1996 Volume 49, No. 3,June 1996

.ed. 2. Nifedipine-lnduced Erythema Multiforme de eia, Sarah]. Barker, Charles D. Bayliff, D.G. McCormack and G.R. Dilworth 11A, rer, INTRODUCTION ol­ :al; ifedipine is widely used for the treatment of Serum chemistries were remarkable for slightly de­ cardiovascular disease. Approximately 30% of creased concentrations of calcium (1.98 mmol/L; N=2. l- N its users experience side effects related to its 2.6), potassium (3.3 mmol/L; N=3.5-5.5), and magne­ m­ vasodilating action such as headache, flushing, and diz­ sium (0.54 mmol/L; N=0.65-1.25). White blood cell : le ziness.1 Severe skin rash is infrequently cited as a count was 4.2 X 109/L (N=4.5-12.5), with a moderate left 2 3 on complication of nifedipine. , We report a patient who shift. The fluid from the blisters was sterile and immu­ Ile developed erythema multiforme (EM) after starting nologic tests for complement were normal. nifedipine. On admission to the community hospital (day three of es re reaction), nifedipine was discontinued and the patient '.S. was treated with IV hydrocortisone followed by oral le CASE prednisone 20 mg tid in addition to hydroxyzine 25 mg )it tid, and acetaminophen pm. The next day, following m 4 7 year-old female presented to a community :a A hospital with a three-day history of fever, malaise, transfer to the tertiary care centre, cloxacillin lg IV q6h headache, and a maculopapular rash. Over the next was initiated on the recommendation of the infectious ts twenty-four hours in hospital, the rash progressed to a disease service. ~e generalized rash with vesicles. At this point, she was The dermatology service considered the rash to be of transferred to a tertiary, health care centre. moderate severity, possibly Stevens-Johnson and most E Her only pre-existing medical condition was hyper­ likely drug-related. There was also a possibility of the tension for which she had been receiving hydrochlo­ rash progressing to toxic epidermal necrolysis (TEN) rothiazide/triamterene for several years. Four to six weeks with a remote chance of pemphigus. However, the prior to her admission, her antihypertensive therapy was results of a punch biopsy from the edge of the blisters on changed to nifedipine XL 30 mg daily. She had no recent her leg supported a diagnosis of EM. Histology showed contact history with any infectious illness and no recent sections with extensive epidermal necrosis and forma­ history of a cough or sore throat. tion of a blister that was intraepidermal. There was no Review of systems was remarkable only for the painful, evidence of acantholysis or eosinophilia but examination non-itchy rash, in addition to swollen ankles and sore of the underlying dermis also revealed a mild to moderate joints. On examination, the patient's blood pressure was degree of lymphoid cellular infiltrate. Direct immuno­ 130/80 mmHg, temperature 39. TC, heart rate 100 beats/ fluorescence and fibrinogen staining ruled out primary minute, and respiratory rate 15/minute. Examination of bullous disease (pemphigus or pemphigoid). her mouth revealed a redness of the palate and a rash on the tongue. The skin rash itself was of the maculopapular type covering approximately 85% of her body surface with red patches of variable size and shape that blanched Sarah J. Barker, BScPhm, is a Pharmacist, London Health Sciences Centre's with pressure. There were vesicles on the lower limbs Children's Hospital of Western Ontario. At the time of this study, Sarah was a Pharmacy Resident, London Health Sciences Centre, London, Ontario. with sore, broken, and peeling skin. The patches were Charles D. Bayliff, PharmD, FCSHP, is Clinical Coordinator of Pharmacy generally coalescent around the trunk and back and Services, London Health Sciences Centre. more discrete on the extremities. There was a denuded D.G. McCormack, MD, FRCPC, is a Consultant, Department of Medicine, area over her back, buttocks, and thighs in addition to London Health Sciences Centre. several non-tense, bullous lesions around her toes on G.R. Dilworth, MD, FRCPC, is a Dermatologist, Department of Dermatology, London Health Science Centre. both feet. Abdominal exam also revealed a palpable, Address correspondence to: Sarah J. Barker, BScPhm, Department of Phar­ painful lymph node approximately 3 cm in diameter in macy Services, London Health Sciences Centre, 800 Commissioners Rd. E., the right groin. London ON N6A 4G5 161 Le Journal canadien de la pharmacie hospitaUere Volume 49, NO 3, juin 1996 Yoh

The blistered areas of the rash were treated with saline­ generalized bullous fixed drug eruption,2 drug-induced relc soaked compresses followed by mupirocin ointment urticarial allergic eruption,8 pemphigus foliaceous, 10 ma three times daily, while the non-blistered areas were exfoliative dermatitis, 11 and morbilliform rash 12 have treated with clobetasol applied twice daily. On the day also been reported. ha\ following transfer to the tertiary centre, the patient began The time course and presentation of our case is similar ti01 to complain of mouth pain for which she received to that of other severe dermatologic reactions to nifedipine. fav acetaminophen with codeine and hydrogen peroxide. An In most reports there has been a lag between the initiation extemporaneous formulation of sucralfate and of nifedipine and onset of rash ranging from two weeks benzydamine was subsequently added. to several months. A prodrome consisting of fever, mal­ REI Over the next few days her skin continued to denude. aise, and myalgias is often evident and the rash is usually At the suggestion of plastic surgery, the patient was progressive. Similarly, biopsy results of other case re­ 1. treated as a burn patient. The cloxacillin was discontin­ ports have included epidermal necrosis, perivascular 2. ued, daily tub baths were started, bacitracin dressings mononuclear cell infiltrates of the dermis, and intra­ were applied to the open areas twice daily, and clobetasol epidermal bullae. In all reported cases, rashes have 3. cream was applied to the non-blistered areas. improved upon nifedipine withdrawal and in many cases Over the next week the rash improved although her positive rechallenges have confirmed nifedipine as the skin continued to peel and one week following her causative agent. 2,8-12 4. transfer to the tertiary care centre she was discharged. Nearly one-third of patients report prodromal symp­ toms occurring one to 14 days prior to the onset of the mucocutaneous diseases. Symptoms, if present, are DISCUSSION variable and nonspecific and may include flu-like M can be categorized as iatrogenic, infectious, or symptoms such as those experienced by this patient of Eidiopathic and many etiologic factors have been malaise, fever, and myalgias in addition to headache, identified in its pathogenesis. 4 While a specific trigger is sore throat, cough, chest pain, nausea, vomiting, and identified in only about half the cases, medications are diarrhea. 5-7 Skin lesions develop over a two- to seven­ frequently implicated. Of those in which a trigger is day period and, as the word "multiforme" suggests, identified, 50 to 60% of cases of EM are felt to be have variable manifestations. They usually appear first secondary to drugs and almost any drug can be impli­ as erythematous macules and become edematous and 4 cated. 5,7 The hypothetical mechanism of this reaction papular with distinctive target lesions. The centre of involves antigen-antibody complex formation with the these lesions may be beefy red, vesicular or a typically resulting hypersensitivity reaction and inflammation caus­ depressed pale area of epidermal necrosis. 5 The earli­ ing epidermal death and separation. est rash is often a symmetric eruption of red macules The product monograph for Adalat XL® describes an and edematous pa pules and plaques. 6 The erythema­ incidence of 2.3% for rashes, a rate similar to that of the tous papular skin lesions enlarge by peripheral expan­ placebo group in some studies. 1 However, a number of sion to cover the body and, as described in our case, cases of serious skin and appendage disorders have been can progress to form bullae and vesicles. 4,7 When described following nifedipine administration. True vesicles and bullae occur, separation from the epider­ urticaria and urticaria exanthema are among the most mis and attached basement membrane from the der­ common reactions noted, while bullous eruption, exfo­ mis is the rule. 5 More severe forms resemble a second liative dermatitis, and EM are less common.8 Stern et al3 degree burn and can result in extensive sloughing of estimated the relative rates of cutaneous reactions with the epidermis. 4 -13 three calcium channel blockers, nifedipine, diltiazem, In the minor variant of EM, mucous membrane in­ and verapamil based on reports provided to the FDA's volvement is mild and, if present, usually limited to the Division of Epidemiology and Drug Surveillance, and the mouth. 5 SJS or EM major is characterized by additional American Academy of Dermatology's Adverse Drug Re­ and more severe mucous membrane involvement. This action Reporting System between 1976and 1985. Of the patient's cutaneous symptoms did extend to her oral total of 3 79 case reports of cutaneous adverse drug mucosa causing severe pain but no additional mucous reactions (serious and nonserious) associated with cal­ membrane involvement was detected. cium channel blockers, 146 cases were associated with Toxic epidermal necrolysis, another variant of EM nifedipine. Some of the more serious reactions requiring major similar to SJS is considered by some to be a hospitalization or treatment included four cases of continuation or progression of EM; however, it is more Stevens-Johnson Syndrome(SJS), two cases of EM, and extensive with greater than 10% of the body surface area 11 cases of exfoliative dermatitis. Severe cutaneous reac­ denuded and mortality ranging from 25 to 70%. 9 Slough­ tions to nifedipine, including: lichenoid drug eruption,9 ing of skin did occur in the case presented here but was 996 Volume 49, No. 3,June 1996 The Canaclian]ournal of Hospital Pharmacy 162

:ed relatively mild with no major fluid or electrolyte abnor­ 5. Raviglione MC, Pablos-Medez A, Battan R. Cinical features . 10 malities. and management of severe dermatological reactions to drugs. In conclusion, a number of severe cutaneous reactions Drug Sat 1990;5:39-64. 6. Cohen B. The many faces of erythema multiforme. Contemp have been associated with nifedipine. Prompt recogni­ Ped 1994; 11: 19-39. Jar tion and withdrawal of the drug are important for a 7. Bryant BG, Mathews BL. Stevens-Johnson syndrome. Drug ne. favourable response and outcome. Intel/ Clin Pharm 1986;20:489-93. on 8. Toner M, White A, Moriarty J, et al. Allergic urticaria! eruption, ~ks leukocytosis and abnormal liver function tests following al­ nifedipine administration. Chest 1988; 93: 1320-1. .lly REFERENCES 9. Reynolds NJ, Jones SK, Crossley J, et al. Exfoliative re­ 1. Krogh CME, ed. Compendium of pharmaceuticals and dermatitis due to nifedipine. Br J Dermatol 1989; 121 :401-4. specialties. Ottawa: Canadian Pharmaceutical Assoc, 1995. 10. Kim SC, Won JH, Ahn SK. Pemphigus foliaceous induced by lar 2. Alcalay J, David M, Sandbank M. Cutaneous reactions to nifedipine. Acta Dermato-Venereolog 1993; 73:210-1. ra­ nifedipine. Dermatologica 1987;175:191-3. 11. Mohammed KN. Nifedipine-induced exfoliative dermatitis and tve 3. Stern R, Khalsa JH. Cutaneous adverse reactions associated pedal edema. Ann Pharmacother 1994;28:967. ,es with calcium channel blockers. Arch Intern Med 1989; 12. Parish LC, Witkowski JA. Truncal morbilliform eruption due to he 149:829-32. nifedipine. Cutis 1992;49:113-4. 4. Crosby SS, Murray KM, Marvin JA, et al. Management of 13. Rayeau JC, Sterns RS. Severe adverse cutaneous reaction to .p­ Stevens-Johnson syndrome. Clin Pharm 1986;5:682-9 . drugs. NEJM 1994;331: 1272-85. he tre ke of le, 1d n­ ts, :st 1d of .ly li- es a­ n- ;e, ~n r­ r- 1d of

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