ARIKAYCE
Generic: AMIKACIN
Basic Information
Manufacturer
Insmed Incorporated
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
RESPIRATORY (INHALATION)
FDA Set ID
499ab990-2b21-474f-aaba-d86388965f40
Indications & Usage
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.
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.
Adverse Reactions
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
( 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