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The spectrum of cutaneous reactions associated with diltiazem: Three cases and a review of the literature
The spectrum of cutaneous reactions associated with diltiazem: Three cases and a review of the literature Sandra Knowles, BScPhm,a,c Aditya K. Gupta, MD, FRCPC,b and Neil H. Shear, MD, FRCPC, FACPa,b,c Toronto, Ontario, Canada Background: Cutaneous reactions ranging from exanthems to severe adverse events have been reported in association with calcium channel blockers. Objective: Our purpose was to document cutaneous eruptions resulting from use of diltiazem. Methods: We describe three patients who experienced a cutaneous reaction (i.e., hypersensitivity syndrome reaction, pruritic exanthematous eruption, and acute generalized exanthematous pustulosis) possibly induced by diltiazem, summarize adverse reaction reports obtained from the Health Protection Branch, and review the literature on calcium channel blockers inducing cutaneous reactions. Results: Of the 315 cases of possible diltiazem-induced adverse reactions that were reported to the Health Protection Branch, 151 (48%) were cutaneous. The number of diltiazem-induced cutaneous events was significantly greater than those induced by either nifedipine or verapamil. However, no difference was found in the proportion of serious cutaneous adverse events to either of the three drugs. Conclusion: Diltiazem has been associated with a variety of cutaneous reactions that appear to occur more frequently than with other calcium channel blockers. (J Am Acad Dermatol 1998;38:201-6.)
Calcium channel blockers are a heterogeneous group of compounds with respect to their pharmacologic properties, therapeutic indications, and adverse effect profile (see Table I). The main side effects of these agents are dose-dependent and are the result of their pharmacologic actions (i.e., vasodilation, negative inotropic effects, and antiarrhythmic effects).1 Cutaneous eruptions in association with calcium channel blockers vary from exanthems to severe cutaneous reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We describe three patients with a cutaneous reaction (i.e., hypersensitivity syndrome reaction, pruritic exanthematous eruption, and acute generFrom the Divisions of Clinical Pharmacologya and Dermatology,b and Glaxo Wellcome—Sunnybrook Drug Safety Clinic, Department of Medicine, Sunnybrook Health Science Centre and the University of Toronto.c Accepted for publication Nov. 10, 1997. Reprint requests: N. H. Shear, MD, FRCPC, FACP, Sunnybrook Health Science Centre, Division of Clinical Pharmacology, E240, 2075 Bayview Ave., Toronto, Ontario, M4N 3M5, Canada. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/87482
alized exanthematous pustulosis [AGEP]) to diltiazem. Information obtained from the Health Protection Branch (HPB), Adverse Drug Reaction (ADR) Monitoring division regarding cutaneous reactions induced by diltiazem is summarized. The literature on cutaneous reactions induced by diltiazem and other calcium channel blockers is also reviewed. METHODS The Glaxo Wellcome–Sunnybrook Drug Safety Clinic (formerly known as the Adverse Drug Reaction Clinic) at Sunnybrook Health Science Centre is a multidisciplinary clinic for patients with a history suggestive of ADRs.2 Most patients are seen in consultation after the adverse event. All patients who were referred to the clinic from January 1985 to May 1996 with a history of a cutaneous eruption, with or without internal organ involvement, possibly induced by a calcium channel blocker (i.e., nifedipine, verapamil, diltiazem) were reviewed. A hypersensitivity syndrome reaction was defined as fever, rash, and internal organ involvement that appeared within 6 weeks after start of therapy. A serious adverse event is one that results in death,
201
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202 Knowles, Gupta, and Shear
Table I. Common side effects of available calcium channel blockers28,29 Drug
Benzothiazepine Diltiazem
Trade name
Common side effects
Cardizem, Cardizem SR, Cardizem CD
Nausea, swelling/edema, arrhythmia, headache, rash, asthenia
Phenylalkylamine Verapamil
Isoptin, Isoptin SR
Constipation, dizziness, nausea, headache, heart failure, hypotension, AV block
Dihydropyridines Nifedipine
Adalat, Adalat PA, Adalat XL
Felodipine
Plendil, Renedil
Nicardipine
Cardene
Amlodipine
Norvasc
Nimodipine Piperazine Flunarizine
Nimotop
Edema, headache, angina pectoris, palpitations, dizziness, fatigue Peripheral edema, headache, warmth/flush, dizziness, fatigue, palpitations, extrasystoles Headache, asthenia, dizziness, pedal edema, flushing, palpitations, dyspepsia, nausea, myalgia, tachycardia, rash, somnolence Edema, headache, palpitations, dizziness, flushing, nausea, fatigue Hypotension, nausea, bradycardia
Sibelium
Drowsiness, weight gain, depression
hospitalization (initial or prolonged), disability, a congenital anomaly, or is life-threatening. Within the spectrum of cutaneous disorders, this would include erythema multiforme, SJS, TEN, and hypersensitivity syndrome reaction. In addition, the HPB in Ottawa, Canada was contacted for all voluntary ADR reports that were submitted to them regarding cutaneous reactions possibly induced by calcium channel blockers from 1966 to November 1995. All patients with an eruption as classified by the HPB, with or without internal organ involvement, were screened for inclusion. A computer-based MEDLINE search was conducted from 1966 to January 1997. Search terms included calcium channel blockers, drug hypersensitivity, liver diseases, and skin diseases. The bibliographies of all pertinent articles were reviewed to identify any additional articles that may have been missed through the computer search. Descriptive statistics were applied. All data are mean ± standard error. The chi-square test was used to compare proportions. Fifteen patients were referred to the Drug Safety Clinic for a possible diltiazem-induced adverse event. Twelve (80%) reported an eruption that included seven of an unspecified type and one each of pruritus, erythema multiforme, hypersensitivity syndrome reaction, AGEP, and urticaria. Three of these cases that had sufficient clinical and laboratory details are described in detail below. The mean age of the patients with a cutaneous reaction was 66.7 years (± 3.9 years), with a male/female ratio of 1:3.
CASE REPORTS Case 1 A 48-year-old man was given diltiazem (120 mg once daily) for the treatment of hypertension. After taking 10 doses, diffuse facial erythema and edema with coalescing nonfollicular pustules occurred. Pustules on an inflammatory base also affected the upper trunk and flanks. This later extended to the extremities, blistered, and peeled. His skin was tender. Other symptoms included fever and malaise. A biopsy specimen revealed that the epidermis contained superficial pustules with some basal keratinocyte degeneration and perivascular inflammatory infiltration. He also had an increased white blood cell count with neutrophilia, but normal eosinophils. He had a transient elevation in liver function tests. A diagnosis of AGEP was made. He was treated with prednisone and slowly recovered in 12 days. At the time of the reaction, the patient was also taking domperidone, alprazolam, and famotidine. He has continued these without any difficulties. Case 2 A 62-year-old woman with a history of hypertension was treated with triamterene-hydrochlorothiazide and enalapril. Her history included drug allergies to penicillin and sulfonamides. Because of poor blood pressure control, she was started on a regimen of diltiazem, 30 mg twice daily. After 10 days of therapy, she experienced widespread erythematous edematous papules and plaques that coalesced in areas on the trunk and limbs and involved the cheeks, forehead, and scalp. She
Journal of the American Academy of Dermatology Volume 38, Number 2, Part 1
Knowles, Gupta, and Shear 203
Table II. Cutaneous ADR reports for diltiazem, verapamil, and nifedipine submitted to HPB 1966–November 1995 Cutaneous reaction
Morphologic description only Exanthematous rash (maculopapular, morbilliform) Urticarial eruption Pruritus Other (including erythema, alopecia) Specific cutaneous disease reaction Angioedema Erythema multiforme Exfoliative dermatitis Rash and arthralgias Other (including Sweet's syndrome, erythema nodosum) Syndromes Rash, fever +/– internal organ involvement TEN/SJS Total No.
Diltiazem
Nifedipine
Verapamil
105 (70) 8 (5) 2 (1) 5 (3)
63 (63) 6 (6) 4 (4) 13 (13)
25 (49) 7 (14) 2 (4) 8 (16)
3 (2) 6 (4) 5 (3) 2 (1) 5 (3)
3 (3) 1 (1) 0 1 (1) 2 (2)
2 (4) 0 1 (2) 0 1 (2)
6 (6) 2 (2) 101
4 (8) 1 (2) 51
9 (6) 1 (0.7) 151
+/–, With or without. Data expressed as number of reports, with percentage given in parentheses.
had a sore throat and a fever, but there was no lymphadenopathy. Her liver function tests were increased (ALP, 145 IU/L; ALT, 268 U/L; AST, 191 U/L), she had a slightly elevated sedimentation rate (39 mm/hr), and her antinuclear antibody (ANA) was positive at 1:40. A diagnosis of hypersensitivity syndrome reaction was made. Her diltiazem was discontinued and she was treated with oral prednisone, hydroxyzine, and fluocinonide cream. Her biopsy specimen showed perivascular lymphocytic infiltrate with extravasation of red blood cells; there was no necrosis of epithelial cells. This was interpreted as compatible with a drug eruption. Within a week after discontinuation of diltiazem, her liver function tests were returning to normal. On follow-up 2 months later, her ANA was negative. Case 3 A 60-year-old woman had been taking diltiazem for approximately 3 months when she had the gradual onset of a pruritic, exanthematous eruption on her legs and trunk. The patient was taking no other medications. The eruption gradually improved with terfenadine and discontinuation of the drug. The patient was given prazosin for her hypertension after the reaction with no recurrence. RESULTS
Of 315 cases of possible diltiazem-induced ADRs that were reported to the HPB, 151 (48%) were cutaneous (see Table II). Serious events (e.g., TEN, SJS, erythema multiforme, exfoliative dermatitis, hypersensitivity syndrome reaction) comprised 17% of the cutaneous reports. The
mean age of patients was 67 (± 0.9) years, with a male/female ratio of 1:1.75. No statistically significant difference was found between the HPB or the Drug Safety Clinic data regarding either the mean age or the male/female ratio. There have been 288 ADR reports submitted to the HPB related to nifedipine. Of these, 101 (35%) were reports of cutaneous events, and 10 (10%) of these were serious cutaneous events. Of the 286 reports submitted to the HPB possibly related to verapamil, 51 (18%) were eruptions, of which six (12%) were classified as serious. The number of diltiazem-induced cutaneous events was significantly greater than either nifedipine (χ2 = 10.2; p < 0.01) or verapamil (χ2 = 61; p < 0.001). However, no difference was found in the proportion of serious cutaneous adverse events in either of the three groups. DISCUSSION
Exanthematous skin eruptions have been reported after initiation of diltiazem therapy.3-7 In the eight cases in the literature, the eruption occurred 206 (± 198) days after initiation of therapy; however, excluding the patient who displayed the eruption after 4 years of diltiazem therapy, the mean number of days to onset was 7.3 (± 2.3) days. Our patient presented with an eruption approximately 3 months after initiation of therapy; when diltiazem was discontinued, the eruption promptly cleared. Although the patient was
Journal of the American Academy of Dermatology February 1998
204 Knowles, Gupta, and Shear Table III. Dermatologic reactions as reported in the literature Calcium channel blocker
Drug-induced cutaneous event classification
Diltiazem
Morphologic description only
Cutaneous disease reactions
Syndromes Verapamil Nifedipine
Morphologic description only Cutaneous disease reactions Syndromes Morphologic description only
Cutaneous disease reactions
Syndromes
receiving no other medication, other causes (e.g., viral) cannot be excluded. There have been five reported cases of diltiazem-associated AGEP.8-11 The mean number of days of therapy with diltiazem to onset of lesions was 8.4 (± 2.2) days. Clearing occurred a mean of 10 (± 1.8) days after diltiazem was discontinued. In our patient, the skin eruption began 10 days after initiation of diltiazem and cleared within 12 days of discontinuation of the drug. Serious cutaneous reactions, which include erythema multiforme, SJS, TEN, and hypersensitivity syndrome reaction, usually occur within 1 to 17 days of initiation of therapy.12 These reactions have been reported in association with diltiazem,
Dermatologic reaction
Exanthematous dermatitis4,21 Gingival hyperplasia30 Maculopapular exanthems3,5-7,10,17,26 Proptosis and periorbital edema31 Skin thickening and sensory loss in feet32 Toxic erythema33 AGEP8-11 Cutaneous vasculitis17,34 Erythema multiforme7,10,17,35,36 Lupus erythematosus–like eruption17 Nonthrombocytopenic purpura24 Exfoliative dermatitis14,17 Photosensitivity10,37,38 Psoriasiform eruptions7,17 Urticarial vasculitis10 Vasculitic leg ulcers39 Stevens-Johnson syndrome,12,15,17 toxic epidermal necrolysis17 Maculopapular rash17 Vasculitis17 SJS17,40 Erythematous edema (erysipelas)41 Fixed drug eruption42 Gingival hyperplasia43,44 Maculopapular rash17,22,45,46 Urticaria47,48 Erythema multiforme17,48 Erythromelalgia17,49,50 Exfoliative dermatitis17,19,51,52 Facial telangiectasia53 Nonthrombocytopenic purpura54 Pemphigus foliaceus55 Photosensitivity reactions38,43,56-58 Psoriasiform eruption17 Vasculitis17,59 None reported
nifedipine, and verapamil (see Table III). Pseudolymphoma from calcium channel blockers has also been reported13; however, in this report, the specific calcium channel blockers were not noted. Another severe adverse reaction that has been reported with diltiazem is the hypersensitivity syndrome reaction.14-18 This usually occurs 2 to 4 weeks after start of therapy and has been associated most commonly with anticonvulsants, dapsone, sulfonamides, and allopurinol.19 Fever, often the initial sign, is followed by an eruption, which is usually exanthematous but may be as severe as TEN. Patients will often demonstrate atypical lymphocytosis early on with a later onset eosinophilia. Internal organ involvement usually
Journal of the American Academy of Dermatology Volume 38, Number 2, Part 1
results in hepatic injury, and pulmonary, hematologic, or renal impairment may occur. In addition, thyroid dysfunction may be present 3 to 4 months after the initial event.20 In the four cases associated with diltiazem, the onset of the eruption occurred 214,15 to 416,18 days after starting diltiazem. Liver involvement occurred in all four patients, as well as in ours. Our patient's symptoms started 10 days after diltiazem was initiated. Corticosteroids are often used in the treatment of this reaction, as in our patient. Because of the severity of the hypersensitivity syndrome reaction, it is recommended that any patient who experiences an eruption and fever while taking diltiazem should have complete laboratory studies done. Patients who have a cutaneous reaction while receiving diltiazem have been rechallenged with nifedipine3,6,8,12,21 or verapamil17 with no further complications. Similarly, patients who had a cutaneous reaction while taking nifedipine have tolerated diltiazem,22,23 although one patient who experienced nonthrombocytopenic purpura with nifedipine24 had a similar eruption with diltiazem. There is a report of another patient5 who suffered from a pruritic exanthem after diltiazem and readministration of amlodipine. In addition, one patient experienced exfoliative dermatitis on two separate occasions from diltiazem and chloroquine. The authors14 suggested that a cross-reaction may exist between diltiazem and chloroquine because of their similar chemical structures. Although nifedipine and amlodipine are both dihydropyridines, cross-reaction between the two agents has not been reported.25 Therefore crossreactivity among diltiazem, verapamil, and nifedipine have not been reported. The mechanism of adverse reactions from diltiazem and other calcium channel blockers is unknown. Because the spectrum of cutaneous reactions is extensive, it is likely that the pathophysiology differs with each reaction. Patch testing4,7,11,26,27 or skin testing3,26 has been used as confirmatory testing in patients with extensive cutaneous reactions to diltiazem. After the information obtained from the HPB had been analyzed, nifedipine and verapamil were associated with significantly fewer eruptions than diltiazem. However, the percentage of serious cutaneous events was not statistically different between diltiazem, nifedipine, and verapamil. This is in contrast to a review of cutaneous reac-
Knowles, Gupta, and Shear 205 tions associated with the calcium channel blockers that were reported to the Food and Drug Administration during the period of 1978 to 1985.17 In this study, diltiazem was associated with a higher frequency of serious skin reactions (i.e., erythema multiforme, SJS, exfoliative dermatitis) than nifedipine or verapamil. However, as the authors suggested, these differences may simply reflect differences in spontaneous reporting rather than true differences in reaction rates. Not unexpectedly, the mean age of the patients who had a cutaneous reaction while receiving a calcium channel blocker was 65 years. The number of women who reported cutaneous events was higher than men (male/female ratio 1:1.8). This may simply reflect a bias in reporting, or may suggest that women are more predisposed to cutaneous events perhaps because of differences in pharmacokinetic or pharmacodynamic factors. We thank the Drugs Directorate, Health Protection Branch for providing data. The interpretation of the results does not reflect the opinions or policies of Health Canada. The reproduced information from the HPB is raw information and has not been scientifically verified. REFERENCES 1. Hedner T. Calcium channel blockers: spectrum of side effects and drug interactions. Acta Pharmacol Toxicol 1986;58 Suppl 2:119-30. 2. Recchia A, Shear N. Organization and functioning of an adverse drug reaction clinic. J Clin Pharmacol 1994;34: 68-79. 3. Hammentgen R, Lutz G, Kohler U, Nitsch J. Makulopapuloses exanthem bei diltiazem-therapie. Dtsch Med Wschr 1988;113:1283-5. 4. Sousa-Basto A, Azenha A, Duarte M, Pardal-Oliveira F. Generalized cutaneous reaction to diltiazem. Contact Dermatitis 1993;28:44-5. 5. Baker B, Cacchione J. Dermatologic cross-sensitivity between diltiazem and amlodipine. Ann Pharmacother 1994;28:118-9. 6. Wirebaugh S, Geraets D. Reports of erythematous macular skin eruptions associated with diltiazem therapy. DICP Ann Pharmacother 1990;24:1046-9. 7. Kitamura K, Kanasashi M, Suga C, Saito S, Yoshida S, Ikezawa Z. Cutaneous reactions induced by calcium channel blocker: high frequency of psoriasiform eruptions. J Dermatol 1993;20:279-86. 8. Lambert D, Dalac S, Beer F, Chavannet P, Portier H. Acute generalized exanthematous pustular dermatitis induced by diltiazem. Br J Dermatol 1988;118:308-9. 9. Janier M, Gerault M, Carlotti A, Vignon M, Daniel F. Acute generalized exanthematous pustulosis due to diltiazem. Br J Dermatol 1993;129:354-5. 10. Wittal R, Fischer G, Georgouras K, Baird P. Skin reactions to diltiazem. Australas J Dermatol 1992;33:11-8. 11. Wakelin S, James M. Diltiazem-induced acute gener-
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12. 13. 14. 15. 16. 17. 18.
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alised exanthematous pustulosis. Clin Exp Dermatol 1995;20:341-4. Taylor J, Cleary J, Atkinson R. Stevens-Johnson syndrome associated with diltiazem. Clin Pharm 1990;9: 948-50. Magro C, Crowson A. Drug-induced immune dysregulation as a cause of atypical cutaneous lymphoid infiltrates: a hypothesis. Hum Pathol 1996;27:125-32. Lavrijsen A, van Dijke C, Vermeer B-J. Diltiazem-associated exfoliative dermatitis in a patient with psoriasis. Acta Derm Venereol (Stockh) 1986;66:536-8. Sanders C, Neumann H. Erythema multiforme, StevensJohnson syndrome, and diltiazem. Lancet 1993;341:967. Scolnick B, Brinberg D. Diltiazem and generalized lymphadenopathy. Ann Intern Med 1985;102:558. Stern R, Khalsa J. Cutaneous adverse reactions associated with calcium channel blockers. Arch Intern Med 1989;149:829-32. Avila J, Bejarano D, Gonzalez M, Miguel del Corral M. Elevation of hepatic enzymes after cutaneous reaction caused by diltiazem [letter]. Ann Pharmacother 1995;29: 317-8. Scoble J, Uff J, Eastwood J. Nifedipine nephritis. Clin Nephrol 1984;21:302. Gupta A, Eggo M, Uetrecht J, et al. Drug-induced hypothyroidism: the thyroid as a target organ in hypersensitivity reactions to anticonvulsants and sulfonamides. Clin Pharm Ther 1992;51:56-67. Jones S, Reynolds N, Crossley J, Kennedy C. Cutaneous reaction to diltiazem resulting in an exacerbation of angina. Clin Exp Dermatol 1989;14:457-8. Leibovici V, Zlotogorski A, Heyman A, Kanner A, Melmed R. Polymorphous drug eruption due to nifedipine. Cutis 1988;41:367. Massimo C, Sebastianelli G, Noera G. Nifedipineinduced parotitis: a hypersensitivity reaction. Am J Cardiol 1988:61:874. Kuo M, Winiarski N, Garella S. Nonthrombocytopenic purpura associated sequentially with nifedipine and diltiazem. Ann Pharmacother 1992;26:1089-90. Bewley A, Feher M, Staughton R. Erythema multiforme following substitution of amlodipine for nifedipine. Br Med J 1993;307:241. Romano A, Pietrantonio F, Garcovich A, et al. Delayed hypersensitivity to diltiazem in two patients. Ann Allergy 1992;69:31-2. Barbaud A, Trechot P, Gillet-Terver M, Zannad F, Schmutz J. Investigations immunoallergologiques dans une toxidermie au diltiazem (Tildiem 300 LP). Therapie 1993;48:499-500. Canadian Pharmaceutical Association. Compendium of pharmaceuticals and specialties. In: Gillis M, editor. Toronto: CK Productions; 1996. Anon. Physicians' Desk Reference. Montvale: Medical Economics Co., 1996. Giustiniani S, Robustelli della Cuna F, Marieni M. Hyperplastic gingivitis during diltiazem therapy. Int J Cardiol 1987;15:247-9. Friedland S, Kaplan S, Lahav M, Shapiro A, Tiqva P. Proptosis and periorbital edema due to diltiazem treatment. Arch Ophthalmol 1993;111:1027-8. Ilia R, Goldfarb B, Gueron M. Skin thickening and sensory loss of the feet during diltiazem therapy. Int J Cardiol 1992;35:115. Wakeel R, Gavin M, Keefe M. Severe toxic erythema caused by diltiazem. Br Med J 1988;296:1071.
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34. Sheehan-Dare R, Goodfield M. Widespread cutaneous vasculitis associated with diltiazem. Postgrad Med J 1988;64:467-8. 35. Berbis P, Alfonso M, Levy J, Privat Y. Diltiazem associated erythema multiforme. Dermatologica 1989;179:904. 36. Brown F, Houston G, Phillips M, Westbrook S. Erythema multiforme following Cardizem therapy: report of a case. Ann Dent 1989;48:39-41. 37. Young L, Shehade S, Chalmers R. Cutaneous reactions to diltiazem. Clin Exp Dermatol 1990;15:466-8. 38. Seggev J, Lagstein Z. Photosensitivity skin reactions to calcium channel blockers. J Allergy Clin Immunol 1996; 97:852-5. 39. Carmichael A, Paul C. Vasculitic leg ulcers associated with diltiazem. Br Med J 1988;297:562. 40. Gonski P. Stevens-Johnson syndrome induced by verapamil [letter]. Med J Aust 1992;156:672. 41. Bridgman J. Erythematous oedema of the legs due to nifedipine. Br Med J 1978;1:578. 42. Alcalay J, David M, Sandbank M. Cutaneous reactions to nifedipine. Dermatologica 1987;175:191-3. 43. Zlotogorski A, Heyman A. Cutaneous reactions to nifedipine. Dermatologica 1988;177:249. 44. Ramon Y, Behar S, Kishon Y, et al. Gingival hyperplasia caused by nifedipine: a preliminary report. Int J Cardiol 1984;5:195-206. 45. Findlay G. Morbilliform erythrodermic fever with purpura. S Afr Med J 1985;68:176-9. 46. Parish L, Witkowski J. Truncal morbilliform eruption due to nifedipine. Cutis 1992;49:113-4. 47. Toner M, White A, Moriarty J, Clancy L. Allergic urticarial eruption, leukocytosis and abnormal liver function tests following nifedipine administration. Chest 1988;93:1320-1. 48. Myrhed M, Wiholm B-E. Nifedipine: a survey of adverse effects: four years' reporting in Sweden. Acta Pharmacol Toxicol 1986;58:133-6. 49. Fisher J, Padnick M, Olstein S. Nifedipine and erythromelalgia. Ann Intern Med 1983;98:671-2. 50. Grunwald Z. Painful edema, erythematous rash, and burning sensation due to nifedipine. Drug Intell Clin Pharm 1982;16:492. 51. Reynolds N, Jones S, Crossley J, Harman R. Exfoliative dermatitis due to nifedipine. Br J Dermatol 1989;121: 401-4. 52. Mohammed K. Nifedipine-induced exfoliative dermatitis and pedal edema. Ann Pharmacother 1994;28:967. 53. Collins P, Ferguson J. Photodistributed nifedipineinduced facial telangiectasia. Br J Dermatol 1993;129: 630-3. 54. Oren R, Polak A, Goldenhersh M, Heyman A, Naparstek Y. Nifedipine-induced nonthrombocytopenic purpura. Drug Intell Clin Pharm 1989;23:88. 55. Kim S, Won J, Ahn S. Pemphigus foliaceus induced by nifedipine. Acta Derm Venereol (Stockh) 1993;73:210-1. 56. Thomas S, Wood M. Photosensitivity reactions associated with nifedipine. Br Med J 1986;292:992. 57. Guarrera M, Parodi A, Rebora A. Is nifedipine phototoxic? Photodermatol Photoimmunol Photomed 1990;7:257. 58. Zenarola P, Gatti S, Lomuto M. Photodermatitis due to nifedipine: report of 2 cases. Dermatologica 1991;182: 196-8. 59. Brenner S, Brau S. Vasculitis following nifedipine. Harefuah 1985;108:139-40.
Calcium channel blockers are a heterogeneous group of compounds with respect to their pharmacologic properties, therapeutic indications, and adverse effect profile (see Table I). The main side effects of these agents are dose-dependent and are the result of their pharmacologic actions (i.e., vasodilation, negative inotropic effects, and antiarrhythmic effects).1 Cutaneous eruptions in association with calcium channel blockers vary from exanthems to severe cutaneous reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We describe three patients with a cutaneous reaction (i.e., hypersensitivity syndrome reaction, pruritic exanthematous eruption, and acute generFrom the Divisions of Clinical Pharmacologya and Dermatology,b and Glaxo Wellcome—Sunnybrook Drug Safety Clinic, Department of Medicine, Sunnybrook Health Science Centre and the University of Toronto.c Accepted for publication Nov. 10, 1997. Reprint requests: N. H. Shear, MD, FRCPC, FACP, Sunnybrook Health Science Centre, Division of Clinical Pharmacology, E240, 2075 Bayview Ave., Toronto, Ontario, M4N 3M5, Canada. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/87482
alized exanthematous pustulosis [AGEP]) to diltiazem. Information obtained from the Health Protection Branch (HPB), Adverse Drug Reaction (ADR) Monitoring division regarding cutaneous reactions induced by diltiazem is summarized. The literature on cutaneous reactions induced by diltiazem and other calcium channel blockers is also reviewed. METHODS The Glaxo Wellcome–Sunnybrook Drug Safety Clinic (formerly known as the Adverse Drug Reaction Clinic) at Sunnybrook Health Science Centre is a multidisciplinary clinic for patients with a history suggestive of ADRs.2 Most patients are seen in consultation after the adverse event. All patients who were referred to the clinic from January 1985 to May 1996 with a history of a cutaneous eruption, with or without internal organ involvement, possibly induced by a calcium channel blocker (i.e., nifedipine, verapamil, diltiazem) were reviewed. A hypersensitivity syndrome reaction was defined as fever, rash, and internal organ involvement that appeared within 6 weeks after start of therapy. A serious adverse event is one that results in death,
201
Journal of the American Academy of Dermatology February 1998
202 Knowles, Gupta, and Shear
Table I. Common side effects of available calcium channel blockers28,29 Drug
Benzothiazepine Diltiazem
Trade name
Common side effects
Cardizem, Cardizem SR, Cardizem CD
Nausea, swelling/edema, arrhythmia, headache, rash, asthenia
Phenylalkylamine Verapamil
Isoptin, Isoptin SR
Constipation, dizziness, nausea, headache, heart failure, hypotension, AV block
Dihydropyridines Nifedipine
Adalat, Adalat PA, Adalat XL
Felodipine
Plendil, Renedil
Nicardipine
Cardene
Amlodipine
Norvasc
Nimodipine Piperazine Flunarizine
Nimotop
Edema, headache, angina pectoris, palpitations, dizziness, fatigue Peripheral edema, headache, warmth/flush, dizziness, fatigue, palpitations, extrasystoles Headache, asthenia, dizziness, pedal edema, flushing, palpitations, dyspepsia, nausea, myalgia, tachycardia, rash, somnolence Edema, headache, palpitations, dizziness, flushing, nausea, fatigue Hypotension, nausea, bradycardia
Sibelium
Drowsiness, weight gain, depression
hospitalization (initial or prolonged), disability, a congenital anomaly, or is life-threatening. Within the spectrum of cutaneous disorders, this would include erythema multiforme, SJS, TEN, and hypersensitivity syndrome reaction. In addition, the HPB in Ottawa, Canada was contacted for all voluntary ADR reports that were submitted to them regarding cutaneous reactions possibly induced by calcium channel blockers from 1966 to November 1995. All patients with an eruption as classified by the HPB, with or without internal organ involvement, were screened for inclusion. A computer-based MEDLINE search was conducted from 1966 to January 1997. Search terms included calcium channel blockers, drug hypersensitivity, liver diseases, and skin diseases. The bibliographies of all pertinent articles were reviewed to identify any additional articles that may have been missed through the computer search. Descriptive statistics were applied. All data are mean ± standard error. The chi-square test was used to compare proportions. Fifteen patients were referred to the Drug Safety Clinic for a possible diltiazem-induced adverse event. Twelve (80%) reported an eruption that included seven of an unspecified type and one each of pruritus, erythema multiforme, hypersensitivity syndrome reaction, AGEP, and urticaria. Three of these cases that had sufficient clinical and laboratory details are described in detail below. The mean age of the patients with a cutaneous reaction was 66.7 years (± 3.9 years), with a male/female ratio of 1:3.
CASE REPORTS Case 1 A 48-year-old man was given diltiazem (120 mg once daily) for the treatment of hypertension. After taking 10 doses, diffuse facial erythema and edema with coalescing nonfollicular pustules occurred. Pustules on an inflammatory base also affected the upper trunk and flanks. This later extended to the extremities, blistered, and peeled. His skin was tender. Other symptoms included fever and malaise. A biopsy specimen revealed that the epidermis contained superficial pustules with some basal keratinocyte degeneration and perivascular inflammatory infiltration. He also had an increased white blood cell count with neutrophilia, but normal eosinophils. He had a transient elevation in liver function tests. A diagnosis of AGEP was made. He was treated with prednisone and slowly recovered in 12 days. At the time of the reaction, the patient was also taking domperidone, alprazolam, and famotidine. He has continued these without any difficulties. Case 2 A 62-year-old woman with a history of hypertension was treated with triamterene-hydrochlorothiazide and enalapril. Her history included drug allergies to penicillin and sulfonamides. Because of poor blood pressure control, she was started on a regimen of diltiazem, 30 mg twice daily. After 10 days of therapy, she experienced widespread erythematous edematous papules and plaques that coalesced in areas on the trunk and limbs and involved the cheeks, forehead, and scalp. She
Journal of the American Academy of Dermatology Volume 38, Number 2, Part 1
Knowles, Gupta, and Shear 203
Table II. Cutaneous ADR reports for diltiazem, verapamil, and nifedipine submitted to HPB 1966–November 1995 Cutaneous reaction
Morphologic description only Exanthematous rash (maculopapular, morbilliform) Urticarial eruption Pruritus Other (including erythema, alopecia) Specific cutaneous disease reaction Angioedema Erythema multiforme Exfoliative dermatitis Rash and arthralgias Other (including Sweet's syndrome, erythema nodosum) Syndromes Rash, fever +/– internal organ involvement TEN/SJS Total No.
Diltiazem
Nifedipine
Verapamil
105 (70) 8 (5) 2 (1) 5 (3)
63 (63) 6 (6) 4 (4) 13 (13)
25 (49) 7 (14) 2 (4) 8 (16)
3 (2) 6 (4) 5 (3) 2 (1) 5 (3)
3 (3) 1 (1) 0 1 (1) 2 (2)
2 (4) 0 1 (2) 0 1 (2)
6 (6) 2 (2) 101
4 (8) 1 (2) 51
9 (6) 1 (0.7) 151
+/–, With or without. Data expressed as number of reports, with percentage given in parentheses.
had a sore throat and a fever, but there was no lymphadenopathy. Her liver function tests were increased (ALP, 145 IU/L; ALT, 268 U/L; AST, 191 U/L), she had a slightly elevated sedimentation rate (39 mm/hr), and her antinuclear antibody (ANA) was positive at 1:40. A diagnosis of hypersensitivity syndrome reaction was made. Her diltiazem was discontinued and she was treated with oral prednisone, hydroxyzine, and fluocinonide cream. Her biopsy specimen showed perivascular lymphocytic infiltrate with extravasation of red blood cells; there was no necrosis of epithelial cells. This was interpreted as compatible with a drug eruption. Within a week after discontinuation of diltiazem, her liver function tests were returning to normal. On follow-up 2 months later, her ANA was negative. Case 3 A 60-year-old woman had been taking diltiazem for approximately 3 months when she had the gradual onset of a pruritic, exanthematous eruption on her legs and trunk. The patient was taking no other medications. The eruption gradually improved with terfenadine and discontinuation of the drug. The patient was given prazosin for her hypertension after the reaction with no recurrence. RESULTS
Of 315 cases of possible diltiazem-induced ADRs that were reported to the HPB, 151 (48%) were cutaneous (see Table II). Serious events (e.g., TEN, SJS, erythema multiforme, exfoliative dermatitis, hypersensitivity syndrome reaction) comprised 17% of the cutaneous reports. The
mean age of patients was 67 (± 0.9) years, with a male/female ratio of 1:1.75. No statistically significant difference was found between the HPB or the Drug Safety Clinic data regarding either the mean age or the male/female ratio. There have been 288 ADR reports submitted to the HPB related to nifedipine. Of these, 101 (35%) were reports of cutaneous events, and 10 (10%) of these were serious cutaneous events. Of the 286 reports submitted to the HPB possibly related to verapamil, 51 (18%) were eruptions, of which six (12%) were classified as serious. The number of diltiazem-induced cutaneous events was significantly greater than either nifedipine (χ2 = 10.2; p < 0.01) or verapamil (χ2 = 61; p < 0.001). However, no difference was found in the proportion of serious cutaneous adverse events in either of the three groups. DISCUSSION
Exanthematous skin eruptions have been reported after initiation of diltiazem therapy.3-7 In the eight cases in the literature, the eruption occurred 206 (± 198) days after initiation of therapy; however, excluding the patient who displayed the eruption after 4 years of diltiazem therapy, the mean number of days to onset was 7.3 (± 2.3) days. Our patient presented with an eruption approximately 3 months after initiation of therapy; when diltiazem was discontinued, the eruption promptly cleared. Although the patient was
Journal of the American Academy of Dermatology February 1998
204 Knowles, Gupta, and Shear Table III. Dermatologic reactions as reported in the literature Calcium channel blocker
Drug-induced cutaneous event classification
Diltiazem
Morphologic description only
Cutaneous disease reactions
Syndromes Verapamil Nifedipine
Morphologic description only Cutaneous disease reactions Syndromes Morphologic description only
Cutaneous disease reactions
Syndromes
receiving no other medication, other causes (e.g., viral) cannot be excluded. There have been five reported cases of diltiazem-associated AGEP.8-11 The mean number of days of therapy with diltiazem to onset of lesions was 8.4 (± 2.2) days. Clearing occurred a mean of 10 (± 1.8) days after diltiazem was discontinued. In our patient, the skin eruption began 10 days after initiation of diltiazem and cleared within 12 days of discontinuation of the drug. Serious cutaneous reactions, which include erythema multiforme, SJS, TEN, and hypersensitivity syndrome reaction, usually occur within 1 to 17 days of initiation of therapy.12 These reactions have been reported in association with diltiazem,
Dermatologic reaction
Exanthematous dermatitis4,21 Gingival hyperplasia30 Maculopapular exanthems3,5-7,10,17,26 Proptosis and periorbital edema31 Skin thickening and sensory loss in feet32 Toxic erythema33 AGEP8-11 Cutaneous vasculitis17,34 Erythema multiforme7,10,17,35,36 Lupus erythematosus–like eruption17 Nonthrombocytopenic purpura24 Exfoliative dermatitis14,17 Photosensitivity10,37,38 Psoriasiform eruptions7,17 Urticarial vasculitis10 Vasculitic leg ulcers39 Stevens-Johnson syndrome,12,15,17 toxic epidermal necrolysis17 Maculopapular rash17 Vasculitis17 SJS17,40 Erythematous edema (erysipelas)41 Fixed drug eruption42 Gingival hyperplasia43,44 Maculopapular rash17,22,45,46 Urticaria47,48 Erythema multiforme17,48 Erythromelalgia17,49,50 Exfoliative dermatitis17,19,51,52 Facial telangiectasia53 Nonthrombocytopenic purpura54 Pemphigus foliaceus55 Photosensitivity reactions38,43,56-58 Psoriasiform eruption17 Vasculitis17,59 None reported
nifedipine, and verapamil (see Table III). Pseudolymphoma from calcium channel blockers has also been reported13; however, in this report, the specific calcium channel blockers were not noted. Another severe adverse reaction that has been reported with diltiazem is the hypersensitivity syndrome reaction.14-18 This usually occurs 2 to 4 weeks after start of therapy and has been associated most commonly with anticonvulsants, dapsone, sulfonamides, and allopurinol.19 Fever, often the initial sign, is followed by an eruption, which is usually exanthematous but may be as severe as TEN. Patients will often demonstrate atypical lymphocytosis early on with a later onset eosinophilia. Internal organ involvement usually
Journal of the American Academy of Dermatology Volume 38, Number 2, Part 1
results in hepatic injury, and pulmonary, hematologic, or renal impairment may occur. In addition, thyroid dysfunction may be present 3 to 4 months after the initial event.20 In the four cases associated with diltiazem, the onset of the eruption occurred 214,15 to 416,18 days after starting diltiazem. Liver involvement occurred in all four patients, as well as in ours. Our patient's symptoms started 10 days after diltiazem was initiated. Corticosteroids are often used in the treatment of this reaction, as in our patient. Because of the severity of the hypersensitivity syndrome reaction, it is recommended that any patient who experiences an eruption and fever while taking diltiazem should have complete laboratory studies done. Patients who have a cutaneous reaction while receiving diltiazem have been rechallenged with nifedipine3,6,8,12,21 or verapamil17 with no further complications. Similarly, patients who had a cutaneous reaction while taking nifedipine have tolerated diltiazem,22,23 although one patient who experienced nonthrombocytopenic purpura with nifedipine24 had a similar eruption with diltiazem. There is a report of another patient5 who suffered from a pruritic exanthem after diltiazem and readministration of amlodipine. In addition, one patient experienced exfoliative dermatitis on two separate occasions from diltiazem and chloroquine. The authors14 suggested that a cross-reaction may exist between diltiazem and chloroquine because of their similar chemical structures. Although nifedipine and amlodipine are both dihydropyridines, cross-reaction between the two agents has not been reported.25 Therefore crossreactivity among diltiazem, verapamil, and nifedipine have not been reported. The mechanism of adverse reactions from diltiazem and other calcium channel blockers is unknown. Because the spectrum of cutaneous reactions is extensive, it is likely that the pathophysiology differs with each reaction. Patch testing4,7,11,26,27 or skin testing3,26 has been used as confirmatory testing in patients with extensive cutaneous reactions to diltiazem. After the information obtained from the HPB had been analyzed, nifedipine and verapamil were associated with significantly fewer eruptions than diltiazem. However, the percentage of serious cutaneous events was not statistically different between diltiazem, nifedipine, and verapamil. This is in contrast to a review of cutaneous reac-
Knowles, Gupta, and Shear 205 tions associated with the calcium channel blockers that were reported to the Food and Drug Administration during the period of 1978 to 1985.17 In this study, diltiazem was associated with a higher frequency of serious skin reactions (i.e., erythema multiforme, SJS, exfoliative dermatitis) than nifedipine or verapamil. However, as the authors suggested, these differences may simply reflect differences in spontaneous reporting rather than true differences in reaction rates. Not unexpectedly, the mean age of the patients who had a cutaneous reaction while receiving a calcium channel blocker was 65 years. The number of women who reported cutaneous events was higher than men (male/female ratio 1:1.8). This may simply reflect a bias in reporting, or may suggest that women are more predisposed to cutaneous events perhaps because of differences in pharmacokinetic or pharmacodynamic factors. We thank the Drugs Directorate, Health Protection Branch for providing data. The interpretation of the results does not reflect the opinions or policies of Health Canada. The reproduced information from the HPB is raw information and has not been scientifically verified. REFERENCES 1. Hedner T. Calcium channel blockers: spectrum of side effects and drug interactions. Acta Pharmacol Toxicol 1986;58 Suppl 2:119-30. 2. Recchia A, Shear N. Organization and functioning of an adverse drug reaction clinic. J Clin Pharmacol 1994;34: 68-79. 3. Hammentgen R, Lutz G, Kohler U, Nitsch J. Makulopapuloses exanthem bei diltiazem-therapie. Dtsch Med Wschr 1988;113:1283-5. 4. Sousa-Basto A, Azenha A, Duarte M, Pardal-Oliveira F. Generalized cutaneous reaction to diltiazem. Contact Dermatitis 1993;28:44-5. 5. Baker B, Cacchione J. Dermatologic cross-sensitivity between diltiazem and amlodipine. Ann Pharmacother 1994;28:118-9. 6. Wirebaugh S, Geraets D. Reports of erythematous macular skin eruptions associated with diltiazem therapy. DICP Ann Pharmacother 1990;24:1046-9. 7. Kitamura K, Kanasashi M, Suga C, Saito S, Yoshida S, Ikezawa Z. Cutaneous reactions induced by calcium channel blocker: high frequency of psoriasiform eruptions. J Dermatol 1993;20:279-86. 8. Lambert D, Dalac S, Beer F, Chavannet P, Portier H. Acute generalized exanthematous pustular dermatitis induced by diltiazem. Br J Dermatol 1988;118:308-9. 9. Janier M, Gerault M, Carlotti A, Vignon M, Daniel F. Acute generalized exanthematous pustulosis due to diltiazem. Br J Dermatol 1993;129:354-5. 10. Wittal R, Fischer G, Georgouras K, Baird P. Skin reactions to diltiazem. Australas J Dermatol 1992;33:11-8. 11. Wakelin S, James M. Diltiazem-induced acute gener-
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