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Home , Fluconazole, Voriconazole

Drug and Biologic Coverage Policy

Effective Date ...... 6/1/2020 Next Review Date… ...... 6/1/2021 Coverage Policy Number ...... 4004

Voriconazole

Table of Contents Related Coverage Resources

Coverage Policy ...... 1 FDA Approved Indications ...... 2 Recommended Dosing ...... 2 General Background ...... 2 Coding/Billing Information ...... 4 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.

Coverage Policy

This coverage policy addresses the use of oral . The use of intravenous voriconazole is not addressed in this coverage policy.

Voriconazole (Vfend®) is considered medically necessary when ANY of the following criteria are met: • and EITHER of the following, o Prophylaxis post transplantation o Treatment of invasive infection • Empiric therapy in febrile neutropenic individuals • Prophylaxis for an individual at high-risk for (for example, allogeneic hematopoietic stem cell transplant [HSCT] recipients, individuals undergoing either intensive remission-induction or salvage-induction chemotherapy for acute leukemia) • Invasive or severe infections (for example, abdomen, bladder wall, candidemia, esophageal, kidney, oropharyngeal, skin) AND, o Documented failure or contraindication per FDA label, intolerance to, or not a candidate for • Meningoencephalitis or pulmonary disease caused by AND, o Documented failure or contraindication per FDA label, intolerance to, or not a candidate for fluconazole • Fungal infection caused by Scedosporium apiospermum and Fusarium spp.

Page 1 of 5 Coverage Policy Number: 4004 • CNS • AND, o Documented failure or contraindication per FDA label, intolerance to, or not a candidate for fluconazole or • AND, o Documented failure or contraindication per FDA label, intolerance to, or not a candidate for itraconazole • Prophylaxis or treatment of a systemic fungal infection in HIV-infected individuals

Voriconazole is considered medically necessary for continued use when the individual continues to meet the initial criteria.

Initial and reauthorization is up to 12 months unless otherwise stated.

Voriconazole is considered experimental, investigational, or unproven for any other use.

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.

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

FDA Approved Indications

FDA Approved Indication Vfend is an indicated for the treatment of adults and pediatric patients 2 years of age and older with: • Invasive aspergillosis • Candidemia in non-neutropenics and other deep tissue Candida infections • Esophageal • Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy

Recommended Dosing

FDA Recommended Dosing Vfend tablets or oral suspension should be taken at least one hour before or after a meal. See full prescribing information for instructions on oral administration of Vfend in adults and pediatric individuals 2 years of age and older.

Drug Availability Tablets Supplied as 50 mg and 200 mg tablets in bottles of 30. Generic formulations of voriconazole tablets are also available.

Powder for Oral Suspension Supplied as 45 g of powder for oral suspension in a bottle providing a usable volume of 70 mL.

General Background

Pharmacology Voriconazole is a broad-spectrum antifungal which inhibits fungal mediated 14 alpha- demethylation and disrupts the synthesis of , resulting in abnormal fungal cell membrane.

Page 2 of 5 Coverage Policy Number: 4004 Professional Societies/Organizations Infectious Diseases Society of America (IDSA) Aspergillosis Early initiation of antifungal therapy in individuals with strongly suspected invasive aspergillosis is warranted while a diagnostic evaluation is conducted. Because of better survival and improved responses of initial therapy with voriconazole, primary therapy with deoxycholate (D-AMB) is not recommended. For primary treatment of invasive pulmonary aspergillosis, IV or oral voriconazole is recommended for most individuals. Oral therapy can be maximized by using a dose of 4 mg/kg rounded up to convenient sizes. For seriously ill individuals, the parenteral formulation is recommended. (IDSA, 2016)

Candidiasis For , fluconazole is the treatment of choice for esophageal candidiasis. For fluconazole- refractory disease, itraconazole, or voriconazole may be administered. and itraconazole capsules are less effective than fluconazole because of variable absorption. Voriconazole is as effective as fluconazole and has also useful in treating mucosal candidiasis refractory to fluconazole.

For oropharyngeal candidiasis, fluconazole is the treatment of choice. For fluconazole refractory disease, itraconazole or posaconazole may be administered. Voriconazole may be considered as third-line therapy when treatment with other agents has failed.

For candidemia in the non-neutropenic setting, intravenous voriconazole is effective for candidemia, but offers little advantage over intravenous fluconazole as initial therapy. Voriconazole is recommended as step-down oral therapy for selected cases of candidemia due to . In neutropenic individuals, intravenous voriconazole can be used in situations in which additional mold coverage is desired. Voriconazole can also be used as step-down therapy during neutropenia in clinically stable individuals who have had documented bloodstream clearance and isolates that are susceptible to voriconazole. (IDSA, 2016)

Coccidioidomycosis Fluconazole and itraconazole are considered first line therapies, while voriconazole is reserved for treatment failures. More severe disease (for example, severe osseous infections) requires intravenous amphotericin B with subsequent transition to long term azole therapy. (IDSA, 2016)

Histoplasmosis Voriconazole has been used in a limited number of individuals with various forms of histoplasmosis and is considered a second-line alternative to itraconazole. (IDSA, 2007)

Neutropenia Antifungal therapy is appropriate in neutropenic individuals who have persistent unexplained fever, despite receipt of 4–7 days of broad-spectrum antibacterial therapy. The choice of antifungal agent is based on likely fungal (e.g., if individual was on antifungal prophylaxis), toxicities, and cost. Amphotericin B has been the standard empirical antifungal agent used for decades with recent trials evaluating potential alternatives.

A randomized trial in individuals with neutropenia and persistent fever did not demonstrate that voriconazole was non-inferior to liposomal amphotericin B as empiric antifungal therapy. However the authors noted that voriconazole was superior to amphotericin B in reducing documented breakthrough fungal infections, infusion- related toxicity, and nephrotoxicity and was similar in individual elements of the composite score. (Walsh, 2002)

National Comprehensive Cancer Network (NCCN) The NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections (version 1.2020) note voriconazole as an option for prophylactic use against fungal infections in patients at risk of neutropenia (for example, individuals with cancer; individuals with graft-versus-host disease [GVHD]; hematopoietic cell transplant [HCT] recipients). (NCCN, 2019)

U.S. Department of Health and Human Services (DHHS) (2016, 2017, 2019) Coccidioidomycosis

Page 3 of 5 Coverage Policy Number: 4004 For HIV-infected adults and adolescents with coccidioidomycosis, voriconazole is an alternative for individuals who failed to respond to fluconazole and itraconazole for the treatment of mild infections (such as focal pneumonia). It is also an alternative to fluconazole for the treatment of meningeal infections. Primary prophylaxis in individuals with low CD4 cell counts, living in areas where Coccidioides is prevalent, is not recommended. (DHHS, 2016)

Esophageal Candidiasis Voriconazole is an alternative therapy for HIV-infected adults and adolescents with esophageal candidiasis. Fluconazole is the preferred therapy. In pediatric individuals, voriconazole is an alternative for fluconazole- refractory esophageal disease. (DHHS, 2017)

Histoplasmosis Voriconazole is listed as an alternative therapy for HIV-infected adults and adolescents with less severe disseminated histoplasmosis who are intolerant to the preferred therapy, itraconazole and are only moderately ill. (DHHS, 2019)

The American Board of Internal Medicine’s (ABIM) Foundation Choosing Wisely® Initiative: No recommendations are available for prophylaxis or treatment of invasive or serious fungal infections.

Centers for Medicare & Medicaid Services - National Coverage Determinations (NCDs) There are no CMS National Coverage Determinations for either prophylaxis or treatment of invasive or serious fungal infections, or for voriconazole.

Off Label Uses The American Hospital Formulary Service (AHFS) Drug Information 2020 Edition supports the following off-label uses: oropharyngeal candidiasis, esophageal candidiasis, coccidiomycosis, Exserohilum infections, Fusarium and Scedosporium infections, histoplasmosis, penicilliosis, and empiric therapy in febrile neutropenic individuals.

Coding/Billing Information

Note: Voriconazole is typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use.

References

1. Clinical Practice Guidelines for the Management of Candidiasis: 2009. Update by the Infectious Diseases Society of America (IDSA). Clinical Infectious Diseases 2009; 48: 503–535. 2. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases® 2016; 62(4): e1–50. 3. Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases 2007; 45: 807–25. 4. Kontoyiannis DP. A clinical perspective for the management of invasive fungal infections: focus on IDSA guidelines. Infectious Diseases Society of America. Pharmacotherapy 2001; 21: 175S-187S. 5. McEvoy GK, ed. 2020. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2020. 6. The NCCN Prevention and Treatment of Cancer-Related Infections Clinical Practice Guidelines in Oncology (version 1.2020 – December 17, 2019). ©2020 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed March 20, 2020. 7. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/ oi_guidelines_pediatrics.pdf.

Page 4 of 5 Coverage Policy Number: 4004 8. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 20, 2020. 9. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America (IDSA) (2008). Clinical Infectious Disease. (2008) 46 (3): 327-360. 10. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America (IDSA) (2008). Clinical Infectious Disease. (2016) 63: 112-146. 11. Vfend® (voriconazole) [prescribing information]. , Inc., New York, NY: January 2019. 12. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: 225-34.

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