DR.

SUNG JEN HUNG (Orcid ID : 0000-0002-9148-2601)

Accepted Article
Received Date : 01-Dec-2016
Revised Date : 06-Mar-2017
Accepted Date : 11-Mar-2017
Article type : Letter to the Editor

Corresponding author mail id:- [Link]@[Link]

Fenofibrate-Induced Photosensitivity

-A Case Series and Literature Review

Kai-Chi Tsai, Jen-Hung Yang, Sung-Jen Hung

Department of Dermatology, Buddhist Tzu-Chi General Hospital and Tzu-Chi University,

Hualien, Taiwan

First author: Kai-Chi Tsai

Corresponding author: Sung-Jen Hung

E-mail address: [Link]@[Link] (Sung-Jen Hung).

Address: Department of Dermatology, Tzu-Chi General Hospital, No. 707,

Sec. 3, Chung Yang Rd., Hualien 970, Taiwan, R. O. C.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/phpp.12305
This article is protected by copyright. All rights reserved.
 TEL: 886-3-8561825ext.3889, FAX: 886-3-8560977
Accepted Article
Funding source: none

Conflicts of interest: none

Introduction

Fenofibrate, a fibric acid derivative, is among the most commonly used

antihyperlipidemic medications. The most common side effects are gastrointestinal problems,

including abdominal discomfort, diarrhea, and constipation. While cutaneous eruption

occurred in 2% of fenofibrate users1, photosensitivity is a rare manifestation. Jeanmougin et

al. presented the first case of fenofibrate induced photosensitivity in 1983.2 Herein we report

4 cases of fenofibrate-induced photosensitization with different types of cutaneous eruptions

as papulovesicular, lichenoid, and sunburn-like rashes, and one among them was confirmed

by photopatch testing. We also perform a systematic review for the reported cases of

fenofibrate-induced photosensitivity since 1983.

Patients and Methods

Case 1

A 33-year-old woman presented with numerous erythematous papulovesicles with itchy

and burning sensation on the sun-exposed areas as the face, V-area of neck, bilateral forearms,

This article is protected by copyright. All rights reserved.

 dorsa of hands, and bilateral shins for one week (Fig. 1A, B). She had underlying hepatitis B
Accepted Article
and hyperlipidemia. Those skin rashes appeared on the third week of taking fenofibrate (200

mg, 1 tablet per day) and silymarin (150 mg, 1 tablet per day). There were no other symptoms

associated with autoimmune disease such as arthralgia, oral ulcer, dry mouth, dry eyes, etc.

She had Fitzpatrick skin phototype V. She was a housewife, and she didn’t have frequent

outdoor activities. Fenofibrate-induced photosensitivity with the papulovesicular pattern was

suggested by the clinical presentation and drug history. Serology test showed negative results

for antinuclear antibodies and extractable nuclear antigen (ENA) antibodies. The skin biopsy

demonstrated spongiosis, focal basal vacuolarization, a superficial perivascular lymphocytic

infiltrate and dermal edema, which were compatible with photosensitive dermatitis (Fig. 1D).

She received intravenous betamethasone (equivalent dose of prednisolone 0.75 mg/kg)

followed by rapidly tapered dose within one week, and the skin lesions resolved 2 weeks

later.

Case 2

A 46-year-old man had multiple pruritic, erythematous to violaceous papules and

plaques on the sun-exposed areas including the face, V-area of neck, bilateral forearms, and

dorsa of hands for 1 month (Fig. 1E). Those skin rashes appeared on the third week of taking

fenofibrate (200 mg, 1 tablet per day). He had Fitzpatrick skin phototype V. Serology test

This article is protected by copyright. All rights reserved.

 showed negative results for antinuclear and ENA antibodies. The skin biopsy demonstrated
Accepted Article
necrotic keratinocytes, basal vacuolarization, and a superficial perivascular and lichenoid

lymphohistiocytic infiltrate (Fig. 1F). Direct immunofluorescence for IgG, IgM, IgA, C1q,

and C3 were all negative. The clinical diagnosis was fenofibrate induced photosensitivity

with the lichen planus-like pattern. The skin lesions resolved gradually after prednisolone 10

mg/day, systemic antihistamines, and topical steroid use for 2 weeks.

Case 3

A 28-year-old man had pruritic, burning, scaly erythematous patches on the

sun-exposed areas including the face, V-area of neck, bilateral forearms, and dorsa of hands

for one week (Fig. 1G, H). He started to take fenofibrate three weeks prior to the skin

eruption. He had Fitzpatrick skin phototype IV. Hemogram showed eosinophilia (13.9%;

absolute eosinophil count: 838/μL). The antinuclear and ENA antibodies were unremarkable.

The skin biopsy demonstrated basal vacuolarization, superficial perivascular lymphocytes

and few eosinophils infiltrate (Fig. 1I). The clinical impression was fenofibrate induced

photoallergy with the sunburn-like reaction. Fenofibrate was discontinued, and the skin

lesions resolved after treatment with systemic prednisolone 0.4 mg/kg/day, systemic

antihistamines and topical steroid for 1 week.

This article is protected by copyright. All rights reserved.

 Case 4
Accepted Article
A 53-year-old man had pruritic erythematous papules over the V-area of neck, bilateral

forearms and knees for 2 weeks. He started to take fenofibrate four weeks prior to the skin

eruption. He had Fitzpatrick skin phototype IV. Serology test showed mildly elevated IgE

(217 U/ml). The antinuclear and ENA antibodies were unremarkable. The skin biopsy

demonstrated basal vacuolarization, focally dermal edema, superficial perivascular

lymphocytes, histiocytes and eosinophils infiltrate, and pigmentary incontinence. The clinical

impression was fenofibrate induced photoallergy with the papulomacular pattern. Fenofibrate

was discontinued, and the skin lesions resolved after treatment with systemic prednisolone

0.5 mg/kg/day, systemic antihistamines and topical steroid for 1 week.

Phototesting

Initial phototest was performed in case 1 after stopping systemic medication for 3 days

with broad-band UVA (UV 181 AL, Waldmann Medizintechnik, Germany) and narrow-band

UVB-311 (100-800 mJ/cm2) (UV 181 BL, Waldmann Medizintechnik, Germany). Two

months later, phototest and photopatch test were also performed. The allergens used in

photopatch test included fenofibrate, silymarin, ketoprofen, gemfibrozil, piroxicam gel, and

sunscreen containing benzophenone. Each drug was tested in concentrations of 10% and 30%.

The patch and photopatch testing were carried out on the upper back in duplicate sets (one set

This article is protected by copyright. All rights reserved.

 on each side of the back). The patch test was removed 3 days later, and no reaction was found.
Accepted Article
The photopatch testing was irradiated with UVA 10 J/cm2 at day 1 and day 2, and the result

was evaluated at day 3.

Results

Case 1

The minimal erythema dose (MED) in initial phototest elicited with 30 joules/cm2 of

broad-band UVA. She had no erythema under narrow-band UVB-311 form 100-800 to

mJ/cm2. The secondary phototesting two months later showed negative findings with UVA

from 10-60 J/cm2 (Table 1). In the photopatch test, positive reactions were found in 10% and

30% of fenofibrate on the irradiated site, and the other drugs showed negative results (Fig. 1C,

Table 1). Thus, fenofibrate-induced photoallergy was diagnosed.

Case 2 to case 4 refused further phototest or photopatch test.

Discussion

Only 33 cases including our four cases were diagnosed of fenofibrate-induced

photosensitivity by PubMed search from 1983 to 2016 (Table 1). Among the 33 cases, most

cases presented with erythematous, papulovesicular, or eczematous eruptions in a

photo-distributed pattern. Lichenoid or sunburn-like eruptions in our cases were relatively

This article is protected by copyright. All rights reserved.

 rare. The duration of drug intake to onset of skin eruptions ranges from three days to four
Accepted Article
weeks, and it seems to be later onset in Fitzpatrick skin phototype IV or V. However, more

case numbers or furthers studies are needed to confirm this observation. A history of

photocontact dermatitis to ketoprofen gel will accelerate the onset of fenofibrate-induced

photosensitivity to days only1, 9.

There are different diagnostic tools including phototest, photopatch, and

photochallenge tests to confirm the diagnosis of fenofibrate-induced photosensitivity. Among

those 33 cases, only 16 cases and 13 cases underwent UVB or UVA phototest test,

respectively. Five cases (31%) had a reduction of MEDs to UVB, and five cases (38%) had a

reduction of MEDs to UVA. After discontinuation of fenofibrate, their MEDs got back into

the normal ranges. Twenty-five cases received photopatch test. Nineteen of them were

irradiated to both UVA and UVB, and the other six cases were irradiated to UVA only.

Fourteen cases (56%) showed positive results to UVA, and six cases showed positive result to

both UVA and UVB. None of them showed positive results to UVB only. Five cases received

oral photochallenge testing. Four cases showed positive results to UVA irradiation, and the

other one had positive reactions to UVB irradiation. The oral photochallenge test is a very

sensitive test for diagnosis of fenofibrate-induced photosensitivity. However, the patient

should avoid sunlight exposure for 24 hours to prevent a recurrence of the sun-exposed

eruptions, because the half-life of fenofibrate is approximately seven hours.5

This article is protected by copyright. All rights reserved.

 The photosensitizing capacity of fenofibrate could be explained by the photoexcited
Accepted Article
chemical structure, the benzophenone (double benzene rings linked by a ketone group) 9.

Among the fibric acid derivatives including fenofibrate, bezafibrate, clofibrate, and

gemfibrozil, fenofibrate has the highest incidence of photosensitivity because of the

benzophenone moiety (Fig. 2). Fenofibrate and ketoprofen have a high prevalence of

cross-photosensitization, which is also attributed to the benzophenone moiety.1 Leroy et al.

reported seven cases of photosensitivity to ketoprofen, and four of them showed a cross

photoreaction between ketoprofen, fenofibrate and benzophenone10. Derivatives

of benzophenone are also common ingredients in sunscreen. Therefore, we suggested a

person photosensitized by fenofibrate should avoid exposure to ketoprofen or other

benzophenone-containing drugs or sunscreen, and vice versa.

Reference

1. Serrano G, Fortea JM, Latasa JM, Millan F, Janes C, Bosca F, et al. Photosensitivity

induced by fibric acid derivatives and its relation to photocontact dermatitis to

ketoprofen. J Am Acad Dermatol 1992 ; 27: 204-208.

2. Jeanmougin M, Civatte J, Duterque M. Photosensibilisation au fenofibrate. [French]

Journées Dermatologiques de Paris, 1983; March 10-12.

3. Leroy D, Dompmartin A, Lorier E, Leport Y, Audebert C. Photosensitivity induced by

This article is protected by copyright. All rights reserved.

 fenofibrate. Photodermatol Photoimmunol Photomed 1990; 7: 136-137.
Accepted Article
4. Gardeazabal J, Gonzalez M, Izu R, Gil N, Aguirre, Diaz-Perez JL. Phenofibrate-induced

lichenoid photodermatitis. Photodermatol Photoimmunol Photomed 1993; 9: 156-158.

5. Leenutaphong V, Manuskiatti W. Fenofibrate-induced photosensitivity. J Am Acad

Dermatol 1996; 35: 775-777.

6. Machet L, Vaillant L, Jan V, Lorette G. Fenofibrate-induced photosensitivity: value of

photopatch testing. J Am Acad Dermatol 1997; 37: 808-809.

7. Conilleau V, Dompmartin A, Michel M, Verneuil L, Leroy D. Photoscratch testing in

systemic drug-induced photosensitivity. Photodermatol Photoimmunol Photomed 2000;

16: 62-66.

8. Hong JH, Wang SH, Chu CY. Fenofibrate-induced photosensitivity-a case report and

literature review. Dermatol Sinica 2009; 27: 37-43.

9. Kuwatsuka S, Kuwatsuka Y, Takenaka M, Utani A. Case of photosensitivity caused by

fenofibrate after photosensitization to ketoprofen. J Dermatol 2016 Feb;43(2):224-5.

10. Leroy D, Dompmartin A, Szczurko C, Michel M, Louvet S. Photodermatitis from

ketoprofen with cross-reactivity to fenofibrate and benzophenones. Photodermatol

Photoimmunol Photomed 1997; 13:93-97.

This article is protected by copyright. All rights reserved.

 11. Table 1 Photopatch Results of Fenofibrate-Induced Photosensitivity
Accepted Article
Authors Gerder Age Fitzpatrick Clinical features Onset MED Oral Photopatch

(year) skin time UVB UVA photochallenge UVA UVB

phototype (UVA)
2
Jeanmougin et al. 1983

Patient 1 F 72 NA Erythematous rash NA Normal Normal NDa +b +b

Patient 2 M 72 NA Erythematobullous rash NA Normal Normal ND + +

3
Leroy et al. 1990

Patient 1 F 33 NA Erythematopapular rash 8 days ND ND ND + +

Patient 2 F 55 NA Eczematous rash NA ND ND ND ND ND

Merino et al. 1990

Patient 1 F 70 NA Erythematovesicular rash NA ND ND ND ND ND

Patient 2 M 53 NA Erythematovesicular rash NA ND ND ND ND ND

Patient 3 F 54 NA Erythematovesicular rash NA ND ND ND ND ND

Patient 4 F 54 NA Erythematovesicular rash NA ND ND ND ND ND

Serrano et al. 19921

Patient 1 F 59 NA Erythematous 3 daysc Decreased Decreased ND + ND

d d
papulovesicular rash Normal Normal

Barbaud et al. 1992

Patient 1 F 40 NA NAe NA ND ND ND + ND

Patient 2 M 32 NA NA NA ND ND ND + ND

Parient 3 F 63 NA NA NA ND ND ND + ND
4
Gardeazabal et al. 1993

Patient 1 F 64 III Erythematous papules 2 weeks Decreased Normal ND － －

Normald Normald

Jeanmougin et al. 1993

Patient 1 M 64 NA NA NA Decreasedd Decreasedd + + +

Leenutaphong et al. 19965

Patient 1 F 40 NA Eczematous rash 1 month Normal ND + (UVA) － －

Patient 2 F 50 NA Eczematous rash 6 weeks Normal ND + (UVA) － －

Patient 3 F 54 NA Erythematous papules 3 months Normal ND + (UVB) － －

Machet et. al 19976

Patient 1 NA NA NA NA NA NA ND NA + ND

Patient 2 NA NA NA NA NA NA ND NA + ND

Pateient 3 NA NA NA NA NA NA ND + － ND

Patient 4 NA NA NA NA NA Decreased ND NA － ND

Normalc

This article is protected by copyright. All rights reserved.

 Conilleau et al. 20007
Accepted Article Patient 1 F 57 NA NA NA Normal Decreased ND － －

d d
Normal Normal

Patient 2 F 69 NA NA NA Normal Decreased ND － －

NDd Normald

Patient 3 F 63 NA NA NA Normal Decreased ND － －

d d
Normal Normal

Patient 4 M 64 NA NA NA Normal Normal ND + +

NDd NDd

Patient 5 M 74 NA NA NA Decreased Normal ND － －

c c
Decreased Normal

Patient 6 F 46 NA NA NA Normal Normal ND － －

Normald Normald

Hong et al. 20068

Patient 1 M 33 IV Erythematous papules 2 weeks ND ND ND + ND

9
Kuwatsuka et al. 2016

Patient 1 M 34 NA Erythematous 6 daysc Normal Normal ND + +

papulovesicles

Our cases

Patient 1 F 33 V Erythematous 3 weeks ND Normal ND + ND

papulovesicles

Patient 2 M 46 V Lichenoid papules 3 weeks ND ND ND ND ND

Patient 3 M 28 IV Erythematous patches 3 weeks ND ND ND ND ND

with desquamations

Patient 4 M 53 IV Lichenoid papules 4 weeks ND ND ND ND ND

a: ND, not done;

b: polychromatic light;

c: history of potocontact dermatitis to ketoprofen gel before

d: phototest after drug discontinuation;

e: NA, not available

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.