皮膚科 王修含醫生

降血脂藥物fenofibrate(非諾貝特)  引起的皮膚光敏感反應

台大皮膚科  洪楨邦、王修含、朱家瑜醫師.

Fenofibrate(非諾貝特，例如「濁血清」微粒膠囊® Down-Lip micronised capule) 是一種常用的降血脂藥物，但服用後，若接觸日光、紫外線，可能會引起皮膚的光敏感反應。以下為一例由台大醫院皮膚科洪楨邦、王修含、朱家瑜醫師發表的病例：

詳細病例論文發表於「中華皮膚科醫學雜誌」，PDF檔案下載：

http://www.dermatol-sinica.com/web/data/200932111313.pdf

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降血脂藥物fenofibrate(非諾貝特)  引起的皮膚光敏感反應-臨床表現


降血脂藥物fenofibrate(非諾貝特)  引起的皮膚光敏感反應-藥物名稱：「濁血清」微粒膠囊® Down-Lip micronized fenofibrate cap (200mg/cap)


Fenofibrate 引起之光敏感反應-組織病理圖(Histopathology)
Interface change with basal vacuolation & Superficial perivascular inflammation


Fenofibrate 引起之光敏感反應-病灶分布區域：臉部、頸部、前臂等日光照射部位

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相關內科專科、皮膚科醫師考試考題：

九十七年度內科專科醫師考試筆試題 -- 皮膚科

Fenofibrate 引起之光敏感反應--病例報告暨文獻回顧

洪楨邦 王修含 朱家瑜
國立台灣大學醫學院附設醫院皮膚部

Fenofibrate是世界上最常用的降血脂藥物之一，其引起皮膚副作用的機率約為2%，
而光敏感反應則被認為是一個少見的表現，我們在此提出一例經由光貼膚測試確認為
fenofibrate引起光敏感反應之本土病例。回顧文獻，自1980年代起至今，fenofibrate
引起光敏感反應的報告並不多見。我們同時也探討fenofibrate及ketoprofen的交叉光敏感反應。（中華皮誌：27: 37-43, 2009）


光貼膚測試(photopatch test)結果-降血脂藥物fenofibrate(非諾貝特)  引起的皮膚光敏感反應


化學結構式-降血脂藥物fenofibrate(非諾貝特)  引起的皮膚光敏感反應

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Fenofibrate-Induced Photosensitivity - A Case Report and Literature Review

Jin-Bon Hong Shiou-Han Wang Chia-Yu Chu

Fenofibrate, a fibric acid derivative, is among the most commonly used antihyperlipidemic
medications. Although variable kinds of cutaneous eruption occurred in about 2% of fenofibrate users, photosensitivity was assumed to be a rare manifestation. Herein we report a case of
fenofibrate-induced photosensitization confirmed by photopatch testing. Reviewing the literature, fenofibrate-induced photosensitivity has been infrequently reported since 1980s. Besides, we also discuss the cross-photosensitization between fenofibrate and ketoprofen.
(Dermatol Sinica 27: 37-43, 2009)

Key words: Fenofibrate, Photosensitization, Photopatch tesing

From the Department of Dermatology, National Taiwan University Hospital
Corresponding author: Jin-Bon Hong, Department of Dermatology, National Taiwan University
Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan
TEL: 886-2-23562141 FAX: 886-2-23934177
Funding source: none
Conflict of interest: none declared

Received: November 08, 2007
Revised: February 27, 2008
Accepted: October 23, 2008
Dermatol Sinica, Mar 2009

INTRODUCTION
Fenofibrate, a fibric acid derivative, is one of the most commonly used antihyperlipidemic medications. It is usually well tolerated and the majority of adverse effects are gastrointestinal. Photosensitivity induced by fenofibrate was assumed to be very rare.1 Herein we present a case of fenofibrate-induced photosensitization confirmed by photopatch testing.

CASE REPORT
A 33-year-old man presented to our clinic with skin eruption on the sun-exposed areas for one day in sunny weather in June. His medical history was unremarkable except for hyperlipidemia. He denied any use of long-term medications or herbal medicine.

He was a motorcycle mechanic and had no new chemical contact before the skin eruption. Two weeks prior to the skin eruption, he started to take fenofibrate (Downlip®, 200 mg, 1 tablet per day) to control his hyperlipidemia. For his right shoulder pain, he began to receive chlorzoxazone (Parafon®) two days prior to this event. On the day prior to the skin eruption, he had fever up to 39.6°C with flu-like symptoms, including nasal stuffiness and sore throat. He took four unidentified medications by himself from the local pharmacy without prescription. Physical examinations revealed numerous variously sized, edematous, erythematous papules and plaques over the sun-exposed areas, involving the face, V-area of the neck, bilateral forearms and dorsa of the hands (Fig. 1). The oral, ocular and genital mucosae were intact. These skin lesions were itchy with burning sensation. The patient had Fitzpatrick skin phototype IV. Based on the clinical presentation, a photosensitive disorder was highly suspected. We suggested him to discontinue all medications. A skin biopsy was taken from one lesion on the left forearm. The skin biopsy demonstrated epidermal spongiosis, scattered dyskeratosis, basal
vacuolarization, superficial perivascular inflammation and dermal edema, which were
compatible with photosensitive dermatitis.

Treatment with oral prednisolone 40 mg/day, levocetirizine 5 mg/day, buclizine 50 mg/day, and topical menthol and camphor lotion was given for two weeks. The skin lesions gradually resolved within three weeks. One month later, photopatch testing including fenofibrate (Downlip®), chlorzoxazone (Parafon®), and the other four unidentified medications was performed. Each drug was tested in various concentrations with “as is”, 30% in petrolatum (pet.), and 30% in dist water (aq.). The photoallergen series (Chemotechnique Diagnostics, Malmö, Sweden) was also included in the evaluation (Table 1). The testing was carried out on the upper part of the patient’s back in duplicate sets (one set to each side of the patient’s back) with Finn Chambers (Epitest Ltd., Helsinki, Finland), which were fixed to the upper back with Scanpor tape and secured by 3M tapes. The patches were removed after 2 days and the sites were examined for evidence of reaction at day (D) 2 after the initial application. One set was then covered with a light opaque material and the other set was irradiated with UVA at a dose of 10 J/cm2 utilizing the UV801KL device (Waldmann Medizintechnik, Villingen-Schwenningen, Germany; wavelength covered was 320-400nm). At D4, both the irradiated and covered sites were evaluated again. The reading was considered positive if the reaction was equal to or stronger than a palpable erythema, according to the guidelines of the International Contact Dermatitis Research Group (ICDRG). A photoallergic reaction was diagnosed when the reaction was positive only at the irradiated site. The only positive reaction was Down-lip® (as is) at D4 reading on the irradiated site, while the other tested drugs were all negative at D2 and D4 reading (Fig. 2). Thus, photosensitivity due to fenofibrate was diagnosed. The patient was informed to avoid any further exposure to this drug.

DISCUSSION
Cutaneous adverse reactions of fenofibrate are not common. A review of European clinical trials involving over 3000 patients reported a low incidence of skin reactions, which was about 2%.1 Fenofibrate was launched in 1975, while the first photosensitive case was described in 1983, confirmed by photopatch testing.2 By PubMed search from 1966 to 2007, only 28 cases, including our case, have been documented to have photosensitive dermatitis caused by fenofibrate.2-11 Most cases presented with erythema, eczema or vesiculobullous eruption in a photodistributed pattern. One case was characterized by lichenoid photodermatitis, which was confirmed by skin pathology.7 Among the 28 cases of fenofibrate-induced photosensitivity, 23 cases have been assessed by photopatch testing (Table 2).2, 4-11 Twelve patients out of these 23 cases showed positive results to fenofibrate, in which the action spectrum seemed to be UVA or UVB-UVA. Five cases received the oral photochallenge studies with concomitant use of fenofibrate and all of them had positive findings. Four cases had positive results with UVA irradiation and 1 case had positive result with UVB irradiation. Furthermore, the MEDs in the UVB and UVA spectra could be either normal or decreased. Upon discontinuation of fenofibrate, those patients who were initially proved to have decreased UVB or UVA MEDs could have their MEDs back into the normal ranges.6, 10-11 These results are consistent with the absorption spectrum of fenofibrate, fenofibric acid and its photoproducts.9, 12 The maximum absorption spectrum of fenofibrate is close to 289 nm but the conjugation of fenofibrate may displace the absorption bands to UVA.7 In addition, fenofibrate is rapidly metabolized to fenofibric acid and other minor compounds, which have different absorption spectra.12

Following photoexcitation, fenofibric acid, the metabolite of fenofibrate, will undergo intersystem crossing to the triplet excited state and result in photosensitized DNA damage and peroxidation of fatty acids.12, 13 This photosensitizing capacity of fenofibrate is mainly determined by the photoexcited chemical structure, the benzophenone moiety, which has also been known to be responsible for photosensitizing properties of some other drugs, such as ketoprofen (Fig. 3).13-16 Fenofibrate and ketoprofen have a high prevalence of cross-photosensitization, ranging from 67% to 100% in different studies.14, 16 Thus, a person photosensitized by fenofibrate should avoid exposure to ketoprofen or other benzophenone-derived drugs, and vice versa.We suggested our patient to avoid these medications.

Fibric acid is among the mainstays of the treatment for hyperlipidemia. The literature review for photosensitivity from fibric acid derivatives showed that fenofibrate has a higher number of photosensitive reports than the other fibric acid derivatives. Each of bezafibrate and clofibrate has one reported photosensitive case.6 Photosensitivity induced by gemfibrozil has never been reported. Analyzing the chemical structures of these different fibric acids, only fenofibrate contains the benzophenone moiety. All these fibric acids have the phenoxyisobutyric acid structure common to fibrates, with the exception of gemfibrozil (Fig. 3A).6

In conclusion, variable kinds of cutaneous eruptions induced by fibric acids for hyperlipidemia have been established, including the photosensitivity in rare cases. Among the fibric acids, fenofibrate has the most cases being reported to have photosensitivity. Besides, cross-photosensitization between fenofibrate and other benzophenone-containing medications, such as ketoprofen, is well known. Thus, physicians should be alerted while a patient develops skin rash over photodistributed areas after taking fenofibrate. The fenofibrate-induced photosensitivity can be confirmed by the photopatch test but a negative result can not exclude this diagnosis. Besides, the oral photochallenge test is a very sensitive study to make the diagnosis. Once a patient has photosensitivity induced by fenofibrate, he had better avoid further exposure to fenofibrate and benzophenonecontaining medicine, such as ketoprofen.

REFERENCES
1. Blane GF: Comparative toxicity and safety profile of fenofibrate and other fibric acid derivatives. Am J Med 83: 26-36, 1987.
2. Jeanmougin M, Civatte J, Duterque M: Photosensibilisation au fenofibrate. [French] Presented in Journées Dermatologiques de Paris, Paris, March 10-12, 1983.
3. Merino V, Llamas R, Iglesias L: Phototoxic reaction to fenofibrate. Contact Dermatitis 23: 284, 1990.
4. Leroy D, Dompmartin A, Lorier E, et al.: Photosensitivity induced by fenofibrate. Photodermatol Photoimmunol Photomed 7: 136-137, 1990.
5. Barbaud A, Schmutz JL, Irechot P, et al.: [Photoallergie au fénofibrate (Lipanthyl®) A propos de 3 cas]. [Italian] La Lettre du GERDA 9: 6-10, 1992.
6 Serrano G, Fortea JM, Latasa JM, et al.: Photosensitivity induced by fibric acid derivatives and its relation to photocontact dermatitis to ketoprofen. J Am Acad Dermatol 27: 204-208, 1992.
7. Gardeazabal J, Gonzalez M, Izu R, et al.: Phenofibrate-induced lichenoid photodermatitis. Photodermatol Photoimmunol Photomed 9: 156-158, 1993.
8. Jeanmougin M, Manciet JR, De Prost Y, et al.: Fenofibrate photoallergy. Ann Dermatol Venereol 120: 549-554, 1993.
9. Leenutaphong V, Manuskiatti W: Fenofibrateinduced photosensitivity. J Am Acad Dermatol 35: 775-777, 1996.
10. Machet L, Vaillant L, Jan V et al.: Fenofibrate induced photosensitivity: value of photopatch testing. J Am Acad Dermatol 37: 808-809, 1997.
11. Conilleau V, Dompmartin A, Michel M, et al.: Photoscratch testing in systemic drug-induced photosensitivity. Photodermatol Photoimmunol Photomed 16: 62-66, 2000.
12. Miranda MA, Bosca F, Vargas F et al.: Photosensitization by fenofibrate. II. In vitro phototoxicity of the major metabolites. Photochem Photobiol 59: 171-174, 1994.
13. Bosca F, Miranda MA: Photosensitizing drugs containing the benzophenone chromophore. J Photochem Photobiol Biol 43: 1-26, 1998.
14. Le Coz CJ, Bottlaender A, Scrivener JN et al.: Photocontact dermatitis from ketoprofen and tiaprofenic acid: cross-reactivity study in 12 consecutive patients. Contact Dermatitis 38: 245-
252, 1998.
15. Albes B, Marguery MC, Schwarze HP, et al.: Prolonged photosensitivity following contact photoallergy to ketoprofen. Dermatology 201: 171-174, 2000.
16. Durieu C, Marguery MC, Giordano-Labadie F, et al.: [Photoaggravated contact allergy and contact photoallergy caused by ketoprofen: 19 cases]. [French] Ann Dermatol Venereol 128: 1020-1024, 2001.

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