Associate professor Centre for Pharmacoepidemiology, Karolinska Institutet, Sweden
Background: Voriconazole is a broad-spectrum systemic antifungal that is used for the treatment of invasive aspergillosis and other serious fungal infections (IFI) and prophylaxis of IFIs in high-risk allogeneic hematopoietic stem cell transplant recipients. Safety profiles are not completely known with long-term exposure. This post-authorization safety study was a commitment to the European Medicines Agency (EUPAS12624).
Objectives: To estimate the incidence rate of hepatic disorders (HD), phototoxicity, visual disorders (VD), periostitis, and squamous cell carcinoma of the skin (SCC), among adult patients receiving long-term compared to short-term voriconazole use.
Methods: This study was based on individually linked data from the Swedish national patient register, the prescribed drug register (PDR), the cancer register, and the causes of death register. Adult patients who filled at least one prescription of voriconazole between Jan 2006 and Dec 2017 were identified in the PDR. The date of the first prescription was considered as index date. All included patients were followed up from index date, until the first occurrence of each incident safety outcome or censoring event (emigration, death, or the end of 2019). The quantity of exposure to voriconazole was assessed according to a defined daily dose (DDD) of 400 mg a day as a proxy for exposure duration. Long-term use was defined as having used ≥180 DDDs and short-term use as having used < 180 DDDs. Crude incidence rates (IR) per 1,000 person-years and the corresponding IR ratios (IRR) with 95% confidence intervals (CI) were estimated for each outcome during long vs. short-term use of voriconazole as reference group.
Results: A total of 2,177 voriconazole-treated patients were included (44% female; median age 62 years). The most common underlying conditions were haematological disease (45.3%), solid organ transplant (14.8%), and cystic fibrosis (2.5%). The IRs per 1,000 person-years for long and short-term use of voriconazole were 2.9 (95%CI 0.1-16.1) and 6.0 (95%CI 2.4-12.3), respectively, for HD; 9 (95%CI 1.8-26.2) and 20.3 (95%CI 12.8-30.4), respectively, for phototoxicity; 10.1 (95%CI 2.1-29.4) and 23.1 (95%CI 15-34.1), respectively, for VD; 0.8 (95%CI 0-4.5) and 1.0 (95%CI 0.4-1.9), respectively, for periostitis; and 4.9 (95%CI 1.8-10.6) and 3.5 (95%CI 2.4-5), respectively, for SCC. The corresponding IRRs for the comparison of long vs. short-term use were 0.48 (95%CI 0.06-3.92) for HD, 0.44 (95%CI 0.13-1.47) for phototoxicity, 0.44 (95%CI 0.13-1.44) for VD, 0.84 (95%CI 0.11-6.71) for periostitis, and 1.38 (95%CI 0.57-3.33) for SCC.
Conclusions: The IRs of the safety outcomes were not found to be significantly higher in long-term use compared to short-term use of voriconazole.
