CONTINUING MEDICAL EDUCATION Fixed Drug Eruptions: A Case Report and Review of the Literature Sarah B. Gendernalik, DO; Kenneth J. Galeckas, MD RELEASE DATE: October 2009 TERMINATION DATE: October 2010 The estimated time to complete this activity is 1 hour. GOAL To understand fixed drug eruption (FDE) to better manage patients with the condition LEARNING OBJECTIVES Upon completion of this activity, you will be able to: 1. Describe the clinical presentation of FDEs including nonpigmenting and generalized bullous FDEs. 2. Name the medications most commonly associated with FDEs. 3. Outline methods to determine the causative medication, including topical and oral provocation testing. INTENDED AUDIENCE This CME activity is designed for dermatologists and general practitioners. CME Test and Instructions on page 221. This article has been peer reviewed and approved by College of Medicine is accredited by the ACCME to provide Michael Fisher, MD, Professor of Medicine, Albert Einstein continuing medical education for physicians. College of Medicine. Review date: September 2009. Albert Einstein College of Medicine designates this edu- This activity has been planned and implemented in cational activity for a maximum of 1 AMA PRA Category 1 accordance with the Essential Areas and Policies of the Credit TM. Physicians should only claim credit commensurate Accreditation Council for Continuing Medical Education with the extent of their participation in the activity. through the joint sponsorship of Albert Einstein College of This activity has been planned and produced in accor- Medicine and Quadrant HealthCom, Inc. Albert Einstein dance with ACCME Essentials. Drs. Gendernalik and Galeckas report no conflict of interest. The authors report no discussion of off-label use. Dr. Fisher reports no conflict of interest. The staff of CCME of Albert Einstein College of Medicine and Cutis ® have no conflicts of interest with commercial interest related directly or indirectly to this educational activity. Fixed drug eruptions (FDEs) have been described naproxen sodium in a 27-year-old woman. We since 1889 with continually evolving documenta- offer an inventory of common causes of FDEs as tion of implicated agents and clinical presenta- well as a discussion of the spectrum of clinical tions. We report a case of FDE as a reaction to presentations and differential diagnoses for this peculiar drug reaction. Dr. Gendernalik is a flight surgeon, Naval Air Station Whidbey Island, Oak Harbor, Washington. Dr. Galeckas is a staff dermatologist, Cutis. 2009;84:215-219. National Naval Medical Center, Bethesda, Maryland. The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Department of ixed drug eruption (FDE) was first described the Navy, the US Department of Defense, or the US Government. 1 Correspondence: Kenneth J. Galeckas, MD, National Naval by Bourns in 1889 and has long been clini- Medical Center, Department of Dermatology, 8901 Rockville Pike, F cally described as a sudden eruption of round Bethesda, MD 20889-5600 ([email protected]). to oval, edematous, dusky red macules or patches on VOLUME 84, OCTOBER 2009 215 Fixed Drug Eruptions the skin and mucous membranes that leave residual ibuprofen was unavailable. At presentation she had a hyperpigmentation, most commonly as a reaction to hyperpigmented 5-cm patch with a 2- to 3-mm ery- orally ingested drugs or drug components.2 Recent thematous border that appeared 24 hours prior. After research has provided histologic and immunologic careful review of the patient’s medical history and insight into the natural course and pathophysiol- both prescription and over-the-counter medication ogy of the disease.3 With the advent of a multitude regimens as well as physical examination, the patient of new medications and preservatives within med- was diagnosed with an FDE in response to naproxen ications, physicians are seeing both typical and sodium. She was instructed to avoid this medication unusual presentations of FDEs often mimicking der- indefinitely and has not had any recurrences. Rechal- matologic entities such as erythema multiforme,4 lenge with ibuprofen proved uneventful and the Stevens-Johnson syndrome,5 toxic epidermal necroly- residual PIH completely faded without intervention. sis (TEN),5,6 cellulitis,7 paronychia,7 and bullous pem- phigoid.8,9 We aim to provide a comprehensive review Comment of FDEs and their implicated offenders. Fixed drug eruption is a unique form of drug allergy that characteristically occurs in the same site(s) with Case Report each administration of the inciting drug. After initial A 27-year-old woman presented to our dermatology use of the offending agent, a variable refractory period clinic with an erythematous patch over her right of weeks, months, or years may pass before the lesions popliteal fossa that had recurred over 2 years and was first appear on the skin of a sensitized individual.2 transient (Figure). She first noticed the lesion during With repeated exposure to the agent, either via oral the first trimester of pregnancy with her third child. or topical administration, acute lesions typically With the exception of intermittent use of pain reliev- develop within 30 minutes to 8 hours and present ers early on, she reported taking only prenatal vita- as single or multiple, round, sharply demarcated, mins and denied using over-the-counter medications. dusky red macules, patches, or plaques that may be Over the ensuing years, the lesion erupted quickly pruritic and edematous.10,11 Pruritus and burning multiple times without a prodrome and resolved in may be the only manifestations of reactivation in a 3 to 4 days with residual postinflammatory hyper- PIH lesion.12 Initial lesions typically are solitary, but pigmentation (PIH). When present, the lesion was with repeated ingestion of the offending drug, new erythematous and pruritic. She previously had used lesions may appear and original lesions may increase pimecrolimus cream 1% for atopic dermatitis without in size. Lesions may blister and erode, leaving residual clinical improvement. Her medical history included and persistent pigmentation changes, especially in atopic dermatitis and von Willebrand disease. She patients with darker skin phototypes (ie, Fitzpatrick reported taking ibuprofen for relief of menstrual skin types IV to VI). However, blister formation and symptoms with occasional use of naproxen sodium if erosion are not necessary to produce the hallmark PIH changes. Clinically, a PIH lesion may be the only remnant between attacks. A refractory phase may occur following an acute flare in which exposure to the offending drug will not exacerbate the lesion for weeks to months.13 The most common cause of FDE (of any type) is trimethoprim-sulfamethoxazole.14 Nonpigmenting FDE was first described in 1987 by Shelley and Shelley15 and is characterized by large, symmetric, well-circumscribed, tender, erythematous plaques, occasionally with large bullae over involved areas,3,15-20 that suddenly appear but fade over 2 to 3 weeks without the residual PIH characteristically seen in the more common FDEs.2 Diagnosis is con- firmed in these cases by appearance of the lesion at the exact location of prior eruptions. Pseudoephed- rine hydrochloride is the most common instigator of this particular eruption.21 It also has been seen follow- ing influenza vaccination and has been mistakenly 8,9 A 27-year-old woman with a recurrent hyperpigmented diagnosed initially as bullous pemphigoid. 5-cm patch with a 2- to 3-mm erythematous border over Generalized bullous FDEs, characterized by mul- the right popliteal fossa. tiple, sharply defined, deep red macules distributed 216 CUTIS® Additional Causes of Fixed Drug Eruptions2,3,7-9,14-20,23,24,27,28 Antibacterial and Psychoactive Agents Anti-inflammatory Agents Miscellaneous Antiviral Agents (continued) Barbituratesa Allopurinol Acyclovir Carbamazepine Ibuprofen Articaine Amoxicillin Chloral hydrate Indomethacin Atenolol Ampicillin Chlordiazepoxide hydrochloride Mefenamic acida Botulinum toxin Chlorhexidine gluconate Chlormezanone Metamizole sodium Cimetidineb Clarithromycin Citicoline Naproxen sodium Colchicine Clindamycin Codeine Nimesulide Contrast mediab Fluoroquinolones Lamotrigine Oxyphenbutazone Cyproterone acetate Foscarnet sodium Lormetazepam Phenacetin Docetaxel p-Aminosalicylic acid Ondansetron hydrochloride Phenazonea Melatonin Penicillin Opium alkaloids Phenylbutazonea Omeprazole Piroxicama Antiparasitic Agents Belladonna Oral contraceptives Papaverine Quinine sulfate Pamabrom Albendazole Oxazepam Tolfenamic acid Phenolphthalein Pyrantel pamoate Phenytoin Antihistamines Procarbazine Tinidazole Prochlorperazine maleate Tartrazine Cetirizine hydrochloride b Antifungal Agents Tropisetron Tetrahydrozoline Cyclizine Ticlopidine hydrochloride Anti-inflammatory Agents Azole antifungals Diphenhydramine hydrochloride Clioquinol Acetaminophena Hydroxyzine hydrochloride Griseofulvin Aspirin Loratadine VOLUME 84, OCTOBER 2009 Terbinafine hydrochloride Celecoxib Orphenadrine Fixed Drug Eruptions Diclofenac sodium Decongestants Diflunisal Dipyrone Amlexanox Ethenzamide Citiolone aKnown causes of generalized bullous fixed drug eruptions.23 b 3,8,9,15-20 217 Known causes of nonpigmenting fixed drug eruptions. Fixed Drug Eruptions bilaterally and often symmetrically2,3,22 may mimic Immunohistochemical studies demonstrate large num- erythema multiforme,4 Stevens-Johnson syndrome,5 bers of CD31CD81 T cells