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.1,2,3,4 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
Also see the following related eMedicine articles:
- Drug Eruptions
- Drug-Induced Bullous Disorders
- Drug-Induced Gingival Hyperplasia
- Drug-Induced Photosensitivity
- Drug-Induced Pigmentation
- Drug-Induced Pseudolymphoma Syndrome
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.5 CD8+ effector/memory T cells play an important role in reactivation of lesions with re-exposure to the offending drug.6,7
The offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, leading to an inflammatory response.8 Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes may locally up-regulate expression of the intercellular adhesion molecule-1 (ICAM1).9 The up-regulated ICAM1 has been shown to help T cells (CD4 and CD8) migrate to the site of an insult.10,11
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.5
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.5 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.5
Frequency
United States
The prevalence of drug eruptions has been reported to range from 2-5% for inpatients and greater than 1% for outpatients.12 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.13
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.14 Localized hyperpigmentation is a common complication, but pain, infection, and, rarely, hypopigmentation, also may occur.1
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.15,16
Sex
One large study of 450 patients revealed a male-to-female ratio of 1:1.1 for fixed drug eruptions.1
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.1
Clinical
History
The initial eruption is often solitary and frequently located on the lip or genitalia. 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.17 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.18 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 medications19 :
- Analgesics
- Muscle relaxants
- Sedatives
- Anticonvulsants
- Antibiotics
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.1
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.20,21,22
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 Media Files 1-5). 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.3
Targetoid fixed drug eruption on the abdomen of a child.
Hyperpigmented fixed drug eruption on the hip of an adult.
Vesicular fixed drug eruption on the glans penis.
Multiple hyperpigmented fixed drug eruptions on the trunk.
Hyperpigmented fixed drug eruption on the right side of the upper lip.
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.1
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.2
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.8
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 have also been reported as causative agents. Ingestion of the causative agent may occur via any route, including oral, rectal, or intravenous.19
The most common cause is trimethoprim-sulfamethoxazole.3 Other substances implicated to cause fixed drug eruptions are as follows1,8,19,23,24,25,26,27,28,29,30,31 :
Open table in new window
Table
| 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 | 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 |
| 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 | 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 |
More on Fixed Drug Eruptions |
 Overview: Fixed Drug Eruptions |
| Differential Diagnoses & Workup: Fixed Drug Eruptions |
| Treatment & Medication: Fixed Drug Eruptions |
| Follow-up: Fixed Drug Eruptions |
| Multimedia: Fixed Drug Eruptions |
| References |
| Next Page » |
References
Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. Nov 1998;37(11):833-8. [Medline].
Ozkaya-Bayazit E. Specific site involvement in fixed drug eruption. J Am Acad Dermatol. Dec 2003;49(6):1003-7. [Medline].
Ozkaya-Bayazit E, Bayazit H, Ozarmagan G. Drug related clinical pattern in fixed drug eruption. Eur J Dermatol. Jun 2000;10(4):288-91. [Medline].
Fischer G. Vulvar fixed drug eruption. A report of 13 cases. J Reprod Med. Feb 2007;52(2):81-6. [Medline].
Teraki Y, Shiohara T. IFN-gamma-producing effector CD8+ T cells and IL-10-producing regulatory CD4+ T cells in fixed drug eruption. J Allergy Clin Immunol. Sep 2003;112(3):609-15. [Medline].
Mizukawa Y, Shiohara T. Fixed drug eruption: a prototypic disorder mediated by effector memory T cells. Curr Allergy Asthma Rep. Jan 2009;9(1):71-7. [Medline].
Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. Aug 2009;9(4):316-21. [Medline].
Weedon D. The lichenoid reaction pattern ('interface dermatitis'). In: Skin Pathology. 2nd ed. London, England: Churchill Livingstone; 2002:42-43.
Smoller BR, Luster AD, Krane JF, et al. Fixed drug eruptions: evidence for a cytokine-mediated process. J Cutan Pathol. Feb 1991;18(1):13-9. [Medline].
Hindsen M, Christensen OB, Gruic V, Lofberg H. Fixed drug eruption: an immunohistochemical investigation of the acute and healing phase. Br J Dermatol. Mar 1987;116(3):351-60. [Medline].
Shiohara T, Nickoloff BJ, Sagawa Y, Gomi T, Nagashima M. Fixed drug eruption. Expression of epidermal keratinocyte intercellular adhesion molecule-1 (ICAM-1). Arch Dermatol. Oct 1989;125(10):1371-6. [Medline].
Krahenbuhl-Melcher A, Schlienger R, Lampert M, Haschke M, Drewe J, Krahenbuhl S. Drug-related problems in hospitals: a review of the recent literature. Drug Saf. 2007;30(5):379-407. [Medline].
Lee AY. Fixed drug eruptions. Incidence, recognition, and avoidance. Am J Clin Dermatol. Sep-Oct 2000;1(5):277-85. [Medline].
Baird BJ, De Villez RL. Widespread bullous fixed drug eruption mimicking toxic epidermal necrolysis. Int J Dermatol. Apr 1988;27(3):170-4. [Medline].
Pellicano R, Ciavarella G, Lomuto M, Di Giorgio G. Genetic susceptibility to fixed drug eruption: evidence for a link with HLA-B22. J Am Acad Dermatol. Jan 1994;30(1):52-4. [Medline].
Pellicano R, Lomuto M, Ciavarella G, Di Giorgio G, Gasparini P. Fixed drug eruptions with feprazone are linked to HLA-B22. J Am Acad Dermatol. May 1997;36(5 Pt 1):782-4. [Medline].
Bolognia JL, Jorizzo JL, Rapini RP. Fixed drug eruptions. In: Dermatology. London, England: Mosby; 2003:344-5.
Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI. Fixed drug eruptions. In: Fitzpatrick's Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill; 2003:1333.
Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. Aug 2006;45(8):897-908. [Medline].
Zawar V, Chuh A. Fixed drug reaction may be sexually induced. Int J Dermatol. Aug 2006;45(8):1003-4; author reply 1004. [Medline].
Berger RE. Fixed drug eruption--a sexually inducible reaction?. J Urol. Jun 2005;173(6):1990. [Medline].
Zawar V, Kirloskar M, Chuh A. Fixed drug eruption - a sexually inducible reaction?. Int J STD AIDS. Aug 2004;15(8):560-3. [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].
Gupta S, Gupta S, Mittal A, David S. Oral fixed drug eruption caused by gabapentin. J Eur Acad Dermatol Venereol. Feb 19 2009;[Medline].
Ghosh SK, Bandyopadhyay D. Clopidogrel-induced fixed drug eruption. J Eur Acad Dermatol Venereol. Jan 20 2009;[Medline].
Oyama N, Kaneko F. Solitary fixed drug eruption caused by finasteride. J Am Acad Dermatol. Jan 2009;60(1):168-9. [Medline].
Knapp CF 3rd, Cooke ER, Sheehan DJ. Bullous fixed drug eruption caused by flecainide. J Am Acad Dermatol. Feb 2009;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. Sep 2008;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. Nov 2008;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. Feb 2007;17(2):485-9. [Medline].
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].
Lammintausta K, Kortekangas-Savolainen O. The usefulness of skin tests to prove drug hypersensitivity. Br J Dermatol. May 2005;152(5):968-74. [Medline].
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. Jun 2002;46(6):352-3. [Medline].
Kelso JM, Keating RM. Successful desensitization for treatment of a fixed drug eruption to allopurinol. J Allergy Clin Immunol. May 1996;97(5):1171-2. [Medline].
Zawar V, Kirloskar M, Chuh A. Fixed drug eruption - a sexually inducible reaction?. Int J STD AIDS. Aug 2004;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. Aug 2004;51(2):57-62. [Medline].
Gonzalo-Garijo MA, de Argila D, Rodríguez-Nevado I. Generalized reaction after patch testing with metamizol. Contact Dermatitis. Sep 2001;45(3):180. [Medline].
Further Reading
Keywords
fixed drug eruption, fixed drug reaction, FDE, adverse drug reaction, adverse cutaneous drug reaction, drug-induced hypersensitivity, drug-induced pigmentation, postinflammatory hyperpigmentation, post-inflammatory hyperpigmentation
