Clinical trial safety profile
Adverse reactions in ≥5% of ARIKAYCE-treated patients with MAC lung disease (n=223) and more frequent than multidrug therapy alone (n=112) in the CONVERT trial1
|Adverse reaction||ARIKAYCE + multidrug therapy (n=223) n (%)||multidrug therapy alone (n=112) n (%)|
|Dysphonia a||106 (48)||2 (2)|
|Cough b||88 (40)||19 (17)|
|Bronchospasm c||64 (29)||12 (11)|
|Hemoptysis||41 (18)||15 (13)|
|Musculoskeletal pain d||40 (18)||10 (9)|
|Upper airway irritation e||39 (18)||2 (2)|
|Ototoxicity f||38 (17)||11 (10)|
|Fatigue and asthenia||36 (16)||11 (10)|
|Exacerbation of underlying pulmonary disease g||34 (15)||11 (10)|
|Diarrhea||28 (13)||5 (5)|
|Nausea||26 (12)||4 (4)|
|Headache||22 (10)||5 (5)|
|Pneumoniah||20 (9)||10 (9)|
|Pyrexia||17 (8)||5 (5)|
|Weight decreased||16 (7)||1 (1)|
|Vomiting i||15 (7)||4 (4)|
|Rash j||14 (6)||1 (1)|
|Change in sputum k||13 (6)||1 (1)|
|Chest discomfort||12 (5)||3 (3)|
No new safety signals detected2,3
In the open-label safety extension study of the CONVERT trial, the safety and tolerability of ARIKAYCE + multidrug therapy remained consistent.
No new safety signals detected with up to 20 months of total ARIKAYCE exposure.
Respiratory AEs following ARIKAYCE initiation were common. Nephrotoxicity-related AEs and measured hearing decline were infrequent over the 12-month treatment phase in the extension study.
INS-312 was a 12-month open-label extension of the CONVERT trial that assessed the long-term safety and tolerability of once-daily ARIKAYCE + multidrug therapy. Eligible patients who completed both Month 6 and Month 8/EOT visits could consent to enroll directly in INS-312, in which case the Month 8/EOT visit served as the INS-312 baseline. All patients were treated with ARIKAYCE in INS-312. The frequency of TEAEs, TEAEs leading to study withdrawal, serious TEAEs, TEAEs of special interest, and clinically significant abnormalities in laboratory results and vital signs constituted the primary endpoint.
Additional adverse reactions in <5% of patients1
Selected adverse reactions that occurred in <5% of patients and at a higher frequency in ARIKAYCE-treated patients in the CONVERT trial included:
- Anxietyl (5% vs 0%)
- Oral fungal infectionm (4% vs 2%)
- Bronchitis (4% vs 3%)
- Dysgeusia (3% vs 0%)
- Hypersensitivity pneumonitisn (3% vs 0%)
- Dry mouth (3% vs 0%)
- Epistaxis (3% vs 1%)
- Respiratory failureo (3% vs 2%)
- Pneumothoraxp (2% vs 1%)
- Exercise tolerance decreased (1% vs 0%)
- Balance disorder (1% vs 0%)
- Neuromuscular disorderq (1% vs 0%)
Treatment-emergent adverse events (TEAEs) over time
TEAEs reported in ≥10% of patients receiving ARIKAYCE + multidrug therapy or multidrug therapy alone4
Data indicate the month at which the events were first reported after initiation of therapy.4
Adapted with permission of the American Thoracic Society. Copyright © 2023 American Thoracic Society. All rights reserved. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. Readers are encouraged to read the entire article for the correct context at https://www.atsjournals.org/doi/pdf/10.1164/rccm.201807-1318OC. The authors, editors, and The American Thoracic Society are not responsible for errors or omissions in adaptations.
Incidence of TEAEs Month 1 to Month 6
- Patients who reported TEAEs and serious TEAEs in the CONVERT trial were 98.2% and 19.7% for ARIKAYCE + multidrug therapy vs 91.1% and 16.1% for multidrug therapy alone, respectively1,4
Discontinuations due to TEAEs primarily occurred early in the trial and declined over time.5
Management strategies may help patients with certain adverse events1,6
Findings from a management strategy survey6
Soothing fluid intake
- This information is not included in the ARIKAYCE full Prescribing Information
- The data are from a telephone survey of 26 patients prescribed ARIKAYCE conducted during a 2-month period at 2 academic medical centers in the United States
- Writing assistance was provided to the authors through funding from Insmed Incorporated. Insmed was not involved with the conceptualization, development, conduct, or analyses of the survey
Learn about additional management strategies for select respiratory AEs from the survey6| Management strategy | Increased coughing | Dysphonia | Dyspnea | Increased sputum | |------------------------------------------------------------------------------------------------------------------|--------------------|-----------|---------|------------------| | Bronchodilator use | * | | * | | | Changing ARIKAYCE administration to evening | * | * | | | | Brief interruptions of ARIKAYCE | * | * | * | | | Antitussive agents | * | * | | | | Lozenges | * | * | | | | Warm water or glycerin gargle postdosing | * | * | | | | Soothing fluid intake | * | * | | | | Limiting physical activity | | | * | | | Increased supplemental oxygen, if already administering | | | * | | | Airway clearance (eg, specific breathing techniques, chest percussion, and positive expiratory pressure therapy) | | | | * |
Customize management strategies to individual patients according to their specific needs
Use your clinical judgment when evaluating which strategy to use, including temporarily interrupting or discontinuing ARIKAYCE treatment, if necessary. Educating both patients and their extended care team may aid in early recognition and management of respiratory AEs, which could help contribute to a successful treatment outcome.3,6
aIncludes aphonia and dysphonia.
bIncludes cough, productive cough, and upper airway cough syndrome.
cIncludes asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, and wheezing.
dIncludes back pain, arthralgia, myalgia, pain/body aches, muscle spasm, and musculoskeletal pain.
eIncludes oropharyngeal pain, oropharyngeal discomfort, throat irritation, pharyngeal erythema, upper airway inflammation, pharyngeal edema, vocal cord inflammation, laryngeal pain, laryngeal erythema, and laryngitis.
fIncludes deafness, deafness neurosensory, deafness unilateral, dizziness, hypoacusis, presyncope, tinnitus, vertigo, and balance disorders.
gIncludes COPD, infective exacerbation of COPD, and infective exacerbation of bronchiectasis.
hIncludes 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.
iIncludes vomiting and post-tussive vomiting.
jIncludes rash, rash maculo-papular, drug eruption, and urticaria.
kIncludes increased sputum, sputum purulent, and sputum discolored.
lIncludes anxiety and anxiety disorder.
mIncludes oral candidiasis and oral fungal infection.
nIncludes allergic alveolitis, interstitial lung disease, and pneumonitis.
oIncludes acute respiratory failure and respiratory failure.
pIncludes pneumothorax, pneumothorax spontaneous, and pneumomediastinum.
qIncludes muscle weakness and neuropathy peripheral.
WARNING: RISK OF INCREASED RESPIRATORY ADVERSE REACTIONS
ARIKAYCE has been associated with an increased risk of respiratory adverse reactions, including hypersensitivity pneumonitis, hemoptysis, bronchospasm, and exacerbation of underlying pulmonary disease that have led to hospitalizations in some cases.
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 background regimen (3.1%) compared to patients treated with background regimen alone (0%). Most patients with hypersensitivity pneumonitis discontinued treatment with ARIKAYCE and received treatment with corticosteroids. If hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage patients as medically appropriate.
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 background regimen (18.4%) compared to patients treated with background regimen alone (13.4%). If hemoptysis occurs, manage patients as medically appropriate.
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 background regimen (28.7%) compared to patients treated with background regimen alone (10.7%). If bronchospasm occurs during the use of ARIKAYCE, treat patients as medically appropriate.
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 (COPD), infective exacerbation of COPD, infective exacerbation of bronchiectasis) have been reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (15.2%) compared to patients treated with background regimen alone (9.8%). If exacerbations of underlying pulmonary disease occur during the use of ARIKAYCE, treat patients as medically appropriate.
Anaphylaxis and Hypersensitivity Reactions: Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE. 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.
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 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). Closely monitor patients with known or suspected auditory or vestibular dysfunction during treatment with ARIKAYCE. If ototoxicity occurs, manage patients as medically appropriate, including potentially discontinuing ARIKAYCE.
Nephrotoxicity was observed during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than background regimen alone. Nephrotoxicity has been associated with the aminoglycosides. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE.
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.
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.
AE=adverse event; EOT=end of treatment; TEAE=treatment-emergent adverse event.