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Cutaneous Reactions to Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs

Cutaneous Reactions to Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs Clinica Universitaria. Milano; C. Vellcr-Fom asa. S. We analyzed the cutaneous reactions to systemic analgesic-antipyretics and non­ Poletto. A. Peserico. Clinica Universitaria. Padova; F. Cusano. A .G . Galluccio. M. Capozzi. Bcnevento; A. steroidal anti-inflammatory drugs reported to the spontaneous reporting system Burroni. A. Nigro. A. Farris. Ospedale San Martino. Genova; A. Fanti, P .E. Lombardi, S. Di Lorio. R. of the G ruppo Italiano Studi Epidemiologici in Dermatologia (G ISED ). The Beech ¡lega. Ravenna; P. Perno, P. Lisi. Clínica Derm a­ system has been active since 1988, with periodic intensive surveillance exercises, tológica. Perugia; A. Pestarino. A. A nnonidc. L. Mas- sone, Genova. E .O . G alliera; M .Iannantuono. M. and 202 dermatologists have collaborated. Up to December 1991, 2,137 reac­ Lomuto. S. Giovanni R otondo; E. R obert. F. Rongio- tions had been collected, of which 713 were reactions to systemic analgesic-anti­ letti. Clinica Universitaria. G enova: R. Betti. C. Crosti. Clinica Universitaria-Ospedale S. Paolo, Milano; T . Di pyretics and nonsteroidal anti-inflammatory drugs. A general profile of the reac­ Prima. A. Sapuppo. Clinica Universitaria, Catania; A. Locatclli. F. Saggiorato, Como; G . Fenizi. L. Alto- tions was identifiable. It included, in order of frequency, urticaria/angioedema, bella. Foggia; S. M oretti. II Clinica Universitaria. fixed eruptions, exanthemas, erythema multiforme and Stevens Johnson syn­ Firenze; L. Barcella. II Clinica Universitaria. Milano; G.M . Pallcschi, II Clinica Universitaria, Firenze: F. drome. Fixed eruptions and Stevens Johnson syndrome were reported with Scardigli, Trento; F. Kokelj. Clinica Universitaria. exceedingly high frequency in association with feprazone. O ur system also Trieste; A. Cimitan, Clinica Universitaria. Modena; P. Taddeucci, Clinica Universitaria. Siena; G . Cannata, revealed previously unreported reactions, including fixed eruption to nimesu- Ospedale di Albenga: V. Ingordo. Ospedale Marina Militare Taranto. lide, fixed eruption to piroxicam and fixed eruption to flurbiprofen. Received: Coordinamcnto Tccnico G ISED (L. Naldi. T. Caineili) © 1993 Karger A G . Basel May 19. 1992 C attedra di Clinica Dcrmosifilopatica 1018-8665/93/1863-0164 Accepted: Universitä degli Studi di Milano $ 2.75A) Septem ber 22. 1992 Ospedali Riuniti di Bergamo L.go Barozzi 1. 1 24100 Bergamo (Italy) Introduction Materials and Methods The aim. general organization and functioning of the spontaneous The nonsteroidal anti-inflammatory and nonnarcotic reporting system of G ISED have been previously reported [9], Brief­ analgesic and antipyretic drugs are a heterogeneous group ly, the program involves thirty-three hospital-based services. In each of compounds, often chemically unrelated, although the center a m onitor, i.c. a specifically trained dermatologist, coordinates vast majority of them are weakly acidic, which share certain the study locally, asking all dermatologists working in the hospital and therapeutic effects on inflammation, fever and pain. The in services outside the hospital in his area to participate by reporting all the adverse reactions they observe in their practice during prespecified inhibition of prostaglandin biosynthesis partly explains the 2-month periods. Up to December 1991, 202 dermatologists had therapeutic effects and, the prototype being aspirin, these agreed to participate. Most of them were practicing dermatologists compounds are sometimes referred to as aspirin-like drugs working both in public services and in private offices and about 35% of [1]. Even if these drugs may have other mechanisms of them worked inside the participating hospitals. The study was based action, it is generally accepted that the rank order of on spontaneous collaboration of dermatologists and we did not attem pt to cover a defined population. However, from administrative potency as inhibitors of prostaglandin synthesis in vitro data provided by the hospitals participating in the study, the popula­ tends to reflect their anti-inflammatory potency in vivo [2], tion base could be estimated at about 10 million people (for severe Differences in the therapeutic activities justify a broad dis­ conditions leading to hospitalization, this would represent a valid esti­ tinction between the analgesic-antipyretics, including weak mate of the surveyed population). Four 2-month monitoring periods, inhibitors of prostaglandin synthesis, e.g. para-amino- one between June and December 1988, one between May and August 1989 and two between April and December 1991, were agreed upon by phenol derivatives like paracetamol and salicylates, and the the dermatologists in each center. Monitoring periods varied from one more potent inhibitors, strictly speaking the nonsteroidal center to another, within the broad intervals specified above, accord­ anti-inflammatory drugs, which are mainly used for rheu- ing to the choices made by each center. In the periods between the matologic disorders [3]. Although cutaneous reactions to monitoring phases, dermatologists were asked to limit signalling the systemic analgesic-antipyretics and nonsteroidal anti­ more serious or unusual reactions. The few reports collected in these periods were not included in this analysis. Adverse drug reactions inflammatory drugs are considered to be frequent, we have were noted on a standard form and the forms collected by the monitor only limited data about the general profile of these reac­ were periodically sent to the study’s coordinating center. The coordi­ tions. The most recent systematic review, based on data nating center carefully evaluated the records, judging in particular the from the Adverse Drug Reaction Reporting System of the completeness and internal consistency, and reclassified the reactions American Academy of Dermatology, was conducted in according to a standardized vocabulary. The degree of confidence in the association between the drug(s) and the cvcnt(s) was reviewed by a 1984 [4]. In recent years, an increasing num ber of new anal­ panel of clinicians, applying a modified version of the decision tabic gesic-antipyretics and nonsteroidal anti-inflammatory proposed by Karch and Lasagna |11] and was expressed as ‘definite’, drugs have been introduced into the m arket, including, for ‘probable’, ‘possible’ and 'n o t related' (reactions in which more than example, in Europe, nimesulide, and oxicams. Specialist one drug was suspected were usually included in the ‘possible’ cate­ assessment and update of dermatologic reactions to these gory). Each form was subsequently codified to allow com puter input for data management. Drugs were entered by trade name, but it was new drugs are needed to have a balanced and satisfactory possible to reclassify them by nonproprietary name and Anatomical profile of the clinical patterns [5-8]. The postmarketing sur­ Therapeutic Chemical (ATC) code. For the purposes of this study we veillance program of the G ruppo Italiano Studi Epidemio- abstracted reactions to anti-inflammatory and antirheumatic products logici in Dermatologia (G ISED ) was started in 1988 and (ATC code M01) and to analgesics (ATC code N02). Specific slow- was conceived as a set of research activities including a acting antirheumatic agents (e.g. gold salts) were excluded from the analysis. Opioid analgesics and antimigrainc preparations were also spontaneous reporting system [9] and selected epidemio­ excluded. Sulfamazone, which is a derivative of 4-formyl-fenazone logic studies [10]. The spontaneous reporting system works and sulfamcthoxypyridazine, classified as both a chemotherapeutic through periodic intensive monitoring exercises, with the agent (ATC code J03) and an antirheumatic, was kept in the analysis. participation of about 200 Italian dermatologists. Up to Cases of toxic epidermal necrolysis were excluded from our sur­ D ecember 1991, 2,137 cutaneous reactions had been col­ veillance. since they were the object of the case-control study we are conducting on this disease [10, 12]. lected, of which 713 were reactions to systemic analgesic- antipyretics and nonsteroidal anti-inflammatory drugs. We have analyzed the profiles of these reactions, with special emphasis on the recently introduced drugs. Results During the four intensive monitoring periods we col­ lected 713 reactions to systemic analgesic-antipyretics and nonsteroidal anti-inflammatory drugs, representing 33% of 165 Table 1. Distribution of the reactions according to the suspected drug and clinical pattern Fixed Erythema Stevens- Exanthema Urticaria/ Purpura Photo- Anaphylactic Cutaneous Lichenoid Total eruption multiforme Johnson s angioedema sensitivity shock necrosis dermatitis 29 8 5 8 8 Feprazone alone 58 30 10 10 3 6 com bination1 59 16 7 1 11 40 1 Acetilsalicylic acid 76 12 2 2 3 23 Dipyrone 42 7 i 3 8 i 20 Propyphenazone" 4 10 Naproxen 16 i 4 7 i Diclofenac 13 Ketoprofen 6 1 10 4 i i 3 Piroxicam i 10 3 4 Paracetamol' 9 3 2 Fcnazonc 9 3 i 3 Sulfamazone 1 2 i 1 i Ibuprofen 6 i 4 Nimesulidc i 4 Indomethacin Etodolac 3 1 2 Flurbiprofen 3 Floctafenine 1 1 Flunoxaprofen 1 1 Tenoxicam 1 1 Tiaprofcnic acid I 1 Benzydaminc 1 1 32 17 55 128 2 1 3 1 1 All drugs 354 ' T h e c o m b in a t io n w ith p a r a c e ta m o l a n d g u a ife n e s in a c c o u n t e d fo r 4 r e a c t io n s a n d th a t w ith p a r a c e ta m o l, c h lo r p h e n a m in e m a le a tc and phenylpropanolamine accounted for 55 reactions. Include the following combinations: with allobarbital (6 reactions), with paracetamol and caffeine (8 reactions), with phenacetin and caffeine (5 reactions). Include the combination with pscudoephedrine and triprolidinc (3 reactions). 4 All the reactions to the combination product with caffeine and butalbital. Table 2. Most serious and/or unusual Reaction Suspected drug(s) Reports, n reactions judged to be possibly related to use of analgesic-antipyretics and Vasculitis flurbiprofen nonsteroidal anti-inflammatory drugs piroxicam 1 feprazone Stcvens-Johnson s. acctylsalicylic acid 3 acctylsalicylic acid; sulfamazone diclofenac; dypirone 1 feprazone; paracetamol dypirone paracetamol 1 paracetamol + chlorphenamine maleatc + phenylpropanolamine + feprazone 1 Lichenoid dermatitis diclofenac 1 feprazone 1 ketoprofen; diclofenac 166 Gruppo Italiano Studi Epidcmiologici in Cutaneous Reactions to Dermatología (GISED) Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs the total num ber of 2.137 reactions collected. The reactions chemically heterogeneous group of compounds, a common were judged to be possibly associated in 346 cases (48%). general profile of reactions was identifiable from our study, including 204 cases in which more than one drug was sus­ including, in order of frequency, urticaria/angioedcma. pected. probably in 220 cases (31%) and definitely associ­ fixed eruptions, exanthemas, erythema multiforme and ated in 134 cases (19%). 13 reactions (2%) were discarded Stevens Johnson syndrome. This pattern, which could be because they were judged not to be associated or because defined as the ‘expected’ reaction profile of the drugs of other major flaws. The distribution of culpability scores examined, is not peculiar to analgesics and nonsteroidal for reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs but seems to reflect a more gen­ anti-inflammatory drugs was quite similar to the distribu­ eral experience in our surveillance. Figures for probable/ tions of reactions to several other major classes of drugs in definite reactions to all classes of systemic drugs, obtained our data base, suggesting that application of assessment cri­ from our data base, rank urticaria/angioedcma first, with teria by participating dermatologists was uniform. To give about one-third of all the reactions, followed by exanthe­ an example, definite/probable reactions represented 50% mas (about 20% ), fixed eruptions (15%) and erythema of all reactions to analgesics and nonsteroidal anti-inflam­ niultiforme/Stevens Johnson syndrome (7% ). These pro­ matory drugs, and 53% of all reactions to antibiotics (ATC files are different from those obtained from traditional code J01). We considered for the main analysis the 354 spontaneous reporting systems, which rank several types of reactions probably/definitely associated with systemic anal­ ‘rash’, urticaria and pruritus as the most frequent patterns gesic-antipyretics and nonsteroidal anti-inflammatory of reactions [13]. Differences could largely be explained by drugs use. The profile of these reactions is reported in table the setting of surveillance, which in our case is speciality- I . Urticaria, fixed eruptions and exanthemas accounted for and mostly hospital-based. more than 80% o f all the reactions reported and these pat­ Besides similarities, differences between drugs were terns of reaction, even with differences between drugs in observed with reference to the relative frequencies of single their relative frequency, were shared by most of the drugs reaction patterns, with fixed eruptions and erythema multi- analyzed. Fixed eruptions represented 50% of all the reac­ forme/Stevcns Johnson syndrome being reported with tions to feprazone reported, while urticaria was only 12%. exceedingly high frequency in association with feprazone. The pattern was the reverse for acetylsalicylic acid. Ery­ This drug alone was responsible for 52% of all cases of fixed thema multiforme, and Stevens Johnson syndrome eruptions and 67% of all cases of erythema multiforme/Ste- accounted for a great part of the remaining reactions, being vens Johnson syndrome attributed to analgesic-antipyretics reported with especially high frequency in association with and nonsteroidal anti-inflammatory drugs. These findings feprazone. Sporadically reported reactions included ana­ arc in agreement with data from surveillance systems in phylactic shock. purpuras, photosensitivity, and vasculitis. other countries in which regulatory actions have been Table 2 lists those reactions judged as possibly related to taken [14]. A nother serious reaction reported with unusual­ drug use which were more serious or unusual. 175 (25%) of ly high frequency was anaphylactic shock, in association the 700 patients experiencing reactions judged as related to with dipyrone. Anaphylactic shock, as an idiosyncratic drug use had histories of previous adverse drug reactions. phenomenon, is a known reaction to the pyrazolone The suspected drug was stopped for 564 (81%) cases; for derivatives aminophenazone and dipyrone [15]. The find­ 356 (51%) cases no other drug, including any treatm ent for ings from our study are in general agreement (although the adverse reaction, was administered. As a consequence comparisons have to be limited to a few drugs) with the of the adverse reaction. 176 (25%) patients were hospital­ experience of the Adverse Drug Reaction Reporting Sys­ ized. tem of the American Academy of Dermatology except for the frequency of photosensitivity and vesicobullous reac­ tions to piroxicam [4]. These reactions are probably rarer Discussion than would be inferred from the data reported to the A m er­ ican Academy system, which gave special emphasis to We analyzed the cutaneous reaction profiles of systemic newly discovered adverse reactions. It is also possible that analgesic-antipyretics and nonsteroidal anti-inflammatory the participating dermatologists underreported photosensi­ drugs, based on reports to the spontaneous reporting sys­ tivity and bullous reactions. Photosensitivity has been tem of G ISED . O u r aim was to look for signals and pre­ reported in association with other analgesic-antipyretics viously unreported reactions. Although analgesic-antipy­ and nonsteroidal anti-inflammatory drugs, including retics and nonsteroidal anti-inflammatory drugs are a naproxen [16], tiaprofenic acid [17], ibuprofen, indometha- 167 cin and ketoprofen (18. 19], and none of these drugs was piroxicam, tiaprofenic acid and meclofenamate [4, 19,24]. associated with photosensitivity in our study. In general, Both lichenoid reactions and vasculitis are reactions diffi­ special caution should be taken when interpreting data for cult to investigate by spontaneous reporting systems, relative frequencies of reactions calculated from sponta­ because of the several possible etiologic factors involved neous reports [20, 21]. Differences could be explained in and, in our opinion, more formal epidemiologic studies are terms of differences in the frequencies of exposure and needed [20], indications for drug use in the populations and of differ­ The spontaneous reporting system of G ISED is a new ences in the frequencies of reporting of the reactions by the mechanism for reporting of adverse reactions by Italian doctors. We tried in our study to reduce the bias of selective dermatologists. The term ‘spontaneous' as applied to our reporting by asking dermatologists to report all the adverse method is probably inaccurate. ‘Spontaneous’ reports orig­ events diagnosed in their current clinical practices during inate in the absence o f sustained external stimuli [25], In intensive monitoring periods and, in this respect, it was our system we asked a network of dermatologists to play an reassuring that the culpability scores were uniformly dis­ active role by both systematically reporting, during limited tributed between different drug classes in our survey. On periods, all the reactions they observed in their practice and the other hand, finding appropriate denominators (i.e. by disseminating the method to other dermatologists. The people exposed to the drug at a given time in the popula­ main advantage of our method, as illustrated by our results, tion) is a formidable task not adequately addressed in any is the accurate clinical definition of cases, producing more study based on spontaneous reporting [21]. Roughly, based specific profiles of adverse skin reactions. The m ethod is on drug utilization surveys recently conducted in selected probably biased toward identification of more serious and/ areas in Italy [22], the most frequently prescribed analgesic- or unusual and/or difficult-to-diagnose cutaneous manifes­ antipyretics and nonsteroidal anti-inflammatory drugs tations (e.g. fixed eruption, Stevens-Johnson syndrome). during the study period included, in order of decreasing Notably, it has been estimated that no more than 10% of frequency (with a ratio between the more and the less severe adverse reactions have been reported to the tradi­ prescribed drug, greater than 1:10), several pyrazolone tional spontaneous monitoring programs [26]. A pitfall of derivatives (i.e. feprazone, dipyronc, propyphenazone), the method is that milder reactions, e.g. pruritus, are prob­ acetylsalicylic acid and paracetamol, followed by diclofe­ ably underreported or not detected. These could include nac, ketoprofen, piroxicam, nimesulide, naproxen, indo- early manifestations of more serious slowly developing methacin, ibuprofen, tiaprofenic acid, and etodolac. These reactions (a striking example are the ocular symptoms figures, however, are based on a sample of only 300 pre­ induced by practolol). In principle, a speciality-based sys­ scribe rs and, for example, do not take into account over the tem could be more susceptible to a ‘notoriety’ bias, i.e. counter drugs and self-prescriptions. underreporting of adverse reactions that are not currently In our survey, to the best of our knowledge, some pre­ of great interest. The low rate of reports excluded by our viously unreported reactions were collected. These coordinating center suggests, to some extent, that there included fixed eruption to nimesulide, fixed eruption to was a conservative attitude in signalling, i.e. only clear pat­ piroxicam, and fixed eruption to flurbiprofen. These are terns of adverse reactions were reported, with doubtful not completely unexpected findings, given the overall pro­ cases neglected. More in general, our method, like any file of reactions to analgesic-antipyretics and nonsteroidal other method based on spontaneous reporting, is subject to anti-inflammatory drugs outlined before. O ther interesting problems of overascertainment (physicians may attribute signals from our study included lichenoid dermatitis and an adverse outcome to a drug when in fact it is not one) or vasculitis as possible reactions. Lichenoid dermatitis was underascertainment and suffers from the lack of good esti­ associated with phenacetin and propyphenazone in a multi­ mates of the population at risk, so that it is not possible to ple agent drug (1 case), with diclofenac (1 case), with fepra­ calculate rates. Signals could only arise based on level of zone (1 case) and with ketoprofen and diclofenac taken causality, severity of reaction and the number of similar together (1 case). Vasculitis was reported in association cases reported [27]. with flurbiprofen (1 case), with piroxicam (1 case) and with In conclusion, in spite of the above-mentioned limita­ feprazone (1 case). Lichenoid dermatitis has been reported tions, our work provides evidence of the usefulness of a before in association with naproxen, aminophenazonc and speciality-based surveillance system for spontaneous phenylbutazone [19, 23]; vasculitis has been previously reporting of adverse reactions to drugs. We were able to reported in association with naproxen, acetylsalicylic acid, collect a large num ber of reports from collaborating derm a­ aclofenac, ibuprofen, indomethacin, phenylbutazone, tologists, increasing our knowledge of the reaction profiles Gruppo Italian« Studi Epidcmiologici in Cutaneous Reactions to Dermatologia (GISED ) Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs Acknowledgements of some recently marketed drugs. Moreover, based on sev­ eral hundred contacts with collaborating dermatologists, we This study was supported in part by the Italian Ministry of Health. believe that our system has increased the dermatologists’ The generous contributions of the following pharmaceutical compa­ awareness of problems connected with identification and nies are gratefully acknowledged: Cilag. Janssen. Roche, Schcring. reporting of adverse reactions. The view of adverse reac­ and Boehringer Ingclheim. We thank the anonymous referees for tions provided by o u r surveillance is limited to one organ, their helpful suggestions. i.c. the skin, and it is desirable, in our opinion, that similar surveillance systems be activated for other specialities. References 10 Naldi L. LocaIi F. Marchesi L. Cainelli T and 18 Bruinsma W: A Guide to Drug Reactions, ed 1 Flower RJ. Moneada S. Vane JR: Analgesic- antipyretics and anti-inflammatory agents: G ISE D : Incidence o f toxic epidermal necroly­ 5. The File o f Medicines. PO Box 2 1. Oosthui- drugs em ployed in the treatment o f gout: in sis in Italy. Arch Dermatol 1990:126: zcn. The Netherlands. 1103-1104. 19 Bork K: Cutaneous Side Effects o f Drugs. Phil­ G oodman Gilman A . G oodm an I.S. Gilman A 11 Karcli FE. Lasagna L: Toward the operational adelphia. Saunders. 1988. (eds): The Pharmacological Basis o f Therapeu­ tics. ed 7. New York. MacMillan. 1985. identification o f adverse drug reactions. Clin 20 Slone D . Shapiro S. Mictlincn OS: C ase-con­ pp 6 7 4-715. Pharmacol Thcr 1977:21:247-254. trol surveillance o f serious illnesses attributable 2 Brooks PM. Day RO: Nonsteroidal antiinflam­ 12 Gruppo Italiano Studi Epidemiologien in D er­ to ambulatory drug use; in C olom bo F. Shapiro matología (G IS E D ). Sorveglianza caso-con- S. Slone D . Tognoni G (eds): Epidemiological matory drugs - differences and similarities. N Evaluation o f Drugs. A m sterdam . Elsevier/ Engl J Med 1991;324:1716-1725. trollo della síndrome di Stevens-Johnson e 3 Simon t,S . Mills JA: Nonsteroidal antiinflam­ della síndrome di Lyell: Presentazione del pro- North Holland. 1977. pp 5 9 -7 0 . matory drugs. N Engl J Med 1980;302(part getto G IS E D . G Ital Dermatol V enereol 21 Carson J. Strom BL: Techniques o f postmar­ keting surveillance. A n overview . Med Toxicol 1 ): 1179— 1185. (part 2)1237-1243. 1989; 124:435-440. 1986:1:237-246. 4 Stern RS. Bigby M: An expanded profile o f 13 Olsson S: International reporting o f adverse cutaneous reactions to nonsteroidal anti­ drug reactions: The WHO program. Sein D er­ 22 Coen D . Tognoni G: Formulario Terapéutico inflammatory drugs. JA M A 1984:252: matol 1989:8:72-74. per la Medicina G enerale. R om a. II Pensiero Scicntifico. 1991. 1433-1437. ' 14 Weber JCP: Epidemiology o f adverse reac­ 23 Heyinann W R. Leman JS. Luftschein S: 5 Bruinsma W: Skin reactions; in Inman WHW tions to nonsteroidal antiinflammatory drugs: (cd): Monitoring for Drug Safety. Lancaster. in Rainsford K D , V elo GP (eds): Advances in Lichen planus induced by naproxen. J Am Inflammation Research. N ew York. Raven Acad Dermatol 1984:10:299-301. MTP Press. 1985. pp 285-288. 6 Stern RS: Identifying adverse reactions to Press. 1984. vol 6 . pp 1-7. 24 Singhal PC. Faulkner M. Vcnkatcsham J . et al: drugs reporting system s. Clin Dermatol 1986: 15 Szczeklik A , Gryglewski RJ. Czerniawska- Hypersensitivity angiitis associated with 4:15-22. Mysik G: Clinical patterns o f hypersensitivity naproxen. Ann Allergy 1989;63:107-109. 25 Faiclt G A: Adverse-drug-reaction monitoring. 7 Shear Nil: Diagnosing cutaneous adverse to nonsteroidal anti-inflammatory drugs and N Engl .1 Med 1986:314:1589-1592. reactions to drugs. Arch Dermatol 1990:126: their pathogenesis. J Allergy Clin Immunol 94-97. 1977:60:276-284. 26 Rawlins MD: Spontaneous reporting o f 16 Sterling JC. Pye RJ: Naproxen-induced adverse reactions. I: The data. Br .1 Pharmacol 8 Zürcher K. Krebs A: Cutaneous Side Effects 1988:26:1-6. o f Systemic Drugs. Basel. Karger. 1980. pseudoporphyria. Br J Rheumatol 1987:26: 9 Gruppo Italiano Studi Epidemiologien in D er­ 210- 211. 27 Vcnulel J: Som e aspects o f drug monitoring. matología (G ISE D ): Spontaneous monitoring 17 Valseechi R. Di Landro A: Tiaprofcnic acid Adv Drug React Pois Rev 1985:3:161-175. photoderm atilis. Contact Dermatitis 1989:21: o f adverse reactions to drugs by Italian derma­ tologists: A pilot study. Dermatológica 1991; 345-346. 182:12-17. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Dermatology Karger

Cutaneous Reactions to Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs

Dermatology , Volume 186 (3): 6 – Jan 1, 1993
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Karger
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© 1993 S. Karger AG, Basel
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1018-8665
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Abstract

Clinica Universitaria. Milano; C. Vellcr-Fom asa. S. We analyzed the cutaneous reactions to systemic analgesic-antipyretics and non­ Poletto. A. Peserico. Clinica Universitaria. Padova; F. Cusano. A .G . Galluccio. M. Capozzi. Bcnevento; A. steroidal anti-inflammatory drugs reported to the spontaneous reporting system Burroni. A. Nigro. A. Farris. Ospedale San Martino. Genova; A. Fanti, P .E. Lombardi, S. Di Lorio. R. of the G ruppo Italiano Studi Epidemiologici in Dermatologia (G ISED ). The Beech ¡lega. Ravenna; P. Perno, P. Lisi. Clínica Derm a­ system has been active since 1988, with periodic intensive surveillance exercises, tológica. Perugia; A. Pestarino. A. A nnonidc. L. Mas- sone, Genova. E .O . G alliera; M .Iannantuono. M. and 202 dermatologists have collaborated. Up to December 1991, 2,137 reac­ Lomuto. S. Giovanni R otondo; E. R obert. F. Rongio- tions had been collected, of which 713 were reactions to systemic analgesic-anti­ letti. Clinica Universitaria. G enova: R. Betti. C. Crosti. Clinica Universitaria-Ospedale S. Paolo, Milano; T . Di pyretics and nonsteroidal anti-inflammatory drugs. A general profile of the reac­ Prima. A. Sapuppo. Clinica Universitaria, Catania; A. Locatclli. F. Saggiorato, Como; G . Fenizi. L. Alto- tions was identifiable. It included, in order of frequency, urticaria/angioedema, bella. Foggia; S. M oretti. II Clinica Universitaria. fixed eruptions, exanthemas, erythema multiforme and Stevens Johnson syn­ Firenze; L. Barcella. II Clinica Universitaria. Milano; G.M . Pallcschi, II Clinica Universitaria, Firenze: F. drome. Fixed eruptions and Stevens Johnson syndrome were reported with Scardigli, Trento; F. Kokelj. Clinica Universitaria. exceedingly high frequency in association with feprazone. O ur system also Trieste; A. Cimitan, Clinica Universitaria. Modena; P. Taddeucci, Clinica Universitaria. Siena; G . Cannata, revealed previously unreported reactions, including fixed eruption to nimesu- Ospedale di Albenga: V. Ingordo. Ospedale Marina Militare Taranto. lide, fixed eruption to piroxicam and fixed eruption to flurbiprofen. Received: Coordinamcnto Tccnico G ISED (L. Naldi. T. Caineili) © 1993 Karger A G . Basel May 19. 1992 C attedra di Clinica Dcrmosifilopatica 1018-8665/93/1863-0164 Accepted: Universitä degli Studi di Milano $ 2.75A) Septem ber 22. 1992 Ospedali Riuniti di Bergamo L.go Barozzi 1. 1 24100 Bergamo (Italy) Introduction Materials and Methods The aim. general organization and functioning of the spontaneous The nonsteroidal anti-inflammatory and nonnarcotic reporting system of G ISED have been previously reported [9], Brief­ analgesic and antipyretic drugs are a heterogeneous group ly, the program involves thirty-three hospital-based services. In each of compounds, often chemically unrelated, although the center a m onitor, i.c. a specifically trained dermatologist, coordinates vast majority of them are weakly acidic, which share certain the study locally, asking all dermatologists working in the hospital and therapeutic effects on inflammation, fever and pain. The in services outside the hospital in his area to participate by reporting all the adverse reactions they observe in their practice during prespecified inhibition of prostaglandin biosynthesis partly explains the 2-month periods. Up to December 1991, 202 dermatologists had therapeutic effects and, the prototype being aspirin, these agreed to participate. Most of them were practicing dermatologists compounds are sometimes referred to as aspirin-like drugs working both in public services and in private offices and about 35% of [1]. Even if these drugs may have other mechanisms of them worked inside the participating hospitals. The study was based action, it is generally accepted that the rank order of on spontaneous collaboration of dermatologists and we did not attem pt to cover a defined population. However, from administrative potency as inhibitors of prostaglandin synthesis in vitro data provided by the hospitals participating in the study, the popula­ tends to reflect their anti-inflammatory potency in vivo [2], tion base could be estimated at about 10 million people (for severe Differences in the therapeutic activities justify a broad dis­ conditions leading to hospitalization, this would represent a valid esti­ tinction between the analgesic-antipyretics, including weak mate of the surveyed population). Four 2-month monitoring periods, inhibitors of prostaglandin synthesis, e.g. para-amino- one between June and December 1988, one between May and August 1989 and two between April and December 1991, were agreed upon by phenol derivatives like paracetamol and salicylates, and the the dermatologists in each center. Monitoring periods varied from one more potent inhibitors, strictly speaking the nonsteroidal center to another, within the broad intervals specified above, accord­ anti-inflammatory drugs, which are mainly used for rheu- ing to the choices made by each center. In the periods between the matologic disorders [3]. Although cutaneous reactions to monitoring phases, dermatologists were asked to limit signalling the systemic analgesic-antipyretics and nonsteroidal anti­ more serious or unusual reactions. The few reports collected in these periods were not included in this analysis. Adverse drug reactions inflammatory drugs are considered to be frequent, we have were noted on a standard form and the forms collected by the monitor only limited data about the general profile of these reac­ were periodically sent to the study’s coordinating center. The coordi­ tions. The most recent systematic review, based on data nating center carefully evaluated the records, judging in particular the from the Adverse Drug Reaction Reporting System of the completeness and internal consistency, and reclassified the reactions American Academy of Dermatology, was conducted in according to a standardized vocabulary. The degree of confidence in the association between the drug(s) and the cvcnt(s) was reviewed by a 1984 [4]. In recent years, an increasing num ber of new anal­ panel of clinicians, applying a modified version of the decision tabic gesic-antipyretics and nonsteroidal anti-inflammatory proposed by Karch and Lasagna |11] and was expressed as ‘definite’, drugs have been introduced into the m arket, including, for ‘probable’, ‘possible’ and 'n o t related' (reactions in which more than example, in Europe, nimesulide, and oxicams. Specialist one drug was suspected were usually included in the ‘possible’ cate­ assessment and update of dermatologic reactions to these gory). Each form was subsequently codified to allow com puter input for data management. Drugs were entered by trade name, but it was new drugs are needed to have a balanced and satisfactory possible to reclassify them by nonproprietary name and Anatomical profile of the clinical patterns [5-8]. The postmarketing sur­ Therapeutic Chemical (ATC) code. For the purposes of this study we veillance program of the G ruppo Italiano Studi Epidemio- abstracted reactions to anti-inflammatory and antirheumatic products logici in Dermatologia (G ISED ) was started in 1988 and (ATC code M01) and to analgesics (ATC code N02). Specific slow- was conceived as a set of research activities including a acting antirheumatic agents (e.g. gold salts) were excluded from the analysis. Opioid analgesics and antimigrainc preparations were also spontaneous reporting system [9] and selected epidemio­ excluded. Sulfamazone, which is a derivative of 4-formyl-fenazone logic studies [10]. The spontaneous reporting system works and sulfamcthoxypyridazine, classified as both a chemotherapeutic through periodic intensive monitoring exercises, with the agent (ATC code J03) and an antirheumatic, was kept in the analysis. participation of about 200 Italian dermatologists. Up to Cases of toxic epidermal necrolysis were excluded from our sur­ D ecember 1991, 2,137 cutaneous reactions had been col­ veillance. since they were the object of the case-control study we are conducting on this disease [10, 12]. lected, of which 713 were reactions to systemic analgesic- antipyretics and nonsteroidal anti-inflammatory drugs. We have analyzed the profiles of these reactions, with special emphasis on the recently introduced drugs. Results During the four intensive monitoring periods we col­ lected 713 reactions to systemic analgesic-antipyretics and nonsteroidal anti-inflammatory drugs, representing 33% of 165 Table 1. Distribution of the reactions according to the suspected drug and clinical pattern Fixed Erythema Stevens- Exanthema Urticaria/ Purpura Photo- Anaphylactic Cutaneous Lichenoid Total eruption multiforme Johnson s angioedema sensitivity shock necrosis dermatitis 29 8 5 8 8 Feprazone alone 58 30 10 10 3 6 com bination1 59 16 7 1 11 40 1 Acetilsalicylic acid 76 12 2 2 3 23 Dipyrone 42 7 i 3 8 i 20 Propyphenazone" 4 10 Naproxen 16 i 4 7 i Diclofenac 13 Ketoprofen 6 1 10 4 i i 3 Piroxicam i 10 3 4 Paracetamol' 9 3 2 Fcnazonc 9 3 i 3 Sulfamazone 1 2 i 1 i Ibuprofen 6 i 4 Nimesulidc i 4 Indomethacin Etodolac 3 1 2 Flurbiprofen 3 Floctafenine 1 1 Flunoxaprofen 1 1 Tenoxicam 1 1 Tiaprofcnic acid I 1 Benzydaminc 1 1 32 17 55 128 2 1 3 1 1 All drugs 354 ' T h e c o m b in a t io n w ith p a r a c e ta m o l a n d g u a ife n e s in a c c o u n t e d fo r 4 r e a c t io n s a n d th a t w ith p a r a c e ta m o l, c h lo r p h e n a m in e m a le a tc and phenylpropanolamine accounted for 55 reactions. Include the following combinations: with allobarbital (6 reactions), with paracetamol and caffeine (8 reactions), with phenacetin and caffeine (5 reactions). Include the combination with pscudoephedrine and triprolidinc (3 reactions). 4 All the reactions to the combination product with caffeine and butalbital. Table 2. Most serious and/or unusual Reaction Suspected drug(s) Reports, n reactions judged to be possibly related to use of analgesic-antipyretics and Vasculitis flurbiprofen nonsteroidal anti-inflammatory drugs piroxicam 1 feprazone Stcvens-Johnson s. acctylsalicylic acid 3 acctylsalicylic acid; sulfamazone diclofenac; dypirone 1 feprazone; paracetamol dypirone paracetamol 1 paracetamol + chlorphenamine maleatc + phenylpropanolamine + feprazone 1 Lichenoid dermatitis diclofenac 1 feprazone 1 ketoprofen; diclofenac 166 Gruppo Italiano Studi Epidcmiologici in Cutaneous Reactions to Dermatología (GISED) Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs the total num ber of 2.137 reactions collected. The reactions chemically heterogeneous group of compounds, a common were judged to be possibly associated in 346 cases (48%). general profile of reactions was identifiable from our study, including 204 cases in which more than one drug was sus­ including, in order of frequency, urticaria/angioedcma. pected. probably in 220 cases (31%) and definitely associ­ fixed eruptions, exanthemas, erythema multiforme and ated in 134 cases (19%). 13 reactions (2%) were discarded Stevens Johnson syndrome. This pattern, which could be because they were judged not to be associated or because defined as the ‘expected’ reaction profile of the drugs of other major flaws. The distribution of culpability scores examined, is not peculiar to analgesics and nonsteroidal for reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs but seems to reflect a more gen­ anti-inflammatory drugs was quite similar to the distribu­ eral experience in our surveillance. Figures for probable/ tions of reactions to several other major classes of drugs in definite reactions to all classes of systemic drugs, obtained our data base, suggesting that application of assessment cri­ from our data base, rank urticaria/angioedcma first, with teria by participating dermatologists was uniform. To give about one-third of all the reactions, followed by exanthe­ an example, definite/probable reactions represented 50% mas (about 20% ), fixed eruptions (15%) and erythema of all reactions to analgesics and nonsteroidal anti-inflam­ niultiforme/Stevens Johnson syndrome (7% ). These pro­ matory drugs, and 53% of all reactions to antibiotics (ATC files are different from those obtained from traditional code J01). We considered for the main analysis the 354 spontaneous reporting systems, which rank several types of reactions probably/definitely associated with systemic anal­ ‘rash’, urticaria and pruritus as the most frequent patterns gesic-antipyretics and nonsteroidal anti-inflammatory of reactions [13]. Differences could largely be explained by drugs use. The profile of these reactions is reported in table the setting of surveillance, which in our case is speciality- I . Urticaria, fixed eruptions and exanthemas accounted for and mostly hospital-based. more than 80% o f all the reactions reported and these pat­ Besides similarities, differences between drugs were terns of reaction, even with differences between drugs in observed with reference to the relative frequencies of single their relative frequency, were shared by most of the drugs reaction patterns, with fixed eruptions and erythema multi- analyzed. Fixed eruptions represented 50% of all the reac­ forme/Stevcns Johnson syndrome being reported with tions to feprazone reported, while urticaria was only 12%. exceedingly high frequency in association with feprazone. The pattern was the reverse for acetylsalicylic acid. Ery­ This drug alone was responsible for 52% of all cases of fixed thema multiforme, and Stevens Johnson syndrome eruptions and 67% of all cases of erythema multiforme/Ste- accounted for a great part of the remaining reactions, being vens Johnson syndrome attributed to analgesic-antipyretics reported with especially high frequency in association with and nonsteroidal anti-inflammatory drugs. These findings feprazone. Sporadically reported reactions included ana­ arc in agreement with data from surveillance systems in phylactic shock. purpuras, photosensitivity, and vasculitis. other countries in which regulatory actions have been Table 2 lists those reactions judged as possibly related to taken [14]. A nother serious reaction reported with unusual­ drug use which were more serious or unusual. 175 (25%) of ly high frequency was anaphylactic shock, in association the 700 patients experiencing reactions judged as related to with dipyrone. Anaphylactic shock, as an idiosyncratic drug use had histories of previous adverse drug reactions. phenomenon, is a known reaction to the pyrazolone The suspected drug was stopped for 564 (81%) cases; for derivatives aminophenazone and dipyrone [15]. The find­ 356 (51%) cases no other drug, including any treatm ent for ings from our study are in general agreement (although the adverse reaction, was administered. As a consequence comparisons have to be limited to a few drugs) with the of the adverse reaction. 176 (25%) patients were hospital­ experience of the Adverse Drug Reaction Reporting Sys­ ized. tem of the American Academy of Dermatology except for the frequency of photosensitivity and vesicobullous reac­ tions to piroxicam [4]. These reactions are probably rarer Discussion than would be inferred from the data reported to the A m er­ ican Academy system, which gave special emphasis to We analyzed the cutaneous reaction profiles of systemic newly discovered adverse reactions. It is also possible that analgesic-antipyretics and nonsteroidal anti-inflammatory the participating dermatologists underreported photosensi­ drugs, based on reports to the spontaneous reporting sys­ tivity and bullous reactions. Photosensitivity has been tem of G ISED . O u r aim was to look for signals and pre­ reported in association with other analgesic-antipyretics viously unreported reactions. Although analgesic-antipy­ and nonsteroidal anti-inflammatory drugs, including retics and nonsteroidal anti-inflammatory drugs are a naproxen [16], tiaprofenic acid [17], ibuprofen, indometha- 167 cin and ketoprofen (18. 19], and none of these drugs was piroxicam, tiaprofenic acid and meclofenamate [4, 19,24]. associated with photosensitivity in our study. In general, Both lichenoid reactions and vasculitis are reactions diffi­ special caution should be taken when interpreting data for cult to investigate by spontaneous reporting systems, relative frequencies of reactions calculated from sponta­ because of the several possible etiologic factors involved neous reports [20, 21]. Differences could be explained in and, in our opinion, more formal epidemiologic studies are terms of differences in the frequencies of exposure and needed [20], indications for drug use in the populations and of differ­ The spontaneous reporting system of G ISED is a new ences in the frequencies of reporting of the reactions by the mechanism for reporting of adverse reactions by Italian doctors. We tried in our study to reduce the bias of selective dermatologists. The term ‘spontaneous' as applied to our reporting by asking dermatologists to report all the adverse method is probably inaccurate. ‘Spontaneous’ reports orig­ events diagnosed in their current clinical practices during inate in the absence o f sustained external stimuli [25], In intensive monitoring periods and, in this respect, it was our system we asked a network of dermatologists to play an reassuring that the culpability scores were uniformly dis­ active role by both systematically reporting, during limited tributed between different drug classes in our survey. On periods, all the reactions they observed in their practice and the other hand, finding appropriate denominators (i.e. by disseminating the method to other dermatologists. The people exposed to the drug at a given time in the popula­ main advantage of our method, as illustrated by our results, tion) is a formidable task not adequately addressed in any is the accurate clinical definition of cases, producing more study based on spontaneous reporting [21]. Roughly, based specific profiles of adverse skin reactions. The m ethod is on drug utilization surveys recently conducted in selected probably biased toward identification of more serious and/ areas in Italy [22], the most frequently prescribed analgesic- or unusual and/or difficult-to-diagnose cutaneous manifes­ antipyretics and nonsteroidal anti-inflammatory drugs tations (e.g. fixed eruption, Stevens-Johnson syndrome). during the study period included, in order of decreasing Notably, it has been estimated that no more than 10% of frequency (with a ratio between the more and the less severe adverse reactions have been reported to the tradi­ prescribed drug, greater than 1:10), several pyrazolone tional spontaneous monitoring programs [26]. A pitfall of derivatives (i.e. feprazone, dipyronc, propyphenazone), the method is that milder reactions, e.g. pruritus, are prob­ acetylsalicylic acid and paracetamol, followed by diclofe­ ably underreported or not detected. These could include nac, ketoprofen, piroxicam, nimesulide, naproxen, indo- early manifestations of more serious slowly developing methacin, ibuprofen, tiaprofenic acid, and etodolac. These reactions (a striking example are the ocular symptoms figures, however, are based on a sample of only 300 pre­ induced by practolol). In principle, a speciality-based sys­ scribe rs and, for example, do not take into account over the tem could be more susceptible to a ‘notoriety’ bias, i.e. counter drugs and self-prescriptions. underreporting of adverse reactions that are not currently In our survey, to the best of our knowledge, some pre­ of great interest. The low rate of reports excluded by our viously unreported reactions were collected. These coordinating center suggests, to some extent, that there included fixed eruption to nimesulide, fixed eruption to was a conservative attitude in signalling, i.e. only clear pat­ piroxicam, and fixed eruption to flurbiprofen. These are terns of adverse reactions were reported, with doubtful not completely unexpected findings, given the overall pro­ cases neglected. More in general, our method, like any file of reactions to analgesic-antipyretics and nonsteroidal other method based on spontaneous reporting, is subject to anti-inflammatory drugs outlined before. O ther interesting problems of overascertainment (physicians may attribute signals from our study included lichenoid dermatitis and an adverse outcome to a drug when in fact it is not one) or vasculitis as possible reactions. Lichenoid dermatitis was underascertainment and suffers from the lack of good esti­ associated with phenacetin and propyphenazone in a multi­ mates of the population at risk, so that it is not possible to ple agent drug (1 case), with diclofenac (1 case), with fepra­ calculate rates. Signals could only arise based on level of zone (1 case) and with ketoprofen and diclofenac taken causality, severity of reaction and the number of similar together (1 case). Vasculitis was reported in association cases reported [27]. with flurbiprofen (1 case), with piroxicam (1 case) and with In conclusion, in spite of the above-mentioned limita­ feprazone (1 case). Lichenoid dermatitis has been reported tions, our work provides evidence of the usefulness of a before in association with naproxen, aminophenazonc and speciality-based surveillance system for spontaneous phenylbutazone [19, 23]; vasculitis has been previously reporting of adverse reactions to drugs. We were able to reported in association with naproxen, acetylsalicylic acid, collect a large num ber of reports from collaborating derm a­ aclofenac, ibuprofen, indomethacin, phenylbutazone, tologists, increasing our knowledge of the reaction profiles Gruppo Italian« Studi Epidcmiologici in Cutaneous Reactions to Dermatologia (GISED ) Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs Acknowledgements of some recently marketed drugs. Moreover, based on sev­ eral hundred contacts with collaborating dermatologists, we This study was supported in part by the Italian Ministry of Health. believe that our system has increased the dermatologists’ The generous contributions of the following pharmaceutical compa­ awareness of problems connected with identification and nies are gratefully acknowledged: Cilag. Janssen. Roche, Schcring. reporting of adverse reactions. The view of adverse reac­ and Boehringer Ingclheim. We thank the anonymous referees for tions provided by o u r surveillance is limited to one organ, their helpful suggestions. i.c. the skin, and it is desirable, in our opinion, that similar surveillance systems be activated for other specialities. References 10 Naldi L. LocaIi F. Marchesi L. Cainelli T and 18 Bruinsma W: A Guide to Drug Reactions, ed 1 Flower RJ. Moneada S. Vane JR: Analgesic- antipyretics and anti-inflammatory agents: G ISE D : Incidence o f toxic epidermal necroly­ 5. The File o f Medicines. PO Box 2 1. Oosthui- drugs em ployed in the treatment o f gout: in sis in Italy. Arch Dermatol 1990:126: zcn. The Netherlands. 1103-1104. 19 Bork K: Cutaneous Side Effects o f Drugs. Phil­ G oodman Gilman A . G oodm an I.S. Gilman A 11 Karcli FE. Lasagna L: Toward the operational adelphia. Saunders. 1988. (eds): The Pharmacological Basis o f Therapeu­ tics. ed 7. New York. MacMillan. 1985. identification o f adverse drug reactions. Clin 20 Slone D . Shapiro S. 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Czerniawska- Hypersensitivity angiitis associated with 4:15-22. Mysik G: Clinical patterns o f hypersensitivity naproxen. Ann Allergy 1989;63:107-109. 25 Faiclt G A: Adverse-drug-reaction monitoring. 7 Shear Nil: Diagnosing cutaneous adverse to nonsteroidal anti-inflammatory drugs and N Engl .1 Med 1986:314:1589-1592. reactions to drugs. Arch Dermatol 1990:126: their pathogenesis. J Allergy Clin Immunol 94-97. 1977:60:276-284. 26 Rawlins MD: Spontaneous reporting o f 16 Sterling JC. Pye RJ: Naproxen-induced adverse reactions. I: The data. Br .1 Pharmacol 8 Zürcher K. Krebs A: Cutaneous Side Effects 1988:26:1-6. o f Systemic Drugs. Basel. Karger. 1980. pseudoporphyria. Br J Rheumatol 1987:26: 9 Gruppo Italiano Studi Epidemiologien in D er­ 210- 211. 27 Vcnulel J: Som e aspects o f drug monitoring. matología (G ISE D ): Spontaneous monitoring 17 Valseechi R. Di Landro A: Tiaprofcnic acid Adv Drug React Pois Rev 1985:3:161-175. photoderm atilis. Contact Dermatitis 1989:21: o f adverse reactions to drugs by Italian derma­ tologists: A pilot study. Dermatológica 1991; 345-346. 182:12-17.

Journal

Dermatology – Karger

Published: Jan 1, 1993

Keywords: Analgesic-antipyretics and nonsteroidal anti-inflammatory drugs; Cutaneous adverse reactions; Spontaneous reporting system

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