ARIKAYCE Inhalation suspension Ref.[27464] Active ingredients: Amikacin

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. 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 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.

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)].

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)]

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:

^* Includes aphonia and dysphonia
^† Includes cough, productive cough, and upper airway cough syndrome
^‡ Includes asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, and wheezing
^§ Includes back pain, arthralgia, myalgia, pain/body aches, muscle spasm and musculoskeletal pain
^¶ Includes oropharyngeal pain, oropharyngeal discomfort, throat irritation, pharyngeal erythema, upper airway inflammation, pharyngeal edema, vocal cord inflammation, laryngeal pain, laryngeal erythema, laryngitis
^# Includes deafness, deafness neurosensory, deafness unilateral, dizziness, hypoacusis, presyncope, tinnitus, vertigo, balance disorders
^Þ Includes COPD, infective exacerbation of COPD, infective exacerbation of bronchiectasis
^ß 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
^à Includes vomiting and post-tussive vomiting
^è Includes rash, rash maculo-papular, drug eruption, and urticaria
^ð Includes increased sputum, sputum purulent, and sputum discolored

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:

^* Includes anxiety and anxiety disorder
^† Includes oral candidiasis and oral fungal infection
^‡ Includes allergic alveolitis, interstitial lung disease, and pneumonitis
^§ Includes acute respiratory failure and respiratory failure
^¶ Includes pneumothorax, pneumothorax spontaneous and pneumomediastinum
^# Includes muscle weakness and neuropathy peripheral

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)].

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.

Immune System Disorders: hypersensitivity, anaphylaxis [see Warnings and Precautions (5.5)]

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.

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.

Risk Summary

There is no information regarding the presence of ARIKAYCE in human milk, the effects on the breastfed infant, or the effects on milk production after administration of ARIKAYCE by inhalation. Although limited published data on other routes of administration of amikacin indicate that amikacin is present in human milk, systemic absorption of ARIKAYCE following inhaled administration is expected to be low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARIKAYCE and any potential adverse effects on the breastfed child from ARIKAYCE or from the underlying maternal condition.

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

In the NTM 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 subjects and younger subjects. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see Warnings and Precautions (5.7)].

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 [see Warnings and Precautions (5.7), Use in Specific Populations (8.5)].

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 [see Clinical Pharmacology (12.3)].