AFREZZA

Indications and Usage ( 1 ) 5/2026 Dosage and Administration Important Administration Information ( 2.2 ) 5/2026 Recommended Starting Mealtime Dosage of AFREZZA ( 2.3 ) 1/2026

1 INDICATIONS AND USAGE AFREZZA ® is indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus. AFREZZA ® 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. ( 1 ) Limitations of Use : Not recommended for the treatment of diabetic ketoacidosis (DKA) ( 1 ) Not recommended in patients who smoke or who have recently stopped smoking ( 1 ) Limitations of Use: AFREZZA is not recommended for the treatment of diabetic ketoacidosis (DKA) [see Warnings and Precautions ( 5.6 )] . The safety and effectiveness of AFREZZA in patients who smoke have not been established. The use of AFREZZA is not recommended in patients who smoke or who have recently stopped smoking [see Warnings and Precautions ( 5.5 )].

2 DOSAGE AND ADMINISTRATION Only administer via oral inhalation using the AFREZZA inhaler ( 2.2 ) Administer at the beginning of each meal ( 2.2 ) See full prescribing information for the recommended starting mealtime dosage in insulin-naïve patients and patients who are using subcutaneous mealtime insulin, or pre-mixed insulin ( 2.3 ) Modify the mealtime AFREZZA dosage based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal ( 2.4 ) If blood glucose control is not achieved with increased AFREZZA dosages, consider discontinuing AFREZZA ( 2.4 ) 2.1 Lung Function Assessment Prior to Administration AFREZZA is contraindicated in patients with chronic lung disease because of the risk of acute bronchospasm in these patients. Before initiating AFREZZA, perform a medical history, physical examination and spirometry (FEV 1 ) in all patients to identify potential lung disease [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. 2.2 Important Administration Information Prior to initiation, train patients and/or their caregiver(s) on proper administration of AFREZZA. After training, adult and pediatric patients aged 10 and older may self-administer AFREZZA if the healthcare provider determines that it is appropriate. Refer patients to the Instructions for Use for detailed instructions and visuals on how to prepare, administer, and store AFREZZA; use the AFREZZA cartridges; and use the AFREZZA inhaler. Only administer AFREZZA via oral inhalation using the AFREZZA Inhaler. Administer AFREZZA at the beginning of each meal. Administer AFREZZA using a single inhalation per cartridge (if the dose is greater than the contents of a single cartridge, more than one cartridge is needed) [see Dosage and Administration ( 2.3 ), Dosage Forms and Strengths ( 3 )]. To administer AFREZZA: Keep the inhaler level with the white mouthpiece on top and purple base on the bottom after a cartridge has been inserted into the inhaler. Loss of drug effect can occur if the inhaler is turned upside down, held with the mouthpiece pointing down, shaken, or dropped after the cartridge has been inserted but before the dose has been administered. If any of the above occur, replace the cartridge before use. Hold the inhaler away from the mouth and fully exhale. After the inhaler is placed in the mouth and the lips form a seal, tilt the inhaler down towards the chin while keeping the head level. With the mouth closed around the mouthpiece, inhale deeply through the inhaler. Hold the breath for as long as comfortable and at the same time remove the inhaler from the mouth. After holding the breath, exhale and continue to breathe normally. The AFREZZA Inhaler can be used for up to 15 days from the date of first use. After 15 days of use, discard the inhaler and replace it with a new inhaler. 2.3 Recommended Starting Mealtime Dosage of AFREZZA Insulin naïve patients The initial dosage of AFREZZA is 4 units inhaled at the beginning of each meal. Switching from Other Mealtime (prandial) Insulin Regimens to AFREZZA When switching from another insulin to AFREZZA, a different insulin dosage may be needed and increased frequency of blood glucose monitoring and monitoring for signs and symptoms of hypoglycemia may be needed [see Warnings and Precautions ( 5.2 , 5.3 ), Clinical Pharmacology ( 12.2 , 12.3 )]. Subcutaneous, Mealtime (prandial) Insulin: Follow the recommendations in Table 1 to convert each injected mealtime insulin dosage (or bolus dosage for patients using insulin pumps) to the recommended mealtime dosage of AFREZZA. Subcutaneous, Pre-Mixed Insulin: Refer to the prescribing information for the pre-mixed insulin to estimate the mealtime subcutaneous insulin dosage based on the product’s pharmacokinetic and pharmacodynamic properties. Follow the recommendations in Table 1 to convert each estimated injected mealtime dosage to an AFREZZA mealtime dose. If basal insulin is clinically indicated, refer to the prescribing …

3 DOSAGE FORMS AND STRENGTHS Inhalation Powder: 3 single-use cartridges of insulin human as white powder labeled “afrezza”. Each AFREZZA inhalation cartridge delivers: 4 units (blue cartridge) 8 units (green cartridge) 12 units (yellow cartridge) Inhalation powder in single-use cartridges of: 4 units, 8 units, or 12 units ( 3 )

4 CONTRAINDICATIONS AFREZZA is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )]. In patients with chronic lung disease, such as asthma or COPD, because of the risk of acute bronchospasm [see Warnings and Precautions ( 5.1 )]. In patients with a 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 [see Warnings and Precautions ( 5.7 )]. During episodes of hypoglycemia ( 4 ) Chronic lung disease, such as asthma, or COPD ( 4 ) Hypersensitivity to any regular human insulin product or any of the inactive ingredients in AFREZZA ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Acute bronchospasm in patients with chronic lung disease [see Warnings and Precautions ( 5.1 )] Hypoglycemia [see Warnings and Precautions ( 5.3 )] Decline in pulmonary function [see Warnings and Precautions ( 5.4 )] Lung cancer [see Warnings and Precautions ( 5.5 )] Diabetic ketoacidosis [see Warnings and Precautions ( 5.6 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.7 )] The most common adverse reactions associated with AFREZZA (2% or greater incidence) are hypoglycemia, cough, and throat pain or irritation ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact MannKind at 1-877-323-8505 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials in Adults with Type 1 or Type 2 Diabetes Mellitus The data described below reflect exposure of 3,017 adult patients to AFREZZA and include 1,026 patients with type 1 diabetes mellitus and 1,991 patients with type 2 diabetes mellitus. The mean exposure duration was 8.2 months for patients with type 1 diabetes mellitus and those with type 2 diabetes mellitus [see Clinical Studies ( 14.2 , 14.3 )] . In the overall population: 1,874 patients with type 1 or type 2 diabetes mellitus were exposed to AFREZZA for 6 months and 724 patients for greater than one year. 620 and 1,254 patients with type 1 or type 2 diabetes mellitus, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 or type 2 diabetes mellitus, respectively, were exposed to AFREZZA for greater than one year (median exposure was 1.8 years). AFREZZA was studied in placebo and active-controlled adult trials (n = 3 and n = 10, respectively). The mean age of the adult population was 50 years and 20 patients were older than 75 years of age; 51% of the population were males; 83% were White, 5% were Black or African American, and 2% were Asian; 10% were Hispanic or Latino ethnicity. At baseline, the type 1 diabetes mellitus population had diabetes mellitus for an average of 17 years and had a mean HbA1c of 8.3%, and the type 2 diabetes mellitus population had diabetes mellitus for an average of 11 years and had a mean HbA1c of 8.8%. At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had a history of cardiovascular disease. Table 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in adults with type 2 diabetes mellitus patients that occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA. Table 2. Common Adverse Reactions That Occurred in ≥ 2% in Adult Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Adverse Reaction AFREZZA (n = 1,991) % Placebo a (n = 290) % Non-placebo comparators (n=1,363) % Cough 26 20 5 Throat pain or irritation 4 4 1 Headache 3 3 2 Diarrhea 3 1 2 Productive cough 2 1 1 Fatigue 2 1 1 Nausea 2 0.3 1 a Carrier particle without insulin was used as placebo [see Description ( 11.1 )]. Table 3 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in adults with type 1 diabetes mellitus. These adverse reactions occurred more commonly on AFREZZA than on comparator and occurred in at least 2% of patients treated with AFREZZA. Table 3. Common Adverse Reactions That Occurred in ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Adverse Reaction AFREZZA (n=1,026) …

2.5 Dosage Modifications for Drug Interactions Dosage modification may be needed when: AFREZZA is used concomitantly with certain drugs that increase and/or decrease the glucose lowering effect [see Drug Interactions ( 7 )]. Switching from another insulin to AFREZZA [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 )]

7 DRUG INTERACTIONS Table 6 presents clinically significant drug interactions with AFREZZA. Table 6. Clinically Significant Drug Interactions with AFREZZA Antidiabetic agents, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blocking Agents, Disopyramide, Fibrates, Fluoxetine, Monoamine Oxidase Inhibitors, Pentoxifylline, Pramlintide, Salicylates, Somatostatin Analogs (e.g., octreotide), and Sulfonamide Antibiotics Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may increase the risk of hypoglycemia. Atypical Antipsychotics (e.g., olanzapine and clozapine), Corticosteroids, Danazol, Diuretics, Estrogens, Glucagon, Isoniazid, Niacin, Oral Contraceptives, Phenothiazines, Progestogens (e.g., in oral contraceptives), Protease inhibitors, Somatropin, Sympathomimetic Agents (e.g., albuterol, epinephrine, terbutaline) and Thyroid Hormones. Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may reduce the blood glucose lowering effect of AFREZZA. Alcohol, Beta-blockers, Clonidine, and Lithium Salts Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use with AFREZZA may either increase or decrease the blood glucose lowering effect of AFREZZA. Pentamidine Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of pentamidine with AFREZZA may cause hypoglycemia, which may sometimes be followed by hyperglycemia Beta-blockers, Clonidine, Guanethidine, and Reserpine Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may blunt the signs and symptoms of hypoglycemia, making it more difficult to recognize See full prescribing information for details regarding concomitant use of drugs that may ( 7 ): Decrease blood glucose lowering effect of AFREZZA Increase or decrease the blood glucose lowering effect of AFREZZA Blunt signs and symptoms of hypoglycemia

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited available data with AFREZZA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. Available information from published studies with human insulin use during pregnancy has not reported a clear association with human insulin and adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy ( see Clinical Considerations ). In animal reproduction studies, there were no adverse developmental outcomes with subcutaneous administration of carrier particles (vehicle without insulin) to pregnant rats during organogenesis at doses 21 times the human daily dose of 99 mg AFREZZA, based on AUC (see Data ) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for DKA, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia- related morbidity. Data Human Data There are limited data with AFREZZA use in pregnant women. Published data do not report a clear association with human insulin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when human insulin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and lack of blinding. Animal Data In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major malformations were observed at doses up to 100 mg/kg/day (21 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC). In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal effects were observed in all dose groups (at human systemic exposure following a daily dose of 99 mg AFREZZA, based on AUC). In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased epididymis and testes weights were observed in F1 male offspring, however, no decrease in fertility was noted, and impaired learning were observed in F1 pups at > 30 mg/kg/day (6 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC). 8.2 Lactation Risk Summary There are no data on the presence of AFREZZA in human milk, the effects on the breastfed infant, or the effects on milk production. One small published study reported that exogenous subcutaneous insulin was present in human milk. No adverse effects in infants were noted. The carrier particles are present in rat milk ( see Data ). Potential adverse reactions that are related to inhalational administration of AFREZZA are unlikely to be associated with potential exposure of AFREZZA through breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AFREZZA and any potential adverse effects on the breastfed infant from AFREZZA or from the underlying maternal condition. Data Subcutaneous administration of the carrier particle in lactating rats resulted in excre …

12.1 Mechanism of Action Insulin lowers blood glucose levels in adult patients with diabetes mellitus by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

11 DESCRIPTION 11.1 AFREZZA Cartridges Human insulin is a rapid acting human insulin produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human insulin has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5808. Human insulin has the following primary amino acid sequence: AFREZZA (human insulin) inhalation powder is available in single-use plastic cartridges filled with a white powder containing insulin (human), which is administered via oral inhalation using the AFREZZA Inhaler only. Insulin is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP) and polysorbate 80. AFREZZA Inhalation Powder is a dry powder supplied as 4 unit, 8 unit or 12 unit cartridges. Primary Amino Acid Sequence 11.2 AFREZZA Inhaler The AFREZZA Inhaler is breath-powered by the patient. When the patient inhales through the device, the powder is aerosolized and delivered to the lung. The amount of AFREZZA delivered to the lung will depend on individual patient factors.

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.8 )] . Mild episodes of hypoglycemia due to insulin overdose can usually be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. Severe episodes of hypoglycemia (due to insulin overdose) with coma, seizure, or neurologic impairment may be treated with intramuscular or subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia should be corrected appropriately. In the event of an overdose of AFREZZA, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING AFREZZA (insulin human) Inhalation Powder is available as 4 unit, 8 unit and 12 unit single-use cartridges. Three cartridges are contained in a single cavity of a blister strip. Each card contains 5 blister strips (each containing three cartridges) separated by perforations for a total of 15 cartridges. Two cards of the same cartridge strength are packaged in a foil laminate overwrap (30 cartridges per foil package). The cartridges are color-coded, blue for 4 units, green for 8 units and yellow for 12 units. Each cartridge is marked with “afrezza” and “4 units”, “8 units” or “12 units”. The AFREZZA Inhaler is individually packaged in a clear overwrap. The inhaler is fully assembled with a removable mouthpiece cover. The AFREZZA Inhaler can be used for up to 15 days from the date of first use. After 15 days of use, the inhaler must be discarded and replaced with a new inhaler. AFREZZA (insulin human) Inhalation Powder is available in the following configurations: NDC Cartridge Strength Quantity of Cartridges per Strength Total Quantity of Cartridges per Kit Total Units in Kit Number of Inhalers 47918-874-90 4 units 90 90 360 Units 2 47918-878-90 8 units 90 90 720 Units 2 47918-891-90 12 units 90 90 1,080 Units 2 47918-898-18 8 units, 12 units 90 180 1,800 Units 2 47918-880-18 (Titration Pack) 4 units, 8 units 90 180 1,080 Units 2 47918-902-18 (Titration Pack) 4 units, 8 units, 12 units 60 180 1,440 Units 2 Storage : Not in Use: Refrigerated Storage 2oC to 8oC (36oF to 46oF) * If a foil package, blister card or strip is not refrigerated, the contents must be used within 10 days. Sealed (Unopened) Foil Package May be stored until the Expiration Date* Sealed (Unopened) Blister Cards and Strips Must be used within 1 month* In Use: Room Temperature Storage 25oC (77oF), excursions permitted 15oC to 30oC (59oF to 86oF) Sealed (Unopened) Blister Cards and Strips Must be used within 10 days Opened Strips Must be used within 3 days Do not put a blister card or strip back into the refrigerator after being stored at room temperature. Inhaler Storage : Store refrigerated or at room temperature 2oC to 25oC (36oF to 77oF); excursions permitted. Inhaler may be stored refrigerated, but should be at room temperature before use. Handling : Before use, cartridges should be at room temperature for 10 minutes.