ADVERSE REACTIONS SECTION.

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)] 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 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 or Type Diabetes MellitusThe data described below reflect exposure of 3,017 adult patients to AFREZZA and include 1,026 patients with type diabetes mellitus and 1,991 patients with type diabetes mellitus. The mean exposure duration was 8.2 months for patients with type diabetes mellitus and those with type diabetes mellitus [see Clinical Studies 14.2 14.3 )]. In the overall population: 1,874 patients with type or type diabetes mellitus were exposed to AFREZZA for months and 724 patients for greater than one year.620 and 1,254 patients with type or type diabetes mellitus, respectively, were exposed to AFREZZA for up to months.238 and 486 patients with type or type 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 = 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 diabetes mellitus population had diabetes mellitus for an average of 17 years and had mean HbA1c of 8.3%, and the type diabetes mellitus population had diabetes mellitus for an average of 11 years and had mean HbA1c of 8.8%. At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had history of cardiovascular disease.Table 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 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 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZAAdverse ReactionAFREZZA(n 1,991)%Placebo (n 290)%Non-placebo comparators (n=1,363)%Cough 26205Throat pain or irritation441Headache332Diarrhea312Productive cough211Fatigue211Nausea20.31a Carrier particle without insulin was used as placebo [see Description 11.1)]. Table 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 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 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZAAdverse ReactionAFREZZA (n=1,026) %Subcutaneous Insulin(n 835)%Cough 295Throat pain or irritation62Headache53Pulmonary function test decreased31Bronchitis32Urinary tract infection22. 1,874 patients with type or type diabetes mellitus were exposed to AFREZZA for months and 724 patients for greater than one year.. 620 and 1,254 patients with type or type diabetes mellitus, respectively, were exposed to AFREZZA for up to months.. 238 and 486 patients with type or type diabetes mellitus, respectively, were exposed to AFREZZA for greater than one year (median exposure was 1.8 years).. HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients treated with AFREZZA [see Warnings and Precautions 5.3)] The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia across clinical trials of AFREZZA or with the incidence of hypoglycemia for other insulin products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type diabetes mellitus is shown in Table 4. hypoglycemic episode was recorded if patient reported symptoms of hypoglycemia with or without blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia. Table 4. Incidence of Severe and Non-Severe Hypoglycemia in Placebo-Controlled Study of Adult Patients with Type Diabetes MellitusHypoglycemia SeverityAFREZZA(N=177)Placebo(N=176)Severe Hypoglycemia5%2%Non-Severe Hypoglycemia67%30%Other Adverse Reactions in Adults with Type or Type Diabetes MellitusOther Adverse Reactions in Adults with Type or Type Diabetes Mellitus. CoughApproximately 27% of adults treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (3% of adult AFREZZA-treated patients).. Pulmonary Function DeclineIn clinical trials lasting up to years, excluding patients with chronic lung disease, adults treated with AFREZZA had 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV 1) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first months of therapy and persisted over years Figure 1). decline in FEV of >= 15% occurred in 6% of AFREZZA-treated patients compared to 3% of comparator-treated patients [see Warnings and Precautions 5.4)]. Figure 1. Mean (+/-SE) Change in FEV1(Liters) from Baseline for Adult Patients with Type and Type Diabetes Mellitus. Figure 1. Weight GainWeight gain has occurred with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria. In clinical trial of adult patients with type diabetes mellitus [see Clinical Studies 14.3)] there was mean 0.49 kg weight gain among AFREZZA-treated patients compared with mean 1.13 kg weight loss among placebo-treated patients. Adverse Reactions in the Clinical Trial in Pediatric Patients Aged Years and Older with Type or Type Diabetes MellitusA 26-week open-label, randomized clinical trial evaluated the safety of AFREZZA versus rapid-acting insulin analog (RAA), both in combination with basal insulin, in 230 pediatric patients with type or type diabetes mellitus [see Clinical Studies 14.4)]. The trial was followed by 26-week safety extension. The mean age of patients was 12.6 years (range: to 17 in the RAA arm, to 17 in the AFREZZA arm). The majority (97.8%) had type diabetes mellitus; small subset (2.2%) had type diabetes mellitus [see Clinical Studies 14.4)] The trial population had the following characteristics: 38% were female, 77% were White, 10% were Black or African American, 3% were Asian, 6% multiracial, and 20% were Hispanic or Latino ethnicity. Table shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA during the pediatric clinical trial. Data observed for 52 weeks was consistent with the 26-week safety profile. These adverse reactions occurred more commonly on AFREZZA than the comparator and occurred in at least 5% of patients treated with AFREZZA. The overall safety profile was similar to that of adults. In this trial, the change in percent predicted FEV1 from baseline to Week 26 was similar in both groups. Table 5. Common Adverse Reactions That Occurred in >= 5% of Pediatric Patients Aged Years and Older With Type and Type Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA and More Commonly on AFREZZA Than on RAAAdverse Reaction AFREZZA(n=117)%RAA(n=113)%Cough213Upper respiratory tract infection1814Oropharyngeal pain114Headache85Vomiting53a This study was not designed to evaluate meaningful comparisons of adverse reaction incidence between AFREZZA and RAA. HypoglycemiaIn the pediatric clinical trial [see Clinical Studies 14.4)] events of severe hypoglycemia (level 3) were defined as an episode associated with severe cognitive impairment requiring external assistance for recovery. Level hypoglycemia was reported in (1.7%) AFREZZA-treated pediatric patients versus (0.9%) RAA-treated patient during the randomized treatment period. 6.2 Postmarketing Experience. The following adverse reaction has been identified during post approval use of AFREZZA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:Respiratory: bronchospasm.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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.. 12.2 Pharmacodynamics. The time course of insulin action (i.e., glucose lowering) may vary considerably in different patients or within the same patient, or when switching from subcutaneous mealtime insulin to AFREZZA. The average pharmacodynamic profile [i.e., glucose lowering effect measured by glucose infusion rate (GIR) over time in euglycemic clamp study] after administration of single AFREZZA dose of 4, 12, and 48 units in 30 patients with type diabetes mellitus is shown in Figure 2(A), and key characteristics regarding the timing of the effects are described in Table 7: Table 7. Timing of Insulin Effect (i.e., mean pharmacodynamics effect) After Administration of Single AFREZZA Dose in Patients (N=30) with Type Diabetes MellitusParameter for Insulin EffectAFREZZA unitsAFREZZA 12 unitsAFREZZA 48 unitsTime to first measurable effect~12 minutes~12 minutes~12 minutesTime to peak effect~35 minutes~45 minutes~55 minutesTime for effect to return to baseline~90 minutes~180 minutes~270 minutesFigure 2. Results After Administration of AFREZZA 4, 12, and 48 Units in Patients with Type Diabetes Mellitus (N=30) A) Mean Insulin Effect (Baseline-Corrected Glucose Infusion Rate); and B) Pharmacokinetic (Baseline-Corrected Serum Insulin Concentration Profiles)On average, the pharmacodynamics effect of AFREZZA, measured as area under the glucose infusion rate time curve (AUC GIR) increased linearly with doses up to 48 units (106, 387, and 1581 mg/kg for 4, 12, and 48 units doses, respectively).Intrapatient variability in AUC GIR and GIRmax was approximately 28% (95% CI 21-42%) and 27% (95% CI 20-40%), respectively.. Figure 2. 12.3 Pharmacokinetics. The area under the plasma concentration versus time curve (AUC) of insulin increased dose proportionally up to 48 units. Intrapatient variability of AUC and peak concentration (C max) of insulin was approximately 16% (95% CI 12-23%) and 21% (95% CI 16-30%), respectively. AbsorptionThe pharmacokinetic profiles for orally inhaled AFREZZA 4, 12, and 48 units from study in 30 patients with type diabetes mellitus are shown in Figure 2(B). higher maximum plasma insulin concentration was achieved at an earlier timepoint in this study when patients were switched from subcutaneous mealtime insulin to AFREZZA [see Dosage and Administration 2.3)]. The time to maximum serum insulin concentration (t max) ranged from 10-20 minutes after oral inhalation of to 48 units of AFREZZA. EliminationThe apparent terminal half-life ranged from 120 to 206 minutes. Serum insulin concentrations declined to baseline by approximately 60 to 240 minutes.. Metabolism and ExcretionThe metabolism and excretion of AFREZZA are comparable to regular human insulin.. Carrier ParticlesClinical pharmacology studies showed that carrier particles [see Description 11.1)] are not metabolized and are eliminated unchanged in the urine following the lung absorption. Following oral inhalation of AFREZZA, mean of 39% of the inhaled dose of carrier particles was distributed to the lungs and mean of 7% of the dose was swallowed. The swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the feces. Specific Populations Pediatric PatientsIn pediatric patients aged years and older, insulin serum concentration profiles (T max and time decline to baseline) showed similar time course between adult and pediatric patients following administration of AFREZZA. Insulin Cmax and AUC increased in dose-dependent manner following single dose of units to 12 units. Drug Interaction Studies. Bronchodilators and Inhaled SteroidsAlbuterol increased the AUC insulin after AFREZZA administration by 25% in patients with asthma [see Drug Interactions 7) ]. AFREZZA is contraindicated in patients with asthma. In study in healthy volunteers no significant change in insulin exposure was observed when fluticasone was administered following AFREZZA administration.. 12.6 Immunogenicity. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of insulin human or of other insulin human products.Increases in anti-insulin antibody concentrations were observed in patients treated with AFREZZA. Increases in anti-insulin antibodies were observed more frequently in patients treated with AFREZZA than in patients treated with subcutaneously injected mealtime insulin. There was no clinically significant effect of anti-drug antibodies on safety or effectiveness (as measured by HbA1c and fasting plasma glucose) of AFREZZA over the treatment duration of the studies which spanned to 24 months.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Overview of Clinical Studies of AFREZZA Adult and Pediatric Patients Years of Age and Older with Diabetes Mellitus. AFREZZA has been studied in adults with type diabetes mellitus in combination with basal insulin. The efficacy of AFREZZA, in combination with basal insulin, in adult patients with type diabetes mellitus was compared to insulin aspart in combination with basal insulin.AFREZZA has been studied in adults with type diabetes in combination with oral antidiabetic drugs. The efficacy of AFREZZA in type diabetes patients was compared to placebo inhalation.AFREZZA has been studied in pediatric patients aged to 17 years with type and type diabetes mellitus in combination with basal insulin. The efficacy of AFREZZA, in combination with basal insulin was compared to rapid-acting insulin analogs (RAA) in combination with basal insulin.. 14.2 Adults with Type Diabetes Mellitus. Patients with inadequately controlled type diabetes mellitus participated in 24-week, open-label, active-controlled study (NCT01445951) to evaluate the glucose lowering effect of mealtime AFREZZA used in combination with basal insulin. Following 4-week basal insulin optimization period, 344 patients were randomized to AFREZZA by oral inhalation (n=174) or insulin aspart given subcutaneously (n=170) at each meal of the day. All patients received basal insulin. Mealtime insulin doses were titrated to glycemic goals for the first 12 weeks and kept stable for the last 12 weeks of the study. The trial population had the following characteristics: mean age was 38, 56% were female, 96% were White, 3% were Black or African American, less than 1% were Asian, less than 1% were Native Hawaiian or Pacific Islander, less than 1% were other races, and 10% were Hispanic or Latino ethnicity.. ResultsAt Week 24, treatment with mealtime AFREZZA and basal insulin provided mean reduction in HbA1c that met the pre-specified non-inferiority margin of 0.4%. AFREZZA and basal insulin provided less HbA1c reduction than insulin aspart and basal insulin, and the difference was statistically significant. More patients in the insulin aspart and basal insulin group achieved the HbA1c target of <=7% Table 8). Table 8. Results at Week 24 in an Active-Controlled Study of Mealtime AFREZZA plus Basal Insulin in Adults with Type Diabetes MellitusEfficacy ParameterAFREZZA Basal Insulin (N=174)Insulin Aspart Basal Insulin (N=170) HbA1c (%) Baseline (adjusted mean a) 7.947.92Change from baseline (adjusted mean a,b) -0.21-0.40Difference from insulin aspart (adjusted mean a,b) (95% CI)0.19 (0.02, 0.36) Percentage of patients achieving HbA1c <= 7% 14%27%Fasting Plasma Glucose (mg/dL)Baseline (adjusted mean a) 153.9151.6Change from baseline (adjusted mean a, b) -25.310.2Difference from insulin aspart (adjusted mean a,b) (95% CI)-35.4 (-56.3, -14.6) Adjusted mean was obtained using Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent variable and treatment, visit, region, basal insulin stratum, and treatment by visit interaction as fixed factors, and corresponding baseline as covariate. An autoregression (1) [AR(1)] covariance structure was used. Data at 24 weeks were available from 131 (75%) and 150 (88%) patients randomized to the AFREZZA and insulin aspart groups, respectively. The percentage was calculated based on the number of patients randomized to the trial. 14.3 Adults with Type Diabetes Mellitus. total of 479 adult patients with type diabetes mellitus inadequately controlled on optimal/maximally tolerated doses of metformin only, or or more oral antidiabetic (OAD) agents participated in 24-week, double-blind, placebo-controlled study (NCT01451398). Following 6-week run-in period, 353 patients were randomized to AFREZZA by oral inhalation (n=177) or an inhaled placebo powder without insulin (n=176). Insulin doses were titrated for the first 12 weeks and kept stable for the last 12 weeks of the study. OADs doses were kept stable in the study. The trial population had the following characteristics: mean age was 57, 56% were female, 87% were White, 11% were Black or African American, less than 1% were Asian, less than 1% were American Indian or Alaska Native, 1% were other races, and 24% were Hispanic or Latino ethnicity.. ResultsAt Week 24, treatment with AFREZZA plus OADs provided mean reduction in HbA1c that was statistically significantly greater compared to the HbA1c reduction observed in the placebo plus OADs group Table 9). Table 9. Results at Week 24 in Placebo-Controlled Study of AFREZZA in Adults with Type Diabetes Mellitus Inadequately Controlled on Oral Antidiabetic AgentsEfficacy ParameterAFREZZA Oral Anti-Diabetic Agents (N=177) Placebo Oral Anti-Diabetic Agents (N=176) HbA1c (%)Baseline (adjusted mean a) 8.258.27Change from baseline (adjusted mean a,b) -0.82-0.42Difference from placebo (adjusted mean a,b) (95% CI) -0.40 (-0.57, -0.23) Percentage (%) of patients achieving HbA1C <=7% 32%15%Fasting Plasma Glucose (mg/dL)Baseline (adjusted mean a) 175.9175.2Change from baseline (adjusted mean a,b) -11.2-3.8Difference from placebo (adjusted mean a,b) (95% CI) -7.4 (-18.0, 3.2) Adjusted mean was obtained using Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent variable and treatment, visit, region, and treatment by visit interaction as fixed factors, and corresponding baseline as covariate. An autoregression (1) [AR(1)] covariance structure was used. Data at 24 weeks without rescue therapy were available from 139 (79%) and 129 (73%) patients randomized to the AFREZZA and placebo groups, respectively. The percentage was calculated based on the number of patients randomized to the trial. 14.4 Pediatric Patients Years of Age and Older with Type and Type Diabetes Mellitus. The efficacy of AFREZZA was assessed in an open-label 26-week, randomized active-controlled trial in 230 pediatric patients with type or type diabetes mellitus (NCT04974528). All patients were required to take basal insulin during the study. Patients were randomized (1:1) to receive either mealtime AFREZZA or RAA (insulin aspart, lispro, or glulisine; per investigators choice) for 26 weeks. The primary efficacy endpoint was change in HbA1c from baseline to Week 26, with pre-specified non-inferiority margin of 0.4% for the between-group difference in HbA1c. The mean age of patients was 12.6 years (range: to 17 years in the RAA arm; to 17 years in the AFREZZA arm). The majority (97.8%) had type diabetes mellitus; small subset (2.2%) had type diabetes mellitus. The trial population had the following characteristics: 38% were female, 77% were White, 10% were Black or African American, 3% were Asian, 6% were multiracial, and 20% were Hispanic or Latino ethnicity.. Results. At Week 26, treatment with mealtime AFREZZA and basal insulin did not meet the primary endpoint of noninferiority, based on noninferiority margin of 0.4% (See Table 10). Treatment with mealtime AFREZZA resulted in nominally inferior mean levels of HbA1c compared to treatment with mealtime RAA (Week 26 HbA1c 8.41% in the AFREZZA group; 8.22% in the RAA group). The confidence interval of the between-group difference in mean HbA1c reduction exceeded the pre-specified non-inferiority margin. Table 10. Results at Week 26 in an Active-Controlled Study of AFREZZA plus Basal Insulin in Pediatric Patients Aged Years and Older with Type or Type Diabetes MellitusEfficacy ParameterIntention-to-treat population AFREZZA(N=117)RAA(N=113)HbA1c (%)Baseline (adjusted mean b) 8.22 (0.87)8.21 (0.96)Change from baseline mean 0.19 (0.09)0.01 (0.09)Difference from RAA b,c (95% CI) 0.18 (-0.07, 0.44) Patients (%) achieving HbA1c <= 7% 12 (10.3)12 (10.6)aThe intent-to-treat population consists of all randomly assigned participants. At Week 26, the HbA1c endpoint was missing for 10% and 7% of patients randomized to Afrezza and RAA, respectively. Missing Week 26 data were imputed using return-to-baseline multiple imputation. bLeast-squares mean from ANCOVA adjusted for baseline value and other stratification factors. cOne-sided adjusted p-value 0.058 0.025 for non-inferiority versus RAA. Statistical significance of non-inferiority of Afrezza was not demonstrated. dThe number is calculated based on observed HbA1c values at Week 26. Missing Week 26 data were treated as non-responder.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 or Type Diabetes MellitusThe data described below reflect exposure of 3,017 adult patients to AFREZZA and include 1,026 patients with type diabetes mellitus and 1,991 patients with type diabetes mellitus. The mean exposure duration was 8.2 months for patients with type diabetes mellitus and those with type diabetes mellitus [see Clinical Studies 14.2 14.3 )]. In the overall population: 1,874 patients with type or type diabetes mellitus were exposed to AFREZZA for months and 724 patients for greater than one year.620 and 1,254 patients with type or type diabetes mellitus, respectively, were exposed to AFREZZA for up to months.238 and 486 patients with type or type 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 = 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 diabetes mellitus population had diabetes mellitus for an average of 17 years and had mean HbA1c of 8.3%, and the type diabetes mellitus population had diabetes mellitus for an average of 11 years and had mean HbA1c of 8.8%. At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had history of cardiovascular disease.Table 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 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 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZAAdverse ReactionAFREZZA(n 1,991)%Placebo (n 290)%Non-placebo comparators (n=1,363)%Cough 26205Throat pain or irritation441Headache332Diarrhea312Productive cough211Fatigue211Nausea20.31a Carrier particle without insulin was used as placebo [see Description 11.1)]. Table 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 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 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZAAdverse ReactionAFREZZA (n=1,026) %Subcutaneous Insulin(n 835)%Cough 295Throat pain or irritation62Headache53Pulmonary function test decreased31Bronchitis32Urinary tract infection22. 1,874 patients with type or type diabetes mellitus were exposed to AFREZZA for months and 724 patients for greater than one year.. 620 and 1,254 patients with type or type diabetes mellitus, respectively, were exposed to AFREZZA for up to months.. 238 and 486 patients with type or type diabetes mellitus, respectively, were exposed to AFREZZA for greater than one year (median exposure was 1.8 years).. HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients treated with AFREZZA [see Warnings and Precautions 5.3)] The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia across clinical trials of AFREZZA or with the incidence of hypoglycemia for other insulin products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type diabetes mellitus is shown in Table 4. hypoglycemic episode was recorded if patient reported symptoms of hypoglycemia with or without blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia. Table 4. Incidence of Severe and Non-Severe Hypoglycemia in Placebo-Controlled Study of Adult Patients with Type Diabetes MellitusHypoglycemia SeverityAFREZZA(N=177)Placebo(N=176)Severe Hypoglycemia5%2%Non-Severe Hypoglycemia67%30%Other Adverse Reactions in Adults with Type or Type Diabetes MellitusOther Adverse Reactions in Adults with Type or Type Diabetes Mellitus. CoughApproximately 27% of adults treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (3% of adult AFREZZA-treated patients).. Pulmonary Function DeclineIn clinical trials lasting up to years, excluding patients with chronic lung disease, adults treated with AFREZZA had 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV 1) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first months of therapy and persisted over years Figure 1). decline in FEV of >= 15% occurred in 6% of AFREZZA-treated patients compared to 3% of comparator-treated patients [see Warnings and Precautions 5.4)]. Figure 1. Mean (+/-SE) Change in FEV1(Liters) from Baseline for Adult Patients with Type and Type Diabetes Mellitus. Figure 1. Weight GainWeight gain has occurred with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria. In clinical trial of adult patients with type diabetes mellitus [see Clinical Studies 14.3)] there was mean 0.49 kg weight gain among AFREZZA-treated patients compared with mean 1.13 kg weight loss among placebo-treated patients. Adverse Reactions in the Clinical Trial in Pediatric Patients Aged Years and Older with Type or Type Diabetes MellitusA 26-week open-label, randomized clinical trial evaluated the safety of AFREZZA versus rapid-acting insulin analog (RAA), both in combination with basal insulin, in 230 pediatric patients with type or type diabetes mellitus [see Clinical Studies 14.4)]. The trial was followed by 26-week safety extension. The mean age of patients was 12.6 years (range: to 17 in the RAA arm, to 17 in the AFREZZA arm). The majority (97.8%) had type diabetes mellitus; small subset (2.2%) had type diabetes mellitus [see Clinical Studies 14.4)] The trial population had the following characteristics: 38% were female, 77% were White, 10% were Black or African American, 3% were Asian, 6% multiracial, and 20% were Hispanic or Latino ethnicity. Table shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA during the pediatric clinical trial. Data observed for 52 weeks was consistent with the 26-week safety profile. These adverse reactions occurred more commonly on AFREZZA than the comparator and occurred in at least 5% of patients treated with AFREZZA. The overall safety profile was similar to that of adults. In this trial, the change in percent predicted FEV1 from baseline to Week 26 was similar in both groups. Table 5. Common Adverse Reactions That Occurred in >= 5% of Pediatric Patients Aged Years and Older With Type and Type Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA and More Commonly on AFREZZA Than on RAAAdverse Reaction AFREZZA(n=117)%RAA(n=113)%Cough213Upper respiratory tract infection1814Oropharyngeal pain114Headache85Vomiting53a This study was not designed to evaluate meaningful comparisons of adverse reaction incidence between AFREZZA and RAA. HypoglycemiaIn the pediatric clinical trial [see Clinical Studies 14.4)] events of severe hypoglycemia (level 3) were defined as an episode associated with severe cognitive impairment requiring external assistance for recovery. Level hypoglycemia was reported in (1.7%) AFREZZA-treated pediatric patients versus (0.9%) RAA-treated patient during the randomized treatment period.

DOSAGE & ADMINISTRATION SECTION.

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-naive patients and patients who are using subcutaneous mealtime insulin, or pre-mixed insulin 2.3) Modify the mealtime AFREZZA dosage based on the patients 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) 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-naive patients and patients who are using subcutaneous mealtime insulin, or pre-mixed insulin 2.3) Modify the mealtime AFREZZA dosage based on the patients 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 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 single inhalation per cartridge (if the dose is greater than the contents of 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 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 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 new inhaler.. Only administer AFREZZA via oral inhalation using the AFREZZA Inhaler.. Administer AFREZZA at the beginning of each meal.. Administer AFREZZA using single inhalation per cartridge (if the dose is greater than the contents of 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 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 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. Keep the inhaler level with the white mouthpiece on top and purple base on the bottom after 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 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 new inhaler.. 2.3 Recommended Starting Mealtime Dosage of AFREZZA. Insulin naive patientsThe initial dosage of AFREZZA is units inhaled at the beginning of each meal.. Switching from Other Mealtime (prandial) Insulin Regimens to AFREZZAWhen switching from another insulin to AFREZZA, 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 1to 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 products pharmacokinetic and pharmacodynamic properties.Follow the recommendations in Table 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 RegimensCurrent Subcutaneous Mealtime Insulin DosageStarting Dosage of AFREZZAUp to units4 units to units units6 to units12 units8 or more units16 units For AFREZZA doses exceeding the contents of single cartridge at mealtime, use more than one cartridge. To achieve the required total mealtime dosage, use combination of unit, unit, and 12 unit cartridges. When titrating dosages above 16 units after the initial conversion dosage, use combinations of different cartridges [see Dosage and Administration 2.4), Dosage Forms and Strengths 3), How Supplied/Storage and Handling 16)]. Refer to the prescribing information for the pre-mixed insulin to estimate the mealtime subcutaneous insulin dosage based on the products pharmacokinetic and pharmacodynamic properties.. Follow the recommendations in Table 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.. 2.4 Mealtime AFREZZA Dosage Modification. Modify the mealtime AFREZZA dosage based on the patients metabolic needs, blood glucose monitoring results, and glycemic control goal.Dosage modifications may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions 5.3) and Use in Specific Populations 8.6, 8.7)]. Increase the frequency of blood glucose monitoring during titration of AFREZZA. If blood glucose control is not achieved with increased AFREZZA dosages, consider discontinuing AFREZZA.. Modify the mealtime AFREZZA dosage based on the patients metabolic needs, blood glucose monitoring results, and glycemic control goal.. Dosage modifications may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions 5.3) and Use in Specific Populations 8.6, 8.7)]. Increase the frequency of blood glucose monitoring during titration of AFREZZA. If blood glucose control is not achieved with increased AFREZZA dosages, consider discontinuing AFREZZA.. 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)] 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling Medication Guide and Instructions for Use). Instruct patients to use AFREZZA only with the AFREZZA inhaler.. Acute Bronchospasm in Patients with Chronic Lung DiseaseAdvise patients that if they experience any respiratory difficulty after inhalation of AFREZZA, they should report it to their healthcare provider immediately for assessment [see Warnings and Precautions 5.1)] . HypoglycemiaInstruct patients on self-management procedures including glucose monitoring, proper inhalation technique, and management of hypoglycemia and hyperglycemia, especially at initiation of AFREZZA therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, or skipped meals [see Warnings and Precautions 5.3)] Inform patients that their ability to concentrate and react may be impaired as result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions 5.2)]. Decline in Pulmonary FunctionInform patients that AFREZZA can cause decline in lung function [see Warnings and Precautions 5.4)]. Lung CancerInform patients to promptly report any signs or symptoms potentially related to lung cancer [see Warnings and Precautions 5.5)]. Diabetic KetoacidosisInstruct patients to carefully monitor their blood glucose during illness, infection, and other risk situations for DKA and to contact their healthcare provider if their blood glucose control worsens [see Warnings and Precautions 5.6)]. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions can occur with insulin therapy including AFREZZA. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions 5.7)]. Manufactured by: MannKind Corporation, Danbury, CT 06810 US License No. 2190 (C) 2016 2026 MannKind Corporation AFREZZA is registered trademark of MannKind Corporation Patent: www.mannkindcorp.com/patent-notices.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEAFREZZA (R) (uh-FREZZ-uh) (insulin human)inhalation powder, for oral inhalation useThis Instructions for Use contains information on how to use AFREZZA (R) (insulin human) inhalation powder dry powder inhaler. Read this Instructions for Use all the way through before you start using AFREZZA and each time you get new AFREZZA Inhaler. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.Your healthcare provider should show you or your child (10 years of age or older) how to use the AFREZZA Inhaler the right way before it is used for the first time. Contact your healthcare provider if you have any questions.Important Information You Need to Know Before Inhaling AFREZZA:AFREZZA starts acting fast, so take your medicine right before you eat meal. For oral inhalation only.AFREZZA is mealtime (short acting) insulin.Contact your healthcare provider before switching insulins.Do not put cartridges in your mouth. Do not swallow cartridges. Do not use AFREZZA cartridges if they are expired. Only use AFREZZA cartridges with the AFREZZA Inhaler.Do not breathe in the AFREZZA powder any other way. Do not open the cartridges. The inhaler opens the cartridge automatically during use. Do not reuse cartridges. Cartridges are single use and should only be used time.You can tell cartridge has been used when the cartridge cup has moved from the front to the middle position in the cartridge base. If your prescribed AFREZZA dose is higher than 12 units, you will need to use more than cartridge. If using more than cartridge for dose, the cartridges can be used in any order, regardless of cartridge strength. Do not insert more than cartridge into the inhaler at time. Always remove the used cartridge from the inhaler before inserting new one. Only use inhaler at time. The same inhaler should be used for the unit, unit or 12 unit cartridges. The same inhaler should be used even when needing to use more than cartridge for your dose. Do not share the AFREZZA Inhaler with anyone else. The inhaler lasts for 15 days. After 15 days of use, throw away your used inhaler and get new one.Warning:After cartridge is loaded into the inhaler, keep the inhaler level until the inhaler mouthpiece is in your mouth to avoid spilling the AFREZZA powder. Do not flip or rotate inhaler. If any AFREZZA powder spills, throw away the cartridge into regular household trash, and wash your hands. Then restart the procedure with new cartridge. AFREZZA Inhaler Parts (Figure A):AFREZZA Cartridge Parts and Strengths (Figure B):Storage Information (Figure C)Additional Storage InformationImportant: Before use, cartridges and inhaler should be left out at room temperature for at least 10 minutes.Do not put blister cards or blister strips back into the refrigerator after being opened or stored at room temperature. Keep AFREZZA and all medicines out of reach of children.Do not let cartridge or inhaler get wet. Do not leave or store cartridges in the inhaler. Use inhaler at time. The same inhaler should be used to take unit, unit or 12 unit cartridges. Always store the inhaler with the mouthpiece cover on.Preparing to Inhale AFREZZAStep 1: Choose cartridges for dose1.1 Figure out what AFREZZA cartridges are needed for your dose.Use the dosage chart below (Figure D) to determine the number of AFREZZA cartridges you can use for your dose. Note: If your prescribed AFREZZA dose is higher than 12 units, you will need to use more than cartridge. If using more than cartridge for dose, the cartridges can be used in any order, regardless of cartridge strength. Step 2: Get and check blister strip(s)2.1 Open Foil package and remove blister card(s) needed for your dose (Figure E). 2.2 Get the blister strip(s) with the cartridges you need for your doseIf needed, tear blister strip from the blister card (Figure F).2.3 Check the expiration date printed on the blister strip(s) (Figure G). Step 3: Remove cartridge(s) from blister strip(s)3.1 Remove cartridge(s) from the strip by pressing on the clear plastic to push the cartridge out (Figure H). Note: Pushing on the clear plastic will not damage the cartridge. 3.2 If stored in the refrigerator, cartridge(s) and inhaler should be left out at room temperature for 10 minutes before use (Figure I). 3.3 Check that you have the correct cartridge(s) for your dose (Figure J). Step 4: Load cartridge4.1 Open the inhaler by lifting the mouthpiece to an upright (vertical) position (Figure K). 4.2 Place Inhaler on flat surface (Figure L) 4.3 Place Cartridge in the inhaler (Figure L) Hold the cartridge with the white cup facing down.Line up the cartridge with the opening in the inhaler. The pointed end of the cartridge should line up with the pointed end in the inhaler.Place the cartridge into the inhaler so that it sits flat.4.4 Close the inhaler. You should feel snap when the inhaler is closed (Figure N). Note: Closing the inhaler automatically opens the cartridge inside. Tilting or flipping your inhaler before dosing may spill AFREZZA powder. Keep the inhaler level until the inhaler mouthpiece is in your mouth. Inhaling AFREZZAStep 5: Remove cover and get ready5.1 Pull off the mouthpiece cover (Figure O). 5.2 Sit upright, looking straight with your head level (Figure P)5.3 While keeping the inhaler level, carefully pick up the inhaler and hold it away from your mouth (Figure P). Step 6: Inhale AFREZZA 6.1 Hold the inhaler away from your mouth or next to the side of your head and fully breathe out (exhale) (Figure Q). 6.2 Place the inhaler into your mouth and close your lips around the mouthpiece (Figure R). 6.3 Tilt the inhaler slightly downward. This helps prevent the powder from being blocked by your tongue (Figure S). 6.4 Breathe in (inhale) quickly and deeply through the mouthpiece (Figure S). 6.5 Remove the inhaler from your mouth. Hold your breath for as long as comfortable (Figure T). Then breathe out normally.After Inhaling AFREZZAStep 7: Remove and throw away cartridge7.1 Put the mouthpiece cover back onto the inhaler (Figure U). This keeps your fingers off the exposed mouthpiece. 7.2 Open the inhaler by lifting up the mouthpiece to an upright (vertical) position (Figure V). 7.3 Remove cartridge.Remove the used cartridge from the purple base (Figure W).The white cup should now be in the middle of the used cartridge (Figure W).7.4 Throw away the used cartridge in your regular household trash (Figure X). Also, the used cartridge (composed of HDPE, assigned recycling number 2) can be recycled. Step 8: Dosing with more cartridges8.1 If your dose requires you to inhale more cartridges repeat Steps to for each AFREZZA cartridge needed to finish your required dose (Figure Y). Caring for Your AFREZZA InhalerCleaning AFREZZA InhalersAfter taking your dose, powder residue inside the mouthpiece is normal; this will not affect your dose.The outside of the inhaler can be wiped with clean, dry cloth only, if needed Do not wash the inhaler or let the inhaler get wet. Always keep the inhaler dry.Storing AFREZZA InhalersStore AFREZZA Inhalers with the mouthpiece cover on, in clean dry place at room temperature.Do not leave or store cartridges in the inhaler. Refer to the Storage Information section for more information.Disposing of your AFREZZA Inhaler after 15 days.Only use inhaler at time. The same inhaler should be used to take unit, unit or 12 unit cartridges. Replace the inhaler 15 days after first use. Keep track of 15 days from when you start using the inhaler with calendar (Figure AA) or use the chart on the box. Throw away (dispose of) used inhaler into household trash 15 days after first use.If you are having problems with your AFREZZA Inhaler, have an adverse event, or if your AFREZZA Inhaler breaks and you need new one, please call 1-877-323-8505.Manufactured by: MannKind Corporation Danbury, CT 06810 US License No. 2190(C) 2016 2026 MannKind CorporationThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: 05/2026AFREZZA is registered trademark of MannKind CorporationPatent: www.mannkindcorp.com/patent-notices. AFREZZA starts acting fast, so take your medicine right before you eat meal. For oral inhalation only.. AFREZZA is mealtime (short acting) insulin.. Contact your healthcare provider before switching insulins.. Do not put cartridges in your mouth. Do not swallow cartridges. Do not use AFREZZA cartridges if they are expired. Only use AFREZZA cartridges with the AFREZZA Inhaler.Do not breathe in the AFREZZA powder any other way. Do not open the cartridges. The inhaler opens the cartridge automatically during use. Do not reuse cartridges. Cartridges are single use and should only be used time.. You can tell cartridge has been used when the cartridge cup has moved from the front to the middle position in the cartridge base. If your prescribed AFREZZA dose is higher than 12 units, you will need to use more than cartridge. If using more than cartridge for dose, the cartridges can be used in any order, regardless of cartridge strength. Do not insert more than cartridge into the inhaler at time. Always remove the used cartridge from the inhaler before inserting new one. Only use inhaler at time. The same inhaler should be used for the unit, unit or 12 unit cartridges. The same inhaler should be used even when needing to use more than cartridge for your dose. Do not share the AFREZZA Inhaler with anyone else. The inhaler lasts for 15 days. After 15 days of use, throw away your used inhaler and get new one.. After cartridge is loaded into the inhaler, keep the inhaler level until the inhaler mouthpiece is in your mouth to avoid spilling the AFREZZA powder. Do not flip or rotate inhaler. If any AFREZZA powder spills, throw away the cartridge into regular household trash, and wash your hands. Then restart the procedure with new cartridge. Important: Before use, cartridges and inhaler should be left out at room temperature for at least 10 minutes.. Do not put blister cards or blister strips back into the refrigerator after being opened or stored at room temperature. Keep AFREZZA and all medicines out of reach of children.. Do not let cartridge or inhaler get wet. Do not leave or store cartridges in the inhaler. Use inhaler at time. The same inhaler should be used to take unit, unit or 12 unit cartridges. Always store the inhaler with the mouthpiece cover on.. Hold the cartridge with the white cup facing down.. Line up the cartridge with the opening in the inhaler. The pointed end of the cartridge should line up with the pointed end in the inhaler.. Place the cartridge into the inhaler so that it sits flat.. Remove the used cartridge from the purple base (Figure W).. The white cup should now be in the middle of the used cartridge (Figure W).. After taking your dose, powder residue inside the mouthpiece is normal; this will not affect your dose.. The outside of the inhaler can be wiped with clean, dry cloth only, if needed . Store AFREZZA Inhalers with the mouthpiece cover on, in clean dry place at room temperature.. Do not leave or store cartridges in the inhaler. Only use inhaler at time. The same inhaler should be used to take unit, unit or 12 unit cartridges. Replace the inhaler 15 days after first use. Keep track of 15 days from when you start using the inhaler with calendar (Figure AA) or use the chart on the box. Throw away (dispose of) used inhaler into household trash 15 days after first use.. A. B. C. FigureD. figE. 2.2. f. 2.3. g. h. 3.2. i. 3.3. j. k. l. Warni. figM. n. 5. 5.1. figO. 5.3. p. 6.1. q. r. s. t. u. v. 7.3. w. x. y. z. aa.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited 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 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 riskPoorly 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 DataThere are limited data with AFREZZA use in pregnant women. Published data do not report 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 DataIn pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day through 17 (organogenesis), no major malformations were observed at doses up to 100 mg/kg/day (21 times the human systemic exposure at 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 through 19 (organogenesis), adverse maternal effects were observed in all dose groups (at human systemic exposure following 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 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 daily dose of 99 mg AFREZZA, based on AUC).

SPL MEDGUIDE SECTION.

MEDICATION GUIDEAFREZZA (R) (uh-FREZZ-uh) (insulin human) inhalation powder, for oral inhalation useWhat is the most important information should know about AFREZZAAFREZZA can cause serious side effects, including:Sudden lung problems (bronchospasms). Do not use AFREZZA if you have long-term (chronic) lung problems such as asthma or chronic obstructive pulmonary disease (COPD). Before starting AFREZZA, your healthcare provider will give you breathing test to check how your lungs are working. What is AFREZZAAFREZZA is man-made insulin that is breathed-in through your lungs (inhaled) and is used to control high blood sugar in adults and children years of age and older, with diabetes mellitus.AFREZZA is not for use to treat diabetic ketoacidosis. AFREZZA must be used with basal insulin in people who have type diabetes mellitus.It is not known if AFREZZA is safe and effective for use in people who smoke. AFREZZA is not for use in people who smoke or have recently stopped smoking (less than months).It is not known if AFREZZA is safe and effective in children under years of age.Who should not use AFREZZADo not use AFREZZA if you:Are having an episode of low blood sugar (hypoglycemia).Have chronic lung problems such as asthma or COPD.Are allergic to regular human insulin or any of the ingredients in AFREZZA. See the end of this Medication Guide for complete list of ingredients in AFREZZA.What should tell my healthcare provider before using AFREZZABefore using AFREZZA, tell your healthcare provider about all your medical conditions, including if you:Have lung problems such as asthma or COPD.Have or have had lung cancer.Are using any inhaled medications.Smoke or have recently stopped smoking.Have kidney or liver problems.Are pregnant, planning to become pregnant, or are breastfeeding. AFREZZA may harm your unborn or breastfeeding baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins or herbal supplements.Before you start using AFREZZA, talk to your healthcare provider about low blood sugar and how to manage it.How should use AFREZZARead the detailed Instructions for Use that comes with your AFREZZA. Take AFREZZA exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much AFREZZA to use and when to use it.Your healthcare provider will train you or your caregiver in how to use AFREZZA.After training, you or your child (10 years of age or older) may self-administer AFREZZA.Know the strength of AFREZZA you use. Do not change the amount of AFREZZA you use unless your healthcare provider tells you to. Take AFREZZA at the beginning of your meal.Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. Keep AFREZZA and all medicines out of the reach of children.Your dose of AFREZZA may need to change because of:Change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.What should avoid while using AFREZZAWhile using AFREZZA do not:Drive or operate heavy machinery, until you know how AFREZZA affects you.Drink alcohol or use over-the-counter medicines that contain alcohol.Smoke.What are the possible side effects of AFREZZAAFREZZA may cause serious side effects that can lead to death, including: See What is the most important information should know about AFREZZALow blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: Dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger.Decreased lung function. Your healthcare provider should check how your lungs are working before you start using AFREZZA, months after you start using it and yearly after that. Lung cancer. In studies of AFREZZA in people with diabetes, lung cancer occurred in few more people who were taking AFREZZA than in people who were taking other diabetes medications. There were too few cases to know if lung cancer was related to AFREZZA. If you have lung cancer, you and your healthcare provider should decide if you should use AFREZZA. Diabetic ketoacidosis. Talk to your healthcare provider if you have an illness. Your AFREZZA dose or how often you check your blood sugar may need to be changed. Severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:A rash over your whole body, trouble breathing, fast heartbeat, or sweating.Low potassium in your blood (hypokalemia).Heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with AFREZZA may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with AFREZZA. Your healthcare provider should monitor you closely while you are taking TZDs with AFREZZA. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: Shortness of breath, swelling of your ankles or feet, sudden weight gain.Treatment with TZDs and AFREZZA may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.Get emergency medical help if you have:Trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.The most common side effects of AFREZZA include:Low blood sugar (hypoglycemia), cough, sore throat.These are not all the possible side effects of AFREZZA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 (1-800-332-1088). General information about the safe and effective use of AFREZZA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use AFREZZA for condition for which it was not prescribed. Do not give AFREZZA to other people, even if they have the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important information about AFREZZA. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about AFREZZA that is written for health professionals.What are the ingredients in AFREZZAActive ingredient: human insulin Inactive ingredients: fumaryl diketopiperazine, polysorbate 80 AFREZZA is registered trademark of MannKind CorporationPatent: www.mannkindcorp.com/patent-noticesManufactured by: MannKind Corporation, Danbury, CT 06810US License No. 2190(C) 2016 2026 MannKind CorporationFor more information, go to www.AFREZZA.com or call MannKind Corporation at 1-877-323-8505.This Medication Guide has been approved by the U.S. Food and Drug Administration Revised 05/2026. Sudden lung problems (bronchospasms). Do not use AFREZZA if you have long-term (chronic) lung problems such as asthma or chronic obstructive pulmonary disease (COPD). Before starting AFREZZA, your healthcare provider will give you breathing test to check how your lungs are working. AFREZZA is man-made insulin that is breathed-in through your lungs (inhaled) and is used to control high blood sugar in adults and children years of age and older, with diabetes mellitus.. AFREZZA is not for use to treat diabetic ketoacidosis. AFREZZA must be used with basal insulin in people who have type diabetes mellitus.. It is not known if AFREZZA is safe and effective for use in people who smoke. AFREZZA is not for use in people who smoke or have recently stopped smoking (less than months).. It is not known if AFREZZA is safe and effective in children under years of age.. Are having an episode of low blood sugar (hypoglycemia).. Have chronic lung problems such as asthma or COPD.. Are allergic to regular human insulin or any of the ingredients in AFREZZA. See the end of this Medication Guide for complete list of ingredients in AFREZZA.. Have lung problems such as asthma or COPD.. Have or have had lung cancer.. Are using any inhaled medications.. Smoke or have recently stopped smoking.. Have kidney or liver problems.. Are pregnant, planning to become pregnant, or are breastfeeding. AFREZZA may harm your unborn or breastfeeding baby.. Read the detailed Instructions for Use that comes with your AFREZZA. Take AFREZZA exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much AFREZZA to use and when to use it.. Your healthcare provider will train you or your caregiver in how to use AFREZZA.. After training, you or your child (10 years of age or older) may self-administer AFREZZA.. Know the strength of AFREZZA you use. Do not change the amount of AFREZZA you use unless your healthcare provider tells you to. Take AFREZZA at the beginning of your meal.. Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. Keep AFREZZA and all medicines out of the reach of children.. Change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.. Drive or operate heavy machinery, until you know how AFREZZA affects you.. Drink alcohol or use over-the-counter medicines that contain alcohol.. Smoke.. Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: Dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger.. Decreased lung function. Your healthcare provider should check how your lungs are working before you start using AFREZZA, months after you start using it and yearly after that. Lung cancer. In studies of AFREZZA in people with diabetes, lung cancer occurred in few more people who were taking AFREZZA than in people who were taking other diabetes medications. There were too few cases to know if lung cancer was related to AFREZZA. If you have lung cancer, you and your healthcare provider should decide if you should use AFREZZA. Diabetic ketoacidosis. Talk to your healthcare provider if you have an illness. Your AFREZZA dose or how often you check your blood sugar may need to be changed. Severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:. rash over your whole body, trouble breathing, fast heartbeat, or sweating.. Low potassium in your blood (hypokalemia).Heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with AFREZZA may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with AFREZZA. Your healthcare provider should monitor you closely while you are taking TZDs with AFREZZA. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: Heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with AFREZZA may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with AFREZZA. Your healthcare provider should monitor you closely while you are taking TZDs with AFREZZA. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: Shortness of breath, swelling of your ankles or feet, sudden weight gain.. Trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.. Low blood sugar (hypoglycemia), cough, sore throat.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLimited 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 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 riskPoorly 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 DataThere are limited data with AFREZZA use in pregnant women. Published data do not report 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 DataIn pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day through 17 (organogenesis), no major malformations were observed at doses up to 100 mg/kg/day (21 times the human systemic exposure at 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 through 19 (organogenesis), adverse maternal effects were observed in all dose groups (at human systemic exposure following 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 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 daily dose of 99 mg AFREZZA, based on AUC). 8.2 Lactation. Risk SummaryThere 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 mothers clinical need for AFREZZA and any potential adverse effects on the breastfed infant from AFREZZA or from the underlying maternal condition. DataSubcutaneous administration of the carrier particle in lactating rats resulted in excretion of the carrier particle in rat milk at levels that were approximately 10% of the maternal exposure. Given the results of the rat study, it is highly likely that the insulin and carrier in AFREZZA are excreted in human milk.. 8.4 Pediatric Use. The safety and effectiveness of AFREZZA to improve glycemic control have been established in pediatric patients years of age and older with diabetes mellitus. Use of AFREZZA for this indication is supported by evidence from an adequate and well controlled trial in pediatric patients aged years and older with type or type diabetes mellitus and from trials in adults with type or type diabetes mellitus [see Adverse Reactions 6.1 ), Clinical Studies 14.2 14.3 14.4)] The overall safety profile in pediatric patients was similar to adults [see Adverse Reactions 6.1 )]. The safety and effectiveness of AFREZZA have not been established in pediatric patients less than years of age.. 8.5 Geriatric Use. In the AFREZZA clinical studies 671 (12%) patients were 65 years of age or older, of which 42 (0.8%) were 75 years of age or older. In these studies, 381 (13%) of AFREZZA-treated patients were 65 years of age or older, of which 20 (0.7%) were 75 years of age or older. No overall differences in effectiveness of AFREZZA have been observed between patients 65 years of age and older and younger adult patients [see Clinical Studies 14)] Clinical studies of AFREZZA did not include sufficient numbers of patients 65 years of age and older to determine whether there were differences in safety between these patients and younger adult patients. Pharmacokinetic and pharmacodynamic studies to assess the effect of age on pharmacokinetics or pharmacodynamics on insulin human, respectively, have not been conducted.. 8.6 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of AFREZZA has not been studied. Frequent glucose monitoring and lower dosage may be necessary in AFREZZA-treated patients with hepatic impairment [see Dosage and Administration 2.2 2.3 and Warnings and Precautions 5.3)] . 8.7 Renal Impairment. The effect of renal impairment on the pharmacokinetics of AFREZZA has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and lower dosage may be necessary in AFREZZA-treated patients with renal impairment [see Dosage and Administration 2.2 2.3 and Warnings and Precautions 5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen: Make necessary changes to patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. For patients with type 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 months of therapy, and annually, even in the absence of pulmonary symptoms. In patients who have decline of >= 20% in FEV 1from 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, 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) Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen: Make necessary changes to patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. For patients with type 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 months of therapy, and annually, even in the absence of pulmonary symptoms. In patients who have decline of >= 20% in FEV 1from 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, 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 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 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 diagnosis of asthma, respectively. In this study, mean decline in FEV of 400 mL was observed 15 minutes after single AFREZZA dose in patients with asthma. In subset study of patients with COPD, mean decline in FEV of 200 mL was observed 18 minutes after 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 patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. For patients with type diabetes mellitus, dosage modifications of concomitant oral antidiabetic treatment may be needed [see Drug Interactions 7)] . 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).AFREZZAs time action profile impacts the timing of hypoglycemia following inhalation of the drug product [see Clinical Pharmacology 12.3)] Hypoglycemia can occur suddenly, and symptoms may differ across patients and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes mellitus, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions 7)], or in patients who experience recurrent hypoglycemia. Risk Factors and Mitigation Strategies for HypoglycemiaThe risk of hypoglycemia after use of AFREZZA is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal [See Clinical Pharmacology 12.3)] The glucose lowering effect time course of AFREZZA may vary in different individuals or at different times in the same individual and depends on many conditions [see Clinical Pharmacology 12.2)] Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitantly administered medication [see Drug Interactions 7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations 8.6, 8.7)]. 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. 5.4 Decline in Pulmonary Function. AFREZZA causes decline in pulmonary function over time as measured by FEV 1. In clinical trials excluding patients with chronic lung disease and lasting up to years, AFREZZA-treated patients experienced small [40 mL (95% CI: -80, -1)] but greater FEV decline than comparator-treated patients. The FEV decline was noted within the first months, and persisted for the entire duration of therapy (up to years of observation). In this population, the annual rate of FEV decline did not appear to worsen with increased duration of use. The effects of AFREZZA on pulmonary function for treatment duration longer than years has not been established. There are insufficient data in long term studies to draw conclusions regarding reversal of the effect on FEV after discontinuation of AFREZZA. The observed changes in FEV were similar in patients with type and type diabetes mellitus. Assess pulmonary function (e.g., spirometry) at baseline, after the first months of therapy, and annually thereafter, even in the absence of pulmonary symptoms. In patients who have decline of >= 20% in FEV from baseline, consider discontinuing AFREZZA. Consider more frequent monitoring of pulmonary function in patients with pulmonary symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue AFREZZA [see Adverse Reactions 6.1 )] . 5.5 Lung Cancer. In clinical trials, two cases of lung cancer, one in controlled trials and one in uncontrolled trials (2 cases in 2,750 patient-years of exposure), were observed in patients exposed to AFREZZA while no cases of lung cancer were observed in patients exposed to comparators (0 cases in 2,169 patient-years of exposure). In both cases, prior history of heavy tobacco use was identified as risk factor for lung cancer. Two additional cases of lung cancer (squamous cell and lung blastoma) occurred in non-smokers exposed to AFREZZA and were reported by investigators after clinical 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, prior history of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of AFREZZA use outweigh this potential risk.. 5.6 Diabetic Ketoacidosis. In clinical trials enrolling patients with type diabetes mellitus, DKA was more common in AFREZZA-treated patients (0.43%; n=13) than in comparator-treated patients (0.14%; n=3). Patients with type 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.. 5.7 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 [see Adverse Reactions 6.1)] AFREZZA is contraindicated in patients with previous severe hypersensitivity reaction to any regular human insulin product or any of the inactive ingredients in AFREZZA [see Contraindications 4)] . 5.8 Hypokalemia. All insulin products, including AFREZZA, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death.Monitor potassium levels in AFREZZA-treated patients at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations and patients receiving intravenously administered insulin).. 5.9 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.Patients treated with insulin, including AFREZZA, and PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, manage according to current standards of care, and consider discontinuing or reducing the dosage of the PPAR-gamma agonist.