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HIGHLIGHTS OF PRESCRIBING INFORMATION ——————————————— CONTRAINDICATIONS ———————————————

These highlights do not include all the information needed to use AFREZZA® safely and • During episodes of hypoglycemia (4)
effectively. See full prescribing information for AFREZZA®. • Chronic lung disease, such as asthma, or chronic obstructive pulmonary disease (4)
• Hypersensitivity to regular human insulin or any of the AFREZZA excipients (4 )
AFREZZA® (insulin human) Inhalation Powder
Initial U.S. Approval: 2014 ————————————— WARNINGS AND PRECAUTIONS —————————————
• Acute Bronchospasm: Acute bronchospasm has been observed in patients with asthma and
COPD. Before initiating, perform spirometry (FEV1) in all patients. Do not use in patients with
chronic lung disease (2.5, 4, 5.1)
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG • Change in Insulin Regimen: Carry out under close medical supervision and increase frequency
DISEASE of blood glucose monitoring. (5.2)
See full prescribing information for complete boxed warning. • Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes
to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical
• Acute bronchospasm has been observed in patients with asthma and COPD using activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3,
AFREZZA. (5.1) 6, 7, 8.6, 8.7)
• AFREZZA is contraindicated in patients with chronic lung disease such as asthma • Decline in Pulmonary Function: Assess pulmonary function (e.g., spirometry) before initiating,
or COPD. (4) after 6 months of therapy, and annually, even in the absence of pulmonary symptoms. (2.5,
• Before initiating AFREZZA, perform a detailed medical history, physical examination, 5.4)
and spirometry (FEV1) to identify potential lung disease in all patients. (2.5), (5.1) • 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
—————————————— RECENT MAJOR CHANGES —————————————— 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,
• Dosage and Administration (2) 4/2015 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 hypoka-
—————————————— INDICATIONS AND USAGE —————————————— lemia and treat if indicated. (5.8)
• AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult • Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe
patients with diabetes mellitus. (1) for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart
Important limitations of use: failure occurs. (5.9)
• In patients with type 1 diabetes, must use with a long-acting insulin. (1)
• Not recommended for the treatment of diabetic ketoacidosis. (1) ——————————————— ADVERSE REACTIONS ———————————————
• Not recommended in patients who smoke (1) The most common adverse reactions associated with AFREZZA (2% or greater incidence) are
hypoglycemia, cough, and throat pain or irritation (6)
————————————— DOSAGE AND ADMINISTRATION —————————————
• Administer using a single inhalation per cartridge (2.1) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at (1-800-633-1610) or
• Administer at the beginning of a meal (2.2) FDA at (1-800-FDA-1088) or www.fda.gov/medwatch.
• Dosing must be individualized (2.2)
• Before initiating, perform a detailed medical history, physical examination, and spirometry ——————————————— DRUG INTERACTIONS ———————————————
(FEV1) in all patients to identify potential lung disease (2.5) Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. (7.1, 7.2, 7.3)
———————————— DOSAGE FORMS AND STRENGTHS ———————————— Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and
AFREZZA is available as single-use cartridges of: (3) symptoms of hypoglycemia may be reduced or absent. (7.3, 7.4)
• 4 units
• 8 units See 17 for PATIENT COUNSELING INFORMATION and FDA-approved Medication Guide
• 12 units Revised: 07/2015

FULL PRESCRIBING INFORMATION: CONTENTS* 7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE AFREZZA
1 INDICATIONS AND USAGE 7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
2 DOSAGE AND ADMINISTRATION 8 USE IN SPECIFIC POPULATIONS
2.1 Route of Administration 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C
2.2 Dosage Information 8.3 Nursing Mothers
2.3 AFREZZA Administration for Doses Exceeding 12 units 8.4 Pediatric Use
2.4 Dosage Adjustment due to Drug Interactions 8.5 Geriatric Use
2.5 Lung Function Assessment Prior to Administration 8.6 Hepatic Impairment
2.6 Important Administration Instructions 8.7 Renal Impairment
3 DOSAGE FORMS AND STRENGTHS 10 OVERDOSAGE
4 CONTRAINDICATIONS 11 DESCRIPTION
5 WARNINGS AND PRECAUTIONS 11.1 AFREZZA Cartridges
5.1 Acute Bronchospasm in Patients with Chronic Lung Disease 11.2 AFREZZA Inhaler
5.2 Changes in Insulin Regimen 12 CLINICAL PHARMACOLOGY
5.3 Hypoglycemia 12.1 Mechanism of Action
5.4 Decline in Pulmonary Function 12.2 Pharmacodynamics
5.5 Lung Cancer 12.3 Pharmacokinetics
5.6 Diabetic Ketoacidosis 13 NONCLINICAL TOXICOLOGY
5.7 Hypersensitivity Reactions 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.8 Hypokalemia 14 CLINICAL STUDIES
5.9 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists 14.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus
6 ADVERSE REACTIONS 14.2 Type 1 Diabetes
6.1 Clinical Trials Experience 14.3 Type 2 Diabetes
7 DRUG INTERACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING
7.1 Drugs That May Increase the Risk of Hypoglycemia 17 PATIENT COUNSELING INFORMATION
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA *Sections or subsections omitted from the full prescribing information are not listed

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glucose monitoring and consider delivery of insulin using an alternate route of administration if indicated 2. If any of the above occur. physical AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult patients with examination and spirometry (FEV1) to identify potential underlying lung disease. Loss of drug effect can occur if the inhaler is turned upside down. including anaphylaxis. • Chronic lung disease. Glucose monitoring is essential for patients receiving insulin therapy. 2 . The FEV1 decline was noted within the first 3 months. can occur with insulin products. Administer half of the total daily injected pre-mixed dose as an injected basal insulin hypoglycemia. 2. 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 • AFREZZA is not a substitute for long-acting insulin. the timing of hypoglycemia. In this study. may be life-threatening. or in patients who experience recurrent the day. n=3).3 Hypoglycemia Administer AFREZZA at the beginning of the meal. 2. diabetes mellitus. administered using a single inhalation per cartridge.. evaluate all patients with a medical history. Mealtime AFREZZA Dose Conversion Table may be at higher risk of hypoglycemia [see Use in Specific Populations (8. and spirometry (FEV1) to identify potential lung disease in all patients [see Dosage and 5 WARNINGS AND PRECAUTIONS Administration (2.6)]. has been inserted into the inhaler.2)]. Before initiating AFREZZA. In patients at risk for DKA. To achieve of lung cancer were observed in comparators (0 cases in 2. • The safety and efficacy of AFREZZA in patients who smoke has not been established. AFREZZA-treated patients experienced a small [40 mL (95% CI: -80. diabetic ketoacidosis (DKA) was more common bronchospasm in these patients. perform a medical history. or in patients at risk for lung cancer.. In both the required total mealtime dose. Adjust the dosage of AFREZZA based on the individual’s metabolic needs. 5. 8 unit and 12 unit cases. -1)] but greater FEV1 decline than comparator-treated patients. a mean decline in FEV1 of 400 mL was observed long-acting insulin in patients with type 1 diabetes mellitus. • Hypersensitivity to regular human insulin or any of the AFREZZA excipients [see Warnings and • Before initiating AFREZZA.3 AFREZZA Administration for Doses Exceeding 12 units in 2.g.2 Changes in Insulin Regimen of AFREZZA is not recommended in patients who smoke or who have recently stopped smoking. AFREZZA has a distinct time action profile [see Clinical Pharmacology (12)].1)]. spirometry) at baseline. Warnings and Precautions (5. in these Adverse Reactions (6)].43%. such as asthma or chronic obstructive pulmonary disease (COPD). Changes in insulin strength.5 Lung Cancer subcutaneous mealtime insulin. use outweigh this potential risk. • Insulin Naïve Individuals: Start on 4 units of AFREZZA at each meal. Consider more frequent monitoring macronutrient content or timing of food intake).6. These data are insufficient to determine whether 2.1)]. or persistent or recurring cough.750 patient-years of exposure). [see Contraindications (4)]. or cause death. n=13) than in subjects receiving comparators (0. See Patient Instructions for Use for complete administration instructions with illustrations. The use 5. including AFREZZA. discontinue AFREZZA. changes in meal patterns (i.6 Diabetic Ketoacidosis AFREZZA is contraindicated in patients with chronic lung disease because of the risk of acute In clinical trials enrolling subjects with type 1 diabetes. Hypoglycemia can happen suddenly and symptoms may differ across individuals and change over time in the same individual.1 Acute Bronchospasm in Patients with Chronic Lung Disease Because of the risk of acute bronchospasm. If.6 Important Administration Instructions [see Limitations of Use (1)]. the cartridge should be replaced contraindicated in patients who have had hypersensitivity reactions to AFREZZA or any of its excipients before use. a prior Dosage adjustment may be needed when AFREZZA is coadministered with certain drugs [see Drug history of lung cancer. In this population. Dosage adjustment may be needed when switching from another insulin to AFREZZA [see Warnings Severe hypoglycemia can cause seizures. reported by investigators after clinical trial completion. a mean • AFREZZA is not recommended for the treatment of diabetic ketoacidosis [see Warning and decline in FEV1 of 200 mL was observed 18 minutes after a single dose of AFREZZA. 5. safety and efficacy of AFREZZA in patients with chronic lung disease has not been established. consider use of 5. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. were observed in participants exposed to AFREZZA while no cases For AFREZZA doses exceeding 12 units. annually thereafter. patients should use a combination of 4 unit. There are insufficient data in long term studies to draw Mealtime Dose Adjustment conclusions regarding reversal of the effect on FEV1 after discontinuation of AFREZZA. examination and spirometry (FEV1) in all patients to identify potential lung disease [see Contraindi. The effects of AFREZZA on pulmonary function for treatment duration longer than 2 years has not been established. and results and glycemic control goal.5). Symptomatic awareness of hypoglycemia may • Individuals Using Subcutaneous Pre-mixed Insulin: Estimate the mealtime injected dose by be less pronounced in patients with longstanding diabetes. AFREZZA must be used in combination with a diagnosis of asthma..FULL PRESCRIBING INFORMATION 3 DOSAGE FORMS AND STRENGTHS AFREZZA (insulin human) Inhalation Powder is available as 4 unit. consider discontinuing AFREZZA. perform a detailed medical history. after the first 6 months of therapy.g.1)]. respectively. because • AFREZZA is contraindicated in patients with chronic lung disease such as asthma or of the risk of acute bronchospasm [see Warnings and Precautions (5. impair concentration ability and reaction time. consider whether the benefits of AFREZZA Interactions (7)]. In patients who have a decline of Dosage adjustments may be needed with changes in physical activity. or changes to co-administered medication [see Drug Interactions (7)]. increase the frequency of cations (4) and Warnings and Precautions (5. Patients with renal or hepatic impairment Figure 1. Hypoglycemia is the most common adverse reaction associated with insulins. patients. this may place an individual and others at risk in Starting Mealtime Dose: situations where these abilities are important (e. and persisted for the entire duration of therapy (up to 2 years of observation).1 Route of Administration hypoglycemia [see Warnings and Precautions (5. changes in renal or hepatic function or during acute of pulmonary function in patients with pulmonary symptoms such as wheezing. In patients with active lung cancer. shaken (or dropped) after the cartridge has been inserted but care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. [see How Supplied/ WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG Storage and Handling (16)].7 Hypersensitivity Reactions Keep the inhaler level with the white mouthpiece on top and purple base on the bottom after a cartridge Severe.14%. changes in level of physical activity. or method of administration may affect glycemic control and predispose to 2. blood glucose monitoring Assess pulmonary function (e. blood glucose control is not achieved with increased AFREZZA doses. These changes should be made AFREZZA should only be administered via oral inhalation using the AFREZZA Inhaler. 5. If hypersensitivity reactions occur.. 15 minutes after a single dose in patients with asthma. Acute bronchospasm has been observed following AFREZZA dosing in patients with asthma and Limitations of Use: patients with COPD.3)] or hyperglycemia. Precautions (5.169 patient-years of exposure). In clinical trials excluding patients with chronic lung disease and lasting up to 2 years. In a study of patients with COPD (n=8). a prior history of heavy tobacco use was identified as a risk factor for lung cancer. For cases of lung cancer (squamous cell) occurred in non-smokers exposed to AFREZZA and were doses above 24 units. COPD.6. 8 unit and 12 unit single use cartridges to be administered via oral inhalation with the AFREZZA Inhaler only. [see Contraindications (4)].4 Dosage Adjustment due to Drug Interactions AFREZZA has an effect on lung or respiratory tract tumors. two cases of lung cancer. and Use in Specific Populations (8. Convert each estimated injected mealtime dose to an appropriate AFREZZA dose using Figure 1. inhalations from multiple cartridges are necessary. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin • Individuals Using Subcutaneous Mealtime (Prandial) Insulin: Determine the appropriate AFREZZA formulation. breathing difficulties.5 Lung Function Assessment Prior to Administration 5. [see Warnings and Precautions (5. [see Carefully monitor blood glucose control in patients requiring high doses of AFREZZA.4 Decline in Pulmonary Function AFREZZA causes a decline in lung function over time as measured by FEV1. combinations of different multiple cartridges can be used. generalized allergy.7)]. Other factors which may increase the risk of hypoglycemia include changes in meal dose. If symptoms persist. pattern (e. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypogly- cemia. Concomitant oral antidiabetic treatment may need to be adjusted. the annual rate of FEV1 decline did not appear to worsen with increased duration of use. In clinical trials.e. 2 DOSAGE AND ADMINISTRATION manufacturer. Two additional cartridges. physical in subjects receiving AFREZZA (0. which impacts dose for each meal by converting from the injected dose using Figure 1. 8. Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD [see Contraindications (4)]. in dividing half of the total daily injected pre-mixed insulin dose equally among the three meals of patients using certain medications [see Drug Interactions (7)]. macronutrient content or timing of meals). driving or operating other machinery).g. AFREZZA is under close medical supervision and the frequency of blood glucose monitoring should be increased. type. Hypoglycemia can and Precautions (5. bronchospasm.1)]. life-threatening. discontinue AFREZZA. 8.7)]. AFREZZA is before the dose has been administered. increased frequency of blood glucose monitoring is recommended.2 Dosage Information 5. even in the absence of pulmonary symptoms. treat per standard of held with the mouthpiece pointing down. ≥ 20% in FEV1 from baseline. physical examination. Examples of cartridge combinations for doses of up to 24 units are shown in Figure 1. one in controlled trials and one in uncontrolled trials (2 cases 2. illness [see Warnings and Precautions (5. such as those with an acute illness or infection.3). DISEASE 4 CONTRAINDICATIONS AFREZZA is contraindicated in patients with the following: • Acute bronchospasm has been observed in patients with asthma and COPD using • During episodes of hypoglycemia AFREZZA. including AFREZZA. The long-term Precautions (5. The observed changes in FEV1 were similar in patients with type 1 and type 2 diabetes. in patients with diabetic nerve disease.7)]. 1 INDICATIONS AND USAGE Before initiating therapy with AFREZZA. In a study of patients with asthma.

18 months for type 1 and 2 diabetes patients.8% of AFREZZA-treated patients).8%.3%. In the overall population. phenothiazines.g.6% had a history of cardiovascular disease. 32. Increases in anti-insulin antibodies are observed more frequently with AFREZZA than with subcutaneously injected mealtime insulins.2 years and 20 patients were older than 75 years of age.0% The risk of hypoglycemia associated with AFREZZA use may be increased with antidiabetic agents.2% AFREZZA.4)] of patients treated with comparator.. and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. disopyramide. Monitor potassium levels in patients at risk for hypokalemia (e.6)] Pulmonary Function Decline • Hypersensitivity reactions [see Warnings and Precautions (5. (N=176) (N=177) If heart failure develops. Table 1.5.4% attributed to the anabolic effects of insulin and the decrease in glycosuria.0% 1. and lithium salts. there was a mean 0.8 years).2% 0. 33.6% were White. isoniazid. can cause dose-related fluid retention. pentoxifylline. resulting from the maximum recommended daily dose of 99 mg AFREZZA based on AUC).1 Clinical Trials Experience AFREZZA had a 40 mL (95% CI: -80. and 100 mg/kg/day of carrier particles (vehicle Hypoglycemia without insulin) from gestation day 6 through 17 (organogenesis). oxidase inhibitors.4% sometimes be followed by hyperglycemia.2% • Decline in pulmonary function [see Warnings and Precautions (5. fibrates. Pulmonary function test decreased 1. 3 . The decline reported in one clinical trial may not be easily compared to the incidence reported in another clinical occurred during the first 3 months of therapy and persisted over 2 years (Figure 2). 620 and 1254 patients with type 1 and type 2 diabetes. Fatigue 0. consistent with hypoglycemia requiring the assistance of another person and associated with either a patients using potassium-lowering medications.7% The signs and symptoms of hypoglycemia may be blunted when beta-blockers. 1874 were exposed to AFREZZA for 6 months and 724 for greater than one year. These adverse reactions were not present at baseline. it should be managed according to current standards of care. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Thiazolidinediones (TZDs).6% 7 DRUG INTERACTIONS 7. corticosteroids. 50.13 kg weight loss among placebo-treated patients.8% 8 USE IN SPECIFIC POPULATIONS Bronchitis 2. the type 1 diabetes population had diabetes for an average of 16. Severe hypoglycemia was defined as an event with symptoms ventricular arrhythmia..5)] discontinuation of AFREZZA therapy (2. Hypoglycemia) Treated with AFREZZA protease inhibitors.3)]. excluding hypoglycemia.9% 2. no major malformations were Hypoglycemia is the most commonly observed adverse reaction in patients using insulin.4% 0.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA were not present at baseline.6% 5.17 Patients months for the overall population and 8. clonidine. 30. occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA. associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients. Pentamidine may cause hypoglycemia. octreotide).g. cough was the most common reason for • Lung cancer [see Warnings and Precautions (5. and may not reflect what is observed in clinical practice. AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. in oral contraceptives).0% 2. 82.0% 2.8% of the population were men. patients taking medications sensitive to serum blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia. possibly leading to hypokalemia.7% 5. somatropin. cause a shift in potassium from the extracellular to intracellular episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose space.7% 2.9 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Table 3. Common Adverse Reactions in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Placebo* AFREZZA Non-placebo comparators Weight Gain (n = 290) (n = 1991) (n=1363) Weight gain may occur with some insulin therapies. AFREZZA 7.9% 29.3% unless the potential benefit justifies the potential risk to the fetus. respectively. and the type 2 diabetes population had diabetes for an average of 10.1% 1. were exposed to AFREZZA for up to 6 months.1 Drugs That May Increase the Risk of Hypoglycemia Nausea 0.16 months and 8.7% were Hispanic. and death. including AFREZZA. The glucose lowering effect of AFREZZA may be decreased when co-administered with atypical antipsychotics (e.8% 4. Headache 2. danazol.9% AFREZZA-treated patients compared with a mean 1. were exposed to AFREZZA for greater than one year (median exposure = 1. Productive cough 1. value consistent with hypoglycemia. ACE inhibitors. which are peroxisome proliferator-activated receptor (PPAR)-gamma Study of Patients with Type 2 Diabetes agonists. Dose adjustment and increased frequency of glucose monitoring may be required Subcutaneous when AFREZZA is co-administered with these drugs. clonidine.g. respectively). terbutaline) and thyroid hormones. A hypoglycemic All insulin products.6 years and had a mean HbA1c of 8. 6 ADVERSE REACTIONS Non-Severe Hypoglycemia 30% 67% 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. • Diabetic ketoacidosis [see Warnings and Precautions (5. potassium concentrations and patients receiving intravenously administered insulin). and Severe Hypoglycemia 1.. compared to approximately 5. oral contraceptives.7 years and had a mean HbA1c of 8. In pregnant rats given subcutaneous doses of 10. Weight gain has been Cough 19. The data described below reflect exposure of 3017 patients to AFREZZA and include 1026 patients Figure 2. which may Cough 4. A decline in FEV1 trial. niacin. monoamine *Carrier particle without insulin was used as placebo [see Description (11)]. 9. The mean age of the population was 50. Untreated hypokalemia may cause respiratory paralysis. sympathomimetic agents (e. excluding hypoglycemia. including AFREZZA. Dose adjustment and increased frequency of glucose Table 2 shows common adverse reactions.9% were Black or African American.5% 8.4 Drugs That May Affect Hypoglycemia Signs and Symptoms Headache 2. patients treated with 6.3)] Approximately 27% of patients treated with AFREZZA reported cough. salicylates.9% as measured by HbA1c and fasting plasma glucose. 5..3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of AFREZZA Insulin (n=1026) (n = 835) The glucose lowering effect of AFREZZA may be increased or decreased when co-administered with alcohol.4% of the population reported peripheral neuropathy. respectively. respectively.49 kg weight gain among Throat pain or irritation 3. angiotensin II receptor blocking agents.8% 3.9% 5. In clinical trials. of ≥ 15% occurred in 6% of AFREZZA-treated subjects compared to 3% of comparator-treated subjects.1 Pregnancy Teratogenic Effects: Pregnancy Category C AFREZZA has not been studied in pregnant women. fluoxetine. epinephrine. and sulfonamide antibiotics.8 Hypokalemia cemia of AFREZZA versus placebo in patients with type 2 diabetes is shown in Table 3.0% 2. -1) greater decline from baseline in forced expiratory volume in Because clinical trials are conducted under widely varying designs. AFREZZA [see Warnings and Precautions (5. estrogens. At baseline. In a clinical trial of patients with type 2 diabetes [see Clinical Studies (14. These adverse reactions 7. particularly when used in combination with insulin. the incidence of adverse reactions one second (FEV1) compared to patients treated with comparator anti-diabetes treatments. 1. diuretics.7)] In clinical trials lasting up to 2 years. Common Adverse Reactions in Patients with Type 1 Diabetes Mellitus (excluding gon. Mean (+/-SE) Change in FEV1 (Liters) from Baseline for Type 1 and Type 2 Diabetes with type 1 diabetes and 1991 patients with type 2 diabetes. AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10. AFREZZA should not be used during pregnancy Urinary tract infection 1.0% reported retinopathy and 19. and occurred in at least 2% of patients treated with AFREZZA. or specific adverse reactions. propoxyphene. gluca- Table 2. beta-blockers.7% 2.3% 2. 238 and 486 patients with type 1 and type 2 diabetes.8% were Asian.7% 25.1)] Cough • Hypoglycemia [see Warnings and Precautions (5. Table 1 shows common adverse reactions. 7. albuterol. and reserpine are co-administered with AFREZZA. olanzapine and clozapine).g. progestogens (e. associated with the use of monitoring may be required when AFREZZA is co-administered with these drugs. Presence of antibody did not correlate with reduced efficacy. guanethidine. Fluid retention may lead to or exacerbate heart failure. The incidence of severe and non-severe hypogly.5% monitoring may be required when AFREZZA is co-administered with these drugs.4% 2. occurred more commonly on AFREZZA than on comparator. and 4.3)]. excluding patients with chronic lung disease.0% 0. Dose adjustment and increased frequency of glucose Throat pain or irritation 1. At baseline. pramlintide.8% Antibody Production Increases in anti-insulin antibody concentrations have been observed in patients treated with Diarrhea 1. The mean exposure duration was 8. somatostatin analogs (e. including Placebo AFREZZA AFREZZA.1% discontinuation or dose reduction of the PPAR-gamma agonist must be considered. including observed at up to 100 mg/kg/day (a systemic exposure 14–21 times the human systemic exposure.8% 4. Patients treated with insulin..g.

5. however. Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precau. or neurologic impairment may be treated with Carrier Particles intramuscular / subcutaneous glucagon or concentrated intravenous glucose. Frequent glucose monitoring and dose adjustment may be necessary for AFREZZA in patients Absorption: The pharmacokinetic profiles for orally inhaled AFREZZA 8 units relative to subcutaneously with renal impairment [see Warnings and Precautions (5. by nose-only inhalation. Baseline-Corrected Glucose Infusion Rate (A) and Baseline-Corrected Serum observed at all dose groups (at human systemic exposure following a 99 mg AFREZZA dose.23 mg/kg/day of insulin. the faster absorption of insulin from Afrezza [see Figure 3(B)] did not result in a faster onset tions (5. 381 patients were 65 years of age or older. however. More subjects in the insulin baseline levels by about 160 minutes. 11. adverse maternal effects were Figure 3.3)]. doses were titrated to glycemic goals for the first 12 weeks and kept stable for the last 12 weeks of istered insulin lispro 8 units from a study in 12 patients with type 1 diabetes is shown in Figure 3(A). AFREZZA was not genotoxic in Ames bacterial mutagenicity assay and in the chromosome aberration assay. The 4 unit fertility at doses up to 100 mg/kg/day (a systemic exposure 14–21 times that following the maximum cartridge contains 0. AFREZZA. and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through lactation day 20 (weaning). measured as area under 8. no significant change in insulin exposure was observed in a study in non-pathogenic laboratory strain of Escherichia coli (K12). The swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the feces.3)].7 Renal Impairment 12.time curve (AUC-GIR) from an euglycemic clamp. rats were given doses up to 46 mg/kg/day of the carrier and up to 1. 8.35 mg of insulin. there were no adverse effects on male AFREZZA Inhalation Powder is a dry powder supplied as 4 unit. Albuterol increased the AUC insulin administered by AFREZZA by 25% in patients with asthma. and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through 19 (organogenesis). which is administered via oral inhalation using the AFREZZA Inhaler only. of which 20 were 75 years *Despite the faster absorption of insulin (PK) from Afrezza. 30. and impaired learning were observed in pups at ≥ 30 mg/kg/day (a systemic exposure 6 times human systemic exposure at the maximum daily AFREZZA dose of 99 mg based on AUC). inhibits controlled study to evaluate the glucose lowering effect of mealtime AFREZZA used in combination with proteolysis. amino acid sequence: 13 NONCLINICAL TOXICOLOGY 13. 8. Severe episodes of hypoglycemia with coma. A decision should be made whether to discontinue nursing or suspend use of the drug since AFREZZA has not been studied in lactating women. the pharmacodynamic effect of AFREZZA. In a 26 week carcinogenicity study. continued observation and additional carbohydrate intake may be and are eliminated unchanged in the urine following the lung absorption. 65 and younger patients. The maximum serum insulin concentration was reached by 12–15 minutes after inhalation of 10 OVERDOSAGE AFREZZA 8 units and serum insulin concentrations declined to baseline by approximately 180 minutes.3 Pharmacokinetics The effect of renal impairment on the pharmacokinetics of AFREZZA has not been studied. increased in a less than The effect of hepatic impairment on the pharmacokinetics of AFREZZA has not been studied. Mealtime insulin The pharmacodynamic profile for orally inhaled AFREZZA 8 units relative to subcutaneously admin.2 Type 1 Diabetes Insulin lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle and Patients with inadequately controlled type 1 diabetes participated in a 24-week. Following a 4-week basal insulin optimization period. The carrier alone was not genotoxic in the in vivo mouse micronucleus assay. administered insulin lispro 8 units from a study in 12 patients with type 1 diabetes are shown in Figure 3(B). the study.2 Pharmacodynamics to AFREZZA (n=174) or insulin aspart (n=170)administered at each meal of the day. Frequent glucose monitoring and dose reduction may be necessary for AFREZZA formula C257H383N65O77S6 and a molecular weight of 5808. human insulin has the empirical healthy volunteers. Impairment of Fertility In a 104 week carcinogenicity study. No overall differences in safety or effectiveness were observed between patients over to insulin lispro. the metabolism and elimination are comparable to regular human insulin.4 Pediatric Use AFREZZA has not been studied in patients younger than 18 years of age. Effect of fluticasone on insulin exposures following AFREZZA administration has not been evaluated in AFREZZA cartridges contain human insulin produced by recombinant DNA technology utilizing a patients with asthma. Disposition: Systemic insulin disposition (median terminal half-life) following oral inhalation of AFREZZA meal patterns. No increased incidence of tumors was observed at systemic exposures equivalent to the insulin at a maximum daily AFREZZA dose of 99 mg based on a comparison of relative body surface areas across species. The efficacy of AFREZZA in type 2 diabetes patients was compared to placebo inhalation. 344 patients were randomized 12. Mutagenesis. Pharmacokinetic/pharmacodynamic studies to assess the effect of age have not been conducted.7 mg of insulin.1 AFREZZA Cartridges Drug Interaction: Bronchodilators and Inhaled Steroids AFREZZA consists of single-use plastic cartridges filled with a white powder containing insulin (human).1 Carcinogenesis. Mild episodes of hypoglycemia can usually be treated with oral glucose. Adjustments in drug dosage.6 Hepatic Impairment the glucose infusion rate . However.8)]. and the difference was statistically significant. using human peripheral lymphocytes with or without metabolic activation. the onset of activity (PD) was comparable of age or older. Insulin is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP) and polysorbate In female rats given subcutaneous doses of 10. of activity compared to insulin lispro [see Figure 3(A)]. 8 unit or 12 unit cartridges. 4 and 32 units was 28–39 minutes. decreased epididymis and testes weights. Following oral inhalation of necessary to avoid recurrence of hypoglycemia. Human insulin has the following primary if it is co-administered with albuterol. seizure. insulin) beginning 2 weeks prior to mating until gestation day 7. In female rats there was increased pre. and 145 minutes for subcutaneous regular human insulin 15 units. which is seen with subcutaneously administered insulin. AFREZZA has been studied in adults with type 2 diabetes in combination with oral antidiabetic drugs.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus the powder is aerosolized and delivered to the lung. and 100 mg/kg/day of carrier (vehicle without 80. The efficacy will depend on individual patient factors. active- fat. open-label. post-implantation loss at 100 mg/kg/day but not at 30 mg/kg/day (14–21 times higher systemic exposure than the maximum daily AFREZZA dose of 99 mg based on AUC). but glucose monitoring and dose adjustment may be necessary for AFREZZA in patients with hepatic it is unknown if the diminishing pharmacodynamic benefit at higher dosage of AFREZZA parallels that impairment [see Warnings and Precautions (5. The amount of AFREZZA delivered to the lung AFREZZA has been studied in adults with type 1 diabetes in combination with basal insulin.5 Geriatric Use In the AFREZZA clinical studies. Frequent dose-proportional manner. Following pulmonary absorption into studies with human insulin have shown increased circulating levels of insulin in patients with renal systemic circulation. Some The insulin contained in AFREZZA is regular human insulin. based Insulin Concentrations (B) after Administration of AFREZZA or Subcutaneous Insulin on AUC). 8. 4 . may be needed. Insulin inhibits lipolysis in adipocytes. a basal insulin.1 Mechanism of Action 14. 12. This effect has been observed for subcutaneously administered insulins. transgenic mice (Tg-ras-H2) given doses up to 75 mg/kg/day of carrier and up to 5 mg/kg/day of AFREZZA. A study in rats indicated that the carrier is excreted in milk at approximately 10% of maternal exposure levels. failure. 30. In a study of 32 healthy subjects.and cartridge contains 1 mg of insulin. 14. and enhances protein synthesis. The 8 unit cartridge contains 0.3 Nursing Mothers Many drugs are excreted in human milk. At Week 24. No increased incidence of tumors was observed. or exercise. It is therefore highly likely that the insulin and carrier in AFREZZA is excreted in human milk. Hypokalemia must be corrected appropriately. and by inhibiting hepatic glucose production. of AFREZZA in type 1 diabetes patients was compared to insulin aspart in combination with basal 12 CLINICAL PHARMACOLOGY insulin.4%. After apparent clinical Clinical pharmacology studies showed that carrier particles [see Description (11)] are not metabolized recovery from hypoglycemia.2 AFREZZA Inhaler 14 CLINICAL STUDIES The AFREZZA Inhaler is breath-powered by the patient. Chemically.In pregnant rabbits given subcutaneous doses of 2. treatment with basal insulin and mealtime AFREZZA provided a mean reduction The median time to maximum effect of AFREZZA (measured by the peak rate of glucose infusion) was in HbA1c that met the pre-specified non-inferiority margin of 0. The 12 unit daily AFREZZA dose of 99 mg based on AUC). aspart group achieved the HbA1c target of ≤7% (Table 4). Lispro in Type 1 Diabetes Patients* In pregnant rats given subcutaneous doses of 10. a mean of 39% of the inhaled dose of carrier particles was distributed to the lungs and a 11 DESCRIPTION mean of 7% of the dose was swallowed. When the patient inhales through the device.3. no decrease in fertility was noted. 8. AFREZZA provided less HbA1c approximately 53 minutes (standard deviation of 74 minutes) and the effect then declined to near reduction than insulin aspart. 10. 11.

23) Advise patients to inform their physicians if they have a history of lung disease.3)]. they should report it to their physician immediately for assessment. 60 – 4 unit (N=174) (N=170) cartridges and 30 . 8 unit and 12 unit single-use Inform patients to promptly report any signs or symptoms potentially related to lung cancer [see cartridges. and treatment Opened Strips Must be used within 3 days by visit interaction as fixed factors. cough. and skipped meals.1)]. and corresponding baseline as a covariate. Instruct patients to use AFREZZA only with the AFREZZA inhaler. and assessment for diabetes complications. region.g. Instruct patients to inform their 5). Store at 2–25°C (36–77°F). the contents must be used within 10 days.†) -0. Inhaler may be stored refrigerated. Following a 6-week run-in period. Each cartridge [see Warnings and Precautions (5. Hypersensitivity Reactions The AFREZZA Inhaler is individually packaged in a clear overwrap. 60 – 8 unit cartridges and 30 . hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or †Data at 24 weeks without rescue therapy were available from 139 (79%) and 129 (73%) subjects operating machinery [see Warnings and Precautions (5. the perforation allows Diabetic Ketoacidosis users to remove a single strip containing 3 cartridges. healthcare provider or pharmacist if they develop any unusual symptom. randomized to the AFREZZA and placebo groups.0.5)]. Baseline (adjusted mean*) 175.1 Sealed (Unopened) Foil Package May be stored until the Expiration Date* Fasting Plasma Glucose (mg/dL) Sealed (Unopened) Blister Cards + Strips May be stored for 1 month* Baseline (adjusted mean*) 153. For convenience.9 175. Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Agents Inform patients about the importance of adherence to dietary instructions. 17 PATIENT COUNSELING INFORMATION double-blind. respectively.02. respectively. proper inhalation Difference from placebo (adjusted mean*. blue for 4 units. of first use. Two cards of the same cartridge strength are Instruct patients to carefully monitor their blood glucose during illness.57. as medication Agents Agents (N=177) (N=176) requirements may change. cartridges should be at room temperature for 10 minutes.42 pregnant while using AFREZZA..36) Percentage of patients achieving HbA1c ≤ 7%‡ 13. inadvertent administration *Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c of an increased insulin dose. and other risk situations packaged in a foil laminate overwrap (30 cartridges per foil package). is marked with ″afrezza″ and ″4 units″.6)]. Inform patients that their ability to concentrate fixed factors. visit.2 -3.6 *If a foil package.7)]. or if any known symptom persists or worsens.8 unit cartridges and 2 inhalers • NDC 0024-5882-36. ″8 units″ or ″12 units″.92 • NDC 0024-5894-63. because information may change. the inhaler must be discarded and replaced with a new inhaler. or 2 or more oral antidiabetic (OAD) agents participated in a 24-week. Each card contains 5 blister Warnings and Precautions (5. green for 8 units and yellow for 12 units. asthma. or other chronic lung Percentage (%) of patients achieving HbA1C ≤7%‡ 32.4 unit cartridges and 2 AFREZZA + Insulin Aspart + inhalers Efficacy Parameter Basal Insulin Basal Insulin • NDC 0024-5884-63. and corresponding baseline as a covariate. 14. or surgery. Inhaler Storage: ‡The percentage was calculated based on the number of patients randomized to the trial. treatment with AFREZZA plus OADs provided a mean reduction in HbA1c that was Instruct patients to read the Medication Guide before starting AFREZZA therapy and to reread it each statistically significantly greater compared to the HbA1c reduction observed in the placebo group (Table time the prescription is renewed.†) -7.9 151. An autoregression (1) [AR(1)] covariance and react may be impaired as a result of hypoglycemia. and throat pain or irritation. 0. HbA1c (%) Inform patients that the most common adverse reactions associated with the use of AFREZZA are Baseline (adjusted mean*) 8.†) -0. AFREZZA (insulin human) Inhalation Powder: 90 cartridges. or FPG as the dependent variable and treatment. excursions permitted. 5 . Three cartridges are contained in a single cavity of a blister strip.82 -0.†) 0.2 Hypoglycemia Change from baseline (adjusted mean*.†) -11. Insulin doses were titrated for the first 12 weeks and kept stable for the last 12 weeks of the study. doses of metformin only. The AFREZZA Inhaler can be used for up to 15 days from the date Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5. Advise patients who have frequent structure was used. stress. The inhaler is fully assembled with Advise patients that hypersensitivity reactions can occur with insulin therapy including AFREZZA. for diabetic ketoacidosis and to contact their healthcare provider if their blood glucose control worsens The cartridges are color-coded.40 Acute Bronchospasm in Patients with Chronic Lung Disease (95% CI) (-0. periodic blood glucose monitoring and HbA1c testing.2 Difference from insulin aspart (adjusted mean*.19 Not in Use: Refrigerated Storage 2–8°C (36–46°F) (95% CI) (0. infection. infection. AFREZZA (insulin human) Inhalation Powder: 90 . †) -35. but should be at room temperature before use. region. and management of hypoglycemia and hyperglycemia especially at initiation of AFREZZA (95% CI) (-18.8 27. trauma.12 unit cartridges and 2 inhalers Change from baseline (adjusted mean*. OADs doses were kept stable. Difference from placebo (adjusted mean*. COPD. basal insulin stratum. excursions permitted 15–30°C (59–86°F) (95% CI) (-56. Instruct patients on handling of special situations such as intercurrent conditions (illness.3. Instructions At Week 24. An autoregression (1) [AR(1)] covariance structure was used. and treatment by visit interaction as Instruct patients on the management of hypoglycemia. AFREZZA (insulin human) Inhalation Powder: 90 cartridges. 30 – 4 unit HbA1c (%) cartridges and 60 . regular physical activity. placebo-controlled study. 16 HOW SUPPLIED/STORAGE AND HANDLING Lung Cancer AFREZZA (insulin human) Inhalation Powder is available as 4 unit. Fasting Plasma Glucose (mg/dL) Advise patients that if they experience any respiratory difficulty after inhalation of AFREZZA. because AFREZZA should not be used in patients with chronic lung disease (e. inadequate food intake. Inform patients that AFREZZA can cause a decline in lung function and their lung function will be evaluated by spirometry before initiation of AFREZZA treatment [see Warnings and Precautions (5.† Advise women with diabetes to inform their physician if they are pregnant or are planning to become Change from baseline (adjusted mean ) -0. Table 4. -14.6) *Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c Sealed (Unopened) Blister Cards + Strips Must be used within 10 days or FPG as the dependent variable and treatment.4)]. Results at Week 24 in a Placebo-Controlled Study of AFREZZA in Adults with Inform patients of the potential risks and benefits of AFREZZA and of alternative modes of therapy. visit. -0. recognition and management of hypoglycemia Efficacy Parameter AFREZZA + Oral Placebo + Oral and hyperglycemia. Decline in Pulmonary Function and Monitoring ‡The percentage was calculated based on the number of patients randomized to the trial. or emotional disturbances). 353 patients were randomized See FDA-approved patient labeling (Medication Guide) to AFREZZA (n=177) or an inhaled placebo powder without insulin (n=176). †Data at 24 weeks were available from 131 (75 %) and 150 (88% ) subjects randomized to the Do not put a blister card or strip back into the refrigerator after being stored at room temperature AFREZZA and insulin aspart groups.8 Instruct patients on self-management procedures including glucose monitoring. Table 5. strips separated by perforations for a total of 15 cartridges. an inadequate or skipped insulin dose. blister card or strip is not refrigerated. After 15 days of use.3 disease(s)) [see Contraindications (4) and Warnings and Precautions (5.2) therapy. AFREZZA (insulin human) Inhalation Powder: 90 cartridges. †) -25.4 In Use: Room Temperature Storage 25°C (77°F). Results at Week 24 in an Active-Controlled Study of Mealtime AFREZZA plus AFREZZA is available in the following configurations: Basal Insulin in Adults with Type 1 Diabetes • NDC 0024-5874-90. Change from baseline (adjusted mean*. 3.3 10.8 unit cartridges and 2 inhalers Baseline (adjusted mean*) 7.94 7. a removable mouthpiece cover.2 15.40 Storage Difference from insulin aspart (adjusted mean*. Advise patients to seek medical advice Anti-Diabetic Anti-Diabetic promptly during periods of stress such as fever.25 8.3 Type 2 Diabetes Handling: A total of 479 adult patients with type 2 diabetes inadequately controlled on optimal/maximally tolerated Before use.4 technique.27 hypoglycemia. *.21 -0.

confusion. anxiety. Talk to your healthcare provider if you have • AFREZZA is not for use to treat diabetic ketoacidosis. planning to become pregnant. AFREZZA. CT 06810 What should I avoid while using AFREZZA? While using AFREZZA do not: Distributed by: sanofi-aventis U. LLC • drive or operate heavy machinery. who smoke. shortness of breath. of AFREZZA you use unless your healthcare provider tells you to. In studies of AFREZZA in people with diabetes. dizzi- ments. sugar levels. which it was not prescribed. your healthcare provider will give you a breathing test • decreased lung function. change in diet. swelling of prescription and over-the-counter medicines. or because of other MannKind Corporation medicines you take. NJ 08807 affects you A SANOFI COMPANY • drink alcohol or use over-the-counter medicines that contain alcohol • smoke 10/2015 What are the possible side effects of AFREZZA? Medication Guide AFREZZA may cause serious side effects that can lead to death. It may harm them. even • Know the strength of AFREZZA you use. sweating. shakiness. you and your healthcare provider should must be used with long-acting insulin in people who have type 1 decide if you should use AFREZZA. fast heartbeat. There diabetes mellitus. weight gain or loss. 6 months after you start using it and yearly after that. how your lungs are working before you start using AFREZZA. What is AFREZZA? • lung cancer. ing AFREZZA. an illness. until you know how AFREZZA Bridgewater. swelling of your ankles or feet. This Medication Guide summarizes the most important information • Take AFREZZA at the beginning of your meal. or throat. your face. extreme drowsiness. For more information. cough. trouble breathing. Tell your healthcare provider if you have any new or • have lung problems such as asthma or COPD worse symptoms of heart failure including: • have or have had lung cancer • shortness of breath. The most common side effects of AFREZZA include: Before you start using AFREZZA. • Take AFREZZA exactly as your healthcare provider tells you to. You can ask your pharmacist or healthcare provider your blood sugar should be and when you should check your blood for information about AFREZZA that is written for health professionals. fast heartbeat. 1-800-633-1610. AFREZZA If you have lung cancer. Signs and symptoms that may AFREZZA can cause serious side effects. were too few cases to know if lung cancer was related to AFREZZA. Who should not use AFREZZA? or sweating. • a rash over your whole body. tell your healthcare provider about all your should monitor you closely while you are taking TZDs with medical conditions. General information about the safe and effective use of AFREZZA. sore throat These are not all the possible side effects of AFREZZA. lung • AFREZZA is a man-made insulin that is breathed-in through your cancer occurred in a few more people who were taking AFREZZA lungs (inhaled) and is used to control high blood sugar in adults with than in people who were taking other diabetes medications. including if you: AFREZZA.S. help right away if you have any of these signs or symptoms of • It is not known if AFREZZA is safe and effective in children under a severe allergic reaction: 18 years of age.com or call sanofi-aventis • Keep AFREZZA and all medicines out of the reach of children. Call your How should I use AFREZZA? doctor for medical advice about side effects. • smoke or have recently stopped smoking Treatment with TZDs and AFREZZA may need to be changed or • have kidney or liver problems stopped by your healthcare provider if you have new or worse heart • are pregnant. Taking certain diabetes pills called thiazolidinediones • are allergic to regular human insulin or any of the ingredients in or ″TZDs″ with AFREZZA may cause heart failure in some people. failure.com/our-technology-patent-notices. Danbury.AFREZZA is a registered trademark owned by MannKind Corporation Your dose of AFREZZA may need to change because of: Patented: http://www. AFREZZA may harm your unborn or breastfeeding baby. including: indicate low blood sugar include: • Sudden lung problems (bronchospasms). • have chronic lung problems such as asthma or COPD. Your Medicines are sometimes prescribed for purposes other than those healthcare provider should tell you how much AFREZZA to use and listed in a Medication Guide. sweating. problems before. tongue. headache. or are breastfeeding. including • trouble breathing. Do not give AFREZZA to other people. Your healthcare provider Before using AFREZZA. talk with your • Check your blood sugar levels. talk to your healthcare provider about low blood sugar and how to manage it.mannkindcorp. Manufactured by: increased stress. irritability or mood change. Your AFREZZA dose or how often you check your blood • It is not known if AFREZZA is safe and effective for use in people sugar may need to be changed. • low blood sugar (hypoglycemia). Do not use AFREZZA if you: • low potassium in your blood (hypokalemia). Do not use AFREZZA for a condition for when to use it.AFREZZA. You may report side effects • Read the detailed Instructions for Use that comes with your to FDA at 1-800-FDA-1088 (1-800-332-1088). • AFREZZA is not for use in place of long-acting insulin. illness. go to www. • heart failure. If you already have heart failure it may get worse What should I tell my healthcare provider before using AFREZZA? while you take TZDs with AFREZZA. a fast heartbeat. confusion. vitamins or herbal supple. AFREZZA. Do not use AFREZZA • dizziness or light-headedness. ness. See the end of this Medication Guide for a complete list This can happen even if you have never had heart failure or heart of ingredients in AFREZZA.htm • Change in level of physical activity or exercise. Get medical recently stopped smoking (less than 6 months). diabetes mellitus. Get emergency medical help if you have: Tell your healthcare provider about all the medicines you take. or chronic obstructive pulmonary disease (COPD). sudden • are using any inhaled medications weight gain. 6 . Before start. • diabetic ketoacidosis. about AFREZZA. AFREZZA is not for use in people who smoke or have • severe allergic reaction (whole body reaction). If you would like more information. hunger. if you have long-term (chronic) lung problems such as asthma blurred vision. slurred speech. AFREZZA® (uh-FREZZ-uh) including: (insulin human) inhalation powder See ″What is the most important information I should know about What is the most important information I should know about AFREZZA?″ AFREZZA? • low blood sugar (hypoglycemia). Do not change the amount if they have the same symptoms that you have. Your healthcare provider should check to check how your lungs are working. Ask your healthcare provider what healthcare provider.

because the cup has moved to the center. one. Your healthcare provider should show you how to use your AFREZZA inhaler the right way before you use it for the first time. The same inhaler should be used for the 4 unit. CT 06810 Distributed by: sanofi-aventis U. call 1-800-633-1610. 8 unit or 12 unit cartridges.What are the ingredients in AFREZZA? If you are having problems with your AFREZZA inhaler or if it Active ingredient: human insulin breaks and you need a new one. Important information about AFREZZA: • AFREZZA comes in 3 strengths (See Figure A): „ 4 units (blue cartridge) „ 8 units (green cartridge) „ 12 units (yellow cartridge) (Figure A) • If your prescribed AFREZZA dose is higher than 12 units. • Use only 1 AFREZZA Inhaler at a time. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. • AFREZZA cartridges should only be used with the AFREZZA Inhaler. There may be new information. Do not put cartridges in your mouth and do not swallow cartridges.com/our-technology-patent-notices. throw away Always be sure you have the right number of AFREZZA cartridges the used cartridge before getting a new one. only be used with the AFREZZA Inhaler. Inactive ingredients: fumaryl diketopiperazine. The AFREZZA Step 1: Select the AFREZZA cartridges for your dose Inhaler opens the cartridge automatically during use. polysorbate 80 Know your AFREZZA® inhaler: Manufactured By: MannKind Corporation AFREZZA® is a registered trademark owned by MannKind Corporation Patented: http://www. LLC Bridgewater. 7 .mannkindcorp. • Do not try to open the AFREZZA cartridges. You can tell when a for your dose available before you start. AFREZZA cartridges must cartridge has been used. you will need to use more than 1 cartridge. • Throw away your AFREZZA Inhaler after 15 days and get a new If your prescribed AFREZZA® dose is more than 12 units you will need to use more than 1 cartridge to get your right dose. NJ 08807 A SANOFI COMPANY Instructions for Use Know your AFREZZA® cartridges: AFREZZA® (uh-FREZZ-uh) (insulin human) inhalation powder Read this Instructions for Use before you start using AFREZZA and each time you get a new AFREZZA inhaler. Do not try to breathe in the AFREZZA insulin powder in any other way.S. How to take your dose of AFREZZA: • If you need to use more than 1 cartridge for your dose.htm MannKind Corporation Danbury.

after removal of the purple mouthpiece cover. Tear along perforation to remove one strip. damage the cartridge. Close Inhaler Remove the right number of cartridges for Lower the mouthpiece to close the inhaler (this your dose. Before you put the AFREZZA cartridge in your inhaler. Select Cartridges Important: Use the AFREZZA dose chart above (See Figure B) to help you choose the right number of AFREZZA cartridges needed for your dose. Open Inhaler Open the inhaler by lifting the white mouthpiece to a vertical position. Step 3: Inhaling AFREZZA Remove the Mouthpiece Cover Before Proceeding: Important: Keep the inhaler level during and Check that you have the right AFREZZA cartridge(s) for your dose. Push Cartridges to Remove Remove a cartridge from the strip by pressing on the clear side to push the cartridge out. Hold the inhaler level in one (1) hand with the white mouthpiece on the top and purple base on the bottom. Open Packages Remove a blister card from the foil package. Pushing on the cup will not will open the drug cartridge). Use only 1 inhaler for multiple cartridges. Line up the cartridge with the opening in the (Figure B) inhaler. Other cartridge Hold Inhaler combinations can be used. make sure it has been at room temperature for 10 minutes. Use the dosage chart below to determine the least number of Step 2: Loading a cartridge AFREZZA® cartridges you can use for your dose. Place Cartridge Hold the cartridge with the cup facing down. 8 . Place the cartridge into the inhaler. You should feel a snap when the inhaler is AFREZZA cartridges left over in an opened closed. The pointed end of the cartridge Example: should line up with the pointed end in the inhaler. Throw away your AFREZZA inhaler after 15 days and get a new one. strip must be used within 3 days. Be sure that the cartridge lies flat in the inhaler.

Step 4: Removing a used cartridge Replace Mouthpiece Cover Place the purple mouthpiece cover back onto *If a foil package. Tilt the inhaler downward while keeping your head level. blister card or strip is not refrigerated. 9 . place the mouthpiece in your mouth and tilt the inhaler down towards your chin. Open Inhaler Open the inhaler by lifting up the white mouthpiece. Throw away the used cartridge in your regular household trash. exhale and continue to breathe normally. the contents the inhaler. Multiple cartridge dosing Caring for your AFREZZA inhaler: If you need more than one (1) AFREZZA cartridge for your dose. See the AFREZZA dosage chart above (Figure B). Position Inhaler in Mouth Keeping your head level. Do not put a blister card or strip back into the refrigerator after Throw away the Cartridge being stored at room temperature. Remove Cartridge Remove the cartridge from the purple base. Close your lips around the mouthpiece to form a seal. must be used within 10 days. Exhale Repeat steps 2 through 4 for each AFREZZA cartridge you Hold the inhaler away from your mouth and need for your prescribed AFREZZA dose. Hold your breath for as long as comfortable and at the same time remove the inhaler from your mouth. as shown. After holding your breath. fully blow out (exhale). How should I store AFREZZA? Inhale Deeply and Hold Breath With your mouth closed around the mouthpiece. inhale deeply through the inhaler.

AFREZZA® is a mealtime insulin.mannkindcorp.htm Manufactured by: MannKind Corporation Danbury. Do not switch from AFREZZA to a long acting insulin. AFREZZA® is a registered trademark owned by MannKind Corporation Patented: See http://www. LLC Bridgewater.S. Do not switch from a long acting insulin to AFREZZA®. CT 06810 Distributed by: sanofi-aventis U.Switching between AFREZZA and injected insulin: Contact your healthcare provider before switching insulins.S. Food and Drug Administration. NJ 08807 A SANOFI COMPANY Approved: 07/2015 INS-FPLR-SL-OCT15 Rx Only 10 .com/our-technology-patent-notices. This Medication Guide and Instructions for Use has been approved by the U.