Changing spectrum of suspected drugs of epidermal necrolysis: A World Health Organization pharmacovigilance database analysis from 1997-2020

Abstract

To the Editor: Epidermal necrolysis (EN), including Stevens–Johnson syndrome and toxic EN, is a rare life-threatening disease characterized by diffuse skin and mucosal detachment.1Duong T.A. Valeyrie-Allanore L. Wolkenstein P. Chosidow O. Severe cutaneous adverse reactions to drugs.Lancet. 2017; 390: 1996-2011Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar Between 70% and 90% of cases of EN are caused by drugs. Prompt identification and discontinuation of the suspected drug(s) are vital.1Duong T.A. Valeyrie-Allanore L. Wolkenstein P. Chosidow O. Severe cutaneous adverse reactions to drugs.Lancet. 2017; 390: 1996-2011Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,2Garcia-Doval I. LeCleach L. Bocquet H. Otero X.L. Roujeau J.C. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?.Arch Dermatol. 2000; 136: 323-327Crossref PubMed Google Scholar To assess the changing spectrum of drugs associated with EN, we performed a multicentre retrospective study using VigiBase, the World Health Organization global database of individual case safety reports3Bate A. Lindquist M. Edwards I.R. et al.A Bayesian neural network method for adverse drug reaction signal generation.Eur J Clin Pharmacol. 1998; 54: 315-321Crossref PubMed Scopus (643) Google Scholar (Appendix I available via Mendeley at https://data.mendeley.com/datasets/nzgxjdtzx4/1). This study included all cases of EN reported in VigiBase. Two periods of interest were extracted: period 1, to assess former associated drugs, from January 1, 1997 to December 31, 2001, encompassing the same time period as the EuroSCAR study4Mockenhaupt M. Viboud C. Dunant A. et al.Stevens–Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study.J Invest Dermatol. 2008; 128: 35-44Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar; and period 2, from January 1, 2016 to January 15, 2020 to assess new associated drugs. Medications were grouped according to the World Health Organization anatomical therapeutic chemical (ATC) classification, as appropriate (Supplemental Table I available via Mendeley). To identify drugs associated with EN, we used the information component, an indicator for disproportionate reporting, and the lower limit of its 95% credibility interval (IC025). IC025 > 0 is the statistical threshold used in VigiBase3Bate A. Lindquist M. Edwards I.R. et al.A Bayesian neural network method for adverse drug reaction signal generation.Eur J Clin Pharmacol. 1998; 54: 315-321Crossref PubMed Scopus (643) Google Scholar (Appendix I). Sensitivity analyses were performed considering only physician's reports. Period 1 accounted for 4092 reports with a total of 6766 suspected drugs (corresponding to 339 drugs or ATC classes) while period 2 accounted for 13,961 reports with 20,711 suspected drugs (621 drugs or ATC classes). Characteristics of reports are presented in Supplemental Table II (available via Mendeley). During period 1, 72 of 339 (21%) different drugs presented a positive IC025. During period 2, 114 of 621 (19%) presented a positive IC025. Sixty-seven drugs or ATC classes were newly associated during period 2. Among them, 11 were antiepileptics or psychotropic drugs (16%), 2 were nonsteroidal antiiflammatory drugs or analgesics (3%), 11 (16%) were antiinfectives, 16 were anticancer therapies (24%), 10 (15%) were cardiovascular drugs, and 17 (25%) were other drugs (Fig 1). Table I shows drugs with positive IC025 in both primary and sensitivity analyses, with ≥1 report as the only suspected drug. Other associated drugs are presented in the Supplemental Table III (available via Mendeley). Period 2 highlighted particularly the entry of zonisamide (IC025 = 3.9), levetiracetam (IC025 = 2.1), and oxcarbazepine (IC025 = 2.4), but the most obvious change was observed among anticancer therapies with 16 new associated drugs, eg, mogamulizumab (IC025 = 3.3), pembrolizumab (IC025 = 1.6), or vemurafenib (IC025 = 2.4) and cobimetinib (IC025 = 2.7).Table IDrugs associated with epidermal necrolysis in both primary and sensitivity analyses, and with ≥1 report as only suspected drugDrug1997-20012016-2020ReportsReports PhyIC025IC025 PhyAlone (%)ReportsReports PhyIC025IC025 PhyAlone (%)Allopurinol∗Received European or US Food and Drug Administration approval before 1997.216165 (76)4.64102 (47)1192474 (40)6.16.3847 (71)Phenytoin∗Received European or US Food and Drug Administration approval before 1997.321188 (59)4.23.5175 (55)1045423 (40)5.54.9777 (74)Carbamazepine∗Received European or US Food and Drug Administration approval before 1997.372291 (78)3.93.4257 (69)1047518 (49)5.44.8804 (77)Lamotrigine∗Received European or US Food and Drug Administration approval before 1997.220113 (51)4.13.5181 (82)830468 (56)54.9501 (60)Sulphonamides∗Received European or US Food and Drug Administration approval before 1997.498364 (73)3.93357 (71)1087362 (33)4.33.1682 (63)Dapsone∗Received European or US Food and Drug Administration approval before 1997.106 (60)216 (60)6922 (32)4.12.546 (67)Phenobarbital∗Received European or US Food and Drug Administration approval before 1997.7158 (82)3.53.126 (36)14255 (39)43.680 (56)Zonisamide†Received European or US Food and Drug Administration approval after 1997.4822 (46)3.92.827 (56)Carbocysteine∗Received European or US Food and Drug Administration approval before 1997.66 (100)0.90.50 (0)4834 (71)3.83.88 (17)Nimesulide†Received European or US Food and Drug Administration approval after 1997.7353 (73)3.73.623 (31)Quinolones∗Received European or US Food and Drug Administration approval before 1997.197136 (69)10.2105 (53)835443 (53)3.42.2390 (47)Mogamulizumab†Received European or US Food and Drug Administration approval after 1997.2018 (90)3.339 (45)Fosphenytoin∗Received European or US Food and Drug Administration approval before 1997.1910 (53)325 (26)Griseofulvin∗Received European or US Food and Drug Administration approval before 1997.175 (29)2.90.211 (65)Oxicams∗Received European or US Food and Drug Administration approval before 1997.7157 (80)1.71.433 (46)12633 (26)2.8260 (48)Nevirapine∗Received European or US Food and Drug Administration approval before 1997.15195 (63)3.32.592 (61)477120 (25)2.80.8331 (69)Cobimetinib†Received European or US Food and Drug Administration approval after 1997.3322 (66)2.71.82 (6)Mexiletine∗Received European or US Food and Drug Administration approval before 1997.117 (64)2.71.92 (11)Penems∗Received European or US Food and Drug Administration approval before 1997.1813 (72)1.20.47 (39)18888 (47)2.62.253 (28)Colchicine∗Received European or US Food and Drug Administration approval before 1997.86 (75)0.90.11 (12)5523 (42)2.61.44 (7)Valproate∗Received European or US Food and Drug Administration approval before 1997.230116 (50)2.5260 (26)Sulfasalazine∗Received European or US Food and Drug Administration approval before 1997.3015 (50)1.90.619 (63)12454 (44)2.5191 (73)Pralatrexate†Received European or US Food and Drug Administration approval after 1997.124 (33)2.50.66 (66)Ayurvedic∗Received European or US Food and Drug Administration approval before 1997.98 (89)2.426 (67)Fenamic acid∗Received European or US Food and Drug Administration approval before 1997.98 (88)0.3-0.46 (66)9248 (52)2.41.928 (30)Vemurafenib†Received European or US Food and Drug Administration approval after 1997.5733 (58)2.41.818 (32)Triazoles∗Received European or US Food and Drug Administration approval before 1997.7662 (81)1.2137 (48)17471 (41)2.41.766 (32)Oxcarbazepine†Received European or US Food and Drug Administration approval after 1997.5121 (41)2.41.634 (67)Cyclo-oxygenase 2 inhibitors†Received European or US Food and Drug Administration approval after 1997.220141 (64)2.32.1129 (59)Glycopeptides∗Received European or US Food and Drug Administration approval before 1997.5633 (59)1.8124 (43)263121 (46)2.21.780 (30)Nystatin∗Received European or US Food and Drug Administration approval before 1997.107 (70)21.31 (10)189 (50)2.227 (39)Acetaminophen∗Received European or US Food and Drug Administration approval before 1997.166153 (92)2.32.121 (13)780490 (63)2.12.5210 (27)Levetiracetam†Received European or US Food and Drug Administration approval after 1997.16488 (54)2.11.738 (23)Penicillins∗Received European or US Food and Drug Administration approval before 1997.313254 (81)1.71.1129 (41)1166547 (47)21.4451 (42)Isoniazid∗Received European or US Food and Drug Administration approval before 1997.1111 (100)0.3-0.12 (18)20795 (46)21.242 (20)Tipepidine†Received European or US Food and Drug Administration approval after 1997.62 (33)2-0.51 (17)Ethambutol∗Received European or US Food and Drug Administration approval before 1997.17789 (50)1.91.315 (8)Rifampicin∗Received European or US Food and Drug Administration approval before 1997.1915 (79)0.7-0.25 (26)228111 (49)1.91.225 (11)Pyrazolones∗Received European or US Food and Drug Administration approval before 1997.10981 (74)2.92.358 (53)6935 (51)1.9123 (33)Cyclins∗Received European or US Food and Drug Administration approval before 1997.7359 (81)1.81.448 (66)15652 (33)1.90.698 (63)Macrolides∗Received European or US Food and Drug Administration approval before 1997.224158 (71)1.50.8115 (51)509227 (45)1.81.8190 (37)Acetic acids∗Received European or US Food and Drug Administration approval before 1997.11699 (85)0.70.847 (40)379189 (50)1.71.6174 (46)Propionic acid∗Received European or US Food and Drug Administration approval before 1997.9074 (82)0.20.335 (39)674335 (50)1.71.6238 (35)Echinocandins†Received European or US Food and Drug Administration approval after 1997.2115 (71)1.71.63 (14)Acyclovir∗Received European or US Food and Drug Administration approval before 1997.2921 (72)10.68 (27)7848 (62)1.71.619 (24)Modafinil†Received European or US Food and Drug Administration approval after 1997.235 (22)1.70.118 (78)Febuxostat†Received European or US Food and Drug Administration approval after 1997.2115 (71)1.61.112 (57)Bendamustine†Received European or US Food and Drug Administration approval after 1997.3623 (64)1.60.87 (19)Pembrolizumab†Received European or US Food and Drug Administration approval after 1997.11681 (70)1.6181 (70)Chloramphenicol∗Received European or US Food and Drug Administration approval before 1997.155 (33)1.604 (27)Aminoglycosides∗Received European or US Food and Drug Administration approval before 1997.3027 (90)0.70.44 (13)11956 (47)1.51.123 (19)Cephalosporines∗Received European or US Food and Drug Administration approval before 1997.227162 (71)1.91.192 (41)942453 (48)1.42315 (33)Pyrazinamide∗Received European or US Food and Drug Administration approval before 1997.99 (100)0.60.10 (0)14071 (51)1.40.79 (6)Aldosterone inhibitors∗Received European or US Food and Drug Administration approval before 1997.140.4-0.30 (0)4925 (51)1.40.713 (26)Artemisinin†Received European or US Food and Drug Administration approval after 1997.98 (89)1.31.32 (22)Loop diuretic∗Received European or US Food and Drug Administration approval before 1997.10394 (91)2.62.15 (5)13160 (46)1.30.710 (8)Nivolumab†Received European or US Food and Drug Administration approval after 1997.15096 (64)10.668 (45)Atovaquone†Received European or US Food and Drug Administration approval after 1997.108 (80)0.91.18 (80)Neuraminidase inhibitors†Received European or US Food and Drug Administration approval after 1997.3511 (31)0.90.425 (71)Imidazoles∗Received European or US Food and Drug Administration approval before 1997.11452 (46)0.80.736 (32)Topiroxostat†Received European or US Food and Drug Administration approval after 1997.44 (100)0.80.63 (75)Eslicarbazepine†Received European or US Food and Drug Administration approval after 1997.95 (55)0.80.17 (78)Bromhexine∗Received European or US Food and Drug Administration approval before 1997.66 (100)1.41.30 (0)133 (23)0.8-0.63 (23)Ipilimumab†Received European or US Food and Drug Administration approval after 1997.4426 (59)0.70.48 (18)Tranexamic acid∗Received European or US Food and Drug Administration approval before 1997.2013 (65)0.71.51 (5)Theophylline∗Received European or US Food and Drug Administration approval before 1997.119 (82)0.715 (45)Homeopathic∗Received European or US Food and Drug Administration approval before 1997.43 (75)0.70.54 (100)Calcium channel blockers∗Received European or US Food and Drug Administration approval before 1997.17475 (43)0.70.126 (15)Fibrates∗Received European or US Food and Drug Administration approval before 1997.2211 (50)0.7011 (50)Acetylcysteine∗Received European or US Food and Drug Administration approval before 1997.5552 (94)3.83.42 (4)2713 (48)0.51.14 (15)Idelalisib†Received European or US Food and Drug Administration approval after 1997.1813 (72)0.50.18 (44)Amphotericin B∗Received European or US Food and Drug Administration approval before 1997.74 (57)0.10.23 (27)2314 (61)0.50.16 (26)Ambroxol∗Received European or US Food and Drug Administration approval before 1997.3029 (97)3.73.20 (0)2614 (54)0.42.45 (19)Temozolomide†Received European or US Food and Drug Administration approval after 1997.2018 (90)0.418 (40)HIV nucleosidic inhibitors∗Received European or US Food and Drug Administration approval before 1997.6651 (77)0.70.28 (12)18882 (44)0.4-0.810 (6)Terbinafine∗Received European or US Food and Drug Administration approval before 1997.4629 (63)0.80.740 (87)179 (53)0.3010 (59)Regorafenib†Received European or US Food and Drug Administration approval after 1997.2217 (77)0.20.216 (73)Tegafur, gimeracil, and oteracil†Received European or US Food and Drug Administration approval after 1997.2016 (80)0.20.214 (70)Salicylates∗Received European or US Food and Drug Administration approval before 1997.147132 (89)21.725 (17)16792 (55)0.1-0.218 (11)Anti-H2∗Received European or US Food and Drug Administration approval before 1997.7337 (51)0.116 (8)Proton pump inhibitor∗Received European or US Food and Drug Administration approval before 1997.359206 (57)01.872 (20)Benzodiazepines∗Received European or US Food and Drug Administration approval before 1997.114107 (94)0.80.78 (7)15683 (53)0-0.316 (10)Chlormezanone‡Received European or US Food and Drug Administration approval before 1997 but withdrawn from market before 2016.2117 (81)3.93.36 (28)Pirenzepine‡Received European or US Food and Drug Administration approval before 1997 but withdrawn from market before 2016.75 (71)2.21.61 (14)Pentamidine∗Received European or US Food and Drug Administration approval before 1997.76 (86)1.31.23 (42)Aztreonam∗Received European or US Food and Drug Administration approval before 1997.54 (80)1.10.42 (40)Amitriptyline∗Received European or US Food and Drug Administration approval before 1997.2117 (81)0.80.46 (28)Misoprostol∗Received European or US Food and Drug Administration approval before 1997.76 (86)0.70.31 (14)Tianeptine‡Received European or US Food and Drug Administration approval before 1997 but withdrawn from market before 2016.44 (100)0.3-0.10 (0)Amifostine‡Received European or US Food and Drug Administration approval before 1997 but withdrawn from market before 2016.77 (100)0.30.24 (57)Associated drugs are ordered by IC025 during 2016-2020 and then 1997-2001. Only drugs with positive IC025 during period 1 or period 2 are shown.IC025, Lower limit of information component 95% credibility interval; Phy, physician.∗ Received European or US Food and Drug Administration approval before 1997.† Received European or US Food and Drug Administration approval after 1997.‡ Received European or US Food and Drug Administration approval before 1997 but withdrawn from market before 2016. Open table in a new tab Associated drugs are ordered by IC025 during 2016-2020 and then 1997-2001. Only drugs with positive IC025 during period 1 or period 2 are shown. IC025, Lower limit of information component 95% credibility interval; Phy, physician. This study shows an increasing variety of molecules associated with EN over time. Because of the significant therapeutic progress of the last decade, anticancer therapies presented with the most striking change. Nonetheless, the association of new antiepileptic medications has also been noted.5Borrelli E.P. Lee E.Y. Descoteaux A.M. Kogut S.J. Caffrey A.R. Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: an analysis of the US Food and Drug Administration Adverse Event Reporting System.Epilepsia. 2018; 59: 2318-2324Crossref PubMed Scopus (33) Google Scholar The main strength of the study is the worldwide scale, allowing rare signals to appear. We acknowledge the limitations, mostly a heterogeneity of reporting between periods and regions and that all EN reports were not reviewed by specialists. Nonetheless, period 1 found the same associated drugs as the EuroSCAR study, and a sensitivity analysis was performed considering only physician reports. This study updates the spectrum of drugs associated with EN. New drugs among antiepileptics (eg, zonisamide, oxcarbazepine, and levetiracetam) and anticancer therapies (eg, mogamulizumab, vemurafenib, and cobimetinib) seem to carry a high risk. None declared.