Figure 1 shows a flowchart of the study. We retrieved 314,328 distinct patients who were administered voriconazole from January 2004 to March 2023. Of these, 75,180 duplicate cases, 1,916 cases in which voriconazole was administered after the occurrence of adverse events, and 1,916 cases in which other drugs were administered were excluded. The numbers of cases administered voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine were 22,839, 90,810, 109,757, 6,435, 20, 83, and 26.
The baseline characteristics of the patients from each group are shown in Table 1. Regarding sex distribution, the groups except for two groups (voriconazole + risperidone and voriconazole + chlorpromazine) consisted of more men than women. The median age of each group was 57, 73, 41, 47, 75, 66, and 41 years, respectively. Median weight of each group was 64.0, 70.3, 75.0, 70.0, 83.9, 49.0, and 53.0 kg. These cases mainly originated in the United States.
Table 1
Demographic characteristics of each patient in the FAERS database from January 2004 to March 2023
| Voriconazole | Levodopa | Risperidone | Chlorpromazine | Voriconazole + Levodopa | Voriconazole + Risperidone | Voriconazole + Chlorpromazine |
Sex, n (%) | | | | | | | |
Female | 7,858 (34.4) | 37,049 (40.8) | 34,419 (31.4) | 2,712 (42.1) | 8 (40.0) | 41 (49.4) | 18 (69.2) |
Male | 12,313 (53.9) | 48,525 (53.4) | 63,699 (58.0) | 3,143 (48.8) | 11 (55.0) | 35 (42.2) | 7 (26.9) |
Unknown | 2,668 (11.7) | 5,236 (5.8) | 11,639 (10.6) | 580 (9.0) | 1 (5.0) | 7 (8.4) | 1 (3.8) |
Age (years) | | | | | | | |
Median [IQR] | 57 [36–68] | 73 [66–79] | 41 [23–60] | 47 [33–61] | 75 [69–79] | 66 [38–66] | 41 [18–51] |
Unknown, n (%) | 4,669 (20.4) | 32,272 (35.5) | 46,174 (42.1) | 1,302 (20.2) | 1 (5.0) | 12 (14.5) | 1 (3.8) |
Weight (kg) | | | | | | | |
Medican [IQR] | 64.0 [50.4–79.0] | 70.3 [59.0–83.0] | 75.0 [60.0–93.0] | 70.0 [55.2–86.0] | 83.9 [59.5–87.3] | 49.0 [18.5–63.0] | 53.0 [32.0-65.3] |
Unknown, n (%) | 16,581 (72.6) | 68,060 (74.9) | 86,925 (79.2) | 4,523 (70.3) | 13 (65.0) | 63 (75.9) | 15 (57.7) |
Country, n (%) | | | | | | | |
United States | 8,729 (38.2) | 45,740 (50.4) | 62,347 (56.8) | 1,978 (30.7) | 8 (40.0) | 39 (47.0) | 9 (34.6) |
France | 2,155 (9.4) | 3,389 (3.7) | 6,755 (6.2) | 887 (13.8) | 0 (0.0) | 3 (3.6) | 6 (23.1) |
United Kingdom | 1,442 (6.3) | 2,804 (3.1) | 5,961 (5.4) | 616 (9.6) | 0 (0.0) | 0 (0.0) | 1 (3.8) |
Germany | 548 (2.4) | 5,773 (6.4) | 4,985 (4.5) | 19 (0.3) | 0 (0.0) | 1 (1.2) | 1 (3.8) |
Japan | 2,426 (10.6) | 3,333 (3.7) | 4,623 (4.2) | 726 (11.3) | 5 (25.0) | 12 (14.5) | 2 (7.7) |
Canada | 543 (2.4) | 1,511 (1.7) | 3,691 (3.4) | 261 (4.1) | 0 (0.0) | 2 (2.4) | 0 (0.0) |
Italy | 518 (2.3) | 2,702 (3.0) | 2,546 (2.3) | 447 (6.9) | 0 (0.0) | 1 (1.2) | 0 (0.0) |
Spain | 633 (2.8) | 2,478 (2.7) | 1,450 (1.3) | 48 (0.7) | 0 (0.0) | 19 (22.9) | 0 (0.0) |
Netherlands | 444 (1.9) | 2,075 (2.3) | 804 (0.7) | 56 (0.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Australia | 388 (1.7) | 1,339 (1.5) | 1,224 (1.1) | 217 (3.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Others | 4,033 (17.7) | 9,503 (10.5) | 10,112 (9.2) | 728 (11.3) | 7 (35.0) | 3 (3.6) | 4 (15.4) |
Unknown | 980 (4.3) | 10,163 (11.2) | 5,259 (4.8) | 452 (7.0) | 0 (0.0) | 3 (3.6) | 3 (11.5) |
Data are presented as medians [IQRs]. IQR, interquartile range. |
The results of the disproportionality analyses of drug-drug interactions between voriconazole and dopaminergic medicine or dopamine antagonists are shown in Table 2. Visual hallucinations emerged with the use of levodopa alone (1.8%, ROR = 1.236, 95% CI = 1.096–1.394, p = 0.001). The occurrence of visual hallucinations induced by the concomitant use of voriconazole and levodopa was more frequently recorded than when voriconazole was used alone (17.6%, ROR = 12.302, 95% CI = 3.587–42.183, p < 0.001). Conversely, the use of risperidone or chlorpromazine alone was not associated with occurrence of visual hallucination (risperidone, 0.4%, ROR = 0.297, 95% CI = 0.258–0.343; chlorpromazine, 0.2%, ROR = 0.163, 95% CI = 0.097–0.274). The concomitant use of risperidone or chlorpromazine with voriconazole was not associated with an increased occurrence of voriconazole-induced visual hallucinations (voriconazole + risperidone, 2.5%, ROR = 1.721, 95% CI = 0.421–7.030; chlorpromazine, 0%; ROR, none; 95% CI, none).
Table 2
Disproportionality analyses and drug interaction approaches for various combinations involving voriconazole
Exposure | Cases | Non-cases | ROR (95% CI) | p-value |
Voriconazole | 323 | 22,516 | Reference | Reference |
Levodopa | 1,582 | 89,228 | 1.236 (1.096–1.394) | 0.001 |
Risperidone | 466 | 109,291 | 0.297 (0.258–0.343) | < 0.001 |
Chlorpromazine | 15 | 6,420 | 0.163 (0.097–0.274) | < 0.001 |
Voriconazole + Levodopa | 3 | 17 | 12.302 (3.587–42.183) | < 0.001 |
Voriconazole + Risperidone | 2 | 81 | 1.721 (0.421–7.030) | 0.449 |
Voriconazole + Chlorpromazine | 0 | 26 | - | - |