Fixed Drug Eruptions

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Fixed Drug Eruptions

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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. [1, 2, 3, 4, 5, 6, 7] 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

Cellulitislike eruption [8]

Also see the following related Medscape articles:

Drug Eruptions

Drug-Induced Bullous Disorders

Drug-Induced Gingival Hyperplasia

Drug-Induced Photosensitivity

Drug-Induced Pigmentation

Drug-Induced Pseudolymphoma Syndrome

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. [9] CD8+ effector/memory T cells play an important role in reactivation of lesions with re-exposure to the offending drug. [10, 11]

The offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, leading to an inflammatory response. [12] Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes may locally up-regulate expression of the intercellular adhesion molecule-1 (ICAM1). [13] The up-regulated ICAM1 has been shown to help T cells (CD4 and CD8) migrate to the site of an insult. [14, 15]

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. [9]

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. [9] 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. [9]

United States

The prevalence of drug eruptions has been reported to range from 2-5% for inpatients and greater than 1% for outpatients. [16] 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. [17]

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. [18, 19]

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

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. [1]

The prognosis is very good, and an uneventful recovery should be expected. No deaths due to fixed drug eruption have been reported. Residual hyperpigmentation is very common, but this is less likely with the nonpigmenting variant.

Widespread lesions may initially mimic toxic epidermal necrolysis, but they have a benign clinical course. [20] Again, localized hyperpigmentation is a common complication, but pain, infection, and, rarely, hypopigmentation, also may occur. [1]

Patients should be counseled on medication avoidance and possible cross-reactions of similar medications. Patients should notify their physicians of all drug allergies they have experienced.

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Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. 2006 Aug. 45(8):897-908. [Medline].

Zawar V, Chuh A. Fixed drug reaction may be sexually induced. Int J Dermatol. 2006 Aug. 45(8):1003-4; author reply 1004. [Medline].

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Vidal C, Prieto A, Pérez-Carral C, Armisén M. Nonpigmenting fixed drug eruption due to pseudoephedrine. Ann Allergy Asthma Immunol. 1998 Apr. 80 (4):309-10. [Medline].

Montoro J, Díaz M, Genís C, Lozano A, Bertomeu F. Non-pigmenting cutaneous-mucosal fixed drug eruption due to piroxicam. Allergol Immunopathol (Madr). 2003 Jan-Feb. 31 (1):53-5. [Medline].

Rasi A, Khatami A. Unilateral non-pigmenting fixed drug eruption associated with cotrimoxazole. Dermatol Online J. 2006 Oct 31. 12 (6):12. [Medline].

Tanabe K, Amoh Y, Mii S, Eto H, Iwamura M, Katsuoka K. Non-pigmenting fixed drug eruption induced by sorafenib. Acta Derm Venereol. 2010 May. 90 (3):307. [Medline].

Das S, Das S, Chowdhury J, Bhanja DC. Non pigmenting mucosal fixed drug eruption due to tadalafil: A report of two cases. Indian Dermatol Online J. 2014 Apr. 5 (2):167-9. [Medline].

Choi SY, Suh JH, Park KY, Li K, Kim BJ, Seo SJ, et al. Fixed Drug Eruption Caused by Sildenafil Citrate. Ann Dermatol. 2017 Apr. 29 (2):247-248. [Medline].

Sánchez-Morillas L, Rojas Pérez-Ezquerra P, González Morales ML, Mayorga C, González-Mendiola R, Laguna Martínez JJ. Fixed drug eruption due to norfloxacin and cross-reactivity with other quinolones. Allergol Immunopathol (Madr). 2012 Jan 20. [Medline].

Pérez-Calderón R, Gonzalo-Garijo MA, Pérez-Rangel I, Sánchez-Vega S, Zambonino MA. Fixed drug eruption due to nabumetone in a patient with previous fixed drug eruptions due to naproxen. J Investig Allergol Clin Immunol. 2011. 21(2):153-4. [Medline].

Leleu C, Boulitrop C, Bel B, Jeudy G, Vabres P, Collet E. Quinoline Yellow dye-induced fixed food-and-drug eruption. Contact Dermatitis. 2013 Mar. 68(3):187-8. [Medline].

Lim WS, Kim DH, Jin SY, Choi YS, Lee SH, Huh HJ, et al. A case of fixed drug eruption due to doxycycline and erythromycin present in food. Allergy Asthma Immunol Res. 2013 Sep. 5(5):337-9. [Medline]. [Full Text].

Ohira A, Yamaguchi S, Miyagi T, et al. Fixed eruption due to quinine in tonic water: a case report with high-performance liquid chromatography and ultraviolet A analyses. J Dermatol. 2013 Aug. 40(8):629-31. [Medline].

Allchurch LG, Crilly H. Fixed drug eruption to propofol. Anaesth Intensive Care. 2014 Nov. 42 (6):777-81. [Medline].

Centers for Disease Control and Prevention. Fixed drug eruption associated with sulfonamides sold in Latino grocery stores – Greater Washington, DC, area, 2012-2013. MMWR Morb Mortal Wkly Rep. 2013 Nov 22. 62(46):914-6. [Medline].

Lopez Abad R, Iriarte Sotes P, Castro Murga M, Gracia Bara MT, Sesma Sanchez P. Fixed drug eruption induced by phenylephrine: a case of polysensitivity. J Investig Allergol Clin Immunol. 2009. 19(4):322-3. [Medline].

Ghosh SK, Bandyopadhyay D. Clopidogrel-induced fixed drug eruption. J Eur Acad Dermatol Venereol. 2009 Jan 20. [Medline].

Oyama N, Kaneko F. Solitary fixed drug eruption caused by finasteride. J Am Acad Dermatol. 2009 Jan. 60(1):168-9. [Medline].

Knapp CF 3rd, Cooke ER, Sheehan DJ. Bullous fixed drug eruption caused by flecainide. J Am Acad Dermatol. 2009 Feb. 60(2):e3. [Medline].

Ozkaya E, Mirzoyeva L, Jhaish MS. Ceftriaxone-induced fixed drug eruption: first report. Am J Clin Dermatol. 2008. 9(5):345-7. [Medline].

Fukushima S, Kidou M, Ihn H. Fixed food eruption caused by cashew nut. Allergol Int. 2008 Sep. 57(3):285-7. [Medline].

Takahama H. A fixed drug eruption that developed cross-sensitivity among amide local anaesthetics, including mepivacaine hydrochloride, lidocaine hydrochloride and propitocaine hydrochloride. J Eur Acad Dermatol Venereol. 2008 Nov. 22(11):1400-1. [Medline].

Bohm I, Medina J, Prieto P, Block W, Schild HH. Fixed drug eruption induced by an iodinated non-ionic X-ray contrast medium: a practical approach to identify the causative agent and to prevent its recurrence. Eur Radiol. 2007 Feb. 17(2):485-9. [Medline].

Benomar S, Ismaili N, Koufane J, Senouci K, Hassam B. [Fixed food eruption caused by liquorice.]. Ann Dermatol Venereol. 2010 Feb. 137(2):121-123. [Medline].

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Zaouak A, Ben Brahim E, Ben Tanfous A, Koubaa W, Sahnoun R, Hammami H, et al. Mucosal fixed drug eruption due to mefenamic acid: Report of a case and a review. Therapie. 2018 Feb 15. [Medline].

Özkaya E. Changing trends in inducer drugs of fixed drug eruption: a 20-year cross-sectional study from Turkey. J Dtsch Dermatol Ges. 2018 Apr. 16 (4):474-476. [Medline].

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Lammintausta K, Kortekangas-Savolainen O. Oral challenge in patients with suspected cutaneous adverse drug reactions: findings in 784 patients during a 25-year-period. Acta Derm Venereol. 2005. 85(6):491-6. [Medline].

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Zedlitz S, Linzbach L, Kaufmann R, Boehncke WH. Reproducible identification of the causative drug of a fixed drug eruption by oral provocation and lesional patch testing. Contact Dermatitis. 2002 Jun. 46(6):352-3. [Medline].

Andrade P, Brinca A, Gonçalo M. Patch testing in fixed drug eruptions–a 20-year review. Contact Dermatitis. 2011 Oct. 65(4):195-201. [Medline].

Kelso JM, Keating RM. Successful desensitization for treatment of a fixed drug eruption to allopurinol. J Allergy Clin Immunol. 1996 May. 97(5):1171-2. [Medline].

Malviya N, Cyrus N, Vandergriff T, Mauskar M. Generalized bullous fixed drug eruption treated with cyclosporine. Dermatol Online J. 2017 Feb 15. 23 (2):[Medline].

Zawar V, Kirloskar M, Chuh A. Fixed drug eruption – a sexually inducible reaction?. Int J STD AIDS. 2004 Aug. 15(8):560-3. [Medline].

Tornero P, De Barrio M, Baeza ML, Herrero T. Cross-reactivity among p-amino group compounds in sulfonamide fixed drug eruption: diagnostic value of patch testing. Contact Dermatitis. 2004 Aug. 51(2):57-62. [Medline].

Acetaminophen

Acyclovir

Allopurinol

Allylisopropyl-acetylurea

Amide local anesthetics

Amlexanox

Amoxicillin

Anticonvulsants

Articaine

Aspirin

Atenolol

Barbiturates

Botulinum toxin

Carbamazepine

Cashew nut

Ceftriaxone

Celecoxib

Cetirizine

Chloral hydrate

Chlordiazepoxide

Chlorhexidine

Chlormezanone

Chlorphenesin carbonate

Citicoline

Clarithromycin

Clioquinol

Clopidogrel

Codeine

Colchicines

Cyclizine

Cyproterone acetate

Dextromethorphan

Dimenhydrinate

Diphenhydramine

Dipyrone

Docetaxel

Eperisone hydrochloride

Erythromycin

Ethenzamide

Feprazone

Finasteride

Flecainide

Fluconazole

Fluoroquinolones

Foscarnet

Gabapentin

Griseofulvin

Hydroxyzine

Ibuprofen

Interferon

Iodinated radiography contrast media

Iomeprol

Kakkon

Ketoconazole

Lactose

Lamotrigine

Lentils

Liquorice

Lomeprol

Lopamidoln

Loratadine

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

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, American College of Rheumatology

Disclosure: Received income in an amount equal to or greater than $250 from: Lilly; Amgen <br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Jordan R Ilse, MD Staff Physician, Scott and White Internal Medicine Residency Program, Scott and White Clinic, Texas A&M University College of Medicine

Jordan R Ilse, MD is a member of the following medical societies: American Medical Association and Texas Medical Association

Disclosure: Nothing to disclose.

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