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ph-1047

Inhaled Antibiotics Duplicate Therapy Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-1047

This program applies to Blue Partner, Commercial, GenPlus, and Health Insurance Marketplace formularies.

POLICY REVIEW CYCLE

Effective Date	Date of Origin
04-01-2024	04-01-2012

FDA APPROVED INDICATIONS AND DOSAGE

Agent(s)	FDA Indication(s)	Notes	Ref#
Bethkis® (tobramycin inhalation solution)* Oral inhalation	Management of cystic fibrosis patients with Pseudomonas aeruginosa Safety and efficacy have not been demonstrated in patients under the age of six years, patients with a forced expiratory volume in one second (FEV1) less than 40% or greater than 80% predicted, or patients colonized with Burkholderia cepacia	* - generic available	1
Cayston^® (aztreonam inhalation solution) Oral inhalation	To improve respiratory symptoms in cystic fibrosis (CF) patients with Pseudomonas aeruginosa Safety and effectiveness have not been established in pediatric patients below the age of 7 years, patients with FEV1 less than 25% or greater than 75% predicted, or patients colonized with Burkholderia cepacia		5
Kitabis^® Pak, Tobramycin Inhalation Solution Pak Oral inhalation	Management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa Safety and efficacy and have been demonstrated in patients under the age of 6 years, patients with FEV1 less than 25% or greater than 75% predicted, or patients colonized with Burkholderia cepacia		3
TOBI® Podhaler^® (tobramycin inhalation powder) Oral inhalation	Management of cystic fibrosis patients with Pseudomonas aeruginosa Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV1 less than 25% or greater than 80%, or patients colonized with Burkholderia cepacia		2
TOBI^® (tobramycin inhalation solution)* Oral inhalation	Management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) less than 25% or greater than 75% predicted, or patients colonized with Burkholderia cepacia	* - generic available	4

See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

Cystic Fibrosis

Cystic fibrosis (CF) is a multi-system disorder caused by mutations in the gene for the CF transmembrane conductance regulator (CFTR), which encodes an ion channel protein in epithelial cells on the airway surface.(6) Defects in the ion channel protein cause abnormal ion transport which alters antimicrobial airway defenses. This impaired host defense results in chronic lower airway bacterial infections, the most common of which are Pseudomonas aeruginosa and Staphylococcus aureus. P. aeruginosa, in particular, is linked to greater airway inflammation and overall decline in health.(9,10) Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF.(6,9)

The approach to treating infection in CF lung disease is multifaceted, involving antibiotics, chest physiotherapy, inhaled medications to promote secretion clearance, and anti-inflammatory agents.(6) It is hypothesized that P. aeruginosa infections initially occur transiently before progressing to chronic infection. Over time, P. aeruginosa adapts to the airway by developing a “mucoid” phenotype that exists within a biofilm, which contributes to the development of chronic, difficult-to-eradicate infection. However, there is evidence that early antibiotic therapy has the potential to clear or “eradicate” initial P. aeruginosa infection and to postpone chronic infection with this organism.(10) Specifically, both inhaled tobramycin and aztreonam are highly effective at eradicating first or very early infection with P. aeruginosa. Success rates are greater than 75%, and this is seen as important progress in treating CF.(6,9,10) The prevalence of chronic P. aeruginosa infection in the United States CF population has steadily decreased over the last several years, with the greatest reductions observed in younger populations where successful eradication strategies may have played a pivotal role.(9) Undoubtedly, improved use of antibiotics is responsible for a substantial portion of the increased survival that has occurred in patients with CF.(6,9) Prophylactic use of antibiotics to prevent P. aeruginosa acquisition is not recommended, as clinical trials of this approach did not show benefit.(6,7,10)

Once P. aeruginosa becomes established in the CF airway, the organisms are difficult to eliminate. Chronic infection is associated with poor growth, more rapid decline in lung function, increased need for antibiotic treatment and hospitalization, and earlier death.(6,10) Eradication remains an important goal, but patients unable to clear P. aeruginosa infection can often be adequately treated for many years with cycled or continuous alternating use of existing antibiotic options.(6,8,9) Chronic treatment with inhaled antibiotics helps to reduce the Pseudomonas bacterial burden and thus lessen its impact. Because most classes of antibiotics that show in vitro activity against P. aeruginosa are ineffective when administered orally, delivery by inhalation presents an attractive alternative since relatively high drug concentrations can be delivered to the site of lung infection with minimal systemic absorption.(6,8) Guidelines for treatment of CF P. aeruginosa infection recommend the use of inhaled tobramycin and inhaled aztreonam.(6,7,9)

Tobramycin is recommended as first-line because of the extensive information supporting its safety and efficacy.(6,7,9,10) Trials have demonstrated that chronic treatment with inhaled tobramycin improves lung function, reduces acute pulmonary exacerbations, and improves quality-of-life outcomes.(1-4,6,9,10) Treatment is routinely administered for 28 days on therapy alternating with 28 days off. Inhaled aztreonam can be used as an alternative to inhaled tobramycin in select patients.(6,7,9,10) Trials have demonstrated that chronic treatment with inhaled aztreonam improves lung function, reduces pulmonary exacerbations, and improves quality-of-life outcomes.(5,6,7,10) Candidates for aztreonam include patients who cannot tolerate tobramycin, patients whose pulmonary status is deteriorating despite tobramycin use, patients who are or are planning to become pregnant, or patients who prefer the use of aztreonam to tobramycin.(6) Treatment is routinely administered for 28 days on therapy alternating with 28 days off.(6)

For patients with deteriorating pulmonary status and/or recurrent pulmonary exacerbations despite cycling between 28 days on and 28 days off of a single inhaled antibiotic, it has become common practice for clinicians to prescribe continuous treatment by alternating between two different antibiotics (e.g., tobramycin and aztreonam), each for a 28-day period. This approach was evaluated in a randomized clinical trial in patients with a wide range of pulmonary function (FEV₁ 25 to 75 percent predicted), in which 28 days of inhaled aztreonam or placebo alternated with 28-day cycles of inhaled tobramycin. The study was terminated early because of inability to meet recruitment targets, in part because many clinicians and patients had already adopted continuously alternating therapy into their treatment regimen. Due to early termination of the study, statistical significance was not reached; however, the study showed 25% reduction in pulmonary exacerbation, 36% reduction in hospitalization for a respiratory event, and median time to first exacerbation was increased. Nonetheless, due to the early termination of the study and lack of statistical significance, there is insufficient evidence for guidelines to support the practice of alternating inhaled antibiotics for all patients with chronic P. aeruginosa infection. Despite this, many experts feel that it is reasonable practice for patients with advanced lung disease or those with frequent pulmonary exacerbations or accelerated decline in pulmonary status.(6,8,9) For individuals with advanced cystic fibrosis lung disease, the Cystic Fibrosis Foundation Consensus Guidelines for the Care of Individuals with Advanced Cystic Fibrosis Lung Disease (2020), recommends a trial of continuous alternating inhaled antibiotics as dictated by bacterial pathogens identified in respiratory cultures.(11)

REFERENCES

Number	Reference
1	Bethkis prescribing information. Chiesi USA, Inc. February 2023.
2	TOBI Podhaler prescribing information. Mylan Pharmaceuticals Inc. February 2023.
3	Kitabis Pak prescribing information. Pari Respiratory Equipment, Inc. August 2023.
4	TOBI prescribing information. Mylan Specialty LP. February 2023.
5	Cayston prescribing information. Gilead Sciences, Inc. November 2019.
6	Simon RH, et al. Cystic Fibrosis: Antibiotic Therapy for Chronic Pulmonary Infection. UpToDate. Last updated September 2023. Literature review current through September 2023.
7	Mogayzel PJ, Naureckas ET, Robinson KA, et al. Cystic Fibrosis Pulmonary Guidelines. Chronic Medications for Maintenance of Lung Health. Am J Respir Crit Care Med. 2013;187(7):680-689.
8	Flume PA, Clancy JP, Retsch-Bogart GZ, et al. Continuous Alternating Inhaled Antibiotics for Chronic Pseudomonal Infection in Cystic Fibrosis. J Cyst Fibros. 2016;15(6):809-815.
9	Nichols DP, Durmowicz AG, Field A, et al. Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities. Ann Am Thorac Soc. 2019;16(5):534-539.
10	Mogayzel PJ, Naureckas ET, Robinson KA, et al. Cystic Fibrosis Foundation Pulmonary Guideline: Pharmacologic Approaches to Prevention and Eradication of Initial Pseudomonas aeruginosa Infection. Ann Am Thorac Soc. 2014;11(10):1640-1650.
11	Cystic Fibrosis Foundation Consensus Guidelines for the Care of Individuals with Advanced Cystic Fibrosis Lung Disease. J Cystic Fibrosis. 2020;19(3):344-354.

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Available MSC	Final Age Limit	Preferred Status

Cayston	aztreonam lysine for inhal soln	75 MG	M ; N ; O ; Y	N
Tobi podhaler	tobramycin inhal cap	28 MG	M ; N ; O ; Y	N
Bethkis	Tobramycin Nebu Soln 300 MG/4ML	300 MG/4ML	M ; N ; O ; Y	O ; Y
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	M	M ; O ; Y
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	M ; N ; O ; Y	M ; O ; Y

POLICY AGENT SUMMARY QUANTITY LIMIT

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	QL Amount	Dose Form	Day Supply	Duration	Addtl QL Info	Allowed Exceptions	Targeted NDCs When Exclusions Exist

Bethkis	Tobramycin Nebu Soln 300 MG/4ML	300 MG/4ML	56	Ampules	56	DAYS
Cayston	aztreonam lysine for inhal soln	75 MG	84	Vials	56
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	56	Ampules	56	DAYS
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	56	Ampules	56	DAYS
Tobi podhaler	tobramycin inhal cap	28 MG	28	Blisters	56	DAYS

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Bethkis	Tobramycin Nebu Soln 300 MG/4ML	300 MG/4ML	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Cayston	aztreonam lysine for inhal soln	75 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Tobi podhaler	tobramycin inhal cap	28 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace

CLIENT SUMMARY – QUANTITY LIMITS

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Bethkis	Tobramycin Nebu Soln 300 MG/4ML	300 MG/4ML	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Cayston	aztreonam lysine for inhal soln	75 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Kitabis pak ; Tobi	Tobramycin Nebu Soln 300 MG/5ML	300 MG/5ML	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace
Tobi podhaler	tobramycin inhal cap	28 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module

Clinical Criteria for Approval

TARGET AGENT(S)

Preferred Inhaled Antibiotic Agent(s):
Generic tobramycin inhalation solution 300 mg/5 mL ampules (neb)

Non-Preferred Inhaled Antibiotic Agent(s):
TOBI Podhaler (tobramycin inhalation powder)

Standalone Inhaled Antibiotic Agent(s):
Bethkis (tobramycin inhalation solution)
Cayston (aztreonam inhalation solution)
Kitabis Pak (tobramycin inhalation solution)
TOBI (tobramycin inhalation solution)

Target Agent(s) will be approved when ALL of the following are met:

The patient has a diagnosis of cystic fibrosis with Pseudomonas aeruginosa respiratory infection AND
ONE of the following:
1. The patient is NOT currently (within the past 60 days) being treated with another inhaled antibiotic (e.g., Arikayce, inhaled aztreonam, inhaled tobramycin) OR
2. The patient is currently (within the past 60 days) being treated with another inhaled antibiotic (e.g., Arikayce, inhaled aztreonam, inhaled tobramycin) AND ONE of the following:
  1. The prescriber has confirmed that the other inhaled antibiotic will be discontinued and that therapy will be continued only with the requested agent OR
  2. The prescriber has provided information in support of another inhaled antibiotic therapy used concurrently with or alternating with (i.e., continuous alternating therapy) the requested agent AND
ONE of the following:

Preferred Inhaled Antibiotic Agent(s)

Generic tobramycin inhalation solution 300 mg/5 mL ampules (neb)

The requested agent is Bethkis, Cayston, Kitabis Pak, or TOBI OR
The requested agent is a preferred inhaled antibiotic agent OR
The patient has tried and had an inadequate response to a preferred inhaled antibiotic agent OR
The patient has an intolerance or hypersensitivity to a preferred inhaled antibiotic agent that is NOT expected to occur with the requested agent OR
The patient has an FDA labeled contraindication to ALL preferred inhaled antibiotic agents that is NOT expected to occur with the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
	Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met: The requested quantity (dose) does NOT exceed the program quantity limit OR ALL of the following: The requested quantity (dose) exceeds the program quantity limit AND The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR ALL of the following: The requested quantity (dose) exceeds the program quantity limit AND The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND The prescriber has provided information in support of therapy with a higher dose for the requested indication Length of Approval: 12 months

Module

Clinical Criteria for Approval

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

The requested quantity (dose) does NOT exceed the program quantity limit OR
ALL of the following:
1. The requested quantity (dose) exceeds the program quantity limit AND
2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
ALL of the following:
1. The requested quantity (dose) exceeds the program quantity limit AND
2. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
3. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval: 12 months

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.