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Fixed exanthema after the ingestion of naproxen with tolerance to ibuprofen and
dexketoprofen

Reguero Capilla M, De Aramburu Mera T, Ochando Díez-Canseco M, Prados Castaño M

Department of Allergology, University Hospital Virgen del Rocío, Seville, Spain

Corresponding:

Marta Reguero Capilla

Department of Allergology, University Hospital “Virgen del Rocío”

Manuel Siurot, Str. 41013, Sevilla, Spain

[email protected]

This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process,
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.18176/jiaci.0518

J Investig Allergol Clin Immunol 2021; Vol. 31(2) © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0518
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Key words: Fixed drug exanthema, Naproxen, Arylpropionics, NSAIDs

Palabras clave: Exantema fijo medicamentoso, Naproxeno, Arilpropiónicos, AINE

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide because of their

analgesic, anti-inflammatory, and antipyretic effects. NSAID are one of the most

frequent causes of drug-induced hypersensitivity reactions, being urticaria and

angioedema the most common clinical forms of presentation [1]. Patients who present

symptoms after the intake of an NSAID do not usually tolerate others from the same

chemical group due to a high cross-reactivity between NSAIDs which are structurally

similar [2,3]. Controlled oral challenge test with the guilty NSAID is actually the gold

standard diagnosis method to confirm a case of NSAID hypersensitivity [1-3].

Naproxen is a nonsteroidal anti-inflammatory drug, which belongs to the aryl-propionic

acid family, and a nonselective COX inhibitor, used to treat menstrual cramps,

inflammatory diseases such as rheumatoid arthritis, and fever. Fixed drug exanthema

describes the appearance of a well-circumscribed erythematous patch, as a consequence

of the systemic exposure to a drug. It is an allergic reaction to a medicine that

characteristically recurs in the same site or sites each time a particular drug is taken.

The number of drugs responsible of fixed drug eruptions is large, but it is frequently

related with NSAID as ibuprofen and antibiotics [1,2,4]. In this paper we describe a

case of fixed exanthema in one patient induced after several hours of taking naproxen,

with tolerance to another aryl-propionic acid derivatives (ibuprofen and dexketoprofen),

confirmed after performing a controlled oral challenge for each drug.

J Investig Allergol Clin Immunol 2021; Vol. 31(2) © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0518
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Our patient was a 25-year-old woman, with no other background than polycystic ovary

syndrome, who was referred to our allergy unit because she presented, ten years ago,

approximately 4 hours after naproxen intake, an itchy erythematoviolaceus patch in the

right lateral side of her neck. No urticaria/angioedema occurred, nor another type of

systemic symptoms.

The exanthema was resolved in 48 hours with no treatment. She did not consume

naproxen again since that day, but she subsequently tolerated ibuprofen and

dexketoprofen after the episode. She also occasionally consumes paracetamol and

metamyzol without problems.

The following diagnosis test was performed, with an interval of at least one week

between the administrations of each drug:

- Patch test (epicutaneous test) with naproxen, ibuprofen and dexketoprofen, read after 48

and 96 hours (preparations were made using petrolatum as a vehicle and at similar

concentrations to those suggested in other studies [6]; naproxen 30%, ibuprofen 5-10%

and ketoprofen 1-10%): NEGATIVE

- Patch-test (epicutaneous test) with naproxen in the patient’s neck, with a control with

vaseline-patch, read after 48 and 96 hours: NEGATIVE

- Day 1: a single-blind placebo-controlled oral challenge (SBPCOC) with ibuprofen at

doses of 50, 100 and 250 mg with intervals of 30, 60 and 120 minutes, and a

observational period of 4:30 hours: NEGATIVE

- Day 2: a SBPCOC with the intake of a single dose of 600mg of ibuprofen (higher dose

than the day before because the patient referred an intake of 600mg at home) and a

observational period of 4:30 hours: NEGATIVE

J Investig Allergol Clin Immunol 2021; Vol. 31(2) © 2020 Esmon Publicidad
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- A SBPCOC with dexketoprofen; giving 6, 6 and 12mg with 30, 30 and 120 minutes of

interval respectively, until reaching therapeutic dose and an observational period of 4

hours: NEGATIVE

- A SBPCOC with naproxen; 50, 150, 300mg every 30 minutes with 240 minutes of

observation: the result was POSITIVE as the patient developed an itchy erythematous

eruption in the lateral side of her neck, with no urticaria, angioedema or systemic

symptoms associated (Figure 1).

We established time intervals between each DPT of 30 to 60 minutes because, once

sensitised, the reaction appeared between 30 minutes and 8 hours after the intake,

although this interval may be shorter with recurrent contacts with the drug [4]

The final diagnosis was fixed drug exanthema induced by naproxen.

Recent data shows that NSAIDs are the most frequent cause related with drugs

hypersensitivity reactions [5]. The second most frequently described cause of these

reactions, after pyrazolones [1], are the aryl-propionic acid derived, specifically

ibuprofen. Fixed drug eruption is also related with ibuprofen in the first place, among

NSAIDs.

Our patient could be included in the single NSAID-induced hypersensibility reactions

because she tolerates NSAID from different chemical groups. Patients with immediate

reactions to 2 or more NSAIDs not structurally related, with ASA tolerance can occur

and this phenotype must be taken into account [7]. She also tolerates another NSAID

structurally similar to naproxen, her drug problem. There had been described cases of

urticaria and/or angioedema related with one drug, but with tolerance to others from the

same family [2], but in this paper we describe a case of fixed drug exanthema after the

administration of one aryl-propionic acid derivative (naproxen) with tolerance to other

J Investig Allergol Clin Immunol 2021; Vol. 31(2) © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0518
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drugs of this family (ibuprofen and dexketoprofen). The time interval between the intake

of the NSAID and the appearance of the erythema in our patient’s neck was about 4 hours.

The usefulness of skin testing has been documented for pyrazolones [8] but its utility

with aryl-propionics is scarce due to poor reliability.

Oral challenge remains the gold standard for diagnosing allergy to NSAID; it is no

indicated in patients with a history of generalized exanthema or when the exanthema

involves mucous tissues. In patients without generalized reaction or extended mucous

involvement, oral challenge is considered relatively safe and remains the gold standard,

confirming the affected area and the culprit agent [4]. Fixed drug eruptions

characteristically reappear in the same location and with similar extension [9]. In this

case, with a small skin area affected, a negative result in epicutaneous test and tolerance

in oral challenge to ibuprofen and dexketoprofen, and due to the remarkable cross-

reactivity between the aryl-propionic family, we decided to perform a diagnosis test

with naproxen in order to prove the reproducibility of the clinic and we found a positive

result when it appeared a erythematoviolaceous oval in the lateral side of the woman’s

neck.

We have described a case of fixed drug erythematous eruption induced after taking

naproxen, with no urticaria/angioedema associated and with no cross-reactivity between

the same structural groups, diagnosed by a single-blinded placebo oral challenge.

Finally, we conclude that aryl-propionic may induce fixed drug eruption as a

hypersensibility reaction in patients with good tolerance to others from the same

chemical group. More studies are needed, but we would like to emphasize the

importance of carrying out tolerance tests with another NSAID within the same group

because of the probability of tolerance, choosing the cases individually.

J Investig Allergol Clin Immunol 2021; Vol. 31(2) © 2020 Esmon Publicidad
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Conflict of interest

The authors declare that they have no conflicts of interest.

Funding

The authors declare that no financial support was received for this study.

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Figure 1. Fixed drug eruption in patient’s neck after oral challenge test with naproxen.

J Investig Allergol Clin Immunol 2021; Vol. 31(2) © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0518