Introduction

Background
Adverse reactions to medications are common and often manifest as a cutaneous eruption.

Drug-induced cutaneous disorders frequently display a characteristic clinical morphology such as morbilliform
exanthem, urticaria, hypersensitivity syndrome, pseudolymphoma, photosensitivity, pigmentary changes, acute
generalized exanthematous pustulosis, lichenoid dermatitis, vasculitis, Stevens-Johnson syndrome, or fixed
drug eruption (FDE). The term fixed drug eruption describes the development of one or more annular or oval
erythematous patches as a result of systemic exposure to a drug; these reactions normally resolve with
hyperpigmentation and may recur at the same site with reexposure to the drug. Repeated exposure to the
offending drug may cause new lesions to develop in addition to "lighting up" the older hyperpigmented lesions.

Several variants of fixed drug eruption have been described, based on their clinical features and the distribution
of the lesions. These include the following:

 Pigmenting fixed drug eruption

 Generalized or multiple fixed drug eruption
 Linear fixed drug eruption
 Wandering fixed drug eruption
 Nonpigmenting fixed drug eruption
 Bullous fixed drug eruption
 Eczematous fixed drug eruption
 Urticarial fixed drug eruption
 Erythema dyschromicum perstans–like fixed drug eruption
 Vulvitis
 Oral
 Psoriasiform

Pathophysiology
Although the exact mechanism is unknown, recent research suggests a cell-mediated process that initiates
both the active and quiescent lesions. The process may involve an antibody-dependent, cell-mediated cytotoxic
response CD8+ effector/memory T cells play an important role in reactivation of lesions with re-exposure to the
offending drug.

The offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, leading to
an inflammatory response.Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes
may locally up-regulate expression of the intercellular adhesion molecule-1 (ICAM1).The up-regulated ICAM1
has been shown to help T cells (CD4 and CD8) migrate to the site of an insult
The newly arriving and residential CD8 cells likely perpetuate tissue damage by their production of the
inflammatory cytokines interferon-gamma and tumor necrosis factor-alpha. CD8 cells isolated from active
lesions have also been shown to express alpha E beta 7, a ligand for E-cadherin, which may further contribute
to the lymphocyte’s ability to localize to the epidermis. Other cell surface molecules, such as
CLA/alpha4beta1/CD4a, that bind E-selectin/vascular cellular adhesion molecule-2/ICAM1 help to further
attract CD8 cells to the area.

Changes in cell surface markers allow vascular endothelium to select CD4 cells for migration into active
lesions. These regulatory CD4 cells likely produce interleukin 10, which has been shown to help suppress
immune function, resulting in a resting lesion. As the inflammatory response dissipates, interleukin 15
expression from keratinocytes is thought to help ensure the survival of CD8 cells, helping them fulfill their
effector memory phenotypes. Thus, when reexposure to the drug occurs, a more rapid response develops in
the exact location of any prior lesions.

Frequency
United States

The prevalence of drug eruptions has been reported to range from 2-5% for inpatients and greater than 1% for
outpatients.Fixed drug eruptions may account for as much as 16-21% of all cutaneous drug eruptions.
The actual frequency may be higher than current estimates, owing to the availability of a variety of over-the-
counter medications and nutritional supplements that are known to elicit fixed drug eruptions.
International

The international prevalence is variable but is likely similar to that in the United States. Most studies report
fixed drug eruptions to be the second or third most common skin manifestation of adverse drug events.

Mortality/Morbidity
No deaths have been attributed to fixed drug eruptions. Widespread lesions may initially mimic toxic epidermal
necrolysis, but they have a benign clinical course. Localized hyperpigmentation is a common complication, but
pain, infection, and, rarely, hypopigmentation, also may occur.

Race
Fixed drug eruptions have no known racial predilection. A genetic susceptibility to developing a fixed drug
eruption with an increased incidence of HLA-B22 is possible.

Sex
One large study of 450 patients revealed a male-to-female ratio of 1:1.1 for fixed drug eruptions

Age
Fixed drug eruptions have been reported in patients as young as 1.5 years and as old as 87 years. The mean
age at presentation is 30.4 years in males and 31.3 years in females.

Clinical

History
The initial eruption is often solitary and frequently located on the lip or genitalia. Rarely, the eruption may be
intraoral. Other common locations of the initial lesion are the hip, lower back/sacrum, or proximal extremity.
With the initial fixed drug eruption attack, a delay of up to 2 weeks may occur from the initial exposure to the
drug to the development of the skin lesion.Skin lesions develop over a period of hours but require days to
become necrotic. Lesions may persist from days to weeks and then fade slowly to residual oval
hyperpigmented patches.

Subsequent reexposure to the medication results in a reactivation of the site, with inflammation occurring within
30 minutes to 16 hours. The reactivation of old lesions also may be associated with the development of new
lesions at other sites.

Patients may not be cognizant that a drug, nutritional supplement, over-the-counter medication, or, rarely, food
(eg, fruits, nuts) triggered the skin problem. They may be convinced that an insect, particularly a spider, may be
the culprit. A careful history is required to elicit the fact that a drug has been taken and is temporally related to
the onset of the eruption. Medications taken episodically, such as pain relievers, antibiotics, or laxatives, are
often to blame. When able to be identified, patients often report ingestion of one the following types of
medications21 :

 Analgesics
 Muscle relaxants
 Sedatives
 Anticonvulsants
 Antibiotics

Local symptoms may include pruritus, burning, and pain. Systemic symptoms are uncommon, but fever,
malaise, nausea, diarrhea, abdominal cramps, anorexia, and dysuria have been reported.

Further questioning may reveal prior episodes of fixed drug eruption, atopic disease, or other past drug
reactions. Family history may render a history of atopy, drug reactions, or diabetes mellitus.

Several cases of fixed drug eruption on the genitalia have been reported in patients who were not ingesting the
drug but whose sexual partner was taking the offending drug and the patient was exposed to the drug through
sexual contact.
Physical
The most common clinical manifestation is the pigmenting fixed drug eruption, which usually manifests as
round or oval, sharply demarcated erythematous/edematous plaques located on the lip, hip, sacrum, or
genitalia.2 These erythematous patches or plaques gradually fade with residual hyperpigmentation (see images
below). The center of the patch may blister or become necrotic. Other less common variants may manifest as
lesions resembling erythema multiforme, toxic epidermal necrolysis, eczema, urticaria, a linear pattern
following Blaschko lines, bullous lesions, a migrating eruption, or a nonpigmenting form with no
postinflammatory hyperpigmentation

Initially, a single lesion or a few lesions develop, but, with reexposure, additional lesions occur. The vast
majority of patients present with 1-30 lesions, ranging in size of 0.5-5 cm, but reports of lesions greater than 10
cm have been published. Lesions may be generalized. The most common reported site is the lips, and these
may be seen in up to half of all cases.

Medications may also follow a site-specific eruption pattern. For example, trimethoprim-sulfamethoxazole
(Bactrim) has been shown to favor the genital region (especially in males) and naproxen and the oxicams
involve the lips.

Resting/inactive lesions tend to appear as round or oval, gray, hyperpigmented macules.

Upon reexposure, the resting hyperpigmented macules activate, developing a violaceous center encircled by
concentric rings of erythema. Re-administration of the medication poses the risk of increased pigmentation,
size, and number of lesions.

Individuals with darker pigmentation may develop postinflammatory hypopigmented macules once the lesions
have resolved.
Causes
The major categories of causative agents of fixed drug eruption include antibiotics, antiepileptics, nonsteroidal
anti-inflammatory agents, and phenothiazines, although numerous other agents and certain foods such as
cashews and licorice have also been reported as causative agents. Ingestion of the causative agent may occur
via any route, including oral, rectal, or intravenous.21

The most common cause is trimethoprim-sulfamethoxazole.3 Other substances implicated to cause fixed drug
eruptions are as follows

Acetaminophen Acyclovir Allopurinol Allylisopropyl- Amide local

acetylurea anesthetics

Amlexanox Amoxicillin Anticonvulsants Articaine Aspirin

Atenolol Barbiturates Botulinum toxin Carbamazepine Cashew nut

Ceftriaxone Celecoxib Cetirizine Chloral hydrate Chlordiazepoxide

Chlorhexidine Chlormezanone Chlorphenesin Citicoline Clarithromycin

carbonate

Clioquinol Clopidogrel Codeine Colchicines Cyclizine

Cyproterone acetate Dextromethorphan Dimenhydrinate Diphenhydramine Dipyrone

Docetaxel Eperisone Erythromycin Ethenzamide Feprazone

hydrochloride

Finasteride Flecainide Fluconazole Fluoroquinolones Foscarnet

Gabapentin Griseofulvin Hydroxyzine Ibuprofen Interferon

Iodinated radiography Iomeprol Kakkon Ketoconazole Lactose

contrast media

Lamotrigine Lentils Liquorice Lopamidoln Loratadine

 Lomeprol

Lormetazepam Magnesium trisilicate Mefenamic acid Melatonin Methaqualone

Metramizole Metronidazole Metaform Minocycline Multivitamins

Naproxen Nimesulide Omeprazole Ondansetron Opium alkaloids

Oxyphenbutazone Paclitaxel Pamabrom Papaverine Para-aminosalicylic

acid

Penicillins Phenazone Phenolphthalein Phenylbutazone Phenylephrine

Phenylpropanolamine Phenytoin Pipemidic acid Piroxicam Procarbazine

Prochlorperazine Pseudoephedrine Quinine Rifampin Scopolia

Sodium benzoate Strawberries Sulfamethoxazole Tartrazine Terbinafine

Tetracyclines Theophylline Thiacetazone Ticlopidine Tinidazole

Tolfenamic acid Tosufloxacin Tranexamic acid Trimethoprim Tropisetron

Acetaminophen Acyclovir Allopurinol Allylisopropyl- Amide local

acetylurea anesthetics

Amlexanox Amoxicillin Anticonvulsants Articaine Aspirin

Atenolol Barbiturates Botulinum toxin Carbamazepine Cashew nut

Ceftriaxone Celecoxib Cetirizine Chloral hydrate Chlordiazepoxide

Chlorhexidine Chlormezanone Chlorphenesin Citicoline Clarithromycin

carbonate

Clioquinol Clopidogrel Codeine Colchicines Cyclizine

Cyproterone acetate Dextromethorphan Dimenhydrinate Diphenhydramine Dipyrone

Docetaxel Eperisone Erythromycin Ethenzamide Feprazone

hydrochloride

Finasteride Flecainide Fluconazole Fluoroquinolones Foscarnet

Gabapentin Griseofulvin Hydroxyzine Ibuprofen Interferon

Iodinated radiography Iomeprol Kakkon Ketoconazole Lactose

contrast media

Lamotrigine Lentils Liquorice Lopamidoln Loratadine

Lomeprol

Lormetazepam Magnesium trisilicate Mefenamic acid Melatonin Methaqualone

Metramizole Metronidazole Metaform Minocycline Multivitamins

Naproxen Nimesulide Omeprazole Ondansetron Opium alkaloids

Oxyphenbutazone Paclitaxel Pamabrom Papaverine Para-aminosalicylic

acid

Penicillins Phenazone Phenolphthalein Phenylbutazone Phenylephrine

Phenylpropanolamine Phenytoin Pipemidic acid Piroxicam Procarbazine

Prochlorperazine Pseudoephedrine Quinine Rifampin Scopolia

Sodium benzoate Strawberries Sulfamethoxazole Tartrazine Terbinafine

Tetracyclines Theophylline Thiacetazone Ticlopidine Tinidazole

Tolfenamic acid Tosufloxacin Tranexamic acid Trimethoprim Tropisetron