Drug-Induced Progressive Multifocal Leukoencephalopathy: A Comprehensive Analysis of the WHO Adverse Drug Reaction Database.
OBJECTIVE
To identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML).


METHODS
All reports containing suspected or interacting PML-related or leukoencephalopathy-related drugs, held in the World Health Organization spontaneous individual case safety reports database as at 1 September 2014, were retrieved. We identified safety signals by analysing the drug-reaction pairs, using the reporting odds ratio as a measure of disproportionality. A safety signal was defined if a drug was reported more than twice in PML cases with a reporting odds ratio >2 and a lower 95 % confidence limit >1.


RESULTS
We retrieved 2452 reports associated with PML (N = 1612), leukoencephalopathy (N = 835) or both (N = 5), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18-64 years), and almost 30 % of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5 %), antivirals for systemic use (10.1 %) or immunostimulants (4.6 %). Significant disproportionality was found for 88 drugs in the overall analysis (of cases with 'progressive multifocal leukoencephalopathy' or 'leukoencephalopathy' as the Preferred Term), and a new safety signal was identified for 59 active substances (e.g. muromonab-CD3, basiliximab and antithymocyte Ig), as no information on a possible risk of PML was acknowledged in their Summary of Product Characteristics documents. Some safety signals were confirmed also after sensitivity analysis adjustment for several confounding factors (underlying diseases and considering only 'progressive multifocal leukoencephalopathy' as the Preferred Term).


CONCLUSIONS
We report a possible association between several drugs and PML that has not been previously described. In addition, we have confirmed previously reported signals in a number of drugs. We highlight the need for follow-up by regulatory agencies.
Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
Mauro
M
Melis
Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
Chiara
C
Biagi
Department of Pharmacy, UiT-The Arctic University of Norway, Tromsø, Norway.
Lars
L
Småbrekke
Medicines and Medical Devices Area - Health and Social Policies Directorate, Emilia-Romagna Region, via Aldo Moro 21, 40127, Bologna, Italy.
Francesco
F
Nonino
Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
Elena
E
Buccellato
Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
Monia
M
Donati
Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
Alberto
A
Vaccheri
Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy. domenico.motola@unibo.it.
Domenico
D
Motola
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D062313:Databases, Pharmaceutical; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced* / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D014944:World Health Organization; D055815:Young Adult