Amikacin Liposome

Pharmacy Benefit Coverage Criteria

Effective Date ...... 12/1/2020 Next Review Date… ...... 12/1/2021 Coverage Policy Number ...... P0093

Amikacin Liposome

Table of Contents Related Coverage Resources

Medical Necessity Criteria ...... 1 FDA Approved Indications ...... 2 Recommended Dosing ...... 2 Background ...... 3 References ...... 4

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Medical Necessity Criteria

Amikacin liposome (Arikayce®) is considered medically necessary when ONE of the following criteria are met: I. Diagnosis of Mycobacterium avium Complex (MAC) Lung Disease and ALL of the following criteria: • Individual is 18 years of age or older • Treatment of Mycobacterium avium complex (MAC) lung disease • In combination with an antibacterial drug regimen • Documented failure/inadequate response (that is, individual does not achieve negative sputum cultures) after at least 6 consecutive months of a multidrug background regimen (for example, a three-drug regimen containing a macrolide, a rifamycin, and ethambutol) • Prescribed by or in consultation with a pulmonologist, infectious diseases physician or a physician who specializes in the treatment of Mycobacterium avium complex lung infections

II. Diagnosis of Cystic Fibrosis and ALL of the following criteria: • Individual has Pseudomonas aeruginosa in culture of the airway (for example, sputum culture, oropharyngeal culture, bronchoalveolar lavage culture) • Prescribed by or in consultation with a pulmonologist, infectious disease physician or a prescriber who specializes in the treatment of cystic fibrosis

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Initial and reauthorization is up to 12 months.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Amikacin liposome is considered experimental, investigational or unproven for ANY other use.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

FDA Approved Indications

FDA Approved Indication 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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.

Recommended Dosing

FDA Recommended Dosing 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.

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.

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.

Page 2 of 4 Pharmacy Benefit Clinical Criteria: P0093 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.

Drug Availability Supplied as liposome suspension for oral inhalation in a unit-dose vial containing amikacin 590 mg/8.4 mL (equivalent to amikacin sulfate 623 mg/8.4 mL).

Background

Professional Societies/Organizations Treatment recommendations for Mycobacterium avium complex (MAC) lung disease are based on disease severity and previous therapies received and almost all are three drug regimens. (Griffith, 2007) For those with nodular/bronchiectatic disease or with fibrocavitary disease who cannot tolerate daily treatment, a three times weekly (TIW), three-drug regimen is recommended. The TIW regimen consists of azithromycin 500 to 600 mg or clarithromycin 1,000 mg, ethambutol 25 mg/kg, and rifampin 600 mg. For select individuals with nodular/bronchiectatic disease (mild disease, medication intolerance, or goal of therapy is disease suppression), a two drug regimen consisting of azithromycin or clarithromycin plus ethambutol daily is acceptable. For individuals with fibrocavitary disease or severe nodular/bronchiectatic disease, daily administration of azithromycin 250 to 300 mg or clarithromycin 500 to 1,000 mg, ethambutol 15 mg/kg, and rifampin 600 mg is recommended. Treatment recommendations for individuals with severe or previously treated disease include azithromycin 250 to 300 mg or clarithromycin 500 to 1,000 mg, ethambutol 15 mg/kg, and rifabutin 150 to 300 mg or rifampin 600 mg daily. Intermittent IV amikacin or streptomycin are recommended for the first 2 to 3 months in individuals with cavitary disease, or previous treatment failure. Individuals should be treated for 12 months beyond the time that the sputum cultures convert to negative. For most individuals conversion occurs within 6 months of initiation of treatment.

According to the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA) statement on the Diagnosis, Treatment and Prevention of Nontuberculous Mycobacterial Disease (2007 version), the role of inhaled antibiotics such as amikacin has not been established. (Griffith, 2007) The guidelines do not mention liposomal amikacin.

The US Cystic Fibrosis Foundation and the European Cystic Fibrosis Society (2016 version) developed consensus recommendations on the treatment of NTM lung disease in which nebulized amikacin is listed as a treatment option for MAC and M. abscessus lung disease in individuals with cystic fibrosis. (Floto, 2016) The guidelines recommend that inhaled amikacin be used in conjunction with other NTM antibiotics.

Off Label Uses Cystic Fibrosis The efficacy of Arikayce in the treatment of Pseudomonas aeruginosa infection in CF patients has been assessed in three studies. (Bilton, 2019) In a Phase III, randomized, open-label, non-inferiority study, 302 patients with CF were randomized to Arikayce 590 mg once daily (QD) or tobramycin inhalation solution (TIS) 300 mg twice daily. Patients received three cycles of treatment which consisted of 28 days on treatment followed by 28 days off treatment. The primary endpoint of the study was the relative change from baseline to the end of the 24-week study in forced expiratory volume in 1 second (FEV1). Secondary endpoints included change in FEV1 and forced expiratory volume % (FEV1 %) predicted at various time points, change in CF Questionnaire-Revised (CFQ-R), time to first exacerbation, change in log10 colony-forming units (CFU), and all-cause hospitalization. The improvement in least squares mean FEV1 at Day 168 was similar between Arikayce and TIS (1.56% and 2.87%, respectively, P = 0.48). The mean difference was -1.31% (95% confidence interval [CI]: -4.95, 2.34) meeting the prespecified criteria for non-inferiority (lower bound of the 95% CI ≥ -5.0%). Change in FEV1 at the end of each treatment course (Day 28, 84, and 140) and change in FEV1 % predicted at the midpoint of cycle 1 (Day 14) and at the end of each treatment course were similar between treatment groups. More patients receiving Arikayce experienced pulmonary exacerbations compared with TIS (63.5% vs. 51.4%, respectively, P = 0.02); however, fewer patients required all-cause hospitalization (16.2% vs. 19.9%). Change in CFQ-R was similar between groups

Page 3 of 4 Pharmacy Benefit Clinical Criteria: P0093 at the end of each treatment course. Mean reductions in P. aeruginosa log10 CFU was similar for Arikayce and TIS at Day 28 (1.2 and 1.7) and at Day 140 (1.5 and 1.6).

A pooled report included 24 patients from two Phase Ib/IIa pharmacokinetic/pharmacodynamic studies with chronic P. aeruginosa infection. (Okusanya, 2009) Patients received liposomal amikacin 500 mg QD by inhalation for 14 days. Statistically significant changes from baseline to Days 7 and 14 were seen in FEV1, FEV1 % predicted, and forced expiratory flow between 25% and 75% of forced vital capacity. Another report included pooled data from two dose-ranging studies (one Phase Ib/IIa and one Phase IIa) in patients with CF (n = 105) chronically infected with P. aeruginosa. (Okusanya, 2009) Patients received 70, 140, 280 or 560 of liposomal amikacin or placebo QD for 28 days and followed for an additional 28 days. In repeated-measures mixed-effect models, the 560 mg dose was associated with statistically significant improvements in FEV1, and FEV1 % predicted and a reduction in log10 CFUs.

References

1. Arikayce [prescribing information], Bridgewater, NJ: Insmed; September 2018. 2. Bilton D, Pressler T, Fajac I, et al. Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis. J Cyst Fibros. 2019; doi: 10.1016/j.jcf.2019.08.001. [Epub ahead of print]. 3. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am J Respir Crit Care Med. 2007;175:367-416. 4. Floto RA, Olivier KN, Saiman L, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 2016;7:i1-i22. 5. Okusanya OO, Bhavnani SM, Hammel J, et al. Pharmacokinetic and Pharmacodynamic Evaluation of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infection. Antimicrob Agents Chemother. 2009;53:3847-3854. 6. Okusanya OO, Bhavnani SM, Hammel JP, et al. Evaluation of the Pharmacokinetics and Pharmacodynamics of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infections Using Data from Two Phase 2 Clinical Studies. Antimicrob Agents Chemother. 2014;58:5005-5015. 7. Okusanya OO, Bhavnani SM, Hammel J, et al. Pharmacokinetic and Pharmacodynamic Evaluation of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infection. Antimicrob Agents Chemother. 2009;53:3847-3854.

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