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Voriconazole prophylaxis mandates cutaneous prophylaxis – and communication

DII small banner By Warren R. Heymann, MD
Sept. 28, 2017

The utilization of allogeneic hematopoietic stem cell transplantation (HSCT) has been increasing dramatically. According to the Health Resources and Services Administration, 92,784 procedures were performed between 2010 and 2014.

Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation HSCT remain a leading cause of morbidity and mortality in HSCT recipients. IFIs following HSCT ranges from 8% to 12% in the first year post-HSCT. Pathogens causing IFIs can be broadly categorized into three groups: Candida species; Aspergillus species; and other molds (including zygomycetes, Fusarium species, and Scedosporium species). Aspergillus species have replaced Candida species as the most common fungal pathogen in recipients of HSCT. The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of HSCT. (1)
In a study of 429 courses of voriconazole antifungal prophylaxis in 249 children, in which the most common underlying diseases were acute lymphoblastic leukemia (51%), non-Hodgkin lymphoma (8.6%), and acute myeloid leukemia (7.7%), the median number of voriconazole courses per patient was 1.7. During the last 2 weeks before the administration of voriconazole, 51% of the patients had received corticosteroids, 43% suffered from severe neutropenia, and 17.3% had mucositis. The median duration of voriconazole prophylaxis was 17 days. A single breakthrough fungemia due to Candida glabrata was recorded. Only 1 patient died due to the underlying disease. The most common adverse effects reported in were elevated liver enzymes , hypokalemia, and ophthalmological disorders. (2)

According to Ilyas et al: “Transplant recipients commonly receive prophylactic voriconazole for the prevention or treatment of fungal infections. Approximately 8% of transplant patients treated with voriconazole show cutaneous side effects, including increased photosensitivity, cheilitis, worsening of psoriasis, alopecia, and pruritus. The most common manifestation is the increased photosensitivity, which presents with isolated erythema, bullous erythema, pseudoporphyria, or erythema with cheilitis, lentigines, or keratosis. There is a genetic polymorphism associated with decreased metabolism of voriconazole that may predispose certain patients to photosensitivity. An alternate antifungal should be considered in place of voriconazole in transplant recipients with a high risk of skin cancer due to cases of phototoxicity leading to photocarcinogenesis. There are reports of patients with prolonged voriconazole therapy who developed increased photosensitivity that resolved on switching to posaconazole; therefore, clinicians should consider posaconazole as an alternative. All transplant recipients treated with voriconazole should be informed about the potential phototoxic side effect and the importance of adequate photoprotection.” (3)
Additionally, Miller et al have reported 5 melanomas-in-situ in two patients with voriconazole-induced chronic photosensitivity. (4)

In a retrospective study of 381 HSCT patients, SCC developed in 26 of 312 patients exposed to voriconazole and in 1 of 69 patients who received alternative antifungal agent(s). Cumulative incidence of SCC was estimated to be 19% at 5 years post-transplant. Cumulative days of voriconazole use was found to be a risk factor for SCC, with a hazard ratio 1.859 for each 180 days of use. (5)

Kuklinksi et al evaluated the effect of voriconazole on the risk for nonmelanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), among those who have undergone allogeneic and autologous HSCT. A total of 1220 patients who had undergone allogeneic HSCT and 1418 that had undergone autologous HSCT were included in a retrospective cohort study. Multivariate analysis included voriconazole exposure and other known risk factors for NMSC. Voriconazole use increased the risk for NMSC (hazard ratio, 1.82) among those who had undergone allogeneic HSCT, particularly for SCC (hazard ratio, 2.25); voriconazole use did not appear to confer increased risk for NMSC among those who had undergone autologous HSCT. The authors concluded that voriconazole is an independent factor that may contribute to increased risk specifically for SCC in the allogeneic HSCT population. (6)

In a revealing study, Chansky et al contacted 91 voriconazole prescribers in the University of Pennsylvania Health System; 29 (32%) providers across 5 specialties (oncology, infectious disease, pulmonology, transplant, and rheumatology) completed the cross-sectional survey. Fifty-nine percent reported never screening for skin cancer when starting a patient on voriconazole, and 45% never recommend self–skin examinations. Only 65% of prescribers always recommend sunscreen, and 41% always recommend sun-protective clothing. Most providers believed that voriconazole is not, or is only rarely, associated with squamous cell carcinoma (52%) and melanoma (83%). The authors concluded that there is a significant knowledge gap among experienced and educated voriconazole prescribers regarding medication side effects and the well-known link between voriconazole and photosensitivity/photocarcinogenesis. They recommended educating medical providers about the increased risk of skin cancer, the need for regular dermatologic examinations, and the importance of sun protection and avoidance among patients taking voriconazole. (7)

I agree wholeheartedly with the recommendations by Chansky et al, yet I understand the nature of these gaps. When I prescribe a new medication, I will usually check for drug interactions and review common and severe adverse reactions. Regardless, you learn more from your patients than reading a list. I recall a patient complaining that topical minoxidil, recommended for pattern alopecia, caused her feet to swell. I was unaware of that adverse reaction but it is clearly listed on the package insert. As patients see multiple specialists, causing polypharmacy, with each drug having its litany of adverse reactions, it may be impossible to be cognizant of every relevant side effect. My advice is to communicate with the other doctors — text, email, or by the old-fashioned technique invented by Alexander Graham Bell in 1876. You’ll be surprised by how effective (and pleasant) a phone to a colleague call can be!

1. Marks DI, et al. Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation. Expert Rev Anti Infect Ther 2017; 15: 493-502.
2. Pana ZD, et al. Voriconazole antifungal prophylaxis in children with malignancies: A nationwide study. J Pediatr Hematol Oncol 2017; Aug 14 [Epub ahead of print]
3. Ilyas M, et al. Cutaneous toxicities from transplantation-related medications. Am J Transplant 2017 Apr 27 [Epub ahead of print]
4. Miller DD, et al. Melanoma associated with long-term voriconazole therapy: A new manifestation of chronic photosensitivity. Arch Dermatol 2010; 146: 300-4.
5. Wojenski DJ, et al. Voriconazole exposure and the risk of cutaneous squamous cell carcinoma in allogeneic hematopoietic stem cell transplant patients. Transpl Infect Dis 2015; 17: 250-8.
6. Kuklinski LF, et al. Effect of voriconazole on risk of nonmelanoma skin cancer after hematopoietic cell transplantation. J Am Acad Dermatol 2017; 77: 706-12.
7. Chansky PB, et al. A cross-sectional survey of voriconazole prescribers: Assessing current practice and knowledge of cutaneous side effects. J Am Acad Dermatol 2017; 769-70.

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