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Incidence of Mucocutaneous Reactions in Children Treated with Niflumic Acid, Other Nonsteroidal Antiinflammatory Drugs, Or Nonopioid Analgesics

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Incidence of Mucocutaneous Reactions in Children Treated with Niflumic Acid, Other Nonsteroidal Antiinflammatory Drugs, Or Nonopioid Analgesics Incidence of Mucocutaneous Reactions in Children Treated With Niflumic Acid, Other Nonsteroidal Antiinflammatory Drugs, or Nonopioid Analgesics Miriam Sturkenboom, PhD*‡; Alfredo Nicolosi, PhD§࿣; Luigi Cantarutti, MD¶; Salvatore Mannino, MD#; Gino Picelli‡; Antonio Scamarcia¶; and Carlo Giaquinto, MD**, for the NSAIDs Paediatric Research Group ABSTRACT. Background and Objective. Results from Participants. Children aged 0 to 14 years and regis- a relatively small case-control study recently showed that tered with 1 of the collaborating pediatricians between niflumic acid increases the risk of serious mucocutane- January 1, 1998, and May 31, 2001. ous reactions in children. As a consequence, the Italian Main Outcome Measures. The incidence rate of se- Ministry of Health sent a “Dear Doctor” letter in June vere (hospitalized or referred) and mild mucocutaneous 2001 to warn pediatricians about the alleged adverse reactions (exanthema, disseminated or localized pruritus, effects. The objective of this study was to estimate and urticaria, angioedema, fixed eruption, dermatitis, ery- compare the incidence of mild and severe mucocutane- thema multiforme, vesicles, bullae, pustules, toxic epi- ous reactions among children using niflumic acid, other dermal necrolysis, purpura, and vasculitis) was estimated nonsteroidal antiinflammatory drugs (NSAIDs), or non- during use of niflumic acid, other NSAIDs, or nonopioid analgesics. For each episode of drug use, the following opioid analgesics. covariates were assessed: age, gender, region, year, indi- Design. Retrospective cohort study. cation for study drug, use of antibiotics, antimycotic Setting. Italy is one of the few countries in which a agents, glucocorticoids, and other NSAIDs. Multivariate specific primary care system is devoted to children up to Poisson regression analysis was used to estimate the 14 years of age: every child is registered at birth and ϳ adjusted relative risk of mucocutaneous disorders during receives free medical care from 1 of the 6000 family use of niflumic acid compared with use of other NSAIDs pediatricians working for the National Health Service. or use of acetaminophen alone. This study was conducted with the Pedianet network of Results. The population included 193 727 children, Italian family pediatricians who use computerized elec- 45 351 of whom received at least 1 of the study drugs. The tronic patient records for routine care; 185 pediatricians most frequently prescribed drugs were niflumic acid, participated in the study. The patient records comprise acetaminophen, and propionic acid derivatives (ketopro- (150 32 ؍ information on demographics, diagnoses, symptoms, fen and flurbiprofen). Users of niflumic acid (n prescriptions, referrals, laboratory examinations, and were younger and slightly more often had otitis media or hospitalizations. upper respiratory tract infections as an indication com- pared with the other NSAIDs. During use of the various study drugs we identified 1451 mild mucocutaneous events and 42 severe reactions. The incidence rates of From the *Departments of Epidemiology & Biostatistics and Medical Infor- severe and mild mucocutaneous reactions after the ad- matics, Erasmus University Medical Center, Rotterdam, Netherlands; ‡In- ministration of any study drug were 10.3 per 100 000 ternational Pharmacoepidemiology and Pharmacoeconomics Research Cen- exposure person-days and 3.7 per 1000 exposure person- ter, Desio, Italy; §Department of Epidemiology and Medical Informatics, Institute of Biomedical Technologies, National Research Council, Segrate days, respectively. Both incidence rates decreased (Milano), Italy; ࿣G. H. Sergievsky Center, School of Public Health, Columbia strongly with increasing age. In comparison with other University, New York, New York; ¶Societa’ Servizi Telematici, Padova, NSAIDs, the adjusted relative risks of niflumic acid were Italy; #Azienda Ospedaliera “Istituti Ospitalieri,” Cremona, Italy; and **De- 0.5 (95% confidence interval: 0.23–1.27) for severe and 0.9 partment of Pediatrics, University of Padova, Padova, Italy. (95% confidence interval: 0.79–1.11) for mild mucocuta- Accepted for publication Dec 30, 2004. neous reactions. The use of acetaminophen as a reference doi:10.1542/peds.2004-0040 category instead of other NSAIDs, restriction of the chil- Conflict of interest: SoSeTe is an independent company running the Pedia- dren to those who received NSAIDs for respiratory tract net network. It receives funds for epidemiological research studies from infections, or restriction to those who did not use antibi- pharmaceutical companies, charities, and health authorities. The studies are conducted in accordance with Italian law, and the sponsors do not have any otics never revealed an increased risk of serious or mild input on the conduct of the study or the publication. Mr Scarmarcia is a data mucocutaneous reactions during use of niflumic acid. manager of Pedianet; Drs Giaquinto and Cantarutti are scientific coordina- Conclusions. In comparison with other NSAIDs or tors of Pedianet Sturkenboom; and Drs Nicolosi and Mannino are external acetaminophen, niflumic acid is not associated with an researchers who are members of the Scientific Committee of the Pedianet increased risk of severe or mild mucocutaneous reactions Network and receive reimbursement for the time dedicated to studies. in children. This was true for the different age groups Mr Picelli and Dr Sturkenboom are the owners of IPPRC, a research center and various types of mucocutaneous reactions, was inde- that conducts epidemiological studies for third parties, including SoSeTe pendent of the concomitant use of antibiotics, and was and various pharmaceutical companies. not sensitive to changes in our assumptions regarding Reprint requests to (C.G.) Dipartimento di Pediatria, Universita`degli Studi di Padova, Via Giustiniani 3, 35100 Padova, Italy. E-mail: carlog@child. exposure and outcomes. Pediatrics 2005;116:e26–e33. pedi.unipd.it URL: www.pediatrics.org/cgi/doi/10.1542/peds.2004-0040; PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad- niflumic acid, NSAIDs, analgesics, mucocutaneous reac- emy of Pediatrics. tions, children, cohort. e26 PEDIATRICS Vol. 116Downloaded No. 1 July from 2005 www.aappublications.org/news www.pediatrics.org/cgi/doi/10.1542/peds.2004-0040 by guest on October 1, 2021 ABBREVIATIONS. NSAID, nonsteroidal antiinflammatory drug; The source population for this study included all of the children FP, family pediatrician; RR, relative risk; CI, confidence interval; registered with 1 of the 185 participating FPs during the study OTC, over-the-counter. period (January 1, 1998, through May 31, 2001). The data for each child were collected from the start of the study period (or the date of FP registration, if later) until the occurrence of a mucocutaneous t was recently alleged that niflumic acid, the only reaction or death, until the patient was transferred or reached the age of 15 years, or until the end of the study period. The collected nonsteroidal antiinflammatory drug (NSAID) data were handled anonymously as required by Italian privacy Ithat was licensed for use in small children in Italy law. in 2001, increases the risk of mucocutaneous reac- tions in children.1 Drug Exposure It is known that NSAIDs may cause dermatologi- We identified all the children in the source population who had cal reactions ranging from rash and urticaria to se- received at least 1 prescription of an NSAID (indomethacin, su- lindac, diclofenac, fentiazac, acemetacin, proglumethacin, ketoro- vere reactions such as Lyell’s syndrome and Stevens- ϩ 2,3 lac, diclofenac misoprostol, cinnoxicam, piroxicam, tenoxicam, Johnson syndrome. These adverse drug reactions droxicam, meloxicam, furprofen, ibuprofen, naproxen, ketopro- are of public health relevance because of the wide- fen, flurbiprofen, tiaprofenic acid, mefenamic acid, amtolmetin, spread use of NSAIDs in both pediatric and adult nabumetone, niflumic acid, nimesulide, morniflumate), a nonopi- clinical practice. The NSAIDs that are prescribed oid analgesic including acetaminophen or acetylsalicylic acid de- rivatives, or pyrazolinone derivatives. To compare effects among most frequently to children in Italy are niflumic acid, drug classes, we separately considered niflumic acid/morniflu- 4 nimesulide, and propionic acid derivatives. In addi- mate, non–niflumic acid NSAIDs, acetaminophen, and nonacet- tion to Italy, niflumic acid is available for children aminophen nonopioid analgesics (acetylsalicylic acid and pyrazo- and adults in France, Spain, and Portugal and only linones). for adults in Belgium, Luxemburg, Switzerland, Ger- Exposure to the study drugs was expressed as person-time and 1 characterized by using the specific active principles (alone or in many, and Greece. combination) and other variables of interest. Mutually exclusive An Italian hospital-based case-control study of ad- treatment periods of current use were defined by applying the verse drug reactions in children found an almost following rules: (1) a fixed duration of 5 days was assigned to all fourfold excess risk of severe mucocutaneous reac- NSAID prescriptions (mean prescribed duration); (2) prescriptions ␤ for different study drugs issued on the same day were considered tions among the users of niflumic acid and its -mor- “combinations”; and (3) if a new study drug was prescribed pholinoethyl ester morniflumate (hereinafter aggre- during treatment with a previously prescribed study drug, it was gated
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