FDA label b0106810-33e6-483e-a8f0-26eb3fcc488d

WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE Acute bronchospasm has been observed in patients with asthma and COPD using AFREZZA. [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 (2.5) , 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 patients with asthma and COPD using AFREZZA. ( 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. ( 2.5 ), ( 5.1 )

5 WARNINGS AND PRECAUTIONS Acute Bronchospasm : Acute bronchospasm has been observed in patients with asthma and COPD. Before initiating, perform spirometry (FEV 1 ) in all patients. Do not use in patients with chronic lung disease ( 2.5 , 4 , 5.1 ) Change in Insulin Regimen : Carry out under close medical supervision and increase frequency of blood glucose monitoring. ( 5.2 ) Hypoglycemia : May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. ( 5.3 , 6 , 7 , 8.6 , 8.7 ) Decline in Pulmonary Function : Assess pulmonary function (e.g., spirometry) before initiating, after 6 months of therapy, and annually, even in the absence of pulmonary symptoms. ( 2.5 , 5.4 ) Lung Cancer : AFREZZA should not be used in patients with active lung cancer. In patients with a history of lung cancer or at risk for lung cancer, the benefit of AFREZZA use should outweigh this potential risk. ( 5.5 ) Diabetic Ketoacidosis : More patients using AFREZZA experienced diabetic ketoacidosis in clinical trials. In patients at risk for DKA, monitor and change to alternate route of insulin delivery, if indicated. ( 5.6 ) Hypersensitivity Reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including AFREZZA. Discontinue AFREZZA, monitor and treat if indicated. ( 5.7 ) Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 5.8 ) Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): 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 all patients with a medical history, physical examination and spirometry (FEV 1 ) to identify potential underlying lung disease. Acute bronchospasm has been observed following AFREZZA dosing in patients with asthma and patients with COPD. In a study of patients with asthma, bronchoconstriction and wheezing following AFREZZA dosing was reported in 29% (5 out of 17) and 0% (0 out of 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 dose in patients with asthma. In a study of patients with COPD (n=8), a mean decline in FEV 1 of 200 mL was observed 18 minutes after a single dose of AFREZZA. The long-term safety and efficacy of AFREZZA in patients with chronic lung disease has not been established. 5.2 Changes in Insulin Regimen Glucose monitoring is essential for patients receiving insulin therapy. Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3) ] or hyperglycemia. These changes should be made under close medical supervision and the frequency of blood glucose monitoring should be increased. Concomitant oral antidiabetic treatment may need to be adjusted. 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). The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. AFREZZA has a distinct time action profile [see Clinical Pharmacology (12) ] , which impacts the timing of hypoglycemia. Hypoglycemia can happen suddenly and symptoms may differ across individuals and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using certain medications [see Drug Interactions (7) ] , or in patients who experience recurrent hypoglycemia. 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 co-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) ] . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.4 Decline in Pulmonary Function AFREZZA causes a decline in lung 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. 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) ]. 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 participants exposed to AFREZZA while no cases of lung cancer were observed in 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) 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 subjects with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in subjects receiving AFREZZA (0.43%; n=13) than in subjects receiving comparators (0.14%; n=3). In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider delivery of insulin using an alternate route of administration if indicated [see Limitations of Use (1) ] . 5.7 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including AFREZZA. If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6) ] . AFREZZA is contraindicated in patients who have had hypersensitivity reactions to AFREZZA or any of its excipients [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 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, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

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 sanofi-aventis at (1-800-633-1610) 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 designs, the incidence of adverse reactions reported in one clinical trial may not be easily compared to the incidence reported in another clinical trial, and may not reflect what is observed in clinical practice. The data described below reflect exposure of 3017 patients to AFREZZA and include 1026 patients with type 1 diabetes and 1991 patients with type 2 diabetes. The mean exposure duration was 8.17 months for the overall population and 8.16 months and 8.18 months for type 1 and 2 diabetes patients, respectively. In the overall population, 1874 were exposed to AFREZZA for 6 months and 724 for greater than one year. 620 and 1254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for greater than one year (median exposure = 1.8 years). AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively). The mean age of the population was 50.2 years and 20 patients were older than 75 years of age. 50.8% of the population were men; 82.6% were White, 1.8% were Asian, and 4.9% were Black or African American. 9.7% were Hispanic. At baseline, the type 1 diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a mean HbA1c of 8.8%. At baseline, 33.4% of the population reported peripheral neuropathy, 32.0% reported retinopathy and 19.6% had a history of cardiovascular disease. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA. Table 1. Common Adverse Reactions in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Placebo Carrier particle without insulin was used as placebo [ see Description (11) ]. AFREZZA Non-placebo comparators (n = 290) (n = 1991) (n=1363) Cough 19.7% 25.6% 5.4% Throat pain or irritation 3.8% 4.4% 0.9% Headache 2.8% 3.1% 1.8% Diarrhea 1.4% 2.7% 2.2% Productive cough 1.0% 2.2% 0.9% Fatigue 0.7% 2.0% 0.6% Nausea 0.3% 2.0% 1.0% Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on comparator, and occurred in at least 2% of patients treated with AFREZZA. Table 2. Common Adverse Reactions in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Subcutaneous Insulin (n = 835) AFREZZA (n=1026) Cough 4.9% 29.4% Throat pain or irritation 1.9% 5.5% Headache 2.8% 4.7% Pulmonary function test decreased 1.0% 2.8% Bronchitis 2.0% 2.5% Urinary tract infection 1.9% 2.3% Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see Warnings and Precautions (5.3) ]. The incidence of severe and non-severe hypoglycemia of AFREZZA versus placebo in patients with type 2 diabetes is shown in Table 3. 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 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Patients with Type 2 Diabetes Placebo (N=176) AFREZZA (N=177) Severe Hypoglycemia 1.7% 5.1% Non-Severe Hypoglycemia 30% 67% Cough Approximately 27% of patients treated with AFREZZA reported cough, compared to approximately 5.2% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (2.8% of AFREZZA-treated patients). Pulmonary Function Decline In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients 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 2). A decline in FEV 1 of ≥ 15% occurred in 6% of AFREZZA-treated subjects compared to 3% of comparator-treated subjects. Figure 2. Mean (+/-SE) Change in FEV 1 (Liters) from Baseline for Type 1 and Type 2 Diabetes Patients Figure 2 Weight Gain Weight gain may occur 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 patients with type 2 diabetes [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. Antibody Production Increases in anti-insulin antibody concentrations have been observed in patients treated with AFREZZA. Increases in anti-insulin antibodies are observed more frequently with AFREZZA than with subcutaneously injected mealtime insulins. Presence of antibody did not correlate with reduced efficacy, as measured by HbA1c and fasting plasma glucose, or specific adverse reactions.

<table width="75%"> <caption>Table 1. Common Adverse Reactions in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA</caption> <col width="40%" align="left" valign="top"/> <col width="20%" align="center" valign="middle"/> <col width="20%" align="center" valign="middle"/> <col width="20%" align="center" valign="middle"/> <thead> <tr> <th/> <th styleCode="Lrule Rrule" valign="top">Placebo<footnote>Carrier particle without insulin was used as placebo <content styleCode="italics">[</content>see <content styleCode="italics"> <linkHtml href="#S11">Description (11)</linkHtml> </content>].</footnote> </th> <th styleCode="Rrule" valign="top">AFREZZA</th> <th styleCode="Rrule" valign="top">Non-placebo comparators</th> </tr> <tr> <th/> <th styleCode="Lrule Rrule" valign="top">(n = 290)</th> <th styleCode="Rrule" valign="top">(n = 1991)</th> <th styleCode="Rrule" valign="top">(n=1363)</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule Toprule">Cough</td> <td styleCode="Rrule Toprule">19.7%</td> <td styleCode="Rrule Toprule">25.6%</td> <td styleCode="Rrule Toprule">5.4%</td> </tr> <tr> <td styleCode="Lrule Rrule">Throat pain or irritation</td> <td styleCode="Rrule">3.8%</td> <td styleCode="Rrule">4.4%</td> <td styleCode="Rrule">0.9%</td> </tr> <tr> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">2.8%</td> <td styleCode="Rrule">3.1%</td> <td styleCode="Rrule">1.8%</td> </tr> <tr> <td styleCode="Lrule Rrule">Diarrhea</td> <td styleCode="Rrule">1.4%</td> <td styleCode="Rrule">2.7%</td> <td styleCode="Rrule">2.2%</td> </tr> <tr> <td styleCode="Lrule Rrule">Productive cough</td> <td styleCode="Rrule">1.0%</td> <td styleCode="Rrule">2.2%</td> <td styleCode="Rrule">0.9%</td> </tr> <tr> <td styleCode="Lrule Rrule">Fatigue</td> <td styleCode="Rrule">0.7%</td> <td styleCode="Rrule">2.0%</td> <td styleCode="Rrule">0.6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">0.3%</td> <td styleCode="Rrule">2.0%</td> <td styleCode="Rrule">1.0%</td> </tr> </tbody> </table>

<table width="75%"> <caption>Table 2. Common Adverse Reactions in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA</caption> <col width="60%" align="left" valign="top"/> <col width="20%" align="center" valign="middle"/> <col width="20%" align="center" valign="middle"/> <thead> <tr> <th/> <th styleCode="Lrule Rrule Toprule">Subcutaneous Insulin (n = 835)</th> <th styleCode="Rrule Toprule">AFREZZA (n=1026)</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule Toprule">Cough</td> <td styleCode="Rrule Toprule">4.9%</td> <td styleCode="Rrule Toprule">29.4%</td> </tr> <tr> <td styleCode="Lrule Rrule">Throat pain or irritation</td> <td styleCode="Rrule">1.9%</td> <td styleCode="Rrule">5.5%</td> </tr> <tr> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">2.8%</td> <td styleCode="Rrule">4.7%</td> </tr> <tr> <td styleCode="Lrule Rrule">Pulmonary function test decreased</td> <td styleCode="Rrule">1.0%</td> <td styleCode="Rrule">2.8%</td> </tr> <tr> <td styleCode="Lrule Rrule">Bronchitis</td> <td styleCode="Rrule">2.0%</td> <td styleCode="Rrule">2.5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Urinary tract infection</td> <td styleCode="Rrule">1.9%</td> <td styleCode="Rrule">2.3%</td> </tr> </tbody> </table>

<table width="75%"> <caption>Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Patients with Type 2 Diabetes</caption> <col width="60%" align="left" valign="top"/> <col width="20%" align="center" valign="middle"/> <col width="20%" align="center" valign="middle"/> <thead> <tr> <th/> <th styleCode="Lrule Rrule Toprule">Placebo (N=176)</th> <th styleCode="Rrule Toprule">AFREZZA (N=177)</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule Toprule">Severe Hypoglycemia</td> <td styleCode="Rrule Toprule">1.7%</td> <td styleCode="Rrule Toprule">5.1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Non-Severe Hypoglycemia</td> <td styleCode="Rrule">30%</td> <td styleCode="Rrule">67%</td> </tr> </tbody> </table>