Photosensitivity Reactions / Life Threatening Cutaneous Reactions:

Such reactions include Stevens–Johnson's Syndrome, Sweet's Syndrome,
T.E.N, as well as painful and disfiguring rashes.

The phototoxic potentials of fluoroquinolones are influenced not only
by the substituent at position 8 (Halogenation at position C8) but
also by those at position 1. Drugs such as Lomefloxacin and
Sparfloxcacin, with a C8-fluorine substituent, and Clinafloxacin,
with a C8-chlorine substituent, exhibit a greater incidence of
phototoxic reactions than drugs without this substituent. However,
severe rashes are class effects of the fluoroquinolones due to
hypersensitivity, regardless of any structural modifications of the
drug.

Two types of photosensitivity reactions have been associated with
fluoroquinolone therapy: photoallergic reactions and phototoxic
responses. Photoallergic reactions require previous exposure to a
drug in the class. In contrast, phototoxic responses can develop
without previous exposure to a fluoroquinolone. Some of the
fluoroquinolones induce photosensitivity reactions, such as erythema
of sun-exposed skin, with varying frequency.

Photosensitivity reactions are postulated to occur as a result of
fluoroquinolone photodegradation, as well as the molecule's ability
to generate free monovalent oxygen radicals. In turn, these oxidative
radicals may attack cellular lipid membranes, initiating inflammatory
processes, and eventually produce DNA damage. Evidence for photo-
induced oxidative DNA damage is demonstrated by the development of
murine tumors in mice treated with Lomefloxacin. Drug-induced purpura
is due to direct capillary damage or hypersensitivity reactions.
(Thus to be considered vascular in nature)

Photosensitivity reactions reported with the fluoroquinolones mimic
those of sunburn, with erythema and edema in the milder forms, and
painful blistering with subsequent peeling when severe. A wide
spectrum of cutaneous ADRs are reported with fluoroquinolones such
as:

Stevens–Johnsons Syndrome
Pemphigus Vulgaris
Sweet's Syndrome (an acute febrile neutrophilic dermatosis)
T.E.N, a life-threatening skin disorder in which the top layers of
skin blister and peel off in sheets.

A previous dematologic adverse reaction to a fluoroquinolone can
sensitize a patient to more severe adverse reactions (with onset
after only a single dose of the subsequent fluoroquinolone) as noted
earlier in this presentation. Patients who develop any kind of rash
to a fluoroquinolone in the past have a potential to develop life
threatening photoallergic reactions when re-challenged with a
fluoroquinolone drug later on in life.

Photoexposed purpuric eruptions are another side effect of
fluoroquinolone therapy in addition to photosensitivity rashes.
Purpura is defined as circumscribed collection of blood 0.5 cm in
diameter. Morphologically it may be of several types as ecchymoses,
petechiae, palpable purpura, pigmented type, or itching purpura. (In
my case such a rash has persisted for over twenty years now)

It is to be noted that within the clinical studies submitted with the
initial submission of NDA 21-158 for Factive (gemifloxacin), a higher
than expected rate of rash was noted in these clinical studies.
During the course of the NDA review of Factive (gemifloxacin)
significant questions arose regarding the safety of gemifloxacin.
These questions centered around the higher than expected rate of rash
reported in patients receiving gemifloxacin and related questions
regarding the mechanism of the observed rash, the potential for cross-
sensitization, and the possibility that the frequent occurrence of
rash may portend a risk for more serious infrequent cutaneous drug
reactions. The drug's sponsor never provided satisfactory answers to
these concerns, in my opinion. In addition, there were also
unresolved questions regarding the hepatic safety profile of
gemifloxacin. Hence the drug was initially rejected in 2002 but later
approved in 2003.

The rates of rash ranged upwards to 25% depending upon the population
or subset of the population being analyzed. Analyses of this rash
data have shown that female gender, age (younger adults), and longer
duration of therapy are associated with an increased rate of this
rash. In spite of the additional risk of the patient developing TEN,
Stevens-Johnson Syndrome as well as Sweet's Syndrome, the FDA
approved the drug anyhow in 2003 after rejecting the drug in 2002 for
these very reason.

The public record of the FDA meeting in which these rashes were
discussed revealed several occasions where the members of the panel
literally laughed out loud at patients reporting such rashes and
ridiculed them. Only to find, four years later, that the real-world
use of Factive has shown what clinical trials previously revealed and
the FDA panel members laughed at: the risk of rashes associated with
Factive are greater than those seen in other fluoroquinolones,
especially for women undergoing treatment with Factive.

In 2006 the FDA convened another panel to take yet another look at
the safety profile of Factive.

Multiple fixed drug eruption due to drug combination. (PL and Levaquin) Yokoyama A, Hara H.

Ann Pharmacother. 2001 Nov;35(11):1388-90.
Ofloxacin: a probable cause of toxic epidermal necrolysis.
Melde SL.

Norfloxacin-induced toxic epidermal necrolysis. Sahin MT, Ozturkcan S, Inanir I, Filiz EE. Medical Faculty, Department of Dermatology, Celal Bayar University, Manisa, Turkey. mustafaturhan@superonline.com

Induced and Photoinduced DNA Damage by Quinolones: Ciprofloxacine, Ofloxacine and Nalidixic Acid determined by Comet Assay. Sanchez G, Hidalgo ME, Vivanco JM, Escobar J. Universidad de Valparaiso.

Ofloxacin: a probable cause of toxic epidermal necrolysis

Norfloxacin-Induced Toxic Epidermal Necrolysis

Ciprofloxacin-induced toxic epidermal necrolysis

[New findings on the structure-phototoxicity relationship and photostability of fluoroquinolones] [Article in Japanese] Hayashi N. New Lead Pharmacology Laboratory, Institute for Medical Research, Wakunaga Pharmaceutical Co., Ltd., Akitakata City 739-1195, Japan. hayashi_n@wakunaga.co.jp

Sweet ’s syndrome (acute febrile neutrophilic dermatosis) associated with norfloxacin in a prostate cancer patient

Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis
Tina Papastavros, Lisa R. Dolovich, Anne Holbrook, Lori Whitehead, and Mark Loeb

[New findings on the structure-phototoxicity relationship and photostability of fluoroquinolones] [Article in Japanese]
Hayashi N.
New Lead Pharmacology Laboratory, Institute for Medical Research, Wakunaga Pharmaceutical Co., Ltd., Akitakata City 739-1195, Japan. hayashi_n@wakunaga.co.jp

Livasy CA, Kaplan AM: Ciprofloxacin-induced toxic epidermal necrolysis: a case report. Dermatology 1997;195(2):173-175.
No Abstract or Article available at this time.

LETTERS TO THE EDITOR
Sparfloxacin-related vascular purpura,
D. smith, n. bernard, ph. morlat, b. begaud, j. beylot
BMJ. 1989 Sep 9;299(6700):658.
No Abstract or Article available at this time.

2    Miolo G, Viola G, Vedaldi D, Dall'Acqua F, Fravolini A, Tabarrini O, Cecchetti V.In vitro phototoxic properties of new 6-desfluoro and 6-fluoro-8-methylquinolones.
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J Photochem Photobiol B. 2000 Oct;58(1):20-5.
PMID: 11195848 [PubMed - indexed for MEDLINE]

8    [No authors listed]Drug-induced cutaneous photosensitivity: some drugs warrant routine precautions.
Prescrire Int. 2000 Aug;9(48):117-22.
PMID: 11067725 [PubMed - indexed for MEDLINE]

9     Shimoda K, Ikeda T, Okawara S, Kato M.Possible relationship between phototoxicity and photodegradation of sitafloxacin, a quinolone antibacterial agent, in the auricular skin of albino mice.
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J Photochem Photobiol B. 1997 Feb;37(3):169-70. Review. No abstract available.
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Ann Pharmacother. 2001 Nov;35(11):1388-90.
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