HumaLOG (insulin lispro), and HumuLIN R U-100 (insulin human regular) and HumuLIN R U-500 (insulin human regular) on the ISMP List of Confused Drug Names, and recommends special safeguards to ensure the accuracy of prescriptions for these drugs.

• The ISMP includes HumuLIN 70/30 (isophane insulin human and insulin human regular) and HumaLOG Mix 75/25 (insulin lispro protamine and insulin lispro) on the ISMP List of Confused Drug Names, and recommends special safeguards to ensure the accuracy of prescriptions for these drugs.

• The ISMP includes NovoLIN (insulin human regular) and HumuLIN (insulin human regular) and NovoLIN (insulin human regular) and NovoLOG (insulin aspart) on the ISMP List of Confused Drug Names, and recommends special safeguards to ensure the accuracy of prescriptions for these drugs.

• The ISMP includes NovoLIN 70/30 (isophane insulin human and insulin human regular) and NovoLOG Mix 70/30 (insulin aspart protamine and insulin aspart) on the ISMP List of Confused Drug Names, and recommends special safeguards to ensure the accuracy of prescriptions for these drugs.

Handling and Disposal

• Instruct patients to place used syringes and needles in an approved sharps disposal container immediately after use; instruct patients not to dispose of syringes or needles in the household trash. Additional information about sharps disposal can be found at[Web].

Administration

Oral Inhalation Administration

Administer insulin human dry powder for inhalation using drug-specific inhaler device. Use single inhaler at a time; same inhaler can be used for all dosages. Single-use cartridges should not be opened; inhaler device opens cartridge automatically during use.

Prior to use, cartridge should be at room temperature for 10 minutes and correct dose of cartridge should be verified. For dosages exceeding contents of a single cartridge, inhalations from multiple cartridges may be necessary.

Administer at beginning of each meal. Inhaler should be kept level with white mouthpiece on top and purple base on bottom after cartridge has been inserted into inhaler. Loss of effect can occur if inhaler is turned upside down, held with mouthpiece pointing down, shaken, or dropped after the cartridge has been inserted but before dose is administered; if any of the above occurs, replace cartridge before use. After use, inhaler should be stored in clean, dry place with mouthpiece cover on until next dose is due. See full prescribing information for additional details on administration.

Sub-Q Administration

Administer insulin human (regular) injection and isophane insulin human suspension usually by sub-Q injection. Administer insulin human (regular) 30 minutes before meals and isophane insulin human 30—45 minutes before meals. Fixed combinations containing insulin human (regular) injection and isophane insulin human suspension also are administered by sub-Q injection. Warming refrigerated insulin to room temperature prior to use will limit local irritation at injection site.

Administer into the thighs, upper arms, buttocks, or abdomen using a 25- to 28-gauge needle, one-half to five-eighths inch in length. Rotate injection sites within same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Areas with lipodystrophy or localized cutaneous amyloidosis should not be used.

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

Since suspensions such as isophane insulin human contain insulin in the precipitate, gently agitate the vial to assure a homogeneous mixture for accurate measurement of each dose. Slowly rotate and invert orcarefully shake the vial several times before withdrawal of each dose. Avoid vigorous shaking since frothing may interfere with correct measurement of a dose.

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. See full prescribing information for additional details on administration.

Manufacturer of Novolin R states that injection should not be used in continuous infusion pumps, as such use may result in adsorption onto pump catheters. Isophane insulin human should not be used in continuous insulin pumps or administered IV.

When concentrated (U-500) insulin human (regular) is used in patients with marked insulin resistance (i.e., daily insulin requirement >200 units), use extreme caution in dosage measurement because inadvertent overdosage may result in irreversible insulin shock. Concentrated (U-500) insulin human (regular) should be administered using only U-500 insulin syringes. To minimize risk of hypoglycemia, do not administer concentrated U-500 insulin intravenously, in an insulin pump, or mix with any other insulin.

IV Administration of Insulin Human (Regular)

Dilution

Administer insulin human (regular) IV under medical supervision with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia or hypokalemia; not recommended for routine use. To minimize the risk of hypoglycemia, do not administer U-500 insulin human (regular) intravenously

For IV infusion, the manufacturer of Novolin R insulin human (regular) states that the injection is usually diluted to a concentration of 0.05–1 unit/mL; the diluted injection is stable in 0.9% sodium chloride, 5% dextrose , or 10% dextrose injection with 40 mEq/L of potassium chloride in polypropylene infusion bags.

For IV infusion, the manufacturer of Humulin R insulin human (regular) injection states that the injection is diluted to a concentration of 0.1–1 unit/mL in 0.9% sodium chloride.

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.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. For additional information on S4S (including updates that may be available), see[Web].

DKA protocols may require units/kg per hour

Dosage

Dosage expressed in USP units.

Dosage must be individualized based on route of administration, patient's metabolic needs, blood glucose monitoring results, and glycemic control goal to attain optimum therapeutic effect.

Any change in insulin regimen should be made with caution and only under medical supervision. Changes in strength, brand, type, and/or method of manufacture may necessitate change in dosage.

Pediatric Patients

Diabetes Mellitus

Sub-Q

Pediatric patients with type 1 diabetes mellitus initially require total daily insulin dosage of 0.4–1 units/kg; requirement may be much lower during partial remission period. May need higher daily dosage in certain clinical situations (e.g., puberty, menses, medical illness).

In patients with type 2 diabetes mellitus, when prandial (mealtime) insulin is needed, initial dosage is 4 units or 10% of the basal insulin dosage administered with largest meal of the day. Alternatively, patients being treated with basal insulin who require addition of prandial insulin can be converted to 2 doses of pre-mixed insulin.

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic States

IV

In children and adolescents, treatment guidelines recommend initially an IV infusion of regular insulin at a rate of 0.05—0.1 units/kg per hour. A lower starting dosage of 0.05 units/kg per hour (or 0.03 units/kg per hour in patients <5 years of age) can be used in patients with pH >7.15. An initial direct IV injection of regular insulin isnot recommended in such patients. Continue IV insulin until resolution (pH >7.3, serum bicarbonate >18 mEq/L, closure of anion gap).

In children and adolescents with hyperosmolar hyperglycemic state, initiate IV insulin (regular) at rate of 0.025—0.05 units/kg per hour when blood glucose no longer decreases with administration of fluid alone. Titrate dosage to decrease blood glucose by 50—75 mg/dL per hour.

† [off-label]Sub-Q, IM† [off-label]

If IV access is unavailable, or for uncomplicated or mild or moderate diabetic ketoacidosis, regular insulin may be given sub-Q or IM in an initial dose of 0.15 units/kg every 2 hours initiated 1 hour after fluid replacement. In mild diabetic ketoacidosis, 0.13—0.17 units/kg sub-Q per dose every 4 hours is recommended; dosage can be increased or decreased 10—20% based on blood glucose and frequency may be increased to every 2 or 3 hours if acidosis not improving.

Dosage Following Resolution of Diabetic Ketoacidosis

IV, then Sub-Q

Upon resolution of ketoacidosis or the hyperosmolar state and when oral intake is tolerated, initiate sub-Q insulin using combination of rapid- or short-acting insulin in addition to basal insulin according to standard recommendations. Overlap IV and rapid-acting sub-Q insulin by 15—30 minutes before stopping IV insulin to prevent rebound hyperglycemia.

Adults

Diabetes Mellitus

Oral Inhalation

Insulin naïve: 4 units inhaled at the beginning of each meal.

Currently using subcutaneous mealtime insulin: Initial dosage based on current injected mealtime insulin dosage (Table 2).

Currently using pre-mixed insulin: Initial dosage based on estimate of current mealtime insulin dosage. Divide one-half of the total daily pre-mixed insulin dosage equally among three meals of the day (Table 2); remaining one-half of the estimated dosage should be administered as basal insulin.

For dosages exceeding contents of a single cartridge at mealtime, inhalation from more than one cartridge is necessary. To achieve required total mealtime dosage, a combination of 4 unit, 8 unit, and 12 unit cartridges may be used.

When switching from another insulin to insulin human dry powder for inhalation, a different insulin dosage may be needed, requiring increased frequency of blood glucose monitoring. Dosage modifications 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.

Sub-Q

Initial total daily insulin dosages in adults with type 1 diabetes mellitus range from 0.4–1 units/kg. May need substantially higher daily dosage in certain situations (e.g., after new diagnosis, during medical illness). Typical treatment plans include a combination of prandial and long-acting insulin; in metabolically stable patients, 0.5 units/kg per day used as typical starting dosage, with approximately one-half administered as prandial insulin and one-half given as basal insulin.

In patients with type 2 diabetes mellitus, when adding prandial insulin, initial dosage is 4 units or 10% of the basal insulin dosage administered with largest meal of the day. Alternatively, patients being treated with basal insulin who require addition of prandial insulin may be converted to two doses of pre-mixed insulin.

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic States

Mild Diabetic Ketoacidosis

Sub-Q or IM^{† [off-label]}

For the treatment ofmild diabetic ketoacidosis (plasma glucose >200 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 0.1 units/kg of regular insulin sub-Q. After the loading dose, administer 0.1 units/kg every hour or 0.2 units/kg every 2 hours of regular insulin sub-Q or IM. When the target glucose concentration has been achieved, the insulin dosage should be decreased to 0.1 units/kg every 2 hours subcutaneously until resolution. While IM route is effective, it is more painful and may increase risk of bleeding in patients receiving anticoagulants.

Moderate to Severe Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic States

IV

For the treatment ofmoderate to severe diabetic ketoacidosis (plasma glucose >200 mg/dL with arterial pH ≤7–7.25 and serum bicarbonate ≤10–15 mEq/L) in adults, the ADA recommends a loading dose of 0.1 units/kg of regular insulin by direct IV injection, followed by continuous IV infusion of 0.1 units/kg per hour.

For the treatment of hyperosmolar hyperglycemia, the ADA recommends a continuous IV infusion of 0.05 units/kg per hour of regular insulin.

When a plasma glucose concentration of <250 mg/dL is achieved, may decrease the insulin infusion rate to 0.05 units/kg per hour. 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., serum glucose <250 mg/dL, patient mentally alert, serum osmolality of ≤300 mOsm/kg, and urine output >0.5 mL/kg per hour).

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.

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. 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. Abrupt discontinuance of IV insulin with the institution of delayed-onset sub-Q insulin may lead to worsened glycemic control or recurrence of ketoacidosis. 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.

Patients with newly diagnosed diabetes mellitus should receive a total daily insulin dosage of 0.5–0.6 units/kg as part of a multiple-dose regimen of short- and long-acting insulin, until an optimal dosage is established. Patients with hypoglycemia risk factors (e.g., renal failure, frailty) may receive 0.3 units/kg per day. May manage some patients with newly diagnosed type 2 diabetes mellitus with diet therapy and oral antidiabetic agents following resolution of hyperglycemic crises.

Special Populations

Hepatic Impairment

No specific dosage adjustments at this time; may be at increased risk of hypoglycemia and may require more frequent dosage adjustment and blood glucose monitoring.

Renal Impairment

No specific dosage adjustments at this time; may be at increased risk of hypoglycemia and may require more frequent dosage adjustment and blood glucose monitoring.

Geriatric Patients

No specific dosage adjustments at this time; may be at increased risk of hypoglycemia due to co-morbid disease states and concomitant medications.

Exercise caution when using insulin human regular U-500; initial dosage, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemia.

Cautions for Insulin Human

Contraindications

• Contraindicated during episodes of hypoglycemia.

• Hypersensitivity to insulin human or its excipients.

• For insulin human dry powder for inhalation, contraindicated in chronic lung disease, such as asthma or COPD, because of risk of acute bronchospasm.

Warnings/Precautions

Warnings

Bronchospasm in Patients with Chronic Lung Disease

Acute bronchospasm observed in patients treated with insulin human dry powder for inhalation (see Boxed Warning).

Insulin human dry powder for inhalation is contraindicated in patients with chronic lung disease, such as asthma or COPD, because of risk of bronchospasm.

Before initiating insulin human dry powder for inhalation, evaluate all patients with a detailed medical history, physical examination, and spirometry (e.g., FEV₁) to identify potential underlying lung disease.

General Precautions

Sharing of Injection Pens, Syringes, or Needles

Injection pens containing insulin human products should never be shared, even if needle is changed. Syringes and needles used with insulin human vials also should not be shared with another person. Sharing poses a risk of transmission of blood-borne pathogens.

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. Any changes to a patient's insulin regimen should be made under close medical supervision and frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, adjustments in concomitant antidiabetic agents may be needed.

Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis reported to result in hyperglycemia and sudden change in injection site (to unaffected area) has been reported to result in hypoglycemia. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change injection site to unaffected areas and monitor for hypoglycemia.

Hypoglycemia

Hypoglycemia is most common adverse reaction of all insulins, including insulin human. Severe hypoglycemia may cause seizures, lead to unconsciousness, may be life threatening, or cause death. Hypoglycemia may impair concentration ability and reaction time; this may place 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 same patient.. Risk of hypoglycemia after injection related to duration of action of the insulin and, in general, is highest when glucose lowering effect of the insulin is maximal. As with all insulins, glucose lowering effect time course of insulin human may vary in different individuals or at different times in same individual and depends on many conditions, including area of injection as well as injection site blood supply and temperature.

Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using medication that block the sympathetic nervous system (e.g., β-adrenergic blocking agents), or in patients who experience recurrent hypoglycemia. Factors that may increase risk of hypoglycemia include changes in nutrition (e.g., changes in macronutrient content or timing of meals), level of physical activity, and concurrent medications. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.

To minimize risk of hypoglycemia, do not administer insulin human regular U-500 intravenously or in insulin pump or mix with any other insulin products or solutions.

Patients and caregivers must be educated to recognize hypoglycemia. Self-monitoring of blood glucose is essential in prevention and management of hypoglycemia. In patients at higher risk of hypoglycemia and those who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

Hypoglycemia Due to Medication Errors

Accidental mix-ups between insulin products reported. To avoid medication errors, instruct patient to always check label before each injection. Insulin human regular U-500 should be administrated using only U-500 syringes to avoid administration errors; no other syringe should be used.

Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Generalized allergy may manifest as whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.

If hypersensitivity occurs, discontinue insulin human; treat according to standard of care and monitor until signs and symptoms resolve. Insulin human contraindicated in patients who have had hypersensitivity reaction to insulin human or its excipients.

Hypokalemia

All insulins, including human insulin, cause shift in potassium from extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmias, and death.

Monitor potassium levels in patients at risk for hypokalemia (e.g., patients taking potassium-lowering medications or medications sensitive to serum potassium concentrations).

Fluid Retention and Heart Failure

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (i.e., thiazolidinediones) can cause dosage-related fluid retention when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure.

Observe patients treated with insulin, including insulin human, and a PPAR-γ agonist for signs and symptoms of heart failure. If heart failure develops, manage according to current standards of care and consider discontinuation or dosage reduction of PPAR-γ agonist.

Decline in Pulmonary Function

Insulin human dry powder for inhalation causes decline in pulmonary function over time as measured by FEV₁. In clinical trials, FEV₁ decline observed within first 3 months and persisted for entire duration of therapy (up to 2 years). Annual rate of FEV₁ decline did not worsen with increased duration of use. Effects of insulin human dry powder for inhalation on pulmonary function with treatment duration >2 years not established. There is insufficient evidence to draw conclusions regarding reversal of effect on FEV₁ after discontinuation of insulin human dry powder for inhalation.

Assess pulmonary function (e.g., spirometry) at baseline, after first 6 months of therapy, and annually thereafter, even in absence of pulmonary symptoms. In patients who have decline in FEV₁ of ≥20% from baseline, consider discontinuing insulin human dry powder for inhalation. Consider more frequent monitoring in patients with symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue insulin human dry powder for inhalation.

Lung Cancer

Two cases of lung cancer observed in clinical trials with insulin human dry powder for inhalation; in both cases, prior history of heavy tobacco use was identified as risk factor for lung cancer. Two additional cases of lung cancer (squamous cell and lung blastoma) reported in nonsmokers exposed to insulin human dry powder for inhalation reported by investigators after clinical trial completion. Data are insufficient to determine whether insulin human dry powder for inhalation has effect on lung or respiratory tract tumors.

In patients with active lung cancer, with prior history of lung cancer, or at risk of lung cancer, consider whether benefits of insulin human dry powder for inhalation outweigh this potential risk.

Diabetic Ketoacidosis

In clinical trials of patients with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in patients receiving insulin human dry powder for inhalation than comparator-treated patients.

Patients with type 1 diabetes should always use insulin human dry powder for inhalation in combination with basal insulin.

In patients at risk for DKA, such as those with acute illness or infection, increase frequency of glucose monitoring and consider discontinuing insulin human dry powder for inhalation and giving insulin using an alternate route of administration.

Immunogenicity

Several studies have shown parental insulin human to be less immunogenic than purified pork insulin (no longer commercially available in the US). Data from several studies have shown that insulin antibodies (IgE type) develop less frequently following administration of insulin human than following purified animal insulins (no longer commercially available in the US). Although a few patients in these studies developed elevated insulin antibody titers (IgE type) following administration of insulin human, they did not develop any signs or symptoms of insulin allergy or adverse reactions.

As with all therapeutic proteins, administration of insulin human may cause anti-insulin antibodies to form. Development of antibodies that react with insulin human have been observed with all insulins, including insulin human. Increases in anti-insulin antibodies were observed more frequently in patients treated with insulin human dry powder for inhalation than in patients treated with SQ injected mealtime insulin; no significant effect of anti-drug antibodies on safety or effectiveness over treatment duration of studies of insulin human dry powder for inhalation that spanned 3 to 24 months observed.

Insulin human contraindicated in patients who are hypersensitive to insulin human or any ingredient in formulation.

Specific Populations

Pregnancy

Published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with insulin human injection use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes; available studies cannot definitely establish absence of risk. Limited available data on use of insulin human dry powder for inhalation in pregnant women; data are insufficient to determine drug-associated risk for adverse developmental outcomes. All available studies on insulin human in pregnancy have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.

Poorly controlled diabetes mellitus in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus in pregnancy increases fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Lactation

Available data suggests exogenously administered insulin human distributed into human milk; no adverse effects reported in breast-fed infant. No data on effects on milk production.

No data on presence of insulin human dry powder for inhalation in human milk, effects on breast-fed infant, or effects on milk production. Based on animal studies, high likelihood that both insulin human and the carrier particles are distributed into human milk. Potential adverse effects related to inhalation administration of insulin human unlikely to be associated with exposure through breast milk.

Development and health benefits of breastfeeding should be considered along with mother's clinical need for insulin human and any potential adverse effects on breast-fed child from insulin human or underlying maternal condition.

Pediatric Use

Most commercially available insulin human products are indicated to improve glycemic control in pediatric patients with diabetes mellitus; dosage must be individualized based on metabolic needs and frequent monitoring of blood glucose to minimize risk of hypoglycemia. Safety and effectiveness of insulin human regular U-500 established in pediatric patients requiring >200 units of insulin per day. Although Novolin 70/30 insulin isophane human-insulin human mixture injectable suspension is labeled for use in pediatric patients with diabetes mellitus, manufacturer of Humulin 70/30 isophane insulin human-insulin human mixture injectable suspension states that safety and effectiveness of HumuLIN 70/30 not established in pediatric patients. Safety and effectiveness of insulin human dry powder for inhalation not established in pediatric patients.

Geriatric Use

Effect of age on pharmacokinetics and pharmacodynamics not established. Elderly patients may be at increased risk of hypoglycemia due to co-morbid disease states and concomitant medications. Exercise caution when using insulin human regular U-500; initial dosage, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics and pharmacodynamics unknown; patients with hepatic impairment may be at increased risk for hypoglycemia and may require more frequent dosage adjustment and more frequent blood glucose monitoring.

Renal Impairment

Effect of renal impairment on pharmacokinetics and pharmacodynamics not studied; patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent dosage adjustment and more frequent blood glucose monitoring. Increased circulating levels of insulin shown in some studies.

Common Adverse Effects

Insulin human (regular): hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, rash.

Isophane insulin human: hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight gain, edema.

Isophane insulin human in fixed combination with insulin human: hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight gain, edema.

Insulin human dry powder for inhalation ≥2%): hypoglycemia, cough, throat pain or irritation.

Drug Interactions

Specific Drugs

Insulin Human Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of insulin human (regular), sub-Q: 48—89%.

Onset

Insulin human (regular), sub-Q: Onset 30 minutes; maximal at 3 hours. Peak concentrations occur between 36—150 minutes (HumuLIN R) and 1.5—2.5 hours (NovoLIN R).

Insulin human (regular), IV: Approximately 10—15 minutes.

Concentrated (U-500) insulin human regular, sub-Q: Peak concentrations at 4—8 hours (range: 0.5—8 hours) in healthy obese individuals.

Isophane insulin human, sub-Q: Peak concentrations at approximately 4 hours (range: 1—12 hours).

Insulin human dry powder for inhalation: Maximum serum concentrations at 10—20 minutes.

Duration

Insulin human (regular): 8 hours.

Special Populations

Rate of absorption and onset activity known to be affected by site of injection, exercise, and other variables.

Elimination

Metabolism

Uptake and degradation predominantly occurs in liver, kidney, muscle, and adipocytes; liver is major organ involved in clearance of insulin human.

Elimination Route

Carrier particles used in insulin human dry powder for inhalation excreted unchanged in the urine.

Half-life

Insulin human (regular), sub-Q: 1.5 hours (range: 40 minutes—7 hours); with higher doses (50 and 100 units), 3.6 hours.

Insulin human (regular), IV: 20 minutes (dose 0.1 units/kg) and 1 hour (dose 0.2 units/kg).

Concentrated (U-500) insulin human regular, sub-Q: Approximately 4.5 hours (range: 1.9—10 hours) in healthy obese individuals.

Isophane insulin human, sub-Q: Approximately 4.4 hours.

Insulin human dry powder for inhalation: 120—206 minutes.

Special Populations

In obese subjects given 50 and 100 unit subcutaneous doses of insulin human (regular), mean time of termination of effect was prolonged to approximately 18 hours (range: 12—24 hours).

Time course of action (i.e., glucose lowering) may vary considerably in different individuals or within the same individual and with different doses.

Manufacturers of some insulin human products state that effects of gender, age, obesity, renal, and hepatic impairment on pharmacokinetics not studied.

Stability

Storage

Oral Inhalation

Dry Powder for Inhalation

When not in use, store insulin human dry powder for inhalation in refrigerator at 2—8°C. Sealed, unopened foil packages may be stored under refrigeration (at 2—8°C) until expiration date. Sealed, unopened blister cards and strips stored at 2—8°C must be used within 1 month. If a foil package, blister card, or strip is not refrigerated, contents must be used within 10 days.

When in use, insulin human dry powder for inhalation in sealed, unopened blister cards and strips may be stored at room temperature up to 25°C but must be used within 10 days. Open strips stored at room temperature up to 25°C must be used within 3 days. A blister card or strip stored at room temperature should not be returned to refrigerator.

Inhaler can be stored at refrigerated or at room temperature (2—25°C); if refrigerated, inhaler should be at room temperature before use. Inhaler can be used for up to 15 days from date of first use; after 15 days, inhaler must be discarded and replaced with new inhaler.

Parenteral

Solution for Injection

With unopened vials or cartridges of insulin human (regular) injections that have not been placed in a delivery device, store at 2–8°C until expiration date; do not freeze. Unopened vials can be stored at room temperature (up to 25°C) for 31 days (HumulinR U-100) or 42 days (Novolin R). Unopened vials of concentrated (U-500) insulin human (regular) can be stored at room temperature (up to 30°C) for up to 40 days. Unopened insulin human pens (Novolin R FlexPens) can be stored at room temperature (up to 30°C) for 28 days. Unopened concentrated (U-500) insulin human pens can be stored at room temperature (up to 30°C) for 28 days.

Opened (in-use) vials of insulin human can be stored refrigerated (2—8°C) or at room temperature for 31 (up to 30°C for Humulin R) or 42 days (up to 25°C for Novolin R). Opened (in-use) insulin human pens (Novolin R FlexPlens) can be stored refrigerated (2—8°C) or at room temperature (up to 30°C).

Discard insulin human (regular) injection exhibiting discoloration, turbidity, or unusual viscosity, since these changes indicate deterioration or contamination.

Solution for IV Infusion

Commercially available IV infusion bags of insulin human (regular) must be stored in original container in refrigerator (2—8°C) protected from light. Infusion bag may be removed from original carton and stored at room temperature (up to 25°C) for up to 30 days; once removed from refrigeration, should not be returned. Do not shake or use if frozen.

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. Unopened vials may be stored at room temperature for 31 days (up to 30°C for Humulin N) or 42 days (up to 25°C for Novolin N). Unopened isophane insulin human pens can be stored at room temperature for 14 days (up to 30°C for Humulin N KwikPen) or 28 days (up to 25°C for Novolin N FlexPen).

For isophane insulin human (Humulin N) vials in use, store refrigerated (2—8°C) or room temperature below 30°C for 31 days; protect from heat and light. For isophane insulin human (Novolin N) vials in use, store at room temperature (up to 25°C) for 42 days; manufacturer states opened vials should not be refrigerated. In-use isophane insulin human pens should not be refrigerated but can be stored at room temperature up to 30°C for 14 days (Humulin N KwikPen) or 28 days (Novolin N FlexPen).

Unopened combination preparations of insulin human and isophane insulin human suspension available with a delivery device are stable below 30°C for 10 days (Humulin 70/30 KwikPen) or 28 days (Novolin 70/30 FlexPen). Protect from excessive heat and light. In-use combination preparations of insulin human and isophane insulin human suspension available with a delivery device are stable at room temperature (up to 30°C) for 10 days Humulin 70/30 KwikPen) or 28 days (Novolin 70/30 KwikPen).

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.

Insulin Human Mechanism of Action

• Biosynthetic protein structurally identical to endogenous insulin secreted by beta cells of human pancreas.

• Lowers blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production.

• Inhibits lipolysis and proteolysis and enhances protein synthesis.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Provide patients with instructions regarding insulin storage and injection or inhalation technique. Advise patients to always check the insulin label before each injection/inhalation to avoid mix-ups between insulin products. When mixing insulin preparations, advise patients of the importance of drawing insulin human (regular) into the syringe first.

• Advise patients that insulin pens, needles, or syringes should never be shared with another person; sharing poses a risk for transmission of blood-borne pathogens. Advise patients of the importance of not changing the order of mixing insulins or the model or brand of syringe or needle without medical supervision. Advise patients on proper disposal of syringes and needles.

• Inform patients of the importance of strict adherence to manufacturer’s instructions regarding assembly, administration, and care of specialized delivery systems, such as insulin pens, inhalers, or pumps.

• Inform patients using insulin human regular U-500 to inform hospital or emergency department clinicians of the dose of insulin human U-500 prescribed, in the event of a future hospitalization or visit to the emergency department.

• Inform patients that hypoglycemia is the most common adverse effect from insulin. Inform patients of the signs, symptoms, and management of hypoglycemia. Provide patient with instructions regarding self-monitoring of blood glucose concentrations and the importance of frequent self-monitoring in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes.

• Inform patients taking insulin human dry powder for inhalation that the most common adverse effects are hypoglycemia, cough, and throat pain or irritation. Inform patients that insulin human dry powder for inhalation can cause a decline in lung function. Advise patients that if they experience any respiratory difficulty after using insulin human dry powder for inhalation, including any signs or symptoms potentially related to lung cancer, they should report it to their clinician immediately for assessment.

• Inform patients of the importance of changing insulin dosage with caution and only under medical supervision. Inform patients of the potential for alterations in insulin requirements in special situations (e.g., illness, concomitant agents that alter glycemic control, travel, emotional disturbances or other stresses). Discuss potential for alterations in insulin requirements as a result of changes in physical activity, missed doses, or inadvertent administration of incorrect doses.

• Inform patients of the importance of informing clinicians of the development of skin reactions (erythema, pruritus, edema, lipodystrophy) at injection site.

• Inform patients that hypersensitivity reactions have occurred with insulin human. Advise patients of the symptoms of hypersensitivity reactions (shortness of breath, hypotension, wheezing, whole body rash, tachycardia, diaphoresis) and to seek medical attention if they occur.

• Provide instructions regarding adherence to meal planning, regular physical exercise, periodic hemoglobin A_1c (HbA_1c) monitoring, and management of hypoglycemia or hyperglycemia.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Advise patients of other important precautionary information.

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 theASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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