Insulin (Oral Inhalation)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Powder, Inhalation:

Afrezza: 4 units (90 ea); 8 units (90 ea); 12 units (90 ea); 4 units & 8 units (90 ea [DSC], 180 ea); 8 units & 12 units (90 ea [DSC]); 90 x 8 UNIT & 90x12 UNIT (180 ea); 4 units & 8 units & 12 units (180 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.

Within the liver, insulin stimulates hepatic glycogen synthesis. Insulin promotes hepatic synthesis of fatty acids, which are released into the circulation as lipoproteins. Skeletal muscle effects of insulin include increased protein synthesis and increased glycogen synthesis. Within adipose tissue, insulin stimulates the processing of circulating lipoproteins to provide free fatty acids, facilitating triglyceride synthesis and storage by adipocytes; also directly inhibits the hydrolysis of triglycerides. In addition, insulin stimulates the cellular uptake of amino acids and increases cellular permeability to several ions, including potassium, magnesium, and phosphate. By activating sodium-potassium ATPases, insulin promotes the intracellular movement of potassium.

Normally secreted by the pancreas, insulin products are manufactured for pharmacologic use through recombinant DNA technology using either E. coli or Saccharomyces cerevisiae. Inhaled human insulin has an identical structure to that of native human insulin and is adsorbed onto carrier particles which dissolve within the lungs after inhalation leading to rapid absorption of insulin in the systemic circulation. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Inhaled insulin is an ultra-rapid acting insulin.

Pharmacokinetics/Pharmacodynamics

Excretion

Urine

Onset of Action

~12 minutes; Peak effect: ~35 to 55 minutes

Time to Peak

10 to 20 minutes

Duration of Action

~90 to 270 minutes (proportional to dose)

Half-Life Elimination

120 to 206 minutes (apparent terminal half-life)

Use: Labeled Indications

Diabetes mellitus, type 1 or type 2: Treatment of diabetes mellitus (type 1 or type 2) to improve glycemic control

Contraindications

Hypersensitivity to regular insulin or any component of the formulation; during episodes of hypoglycemia; chronic lung disease such as asthma or COPD, due to risk of bronchospasm.

Documentation of allergenic cross-reactivity for insulin is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Diabetes mellitus: Note: Insulin requirements vary dramatically between patients and therapy requires dosage adjustments with careful medical supervision. Inhaled insulin must be used concomitantly with long-acting (basal) insulin in patients with type 1 diabetes. In patients with type 2 diabetes, rapid-acting insulins (including inhaled insulin) are typically added at one or more meals if adequate glycemic control is not achieved with basal insulin alone (ADA 2019).

Inhalation:

Initial dose:

Insulin-naive patients: 4 units at each meal

Patients previously on SubQ mealtime (prandial) insulin:

≤4 units injected dose per meal: 4 units inhalation dose per meal

5 to 8 units injected dose per meal: 8 units inhalation dose per meal

9 to 12 units injected dose per meal: 12 units inhalation dose per meal

13 to 16 units injected dose per meal: 16 units inhalation dose per meal

17 to 20 units injected dose per meal: 20 units inhalation dose per meal

21 to 24 units injected dose per meal: 24 units inhalation dose per meal

Patients previously on SubQ premixed insulin: Estimate the mealtime injected dose by dividing half of the total daily injected premixed insulin dose equally among the three meals of the day. Convert each estimated injected mealtime dose to a mealtime inhalation dose based upon the following scale. In addition, administer half of the total daily injected premixed dose as an injected basal insulin dose.

≤4 units injected dose per meal: 4 units inhalation dose per meal

5 to 8 units injected dose per meal: 8 units inhalation dose per meal

9 to 12 units injected dose per meal: 12 units inhalation dose per meal

13 to 16 units injected dose per meal: 16 units inhalation dose per meal

17 to 20 units injected dose per meal: 20 units inhalation dose per meal

21 to 24 units injected dose per meal: 24 units inhalation dose per meal

Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose based on metabolic needs, blood glucose monitoring results and glycemic control goal. Carefully monitor blood glucose control in patients requiring high inhalation doses. If blood glucose control is not achieved with increased inhalation doses, consider the use of SubQ mealtime insulin. Treatment and monitoring regimens must be individualized.

Inhaled insulin is adjusted in 4-unit increments. The following dosage adjustments for injectable prandial insulin are recommended in patients with type 2 diabetes (ADA 2019):

To reach self-monitoring glucose target: Adjust dose by 10% to 15%.

For hypoglycemia: If no clear reason for hypoglycemia, decrease dose by 10% to 20%; for severe hypoglycemia (ie, requiring assistance from another person or blood glucose <40 mg/dL) reduce dose by 20% to 40%.

Dosing: Geriatric

Refer to adult dosing.

Administration

For oral inhalation only. Administer at the beginning of the meal. Remove the amount/strength of cartridges needed for a single dose from packaging; multiple cartridges may be needed to achieve the correct dose. Allow cartridges to sit at room temperature for 10 minutes. Insert cartridge into the inhaler and snap to close. Keep inhaler level with mouthpiece on top and base on the bottom. Loss of drug may occur if inhaler is inverted, held with mouthpiece pointing down, shaken or dropped after cartridge is inserted but prior to dose administration. If any of these actions occur, a new cartridge must be loaded into the inhaler. Exhale fully. Close lips tightly around mouthpiece; do not exhale into inhaler. Tilt inhaler downward while keeping head level and inhale (rapidly, steadily and deeply). Hold breath for as long as comfortable at the same time removing the inhaler from the mouth. Exhale and continue to breathe normally. Throw away empty cartridge by removing it from the base; do not leave in inhaler. Repeat the steps for each cartridge needed for the correct total dose; use only one inhaler for multiple cartridges. Replace the inhaler every 15 days to maintain accurate drug delivery.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

Prior to use (sealed package): Store at 2ºC to 8ºC (36°F to 46°F). If foil package is not refrigerated, contents must be used within 10 days.

In use: Once foil package has been opened, store blister cards and strips at room temperature 25ºC (77ºF); excursions are permitted between 15°C and 30°C (59°F and 86°F). Unopened blister cards and strips must be used within 10 days; opened strips must be used within 3 days. Inhaler may be stored refrigerated, but should be at room temperature prior to use. Cartridges should also be at room temperature for 10 minutes before administration.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Monitor therapy

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Exceptions: Liraglutide. Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Avoid combination

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Metreleptin: May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

>10%:

Endocrine & metabolic: Hypoglycemia (67%)

Respiratory: Acute bronchospasm (patients with asthma: 29%), cough (26% to 29%)

1% to 10%:

Central nervous system: Headache (5%), fatigue (2%)

Endocrine & metabolic: Severe hypoglycemia (5%)

Gastrointestinal: Sore throat (≤6%), diarrhea (3%), nausea (2%)

Genitourinary: Urinary tract infection (2%)

Respiratory: Reduced forced expiratory volume (6%; ≥15% decline), throat irritation (≤6%), bronchitis (3%), decreased lung function (3%), productive cough (2%)

<1%, postmarketing, and/or case reports: Antibody development (drug efficacy not affected), diabetic ketoacidosis (diabetes mellitus, type 1), hypersensitivity reaction, hypokalemia

Warnings/Precautions

Concerns related to adverse effects:

• Diabetic ketoacidosis: In clinical trials involving type 1 diabetic patients, diabetic ketoacidosis (DKA) was observed more commonly with inhaled insulin than with comparators; increase glucose monitoring in patients at risk of DKA (eg, acute illness, infection) and if necessary, consider an alternative route of insulin administration. Inhaled insulin is not recommended for treatment of diabetic ketoacidosis.
• Hypersensitivity: Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur. If hypersensitivity reactions occur, discontinue therapy, treat the patient with supportive care and monitor until signs and symptoms resolve.
• Hypoglycemia: The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia.
• Hypokalemia: Insulin causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium in patients at risk for hypoglycemia.
• Lung cancer: Rare cases of cancer have been reported. In clinical trials, 2 cases were reported in patients with a history of heavy tobacco use; after clinical trial completion, 2 additional cases were reported in nonsmokers. The effect of inhalation powder on the development of lung or respiratory tract tumors is unknown. Use caution in patients with active lung cancer, a prior history of lung cancer, or in patients at risk for lung cancer.
• Pulmonary lung function decline: May cause a decline in lung function (measured by FEV₁) over time; decline was observed within the first 3 months of therapy and persisted, but did not worsen, for therapy duration, up to 2 years. Assess PFTs at baseline, after the first 6 months of therapy and yearly thereafter, even in the absence of pulmonary symptoms. If FEV₁ decline of ≥20% is observed, consider discontinuation. Frequently monitor patients with wheezing, persistent or recurring cough, bronchospasm, or breathing difficulties. If symptoms persist, discontinue the product.

Disease-related concerns:

• Bariatric surgery: ­

– Type 2 diabetes, hypoglycemia: Closely monitor insulin dose requirement throughout active weight loss with a goal of eliminating antidiabetic therapy or transitioning to agents without hypoglycemic potential; hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band may occur (Mechanick 2013). Insulin secretion and sensitivity may be partially or completely restored after these procedures (Korner 2009; Peterli 2012). Rates and timing of type 2 diabetes improvement and resolution vary widely by patient. Insulin dose reduction of at least 75% has been suggested after gastric bypass for patients without severe β-cell failure (fasting c-peptide <0.3 nmol/L) (Cruijsen 2014). Avoid the use of bolus insulin injections or dose conservatively with close clinical monitoring in the early phases after surgery. ­

– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).

• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) may cause dose-related fluid retention and lead to or exacerbate heart failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.
• Chronic lung disease: [US Boxed Warning]: Acute bronchospasm has been observed in patients with asthma and COPD using inhaled insulin. Use is contraindicated in patients with chronic lung disease such as asthma or COPD. Before initiating inhaled insulin, perform a detailed medical history, physical examination, and spirometry (FEV₁) to identify potential lung disease in all patients.
• Hepatic impairment: Use with caution in patients with hepatic impairment (has not been studied). Dosage requirements may be reduced and patients may require more frequent glucose monitoring.
• Renal impairment: Use with caution in patients with renal impairment (has not been studied). Dosage requirements may be reduced and patients may require more frequent glucose monitoring.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen (insulin regular) in the inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion (insulin regular) has been shown to best achieve glycemic targets. In noncritically ill patients with either poor oral intake or taking nothing by mouth, basal insulin or basal plus bolus is preferred. In noncritically ill patients with adequate nutritional intake, a combination of basal insulin, nutritional, and correction components is preferred. An effective insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia). A blood glucose value <70 mg/dL should prompt a treatment regimen review and change, if necessary, to prevent further hypoglycemia (ADA 2019).
• Smokers: Use is not recommended in smokers or patients who have recently stopped smoking (safety and efficacy has not been established).

Other warnings/precautions:

• Appropriate use: Inhaled insulin is not a substitute for long-acting insulin and must be used in combination with long-acting insulin in patients with type 1 diabetes mellitus.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Plasma glucose, electrolytes, HbA_1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2019]); renal function; hepatic function, weight; PFTs at baseline, after the first 6 months of therapy and yearly thereafter. Frequently monitor patients with wheezing, persistent or recurring cough, bronchospasm, or breathing difficulties. In patients at risk for DKA (eg, acute illness or infection), increase glucose monitoring frequency.

Pregnancy

Pregnancy Considerations

Information specific to the use of inhaled insulin during pregnancy is limited (Makam 2009).

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Due to pregnancy-induced physiologic changes, insulin requirements tend to increase as pregnancy progresses, requiring frequent monitoring and dosage adjustments. Following delivery, insulin requirements decrease rapidly (ACOG 201 2018; ADA 2020).

Insulin is the preferred treatment of type 1 and type 2 diabetes mellitus in pregnancy, as well as gestational diabetes mellitus when pharmacologic therapy is needed. Agents other than inhaled insulin are currently preferred (ACOG 190 2018; ACOG 201 2018; ADA 2020).

Refer to the Insulin Regular monograph for additional information related to the use of insulin in pregnancy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience weight gain, throat pain, cough, or sore throat. Have patient report immediately to prescriber signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating), severe fatigue, difficulty breathing, anxiety, vision changes, chills, dizziness, passing out, mood changes, seizures, slurred speech, wheezing, or persistent cough (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.