Drug-Induced Photosensitivity

Home , Photodermatitis, Photosensitivity

Acta Dermatovenerol Croat 2016;24(1):55-64 REVIEW

Ewelina Bogumiła Zuba1, Sandra Koronowska1, Agnieszka Osmola- Mańkowska2, Dorota Jenerowicz2

1Student Scientific Group at the Department of Dermatology, Medical University of Poznan, Poznan, Poland; 2Department of Dermatology, Medical University of Poznan, Poznan, Poland

Corresponding author: ABSTRACT Ultraviolet radiation is considered the main environmental Ewelina Bogumiła Zuba MD physical hazard to the skin. It is responsible for photoaging, sunburns, carcinogenesis, and photodermatoses, including drug-induced photo- Medical University of Poznan sensitivity. Drug-induced photosensitivity is an abnormal skin reaction 49 Przybyszewskiego St either to sunlight or to artificial light. Drugs may be a cause of photoal- 60-355 Poznan lergic, phototoxic, and photoaggravated dermatitis. There are numerous medications that can be implicated in these types of reactions. Recently, Poland non-steroidal anti-inflammatory drugs have been shown to be a com- [email protected] mon cause of photosensitivity. As both systemic and topical medications may promote photosensitive reactions, it is important to take into Received: November 17, 2014 consideration the potential risk of occurrence such reactions, especially Accepted: January 10, 2016 in people chronically exposed to ultraviolet radiation.

KEY WORDS: photoallergic contact dermatitis, photosensitizing agents, phototoxic dermatitis

INTRODUCTION Drug-induced photosensitivity is an undesirable Photosensitivity might be associated with differ- effect of topically applied or systemically adminis- ent mechanisms such as phototoxicity, photoallergy, trated pharmaceuticals, followed by exposition to pellagra, pseudoporphyria, lichenoid, and lupus ery- sunlight, mainly ultraviolet A (UVA) or/and ultraviolet thematosus reactions. The most common are pho- B (UVB) radiation as well as visible light. Such reac- totoxicity and photoallergy. The difference between tions usually affect the skin but the eye involvement them is shown in Table 1 (4-5). There are numerous is also possible. There has recently been a substantial drugs which can trigger sun-related skin reactions. increase of drug-induced photoreactions as a conse- Table 2 illustrates which drugs may induce photoal- quence of the ozone-layer depletion that allows in- lergic or phototoxic reactions (6). tense sunlight to reach the surface of Earth. Photosensitivity may be triggered by UVA and Phototoxicity UVB radiation in individuals who take certain medica- Phototoxicity is an abnormal chemical reaction tions or who suffer from particular disorders. Photo- induced by light. Phototoxic drugs are those which sensitivity skin lesions represent 8% of all cutaneous are able to absorb radiation. They must have a single adverse drug reactions (1-3). or double bond or halogenated aromatic rings in the

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Table 1. Phototoxic versus photoallergic reaction (4) Phototoxicity Photoallergy Onset of reaction minutes to hours 1-3 days Incidence more common less common Required exposure to agent single more than one Mechanism reactive oxygen radicals cause UV rays activate immune system promoting activation change in skin molecules leading to of macrophages which leads to the formation of long-term damage or cell death typical for contact dermatitis skin lesions Immunologically mediated no yes, type IV and its subtypes (5) Localization of lesions confined to the sun-exposed skin outbreak is not limited to the sun-exposed skin, it can area spread to the whole body area

(less inclined to affect submental, retroauricular areas and upper eyelids) Duration of the reaction active process (sometimes for years) until the trigger is removed, it can persist very even after the triggering factor was rarely for years without further exposure to the removed photosensitizing agent Clinical manifestation exaggerated sunburn with dermatitis blistering, desquamation and hyperpigmentation Concentration relation concentration related concentration not related *UV: ultraviolet molecule that determine the absorption spectrum. toallergen is required. Two mechanisms of photoaller- Typically wavelength causing photosensitive reac- gic reactions have been proposed. In the first case, a tions is above 310 nm. stable photoproduct formed from the reaction of the A molecule that absorbs photons is called a chro- drug with UV radiation serves as a hapten. A complete mophore. The energy of the photon causes promo- antigen is created by a combination of a hapten and tion of the electrons from a ground state to an ex- a carrier molecule. Alternatively, a drug able to absorb cited state. The so-called singlet or triplet state of the light might be shifted to an excited, unstable state. A photosensitizer is an unstable state and exists only molecule reverting to its ground state results in ener- for a short time, typically up to 10-10 s for singlet and gy release that may lead to conjugation with a carrier. 10-6 s for triplet states. Returning to a ground state is After formation of the complete antigen, the mecha- associated with a discharge of energy by radiation, nism of photoallergic dermatitis is identical to the heat emission, or a chemical reaction that results in pathogenesis of allergic contact dermatitis. The anti- the formation of a photoproduct. The energy transfer gen is processed and presented by Langerhans cells, from excited photosensitizer to oxygen leads to the in association with human leukocyte antigen (HLA) II production of excited single oxygen atoms that can antigens. T lymphocytes are activated by Langerhans participate in lipid and/or protein oxidation or deoxy- cells in regional lymph nodes. Skin lesions will occur ribonucleic acid (DNA) damage. That leads to direct when activated T-cells recirculate to the light-exposed cellular damage and may induce an immunological sites and recognize the photoallergen (8). inflammation (7). DNA damage may also lead to pho- togenotoxicity that results in cancerogenesis and de- Clinical features velopment of squamous cell carcinoma. Phototoxic reactions may occur in patients of any age, predominantly in women. Symptoms of photo- Photoallergy toxic skin reaction resemble an exaggerated sunburn Photoallergy may be elicited by systemic as well as and are limited to the sun-exposed areas. topical drugs. In both cases, photoallergic dermatitis Phototoxicity provokes the occurrence of erythe- is a delayed, T-cell mediated hypersensitivity reaction ma and edema within minutes to hours. Vesiculation (IV type Coombs and Gell classification). Photoaller- and blistering are rare. Persistent hyperpigmentation gic responses produced by systemically administered is also possible. The reaction is an active process of substances are much rarer than those caused by topi- skin cell damage and can persist for years, long after cally applied drugs. Previous sensitization to the pho- the triggering factor has been removed (4).

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Table 2. Common phototoxic and photoallergic drugs (6) Group of drugs Medication Phototoxic reaction Photoallergic Action spectrum reaction Oral treatment Cardiovascular and Furosemide + - Unknown diuretic agents Amiodarone + - UVA Quinidine + + UVA Thiazides + + UVA/UVB Antibiotic Dapsone - + Unknown Sulfonamide + + UVB Tetracycline + - UVA/UVB Ciprofloxacine + - UVA Antifungal Griseofulwin + - UVA Ketoconazole + - Unknown DMARD Hydroxychloroquine - + Unknown NSAID Naproxen + - UVA Piroxicam + UVA Tiaprofen + + UVA Ibuprofen + - UVA Ketoprofen + + UVA Topical treatment Antineoplastics 5-FU + + Unknown Furocoumarins Psoralen + + UVA Keratoplastics Coal tar + - UVA PDT Pro-photosensitizer 5-Aminolevulinic acid + - UVA/visible spectrum NSAID Ketoprofen + + UVA Naproxen + + UVA *UVA: ultraviolet A; UVB: ultraviolet B; DMARD: disease-modifying antirheumatic drugs; NSAID: nonsteroidal anti-inflammatory drugs; 5FU: Fluorouracil; PTD: photodynamic therapy

Photoallergic dermatitis occurs in patients of any most widely used by elderly patients. Tetracyclines and age. Men are affected more commonly than women. quinolones are often prescribed by dermatologists Onset of these reactions is 24-72 h after exposure. and physicians of other specialties due to their anti- Photoallergic dermatitis generally affects the light- microbial properties. Voriconazole and verumafenib exposed areas: the face, neck, upper chest, and dor- may lead to severe photosensitivity reactions, but sum of hands. Lesions may spread to unexposed ar- their photosensitive potential is not well-known. eas. Symptoms of photoallergic dermatitis are similar Non-steroidal anti-inflammatory drugs to those of contact dermatitis. Consequently, desquamation and residual hyperpigmentation occur and Non-steroidal anti-inflammatory drugs are widely can persist for more than a year. The predominant prescribed by physicians of all specialties. They have form of this reaction is eczematous (4). been found to elicit a high level of adverse photosensitivity. Some NSAIDs, including ibuprofen and naproxen, are also available over-the-counter (9). Drugs associated with Both systemic and topical administration of non-ste- photosensitivity roidal anti-inflammatory drugs may promote photo- This paper describes drug-induced photosensitiv- allergic and phototoxic reactions. ity related to: non-steroidal anti-inflammatory drugs NSAIDs are a heterogeneous group. Photosen- (NSAIDs), cardiovascular drugs, tetracyclines, quino- sitivity reactions induced by the use of ketoprofen, lones, voriconazole, and vemurafenib. NSAIDs are the naproxen, tiaprofenic acid, ibuprofen, diclofenac, pik- most common cause of drug-induced photosensitiv- etoprofen, piroxicam, celecoxib, benzydamine, and ity. Cardiovascular drugs are one of the medications etofenamate have been reported (10-15).

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Ketoprofen There are numerous case reports of photosensi- Ketoprofen has been shown to cause most cases tivity reactions in the literature, mainly to topical ke- of NSAIDs-induced photosensitivity (9-10). Its admin- toprofen. istration may induce phototoxic, photoallergic, and Matthieu et al. (24) performed patch tests and phototaggravated contact dermatitis. photopatch tests in 20 patients suspected of keto- Ketoprofen-induced phototoxicity is dependent profen-induced dermatitis. Photoallergic contact der- on the presence of this drug in the skin and may oc- matitis to ketoprofen was confirmed in 17 patients. cur in anyone, given sufficient UV radiation. Accord- Patch and photopatch tests demonstrated a contact ing to Nakajima et al. (16), ketoprofen phototoxic- allergy in 1 patient and a photoaggravated contact ity may involve production of oxygen free radicals, allergy in 2 patients. Severe skin lesions requiring sys- which are highly reactive towards proteins and lipids. temic corticotherapy were present in 47% of patients. In addition, Constanzo et al. (17) demonstrated that 26% of patients required hospitalization. Prolonged ketoprofen irritation causes the photolysis of erythro- photosensitivity was observed in one patient. cyte suspension. Photolysis of erythrocytes has been Caterina et al. (25) reported 2 cases of photoder- noted as an indicator of membrane damage. The use matitis due to systemic ketoprofen in patients with of radical scavengers resulted in significant reduction previous reactions to topical application of this drug. of photosensitized lysis of red blood cells, suggesting Both patients developed eczematous skin lesions the involvement of free radicals in these processes. within photoexposed areas of a body after oral ad- According to Chouini-Lalanne et al., (18) DNA may ministration of ketoprofen. These cases highlight a be another biological target of ketoprofen-induced possibility of photosensitivity reactions due to oral phototoxicity. Ketoprofen may cause DNA cleavage in ketoprofen in patients with a history of photocontact vitro upon irradiation. In the presence of ketoprofen, dermatitis after previous topical application of this pyrimidine dimers are formed by an energy transfer medicine. mechanism involving single strand breaks. There were 3 cases of photoallergic contact der- Phototallergy due to ketoprofen is a classical de- matitis after topical use of ketoprofen reported in pa- layed T-cell mediated hypersensitivity reaction. Keto- tients diagnosed at the Department of Dermatology profen is a propionic acid derivative, as well as a sub- of the Poznan University of Medical Sciences. All pa- stituted benzophenone. Considering the chemical tients experienced eczematous skin lesions. In 2 pa- structure of ketoprofen, many authors (19-20), point tients skin lesions had a bullous manifestation. In all out benzophenone moiety as a cause of photoaller- cases, the skin lesions were restricted to the skin area gic dermatitis induced by this drug. Benzophenone of drug application. The delay between the applica- moiety may also explain cross-reactions between ke- tion of ketoprofen and the reaction was between 2 toprofen and benzophenone-derived chemicals, i.e. and 60 days. One patient presented with a recurrence benzophenone-3 (component of sunscreen creams), of the photosensitivity phenomenon after 1 year tiaprofenic acid and fenofibrate. since the previous reaction (26). Cross-reactivity between ketoprofen and nonbenzophenone-containing molecules has recently been Piroxicam also observed. Photopatch testing was positive for fen- Piroxicam has been known as an important photo- tichlor, tetrachlorosalicylanilide, triclosan, and hexa- sensitizer since 1983, when Fjellner (27) reported the chlorophene in patients with contact photodermati- first case of piroxicam-induced photosensitivity. Fjell- tis to ketoprofen (21). All these molecules, including ner observed an erythematous-bullous eruption on ketoprofen, share a benzene ring linked to an oxygen light-exposed skin areas in a woman who was treated group, which may be involve in a cross-photosensiti- with systemic piroxicam due to rheumatoid arthritis. zation phenomenon. However, a benzene ring linked Photopatch tests were performed and showed a posi- to an oxygen group is not specific for ketoprofen. tive reaction to piroxicam. There are numerous case Patients with photoallergy due to ketoprofen of- reports in the literature of photodermatitis caused by ten present with photosensitivity to octocrylene. In both oral and systemic piroxicam (9,28). the study by Karlsson at al. (22), all patients who had Photosensitivity induced by piroxicam may result positive photopatch tests to ketoprofen also had pos- in both phototoxic and photoallergic reactions and itive photopatch tests to octocrylene. Patients who can be due to topical or systemic administration (29). experienced photoallergic reaction to ketoprofen Piroxicam is widely used in treatment of rheumato- should avoid sunscreens containing benzophenone- logic diseases, and 1-3% of patients taking this drug 3 and octocrylene (23). experience adverse cutaneous reactions (28). Upon

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low UVA irradiation, a photoproduct of piroxicam cheek where the topical diclofenac was applied. She is formed which is chemically similar to thiosalicylic presented with positive patch and photopatch test acid (moiety of thimerosal). This mechanism may be results. responsible for cross-reactivity between piroxicam, One case of photoallergic contact dermatitis thiosalicylic acid, and thimerosal (30). Most data do due to topical use of diclofenac was reported in a not support cross-reactivity between different oxi- 29-year-old male patient who was diagnosed at the cams (10,31), although a case photodermatitis elic- Department of Dermatology of the Poznan Univer- ited by piroxicam with a positive photopatch test to sity of Medical Sciences. The patient presented with other oxicams has been reported (29). eczematous skin lesions on the right foot 7 days after application of the drug (26). Benzydamine Benzydamine is an indazole non-steroidal anti-in- Cardiovascular and diuretic agents flammatory drug. It is available in Poland as a vaginal Amiodarone solution, mouth aerosol, and throat lozenges. Pho- tosensitivity from benzydamine may be underdiag- Amiodarone is a systemic antidysrhythmic drug nosed and has been occasionally described. that may provoke a wide range of photosensitive reactions. The phenomenon is UVA and visible light de- Benzydamine has phototoxic and photoallergic pendent and may be provoked by glass-transmitted properties (32). Used as a mouth aerosol or solution, light even on cloudy days or during winter time. Dur- it can induce cheilitis and chin dermatitis as a mani- ing sun exposure an immediate erythema, stinging, festation of photoallergy. or burning may occur. The agent is prone to induc- Canelas et al. (33) investigated photocontact al- ing exaggerated sunburn, pseudoporphyria, hyper- lergy to benzydamine in a group of 74 patients They pigmentation, and delayed erythema. Urticaria and performed photopatch testes with an extended series edema may occur with higher doses. A minority of of allergens including benzydamine. In 10 patients a patients may present an abnormal golden-brown or positive photopatch test to benzydamine was detect- unsightly grey pigmentation that does not disappear ed. Nine patients presented with lower lip cheilitis immediately after drug cessation and may persist for and one lichenified eczema on photoexposed areas months along with photosensitivity. When amioda- (face, neck, upper chest, forearms, dorsum of hands). rone is a drug of last resort, dosage reduction com- Another description of photocontact allergy bined with photoprotection is the only possibility of caused by benzydamine was published by Elgezua et management (3). al. (34). They reported a case of a photoallergic hand eczema due to benzydamine present in a gyneco- Statins logical washing solution. Eczema presented on the Statins are one of the most frequently adminis- dorsum of both hands. The rest of the skin, including tered lipid-lowering agents worldwide (36). Cutane- external genital organs, was unaffected. The diagno- ous reactions have been reported among the mul- sis was confirmed using photopatch tests. tiple adverse effects of these 3-hydroxy-3-methylglu- taryl coenzyme A (HMG-CoA) reductase inhibitors, Diclofenac mainly due to photosensitivity. Photophysical and Although diclofenac is a well-known possible pho- photochemical results indicate that singlet oxygen tosensitizer, there are only a few reports of it causing formation generated by the phenanthrene-like pho- photosensitivity reactions. toproduct of atorvastatin can induce phototoxic re- Portuguese researchers performed photopatch action (36). UVB-mediated phototoxicity due to ator- tests in 30 patients with suspected photoaggravated vastin was reported (37). Rosuvastatin was described facial dermatitis or systemic photosensitivity. One as a potential sensitizer through its dihydrophenan- patient had a positive reaction to diclofenac. Diclofe- threne-like compound (38). nac-induced photoallergy was attributed to systemic Fluvastatin has been proven to act as a phototoxic photosensitivity (31). agent after UVA irradiation through its benzocarba- Kowalzick et al. (35) reported a case of photoal- zole-like photoproduct. It has been reported that the lergic contact dermatitis from topical diclofenac in a phototoxic compound of fluvastatin mainly caused 77-year old female patient who was treated with 3% necrosis of the analyzed keratynocites (39). topical diclofenac due to actinic keratosis. The patient Simvastatin and pravastatin are known causes of developed exsudative, itching erythema on the right photoinduced erythema multiforme (40).

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The literature of case reports of phototoxic and Yap et al. (46) reported a case of solar utricaria photoallergic skin reactions of HMG-CoA reductase caused by tetracycline. A 28-year-old woman treated inhibitors is scarce. Thus it may appear that photo- with oral tetracycline developed macular erythema sensitivity is not a common clinical problem in this and pruritus. Skin lesions were restricted to the sun- group of drugs. exposed area of the body. Photopatch testing demonstrated urticarial reaction within 15 minutes. After ces- Thiazides and Furosemide sation of tetracycline, phototesting was negative. Thiazide diuretics may provoke exaggerated sun- Quinolones burn, which if recurrent, may induce chronic actinic dermatitis. Some patients present lupus and lichen Quinolones are broad spectrum antibacterial planus-like eruptions. The photochemical activity is drugs which may induce photosensitization reactions due to a chlorine substituent which is present in the of a varying degree of severity. There are four genera- structure of thiazides and furosemide. The UV disso- tions of quinolones. Presently, the therapeutic use of ciation of the chlorine substituent leads to reactions first generation quinolones is very limited in Europe, with lipids, proteins, and DNA (7). Photosensitivity is although some of them are still marketed in several idiosyncratic and rare. The management involves a countries, for instance nalidixic acid and pipemidic substitution of the thiazide with a relatively less pho- acid (47). There are many reports proving the photo- toactive loop diuretic (2). toxicity potential of representatives of all quinolone generations, for example nalidixic acid, pipemidic Qunidine acid, ciprofloxacin, fleroxacin, norfloxacin, moxifloxacin, lomefloxacin, ofloxacin, and rufloxacin (48). The photosensitive reaction provoked by quni- Quinolones mostly cause phototoxic reactions, al- dine sulphate has been known since 1942. The mech- though there are also some reports of photoallergy. anism is a type-IV allergic reaction (2). There has been evidence of the photoallergic potential of lomefloxacin and nalidixic acid (49,50). Antibacterial drugs The study of Wagai et al. and Marutani et al. dem- Tetracyclines onstrate that lomefloxacin is the most phototoxic Tetracyclines are one of the most frequent photo- of fluoroquinolones. In the first study its photosen- sensitizing agents among antibacterial drugs. There sitizing action was stronger than nalidixic acid. Fur- is a significant difference in the phototoxic index thermore, empirical studies have suggested that among the derivatives. moxifloxacin may be a mild photosensitizer. Methoxy group substitution may reduce the photosensitizing Demethylchlortetracycline and doxycycline have activity of moxifloxacin (48,51,52). the highest phototoxic potential; tetracycline and oxytetracycline are less photoactive. Minocycline and Novel drugs lymecycline have the lowest index of phototoxicity among tetracyclines (41-43). Layton et al. (44) report- Several recently produced drugs have photosen- ed that the phototoxic phenomenon of doxycycline sitising potential. Such drugs include antifungal vori- is dose dependent (Table 3). conazole (53,54) or anticancer drugs eg. vemurafenib. Voriconazole, which is a triazol antifungal agent and The typical clinical manifestation of phototoxic is widely used as a prophylaxis in patients after trans- reaction to tetracycline is sunburn, which may be as- plantations, exhibits its phototoxic potential in par- sociated with papular eruption or blistering (43). Tet- ticular during long-term treatment. This agent may racycline-induced photoonycholysis may also occur, be associated with chronic phototoxicity, accelerated usually at least 2 weeks after drug administration (45). Table 4. Classification criteria for photopatch test Table 3. Dose-dependent phototoxicity to doxy- reaction (54) cycline (44) Point Scale Skin lesion type Dose of doxycycline Incidence of phototoxicity 0 No reaction (mg/day) (%) 1 Erythema 100 3 2 Erythema and dermal infiltrate 150 20 3 Erythema and papulovesicles 200 42 4 Erythema and blisters or erosion

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Table 5. Interpretation of photopatch test results duplicate set on either side of the vertebrae. One set (54) is fixed to the skin for 24 hours. After 24 hours it is removed and irradiated with UVA (psoralen combined Non-irradiated Irradiated Conclusion with ultraviolet A (PUVA) fluorescent lamp of broad site site spectrum) of 5 J cm2. The control non-irradiated set - - No reaction can be fixed for either 24 or 48 hours, after which is - + Photoallergic removed. The irradiated test site is read before, imme- reaction diately, and 48, 72, and 96 hours after irradiation. The + + Contact reaction un-irradiated test site has to be evaluated after patch + +++ Phototaggravated test removal as well as after 48, 72, and 96 hours. Ery- reaction thema, dermal infiltrate, papulovesicles, blisters, and erosion indicate a positive reaction (Table 4) (62). A photo-aging, and, most likely, development of squa- positive response at an irradiated site and negative at mous cell carcinoma. Vemurafenib is an orally admin- a control site is interpreted as a positive photopatch istered inhibitor of BRAF kinase used in the treatment test reaction. Positive reaction at both sites is regard- of late-stage melanoma (55,56). During the treatment, ed as a contact reaction that may be aggravated by patients frequently experience immediate phototoxic the UV light (Table 5) (61,62). reactions among othercutaneous side effects. Stud- ies have shown that this reaction is UVA dependent Conclusion and probably related to decreased vitamin PP level Drug-induced photosensitivity may cause seri- and increased porphyrins levels (57). It is essential ous diagnostic difficulties, especially when it comes when developing new drugs to predict the potential to systemic medications. Knowledge of drugs prone for phototoxicity of its compounds. Over the past few to inducing such an adverse reaction is crucial when years some effective methodologies have led to the choosing the right treatment modality. It is important formation of some regulatory guidelines of drug pho- to establish the potential risk of causing a photosen- tosafety (58). sitive reaction before beginning phototherapy or la- ser therapy, especially in patients chronically exposed Over-the-counter photosensitisers to sunlight due to professional reasons. Cosmetics such as sunscreens or anti-aging prod- ucts that contain benzophenones or octocrylenes References: may also be a cause of photosensitive reactions 1. Willis I. Photosensitivity and Phototherapy. In: (58,59). Fitzpatrick TB, Eisen AZ, Wolff K, Freedburg IM, Some photosensitizers such as ibuprofen, naprox- Austen KF, eds. Dermatology in General Medicine. en, diclofenac, and some plant extracts eg. Hypericum New York: McGraw-Hill; 1979. perforatum are available over-the-counter in Poland. 2. Ferguson J. Drug-induced photosensitivity. In: J Patients are seldom aware of the potential risk of Ferguson, JS Dover, eds. Photodermatology. Lon- an adverse skin reaction and use medications with- don: Manson Publishing; 2006. pp. 67-72. out consulting their physician. Thus, it is important to 3. Yin B, Jiang X. Telomere shortening in cultured educate and increase awareness of possible photo- human dermal fibroblasts is associated with acute sensitivity. photodamage induced by UVA irradiation. Postep Derm Alergol 2013;30:13-8. Photopatch testing 4. Habif TP. Exanthems and drug eruptions. In: Habif Phototesting is a helpful tool in diagnosing drug- TP, ed. Clinical dermatology. St. Louis: Mosby Else- induced photosensitivity. Ketoprofen, etofenamate, vier; 2010. pp. 580. piroxicam, and benzydamine are the only NSAIDs 5. Posadas SJ, Pichler WJ. Delayed drug hypersensi- included in the standard photopatch test series (60). tivity reactions – new concepts. Clin Exp Allergy This procedure should not be performed while der- 2007;37:989-99. matitis is active. Photopatch testing should be under- taken on skin that has not been affected for the last 2 6. Gould JW, Mercurio MG, Elmets CA. Cutaneous weeks to avoid the effects of the so-called the “angry photosensitivity diseases induced by exogenous back” syndrome. The best choice for the testing area agents. J Am Acad Dermatol 1995;33:551-73. is the skin of the upper back, avoiding the paraver- 7. Mang R, Stege H, Krutmann J. Mechanisms of Pho- tebral area (61). Patch series have to be applied in a totoxic and Photoallergic Reactions, In: Frosch PJ,

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Menné T, Lepoittevin JP, eds. Contact Dermatitis. of ketoprofen associated with the benzophenone Berlin: Springer; 2006. pp. 97-104. chromophore. Photochem Photobiol 1994;60:96- 8. Mang R, Krutmann J. Mechanisms of phototoxic 101. and photoallergic reactions. In: Rycroft RJG, Men- 21. Durbize E, Vigan M, Puzenat E, Girardin P, Adessi né T, Frosc PJ, Lepoittevin JP, eds. Textbook of con- B, Desprez PH, et al. Spectrum of cross-photosen- tact dermatitis. Berlin: Springer; 2001. pp. 134-43. sitization in 18 consecutive patients with contact 9. Mammen L, Schmidt ChP. Photosensitivity reac- photoallergy to ketoprofen: associated photoal- tions: a case report involving NSAIDs - nonsteroi- lergies to nonbenzophenone-containing molecu- dal anti-inflammatory drugs. Am Fam Physician les. Contact Dermatitis 2003;48:144-9. 1995;52:575-9. 22. Karlsson I, Broecke KV, Martensson J, Goossens 10. De la Cuadra-Oyanguren J, Pérez-Ferriols A, Lecha- A, Börje A. Clinical and experimental studies of Carrelero M, Giménez-Arnau AM, Fernández-Re- octocrylene’s allergic potency. Contact Dermatitis dondo V, Ortiz de Frutos FJ, et al. Results and as- 2011;64:343-52. sessment of photopatch testing in spain: towards 23. Evenel-Audran M, Dutartre H, Goossend A, Jean- a new standard set of photoallergens. Actas Der- mougin M, Comte C, Bernier C, et al. Octocry- mosifiliogr 2007;98:96-101. lene, an emerging photoallergen. Arch Dermatol 11. Pigatto PD, Guzzi G, Schenna D, Guarrera M, Foti 2010;146:753-7. C, Francalanci S, et al. Photopatch tests: an Italian 24. Matthieu L, Meuleman L, Van Hecke E, Blondeel multicentre study from 2004 to 2006. Contact A, Dezfoulian B, Constandt L, et al. Contact and Dermatitis 2008;59:103-8. photocontact allergy to ketoprofen. The Belgian 12. Fernández-Jorge B, Goday Buján JJ, Paradela S, experience. Contact Dermatitis 2004;50:238-41. Mazaira M, Fonseca E. Consort photocontact der- 25. Foti C, Cassano N, Vena GA, Angelini G. Photoder- matitis from piketoprofen. Contact Dermatitis matitis caused by oral ketoprofen: two case re- 2008;58:113-5. ports. Contact Dermatitis 2011;64:181-3. 13. Sugiura M, Hayakawa R, Kato Y, Sugiura K, Ueda 26. Jenerowicz D, Jakubowicz O, Polańska A, Sa- H. Four cases of photocontact dermatitis due to dowska-Przytocka A, Dańczak-Pazdrowska A, ketoprofen. Contact Dermatitis 2000;1:16-9. Żaba R. Photosensitivity to selected topical nons- 14. Diffey BL, Daymond TJ, Faigeaves H. Phototoxic teroidal ani-inflammatory drugs preparations – a reactions to piroxicam, naproxen and and tiapro- review of literature data and authors’s own expe- fenic acid. Rheumatology 1983;22:239-42. rience. Centr Eur J of Immunol 2011;36:197-203. 15. Yazici AC, Baz K, Ikizoglu G, Kokturk A, Uzumlu 27. Fjellner B. Photosensitivity induced by piroxicam. H, Tataroglu C. Celecoxib-induced photoallergic Acta Derm Venereol 1983;63:557-8. drug eruption. Int J Dermatol 2004;43:459-61. 28. Youn JI, Lee HG, Yeo UC, Lee YS. Piroxicam photo- 16. Nakajima A, Tahara M, Yoshimura Y, Nakazawa H. sensitivity associated with vesicular hand derma- Determination of free radicals generated from titis. Clin Exp Dermatol 1993;18:52-4. light exposed ketoprofen. J Photochem Photobiol 29. Lim HW, Hawk J. Photodermatoses. In: Bolognia A 2005;174:89-97. JL, Jorizzo JL, Rapini RP, editors. Dermatology. 17. Costanzo LL, De Guidi G, Condorelli G, Cambria A, London: Mosby; 2007. pp. 1333-51. Fama M. Molecular mechanism of drug photosen- 30. Gonçalo M, Figueiredo A, Tavares P, Ribeiro CA, Te- sitization. II. Photohemolysis sensitized by keto- ixeira F, Baptista AP. Photosensitivity to piroxicam: profen. Photochem Photobiol 1989;50:359-65. absence of cross-reaction with tenoxicam. Con- 18. Chouini-Lalanne N, Defaisn M, Paillous N. Nons- tact Dermatitis 1992;27:287-90. teroidal antiinflammatory drug-photosensitized 31. Cardoso JC, Canelas MM, Gonçalo M, Figueiredo formation of pyrimidine dimer in DNA. Biochem A. Photopatch testing with an extended series of Pharmacol 1998;55:441-6. photoallergens: a 5-year study. Contact Dermati- 19. Nakazawa T, Shimo T, Chikamatsu N, Igarashi T, tis 2009;60:325-9. Nagata O, Yamamoto M. Study on the mechanism 32. Moore D E, Wang J. Electron-transfer mechanisms of photosensitive dermatitis caused by ketopro- in photosensitization by the anti-inflammatory fen in the guinea pig. Arch Toxicol 2006;80:442-8. drug benzydamine. J Photochem Photobiol B 20. Bosca F, Miranda MA, Carganico G, Mauleón D. 1998;43:175-80. Photochemical and photobiological properties 33. Canelas MM, Cardoso JC, Goncalo M, Figueiredo

62 ACTA DERMATOVENEROLOGICA CROATICA Zuba et al. Acta Dermatovenerol Croat Drug-induced photosensitivity 2016;24(1):55-64

A. Photoallergic contact dermatitis from benzyda- duced solar urticaria due to tetracycline. Australas mine presenting mainly as lip dermatitis. Contact J Dermatol 2000;41:181-4. Dermatitis 2010;63:85-8. 47. Adriaenssens N, Coenen S, Versporten A, Muller 34. Elgezua OA, Gorrotxategi PE, Garcia JG, Nieto A, Minalu G, Faes Ch, et al. European Surveillance JA, Ratón Nieto JA, Pérez JL. Photoallergic hand of Antimicrobial Consumption (ESAC): outpatient eczema due to benzydamine. Eur J Dermatol quinolone use Europe (1997–2009). J. Antimicrob. 2004;14:69-70. Chemother 2011;66:47-56. 35. Kowalzick L, Ziegler H. Photoallergic contact der- 48. de Guidi G, Bracchitta G, Catalfo A. Photosensi- matitis from topical diclofenac in Solaraze gel. tization reactions of fluoroquinolones and their Contact Dermatitis 2006;54:348-9. biological consequences. Photochem Photobiol 36. Montanaro S, Lhiaubet-Vallet V, Iesce MI, Previtera 2011;87:1214-29. L, Miranda MA. A mechanistic study on the photo- 49. Kurumaji Y, Shono M. Scarified photopatch testing toxicity of atorvastatin: singlet oxygen generation in lomefloxacin photosensitivity. Contact Derma- by a phenanthrene-like photoproduct. Chem Res titis 1992;26:5-10. Toxicol 2009;22:173-8. 50. Horio T, Miyauchi H, Asada Y, Aoki Y, Harada M. 37. Marguery, MC, Chouini-Lalanne N, Drugeon C, Phototoxicity and photoallergenicity of quinolo- Gadroy A, Bayle P, Journe F, et al. UV-B phototoxic nes in guinea pigs. J Dermatol Sci 1994;7:130-5. effects induced by atorvastatin. Arch Dermatol 51. Wagai N, Yamaguchi F, Sekiguchi M, Tawara K. 2006;142:1082-4. Phototoxic potential of quinolone antibacterial 38. Nardi G, Lhiaubet-Vallet V, Leandro-Garcia P, Mi- agents in Balb/c mice. Toxicol Lett 1990; 54:299- randa MA. Potential phototoxicity of rosuvastatin 308. mediated by its dihydrophenanthrene-like pho- 52. Marutani K, Matsumoto M, Otabe Y, Nagamuta M, toproduct. Chem Res Toxicol 2011;24:1779-85. Tanaka K, Miyoshi A, et al. Reduced phototoxicity 39. Viola G, Grobelny P, Linardi MA, Salvador A, Basso of a fluoroquinolone antibacterial agent with a G, Mielcarek J, et al. The phototoxicity of fluvasta- methoxy group at the 8 position in mice irradia- tin, an HMG-CoA reductase inhibitor, is mediated ted with long-wavelength UV light. Anitimicrob by the formation of a benzocarbazole-like photo- Agents Chemother 1993;37:221723. product. Toxicol Sci 2010;118:236-50. 53. Haylett AK, Felton S, Denning DW, Rhodes LE. Vo- 40. Rodriguez-Pazos L, Sanchez-Aguilar D, Rodri- riconazole-induced photosensitivity: photobiolo- guez-Granados MT, Pereiro-Ferreiros M, Toribio gical assessment of a case series of 12 patients. Br J. Erythema multiforme photoinduced by sta- J Dermatol 2013;168:179-85. tins. Photodermatol Photoimmunol Photomed 54. Clancy CJ, Nguyen MH. Long-term voriconazole 2010;26:216-8. and skin cancer: is there cause for concern? Curr 41. Bjellerup M, Ljunggren. Double blind cross-over Infect Dis Rep 2011;13:536-43. studies on phototoxicity to three tetracycline de- 55. Cowen EW, Nguyen JC, Miller DD, McShane D, Ar- rivatives in human volunteers. Photodermatology ron ST, Prose NS. Chronic phototoxicity and ag- 1987;4:281-7. gressive squamous cell carcinoma of the skin in 42. Harber LC, Bickers DR. Drug induced photosen- children and adults during treatment with vorico- sitivity (phototoxic and photoallergic drug reac- nazole. J Am Acad Dermatol 2010;62:31-7. tions). In: Harber LC, Bickers DR, eds. Photosensi- 56. Lacouture ME, Duvic M, Hauschild A, Prieto VG, tivity Diseases. Principles of Diagnosis and Treat- Robert C, Schadendorf D, et al. Analysis of derma- ment. Toronto: B. C: Decker; 1989. pp. 160-202. tologic events in vemurafenib-treated patients 43. Frost P, Weinstein GD, Gomez EC. Phototoxic po- with melanoma. Oncologist 2013;18:314-22. tential of minocycline and doxycycline. Arch Der- 57. Gelot P, Dutartre H, Khammari A, Boisrobert A, matol 1972;105:681-3. Schmitt C, Deybach JC, et al. Vemurafenib: an unu- 44. Layton AM, Cunliffe WJ. Phototoxic eruptions due sual UVA-induced photosensitivity. Exp Dermatol to doxycycline – a dose related phenomenon. Clin 2013;22:297-8. Exp Dermatol 1993;18:425-7. 58. Seto Y, Hosoi K, Takagi H, Nakamura K, Kojima H, 45. Baran R, Juhlin L. Drug induced photo-onycholy- Yamada S, et al. Exploratory and regulatory as- sis. J Am Acad Dermatol 1987;17:1013-6. sessments on photo safety of new drug entities. 46. Yap LM, Foley PA, Crouch RB, Baker ChS. Drug-in- Curr Drug Saf 2012;7:140-8.

ACTA DERMATOVENEROLOGICA CROATICA 63 Zuba et al. Acta Dermatovenerol Croat Drug-induced photosensitivity 2016;24(1):55-64

59. Drucker AM, Rosen CF. Drug-induced photosensi- 61. Spiewak R, ed. Photoallergy and Photopatch Tes- tivity: culprit drugs, management and prevention. ting. Krakow: Institute of Dermatology Krakow; Drug Saf 2011;34:821-37. 2009. pp. 1-33. 60. Gonçalo M, Ferguson J, Bonevalle A, Bruynzeel DP, 62. Bruynzeel DP, Ferguson J, Andersen K, Gonçalo M, Giménez-Arnau A, Goossens A, et al. Photopatch English J, Goossens A, et al. Photopatch testing: a testing: recommendations for a European pho- consensus methodology for Europe. J Eur Acad topatch test baseline series. Contact Dermatitis Dermatol Venereol 2004;18:679-82. 2013;68:239-43.

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