What are the characteristics, causes, and treatment options for fixed drug eruptions in patients of any age?

Fixed Drug Eruptions: Characteristics, Causes, and Management

Fixed drug eruptions (FDEs) are distinct, well-demarcated, dusky violaceous to erythematous patches that recur at identical anatomical sites upon re-exposure to the causative medication, typically resolving with residual hyperpigmentation. 1, 2

Clinical Characteristics

Morphology and Distribution

• FDEs present as sharply demarcated, circular erythematous-violaceous patches that may progress to bullous lesions in severe cases 1, 3
• The lesions characteristically recur at precisely the same anatomical location with each drug exposure, which is the defining feature of this condition 1, 4
• Common sites include the genitalia, lips, hands, feet, and trunk, with a notable sex-dependent distribution pattern: women more frequently develop lesions on hands and feet, while men more commonly have genital involvement 5
• Lesions typically appear within 2 days (average) of drug intake, though timing can vary 5

Clinical Variants

• Multiple variants exist including bullous, generalized bullous (GBFDE), nonpigmenting, linear, papular, erythema multiforme-like, annular, psoriasiform, and cribriform patterns 2, 3
• Generalized bullous fixed drug eruption (GBFDE) is a severe variant that can mimic Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), making differentiation critical 3
• Nonpigmenting variants occur frequently enough that residual hyperpigmentation should not be considered an essential diagnostic criterion 5

Associated Symptoms

• Patients may experience mild pain, pruritus, or burning at the affected sites 1, 4
• Some cases present asymptomatically, contributing to underdiagnosis 1

Common Causative Medications

Most Frequently Implicated Drugs

• Paracetamol (acetaminophen) is the most common causative agent, followed by NSAIDs including ibuprofen and naproxen 5, 1
• NSAIDs including ibuprofen can cause fixed drug eruption (FDE), as documented in FDA labeling 6
• Trimethoprim-sulfamethoxazole is a well-documented cause, with cases reported even from indirect exposure through sexual contact 4

Drug Classes Associated with FDEs

• Tyrosine kinase inhibitors (TKIs) used in oncology can cause fixed-pattern skin reactions, though these are more commonly generalized rashes 7
• Multiple chemotherapeutic agents and targeted therapies can produce fixed eruptions as part of their cutaneous adverse effect profile 7

Pathophysiology

• FDE is a type IV delayed hypersensitivity reaction mediated by memory CD8+ T cells that persist in the basal epidermis at previously affected sites 2
• The pathogenesis involves T lymphocytes, mast cells, keratinocytes, and cytokines, though the exact mechanism remains incompletely understood 4
• Distinguishing GBFDE from SJS/TEN relies on granulysin levels: significantly elevated lesional and serum granulysin characterizes SJS/TEN, while GBFDE shows markedly lower levels 3

Diagnostic Approach

Clinical Diagnosis

• Diagnosis is primarily clinical, based on the characteristic recurrence at identical sites with repeated drug exposure 5
• Document the temporal relationship between drug intake and lesion appearance (typically 2 days) 5
• Obtain a comprehensive medication history including over-the-counter drugs, supplements, and herbal remedies 1, 7
• Ask specifically about previous similar eruptions at the same anatomical sites, as this history is pathognomonic 1

Confirmatory Testing

• Patch testing at the affected site can confirm the diagnosis when clinical suspicion exists but the culprit drug is uncertain 5
• Skin biopsy may be performed but is not routinely necessary for typical presentations 5
• For suspected GBFDE mimicking SJS/TEN, immunochromatographic testing for granulysin levels can facilitate rapid differentiation 3

Critical Differential Diagnoses

• FDEs are frequently misdiagnosed as insect bites, urticaria, or erythema multiforme 1
• GBFDE must be distinguished from SJS/TEN due to vastly different prognoses and management approaches 3
• Consider drug-induced pemphigus, though this typically lacks the fixed recurrence pattern 7

Management and Treatment

Immediate Management

• The cornerstone of treatment is immediate and permanent discontinuation of the offending medication 1, 6
• For mild to moderate cases, apply medium-potency topical corticosteroids (e.g., prednicarbate cream 0.02%) twice daily to reduce inflammation and relieve symptoms 1, 7
• Systemic antihistamines may provide symptomatic relief for pruritus 7

Severity-Based Treatment Algorithms

Mild FDE (localized, <10% body surface area):

• Continue topical corticosteroids twice daily 7
• Oral antihistamines for pruritus (cetirizine, loratadine, fexofenadine) 7
• Outpatient management with close follow-up 8

Moderate FDE (multiple sites, significant symptoms):

• Topical corticosteroids plus short course of oral corticosteroids if needed 7
• Consider dermatology referral if no improvement within 2 weeks 9
• Monitor for progression to more severe variants 9

Severe/GBFDE (>10% BSA, mucosal involvement, bullous lesions):

• Immediate hospitalization in burn unit or ICU is required 8
• Discontinue all potentially causative medications 8
• Initiate supportive care identical to burn management: fluid/electrolyte management, temperature regulation, infection prevention 8
• Systemic corticosteroids (prednisone 1 mg/kg daily) with gradual taper over 4-6 weeks 7, 10
• Rule out SJS/TEN through granulysin testing if available 3

Follow-Up and Prevention

• Document the drug allergy prominently in all medical records and provide written information to the patient about medications to avoid 8
• Educate patients that re-exposure will cause recurrence at the same sites, often with increased severity 1, 2
• Schedule dermatology follow-up within 2-4 weeks for moderate to severe cases 8
• Lesions typically resolve completely within 4 weeks of drug discontinuation, leaving residual hyperpigmentation in most cases 1

Critical Pitfalls and Caveats

Diagnostic Pitfalls

• Do not dismiss the diagnosis based on absence of hyperpigmentation, as nonpigmenting variants are common 5
• Failure to obtain a thorough medication history including recent restarts of previously used medications leads to missed diagnoses 1
• Consider indirect drug exposure through sexual contact or other unusual routes when the history seems inconsistent 4

Management Pitfalls

• Do not continue ineffective treatment beyond 2 weeks—persistent eruptions require diagnostic reassessment and dermatology referral 9
• Avoid reintroducing the causative medication even at lower doses, as reactions typically recur and may be more severe 6
• For GBFDE, do not delay hospitalization—these patients require burn unit-level care despite the benign-sounding name "fixed drug eruption" 8, 3
• NSAIDs can cause both FDE and more severe reactions including SJS/TEN; immediate discontinuation is mandatory at first sign of skin reaction 6

Special Populations

• In elderly or debilitated patients taking NSAIDs, maintain heightened vigilance as they are at increased risk for severe cutaneous reactions 6
• Pregnant women should avoid NSAIDs particularly after 20 weeks gestation due to fetal risks, making alternative analgesics essential if FDE to NSAIDs is documented 6