Fixed drug eruptions (FDEs) are cutaneous type 4 hypersensitivity reactions to medications that recur at the same site after each exposure to an offending agent.1-3 They typically occur between 24 hours to a few days after medication administration, and can present variably with erythematous macules, patches, and vesicles.1,2,4 With continued exposure to the causative drug, FDEs can become more severe, leading to ulcers and bullae.1,2 Cutaneous FDEs often mimic other vesiculobullous dermatoses, posing a diagnostic challenge.1,2

Family physicians play a crucial role as the first point of contact for the assessment of skin lesions and are well positioned to oversee medication use.5-7 As such, family physicians are uniquely equipped to identify FDEs, discontinue offending agents, and modify treatment plans; however, establishing a diagnosis may be difficult as patients do not often report over-the-counter medications as part of their medication use.8 Herein, we present the case of a 28-year-old male patient with worsening episodes of naproxen-induced FDEs that was misdiagnosed as a herpes simplex virus (HSV) infection.

A 28-year-old male medical student reported a 9-month history of worsening episodes of cutaneous facial eruptions occurring every 2 to 3 months. The first episode involved an erythematous macule on the chin that was not bothersome, and self-resolved within 2 to 3 days. The second episode involved the same erythematous chin lesion, but presented as a larger macule oozing honey-coloured exudate before self-resolving within 5 days; minor residual hyperpigmentation remained. A third episode involved erythematous macules on the cheek and lips (Figure 1), as well as on the chin, forehead, clavicle, and right earlobe. All lesions were intensely pruritic, some containing vesicles that oozed clear or yellow exudate. Additionally, large fluid-filled bullae developed on the upper and lower lips as well as ulcerations on the hard palate (Figure 2). This prompted a visit to the emergency department, where he denied a personal history of HSV but reported a roommate with a cold sore. He was prescribed 1000 mg of valacyclovir twice daily for 7 days for a suspected orolabial herpetic outbreak. The episode resolved within 2 weeks, leaving residual postinflammatory hyperpigmentation.

The patient presented to his family physician for prophylactic treatment to avoid further episodes during his residency interviews and was empirically prescribed 2 g of suppressive valacyclovir twice daily for 3 days to prevent recurrence. After 2 months, he presented to his family physician again due to another episode with similar pruritic erythematous vesicular macules on the chin, forehead, inner cheek, clavicle, and right earlobe, as well as bullae on the lips. The bullae on the lips were swabbed and results were negative for HSV 1 and 2. Bloodwork results, which included a complete blood count and a C-reactive protein test, were normal. A serology test for human immunodeficiency virus yielded negative results. He was prescribed 50 mg of prednisone once daily for 5 days, which mildly decreased the severity of this episode. He was referred to a dermatologist where he revealed using ibuprofen and acetaminophen intermittently over the past year for joint pain. He was diagnosed with an FDE induced by ibuprofen and acetaminophen and was advised to avoid these medications. However, he later recalled using naproxen 72 hours before his last episode and prior to previous episodes as well. He avoided naproxen but continued to use ibuprofen and acetaminophen without any issue.

Erythematous macules on the cheek, lips, and chin

Large fluid-filled bullae on the upper and lower lips and ulcerations on the hard palate

As many as 2% to 3% of patients taking medications develop a cutaneous drug reaction.9 FDEs occur in both sexes and all age groups, and, in 50% of cases, involve oral and genital mucosa.10,11 Common offending agents include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, sulfonamides, a combination of trimethoprim and sulfamethoxazole, and salicylates, all of which are frequently used in primary care.9,12 Fixed localization of FDEs is a key diagnostic hallmark; however, additional sites may become involved with continued exposure,1 as seen in our patient. FDEs are a clinical diagnosis, but a biopsy can reveal vacuolar interface dermatitis with deep and superficial perivascular infiltration of eosinophils and lymphocytes.1,13 In addition to HSV, differential diagnoses include erythema multiforme and aphthous stomatitis, both of which may also be induced by NSAIDs.14-16 FDEs are self-limiting upon discontinuation of the causative medication.14 For symptomatic relief, topical corticosteroids and antihistamines may be prescribed, although FDEs owing to levocetirizine have been reported.14,17

A search of PubMed, MEDLINE, and Embase with no language or date restrictions was conducted using the term fixed drug eruption. A retrospective study of 61 patients with oral mucosal FDEs found that naproxen and cotrimoxazole were the main contributors.18 Benedix et al reported a 23-year-old woman with recurrent episodes of herpetiform vesicles on the lower lip.2 After failing to respond to acyclovir, she was ultimately diagnosed with an FDE to fluconazole, which developed 6 months after intermittent fluconazole use.2 Boyle et al described an FDE misdiagnosed as HSV in a 38-year-old woman taking combination aspirin, meprobamate, and ethoheptazine.19 The eruption initially presented as erythematous lip lesions, with similar lesions later developing on the thigh, abdomen, and dorsal hand.19 Sławinska et al reported a 25-year-old woman with a 6-month history of recurrent perioral vesicles misdiagnosed as drug-resistant recurrent HSV.20 Her lesions progressed to bullae, and she was diagnosed with bullous FDE secondary to fluconazole; the patient believed fluconazole was not a relevant medication to disclose.20

This case highlights several critical lessons for family physicians: When evaluating a new skin eruption, explicit questioning about medication use is imperative, as patients may fail to disclose medications they take intermittently, such as over-the-counter agents or nonorally administered drugs (including sublingual, intravenous, rectal, and intradermal agents).2,20 Moreover, the diagnosis of an FDE was ultimately made by a dermatologist, as acetaminophen and ibuprofen were initially misidentified as the causative agents in our patient’s case. Therefore, increased awareness of FDEs among family physicians is important to prevent unnecessary referrals to other specialists. Despite the typical onset of FDEs between 24 hours to a few days following drug exposure, some cases arise after a prolonged sensitization phase, ranging from weeks to years after medication initiation.2,4 Thus, FDEs should remain a diagnostic consideration even in the absence of new or altered medication use.

Family physicians should maintain a high index of suspicion for FDEs in the evaluation of persistent cutaneous eruptions unresponsive to treatment for alternative diagnoses. A comprehensive medication review can avoid misdiagnosis and prompt cessation of the offending agent.

▸ Fixed drug eruptions (FDEs) should be considered when evaluating new cutaneous eruptions unresponsive to treatment for alternative diagnoses.

▸ FDEs can mimic cutaneous eruptions such as herpes simplex virus infection, erythema multiforme, and aphthous stomatitis.

▸ Comprehensive medication reviews, with inquiry about intermittent, over-the-counter, and non-oral medications, can identify causative agents.

▸ Des éruptions médicamenteuses fixes (EMF) devraient être envisagées dans l’évaluation de nouvelles éruptions cutanées qui ne répondent pas au traitement pour d’autres diagnostics.

▸ Les EMF peuvent ressembler à des éruptions cutanées comme une infection par le virus de l’herpès simplex, un érythème multiforme et une stomatite aphteuse.

▸ Il faut passer rigoureusement en revue la médication et s’informer des médicaments pris de manière intermittente, en vente libre ou sous forme autre qu’orale pour identifier les agents causatifs.