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Insulin (Oral Inhalation)

Pronunciation

(IN soo lin)

Index Terms

  • Inhaled Insulin
  • Technosphere Insulin (TI)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Powder, Inhalation:

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

Brand Names: U.S.

  • Afrezza

Pharmacologic Category

  • Insulin, Rapid-Acting

Pharmacology

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.

Excretion

Urine

Onset of Action

Peak effect: ~53 minutes

Time to Peak

12 to 15 minutes

Duration of Action

~160 to 180 minutes

Half-Life Elimination

28 to 39 minutes

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.

Dosing: Adult

Diabetes mellitus: Note: Insulin requirements vary dramatically between patients and therapy requires dosage adjustments with careful medical supervision.

Inhalation:

Initial dose:

Insulin-naive patients: 4 units at each meal

Patients previously on SubQ mealtime (prandial) insulin: Dosage of inhalation powder for each meal based upon the following scale:

≤4 units injected dose per meal: 4 units

5 to 8 units injected dose per meal: 8 units

9 to 12 units injected dose per meal: 12 units

13 to 16 units injected dose per meal: 16 units

17 to 20 units injected dose per meal: 20 units

21 to 24 units injected dose per meal: 24 units

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

5 to 8 units injected dose per meal: 8 units

9 to 12 units injected dose per meal: 12 units

13 to 16 units injected dose per meal: 16 units

17 to 20 units injected dose per meal: 20 units

21 to 24 units injected dose per meal: 24 units

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

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 Insulin. Exceptions: Levobunolol; Metipranolol. Monitor therapy

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

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

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

GLP-1 Agonists: May enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Consider therapy modification

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 Insulin. 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

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

Metreleptin: May enhance the hypoglycemic effect of Insulin. 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

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

Pioglitazone: May enhance the adverse/toxic effect of Insulin. 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 Insulin. 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

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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

Rosiglitazone: Insulin 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

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Insulin. 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% (Limited to important or life-threatening): Antibody development (drug efficacy not affected), diabetic ketoacidosis (diabetes milletus, type 1), hypersensitivity reaction

ALERT: U.S. Boxed Warning

Risk of Acute Bronchospasm in Patients with Chronic Lung Disease

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.

Warnings/Precautions

Concerns related to adverse effects:

• 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 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:

• 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. 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: [U.S. 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; pharmacokinetics have not been studied. Dosage requirements may be reduced.

• Renal impairment: Use with caution in patients with renal impairment; pharmacokinetics have not been studied. Dosage requirements may be reduced.

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:

• 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. The general objective of exogenous insulin therapy is to approximate the physiologic pattern of insulin secretion which is characterized by two distinct phases. Phase 1 insulin secretion suppresses hepatic glucose production and phase 2 insulin secretion occurs in response to carbohydrate ingestion; therefore, exogenous insulin therapy may consist of basal insulin (eg, intermediate- or long-acting insulin via continuous subcutaneous insulin infusion [CSII]) and/or preprandial insulin (eg, short- or rapid-acting insulin) (see Related Information: Insulin Products). Patients with type 1 diabetes do not produce endogenous insulin; therefore, these patients require both basal and preprandial insulin administration. Patients with type 2 diabetes retain some beta-cell function in the early stages of their disease; however, as the disease progresses, phase 1 insulin secretion may become completely impaired and phase 2 insulin secretion becomes delayed and/or inadequate in response to meals. Therefore, patients with type 2 diabetes may be treated with oral antidiabetic agents, basal insulin, and/or preprandial insulin depending on the stage of disease and current glycemic control. Since treatment regimens often consist of multiple agents, dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient’s impaired glycemic control. Treatment and monitoring regimens must be individualized.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Plasma glucose, electrolytes, HbA1c (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 2016a]); 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 Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies conducted using the carrier particles (vehicle) used to deliver regular insulin for inhalation.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2016c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2016c; Blumer 2013; Kitzmiller 2008; Lambert 2013). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (ADA 2016c; Kitzmiller 2008).

Insulin requirements tend to fall during the first trimester of pregnancy and increase in the later trimesters, peaking at 28 to 32 weeks of gestation. Following delivery, insulin requirements decrease rapidly (ACOG 2005).

Rapid acting insulins, such as insulin aspart or insulin lispro may be preferred over regular human insulin in women trying to conceive (Blumer 2013). Information specific to the use of inhaled insulin during pregnancy is limited (Makam 2009). 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 or pharyngitis. 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, a fast heartbeat, confusion, hunger, or sweating), difficulty breathing, anxiety, vision changes, chills, severe dizziness, passing out, mood changes, seizures, slurred speech, wheezing, or cough that will not go away or comes back (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.

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