ARIKAYCE

1 INDICATIONS AND USAGE LIMITED POPULATION: ARIKAYCE ® is indicated in adults, who have limited or no alternative treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. As only limited clinical safety and effectiveness data for ARIKAYCE are currently available, reserve ARIKAYCE for use in adults who have limited or no alternative treatment options . This drug is indicated for use in a limited and specific population of patients. This indication is approved under accelerated approval based on achieving sputum culture conversion (defined as 3 consecutive negative monthly sputum cultures) by Month 6. Clinical benefit has not yet been established [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials . LIMITED POPULATION: ARIKAYCE is an aminoglycoside antibacterial indicated in adults who have limited or no alternative treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. As only limited clinical safety and effectiveness data for ARIKAYCE are currently available, reserve ARIKAYCE for use in adults who have limited or no alternative treatment options. This drug is indicated for use in a limited and specific population of patients. ( 1 ) This indication is approved under accelerated approval based on achieving sputum culture conversion (defined as 3 consecutive negative monthly sputum cultures) by Month 6. Clinical benefit has not yet been established. ( 1 ) Limitation of Use: ARIKAYCE has only been studied in patients with refractory MAC lung disease defined as patients who did not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. The use of ARIKAYCE is not recommended for patients with non-refractory MAC lung disease. Limitation of Use : ARIKAYCE has only been studied in patients with refractory MAC lung disease defined as patients who did not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. The use of ARIKAYCE is not recommended for patients with non-refractory MAC lung disease.

2 DOSAGE AND ADMINISTRATION For oral inhalation use only. ( 2.1 ) Use ARIKAYCE vials only with the Lamira Nebulizer System. ( 2.1 ) Pre-treatment with inhaled bronchodilator should be considered in patients with a history of hyperreactive airway disease. ( 2.1 ) The recommended dosage in adults is once daily oral inhalation of the contents of one 590 mg/8.4 mL ARIKAYCE vial. ( 2.2 ) 2.1 Important Administration Instructions ARIKAYCE is for oral inhalation use only. Administer by nebulization only with the Lamira ® Nebulizer System. Refer to the Instructions for Use for full administration information on use of ARIKAYCE with the Lamira Nebulizer System. Instruct patients using a bronchodilator ('reliever') to first use the bronchodilator following the bronchodilator leaflet for use information before using ARIKAYCE. Pre-treatment with short-acting selective beta-2 agonists should be considered for patients with known hyperreactive airway disease, chronic obstructive pulmonary disease, asthma, or bronchospasm [see Warnings and Precautions (5.3) ] . 2.2 Recommended Dosage The recommended dosage of ARIKAYCE in adults is once daily inhalation of the contents of one 590 mg/8.4 mL ARIKAYCE vial (590 mg of amikacin) using the Lamira Nebulizer System [see Clinical Studies (14) ] . Administer ARIKAYCE with the Lamira Nebulizer System only. ARIKAYCE should be at room temperature before use. Prior to opening, shake the ARIKAYCE vial well for at least 10 to 15 seconds until the contents appear uniform and well mixed. The ARIKAYCE vial is opened by flipping up the plastic top of the vial then pulling downward to loosen the metal ring. The metal ring and the rubber stopper should be removed carefully. The contents of the ARIKAYCE vial can then be poured into the medication reservoir of the nebulizer handset. If a daily dose of ARIKAYCE is missed, administer the next dose the next day. Do NOT double the dose to make up for the missed dose.

4 CONTRAINDICATIONS ARIKAYCE is contraindicated in patients with a known hypersensitivity to any aminoglycoside. ARIKAYCE is contraindicated in patients with a known hypersensitivity to any aminoglycoside. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Pneumonitis : Reported with ARIKAYCE treatment; if hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage patients as medically appropriate. ( 5.1 ) Hemoptysis : Higher frequency of hemoptysis has been reported with ARIKAYCE treatment. If hemoptysis occurs, manage the patients as medically appropriate. ( 5.2 ) Bronchospasm : Higher frequency of bronchospasm has been reported with ARIKAYCE treatment. Treat patients as medically appropriate if this occurs during treatment with ARIKAYCE. ( 5.3 ) Exacerbations of Underlying Pulmonary Disease: Higher frequency of exacerbations of underlying pulmonary disease has been reported with ARIKAYCE treatment. Treat patients as medically appropriate if this occurs during treatment with ARIKAYCE. ( 5.4 ) Anaphylaxis and Hypersensitivity Reactions : Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE. If anaphylaxis or a hypersensitivity reaction occurs, discontinue ARIKAYCE and institute appropriate supportive measures. ( 5.5 ) Ototoxicity: Higher frequency of ototoxicity has been reported with ARIKAYCE treatment. Closely monitor patients with known or suspected auditory or vestibular dysfunction. If patients develop tinnitus this may be an early symptom of ototoxicity. ( 5.6 ) Nephrotoxicity : Nephrotoxicity was observed during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than the background regimen alone. Aminoglycosides have been associated with nephrotoxicity. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE. ( 5.7 ) Neuromuscular Blockade: Aminoglycosides may aggravate muscle weakness by blocking the release of acetylcholine at neuromuscular junctions. Closely monitor patients with known or suspected neuromuscular disorders, such as myasthenia gravis. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical respiratory assistance may be necessary. ( 5.8 ) Embryo-Fetal Toxicity : Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero . Advise pregnant women of the potential risk to a fetus. ( 5.9 , 8.1 ) 5.1 Hypersensitivity Pneumonitis Hypersensitivity pneumonitis has been reported with the use of ARIKAYCE in the clinical trials. Hypersensitivity pneumonitis (reported as allergic alveolitis, pneumonitis, interstitial lung disease, allergic reaction to ARIKAYCE) was reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (3.1%) compared to patients treated with a background regimen alone (0%). Most patients with hypersensitivity pneumonitis discontinued treatment with ARIKAYCE and received treatment with corticosteroids [see Adverse Reactions (6.1) ] . If hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage the patient as medically appropriate . 5.2 Hemoptysis Hemoptysis has been reported with the use of ARIKAYCE in the clinical trials. Hemoptysis was reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (18.4%) compared to patients treated with a background regimen alone (13.4%) [see Adverse Reactions (6.1) ] . If hemoptysis occurs, manage the patients as medically appropriate . 5.3 Bronchospasm Bronchospasm has been reported with the use of ARIKAYCE in the clinical trials. Bronchospasm (reported as asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, wheezing) was reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (28.7%) compared to patients treated with a background regimen alone (10.7%) [see Adverse Reactions (6.1) ] . If bronchospasm occurs during the use of ARIKAYCE, treat the patients as medically appropriate . 5.4 Exacerbation of Underlying Pulmonary Disease Exacerbations of underlying pulmonary disease have been reported with the use of ARIKAYCE in the clinical trials. Exacerbations of underlying pulmonary disease (reported as chronic obstructive pulmonary disease, infective exacerbation of chronic obstructive pulmonary disease, infective exacerbation of bronchiectasis) have been reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (15.2%) compared to patients treated with background regimen alone (9.8%) [see Adverse Reactions (6.1) ] . If exacerbations of underlying pulmonary disease occur during the use of ARIKAYCE, treat the patients as medically appropriate . 5.5 Anaphylaxis and Hypersensitivity Reactions Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE [see Adverse Reactions (6.1 , 6.2) ] . Signs and symptoms include acute onset of skin and mucosal tissue hypersensitivity reactions (hives, itching, flushing, swollen lips/tongue/uvula), respiratory difficulty (shortness of breath, wheezing, stridor, cough), gastrointestinal symptoms (nausea, vomiting, diarrhea, crampy abdominal pain), and cardiovascular signs and symptoms of anaphylaxis (tachycardia, low blood pressure, syncope, incontinence, dizziness). Before therapy with ARIKAYCE is instituted, evaluate for previous hypersensitivity reactions to aminoglycosides. If anaphylaxis or a hypersensitivity reaction occurs, discontinue ARIKAYCE and institute appropriate supportive measures. 5.6 Ototoxicity Ototoxicity with use of ARIKAYCE Ototoxicity has been reported with the use of ARIKAYCE in the clinical trials. Ototoxicity (including deafness, dizziness, presyncope, tinnitus, and vertigo) were reported with a higher frequency in patients treated with ARIKAYCE plus a background regimen (17%) compared to patients treated with background regimen alone (9.8%). This was primarily driven by tinnitus (8.1% in ARIKAYCE plus background regimen vs. 0.9% in the background regimen alone arm) and dizziness (6.3% in ARIKAYCE plus background regimen vs. 2.7% in the background regimen alone arm) [see Adverse Reactions (6.1) ] . Closely monitor patients with known or suspected auditory or vestibular dysfunction during treatment with ARIKAYCE. If ototoxicity occurs, manage the patient as medically appropriate, including potentially discontinuing ARIKAYCE. Risk of Ototoxicity Due to Mitochondrial DNA Variants Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene ( MT-RNR1 ), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies. 5.7 Nephrotoxicity Nephrotoxicity was observed during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than the background regimen alone [see Adverse Reactions (6.1) ] . Nephrotoxicity has been associated with the aminoglycosides. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE. 5.8 Neuromuscular Blockade Patients with neuromuscular disorders were not enrolled in ARIKAYCE clinical trials. Aminoglycosides may aggravate muscle weakness by blocking the release of acetylcholine at neuromuscular junctions. Closely monitor patients with known or suspected neuromuscular disorders, such as myasthenia gravis. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical respiratory assistance may be necessary. 5.9 Embryo-Fetal Toxicity Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero . Patients who use ARIKAYCE during pregnancy, or become pregnant while taking ARIKAYCE should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ] .

7 DRUG INTERACTIONS 7.1 Drugs with Neurotoxic, Nephrotoxic, or Ototoxic Potential Avoid concomitant use of ARIKAYCE with medications associated with neurotoxicity, nephrotoxicity, and ototoxicity. 7.2 Ethacrynic Acid, Furosemide, Urea, or Mannitol Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in serum and tissue. Avoid concomitant use of ARIKAYCE with ethacrynic acid, furosemide, urea, or intravenous mannitol.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of labeling: Hypersensitivity pneumonitis [see Boxed Warning and Warnings and Precautions (5.1) ] Hemoptysis [see Boxed Warning and Warnings and Precautions (5.2) ] Bronchospasm [see Boxed Warning and Warnings and Precautions (5.3) ] Exacerbation of Underlying Pulmonary Disease [see Boxed Warning and Warnings and Precautions (5.4) ] Anaphylaxis and Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Ototoxicity [see Warnings and Precautions (5.6) ] Nephrotoxicity [see Warnings and Precautions (5.7) ] Neuromuscular Blockade [see Warnings and Precautions (5.8) ] Most common adverse reactions (incidence ≥10% and higher than control) in the patients with refractory MAC lung disease were: dysphonia, cough, bronchospasm, hemoptysis, musculoskeletal pain, upper airway irritation, ototoxicity, fatigue/asthenia, exacerbation of underlying pulmonary disease, diarrhea, nausea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Insmed Incorporated at 1-844-4-INSMED 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. Overview of Clinical Trials for Safety Evaluation Within the refractory NTM clinical program, 404 patients that participated in three clinical trials were treated with ARIKAYCE at the dose of 590 mg/day (median duration of exposure to ARIKAYCE was 236.5 days). Trial 1 (NCT#02344004) was an open-label, randomized (2:1), multi-center Phase 3 trial in patients with refractory Mycobacterium avium complex (MAC) lung disease. Patients were randomized to either 8 months of ARIKAYCE plus a background regimen (n=223) or background regimen alone (n=112). Trial 2 (NCT#02628600) was a single-arm extension of Trial 1 for refractory MAC lung disease patients that failed to achieve negative sputum cultures after 6 months of treatment or had a relapse or recurrence by Month 6 from either study arm of Trial 1. A total of 163 patients (n=90 from the prior background regimen alone arm of Trial 1, and n=73 from the prior ARIKAYCE plus background regimen arm in Trial 1) participated in the trial. Trial 3 (NCT#01315236) was a double-blind, randomized, placebo-controlled Phase 2 study in patients with refractory nontuberculous mycobacterial (NTM) lung disease caused by MAC and Mycobacterium abscessus . Patients were randomized to either ARIKAYCE plus background regimen (N=44) or an inhaled diluted empty liposome placebo plus background regimen (N=45) for 84 days. Across all clinical trials of patients with and without refractory NTM lung infection, 818 patients were exposed to multiple doses of ARIKAYCE. Adverse Reactions Leading to Treatment Discontinuation In the three NTM studies, there was a higher incidence of premature discontinuation of ARIKAYCE. In Trial 1, 34.5% discontinued ARIKAYCE prematurely; most were due to adverse reactions (18.8%) and withdrawal by subject (9.9%). In the comparator arm, 10.7% of subjects discontinued their background regimen, with 0.9% due to adverse reactions and 5.4% due to withdrawal by subject. In Trial 2 (the single-arm extension of Trial 1), 37.8% of patients starting on ARIKAYCE discontinued prematurely with 24.4% discontinuing due to adverse reactions. In Trial 3, all 9 (20.5%) premature discontinuations occurred in the ARIKAYCE plus background regimen-treated patients and there were no premature discontinuations in the placebo plus background regimen arm. Serious Adverse Reactions in Trials 1 and 3 In Trial 1, 19.7% of patients treated with ARIKAYCE plus background regimen reported SAR as compared to 16.1% of patients treated with background regimen alone. In addition, in Trial 1 [2 to 1 randomization, ARIKAYCE plus background regimen versus background regimen alone], there were 80 hospitalizations in 41 patients (18.4%) treated with ARIKAYCE plus background regimen compared to 29 hospitalizations in 15 patients (13.4%) treated with background regimen alone. The most common SARs and reasons for hospitalization in the ARIKAYCE plus background regimen arm were related to exacerbation of underlying pulmonary disease and lower respiratory tract infections, such as pneumonia. In Trial 3, 18.2% of patients treated with ARIKAYCE plus background regimen reported SARs compared to 8.9% of patients treated with background regimen plus inhaled placebo. Common Adverse Reactions The incidence of adverse reactions in Trial 1 are displayed in Table 1. Only those adverse reactions with a rate of at least 5% in the ARIKAYCE plus background regimen group and greater than the background regimen alone group, are shown. Table 1: Adverse Reactions in ≥ 5% of ARIKAYCE-treated MAC Patients and More Frequent than Background Regimen Alone in Trial 1 Adverse Reaction ARIKAYCE plus Background Regimen Background Regimen Alone (N=223) n (%) (N=112) n (%) Dysphonia Includes aphonia and dysphonia 106 (48) 2 (2) Cough Includes cough, productive cough, and upper airway cough syndrome 88 (40) 19 (17) Bronchospasm Includes asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, and wheezing 64 (29) 12 (11) Hemoptysis 41 (18) 15 (13) Musculoskeletal pain Includes back pain, arthralgia, myalgia, pain/body aches, muscle spasm and musculoskeletal pain 40 (18) 10 (9) Upper airway irritation Includes oropharyngeal pain, oropharyngeal discomfort, throat irritation, pharyngeal erythema, upper airway inflammation, pharyngeal edema , vocal cord inflammation, laryngeal pain, laryngeal erythema, laryngitis 39 (18) 2 (2) Ototoxicity Includes deafness, deafness neurosensory, deafness unilateral, dizziness, hypoacusis, presyncope, tinnitus, vertigo, balance disorders 38 (17) 11 (10) Fatigue and asthenia 36 (16) 11 (10) Exacerbation of underlying pulmonary disease Includes COPD, infective exacerbation of COPD, infective exacerbation of bronchiectasis 34 (15) 11 (10) Diarrhea 28 (13) 5 (5) Nausea 26 (12) 4 (4) Headache 22 (10) 5 (5) Pneumonia Includes atypical pneumonia, empyema, infection pleural effusion, lower respiratory tract infection, lung infection, lung infection pseudomonas, pneumonia, pneumonia aspiration, pneumonia pseudomonas, pseudomonas infection, and respiratory tract infection 20 (9) 10 (9) Pyrexia 17 (8) 5 (5) Weight decreased 16 (7) 1 (1) Vomiting Includes vomiting and post-tussive vomiting 15 (7) 4 (4) Rash Includes rash, rash maculo-papular, drug eruption, and urticaria 14 (6) 1 (1) Change in sputum Includes increased sputum, sputum purulent, and sputum discolored 13 (6) 1 (1) Chest discomfort 12 (5) 3 (3) Selected adverse drug reactions that occurred in <5% of patients and at higher frequency in ARIKAYCE-treated patients in Trial 1 are presented in Table 2. Table 2: Selected Adverse Reactions in < 5% of ARIKAYCE-treated MAC Patients and More Frequent than Background Regimen Alone in Trial 1 Adverse Reaction ARIKAYCE plus Background Regimen N=223 n (%) Background Regimen Alone N=112 n (%) Anxiety Includes anxiety and anxiety disorder 10 (5) 0 (0) Oral fungal infection Includes oral candidiasis and oral fungal infection 9 (4) 2 (2) Bronchitis 8 (4) 3 (3) Dysgeusia 7 (3) 0 (0) Hypersensitivity pneumonitis Includes allergic alveolitis, interstitial lung disease, and pneumonitis 7 (3) 0 (0) Dry mouth 6 (3) 0 (0) Epistaxis 6 (3) 1 (1) Respiratory failure Includes acute respiratory failure and respiratory failure 6 (3) 2 (2) Pneumothorax Includes pneumothorax, pneumothorax spontaneous and pneumomediastinum 5 (2) 1 (1) Exercise tolerance decreased 3 (1) 0 (0) Balance disorder 3 (1) 0 (0) Neuromuscular disorder Includes muscle weakness and neuropathy peripheral 2 (1) 0 (0) Refer to Table 1 and Table 2 for the incidence rate of hypersensitivity pneumonitis, bronchospasm, cough, dysphonia, exacerbation of underlying disease, hemoptysis, ototoxicity, upper airway irritation, and neuromuscular disorders [see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , 5.6 , 5.7) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified from postmarketing surveillance. Because these adverse reactions are reported voluntarily from a population of unknown size, precise estimates of frequency cannot be made and a causal relationship to drug exposure cannot be established. Gastrointestinal disorders: dysphagia, glossitis, glossodynia, salivary hypersecretion, stomatitis, abdominal pain, abdominal distension Immune system disorders: hypersensitivity, anaphylaxis, pharyngeal swelling [see Warnings and Precautions (5.5) ] Respiratory, thoracic, and mediastinal disorders: nasal dryness, rhinorrhea, sneezing, nasal congestion

8.1 Pregnancy Risk Summary There are no data on ARIKAYCE use in pregnant women to evaluate for any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Although systemic absorption of amikacin following oral inhalation is expected to be low [see Clinical Pharmacology (12.3) ], systemic exposure to aminoglycoside antibacterial drugs, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness when administered to pregnant women [see Warnings and Precautions (5.9) ] . Advise pregnant women of the potential risk to a fetus. Animal reproductive toxicology studies have not been conducted with inhaled amikacin. Subcutaneous administration of amikacin to pregnant rats (up to 100 mg/kg/day) and mice (up to 400 mg/kg/day) during organogenesis was not associated with fetal malformations. Ototoxicity was not adequately evaluated in offspring in animal studies. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data No animal reproductive toxicology studies have been conducted with ARIKAYCE or non-liposomal amikacin administered by inhalation. Amikacin was subcutaneously administered to pregnant rats (Gestation Days 8-14) and mice (Gestation Days 7-13) at doses of 25, 100, or 400 mg/kg to assess developmental toxicity. These doses did not cause fetal visceral or skeletal malformations in mice. The high dose was excessively maternally toxic in rats (nephrotoxicity and mortality were observed), precluding the evaluation of offspring at this dose. Fetal malformations were not observed at the low or mid dose in rats. Postnatal development of the rats and mice exposed to these doses of amikacin in utero did not differ significantly from control. Ototoxicity was not adequately evaluated in offspring in animal developmental toxicology studies.