Clinical trial safety

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Most adverse events were respiratory in nature1,2

Patients who reported treatment-emergent adverse events (TEAEs) and serious TEAEs in the CONVERT trial1,2*

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98.2% of patients in the ARIKAYCE (amikacin liposome inhalation suspension) + standard therapy arm reported TEAEs compared with 91.1% of patients in the standard therapy alone arm. 20.2% of patients in the ARIKAYCE + standard therapy arm reported serious TEAEs compared with 16.1% of patients in the standard therapy alone arm.
Footnotes

*Adverse events that occurred from Day 1 to Day 247 (Month 8) were considered TEAEs.3

Serious TEAEs were defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect.4

Adverse reactions in ≥5% of ARIKAYCE-treated MAC patients and more frequent than standard therapy alone in the CONVERT trial1

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In the CONVERT trial, adverse reactions that occurred in 5% or more of patients in the ARIKAYCE (amikacin liposome inhalation suspension) + standard therapy arm (n=223) that were more frequent than in the standard therapy alone arm (n=112) included: dysphonia (47% vs 1%), cough (39% vs 17%), bronchospasm (29% vs 11%), hemoptysis (18% vs 13%), ototoxicity (17% vs 10%), upper airway irritation (17% vs 2%), musculoskeletal pain (17% vs 8%), fatigue and asthenia (16% vs 10%), exacerbation of underlying pulmonary disease (15% vs 10%), diarrhea (13% vs 5%), nausea (12% vs 4%), pneumonia (10% vs 8%), headache (10% vs 5%), pyrexia (7% vs 5%), vomiting (7% vs 4%), rash (6% vs 2%), weight decreased (6% vs 1%), change in sputum (5% vs 1%), and chest discomfort (5% vs 3%).
Footnotes

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.

Dysphonia and cough were the 2 most common adverse reactions in the CONVERT trial.1

Dysphonia

In the CONVERT clinical trial, dysphonia was the most commonly reported adverse reaction in the ARIKAYCE + standard therapy arm (48% ARIKAYCE + standard therapy vs 2% standard therapy alone). In the CONVERT trial, the discontinuation rate due to dysphonia was 2.2%.1,2,4

Cough

Cough is a common symptom of MAC lung disease. In the CONVERT trial, cough was a frequently reported adverse reaction and was more common in the ARIKAYCE + standard therapy arm (40% ARIKAYCE + standard therapy vs 17% standard therapy alone). There was a higher rate of cough AE reporting, particularly in the first month of active treatment with ARIKAYCE. In the CONVERT trial, the discontinuation rate due to cough was 0.9%.1,2,4

Of the patients who experienced cough, most events were episodic and occurred either during or after ARIKAYCE administration. The majority of cough episodes lasted less than 1 minute with most episodes lasting less than 10 minutes.4

Drug holiday icon showing the interruption of ARIKAYCE (amikacin liposome inhalation suspension).

In the CONVERT trial, investigators were permitted to manage local respiratory AEs (such as dysphonia and cough) with temporary interruption of ARIKAYCE. It was recommended in the trial that ARIKAYCE be reintroduced after this short interruption when symptoms subsided.4

Selected adverse reactions in <5% of ARIKAYCE-treated MAC patients and more frequent than standard therapy alone in the CONVERT trial1

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In the CONVERT trial, selected adverse reactions in <5% of patients in the ARIKAYCE (amikacin liposome inhalation suspension) + standard therapy arm (n=223) that occurred more frequently than in the standard therapy alone arm (n=112) included: anxiety (4.5% vs 0%), oral fungal infection (4% vs 1.8%), bronchitis (3.6% vs 2.7%), hypersensitivity pneumonitis (3.6% vs 0%), dysgeusia (3.1% vs 0%), respiratory failure (2.7% vs 0.9%), epistaxis (2.7% vs 0.9%), neuromuscular disorder (2.2% vs 0%), dry mouth (2.2% vs 0%), pneumothorax (2.2% vs 0.9%), exercise tolerance decreased (1.3% vs 0%), and balance disorder (1.3% vs 0%).
Footnotes

aIncludes anxiety and anxiety disorder.

bIncludes oral candidiasis and oral fungal infection.

cIncludes allergic alveolitis, interstitial lung disease, and pneumonitis.

dIncludes acute respiratory failure and respiratory failure.

eIncludes pneumothorax, pneumothorax spontaneous, and pneumomediastinum.

fIncludes muscle weakness and neuropathy peripheral.

ARIKAYCE + standard therapy was associated with hospitalizations and discontinuations1

Hospitalization rates

In the CONVERT trial, there were 80 hospitalizations in 41 patients (18.4%) treated with ARIKAYCE + standard therapy compared to 29 hospitalizations in 15 patients (13.4%) treated with standard therapy alone. The most common serious adverse reactions and reasons for hospitalization in the ARIKAYCE + standard therapy arm were related to exacerbation of underlying pulmonary disease and lower respiratory tract infections, such as pneumonia.1

Discontinuation rates

In the CONVERT trial, there was a higher incidence of premature discontinuation of ARIKAYCE. 34.5% discontinued ARIKAYCE prematurely; most were due to adverse reactions (18.8%) and withdrawal by patient (9.9%). In the comparator arm, 10.7% of patients discontinued their standard therapy, 0.9% due to adverse reactions and 5.4% due to withdrawal by patient.1

Aminoglycoside-related toxicities with ARIKAYCE

Ototoxicity has been reported with the use of ARIKAYCE in the clinical trials. Ototoxicity (including deafness, dizziness, presyncope, tinnitus, and vertigo) was reported with a higher frequency in patients treated with ARIKAYCE + standard therapy (17%) compared to patients treated with standard therapy alone (9.8%). This was primarily driven by tinnitus (8.1% in ARIKAYCE + standard therapy vs 0.9% in the standard therapy alone arm) and dizziness (6.3% in ARIKAYCE + standard therapy vs 2.7% in the standard therapy alone arm).1

In the CONVERT trial, a total of 17 (7.6%) patients experienced 20 events of tinnitus in the ARIKAYCE + standard therapy arm compared to 1 (0.9%) patient in the standard therapy alone arm. Most cases of tinnitus were mild in severity (17/20 events were mild and 3/20 were moderate in severity). The study drug was not interrupted in 13 out of 20 events, was interrupted in 6 out of 20 events, and was withdrawn for 1 event. Of the 20 events, 10 had resolved based on the latest report.2,4

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.1

Nephrotoxicity (including hematuria, proteinuria, and leukocyturia, as well as glomerular filtration rate decreased, blood creatinine increased, blood urine present, urinary casts, and urinary casts present) was observed infrequently during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than the standard therapy alone.1,2,4,5

Nephrotoxicity observed in the CONVERT trial5

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Investigations in the ARIKAYCE (amikacin liposome inhalation suspension) + standard therapy arm (n=223) vs the standard therapy alone arm (n=112) included: overall investigations (1.8% vs 1.8%), glomerular filtration rate decreased (0.4% vs 0.9%), blood creatinine increased (0.4% vs 0%), blood urine present (0.4% vs 0%), urinary casts (0.4% vs 0%), urinary casts present (0% vs 0.9%). Renal and urinary disorders in the ARIKAYCE + standard therapy arm vs the standard therapy alone arm included: overall renal and urinary disorders (1.3% vs 4.5%), hematuria (0.4% vs 1.8%), proteinuria (0.4% vs 1.8%), and leukocyturia (0.4% vs 0.9%).

Nephrotoxicity has been associated with the use of aminoglycosides. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE.1

Important safety considerations

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 + standard therapy (3.1%) compared to patients treated with a standard therapy 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.1

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 + standard therapy (18.4%) compared to patients treated with a standard therapy alone (13.4%). If hemoptysis occurs, manage patients as medically appropriate.1

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 + standard therapy (28.7%) compared to patients treated with a standard therapy alone (10.7%). If bronchospasm occurs during the use of ARIKAYCE, treat patients as medically appropriate.1

Exacerbations of underlying pulmonary disease have been reported with the use of ARIKAYCE in the clinical trials. Exacerbations of underlying pulmonary disease (reported as COPD, infective exacerbation of COPD, infective exacerbation of bronchiectasis) have been reported at a higher frequency in patients treated with ARIKAYCE + standard therapy (15.2%) compared to patients treated with standard therapy alone (9.8%). If exacerbations of underlying pulmonary disease occur during the use of ARIKAYCE, treat the patients as medically appropriate.1

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.1

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.1

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.1

Contraindications: ARIKAYCE is contraindicated in patients with known hypersensitivity to any aminoglycoside.1

Additional safety considerations

Pediatric use

Safety and effectiveness of ARIKAYCE in pediatric patients below 18 years of age have not been established.1

Geriatric use

In the MAC clinical trials, of the total number of patients receiving ARIKAYCE, 208 (51.5%) were ≥65 years and 59 (14.6%) were ≥75 years. No overall differences in safety and effectiveness were observed between elderly patients and younger patients. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.1

Hepatic impairment

ARIKAYCE has not been studied in patients with hepatic impairment. No dose adjustments based on hepatic impairment are required since amikacin is not hepatically metabolized.1

Renal impairment

ARIKAYCE has not been studied in patients with renal impairment. Given the low systemic exposure to amikacin following administration of ARIKAYCE, clinically relevant accumulation of amikacin is unlikely to occur in patients with renal impairment. However, renal function should be monitored in patients with known or suspected renal impairment, including elderly patients with potential age-related decreases in renal function.1

MAC=Mycobacterium avium complex; TEAE=treatment-emergent adverse event.

References

  1. ARIKAYCE [package insert]. Bridgewater, NJ: Insmed Incorporated; 2020.
  2. Griffith DE, Eagle G, Thomson R, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study. Am J Respir Crit Care Med. 2018;198(12):1559-1569.
  3. Center for Drug Evaluation and Research. NDA Multi-Disciplinary Review and Evaluation–NDA 207356. 2018. Accessed October 16, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207356Orig1s000MultidisciplineR.pdf.
  4. Data on file. Insmed Incorporated. Bridgewater, NJ.
  5. Griffith DE, Eagle G, Thomson R, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex. Online data supplement. Am J Respir Crit Care Med. 2018;198(12)(suppl):E1-E28. Accessed October 16, 2020. https://www.atsjournals.org/doi/suppl/10.1164/rccm.201807-1318OC/suppl_file/griffith_data_supplement.pdf.
  6. Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416.