Fixed Drug Eruption: Comprehensive Overview
Definition and Clinical Presentation
Fixed drug eruption (FDE) is a distinctive cutaneous adverse drug reaction characterized by well-defined, dusky violaceous to erythematous patches that recur at precisely the same anatomical site each time the offending medication is ingested. 1, 2 The lesions resolve with residual hyperpigmentation and can involve additional sites with each subsequent exposure. 1, 3
Key Clinical Features
- Morphology: Circular, erythematous-violaceous patches ranging from localized spots to large plaques, often with overlying vesicles or bullae 1, 3
- Distribution: Extremities are most commonly affected (43%), followed by trunk (29%), face (11%), with generalized involvement in approximately 17% of cases 4
- Symptoms: Lesions may be asymptomatic or associated with mild pain and pruritus 3
- Timing: Lesions typically appear within 24 hours of drug re-exposure 5
- Residual changes: Black, non-blanching macules with surrounding erythema that eventually leave hyperpigmentation 3
Clinical Variants
Multiple FDE variants have been described including bullous, generalized bullous (GBFDE), nonpigmenting, linear, papular, erythema multiforme-like, annular, psoriasiform, and cribriform patterns. 2
Pathophysiology
FDE is a type IV hypersensitivity reaction mediated by effector memory CD8+ T cells that remain dormant in the basal layer of the epidermis at previous lesion sites. 2, 5 Upon re-exposure to the causative drug, these resident T cells are rapidly reactivated, triggering localized inflammation at the same anatomical locations. 2
In typical FDE, regulatory T cells infiltrate the epidermis approximately 24 hours after CD8+ T cell activation to suppress inflammation and promote resolution. 5 However, in multiple FDE, CD8+ T cell activity may overwhelm regulatory T cell function, leading to uncontrolled inflammation with poorly-demarcated lesions that can progress to severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). 5
Causative Medications
Most Common Offending Drugs
NSAIDs are the most frequent cause of FDE (52%), followed by antimicrobials (45%) and antiepileptics (3%). 4
Specific drugs implicated (in descending order of frequency):
- Ibuprofen (20%) - the single most common causative agent 4
- Doxycycline (18%) 4
- Diclofenac and fluconazole (14% each) 4
- Naproxen (9%) 4
- Ciprofloxacin (8%) 4
- Paracetamol (6%) 4
- Metronidazole (5%) 4
- Carbamazepine (3%) 4
- Aspirin (3%) 4
Critical Clinical Pitfall
Ibuprofen-induced FDE is particularly challenging to diagnose because patients often do not report over-the-counter medication use during history-taking. 5 Physicians must specifically inquire about all OTC medications, including NSAIDs, when evaluating suspected FDE. 3
Diagnosis
Clinical Diagnosis
The diagnosis of FDE is primarily clinical, based on three essential historical features:
- Recurrence at the same anatomical site - the pathognomonic feature that distinguishes FDE from other drug eruptions 1, 3
- Temporal relationship to drug exposure - lesions appear within hours to days of drug ingestion 3, 5
- Resolution with hyperpigmentation after drug discontinuation 1, 2
Essential History Questions
When FDE is suspected, obtain:
- Complete medication history covering the previous 2 months, including prescription drugs, OTC medications, and complementary/alternative therapies 6, 7
- Exact dates when medications were started, stopped, or dose-escalated 6, 7
- History of similar rashes in the same locations previously 3
- Index date (when first symptoms appeared) 6, 7
- Previous drug allergies with reaction details 6
Diagnostic Testing
Delayed skin testing (intradermal testing and patch testing) has poor sensitivity for FDE and is not recommended for routine diagnosis. 6 The diagnosis is confirmed by:
- Drug rechallenge - the gold standard, showing recurrence at the same site, though this carries risk of progression to severe reactions 5
- Histopathology - biopsy from lesional skin showing interface dermatitis with basal vacuolar changes and pigment incontinence 6, 3
- Clinical observation - resolution after drug discontinuation with residual hyperpigmentation 3
Differential Diagnosis
FDE is commonly misdiagnosed as:
- Insect bites 3
- Urticaria 3
- Erythema multiforme 3
- Stevens-Johnson syndrome/toxic epidermal necrolysis (particularly GBFDE) 1
- Bullous pemphigoid 6
The key distinguishing feature is the fixed location of recurrent lesions, which does not occur in these other conditions. 1, 3
Treatment
Immediate Management
The cornerstone of FDE management is immediate and permanent discontinuation of the causative drug. 7, 1 This is the single most important intervention and directly impacts prognosis. 7
Localized/Mild FDE (<10% Body Surface Area)
For limited disease, apply topical moderate-to-high potency corticosteroids (mometasone furoate 0.1% or betamethasone valerate 0.1% ointment) twice daily to affected areas. 7, 8
Add oral antihistamines for symptomatic relief of pruritus:
- Second-generation agents (loratadine 10 mg daily) for daytime use 7, 8
- First-generation agents (diphenhydramine 25-50 mg or hydroxyzine 25-50 mg) for nighttime sedation 7, 8
Widespread/Moderate FDE (>10% Body Surface Area)
Continue topical high-potency corticosteroids and oral antihistamines. 7, 8
For persistent pruritus unresponsive to antihistamines, add GABA agonists as second-line therapy:
Severe/Generalized Bullous FDE (GBFDE)
For extensive involvement with widespread skin denudation, consider systemic corticosteroids (prednisone 0.5-1 mg/kg body weight), though use cautiously as they may be deleterious in advanced toxic epidermal necrolysis. 7
Hospitalization is indicated for:
Recently, cyclosporine has been described as a treatment option for GBFDE, though evidence is limited. 1
Supportive Care
- Apply emollients at least once daily to the whole body 8
- Avoid hot showers and excessive soap use 8
- Apply moisturizers and urea- or polidocanol-containing lotions for xerosis 8
- Avoid skin irritants including OTC anti-acne medications, solvents, and disinfectants 8
- Limit sun exposure 8
Infection Management
Obtain bacterial cultures if superinfection is suspected or if there is failure to respond to initial treatment. 7, 8 Culture-directed antibiotic therapy should be initiated if bacterial superinfection is confirmed. 7
Critical Management Pitfalls
Misdiagnosis as Drug Allergy vs. Disease Manifestation
In some patients treated with sulfonamide or beta-lactam drugs, development of a rash may be mistaken for a drug eruption rather than recognized as a manifestation of underlying rickettsial illness, delaying appropriate treatment. 6 Always consider whether the rash represents the drug reaction or the underlying disease process.
Risk of Progression to Severe Reactions
Repeated administration of the causative drug in multiple FDE can lead to uncontrolled CD8+ T cell activation and progression to severe cutaneous adverse reactions including SJS/TEN. 5 This underscores the critical importance of:
- Accurate diagnosis on first presentation 3
- Strict discontinuation of the offending drug 5
- Patient education about permanent avoidance 8
Documentation Requirements
Document the reaction thoroughly in the medical record to prevent future re-exposure to the causative agent. 8 This should include:
- The specific drug implicated 8
- Description of the reaction 8
- Sites of involvement 3
- Temporal relationship to drug exposure 3
Prognosis and Follow-Up
In 50% of cases, FDE will resolve completely with drug withdrawal alone, while resolution typically occurs within 2-4 weeks. 3 The residual hyperpigmentation may persist for months but gradually fades. 1, 2
Follow-up at 4 weeks is recommended to confirm resolution and reinforce avoidance of the causative medication. 3 Patients should be educated that: