TOBI, Tobramycin KITABIS PAK, Tobramycin BETHKIS, Tobramycin TOBI PODHALER, Tobramycin Form

Tobramycin (Bethkis®, Kitabis™ Pak, TOBI®, TOBI® Podhaler™) is an aminoglycoside antibacterial drug. ____ *For Health Insurance Marketplace (HIM), Bethkis, brand Kitabis Pak, brand TOBI, and TOBI Podhaler are non- formulary and should not be approved using these criteria; refer to the formulary exception policy, HIM.PA.103.
FDA Approved Indication(s) Bethkis, Kitabis Pak, TOBI, and TOBI Podhaler are indicated for the management of cystic fibrosis (CF) in patients with Pseudomonas aeruginosa. Kitabis Pak and TOBI are specifically indicated for patients 6 years of age and older. Limitation(s) of use: Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients colonized with Burkholderia cepacia, or patients with forced expiratory volume in one second (FEV1): • < 25% or > 75% predicted for Kitabis Pak and TOBI • < 25% or > 80% predicted for TOBI Podhaler • < 40% or > 80% predicted for Bethkis Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Bethkis, Kitabis Pak, TOBI, and TOBI Podhaler are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Cystic Fibrosis (must meet all):

1. Diagnosis of CF;
   2. Prescribed by or in consultation with a pulmonologist, an infection disease specialist, or an expert in treatment of cystic fibrosis;

2. Age ≥ 6 years;

   4. Pseudomonas aeruginosa is present in at least one airway culture;
   5. If request is for Bethkis, Kitabis Pak, or TOBI, member must use generic tobramycin nebulized solution, unless contraindicated or clinically significant adverse effects are experienced; Page 1 of 8

   CLINICAL POLICY Tobramycin

3. If tobramycin is prescribed concurrently (or for alternating use) with Cayston®, documentation supports inadequate response to either agent alone (e.g., deteriorating pulmonary status, recurrent pulmonary exacerbations);
4. Dose does not exceed one of the following (a or b): a. Inhalation solution (Bethkis, Kitabis Pak, TOBI): 600 mg per day administered on a 28 days on/28 days off cycle;
   b. Inhalation powder (TOBI Podhaler): 224 mg per day administered on a 28 days on/28 days off cycle. Approval duration:
   Medicaid – 6 months HIM – 6 months for tobramycin nebulized solution (refer to HIM.PA.103 for Bethkis, brand Kitabis Pak, brand TOBI, and TOBI Podhaler) Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):
5. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
6. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Cystic Fibrosis (must meet all):
7. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);

8. Member is responding positively to therapy as evidenced by reduction in respiratory symptoms (e.g., cough, wheezing, sputum production, or pulmonary exacerbations due to Pseudomonas aeruginosa); Page 2 of 8

   CLINICAL POLICY Tobramycin

9. If request is for Bethkis, Kitabis Pak, or TOBI, member must use generic tobramycin nebulized solution, unless contraindicated or clinically significant adverse effects are experienced;
10. If tobramycin is prescribed concurrently (or for alternating use) with Cayston, documentation supports inadequate response to either agent alone (e.g., deteriorating pulmonary status, recurrent pulmonary exacerbations);
11. If request is for a dose increase, new dose does not exceed one of the following (a or b):
    a. Inhalation solution (Bethkis, Kitabis Pak, TOBI): 600 mg per day administered on a 28 days on/28 days off cycle;
    b. Inhalation powder (TOBI Podhaler): 224 mg per day administered on a 28 days on/28 days off cycle. Approval duration:
    Medicaid – 12 months HIM – 12 months for tobramycin nebulized solution (refer to HIM.PA.103 for Bethkis, brand Kitabis Pak, brand TOBI, and TOBI Podhaler) Commercial – 12 months or duration of request, whichever is less
    B. Other diagnoses/indications (must meet 1 or 2):
12. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

13. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key CF: cystic fibrosis Page 3 of 8

    CLINICAL POLICY Tobramycin FDA: Food and Drug Administration FEV1: forced expiratory volume in one second Appendix B: Therapeutic Alternatives
    Not applicable Appendix C: Contraindications/Boxed Warnings • Contraindication(s): known hypersensitivity to any aminoglycoside • Boxed warning(s): none reported Appendix D: General Information • Tobramycin is recommended for chronic use in both mild and moderate-to-severe disease per the American Thoracic Society 2013 CF guidelines. Severity of lung disease is defined by FEV1 predicted as follows: normal, > 90% predicted; mildly impaired, 70- 89% predicted; moderately impaired, 40-69% predicted; and severely impaired, < 40% predicted. • The use of continuous alternating therapy (i.e., alternating different inhaled antibiotics in order to provide continuous therapy) lacks sufficient evidence. The efficacy of this practice was evaluated in a randomized, double-blind, phase 3 trial. A total of 90 patients received 28-days inhaled tobramycin alternating with either 28-days inhaled aztreonam or placebo. Although the study found reduced exacerbation and respiratory hospitalization rates with the alternating tobramycin/aztreonam regimen compared to tobramycin/placebo, it was underpowered, and these results were not statistically significant.
    V. Dosage and Administration
    Drug Name Tobramycin inhalation solution (Bethkis, Kitabis Pak, TOBI) Tobramycin inhalation powder (TOBI Podhaler) Dosing Regimen 300 mg inhaled BID for 28 days (followed by 28 days off tobramycin therapy) 112 mg (4 capsules) inhaled BID for 28 days (followed by 28 days off tobramycin therapy) Maximum Dose 600 mg/day 224 mg/day VI. Product Availability
    Drug Name Tobramycin inhalation solution (Bethkis) Tobramycin inhalation solution (Kitabis Pak) Availability 4 mL single-dose ampule: 300 mg 5 mL single-dose ampule: 300 mg Co-packaged with a PARI LC PLUS Reusable Nebulizer 5 mL single-dose ampule: 300 mg Tobramycin inhalation solution (TOBI) Tobramycin inhalation powder (TOBI Podhaler) Capsule: 28 mg Page 4 of 8

    CLINICAL POLICY Tobramycin VII. References

    1. Bethkis Prescribing Information. Woodstock, IL: Catalent Pharm Solutions, LLC; December
14. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/201820s005lbl.pdf. Accessed October 7, 20202.
15. Kitabis Pak Prescribing Information. Woodstock, IL: Catalent Pharm Solutions, LLC; December 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/205433s005lbl.pdf. Accessed October 22, 2021.
16. TOBI Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/050753s022lbl.pdf. Accessed October 22, 2021.
17. TOBI Podhaler Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; July 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/201688s010lbl.pdf. Accessed October 22, 2021.
18. 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. April 1, 2013; 187 (7): 680-689.
19. Flume PA, Clancy JP, Retsch-Bogart GZ, et al. Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis. J Cyst Fibrosis. 2016; 15(6): 809-815.

20. Kapnadak SG, Dimango E, Hadjiliadis D, et al. Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease. J Cyst Fibros 2020 May;19(3):344-354. doi: 10.1016/j.jcf.2020.02.015.

    8. Cystic Fibrosis Foundation: Clinical Care Guidelines. Available at: https://www.cff.org/medical-professionals/clinical-care-guidelines. Accessed October 7,
    9. Coding Implications Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to- date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services. HCPCS Codes
       J7682 J7685

    Tobramycin, inhalation solution, FDA-approved final product, noncompounded, unit dose form, administered through DME, per 300 mg Tobramycin, inhalation solution, compounded product, administered through DME, unit dose form, per 300 mg Page 5 of 8

    CLINICAL POLICY Tobramycin Reviews, Revisions, and Approvals 1Q18 annual review:

    • Policies combined for Centene Medicaid and Commercial lines of business.
    • Medicaid: Removed baseline FEV requirement.
    • Commercial: Added initial requirement for no concurrent/alternating use with aztreonam.
    • Both: Added allowance for concurrent/alternating use with aztreonam pending supportive documentation of inadequate response to either agent alone.
    • Added Appendix C: General Information
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