AFREZZA® Closely Mimics Physiologic Insulin

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AFREZZA® outpaces RAA, with a faster start and earlier peak effect1-4

People without diabetes: Time to peak insulin concentration is ~45 minutes5

Insulin concentration in people without diabetes (mobile view)

Time-action profiles: AFREZZA and SC RAA comparison1-4

Data are from an open-label, randomized, controlled, crossover study that compared the area under the glucose infusion rate versus time curve (GIR AUC) of AFREZZA (12 units) with SC RAA lispro (8 units) in 30 adult patients with T1D. Each volunteer received 3 different doses of each treatment over a series of 6 euglycemic clamps. The time course of insulin action may vary considerably in different individuals or within the same individual.1,2

AFREZZA closely mimics physiologic insulin, aligning with real-time eating.1,5-7

How does the onset of action of AFREZZA compare with injectable rapid-acting insulin?

AFREZZA has an ultra-rapid onset of approximately 12 minutes, which is faster than available SC RRAs that have an onset of approximately 15 to 20 minutes.2,4 The shorter duration of action of AFREZZA more closely mimics physiologic postprandial insulin secretion, which may reduce the risk of late postprandial hypoglycemia.2,3,5,8

Comparing the time-action of AFREZZA vs physiologic insulin and SC RAA1,2,5,9,10

aData shown are for the 12-unit doses. The 48-unit doses have a time to peak effect of 55 minutes and time for effect to return to baseline of 270 minutes.2
Insulin secretion data obtained from a study in healthy subjects (n=10) to estimate insulin sensitivity based on a MGTT. Delivery data obtained from the prescribing information for inhaled and SC RAA insulin therapies and a quantitative comparison of GIR profiles for AFREZZA and lispro.1,2,9,10

• Comparisons of efficacy and safety should not be made in the absence of head-to-head studies
• The clinical significance of the differences in PD parameters has not been established
• AFREZZA can be taken at the start of a meal, since it mimics physiologic insulin: no pre-bolus required2,3,8

AFREZZA is an ultra rapid-acting inhaled insulin2

Anatomical illustration of pulmonary insulin delivery: AFREZZA microparticles, sized to reach the deep lung, dissolve at lung pH and release insulin into systemic circulation reaching maximum concentration within 15 minutes. Anatomical illustration of pulmonary insulin delivery (mobile view)

The lungs are well suited for ultra-rapid delivery6,11

When inhaled, these microparticles are appropriately sized to reach and deposit in the deep lung12,13
The pH in the lungs will cause dissolution of the microspheres, releasing insulin which rapidly reaches systemic circulation and attains maximum concentration within 15 minutes12

AFREZZA is absorbed through the lungs without having to change molecular structure, pass through SC tissue, or undergo first-pass metabolism, thereby facilitating ultra-rapid absorption and ultra-rapid onset2,5,14

AUC, area under curve; GIR, glucose infusion rate; MGTT, mean glucose tolerance test; PD, pharmacodynamics; RAA, rapid-acting analog; SC, subcutaneous; SC RAA, subcutaneous rapid-acting analog; T1D, type 1 diabetes.

References: 1. Grant M, Heise T, Baughman R. Comparison of pharmacokinetics and pharmacodynamics of inhaled Technosphere insulin and subcutaneous insulin lispro in the treatment of type 1 diabetes mellitus. Clin Pharmacokinet. 2022;61(3):413-422. 2. AFREZZA. Prescribing information. MannKind Corporation; 2026. 3. Data on file (PK/PD). MannKind Corporation. 4. Data on file (PD Graph). MannKind Corporation. 5. Caumo A, Bergman RN, Cobelli C. Insulin sensitivity from meal tolerance tests in normal subjects: a minimal model index. J Clin Endocrinol Metab. 2000;85(11):4396-4402. 6. Heinemann L, Baughman R, Boss A, Hompesch M. Pharmacokinetic and pharmacodynamic properties of a novel inhaled insulin. J Diabetes Sci Technol. 2017;11(1):148-156. 7. Rave K, Heise T, Heinemann L, Boss AH. Inhaled Technosphere insulin in comparison to subcutaneous regular human insulin: time action profile and variability in subjects with type 2 diabetes. J Diabetes Sci Technol. 2008;2(2):205-212. 8. Levin P, Hoogwerf BJ, Snell-Bergeon J, Vigers T, Pyle L, Bromberger L. Ultra rapid-acting inhaled insulin improves glucose control in patients with type 2 diabetes mellitus. Endocr Pract. 2021;27(5):449-454. 9. FIASP. Prescribing information. Novo Nordisk; 2023. 10. LYUMJEV. Prescribing information. Eli Lilly and Company; 2022. 11. Heinemann L, Parkin CG. Rethinking the viability and utility of inhaled insulin in clinical practice. J Diabetes Res. 2018:4568903. 12. Sarala N, Bengalorkar G, Bhuvana K. Technosphere: new drug delivery system for inhaled insulin. Fut Prescriber. 2012;13:14-16. 13. Leone-Bay A, Baughman R, Smutney C, Kocinsky J. Innovation in drug delivery by inhalation. OnDrugDelivery Magazine. 2010;4-8. 14. Data on file (Effect of different doses). MannKind Corporation. 15. Grant M, Harris E, Leone-Bay A, Rousseau K. Technosphere®/insulin: method of action. Poster presented at: Diabetes Technology Society Meeting; November 2-4, 2006; Atlanta, GA.

© MannKind Corporation May 2026. US-AFR-2897

Indications and Usage:

Afrezza® (insulin human) Inhalation Powder is a rapid acting inhaled human insulin indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus.

Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis, not recommended in patients who smoke or have recently stopped smoking.

Important Safety Information

WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE

  • Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and Chronic Obstructive Pulmonary Disease (COPD).
  • AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD.
  • Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients.

Indications and Usage:

Afrezza® (insulin human) Inhalation Powder is a rapid acting inhaled human insulin indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus.

Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis, not recommended in patients who smoke or have recently stopped smoking.

Important Safety Information

WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE

  • Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and Chronic Obstructive Pulmonary Disease (COPD).
  • AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD.
  • Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients.

Contraindications

AFREZZA is contraindicated: during episodes of hypoglycemia, in patients with chronic lung disease (such as asthma or COPD) because of the risk of acute bronchospasm, and in patients with previous severe hypersensitivity reaction to any regular human insulin product or any of the inactive ingredients in AFREZZA. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with AFREZZA.

Warnings and Precautions

Acute Bronchospasm in Patients with Chronic Lung Disease: In a study of patients with asthma whose bronchodilators were temporarily withheld for assessment, bronchoconstriction and wheezing following AFREZZA dosing was reported. Before initiating therapy, evaluate all patients with a medical history, physical examination, and spirometry (FEV1) to identify potential underlying lung disease. Do not use in patients with chronic lung disease such as asthma or COPD.

Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen: Changes in an insulin regimen (e.g., insulin strength, manufacturer, injection site or type, or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. If clinically indicated, make any necessary changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. For patients with type 2 diabetes dosage modification of concomitant oral antidiabetic treatment may be needed.

Hypoglycemia: Hypoglycemia is the most common adverse reaction associated with insulins, including AFREZZA. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual 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 across patients and change over time in the same patient. Advise patients to recognize and manage hypoglycemia and self-monitor glucose. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of glucose monitoring is recommended.

Decline in Pulmonary Function: AFREZZA causes a decline in lung pulmonary function over time as measured by FEV1. In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-treated patients experienced a small (40 mL) but greater FEV1 decline than comparator-treated patients. Assess pulmonary function with spirometry at baseline, after the first 6 months of therapy and annually thereafter even in the absence of pulmonary symptoms. In patients who have a decline of ≥20% in FEV1 from baseline, consider discontinuing AFREZZA. Consider more frequent lung function assessment in patients with pulmonary symptoms, e.g., wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue AFREZZA.

Lung Cancer: In clinical trials, 2 cases of lung cancer were observed in patients exposed to AFREZZA while no cases were reported for the comparators. In both cases, a prior history of heavy tobacco use was identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous cell and lung blastoma) were reported in non-smokers exposed to AFREZZA after the trial completion. These data are insufficient to determine whether AFREZZA has an effect on lung or respiratory tract tumors. In patients with active lung cancer, a prior history of lung cancer, or in patients at risk of lung cancer, consider whether the benefits of AFREZZA use outweigh this potential risk.

Diabetic Ketoacidosis (DKA): In clinical trials enrolling patients with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in AFREZZA-treated patients (0.43%; n=13) than in comparator-treated patients (0.14%; n=3). Patients with type 1 diabetes should always use AFREZZA concomitantly with basal insulin. In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider discontinuing AFREZZA and giving insulin using an alternate route of administration.

Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products. If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve.

Hypokalemia: All insulin products, including AFREZZA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Closely monitor potassium levels in patients at risk of hypokalemia and treat if indicated.

Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Observe these patients for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the TZD should be considered.

Adverse Reactions

The most common adverse reactions associated with AFREZZA are hypoglycemia, cough, and throat pain or irritation.

Drug Interactions

Certain drugs may affect glucose metabolism, increasing the risk of hypoglycemia, or decreasing or increasing the blood glucose lowering effect of AFREZZA. Dosage modification and increased frequency of blood glucose monitoring may be required. Co-administration of beta-blockers, clonidine, guanethidine, and reserpine with AFREZZA may reduce the signs and symptoms of hypoglycemia. For full list, see Prescribing Information.

To report SUSPECTED ADVERSE REACTIONS, contact MannKind Corporation at 1-877-323-8505 or FDA at www.fda.gov/medwatch or call 1-800-FDA-1088 (1-800-332-1088).

Please see full Prescribing Information, including BOXED WARNING for AFREZZA.