Download Cutaneous Adverse Reactions to Valdecoxib Distinct From Stevens

STUDY
Cutaneous Adverse Reactions to Valdecoxib Distinct
From Stevens-Johnson Syndrome and Toxic
Epidermal Necrolysis
Mirjana Ziemer, MD; Christiane L. Wiesend, MD; Robert Vetter, MD; Johannes Weiss, MD, PhD;
Sabine Blaschke, MD; Johannes Norgauer, MD, PhD; Maja Mockenhaupt, MD, PhD
Objective: To assess the type of severe skin reactions
caused by valdecoxib treatment.
Design: Case registry of severe skin reactions such
as Stevens-Johnson syndrome and toxic epidermal
necrolysis.
Setting: All hospitals in Germany that treat patients with
severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
Results: A thorough review of all reported cases of severe skin reactions caused by valdecoxib revealed extensive erythematous, targetlike skin eruptions in addition
to facial edema and dyspnea. Histologic changes, clinical pattern, and outcome demonstrated a distinct disease entity.
Conclusion: Valdecoxib induces severe skin reactions
different from those of Stevens-Johnson syndrome and
toxic epidermal necrolysis in clinical and histopathologic findings, course, and outcome.
Patients: Five case notifications of Stevens-Johnson syn-
drome after the use of valdecoxib were reevaluated following the withdrawal of valdecoxib on April 7, 2005.
S
Author Affiliations:
Departments of Dermatology,
University of Jena, Jena
(Drs Ziemer, Wiesend, and
Norgauer), University of
Magdeburg, Magdeburg
(Dr Vetter), University of Ulm,
Ulm (Dr Weiss), and
Dokumentationszentrum
schwerer Hautreaktionen,
University of Freiburg, Freiburg
(Dr Mockenhaupt); and
Department of Nephrology and
Rheumatology, University of
Göttingen, Göttingen
(Dr Blaschke), Germany.
Arch Dermatol. 2007;143:711-716
TEVENS-JOHNSON SYNDROME
(SJS) and toxic epidermal
necrolysis (TEN) are severe,
life-threatening skin reactions mainly caused by
drugs.1 The consensus definition of these
skin reactions is based on the type and distribution of lesions and the extent of blisters and erosions related to the body surface area (BSA).2 The lesions found in
severe skin reactions are typical targets,
with regular round, well-defined borders
with at least 3 different concentric zones:
a purpuric central disk with or without a
blister, a raised edematous intermediate
ring, and an erythematous outer ring. In
contrast, raised atypical targets present
with only 2 zones and a poorly defined border, while flat atypical targets are characterized by vesicular or bullous lesions in
the center, which may be confluent. Targetlike lesions are less clearly demarcated but still have an appearance reminiscent of targets. Manifestations of SJS and
TEN include widespread purpuric macules and flat targetlike lesions, mainly on
the trunk, preceding epidermal detachment. In contrast, erythema exudativum
multiforme majus (also called erythema
exudativum multiforme with mucosal in-
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711
volvement) is characterized by typical targetlike lesions mainly on the limbs without confluent exanthema. This is
important because erythema exudativum
multiforme majus is not induced by drugs
but by infection.3 Furthermore, hemorrhagic erosions of at least 1 site of mucous membranes are present. In SJS, skin
detachment is limited to less than 10% of
the BSA, whereas a diagnosis of TEN requires epidermal detachment of more than
30%. An overlap group of SJS/TEN has
been defined with blisters and erosions
covering 10% to 30% of the BSA.
Some generalized drug-induced eruptions may be misinterpreted as SJS or TEN
because of their extensive targetlike skin
lesions. However, severity and course of
such drug-induced eruptions and, therefore, prognosis and outcome differ substantially from SJS and TEN.
Because of severe cardiac adverse effects, the use of all cyclooxygenase-2 inhibitors was heavily disputed and the marketing strategies of pharmaceutical
companies were questioned.4 In November 2002, the Food and Drug Administration mandated product label changes for
valdecoxib based on reports of serious skin
reactions such as SJS and TEN. As a con-
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A
B
Figure 1. Patient 1. Clinical and histopathlogic views of the patient’s reaction to
valdecoxib treatment. A, Extensive, confluent, erythematous-violaceous, targetlike
macules cover the entire body. B, Normal epidermis. Note a sparse perivascular and
interstitial lymphocytic infiltrate in the superficial dermis and a few lymphocytes in the
epidermis (hematoxylin-eosin, original magnification ⫻40).
sequence, valdecoxib was withdrawn from the market in
April 2005. To elucidate the situation, the database of the
registry for severe skin reactions in Germany, the Dokumentationszentrum schwerer Hautreaktionen (dZh),
was reevaluated.
METHODS
The dZh organizes a permanent communication structure with
all hospitals in Germany that treat patients with severe skin reactions. More than 1700 hospitals and departments, including
internal medical departments with intensive care facilities, departments of pediatrics, departments of dermatology, and burn
units, are included and are routinely checked by quarterly surveillance. Thus, it can be assumed that all hospitalized patients with severe skin reactions are monitored or retrospectively identified during the quarterly surveillance check.5
All cases of severe skin reactions ascertained by the population-based registry in Germany are reviewed by an independent dermatologic expert committee based on clinical information, histopathologic findings, and photographs of the
cutaneous and mucosal lesions. The experts are blinded to potential causes of the disease during the clinical review process
and classify the cases as “definite,” “probable,” or “possible”
SJS, SJS/TEN overlap, or TEN or exclude these diagnoses in favor of another. Erythema exudativum multiforme majus is clearly
differentiated from SJS based on the consensus definition for
severe skin reactions.2,5,6 For this specific analysis, all potential cases reported in association with the use of valdecoxib were
reevaluated using the histopathologic expertise provided by the
Department of Dermatology at the University of Jena, Jena, Germany, based on validated criteria.5,6
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712
REPORT OF CASES
PATIENT 1
A 68-year-old man had received 1 intramuscular injection of 40 mg of parecoxib sodium (Dynastat; Pfizer Inc,
New York, NY), a prodrug of valdecoxib, followed by daily
oral use of 20 mg of valdecoxib (Bextra; Pfizer Inc) for
treatment of lumboischialgia. On the sixth day of treatment, the patient developed generalized skin eruption,
facial swelling, and several small erosions on the upper
lip as well as restricted hemorrhagic erosions of the oral
mucosa and erythema of the glans penis. The next day,
mild dyspnea and temperature up to 39.7°C were noted.
At clinical examination, almost the entire body was affected with extensive, confluent, targetlike, erythematousviolaceous macules (Figure 1A). Aside from hypertension, treated with metoprolol since May 2001, the patient
was otherwise healthy.
The patient was given 100 mg/d of prednisolone systemically, with subsequent dose reduction during 3 weeks.
In addition, intravenous fluid substitution, antioxidants, proton pump inhibitors, and low-dose heparin were
given. The lesions regressed and fever resolved. The patient was discharged from the hospital in good condition after 2 weeks.
Histopathologic analysis of a skin biopsy specimen
showed a normal epidermis. In the superficial dermis,
there was a sparse perivascular and interstitial lymphoWWW.ARCHDERMATOL.COM
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cytic infiltrate. A few lymphocytes were found in the epidermis (Figure 1B). Typical histologic features of SJS or
TEN, such as necrotic keratinocytes, could not be proved.
PATIENT 2
A 70-year-old woman was administered valdecoxib (Bextra) to treat lumboischialgia. On the fourth day of treatment, facial swelling developed, which was followed by
generalized pruritus. Two days later, a measlelike eruption that progressed to erythroderma, on which focally
tense blisters occurred, led to hospitalization. The extent of erythema was almost 80%, but blisters covered
only approximately 4% of the BSA. Skin symptoms were
accompanied by vomiting, diarrhea, hypotension (70/30
mm Hg), temporary tachycardia, and temperature up to
38.8°C. Mucosal involvement was present with a few hemorrhagic areas on the lips. The patient had no comedication with drugs initiated within 1 month before the onset of the adverse reaction despite taking tetrazepam and
flupirtin. Prednisolone was given systemically at an initial dose of 250 mg/d, followed by dose reduction for approximately 2 weeks. After 10 days of intensive care, the
patient was transferred to the Department of Dermatology and 4 weeks later the patient was discharged from
the hospital having only a few residual lesions on the
breast.
The biopsy specimen showed an almost intact epidermis, which was detached from the underlying skin as
a result of severe edema in the papillary dermis. There
was a sparse perivascular and interstitial infiltrate of lymphocytes. The specimen showed no features of SJS or TEN.
PATIENT 3
An 83-year-old woman had disseminated, partly confluent, targetlike erythematous macules without mucosal
involvement. Three days before, she had developed generalized pruritus. The patient had taken both 20 mg of
valdecoxib (Bextra) and 4 mg of methylprednisolone for
14 days to treat rheumatoid arthritis. No other comedication had been initiated within 1 month before the onset of the adverse reaction. The patient received topical
treatment with steroids and was discharged from the hospital after 2 weeks of therapy. The biopsy specimen did
not prove typical changes of SJS or TEN. The epidermis
was normal and the papillary dermis showed sparse perivascular and interstitial lymphocytic infiltrate with a few
lymphocytes within the epidermis.
PATIENT 4
A 77-year-old woman was admitted to the Department
of Internal Medicine. The patient reported intake of 20
mg/d of valdecoxib (Bextra) for 4 days. The drug use was
stopped 4 days before symptoms developed. At admission the patient had widespread exanthema (approximately 20% of BSA) covered by localized blisters and accompanied by malaise, facial edema, and dyspnea that
had developed 2 days before. Her lips were swollen and
the oral mucosa showed erythema and single erosions.
The patient’s temperature was 39.7°C. She had no co(REPRINTED) ARCH DERMATOL/ VOL 143, JUNE 2007
713
medication with drugs initiated within 1 month before
the onset of the adverse reaction despite taking oral magnesium, intravenous mepivacaine hydrochloride with glucose, and lidocaine hydrochloride.
The patient was treated with a low dose of systemic
steroids. Resolution of the skin lesions was accompanied by improvement in her general clinical condition,
and the patient was discharged from the hospital after 2
weeks. A skin biopsy specimen was obtained from an older
skin lesion and showed only superficial necrosis and an
infiltrate of neutrophilic granulocytes. Therefore, a definite histopathologic judgment was impossible.
PATIENT 5
A 46-year-old man received 20 mg of valdecoxib (Bextra) for 8 consecutive days. On the first and second days,
the patient had taken 1 tablet of novaminsulfone. On the
last day of valdecoxib use, the patient developed generalized exanthema along with pruritus, shivering, mild dyspnea, and facial swelling. Within the next 3 days, skin
lesions progressed and the patient was hospitalized. Clinical examination revealed generalized erythematousviolaceous, maculopapular exanthema. The primary lesions had a targetlike appearance (Figure 2A). Mucous
membranes were not involved. The patient was treated
systemically with prednisolone at an initial dose of 200
mg/d with rapid dose reduction. The skin lesions regressed quickly and, after 5 days, the patient was discharged from the hospital taking an oral dose of 40 mg
of prednisolone during the next few days.
A biopsy specimen revealed a normal epidermis along
with a superficial perivascular and interstitial lymphocytic infiltrate that consisted of a few eosinophilic granulocytes (Figure 2B). Histopathologic analysis demonstrated features compatible with a drug reaction, but
changes of SJS or TEN could not be proved.
ADDITIONAL PATIENT DATA
Patient data and specific findings are given in Table 1
and Table 2, respectively. In addition, the following
laboratory findings were abnormal: C-reactive protein
concentration was elevated in all 5 patients, serum urea
concentration was elevated in patient 1, both serum
urea and serum creatinine concentrations were slightly
elevated in patient 4, and the percentage of eosinophils
was increased in patients 1 (8%), 3 (6%), and 4 (10%).
Lung function tests were not performed. Chest x-ray
films demonstrated perihilous and basal infiltrates in
patient 2.
COMMENT
Valdecoxib (Bextra) became available on the pharmaceutical market in March 2002. Based on reports of serious skin reactions including SJS and TEN, the Food and
Drug Administration informed health care professionals in November 2002 about the new warnings. Finally,
on April 7, 2005, valdecoxib was withdrawn from the market. Since 1990, the dZh has organized a permanent comWWW.ARCHDERMATOL.COM
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A
B
Figure 2. Patient 5. Clinical and histopathologic views of the patient’s reaction to valdecoxib treatment. A, Erythematous-violaceous, maculopapular exanthema.
Primary lesions had a targetlike appearance. B, Normal epidermis. Note a superficial perivascular and interstitial lymphocytic infiltrate with some eosinophilic
granulocytes (hematoxylin-eosin, original magnification ⫻40).
Table 1. Patient Data
Variable
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Female
70
5
Valdecoxib (Bextra),
20 mg/d
Female
83
12
Valdecoxib (Bextra),
20 mg/d
Female
77
8
Valdecoxib (Bextra),
20 mg/d
Male
46
8
Valdecoxib (Bextra),
20 mg/d
Indication
Male
68
7
Day 1: 40 mg of
parecoxib sodium
(Dynastat), 1
injection IM
Days 2-7: valdecoxib
(Bextra), 20 mg/d
Lumboischialgia
Lumboischialgia
Rheumatoid arthritis
Fibromyalgia
rheumatica
Comedication*
None
Tetrazepam and
flupirtin
None
Infection†
None
None
None
Mepivacaine
hydrochloride
with glucose, and
lidocaine
hydrochloride IV
None
After tendon
surgery
of the thumb
Novamine sulfone
for 1-2 d
Gender
Age, y
Duration of intake, d
Dose
None
Abbreviations: IM, intramuscularly; IV, intravenously.
*With suspected drugs initiated within 1 month before the onset of the adverse reaction.
†Within 1 month before the onset of the adverse reaction.
munication network with all hospitals in Germany that
are likely to treat patients with severe skin reactions such
as SJS and TEN. After withdrawal of valdecoxib, 5 case
notifications of SJS were reevaluated following the use
of this drug. All patients developed extensive skin eruptions 5 to 11 days after daily intake of valdecoxib (Table 1).
Clinically, generalized erythema developed initially, followed by a maculopapular exanthema, and targetlike lesions appeared in 4 of the 5 patients. In addition, all 5
patients had facial edema, 4 patients had temperatures
up to 39.7°C, and 3 patients each had mild dyspnea and
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714
pruritus (Table 2). These skin reactions and systemic
symptoms do not fit the consensus definition of severe
skin reactions.2 Moreover, only 2 of our patients developed small blisters focally (1%-4% of the BSA). Extensive hemorrhagic erosions of at least 1 site of mucous
membranes is another important criterion for the diagnosis of SJS and TEN, but our patients showed none or
only mild mucosal involvement, with erythema, minor
hemorrhage, and small erosions. In particular, our patients consistently displayed symptoms like facial edema
and dyspnea.
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Table 2. Specific Findings in 5 Patients
Patient No.
Targetlike Lesions
Facial Edema
Mild Dyspnea
Fever
Pruritus
1
2
3
4
5
⫹
−
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
−
−
⫹
⫹
⫹
⫹
−
⫹
⫹
−
⫹
⫹
−
⫹
Abbreviations: ⫹, present; −, absent.
In addition to these 5 cases, the dZh validated 1 case
of SJS (final expert review in clinical terms, “definite case
of SJS”) after long-term use of several medications including valdecoxib. Causality assessment by the expert
committee could not identify any particular “culprit” drug,
and all drugs used by this 61-year-old woman were considered doubtful as causes of the adverse event. During
the same period when valdecoxib was available in Germany and when the 6 cases described were reported, 240
cases of severe skin reactions were validated by the dZh.
Almost 70% of SJS-TEN cases could be attributed to at
least 1 of the following drugs known to induce severe skin
reactions: allopurinol, antibacterial sulfonamides, various antiepileptic agents, nevirapine, and oxicam nonsteroidal anti-inflammatory drugs.
It seems that the pattern of the reactions described
after the intake of cyclooxygenase-2 inhibitors is a
widespread, erythematous, to some extent targetlike,
or purpuric skin eruption.7 Our data are supported by
the earlier observations of a Canadian group that
reported similar skin reactions associated with valdecoxib in 2 patients.8 To date, to our knowledge only 1
case report of TEN after the intake of valdecoxib (Bextra) has been published; the patient had a known allergy to sulfa drugs.9 However, the mechanism of SJS and
TEN is not yet clearly understood. They are considered
to be T-cell–mediated reactions, which might also be true
of the targetlike skin eruptions described after the use
of valdecoxib.
Considering other published case reports, we must be
aware of the possibility that cyclooxygenase-2 inhibitors are able to induce widespread erythematous targetlike skin reactions with certain additional symptoms, especially dyspnea and facial edema, and often also dermal
edema as a histopathological characteristic.8 Similar reactions have been noted in other patients; however, those
cases have not been registered because criteria for SJS or
TEN were not fulfilled. Therefore, the incidence of the
described valdecoxib-induced drug reactions cannot be
calculated. However, the dZh continues to register all patients hospitalized with SJS or TEN. To date, no lethal
case of SJS or TEN associated with the use of valdecoxib
has been identified in Germany, where sales rates of Bextra were high.
Our results demonstrate that, despite the unquestionable value of spontaneous reports for raising alerts, thorough expert evaluation of systematically ascertained cases
of severe skin reactions is important for further decisions about drugs thought to be responsible for severe
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715
cutaneous adverse effects. Governments should provide
financial resources for monitoring networks of adverse
drug events to enable reliable risk estimation for specific drugs or drug groups and certain types of adverse
reactions.
Identification and criticism of questionable marketing and education practices of pharmaceutical manufacturers may be appropriate but does not solve the problem. Regulatory agencies and pharmacovigilance
institutions are required to address drug safety issues as
soon as possible in a professional manner.4 However, independent, often university-based, research institutions could provide important information if funded appropriately.
Accepted for Publication: October 19, 2006.
Correspondence: Mirjana Ziemer, MD, Department of
Dermatology, University of Jena, Erfurter Strasse 35,
D-07743 Jena, Germany ([email protected]
.de) or Maja Mockenhaupt, MD, PhD, Dokumentationzentrum schwerer Hautreationen, University Medical Center, Freiburg, Hauptstr 7, D-79104 Freiburg, Germany
([email protected]).
Author Contributions: Dr Ziemer had full access to all
the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Drs Ziemer and Wiesend contributed equally to this work.
Study concept and design: Ziemer and Mockenhaupt.
Acquisition of data: Wiesend, Vetter, Weiss, Blaschke,
and Mockenhaupt. Analysis and interpretation of data:
Ziemer, Wiesend, Vetter, Blaschke, Norgauer, and
Mockenhaupt. Drafting of the manuscript: Ziemer,
Wiesend, Weiss, and Blaschke. Critical revision of the
manuscript for important intellectual content: Ziemer,
Wiesend, Vetter, Blaschke, Norgauer, and Mockenhaupt.
Obtained funding: Mockenhaupt. Administrative, technical, and material support: Ziemer, Wiesend, Weiss,
Norgauer, and Mockenhaupt. Study supervision: Blaschke
and Mockenhaupt.
Financial Disclosure: Dr Mockenhaupt has recently
served as an independent member of the Pfizer Expert
Panel to review cases of severe skin reactions reported
to the company and the Food and Drug Administration.
Funding/Support: This study was supported by European Commission Project QLG1/CT//2002/01737 (Dr
Mockenhaupt).
Acknowledgment: We thank the patients who participated in this study, the collaborating hospitals and colleagues for their enthusiastic support, and especially the
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Dermatologic Expert Committee for reviewing all cases
ascertained by dZh (Konrad Bork, MD, PhD, Department of Dermatology, University of Mainz, Mainz, Germany; Uwe-Frithjof Haustein, MD, PhD, Department of
Dermatology, University of Leipzig, Leipzig, Germany;
and Dieter Vieluf, MD, PhD, Fachklinikum Borkum
GmbH, Borkum, Germany).
4.
5.
6.
REFERENCES
1. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of StevensJohnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333:16001607.
2. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and
erythema multiforme. Arch Dermatol. 1993;129:92-96.
3. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau JC;
SCAR Study Group. Correlations between clinical patterns and causes of ery-
7.
8.
9.
thema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal
necrolysis. Arch Dermatol. 2002;138:1019-1024.
Waxman HA. The lessons of Vaux: drug safety and sales. N Engl J Med. 2005;352:
2576-2578.
Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology of erythema exsudativum
multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis
in Germany (1990-1992): structure and results of a population-based registry.
J Clin Epidemiol. 1996;49:769-773.
Rzany B, Hering O, Mockenhaupt M, et al. Histopathological and epidemiological
characteristics of patients with erythema exudativum multiforme majus, StevensJohnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 1996;135:
6-11.
Hering O, Mockenhaupt M, Rzany B, Schröder W, Schöpf E. The dermal type of
erythema multiforme: a rare variant of Stevens-Johnson syndrome or cases of
clinical misclassification? Acta Derm Venereol. 1997;77:217-218.
Knowles SR, Phillips EJ, Wong G, Shear NH. Serious dermatologic reaction associated with valdecoxib: report of two cases. J Am Acad Dermatol. 2004;51:
1028-1029.
Glasser DL, Burroughs SH. Valdecoxib-induced toxic epidermal necrolysis in a
patient allergic to sulfa drugs. Pharmacotherapy. 2003;23:551-553.
Correction
Incorrect Trial Registration Identifier. In the article titled
“A Randomized, Double-blind, Placebo-Controlled Trial
of Pentoxifylline for the Treatment of Recurrent Aphthous Stomatitis” by Thornhill et al, published in the April
issue of the Archives (2007;143:463-470), the trial registration identifier at the end of the “Abstract” on page
463, right-hand column, should have read as follows:
NCT00315679. Online versions of this article on the
Archives of Dermatology Web site were corrected on April
16, 2007.
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