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Drug-Induced Photosensitivity

  • Author: Alexandra Y Zhang, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: May 31, 2016
 

Background

Drug-induced photosensitivity refers to the development of cutaneous disease as a result of the combined effects of a chemical and light. Exposure to either the chemical or the light alone is not sufficient to induce the disease; however, when photoactivation of the chemical occurs, one or more cutaneous manifestations may arise. These include phototoxic and photoallergic reactions, a planus lichenoides reaction, pseudoporphyria, and subacute cutaneous lupus erythematosus. Photosensitivity reactions may result from systemic medications and topically applied compounds (see Table 1 below).

UV-A–associated phototoxicity is also common with vemurafenib,[1, 2, 3] with reduced UV-A minimal erythema dose in 94% of those tested.[1]

Wavelengths within the UV-A (320-400 nm) range and, for certain compounds, within the visible range, are more likely to cause drug-induced photosensitivity reactions, although occasionally UV-B (290-320 nm) can also be responsible for such effects. UV-B wavelengths are most efficient at causing sunburn and nonmelanoma skin cancer. In patients who present with photosensitivity, it is often difficult to differentiate phototoxic from photoallergic reactions. However, they have a number of distinguishing characteristics (see Table 2 below).

Table 1. Common Photosensitizing Medications (Open Table in a new window)

Class Medication Photo-toxic Reaction Photo-allergic Reaction Lichenoid Reaction Pseudo-porphyria Subacute Cutaneous Lupus Erythematosus
Antibiotics Tetracyclines (doxycycline, tetracycline) Yes No Yes Yes No
Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin)[4] Yes No No No No
Sulfonamides Yes No No No No
Nonsteroidal anti-inflammatory drugs[5] Ibuprofen Yes No Yes No No
Ketoprofen Yes Yes No No No
Naproxen[6] Yes No Yes Yes No
Celecoxib[7] No Yes No Yes No
Diuretics Furosemide Yes No No Yes No
Bumetanide No No No Yes No
Hydro-chlorothiazide Yes No No No Yes
Retinoid Isotretinoin Yes No No No No
Acitretin Yes No No No No
Hypoglycemics Sulfonylureas (glipizide, glyburide)[4] No Yes Yes Yes No
HMG-CoA* reductase inhibitors Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)[8] Yes Yes Yes Yes No
Epidermal growth factor receptor inhibitors Cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, vandetanib[9] Yes Yes Yes Yes No
BRAF inhibitors Vemurafenib,[1, 2, 3] sorafenib Yes No No No Yes
Photodynamic therapy prophoto-sensitizers 5-Aminolevulinic acid[10] Yes No No No No
Methyl-5-aminolevulinic acid Yes No No No No
Verteporfin[11] Yes No No No No
Photofrin[12] Yes No No No No
Neuroleptic drugs[13] Phenothiazines (chlorpromazine, fluphenazine, perazine, perphenazine, thioridazine)[14] Yes Yes Yes No No
Thioxanthenes (chlorprothixene, thiothixene) Yes No No No No
Antifungals Terbinafine No No No No Yes
Itraconazole Yes Yes No No No
Voriconazole[15, 16, 17, 18] Yes No No Yes No
Griseofulvin Yes Yes No No Yes
Other drugs Para-aminobenzoic acid Yes Yes No No No
5-Fluorouracil Yes Yes Yes Yes No
Paclitaxel[5, 19] Yes No No No Yes
Amiodarone Yes No No Yes No
Diltiazem Yes No No No Yes
Quinidine Yes Yes Yes No No
Hydroxychloroquine No No Yes No No
Coal tar Yes No No No No
Enalapril No No No No Yes
Dapsone No Yes Yes Yes No
Oral contraceptives[20, 21] No Yes No Yes No
Sunscreens[22] Para-aminobenzoic acid No Yes No No No
Cinnamates No Yes No No No
Benzophenones No Yes No No No
Salicylates No Yes No No No
Fragrances Musk ambrette No Yes No No No
6-Methylcoumarin No Yes No No No
*3-Hydroxy-3-methylglutaryl coenzyme A.

Phototoxic reactions occur because of the damaging effects of light-activated compounds on cell membranes and, in some instances, DNA. By contrast, photoallergic reactions are cell-mediated immune responses to a light-activated compound. Phototoxic reactions develop in most individuals if they are exposed to sufficient amounts of light and drug. Typically, they appear as an exaggerated sunburn response, as shown in the image below.

Phototoxic reaction. Phototoxic reaction.

Photoallergic reactions resemble allergic contact dermatitis, with a distribution limited to sun-exposed areas of the body. However, when the reactions are severe or prolonged, they may extend into covered areas of skin.

Table 2. Distinguishing Characteristics of Phototoxic and Photoallergic Reactions (Open Table in a new window)

Feature Phototoxic Reaction Photoallergic Reaction
Incidence High Low
Amount of agent required for photosensitivity Large Small
Onset of reaction after exposure to agent and light Minutes to hours 24-72 hours
More than one exposure to agent required No Yes
Distribution Sun-exposed skin only Sun-exposed skin, may spread to unexposed areas
Clinical characteristics Exaggerated sunburn Dermatitis
Immunologically mediated No Yes; Type IV

 

Photoallergic reactions develop in only a minority of individuals exposed to the compound and light; they are less prevalent than phototoxic skin reactions. The amount of drug required to elicit photoallergic reactions is considerably smaller than that required for phototoxic reactions. Moreover, photoallergic reactions, as shown in the image below, are a form of cell-mediated immunity; their onset often is delayed by as long as 24-72 hours after exposure to the drug and light. By contrast, phototoxic responses often occur within minutes or hours of light exposure.

Photoallergic reaction. Photoallergic reaction.
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Pathophysiology

Phototoxicity

Phototoxic reactions result from direct damage to tissue caused by a photoactivated compound. Many compounds have the potential to cause phototoxicity. Most have at least one resonating double bond or an aromatic ring that can absorb radiant energy. Most compounds are activated by wavelengths within the UV-A (320-400 nm) range, although some compounds have a peak absorption within the UV-B or visible range.

In most instances, photoactivation of a compound results in the excitation of electrons from the stable singlet state to an excited triplet state. As excited-state electrons return to a more stable configuration, they transfer their energy to oxygen, leading to the formation of reactive oxygen intermediates. Reactive oxygen intermediates such as an oxygen singlet, superoxide anion, and hydrogen peroxide damage cell membranes and DNA. Signal transduction pathways that lead to the production of proinflammatory cytokines and arachidonic acid metabolites are also activated. The result is an inflammatory response that has the clinical appearance of an exaggerated sunburn reaction.

The exception to this mechanism of drug-induced phototoxicity is psoralen-induced phototoxicity. Psoralens intercalate within DNA, forming monofunctional adducts. Exposure to UV-A radiation produces bifunctional adducts within DNA. Exactly how bifunctional adducts cause photosensitivity is unknown.

Photoallergic reactions

Photoallergic reactions are cell-mediated immune responses in which the antigen is a light-activated drug. Photoactivation results in the development of a metabolite that can bind to protein carriers in the skin to form a complete antigen. The reaction then proceeds exactly as other cell-mediated immune responses do. Specifically, Langerhans cells and other antigen-presenting cells take up the antigen and then migrate to regional lymph nodes. In those locations, the Langerhans cells present the photoallergen to T lymphocytes that express antigen-specific receptors. The T cells become activated and proliferate, and they return to the site of photoallergen deposition. In the skin, the T cells orchestrate an inflammatory response that usually has an eczematous morphology if the photoallergen is applied topically or the characteristics of a drug eruption if the photoallergen is administered systemically.

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Epidemiology

Frequency

United States

The incidence of drug-induced photosensitivity in the United States is uncertain. Phototoxic reactions are considerably more common than photoallergic reactions.

International

The incidence of drug-induced photosensitivity is unknown.

Race

The racial incidence of drug-induced photosensitivity reactions is unknown. Photosensitivity reactions can occur in races with heavily pigmented skin.

Sex

Men are more likely to have photoallergic reactions than women.

Age

Drug-induced photosensitivity reactions can occur in persons of any age.

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Prognosis

In most patients, the prognosis is excellent once the offending agent is removed. However, complete resolution of the photosensitivity may take several weeks to months with some compounds. Occasionally, patients have persistent light reactivity for which the prospects for resolution are poor.

Drug-induced photosensitivity is associated with death only in rare individuals who are exposed to large amounts of sunlight after taking large doses of psoralens. Although mortality is rare, drug-induced photosensitivity can cause significant morbidity in some individuals, who must severely limit their exposure to natural or artificial light.

Voriconazole photosensitivity is associated with a risk of skin cancer.[23, 24] The changes that occur with long-term exposure resemble accelerated photo-aging. Acute photosensitivity occurs in 1–2% or more of patients taking voriconazole for more than 12 weeks. It appears to be UV-A induced, but it is not strictly dose-dependent. Cheilitis and facial erythema are typical initial manifestations.

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Patient Education

Patients need to be counseled regarding the possible photosensitizing properties of both prescription and nonprescription medications. Most often, appropriate sun protection measures prevent drug-induced photosensitivity reactions.

For patient education resources, see the Burns Center, as well as Sunburn.

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Contributor Information and Disclosures
Author

Alexandra Y Zhang, MD Staff Physician, Dermatology and Plastic Institute, Cleveland Clinic Foundation

Alexandra Y Zhang, MD is a member of the following medical societies: American Academy of Dermatology, Women's Dermatologic Society, Dermatology Foundation

Disclosure: Nothing to disclose.

Coauthor(s)

Craig A Elmets, MD Professor and Chair, Department of Dermatology, Director, Chemoprevention Program Director, Comprehensive Cancer Center, UAB Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine

Craig A Elmets, MD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, American College of Physicians, American Federation for Medical Research, Society for Investigative Dermatology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: University of Alabama at Birmingham; University of Alabama Health Services Foundation<br/>Serve(d) as a speaker or a member of a speakers bureau for: Ferndale Laboratories<br/>Received research grant from: NIH, Veterans Administration, California Grape Assn<br/>Received consulting fee from Astellas for review panel membership; Received salary from Massachusetts Medical Society for employment; Received salary from UpToDate for employment. for: Astellas.

Specialty Editor Board

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: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

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: XOMA; Biogen/IDEC; Novartis; Janssen Biotech, Abbvie, CSL pharma<br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor and intermittent author; 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: Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Chief Editor

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.

Additional Contributors

Abdul-Ghani Kibbi, MD Professor and Chair, Department of Dermatology, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

References
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Phototoxic reaction.
Photoallergic reaction.
Pseudoporphyria.
Subacute cutaneous lupus erythematosus exacerbated by terbinafine. Courtesy of Jeffrey P. Callen.
Table 1. Common Photosensitizing Medications
Class Medication Photo-toxic Reaction Photo-allergic Reaction Lichenoid Reaction Pseudo-porphyria Subacute Cutaneous Lupus Erythematosus
Antibiotics Tetracyclines (doxycycline, tetracycline) Yes No Yes Yes No
Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin)[4] Yes No No No No
Sulfonamides Yes No No No No
Nonsteroidal anti-inflammatory drugs[5] Ibuprofen Yes No Yes No No
Ketoprofen Yes Yes No No No
Naproxen[6] Yes No Yes Yes No
Celecoxib[7] No Yes No Yes No
Diuretics Furosemide Yes No No Yes No
Bumetanide No No No Yes No
Hydro-chlorothiazide Yes No No No Yes
Retinoid Isotretinoin Yes No No No No
Acitretin Yes No No No No
Hypoglycemics Sulfonylureas (glipizide, glyburide)[4] No Yes Yes Yes No
HMG-CoA* reductase inhibitors Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)[8] Yes Yes Yes Yes No
Epidermal growth factor receptor inhibitors Cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, vandetanib[9] Yes Yes Yes Yes No
BRAF inhibitors Vemurafenib,[1, 2, 3] sorafenib Yes No No No Yes
Photodynamic therapy prophoto-sensitizers 5-Aminolevulinic acid[10] Yes No No No No
Methyl-5-aminolevulinic acid Yes No No No No
Verteporfin[11] Yes No No No No
Photofrin[12] Yes No No No No
Neuroleptic drugs[13] Phenothiazines (chlorpromazine, fluphenazine, perazine, perphenazine, thioridazine)[14] Yes Yes Yes No No
Thioxanthenes (chlorprothixene, thiothixene) Yes No No No No
Antifungals Terbinafine No No No No Yes
Itraconazole Yes Yes No No No
Voriconazole[15, 16, 17, 18] Yes No No Yes No
Griseofulvin Yes Yes No No Yes
Other drugs Para-aminobenzoic acid Yes Yes No No No
5-Fluorouracil Yes Yes Yes Yes No
Paclitaxel[5, 19] Yes No No No Yes
Amiodarone Yes No No Yes No
Diltiazem Yes No No No Yes
Quinidine Yes Yes Yes No No
Hydroxychloroquine No No Yes No No
Coal tar Yes No No No No
Enalapril No No No No Yes
Dapsone No Yes Yes Yes No
Oral contraceptives[20, 21] No Yes No Yes No
Sunscreens[22] Para-aminobenzoic acid No Yes No No No
Cinnamates No Yes No No No
Benzophenones No Yes No No No
Salicylates No Yes No No No
Fragrances Musk ambrette No Yes No No No
6-Methylcoumarin No Yes No No No
*3-Hydroxy-3-methylglutaryl coenzyme A.
Table 2. Distinguishing Characteristics of Phototoxic and Photoallergic Reactions
Feature Phototoxic Reaction Photoallergic Reaction
Incidence High Low
Amount of agent required for photosensitivity Large Small
Onset of reaction after exposure to agent and light Minutes to hours 24-72 hours
More than one exposure to agent required No Yes
Distribution Sun-exposed skin only Sun-exposed skin, may spread to unexposed areas
Clinical characteristics Exaggerated sunburn Dermatitis
Immunologically mediated No Yes; Type IV
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