Sofosbuvir, mirabegron, nintedanib ‘incriminated’ in ANCA-associated vasculitis
Sofosbuvir, mirabegron and nintedanib — all approved within the past 9 years — are among the drugs associated with the highest disproportionate reporting of ANCA-associated vasculitis, according to data.
“The identification of drugs involved in this adverse drug reaction (ADR) has important epidemiological and clinical impacts because patients diagnosed with [drug-associated ANCA-associated vasculitis (DA-AAV)] seem to have a better prognosis with less severe vasculitis, resulting in better overall and renal survival and less frequent relapses than those diagnosed with primary AAV,” Samuel Deshayes, MD, of the University of Normandy, in Caen, France, and colleagues wrote in Arthritis & Rheumatology.
“In addition, the withdrawal of the culprit drug is sometimes sufficient to achieve vasculitis self-healing in mild cases without the need for immunosuppressants and may obviate the need for maintenance treatment,” they added. “However, it is difficult to attribute AAV to a suspected drug, and the data in the literature supporting the role of a drug in the onset of AAV mainly rely on case reports or short series and mostly implicate old treatments, such as propylthiouracil, hydralazine, allopurinol, D penicillamine, minocycline, leukotriene antagonists, and, more recently, antitumor necrosis factor-. The advent of new treatments may have modified the epidemiology of these ADRs.”
To update this list of implicated drugs, Deshayes and colleagues conducted a retrospective disproportionality analysis of data from the WHO pharmacovigilance database. As of 2020, this database contained more than 23 million individual case safety reports from more than 130 countries. The researchers collected all adverse drug reactions reported with the term “anti-neutrophil cytoplasmic antibody positive vasculitis,” focusing on the period from the introduction of this preferred term in 2006 to November 2020.
For each drug retrieved in the data, the researchers performed a case/non-case analysis and calculated disproportionate reporting using the information component (IC). A positive IC025 value — the lower end of the 95% credibility interval — was defined as significant.
The following drugs were excluded from the analysis, because of the potential for indication bias as they are used in the management of ANCA-associated vasculitisv: Azathioprine, cyclophosphamide, leflunomide, methotrexate, methylprednisolone, mycophenolic acid, prednisolone, prednisone, rituximab (Rituxan, Genentech), corticosteroids and sulfamethoxazole/trimethoprim.
According to the researchers, there were 483 unique individual case safety reports of DA-AAV, related to 15 drugs with an IC025 greater than 0. Among the reports, 71.2% reportedly occurred in women, with a median age of onset of 62 years, and a median period of 9 months between the initiation of the suspected drug and the emergence of DA-AAV. In all, 97.7% of cases were considered serious, and 8.9% were fatal. Drugs associated with the highest disproportionate reporting were hydralazine, propylthiouracil, thiamazole, sofosbuvir, minocycline, carbimazole, mirabegron (Myrbetriq, Astellas Pharma) and nintedanib (Ofev, Boehringer Ingelheim).
“This first worldwide systematic pharmacovigilance study described the largest series of DA-AAV cases, incriminating several drugs, some of which were already suspected to be a cause of DA-AAV,” Deshayes and colleagues wrote.
“In addition to confirming significant pharmacovigilance signals associated with previously incriminated drugs, such as hydralazine and antithyroid drugs, this study also shows a significant overreporting of recent drugs in DA-AAV, including mirabegron and two targeted therapies, sofosbuvir and nintedanib,” they added. “Specific prescriber attention to these drugs is needed, as well as experimental and observational studies to confirm these epidemiological data.”
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