AFREZZA

WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and Chronic Obstructive Pulmonary Disease (COPD) [see Warnings and Precautions ( 5.1 )]. AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD [see Contraindications ( 4 )]. Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV 1 ) to identify potential lung disease in all patients [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 )]. WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE See full prescribing information for complete boxed warning. Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and Chronic Obstructive Pulmonary Disease (COPD). ( 5.1 ) AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD. ( 4 ) Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV 1 ) to identify potential lung disease in all patients. ( 2.1 ), ( 5.1 )

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 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). AFREZZA's 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 Hypoglycemia The 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 a decline in pulmonary function over time as measured by FEV 1 . In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-treated patients experienced a small [40 mL (95% CI: -80, -1)] but greater FEV 1 decline than comparator-treated patients. The FEV 1 decline was noted within the first 3 months, and persisted for the entire duration of therapy (up to 2 years of observation). In this population, the annual rate of FEV 1 decline did not appear to worsen with increased duration of use. The effects of AFREZZA on pulmonary function for treatment duration longer than 2 years has not been established. There are insufficient data in long term studies to draw conclusions regarding reversal of the effect on FEV 1 after discontinuation of AFREZZA. The observed changes in FEV 1 were similar in patients with type 1 and type 2 diabetes mellitus. Assess pulmonary function (e.g., spirometry) at baseline, after the first 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a decline of ≥ 20% in FEV 1 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, a prior history of heavy tobacco use was identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous cell and lung blastoma) 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, 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. 5.6 Diabetic Ketoacidosis In clinical trials enrolling patients with type 1 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 1 diabetes should always use AFREZZA concomitantly with basal insulin. In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider discontinuing AFREZZA and giving insulin using an alternate route of administration. 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 a 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 a 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 a 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Acute bronchospasm in patients with chronic lung disease [see Warnings and Precautions ( 5.1 )] Hypoglycemia [see Warnings and Precautions ( 5.3 )] Decline in pulmonary function [see Warnings and Precautions ( 5.4 )] Lung cancer [see Warnings and Precautions ( 5.5 )] Diabetic ketoacidosis [see Warnings and Precautions ( 5.6 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.7 )] The most common adverse reactions associated with AFREZZA (2% or greater incidence) are hypoglycemia, cough, and throat pain or irritation ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact MannKind at 1-877-323-8505 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials in Adults with Type 1 or Type 2 Diabetes Mellitus The data described below reflect exposure of 3,017 adult patients to AFREZZA and include 1,026 patients with type 1 diabetes mellitus and 1,991 patients with type 2 diabetes mellitus. The mean exposure duration was 8.2 months for patients with type 1 diabetes mellitus and those with type 2 diabetes mellitus [see Clinical Studies ( 14.2 , 14.3 )] . In the overall population: 1,874 patients with type 1 or type 2 diabetes mellitus were exposed to AFREZZA for 6 months and 724 patients for greater than one year. 620 and 1,254 patients with type 1 or type 2 diabetes mellitus, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 or type 2 diabetes mellitus, respectively, were exposed to AFREZZA for greater than one year (median exposure was 1.8 years). AFREZZA was studied in placebo and active-controlled adult trials (n = 3 and n = 10, respectively). The mean age of the adult population was 50 years and 20 patients were older than 75 years of age; 51% of the population were males; 83% were White, 5% were Black or African American, and 2% were Asian; 10% were Hispanic or Latino ethnicity. At baseline, the type 1 diabetes mellitus population had diabetes mellitus for an average of 17 years and had a mean HbA1c of 8.3%, and the type 2 diabetes mellitus population had diabetes mellitus for an average of 11 years and had a mean HbA1c of 8.8%. At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had a history of cardiovascular disease. Table 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in adults with type 2 diabetes mellitus patients that occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA. Table 2. Common Adverse Reactions That Occurred in ≥ 2% in Adult Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Adverse Reaction AFREZZA (n = 1,991) % Placebo a (n = 290) % Non-placebo comparators (n=1,363) % Cough 26 20 5 Throat pain or irritation 4 4 1 Headache 3 3 2 Diarrhea 3 1 2 Productive cough 2 1 1 Fatigue 2 1 1 Nausea 2 0.3 1 a Carrier particle without insulin was used as placebo [see Description ( 11.1 )]. Table 3 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in adults with type 1 diabetes mellitus. These adverse reactions occurred more commonly on AFREZZA than on comparator and occurred in at least 2% of patients treated with AFREZZA. Table 3. Common Adverse Reactions That Occurred in ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Adverse Reaction AFREZZA (n=1,026) % 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 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 2 diabetes mellitus is shown in Table 4 . A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a 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 a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia. Table 4. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Adult Patients with Type 2 Diabetes Mellitus Hypoglycemia Severity AFREZZA (N=177) Placebo (N=176) Severe Hypoglycemia 5% 2% Non-Severe Hypoglycemia 67% 30% Other Adverse Reactions in Adults with Type 1 or Type 2 Diabetes MellitusOther Adverse Reactions in Adults with Type 1 or Type 2 Diabetes Mellitus Cough Approximately 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 Decline In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, adults treated with AFREZZA had a 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 3 months of therapy and persisted over 2 years ( Figure 1 ). A decline in FEV 1 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 FEV 1 (Liters) from Baseline for Adult Patients with Type 1 and Type 2 Diabetes Mellitus Figure 1 Weight Gain Weight 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 a clinical trial of adult patients with type 2 diabetes mellitus [see Clinical Studies ( 14.3 )] , there was a mean 0.49 kg weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss among placebo-treated patients. Adverse Reactions in the Clinical Trial in Pediatric Patients Aged 6 Years and Older with Type 1 or Type 2 Diabetes Mellitus A 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 1 or type 2 diabetes mellitus [see Clinical Studies ( 14.4 )]. The trial was followed by a 26-week safety extension. The mean age of patients was 12.6 years (range: 4 to 17 in the RAA arm, 6 to 17 in the AFREZZA arm). The majority (97.8%) had type 1 diabetes mellitus; a small subset (2.2%) had type 2 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 5 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 6 Years and Older With Type 1 and Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA and More Commonly on AFREZZA Than on RAA Adverse Reaction a AFREZZA (n=117) % RAA (n=113) % Cough 21 3 Upper respiratory tract infection 18 14 Oropharyngeal pain 11 4 Headache 8 5 Vomiting 5 3 a This study was not designed to evaluate meaningful comparisons of adverse reaction incidence between AFREZZA and RAA. Hypoglycemia In 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 3 hypoglycemia was reported in 2 (1.7%) AFREZZA-treated pediatric patients versus 1 (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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Respiratory : bronchospasm.

<table border="0" ID="t2"><caption>Table 2. Common Adverse Reactions That Occurred in &#x2265; 2% in Adult Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA</caption><tbody><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Adverse Reaction</content></td><td align="center" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">AFREZZA</content><paragraph/><content styleCode="bold">(n = 1,991)</content><paragraph/><paragraph/><content styleCode="bold">%</content><paragraph/><paragraph/></td><td align="center" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Placebo ^a</content><paragraph/><content styleCode="bold">(n = 290)</content><paragraph/><content styleCode="bold">%</content><paragraph/></td><td align="center" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Non-placebo comparators </content><paragraph/><content styleCode="bold">(n=1,363)</content><paragraph/><content styleCode="bold">%</content><paragraph/></td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Cough <paragraph/></td><td align="center" styleCode="Lrule Rrule Toprule Botrule">26</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">20</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">5</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Throat pain or irritation</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">4</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">4</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Headache</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">3</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">3</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Diarrhea</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">3</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Productive cough</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Fatigue</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Nausea</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">0.3</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td></tr><tr><td colspan="4" align="center" styleCode="Lrule Rrule Toprule Botrule">^a Carrier particle without insulin was used as placebo <content styleCode="italics">[see Description ( <linkHtml href="#s58">11.1</linkHtml>)]. </content></td></tr></tbody></table>

<table border="0" ID="t3"><caption>Table 3. Common Adverse Reactions That Occurred in &#x2265; 2% in Adult Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA</caption><tbody><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Adverse Reaction</content></td><td align="center" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">AFREZZA (n=1,026) </content><paragraph/><content styleCode="bold">%</content></td><td align="center" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Subcutaneous Insulin</content><paragraph/><content styleCode="bold">(n = 835)</content><paragraph/><content styleCode="bold">%</content></td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Cough <paragraph/></td><td align="center" styleCode="Lrule Rrule Toprule Botrule">29</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">5</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Throat pain or irritation</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">6</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Headache</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">5</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">3</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Pulmonary function test decreased</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">3</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">1</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Bronchitis</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">3</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Urinary tract infection</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2</td></tr></tbody></table>

<table border="0" ID="t4"><caption>Table 4. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Adult Patients with Type 2 Diabetes Mellitus</caption><tbody><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Hypoglycemia Severity</content></td><td align="center" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">AFREZZA</content><paragraph/><content styleCode="bold">(N=177)</content></td><td align="center" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Placebo</content><paragraph/><content styleCode="bold">(N=176)</content></td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule"><paragraph>Severe Hypoglycemia</paragraph></td><td align="center" styleCode="Lrule Rrule Toprule Botrule">5%</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">2%</td></tr><tr><td align="left" styleCode="Lrule Rrule Toprule Botrule">Non-Severe Hypoglycemia</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">67%</td><td align="center" styleCode="Lrule Rrule Toprule Botrule">30%</td></tr></tbody></table>