AFREZZA® Safety in Adults

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Common adverse reactions observed in ≥2%, excluding hypoglycemia1

These adverse reactions, which exclude hypoglycemia, were not present at baseline, occurred more commonly on AFREZZA than placebo and/or comparator.1

What are the most common adverse reactions with AFREZZA?

The most common adverse reactions associated with AFREZZA are hypoglycemia, cough, and throat pain or irritation. In clinical trials, cough occurred in AFREZZA-treated patients with T1D and T2D at rates of 29% and 26%, respectively; in SC insulin comparators with T1D, 5%; and in placebo-treated patients with T2D, 20%.1 The majority of cough episodes were intermittent or single-defined events. Approximately 3% of patients discontinued AFREZZA due to cough in clinical trials.2

Cough was generally mild, and declined with use3

Incidence of cough in pooled safety population3

Incidence of cough events in pooled AFREZZA safety population by week of therapy: approximately 11% at week 1, ~4% at week 2, ~3% at week 3, ~2% at week 4, declining to ~1% by weeks 9-12. Pooled data from 13 phase 2/3 clinical studies (n=5505). 93.2% of cough episodes were intermittent or single defined episodes; 3% of patients discontinued AFREZZA due to cough.
3% of patients discontinued due to cough1
Incidence of cough events in pooled AFREZZA safety population by week of therapy: approximately 11% at week 1, ~4% at week 2, ~3% at week 3, ~2% at week 4, declining to ~1% by weeks 9-12. Pooled data from 13 phase 2/3 clinical studies (n=5505). 93.2% of cough episodes were intermittent or single defined episodes; 3% of patients discontinued AFREZZA due to cough.
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3% of patients discontinued due to cough1

Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1D or T2D treated with AFREZZA, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events. Study sample size reduced over time: from 3017 (AFREZZA) and 2198 (comparators) at Week 1 to 2563 (AFREZZA) and 2034 (comparators) by Week 12.2,3

• 93.2% of cough episodes were characterized as intermittent or single defined episodes2

Safety—lung function1

Monitor lung function with AFREZZA1

• Measure FEV1 before starting patients on AFREZZA, then again at 6 months, and annually thereafter1
• In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-treated patients experienced a small [40 mL (95% CI: -80, -1)] but greater FEV1 decline than comparator-treated patients1
• In healthy individuals, total lung capacity is about 4200 to 6000 mL4
— The 40-mL average difference between AFREZZA- and comparator-treated patients represents about 1% decline in total lung capacity1
— In clinical trials lasting up to 2 years, differences manifested in the first few months of exposure and were non-progressive5
Upper respiratory infection did not impact the absorption or action of AFREZZA6
FEV1 testing device illustration for HCP office spirometry FEV1 testing device illustration for HCP office spirometry

FEV1 test provided when patients start on AFREZZA

• The FEV1 test is one of the tools that can be used to establish a baseline assessment before initiating AFREZZA; monitor lung function after 6 months of therapy and annually thereafter1

Request information about an FEV1 kit

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Conducting a FEV1 test7

STEP 1

Insert mouthpiece and switch device on

FEV1 spirometry test Step 1: inserting mouthpiece and switching device on
STEP 2

Instruct patient to exhale 3 times

FEV1 spirometry test Step 2: patient exhaling forcefully 3 times
STEP 3

Record best FEV1 result

FEV1 spirometry test Step 3: recording best FEV1 result on device display

What pulmonary monitoring is required for all patients on AFREZZA?
Spirometry (FEV1) is required for all patients before initiating AFREZZA, at 6 months after starting therapy, and annually thereafter—even in the absence of pulmonary symptoms. AFREZZA causes a small but greater decline in FEV1 compared with comparators (mean difference, 40 mL over 2 years in clinical trials). In patients with a FEV1 decline of ≥20% from baseline, discontinuation should be considered. The 40-mL average difference represents approximately 1% of total lung capacity and differences were nonprogressive in trials lasting up to 2 years.1,4

FEV1, forced expiratory volume in 1 second; SC, subcutaneous; T1D, type 1 diabetes; T2D, type 2 diabetes; TP, Technosphere placebo.

References: 1. AFREZZA. Prescribing Information. MannKind Corporation; 2026. 2. McGill JB, Peters A, Buse JB, et al. Comprehensive pulmonary safety review of inhaled Technosphere® insulin in patients with diabetes mellitus. Clin Drug Investig. 2020;40(10):973-983. 3. Data on file (ISS). MannKind Corporation. 4. Oches M, O’Brodovich H. 5 – The structural and physiologic basis of respiratory disease, In: Kendig & Chernick’s Disorders of the Respiratory Tract in Children. 8 ed. W.B. Saunders; 2012:35-74. 5. Raskin P, Heller S, Honka M, et al. Pulmonary function over 2 years in diabetic patients treated with prandial inhaled Technosphere insulin or usual antidiabetes treatment: a randomized trial. Diabet Obes Metab. 2012;14(2):163-173. 6. Levin PA, Heinemann L, Boss A, Rosenblit PD. Impact of symptomatic upper respiratory tract infections on insulin absorption and action of Technosphere inhaled insulin. BMJ Open Diabetes Res Care. 2016;4(1):e000228. 7. Sonmol PEF. User manual. 2023.

© MannKind Corporation May 2026. US-AFR-2898

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.