AFREZZA® Safety in Children and Adolescents

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Safety

The INHALE-1 trial showed a similar safety profile in pediatrics as previously seen in adult trials.1-3

Safety

The INHALE-1 trial showed a similar safety profile in pediatrics as previously seen in adult trials.1-3

Most common adverse reactions

Safety outcomes for the first 26 weeks of the trial (RCT phase)2

INHALE-1: Common adverse reactions observed in ≥5%, excluding hypoglycemia2,a

INHALE-1 pediatric adverse reactions table: Cough 21% AFREZZA (n=117) vs 3% RAA (n=113); Upper respiratory tract infection 18% vs 14%; Oropharyngeal pain 10% vs 4%; Headache 8% vs 5%; Vomiting 5% vs 3%. INHALE-1 pediatric AE table (mobile view)

aAdverse reactions were not present at baseline and occurred more frequently with AFREZZA than with the comparator.2

INHALE-1: Cough characterization among children and adolescents

• 4% of patients discontinued due to cough1
• 96% of cough episodes were characterized as mild or moderate4

The study included a 26-week RCT phase, followed by a 26-week safety extension, with safety findings through 52 weeks remaining consistent with the 26-week safety profile.1,5

What is the safety profile of AFREZZA in children and adolescents?

In the INHALE-1 trial, the safety profile of AFREZZA in children and adolescents was consistent with that observed in adults and comparable to rapid-acting insulin analogs. The most common adverse reaction was cough (21% with AFREZZA vs 3% with RAA). Upper respiratory tract infection occurred in 18% of children and adolescents who received AFREZZA vs 14% of children and adolescents who received RAA.2

• No clinically meaningful differences in lung function were observed between treatment groups through 26 weeks, and findings remained consistent throughout the 52-week extension study6
Lung function

No difference in FEV1 between AFREZZA and RAA7

INHALE-1: Change in percent predicted FEV1 over 56 weeks7

INHALE-1 lung function chart: Change in percent predicted FEV1 over 56 weeks comparing AFREZZA, RAA, and RAA-switched-to-AFREZZA arms. Mean change at Week 26: -3.2% AFREZZA vs -3.9% RAA (P=0.34, n=117 vs n=113). FEV1 levels trended toward baseline in both groups through end of study. INHALE-1 lung function chart: Change in percent predicted FEV1 over 56 weeks comparing AFREZZA, RAA, and RAA-switched-to-AFREZZA arms. Mean change at Week 26: -3.2% AFREZZA vs -3.9% RAA (P=0.34, n=117 vs n=113). FEV1 levels trended toward baseline in both groups through end of study.
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INHALE-1 hypoglycemia CGM percentage time <54 mg/dL chart: AFREZZA Baseline 0.37%, Week 26 0.43%; RAA Baseline 0.50%, Week 26 0.55%. P=0.70.

bP=0.54 for between-group differences in FEV1 from baseline to Week 26 in the RCT and to Week 52 in the extension study.7

Monitor patients

Assess pulmonary function at baseline, at 6 months, and annually thereafter.2

Does AFREZZA cause clinically meaningful lung function decline in children and adolescents?
No. In the INHALE-1 trial, AFREZZA did not cause clinically meaningful lung function decline compared with RAA. Mean change in percent predicted FEV1 at 26 weeks was -3.2% with AFREZZA vs -3.9% with RAA, P=0.54. At Week 56 (end of study), the percent predicted FEV1 levels trended upward toward baseline in both the AFREZZA and crossover RAA groups.7

• Pulmonary function (FEV1) should be assessed before initiating AFREZZA and monitored at 6 months and annually thereafter2

Monitoring lung function

Patients starting AFREZZA receive an FEV1 kit and guidance conducting an FEV1 test.

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Hypoglycemia changes

No difference in hypoglycemia between AFREZZA and RAA1

INHALE-1: Hypoglycemia CGM percentage time <70 mg/dL1,c,d

INHALE-1: Hypoglycemia CGM percentage time <54 mg/dL1,c,d

cWeek 26 adjusted treatment differences were -0.19 (95% CI: -0.92, 0.91; P=0.70) for time at <70 mg/dL and -0.06 (95% CI: -0.34, 0.37; P=0.70) for time at <54 mg/dL. These were estimated using a repeated-measures model adjusted for baseline and randomization strata.1
dBecause the hypoglycemia endpoints had skewed distributions, values were winsorized at the 10th and 90th percentiles. P values and CIs for the treatment effects for these outcomes were calculated using bootstrap.1

How does AFREZZA affect body weight and BMI in children and adolescents compared with injectable insulin?

In the INHALE-1 trial, children and adolescents treated with AFREZZA maintained stable BMI percentiles over 26 weeks, whereas children and adolescents receiving rapid-acting insulin analog experienced increases. BMI percentile remained 73.3 at baseline and Week 26 with AFREZZA vs increasing from 75.5 to 79.1 with RAA (difference, -4.2; 95% CI: -7.4, -0.9; P=0.009).1

• Weight gain was lower with AFREZZA across both children and adolescents1

BMI, body mass index; CGM, continuous glucose monitoring; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RAA, rapid-acting analog; RCT, randomized controlled trial.

References: 1. Haller MJ, Kanapka L, Monzavi R, et al; INHALE-1 Study Group. INHALE-1: a multicenter randomized trial of inhaled Technosphere insulin in children with type 1 diabetes. Diabetes Care. 2026;49(1):179-187. 2. AFREZZA. Prescribing information. MannKind Corporation; 2026. 3. Hirsch IB, Beck RW, Marak MC, et al; INHALE-3 Study Group. A randomized trial comparing inhaled insulin plus basal insulin versus usual care in adults with type 1 diabetes. Diabetes Care. 2025;48(3):353-360. 4. Data on file (Cough Characterizations). MannKind Corporation. 5. Beck RW, Kanapka L, Monzavi R, et al; INHALE-1 Study Group. Inhaled Technosphere insulin in children with diabetes: the INHALE-1 extension study. Diabetes Technol Ther. 2026:15209156261420176. 6. Data on file (INHALE-1 Clinical Study Report 2025). MannKind Corporation. 7. Haller MJ, Wood J. INHALE-1: a 26-week primary treatment with 26-week extension, open-label, randomized clinical trial evaluating the efficacy and safety of Afrezza® vs rapid-acting analogue insulin in pediatric subjects with diabetes. Poster presented at: ISAPD; November 5-8, 2025; Montreal, Canada.

© MannKind Corporation May 2026. US-AFR-2892

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.