Acute Kidney Injury and Neuropsychiatric Reactions with Anti-Herpesvirus Drugs: Analysis of Spontaneously Reported Adverse Events
Objectives: Acute kidney injury and neuropsychiatric reactions have been reported with intravenous (IV) acyclovir, oral acyclovir, valacyclovir and famciclovir. The aims of this study were to explore acute kidney injury and neuropsychiatric reactions signals with these anti-herpesvirus drugs by using the public release version of the U.S. FDA adverse event reporting system (AERS) database from 2004 to second quarter 2012. Methods: Medical Dictionary for Regulatory Activities (MedDRA) terms were mapped to predeﬁned categories of acute kidney injury and neuropsychiatric reactions. Disproportionality analysis was used to calculate the reporting odd ratio (ROR) and corresponding 95% conﬁdence intervals (CI) for adverse event categories, and stratified by indication. Results: IV acyclovir, oral acyclovir, valacyclovir and famciclovir were identiﬁed as the suspect medications in 8,037 reports in the FDA AERS database. Neuropsychiatric reactions were the most frequently reported ADRs. We identiﬁed a signal for acute kidney injury with IV acyclovir, oral acyclovir, valacyclovir and famciclovir (ROR 17.68, ROR 3.09, ROR 3.97, ROR 2.93, respectively), and a signal for neuropsychiatric reactions with famciclovir (ROR 2.93). Acute kidney injury and neuropsychiatric reactions were more frequently reported in patients with varicella zoster virus (VZV) infection than in those with herpes simplex virus (HSV) infection. Conclusion: The results of the present paper conﬁrmed the higher frequency of acute kidney injury and neuropsychiatric reactions with IV acyclovir, oral acyclovir, valacyclovir and famciclovir, although more data were needed. Clinicians should stress this risk in the shared decision-making process.
Acute Kidney Injury, Neuropsychiatric Reactions, Acyclovir, Valacyclovir, Famciclovir, Postmarketing Safety Surveillance
Abudalu M, Tyring S, Koltun W, Bodsworth N, Hamed K. Single-day, patient-initiated famciclovir therapy versus 3-day valacyclovir regimen for recurrent genital herpes: a randomized, double-blind, comparative trial. Clin Infect Dis 2008; 47 (5):651-8.
Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ. Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 2000; 9 (9):863-9.
Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL,Wood MJ. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39 (7):1546-53.
Meng J, Zheng X, Zhang G, Fang Q, Oral acyclovir induced acute renal failure. World J Emerg Med 2011; 2 (4):310-3
Sugimoto T, Yasuda M, Sakaguchi M, Koyama T, Uzu T, Kashiwagi A, Isshiki K, Kanasaki M. Oliguric acute renal failure following oral valacyclovir therapy. QJM 2008 Feb; 101 (2):164-6.
Lam NN, Weir MA, Yao Z, Blake PG, Beyea MM, Gomes T, Gandhi S, Mamdani M, Wald R, Parikh CR, Hackam DG, Garg AX. Risk of acute kidney injury from oral acyclovir: a population-based study. Am J Kidney Dis 2013 May; 61 (5):723-9.
Asahi T, Tsutsui M, Wakasugi M, Tange D, Takahashi C, Tokui K, Okazawa S, Okudera H. Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol 2009 Apr; 16 (4):457-60.
Sacks SL, Aoki FY, Martel AY, Shafran SD, Lassonde M. Clinic-initiated, twice-daily oral famciclovir for treatment of recurrent genital herpes: a randomized, double-blind, controlled trial. Clin Infect Dis 2005 Oct 15; 41 (8):1097-104.
Oshima Y. Characteristics of drug-associated rhabdomyolysis: analysis of 8,610 cases reported to the US Food and Drug Administration. Intern Med 2011; 50 (8):845–53.
Yue Z, Jiang P, Sun H, Wu J. Association between an excess risk of acute kidney injury and concomitant use of ibuprofen and acetaminophen in children, retrospective analysis of a spontaneous reporting system. Eur J Clin Pharmacol. 2014 Apr; 70 (4):479-82.
Hauben M, Reich L, DeMicco J, Kim K. ‘Extreme duplication’ in the US FDA Adverse Events Reporting System database. Drug Saf 2007; 30: 551–4.
Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 2009,18:427–36
Bate A, Edwards IR. Data mining techniques in pharmacovigilance. In: Hartzema AG, Tilson HH, Chan KA, editors. Pharmacoepidemiology and Therapeutic Risk Management. 1st ed. Cincinnati, OH: Harvey Whitney Books Co; 2008.
Almenoff J, Tonning JM, Gould AL, et al. Perspectives on the use of data mining in pharmaco-vigilance. Drug Saf 2005; 28: 981–1007.
Anders Helldén. Aciclovir-induced neuropsychiatric symptoms- a clinical pharmacology study. Karolinska institutet, 2010.
Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis 2005; 45 (5):804-817.
Mason WJ, Nickols HH. Images in clinical medicine. Crystalluria from acyclovir use. N Engl J Med 2008; 358 (13):e14.
Hennessy S. Disproportionality analyses of spontaneous reports. Pharmacoepidemiol Drug Saf 2004; 13: 503–4.
Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 2001; 10: 483–6.
Yue Z, Shi J, Jiang P, Sun H. Acute kidney injury during concomitant use of valacyclovir and loxoprofen: detecting drug-drug interactions in a spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2014 Nov; 23 (11):1154-9.
Waller P. Dealing with uncertainty in drug safety: lessons for the future from sertindole. Pharmacoepidemiol Drug Saf 2003; 12: 283–7; discussion 289–90.