Erythema multiforme associated with candesartan cilexetil.

Abstract: Candesartan cilexetil is an angiotensin II receptor antagonist that is widely used in the treatment of hypertension. It is generally well tolerated and rarely has adverse effects. We report the case of a 50-year-old man with a 3-year history of hypertension that was difficult to manage because of intolerance to multiple medications. Treatment with candesartan cilexetil was initiated, and blood pressure control improved markedly. Five weeks later, the patient presented with a 2 X 3-cm ulcerative plaque covered with a fibrinous exudate on the right upper lip. Findings from a biopsy of the upper lip were diagnostic for erythema multiforme. Treatment with candesartan cilexetil was discontinued, and the lesions resolved completely within a few weeks. To our knowledge, this is the first report of erythema multiforme induced by the antihypertensive medication candesartan cilexetil.

Key Words: candesartan cilexetil, erythema multiforme

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Candesartan cilexetil (Atacand; AstraZeneca LP, Wilmington, DE) is a selective angiotensin II type 1 receptor antagonist indicated in the treatment of hypertension. It has been evaluated extensively for safety and is generally well tolerated. In clinical trials, the rate of withdrawal of candesartan cilexetil due to adverse events was low. (1,2) The most common reasons for discontinuation of therapy were headache (0.6%) and dizziness (0.3%). In this article, we report a case in which development of erythema multiforme necessitated withdrawal of antihypertensive therapy with candesartan cilexetil.

Case Report

A 50-year-old white male with a 3-year history of hypertension was evaluated for uncontrolled high blood pressure. Management of the hypertension had previously been difficult because of intolerance to multiple medications. The patient had been taking labetalol, an adrenergic receptor-blocking agent that has both selective [[alpha].sub.1]-adrenergic and nonselective [beta]-adrenergic receptor blocking actions, for blood pressure control. However, this medication had been discontinued 3 weeks before the evaluation because it had been poorly tolerated. His current medications included the proton pump inhibitor esomeprazole and the cyclooxygenase-2 inhibitor rofecoxib.

Physical examination of the patient, including funduscopic examination, was unremarkable. His blood pressure was 180/90 mm Hg and his pulse was 88 beats/min. A chest radiograph, an electrocardiogram, and results of routine laboratory tests, including serum potassium and creatinine values, were normal. Urinalysis was negative for protein. Renal ultrasound examination demonstrated symmetric kidney size.

Rofecoxib was discontinued and treatment of the hypertension was initiated with candesartan cilexetil. During the next several days, blood pressure control improved markedly. Five weeks later, the patient presented with a 2 X 3-cm ulcerative plaque covered with a fibrinous exudate on the right upper lip. Twenty-four hours later, two similar lesions were noted on the penis (Fig. 1). Viral culture for herpes simplex and varicella zoster was negative. Findings from a biopsy of the upper lip were diagnostic for erythema multiforme. Individual epithelial necrosis was observed, with focal separation of the epithelium from the underlying submucosa. In addition, submucosal edema and a mixed inflammatory infiltrate composed of lymphocytes, eosinophils, and neutrophils were present (Fig. 2). Direct cutaneous immunofluorescence studies showed no evidence of immunobullous tissue disorders.

Treatment with candesartan cilexetil was discontinued and the lesions resolved completely within a few weeks. The patient's blood pressure was then controlled with amlodipine besylate, a calcium channel blocker.

Discussion

Erythema multiforme is an acute, self-limited, hypersensitivity reaction characterized by round to oval, erythematous, iris-shaped or targetoid papules and vesicobullous lesions. (3) The lesions commonly occur on acral surfaces of skin and on mucous membranes. The condition may be associated with an infectious process, such as herpes virus infection, or with collagen vascular disorders, or medications. Drugs commonly implicated include sulfonamides, penicillin, and phenytoin. (4) Constitutional symptoms such as fever and malaise are often present, and circulating immune complexes have been identified in some patients. (5) Clinical severity may range from mild cases, such as in our patient, to extensive involvement of skin and mucous membranes, with a serum sickness-like picture. The Naranjo adverse drug event probability score was "probable" in our patient and was further confirmed by biopsy. (6)

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Conclusion

To our knowledge, this is the first report of erythema multiforme induced by the antihypertensive medication candesartan cilexetil. The possibility of such reactions should be considered in the treatment of hypertension in patients with intolerance to multiple medications.

Accepted June 24, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0614

References

1. Trenkwalder P. Efficacy and tolerability of candesartan cilexetil in special patient groups. Blood Press Suppl 2000;1:27-30.

2. Gleiter CH, Morike KE. Clinical pharmacokinetics of candesartan. Clin Pharmacokinet 2002;41:7-17.

3. Leaute-Labreze C, Lamireau T, Chawki D, et al. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child 2000;83:347-352.

4. Kaplan AP. Drug-induced skin disease. J Allergy Clin Immunol 1984;74:573-579.

5. Delafuente JC. Drug-induced erythema multiforme: a possible immunologic pathogenesis. Drug Intell Clin Pharm 1985;19:114-117.

6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.

RELATED ARTICLE: Key Points

* The angiotensin II receptor antagonist candesartan cilexetil is widely used in the treatment of hypertension.

* Adverse effects are rare and usually consist of headache (0.6%) or dizziness (0.3%).

* Candesartan cilexetil may induce erythema multiforme in patients with intolerance to multiple medications.

A. Ahsan Ejaz, MD, John S. Walsh, MD, and Andrew Wasiluk, MD

From the Division of Nephrology and Hypertension and the Department of Dermatology, Mayo Clinic, Jacksonville, FL.

No financial support was received for this study.

Correspondence to A. Ahsan Ejaz, MD, 105 Oak View Circle, Ponte Vedra Beach, FL 32082. Email: [e-mail]