Levocetirizine-induced paradoxical fixed drug eruption: A case report with causality assessment

Abstract

Fixed drug eruptions (FDE) are drug-induced skin reactions that repeatedly occur at the same anatomical site. The skin lesions are usually clear hyperpigmented patches that may develop into blisters. The skin response involves type IV delayed hypersensitivity reactions and is caused by drug-specific memory CD8 T-cells located at the affected skin site. Levocetirizine, an H1-selective second-generation piperazine antihistamine, has a good safety profile and is used to treat the skin reactions. Its nonprescription availability leads to self-medication and unrecognised adverse drug reactions (ADR). FDE due to levocetirizine, as well as with cetirizine, is less common in the literature. This case was reported to our ADR Monitoring Center and causality was assessed as probable and preventable. This case shows that antihistamines such as levocetirizine can trigger FDE in susceptible individuals. Improving clinical awareness through robust Pharmacovigilance activities, educating patients about triggers, and discouraging self-medication are crucial for preventing recurrence.

Introduction

Cutaneous adverse drug reactions (ADRs) are very common and often least understood.[1] Levocetirizine, an R-enantiomer of cetirizine, is a second-generation H1-antihistamine commonly used to treat allergic rhinitis, urticaria, and drug eruptions.[2] Fixed drug eruption (FDE) is not an infrequent ADR and occurs as skin lesions after re-exposure to the causative drug. According to the World Health Organization (WHO)-VigiAccess, Levocetirizine accounts for about 8% of reported adverse reactions related to skin and subcutaneous tissue disorders. However, in the case of FDEs, there are fewer than 100 (75 reports) in the entire world.[3] This report discusses a less common case of levocetirizine-induced FDE.[4] A strong temporal association and a positive de-challenge support the clinical diagnosis. The causality assessment used the WHO-Uppsala Monitoring Center (UMC) and Naranjo scales; severity was classified using the Hartwig and Siegel scales.[5,6,7] The preventability was assessed using the Schumock and Thornton scales.[8] This case serves as a reminder to clinicians of the importance of recognising ADRs to ensure safe prescribing and effective patient counseling.

Case Report

This case report complies with the CARE case reporting guideline. A 26-year-old male presented with well-defined hyperpigmented lesions on the bilateral hands and the left cubital fossa [Figure 1]. The lesions appeared a few hours after the patient ingested a 5 mg dose of Levocetirizine, which was used as an over-the-counter remedy for common cold symptoms, establishing a temporal association. The lesions were sharply demarcated, round-to-oval erythematous plaques with a dusky violaceous center and residual hyperpigmentation – characteristic of FDE [Figure 2].

Figure 1.

Well-defined erythematous plaque over the left palm within hours of levocetirizine ingestion

Figure 2.

Dusky violaceous plaque with central hyperpigmentation over left cubital fossa

The patient had reported three instances of a similar drug eruption; after taking medication for acute illnesses, most likely upper respiratory infections, where the medications were acquired over the counter. These reactions occurred within hours of taking the medication and resolved after the medication was stopped; some hyperpigmentation remained. However, the potential drug/s that could have caused the eruptions remained unidentified. There was no relevant family history, and no systemic or mucosal involvement was noted. Because of ethical issues, no further provocation tests were done due to the potential risk of causing a serious reaction.[9] The patient also refused the skin biopsy and patch testing. FDEs have shown varying degrees of sensitivity to patch testing, and current literature points to the need for reliable and safer methods to be developed.[10]

The diagnosis was primarily clinical, supported by a robust temporal relationship and a positive de-challenge [Figure 3]. The images depict multiple anatomical locations rather than a single skin lesion at different points in its evolution. Using the WHO–UMC criteria and Naranjo scale for causality assessment, the reaction was classified as probable.[5] The patient was not on any concomitant medications, and no alternative etiological factors (e.g., infection, food triggers, and systemic illness), etc., were found. The temporal relation, positive de-challenge, and lack of alternative explanations or concomitant medications provide support for “Probable” causality (WHO–UMC and Naranjo score = 8). The moderate severity and preventability of the reaction warrant mention and point to early identification and withdrawal of the offending drug [Table 1].

Figure 3.

Residual hyperpigmented patch following resolution after drug withdrawal

Table 1.

Assessment of causality, severity, and preventability

Category	Tool used	Result
Causality	WHO–UMC	Probable
Causality	Naranjo ADR Scale	Score 8 – Probable
Severity	Hartwig and Siegel Scale	Level 3 – Moderate
Preventability	Schumock and thornton criteria	Probably preventable

WHO=World Health Organization, UMC=Uppsala Monitoring Center, ADRs=Adverse Drug Reactions

Management and outcome: after the suspected ADR was recognized, LEVOCETRIZINE was stopped. The rest of the treatment was supportive, with oral Methyl Prednisolone (T. ZEMPRED) 8 mg for 5 days, and emollient therapy. The patient was educated on FDE and self-medication, and within a week, everything resolved except for some hyperpigmentation.

Discussion

FDEs represent a distinctive type of drug reaction manifesting with identical lesions at the same body sites on subsequent exposures to the drug. At the core of the pathogenesis is the persistence of intraepidermal CD8+ effector memory T-lymphocytes, which drive massive release of inflammatory mediators and cytotoxic responses, thereby triggering skin epithelial cell death upon re-exposure to the drug. The most common drugs associated with FDEs include sulphonamide antibiotics, tetracycline antibiotics, nonsteroidal anti-inflammatory drugs, some anticonvulsants, and certain antifungal agents.

Levocetirizine is a prescription medication for allergy symptoms and an H1 receptor-selective antihistamine; it is generally well-tolerated. Contrary to the expectation, antihistamines themselves cause cutaneous reactions, including FDE. Data from the WHO global pharmacovigilance database indicate that although skin and subcutaneous tissue disorders account for approximately 8% of reported adverse reactions to levocetirizine, fewer than 100 cases of FDE have been documented worldwide, suggesting that this association is infrequently reported.

Levocetirizine may trigger an immune response by binding to haptens, potentially leading to hypersensitivity. In addition, genetic factors can influence individual responses to medications, causing unpredictable reactions due to variations in immune regulation and drug metabolism. The strong temporal relationships, positive de-challenge, absence of alternative etiologies, and a Naranjo score of eight are evidence of a probable causal relationship.

One of the cases documented by Mathur et al. involved a widespread, blistering FDE secondary to LEVOCETIRIZINE.[11] In 2023, Pereira et al. reported a case of FDE caused by cetirizine.[12] This reaction also showed cross-reactivity to LEVOCETIRIZINE and HYDROXYZINE, suggesting a class effect among piperazine derivatives. These cases highlight the importance of documenting an individual’s drug history in detail and avoiding related drugs in patients who are known to be sensitized.

Our report outlines the importance of clinical awareness of cutaneous adverse reactions to commonly prescribed antihistamines and the value of pharmacovigilance in the clinical settings.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.