AFREZZA

1 INDICATIONS AND USAGE AFREZZA ® is indicated to improve glycemic control in adult patients with diabetes mellitus. AFREZZA ® is a rapid acting inhaled human insulin indicated to improve glycemic control in adult patients 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 Warning 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.

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 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 information for the chosen basal insulin for dosage recommendations. Table 1. Recommended Starting Mealtime Dosage of AFREZZA when Switching from Other Mealtime Insulin Regimens * For AFREZZA doses exceeding the contents of a single cartridge at mealt…

5 WARNINGS AND PRECAUTIONS Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen : Make 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 mellitus, oral antidiabetic treatment dosage modifications may be needed. ( 5.2 ) Hypoglycemia (may be life-threatening): Increase frequency of glucose monitoring in patients at higher risk for hypoglycemia and those who have reduced symptomatic awareness of hypoglycemia. ( 5.3 ) Decline in Pulmonary Function : Assess pulmonary function (e.g., spirometry (FEV 1 )) at baseline, after 6 months of therapy, and annually, even in the absence of pulmonary symptoms. In patients who have a decline of ≥ 20% in FEV 1 from baseline, consider discontinuing AFREZZA. Consider more frequent monitoring of pulmonary function in patients with pulmonary symptoms ( 5.4 ) Lung Cancer : In patients with active lung cancer, a prior history of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of AFREZZA use outweigh this potential risk. ( 5.5 ) Diabetic Ketoacidosis : In patients at risk for DKA, increase the frequency of glucose monitoring and consider changing to alternate route of insulin delivery. ( 5.6 ) Hypersensitivity Reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with AFREZZA. If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve. ( 5.7 ) Hypokalemia (may be life-threatening): Monitor potassium levels in patients at risk of hypokalemia. ( 5.8 ) Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.9 ) 5.1 Acute Bronchospasm in Patients with Chronic Lung Disease Because of the risk of acute bronchospasm, AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD [see Contraindications ( 4 )] . Before initiating therapy with AFREZZA, evaluate patients with a medical history, physical examination, and spirometry (FEV 1 ) to identify potential underlying lung disease. Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and COPD. In a study of patients with asthma whose bronchodilators were temporarily withheld for assessment, bronchoconstriction and wheezing following AFREZZA dosing was reported in 29% (5/17) and 0% (0/13) of patients with and without a diagnosis of asthma, respectively. In this study, a mean decline in FEV 1 of 400 mL was observed 15 minutes after a single AFREZZA dose in patients with asthma. In a subset study of 8 patients with COPD, a mean decline in FEV 1 of 200 mL was observed 18 minutes after a single AFREZZA dose. 5.2 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 [see Warnings and Precautions ( 5.3 )] 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 modifications of concomitant oral antidiabetic treatment may be needed [see Drug Interactions ( 7.1 , 7.2 , and 7.3 )] . 5.3 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). AFREZZA's time action profile impacts the timing of hypoglycemia following inhalat…

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 )

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 ( 7.1 , 7.2 , 7.3 )]. Switching from another insulin to AFREZZA [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 )] 7 DRUG INTERACTIONS Drugs that may increase the risk of hypoglycemia ( 7.1 , 7.3 ) Drugs that may decrease blood glucose lowering effect of AFREZZA ( 7.2 , 7.3 ) Drugs that may affect hypoglycemic signs and symptoms ( 7.4 ) 7.1 Drugs That May Increase the Risk of Hypoglycemia The risk of hypoglycemia associated with AFREZZA use may be increased with antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs. 7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA The glucose lowering effect of AFREZZA may be decreased when given concomitantly with 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. Dosage modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs. 7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of AFREZZA The glucose lowering effect of AFREZZA may be increased or decreased when used concomitantly with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dosage modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs. 7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are given concomitantly with AFREZZA.

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 ³ 30 mg/kg/day (6 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC).

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. The data described below reflect exposure of 3,017 patients to AFREZZA and include 1,026 patients with type 1 diabetes and 1,991 patients with type 2 diabetes. The mean exposure duration was 8.2 months for patients with type 1 diabetes and those with type 2 diabetes. In the overall population: 1,874 patients were exposed to AFREZZA for 6 months and 724 patients for greater than one year. 620 and 1,254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for greater than one year (median exposure was 1.8 years). AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively). The mean age of the 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. At baseline, the type 1 diabetes population had diabetes for an average of 17 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes 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 type 2 diabetes 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 Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA *Carrier particle without insulin was used as placebo [see Description ( 11.1 )] . AFREZZA (n = 1,991) % Placebo* (n = 290) % Non-placebo comparators (n=1,363) % Cough 26 4 3 3 2 2 2 20 4 3 1 1 1 0.3 5 1 2 2 1 1 1 Throat pain or irritation Headache Diarrhea Productive cough Fatigue Nausea 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 type 1 diabetes patients. These adverse reactions were not present at baseline, 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 Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA AFREZZA (n=1,026) Subcutaneous Insulin (n = 835) Cough 29 5 Throat pain or irritation 6 2 Headache 5 3 Pulmonary function test decreased 3 1 Bronchitis 3 2 Urinary tract infection 2 2 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see Warnings and Precautions ( 5.3 )] . The incidence of…