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AOPXXX10.1177/1060028015627664Annals of Pharmacotherapy

Letter to the Editor

Reply: Adverse Drug Reactions in Pediatric Emergency Medicine

We appreciate the valuable comments on our recent work and agree with most of them. The purpose of our study was to assess the incidence of adverse drug reactions (ADRs) suspected to be caused by medication at the Pediatric Emergency Department (PED) of Nantes University Hospital (CHU). The definition of ADR meets that in the new pharmacovigilance legislation and includes ADRs resulting not only from the authorized use of a medicinal product at normal doses, but also outside the terms of the marketing authorization.1 During our monocentric study lasting 4 months, we found that 1.88% of ADRs resulted from off-label drug use. This corresponds to the use of neuroleptics in 3 children. In our study, the off-label drugs were prescribed in an outpatient setting and not during hospitalization in the PED, a medical department where off-label drug administration is less important than in other pediatric medical units (neonatology and neonatal intensive care units, for instance).2 As mentioned in the strengths and limitations section, our study design is not appropriate to estimate the number of children exposed to a drug among the studied population (11 095 patients), and thus, the incidence of off-label drug use in the study population cannot be known. So it is difficult to extrapolate the rate of ADRs linked to an off-label drug use in the population. To discuss our results and conclude that “prescribing medications off-label is a real problem because it appears to increase the risk of iatrogenic consequences in children,” we relied on data from the literature. A review of studies of off-label medicine prescribing in children showed that it ranged from 3.3% to 56% of prescriptions in the outpatient setting, and some data showed a higher rate of ADRs associated with off-label drug use.3 In a French study titled, “Adverse drug reaction and offlabel drug use in pediatric outpatients,” Horen et al4 investigate the potential relationship between off-label drug use and increased risk of ADRs in pediatric outpatients. Among the 1419 children included in this study, 42% were exposed to at least 1 off-label prescription. Off-label drug use was significantly associated with ADRs (relative risk = 3.44; 95% CI = 1.26, 9.38). The authors concluded that further studies are necessary to evaluate the expected efficacy of off-label drug use because the risk of ADRs could be acceptable if the therapeutic benefits were much greater. In another recent study, Eguale et al5 monitored and evaluated off-label use of prescription drugs and its effect on ADRs in a cohort of 46 021 adult patients. The rate of ADRs

Annals of Pharmacotherapy 2016, Vol. 50(4) 332­–333 © The Author(s) 2016 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015627664 aop.sagepub.com

for the off-label prescriptions (11.8%) was higher than that for on-label use. More precisely, off-label prescriptions with strong scientific evidence increased the ADR risk by 10% (without significant difference). In contrast, prescriptions without strong scientific evidence increased the risk of ADRs by 54% when compared with the prescriptions with marketing authorization. The authors estimate that this increase could be a result of the lack of approval by a regulatory body, which implies a lack of safe dose ranges and inadequate information as well as contraindications. The marketing authorization guarantees an acceptable benefit-risk ratio in accordance with the indications specified in the summary of product characteristics. Indeed, the off-label use may be clinically appropriate—especially in children, because trials in children have not usually been performed during the drug development process—given the complexity of the patient’s condition, the lack of alternative effective drugs, or after exhausting approved drugs. We agree with the fact that the clinical decision of off-label use should always be guided by the best available evidence in a collegial manner and taking into account the individual patient’s needs. Pharmacovigilance, through continuous assessment of the benefits and risks of a drug, provides additional information for the physician to prescribe a drug with the best available evidence. Our pharmacovigilance study in the PED is in agreement with the objectives of the European Medicines Agency (EMA). On April 28, 2014, the EMA organized a workshop to address the needs and priorities for pharmacovigilance in the pediatric population.6 Although the results of previous studies have indicated that there may be some association between off-label medicine use and ADR risk, there is still a lack of clarity. This stems from the fact that some of these previous studies were small and used different methodologies as well as inexact and varying definitions.7 However, one of the challenges in pediatric pharmacovigilance concerns the possible risk of ADRs being greater in off-label use in children. Further studies in this area are required, and these studies need to be designed with attention to detail to ensure that the results are reliable, interpretable, and useful. Julien Mahé, PharmD Domitille Darnis, PharmD Gwenaelle Veyrac, MD Pascale Jolliet, MD, PhD Nantes University Hospital, France

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Mahé et al Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The authors received no financial support for the research, authorship, and/or publication of this article.

References 1.  Borg JJ, Aislaitner G, Pirozynski M, Mifsud S. Strengthening and rationalizing pharmacovigilance in the EU: where is Europe heading to? Drug Saf. 2011;34:187-197. 2.   Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics. 2006;117:1979-1987.

3.  Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf. 2006;5:703-718. 4.  Horen B, Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol. 2002;54:665-670. 5.   Eguale T, Buckeridge DL, Verma A, et al. Association of offlabel drug use and adverse drug events in an adult population. JAMA Intern Med. 2015;2:1-9. 6.  European Medicines Agency. Report on the EMA workshop of pharmacovigilance in the paediatric population. http://www. ema.europa.eu/docs/en_GB/document_library/Report/2014/08/ WC500171787.pdf. Accessed December 21, 2015. 7.   Mason J, Pirmohamed M, Nunn T. Off-label and unlicensed medicine use and adverse drug reactions in children: a narrative review of the literature. Eur J Clin Pharmacol. 2012;68:21-28.

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Reply: Adverse Drug Reactions in Pediatric Emergency Medicine.

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