Fixed drug eruption- paracetamol as the unseen trigger: A case series

INTRODUCTION

Adverse drug reaction (ADR) is defined as any response to a drug that is noxious and unintended, and that occurs at doses used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.¹

Fixed drug eruption (FDE) is a recurrent, immune-mediated hypersensitivity reaction to specific drugs, characterized by erythematous or hyperpigmented lesions that recur at the same site upon re-exposure. One of the most commonly used drugs, paracetamol (acetaminophen), is widely used as an antipyretic and pain reliever. It is accessible without a prescription, either as a single drug or FDE. It is a preferred medication in patients among whom use of non-steroidal anti-inflammatory drugs (NSAIDs) is contraindicated, e.g., with gastric ulcers, hypersensitivity to aspirin, blood coagulation disorders, pregnant women, nursing mothers, and children with fever from a disease.² Paracetamol has a central analgesic action similar to aspirin, by increasing pain threshold, but has a weak peripheral anti-inflammatory component. Paracetamol, which is thought to act by inhibiting COX-3 in the central nervous system (showing similar predilection to COX-1 functionally), involves pain perception and fever, but not inflammation. It classically exhibits little anti-inflammatory activity due to its poor inhibition of COX-1 in the presence of superoxide produced by leukocytes at inflammatory sites.³ Paracetamol is generally well tolerated at the indicated dosage. Prolonged daily use might result in serious side effects such as kidney or liver damage,³ and stomach bleeding. Although they are uncommon, hypersensitivity reactions (anaphylaxis and permanent drug eruptions) and dermatological side effects, such as erythematous skin rashes linked to paracetamol, have been observed.

CASES SERIES

This case series includes three patients who reported using paracetamol and subsequently developed cutaneous lesions. These patients had drug-related skin manifestations.

Case 1

A 70-year-old male presented with violaceous macules that were erythematous to hyperpigmented and had erosions. Two days after using paracetamol 650 mg to treat fever and loose stools, lesions formed bilaterally on the upper and lower limbs, as well as the trunk. The patient had no history of medication reactions. The lesions were painful and well-defined, eventually evolving into hyperpigmented patches [Figure 1a,b]. The temporal association between drug intake and the appearance of the lesion was present. The adverse event could not be explained by any underlying disease or other drugs. FDE is a well-known adverse drug reaction to paracetamol. The lesions improved after discontinuing paracetamol and starting symptomatic treatment, indicating a positive dechallenge. Rechallenge was not done in this case. Thus, causality came out to be probable by the WHO-Uppsala monitoring centre (WHO-UMC) scale. With a total score of 7, the Naranjo scale’s causality assessment indicated a probable link between paracetamol and the adverse drug reaction. This case was reported by our AMC in Vigiflow, report id: IN-IPC-301086218.

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Figure 1:

(a) Well-defined violaceous macule with central hyperpigmentation (red arrow and circle). (b) Erythematous erosive plaque with hyperpigmented border (red arrow and circle).

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Case 2

A 45-year-old female had recurring violaceous macules on her trunk and limbs. These lesions formed quickly after taking paracetamol 500 mg for a fever. The patient reported a consistent pattern of lesion recurrence at the same places with each dose of the medicine. The macules were well-defined, non-blanching, and accompanied by mild pruritus [Figure 2a]. Mucosal surfaces were not affected, and there were no systemic symptoms. FDE was diagnosed based on a complete medication history and clinical examination. All the parameters were positive, but recurrence of lesions occurred at the same site after re-exposure. Thus, the rechallenge was positive but accidental, unknowingly by the patient. Thus, causality came out to be certain by the WHO-UMC scale. With a total score of 10, the Naranjo scale’s causality assessment indicated a definitive link between paracetamol and the adverse drug reaction. This case was reported by our AMC in Vigiflow, report id: IN-IPC-301058080.

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Figure 2:

(a) Multiple well defined violaceous macules on the upper limb (red arrow and circle). (b) Recurrent hyperpigmented lesion with peripheral erythema (red arrow and circle).

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DISCUSSION

FDE is a well-known cutaneous adverse drug reaction defined by the recurrence of skin lesions at the same locations upon re-exposure to the offending drug. Clinically, FDE appears as erythematous to violaceous, well-defined macules or patches that usually disappear with persistent hyperpigmentation. Immunopathologically, it is a type IV hypersensitivity reaction caused by CD8+ memory T cells that persist in the lesional skin and reactivate upon re-exposure.⁴ paracetamol (acetaminophen), a widely used antipyretic and analgesic, is generally considered safe. Despite its widespread use and apparent minimal risk, it is becoming more recognized as a potential FDE cause. Dermatologic responses such as urticaria, maculopapular rashes, and fixed drug eruptions have been reported, but infrequently.^5,6 Several recent case studies suggest that paracetamol-induced FDE may be underreported due to the drug’s over-the-counter availability and patients’ inclination to leave it out when listing prescriptions.⁷

In this case series, three individuals developed typical cutaneous lesions shortly after consuming paracetamol. In Cases 1 and 3, the temporal relationship between drug intake and lesion manifestation, as well as improvement after drug withdrawal, according to WHO-UMC causality assessment system⁸ for a “probable” adverse drug reaction. Furthermore, Naranjo scale scores of 7 in both cases indicated a plausible relationship.⁹ In Case 2, recurrence of lesions at the same areas following unintended repeated re-exposure to paracetamol resulted in a “certain” categorization by WHO-UMC, with a Naranjo score of 10 indicating certain causality. The diagnosis of FDE is primarily clinical, based on the lesion pattern, recurrence with drug re-exposure, and a detailed medication history. Patch testing, especially when performed on previously afflicted skin, may aid in diagnosis but has variable sensitivity and is not generally suggested due to the possibility of lesion reactivation.¹⁰ Oral provocation or rechallenge testing is decisive, but it should be avoided unless absolutely essential for ethical and safety reasons.¹⁰ Our patients’ lesion distribution - trunk, limbs, face, and neck- follows typical FDE patterns. The delay in identifying paracetamol as a culprit emphasizes the significance of complete medication histories and clinical knowledge, particularly for routinely used non-prescription medicines. Patients frequently fail to report such drugs unless specifically requested.

Management includes discontinuing the offending drugs immediately, controlling symptoms with topical corticosteroids and antihistamines, and providing long-term patient education. Patients should be advised about the risk of recurrence and the significance of avoiding paracetamol in all forms, including fixed-dose combinations. In most circumstances, other medications like ibuprofen or tramadol can be taken safely. Wearing medical warning bracelets or carrying an allergy card are good preventive techniques. Future studies should focus on identifying genetically sensitive individuals. HLA typing and pharmacogenomic profiling can assist in identifying patients who are more likely to develop drug-induced hypersensitivity, such as FDE. Personalized medicine methods that include genetic screening could become critical tools in preventing severe medication responses and increasing drug safety.

CONCLUSION

Paracetamol-induced FDE is a possibly underdiagnosed and clinically significant event, despite its rarity. To ensure drug safety and prevent recurrence, it is critical to identify problems early, employ causality evaluation methods such as the WHO-UMC and Naranjo scale, and provide effective patient counselling.