Antifungal Agents - Cresemba (isavuconazonium), Noxafil (posaconazole), Vfend (voriconazole) Prior Authorization Program Summary FDA APPROVED INDICATIONS DOSAGE 1,2,14 Drug FDA Indication(s) Dosing Cresemba (isavuconazonium) capsules, injection Noxafil (posaconazole) oral suspension Noxafil (posaconazole) delayed-release tablet, injection Vfend (voriconazole) tablets a, oral suspension a, injection a a available as generic Treatment of invasive aspergillosis and invasive mucormycosis Prophylaxis against invasive aspergillosis or candida in patients at high risk Treatment of oropharyngeal candidiasis refractory to itraconazole or fluconazole Prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised Treatment of invasive aspergillosis, candidemia, esophageal candidiasis, serious fungal infections caused by Scedosporium and Fusarium Loading Dose - 372 mg every 8 hours for 6 doses. Maintenance Dose - 372 mg once daily starting 12-24 hours after the last loading dose. Prophylaxis against invasive aspergillosis or candida Suspension - 200 mg 3 times daily Tablets, Injection - 300 mg twice daily first day, then 300 mg once a day Oropharyngeal candidiasis, non refractory - 100 mg twice on day one then 100 mg daily Refractory oropharyngeal candidiasis - 400 mg twice daily Loading dose - 300 mg IV/delayedrelease tablet twice a day on the first day. Maintenance dose - 300 mg IV/delayed release tablet once a day thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression. 200 mg every 12 hours for all indications CLINICAL RATIONALE Isavuconazonium is not included in guidelines as it was approved after guidelines publication. Esophageal candidiasis and candidemia 3,7 Infectious Diseases Society of America (IDSA) guidelines recommend oral fluconazole as the first line therapy for candidemia in nonneutropenic patients and for esophageal candidiasis. 3 Fluconazole is also recommended for prophylaxis against esophageal candidiasis in at risk patients. 3 For patients with fluconazole-refractory disease, guidelines recommend itraconazole or voriconazole. 7 Up to 80% of patients with fluconazole refractory esophageal candidiasis will respond to itraconazole. Voriconazole has demonstrated effectiveness for both mucosal and Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 1 of 8
invasive candidiasis. Its clinical use has been primarily for step-down oral therapy in patients with infection due to C. krusei and fluconazole-resistant, voriconazole-susceptible C. glabrata. 3 Aspergillus and rare fungal infections 4,7,11-13 IDSA guidelines recommend posaconazole for prophylaxis against aspergillus in hematopoietic stem cell transplant (HSCT) recipients with graft versus host disease (GVHD) at high risk, acute myeloid leukemia (AML), or myelodysplastic syndrome at high risk. IDSA guidelines recommend voriconazole for treatment of invasive aspergillosis in most patients, with posaconazole a possible second line therapy. IDSA has not published guidelines for treatment of the rare fungal infections scedosporiosis or zygomycosis (mucormycosis). Voriconazole demonstrated superiority compared to amphotericin B in the treatment of invasive aspergillosis. Infectious diseases guidelines indicate voriconazole as a first line agent for the treatment of invasive aspergillosis, fusariosis, and scedosporiosis, but currently do not list it as an alternative for zygomycosis. Posaconazole is an alternative for the treatment of invasive aspergillosis, scedosporiosis, and zygomycosis. Many of these fungal infections are lifethreatening with high mortality rates. Isavuconazonium for the treatment of aspergillus or other filamentous fungi was studied in a randomized, double-blind, non-inferiority active controlled trial which evaluated the safety and efficacy of isavuconazonium (N=258) versus voriconazole (N=258) in patients. All-cause mortality through Day 42 in the overall population (ITT) was 18.6% in the isavuconazonium treatment group and 20.2% in the voriconazole treatment group for an adjusted treatment difference of -1.0% with 95% confidence interval of -8.0% to 5.9%. Similar results were seen in patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology. Overall success at End-of-Treatment (EOT) was assessed by a blinded, independent Data Review Committee (DRC) using pre-specified clinical, mycological, and radiological criteria. In the subgroup of patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology, overall success at EOT was seen in 35% of isavuconazoniumtreated patients compared to 38.9% of voriconazole-treated patients. Invasive mucormycosis is a serious and rare disease in which active controlled clinical trials are not feasible. 19 The only antifungal drug approved for this indication is amphotericin B, which can be associated with several adverse events and also has limitations with regard to use in patients with renal impairment. 19 Epidemiological reports have found a high mortality rate in patients with mucormycosis who did not receive treatment. 16-18 Isavuconazonium was studied in the treatment of mucormycosis open-label non-comparative trial, evaluated the safety and efficacy of a subset of patients with invasive mucormycosis. All cause mortality through day 42 for pimary treatment, treatment refractory to, or patients intolerant to other antifungal therapy were 7 (33%), 5 (46%), and 2 (40%) respectively. The overall success rate at endof-treatment for primary treatment, treatment refractory to, or patients intolerant of other antifungal therapy were 6 (32%), 4 (36%), and 1 (20%) respectively. 14 Isavuconazonium is contraindicated in those with hypersensitivity to isavuconazonium; coadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir; coadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John s wort, or long acting barbiturates; use in patients with familial short QT syndrome. 14 The ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis strongly recommend diagnosis of mucormycosis using direct microscopy, histopathology, and culture are strongly recommended. Imaging is strongly recommended to determine the extent of the disease. The use of galactomannan detection is moderately supported for the diagnosis of invasive mucormycosis. For adults and children, surgical debridement in addition to immediate first-lineantifungal treatment with liposomal or lipidcomplex amphotericin B is strongly recommended. For salvage treatment, we strongly recommend posaconazole. Reversal of predisposing condition is strongly recommended. Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 2 of 8
Continued treatment is strongly recommended until a complete response is demonstrated on imaging and permanent reversal of predisposing factors. 15 Blastomycosis and histoplasmosis 5-7 Itraconazole is the recommended therapy for the treatment of chronic cavity pulmonary histoplasmosis. Other forms of histoplasmosis are generally treated with amphotericin B. IDSA guidelines recommend itraconazole as the first line oral agent for the treatment of mild to moderate blastomycosis. Itraconazole is also recommended in patients as a step down from amphotericin B for more severe cases of blastomycosis. Fluconazole and voriconazole are considered alternatives for the treatment of blastomycosis. Solid Organ Transplant Patients Solid organ transplant patients, especially those with liver, pancreas, lung, or heart-lung transplants, may be at risk for fungal infections. The most common infecting fungal organisms are Candida and Aspergillus. 8 Since prophylactic drug therapy may be associated with toxicity and resistance, guidelines recommend that it be targeted to patients at highest risk of morbidity and mortality. 8,9 Factors that may place a patient at high risk of a fungal infection include: primary allograft dysfunction, nonfunction, or retransplantation; prolonged operative duration; high intra-operative blood product requirement and bleeding complications; pretransplant immunosuppression; pre-operative CMV infection; prolonged ICU requirement or mechanical ventilation; prolonged use of broad-spectrum antibacterial therapy; renal failure; fungal colonization, unrecognized recipient fungal infection, or donor fungemia or positive fungal cultures; gastrointestinal translocation or transplantation of a colonic segment. 8,9 The 2004 guidelines from the American Society of Transplantation recommend amphotericin B, itraconazole and/or fluconazole, depending on the specific situation. 8 Due to development of increased resistance to itraconazole and fluconazole, posaconazole and voriconazole have been studied as prophylactic therapy in solid organ transplant patients and may be recommended by some clinicians. 7,9 Hematopoietic Stem Cell Transplant (HSCT) Recipients Patients undergoing hematopoietic stem cell transplants are at an increased risk of infection with infection being the primary cause of death in 8% of autologous HSCT patients and 17%- 20% of allogeneic HCT recipients. 10 Risk factors for fungal infection in this population includes mucositis, neutropenia, and GVHD. 10 Additionally, allogeneic transplant recipients are at a significantly higher risk for fungal infection than those receiving autologous marrow stem cells. Guidelines recommend fluconazole as the drug of choice for the prophylaxis of invasive candidiasis though there is increasing resistance to fluconazole. 10 The IDSA guidelines for treatment of Aspergillosis, published in 2008, recommend posaconazole for antifungal prophylaxis in HSCT recipients with GVHD at high risk of infection. Itraconazole may be an alternative but its utility is limited by tolerability issues. 4 Voriconazole has demonstrated efficacy in secondary prophylaxis of invasive aspergillosis. 4,10 For additional clinical information see the Prime Therapeutics Formulary Chapter 1.9A: Antifungal Agents, Imidazole and Triazole Agents. REFERENCES 1. Vfend prescribing information. Pfizer. Februrary 2015. 2. Noxafil prescribing information. Schering. November 2015. 3. Clin Infect Dis 2016; accessed in April 2016 at: http://cid.oxfordjournals.org/content/early/2015/12/15/cid.civ933.full.pdf+html 4. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327-360. Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 3 of 8
5. Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Disease Society of America. Clin Infec Dis. 2009;48:503-535. 6. Wheat LJ, Freifeld AG, Lkeiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45:807-25. 7. Antifungal Drugs. Medical Letter Treatment Guidelines. 2009;7(88):95-102. 8. Fungal infections. Am J Transplant. 2004;4(Suppl 10):110-134. 9. Gabardi S, Kubiak DW, Chandraker AK, Tullius SG. Invasive fungal infections and antifungal therapies in solid organ transplant recipients. Transplant International. 2007;20(12):993-1015. 10. Tomblyn M, Chiller T, Einele H et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-238. 11. Crum-Cianflone NF. Mucomycosis. Available at: http://emedicine.medscape.com/article/222551-overview. Accessed September 2013. 12. Vazquez JA. Zycomycosis. Available at: http://emedicine.medscape.com/article/232465-overview. Accessed September 2013. 13. Centers for Disease Control and Prevention (CDC). Mucomycosis (Zycomycosis). Available at: http://www.cdc.gov/fungal/mucormycosis/. Accessed September 2013. 14. Cresemba prescribing information. Astellas Pharma US, Inc. April 2015. 15. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mcormycosis 2013. Clin Microbiol Infect 2014; 20 (suppl.3): 5-26. 16. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41(5):634-53. 17. Skiada A, Pagano L, Groll A, et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect 2011; 17(12):1859-67. 18. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008;47(4):503-9. 19. Center for Drug Evaluation and Research. Application number: 207500Orig1s000/207501Orig1s000. FDA Medical review. Accessed in May 2015 at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500orig1207501orig1s 000MedR.pdf Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 4 of 8
Cresemba (isavuconazonium), Noxafil (posaconazole), and Vfend (voriconazole) Prior Authorization OBJECTIVE The intent of the Cresemba (isavuconazonium), Noxafil (posaconazole), and Vfend (voriconazole) Prior Authorization (PA) program is to ensure appropriate selection of patients for treatment according to product labeling and/or clinical studies and/or clinical practice guidelines. The PA process allows for approval for labeled indications and may require trial and failure of another antifungal agent when Cresemba, Noxafil, and Vfend are indicated in clinical practice guidelines as an alternative agent for the diagnosis, unless the patient has documented intolerance, FDA labeled contraindication, or hypersensitivity to the recommended initial treatment choice. Cresemba, Noxafil, or Vfend may also be evaluated for a nonlabeled indication if recommended in clinical practice guidelines or if the prescriber submits documentation in support of the requested therapeutic use. TARGET DRUGS Cresemba (isavuconazonium) Noxafil (posaconazole) Vfend (voriconazole) a a available as generic; included as target in PA program PRI AUTHIZATION CRITERIA F APPROVAL Initial Evaluation: Cresemba (isavuconazonium) will be approved when BOTH of the following are met: 1. The patient does NOT have any FDA labeled contraindication(s) to the requested agent 2. ONE of the following: a. The patient has a diagnosis of invasive aspergillosis b. The patient has a diagnosis of invasive mucormycosis c. The prescriber has submitted documentation supporting use of the requested agent for the intended diagnosis for this patient which has been reviewed and approved by the Clinical Review pharmacist Length of approval: 6 months Noxafil (posaconazole) will be approved when BOTH of the following are met: 1. The patient does NOT have any FDA labeled contraindication(s) to the requested agent 2. ONE of the following: a. The patient has a diagnosis of oropharyngeal candidiasis patient has tried fluconazole or an alternative antifungal agent or patient has documented intolerance, FDA labeled contraindication, or hypersensitivity to fluconazole or an alternative antifungal agent b. The patient is severely immunocompromised, such as a hematopoietic stem cell transplant [HSCT] recipient; or a patient with a hematologic malignancy with prolonged neutropenia from chemotherapy; or is a high-risk solid organ (lung, heart-lung, liver, pancreas, small bowel) transplant patient the requested agent is prescribed for prophylaxis of invasive Aspergillus or Candida c. The patient has an infection caused by Scedosporium or Zygomycetes Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 5 of 8
d. The patient has a diagnosis of invasive Aspergillus patient has tried an alternative antifungal agent or patient has documented intolerance, FDA labeled contraindication, or hypersensitivity to an alternative antifungal agent e. The prescriber has submitted documentation supporting use of the requested agent for the intended diagnosis for this patient which has been reviewed and approved by the Clinical Review pharmacist Length of approval: one month for oropharyngeal, 6 months for all other indications Vfend (voriconazole) will be approved when BOTH of the following are met: 1. The patient does NOT have any FDA labeled contraindication(s) to the requested agent 2. ONE of the following: a. The patient has a diagnosis of invasive Aspergillus, Scedosporium apiospermum, or Fusarium b. The patient has a diagnosis of esophageal candidiasis or candidemia in nonneutropenic patient patient has tried fluconazole or an alternative antifungal agent or patient has documented intolerance, FDA labeled contraindication, or hypersensitivity to an alternative antifungal agent c. The patient has a diagnosis of blastomycosis patient has tried itraconazole patient has documented intolerance, FDA labeled contraindication, or hypersensitivity to itraconazole d. The patient is severely immunocompromised, such as a hematopoietic stem cell transplant [HSCT] recipient; or a patient with a hematologic malignancy with prolonged neutropenia from chemotherapy; or is a high-risk solid organ (lung, heart-lung, liver, pancreas, small bowel) transplant patient e. The prescriber has submitted documentation supporting use of the requested agent for the intended diagnosis for this patient which has been reviewed and approved by the Clinical Review pharmacist Length of approval: one month for oropharyngeal and esophageal candidiasis, 6 months for all other indications Renewal Evaluation Cresemba (isavuconazonium) will be approved when ALL of the following are met: 1. The patient has been previously approved for the requested agent through the Prime Therapeutics Prior Authorization process 2. The patient does NOT have any FDA labeled contraindication(s) to the requested agent 3. ONE of the following: a. The patient has a diagnosis of invasive aspergillosis and the patient has continued indicators of active disease (e.g. continued radiologic findings, positive cultures, positive serum galactomannan assay) b. The patient has a diagnosis of invasive mucormycosis and the patient has continued indicators of active disease (e.g. continued radiologic findings, direct Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 6 of 8
microscopy findings, histopathology findings, positive cultures, positive serum galactomannan assay) c. The prescriber has submitted documentation supporting continued use of the requested agent for the intended diagnosis for this patient which has been reviewed and approved by the Clinical Review pharmacist Length of approval: 6 months Noxafil (posaconazole) will be approved when ALL of the following are met: 1. The patient has been previously approved for the requested agent through the Prime Therapeutics Prior Authorization process 2. The patient does NOT have any FDA labeled contraindication(s) to the requested agent 3. ONE of the following: a. The requested agent is being prescribed for prophylaxis of invasive Aspergillus or Candida and the patient continues to be severely immunocompromised as indicated by: neutropenia, ongoing graft versus host disease, and/or long term use of high dose corticosteroids (> 1 mg/kg/day of prednisone or equivalent) b. The patient has a diagnosis of invasive Aspergillus or has an infection caused by Scedosporium, or Zygomycetes and the patient has continued indicators of active disease (e.g. continued radiologic findings, positive cultures, positive serum galactomannan assay for Aspergillus) c. The prescriber has submitted documentation supporting continued use of the requested agent for the intended diagnosis for this patient which has been reviewed and approved by the Clinical Review pharmacist -For patients with a diagnosis of oropharyngeal candidiasis see Initial Evaluation criteria Length of approval: 6 months Vfend (voriconazole) will be approved when ALL of the following are met: 1. The patient has been previously approved for the requested agent through the Prime Therapeutics Prior Authorization process 2. The patient does NOT have any FDA labeled contraindication(s) to the requested agent 3. ONE of the following: a. The patient has a diagnosis of invasive Aspergillus, Scedosporium apiospermum, Fusarium, esophageal candidiasis, candidemia in nonneutropenic patient or blastomycosis and the patient has continued indicators of active disease (e.g. continued radiologic findings, positive cultures, positive serum galactomannan assay for Aspergillus) b. The requested agent is being prescribed for prophylaxis and the patient continues to be severely immunocompromised as indicated by: neutropenia, ongoing graft versus host disease, and/or long term use of high dose corticosteroids (> 1 mg/kg/day of prednisone or equivalent) c. The prescriber has submitted documentation supporting continued use of the requested agent for the intended diagnosis for this patient which has been reviewed and approved by the Clinical Review pharmacist Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 7 of 8
Length of approval: one month for esophageal candidiasis 6 months for all other indications Choice_PS_Cresemba_Noxafil_Vfend_PA_ProgSum_0117_r0517 Page 8 of 8