Toxic epidermal necrolysis after fluvoxamine

under placental dysfunction, the resulting cortisol and attenuated total body 11&bgr;OHSD may lead to adult hypertension synergistically.

fetal hippocampus hypersecretion of

Kitaro Oka, Toshihiko

Hirano, Masato Homma

Department of Clinical Pharmacology, Tokyo College of Pharmacy, Hachioji, Tokyo 192-03, Japan

Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CRW. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 1993; 341: 339-41. Edwards CRW, Benediktsson R, Lindsay RS, Seckle JR. Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertenson? Lancet 1993; 341: 355-57. Funder JW. Mineralocorticoids, glucocorticoids, receptors and response elements. Science 1993; 259: 1132-33. Walker BR, Campbell JC, Fraser R, Stewart PM, Edwards CRW. Mineralocorticoid excess and inhibition of 11 &bgr;-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol 1992; 37: 483-92. Greene MF, Fend MM, Tulchinsky D. Biochemical aspects of pregnancy. In: Tietz NW, ed. Textbook of clinical chemistry. Philadelphia: Saunders, 1986. Barker DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ 1990; 301: 259-62. Meaney MJ, Aitken DH, Van Berkel C, Bhatnagar S, Sapolsky RM. Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 1988; 239: 766-68. Raff MC. Social controls on cell survival and cell death. Nature 1992; 356: 397-400. Williams GT. Programmed cell death: apoptosis and oncogenesis. Cell

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1991; 65: 1097-98.

Captopril-induced taste disturbance SIR—Zazgornik and colleagues (June 12, p 1542) report a case of captopril-induced dysgeusia. In Australia, the adverse drug reactions section of the Therapeutic Goods Administration receives voluntary reports of suspected adverse reactions to drugs forwarded by general practitioners, hospital staff, pharmacists, dentists, and other health professionals. These reports are reviewed by the Adverse Drug Reactions Advisory Committee (ADRAC), a subcommittee of the Australian Drug Evaluation Committee. Captopril is the most commonly reported suspected drug in association with taste disturbance. Of 279 reports of taste disturbance, 47 concerned captopril, and of the 116 reports of taste loss, captopril was suspected in 59. Overall, there have been 102 reports of taste disturbance in association with captopril, which includes 4 reports in which loss of taste was preceded by dysgeusia. For captopril, taste loss is more commonly reported in Australia than taste disturbance. Of those 28 reports in which the nature of the taste disturbance was specified, the most common descriptions were offensive or foul (8 reports), salty (6), metallic (6), reduced flavour (4), and by contrast with Zazgornik’s case, 3 reports described a reduction in the taste of sweet foods. In those for which the information was available, all but one patient recovered on cessation of the drug. In this one case, dysgeusia was still partly present after 10 months. Most patients (83%) were receiving daily doses of 50 mg or more. Taste loss also seems dose related, with 91 % of the reports detailing a daily dose of 50 mg or more. Most of these patients recovered on cessation of captopril, although in one case the sense of taste has not returned 7 months after discontinuation. In 2 of these reports anosmia was also documented. Although taste disturbance is not usually a serious reaction, it is one that can affect the quality of life of patients and influence compliance. Ian

Boyd

Adverse Drug Reactions Section, Drug Evaluation Branch, Therapeutic Goods Administration, Woden ACT 2606, Australia

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Filgrastim for low-dose, captopril-induced agranulocytosis SiR-Wyatt and colleagues (June 5, p 1476) report a patient with drug-induced neutropenia treated with filgrastim (recombinant human granulocyte-colony-stimulating factor), who subsequently died. We describe a patient with agranulocytosis induced by low-dose captopril (37.5mg daily) whose treatment with filgrastim was successful. A 76-year-old man with paroxysmal atrial fibrillation, congestive cardiac failure, and polymyalgia rheumatica was admitted as an emergency with fever. No clinically significant abnormalities were detected. His haemoglobin was 13-3 g/dL, platelets 476 x 109/L, and white blood cell count 1-1x109/L, with predominantly lymphocytes and no neutrophils. Renal and liver function tests were normal. Six weeks before admission, captopril 12-5 mg thrice daily was started for heart failure. Full blood count at that time was normal, with a white blood cell count of 11 x 109/L and neutrophils 65 x 109/L. He had been on prednisolone 10 mg once daily, frusemide 80 mg once daily, and amiodarone 200 mg once daily for over a year. Bone marrow aspirate showed striking left-shifted granulopoeisis with little maturation beyond the myelocyte stage. Captopril was stopped and the patient was started on subcutaneous filgrastim 300 µg daily. Neutrophil recovery was evident within 12 h (neutrophils 0,6 x 109/L, rising to 5.1 x 109/L by 48 h) Filgrastim was stopped. The neutrophil count peaked at 18-2 x 109/L and returned to normal within 4 days. Neutrophils remain normal 6 months after discharge. Neutropenia and agranulocytosis associated with captopril therapy typically occur within 3-12 weeks of the start of treatment. Although the neutrophil count usually returns to normal within 3 weeks of discontinuing the drug, there have been several reported deaths from septicaemia.1,2 The use of filgrastim in accelerating neutrophil recovery has been reported in agranulocytosis induced by chemotherapy,3 analgesics,4 and antibiotics.5 Such treatment may avoid morbidity and mortality in drug-induced agranulocytosis. Hendrick M Chia, Lalit Kalra, Anil K Lakhani, Ilanga R Samaratunga Department of Medicine for Elderly People, Hospital, Orpington, Kent BR6 9JU, UK

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Department of Haematology, Orpington

Captopril-associated agranulocytosis. S Afr Med J 1991; 79: 399-400. Suarex M Lye PW, Johnson ES, Perez G. Angioneurotic oedema, agranulocytosis, and fatal septicaemia following captopril therapy. Am J Med 1986; 81: 336-38. Morstyn G, Campbell L, Souza LM, et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1988; i: 667-72. Muroi K, Ito M, Sasaki R, et al. Treatment of drug induced agranulocytosis with granulocyte colony stimulating factor. Lancet Pillans PI, Koopowitz A.

1989; ii: 55. Patton WN, Holyoake TL, Yates JM, et al. Accelerated recovery from drug induced agranulocytosis following G-CSF therapy. Br J Haem 1992; 80: 564-65.

Toxic

epidermal necrolysis after fluvoxamine

SIR—Fluvoxamine is a second-generation antidepressant which has been available in France since 1986. It is supposed to be safe and well tolerated. In a recent review of 24 624 patients no unexpected serious adverse events were identified.’ We report a patient who developed severe toxic epidermal necrolysis (TEN) after starting fluvoxamine. A 16-year-old girl with no family history of skin disease was in hospital for depression. Clomipramine 100 mg daily and

clorazepate 50 mg daily were prescribed. Metoclopramide was given once. A week later clomipramine was withdrawn and

replaced by fluvoxamine 100 mg daily. Within 8 days of starting fluvoxamine, she developed a widespread bullous eruption with membrane involvement. Two days later she had epidermal detachment of the trunk, face, and proximal limbs involving 30% of body surface area. Nikolsky’s sign was positive over large areas. Painful oral, ocular, and genital erosions were present. The temperature was 40.2°C. She rapidly developed severe dyspnoea requiring mechanical ventilation. Bronchoscopy confirmed destruction of the tracheal and bronchial epithelium. At this time epidermal detachment involved 60% of body surface area. After 5 weeks of multiple septic complications, she was discharged. Histological examination of the skin showed total necrosis of the epidermis typical of TEN. Indirect and direct immunofluorescence was negative. Investigations for viruses and Mycoplasma pneumoniae eliminated infection-induced TEN. According to the standards of the French drug surveillance system, clorazepate, clomipramine, and fluvoxamine could be culpable. Metoclopramide was taken once, so was excluded. Clorazepate and clomipramine have been available for prescription since the 1960s, and have never been implicated as TEN inducers.2 Since 1986, one case of Stevens-Johnson syndrome was reported to the French drug surveillance system, possibly due to fluvoxamine. Thus, to our knowledge, we report the first case of TEN observed after mucous

fluvoxamine treatment.

Second-generation antidepressant drugs, especially serotonin-reuptake inhibitors, are supposed to be safe. Nevertheless one case of TEN and one case of Stevens-Johnosn syndrome with fluoxetine have been reported3—serious side effects may be rare but potentially very severe. P Wolkenstein, J Revuz Department of Dermatology, Hôpital Henri-Mondor, University of Paris XII, 94010 Créteil, France

J L Diehl, O Langeron, E Roupie Intensive Care Unit,

Hôpital Henri-Mondor

L Machet Department of Dermatology, Hôpital Trousseau, Tours

1 Wagner W, Plekkenpol B, Gray TE, Vlaskamp H, Essers H. Review of fluvoxamine safety database. Drugs 1992; 43: 48-54. 2 Srebrnik A, Hes JP, Brenner S. Adverse cutaneous reactions to psychotropic drugs. Acta Derm Ven 1991; 71: 3-12. 3 Bodokh I, Lacour Ph, Rosenthal E, et al. Syndrome de Lyell ou nécrolyse épidermique toxique et syndrome de Stevens-Johnson après traitement par fluoxétine. Thérapie 1992; 47: 441.

Premenopausal oopherectomy versus CMF chemotherapy In stage II breast carcinoma SIR—The Scottish trial (May 22, p 1293) raises several issues. First, the information provided about the doses of cyclophosphamide/methotrexate/5-fluorouracil (CMF) received is important to judge whether the dose intensity of drug delivered would meet present standards of chemotherapy. The CMF combination given on day 1 of each 21-day course is inferior toa

day 1 and day 8 administration of a 28-day course in advanced breast cancer. In the adjuvant setting, reduced cytotoxic dose is detrimental for treatment outcome.2 The actual dose of cytotoxics received by the patients (not merely the protocolspecified dose) should be reported with the results. We are concerned that the doses received might have been suboptimum because the trial recruited 332 patients between 1980 and 1992, and the investigators were willing to offer oophorectomy instead of CMF to their patients, probably to avoid drug side-effects. Second, the data suggest that adding prednisolone to CMF increases the chance of receiving higher doses of drug (because

of less

myelosuppression), but decreases the efficacy of CMF, especially among women with oestrogen-receptor-negative primaries who are most likely to benefit from chemotherapy. The International Breast Cancer Study Group (IBCSG: formerly Ludwig group) has recorded a similar modest antagonistic effect of adding continuous low-dose prednisolone to CMF in a trial of 491 premenopausal women with 1-3 positive axillary lymph nodes. The CMF dose schedule was day 1 and day 8 every 28 days, as first described by Bonnadonna; on average, 83% of the full CMF dose in cycles one to six was received by CMF/prednisolone-treated patients compared with 72% for CMF-treated patients (p=0-001).3 At 12 years’ median follow-up, the 12-year disease-free survival probabilities are 51 % for the CMF/prednisolone group compared with 55% for the CMF group (relative risk [RR], 1 13, 95% CI, 087-146; p=0-36), and the 12-year overall survival probabilities are 62% and 67%, respectively (RR 1-17, 95% CI, 0 87-1 58, p = 0 29). The issue of adding prednisolone to cytotoxics in the adjuvant setting remains controversial. Although trials in advanced disease favour the use of prednisolone, the IBCSG triaP in premenopausal patients clearly demonstrated an excess of delayed appearance of bone relapses in the groups treated with CMF plus prednisolone. Such an adverse effect of prednisolone added to chemotherapy could possibly be prevented by oophorectomy,4 which might be the reason for a positive effect of ovarian ablation in patients also receiving prednisolone.s Third, The Early Breast Cancer Trialists’ Collaborative Group overview6 showed that combined chemoendocrine therapy is probably better than either treatment alone. This finding makes trials that compare multiagent cytotoxic therapy ’

ovarian ablation alone in an attempt to search for the best less important than defining the optimum role for the combination. The Scottish trial, which took 12 years to recruit 332 patients, illustrates both the difficulty and importance of conducting trials of ovarian ablation. The IBCSG has a continuing trial (trial VIII) in premenopausal women with node-negative disease, comparing CMF for six cycles versus GnRH analogue (Zoladex) for 2 years versus the combination of CMF for six cycles followed by Zoladex for 18 months. 303 patients have been enrolled since 1988, and the target sample size is 1200 patients. The IBCSG invites other groups with a proven record of excellence in clinical trial conduct to participate as subunits in this very important study. to

treatment

R D Gelber, A Goldhirsch, M Castiglione, C-M Rudenstram, J Collins, H-J Senn on behalf of The International Breast Cancer Study Group (IBCSG) IBCSG, Konsumstrasse 13, Bern CH-3010, Switzerland

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Engelsman E, Klijn JC, Rubens RD, Wildiers J, Beex LV, Nooij MA. "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. Eur J Cancer 1991; 27: 966-70. Budman DR, Wood W, Henderson IC, et al. Initial findings of CALGB 8541: a dose and dose intensity trial of cyclophosphamide (C), doxorubicin (A), and 5-fluorouracil (F) as adjuvant treatment of stage II, node+, female breast cancer. Proc ASCO (May 17-19) 1992: abstr 29: 51.

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Ludwig Breast Cancer Study Group. A randomized trial of adjuvant combination chemotherapy with or without prednisone in premenopausal breast cancer patients with metastases in one to three axillary lymph nodes. Cancer Res 1985; 45: 4454-59. The International Breast Cancer Study Group. Late effects of adjuvant oophorectomy and chemotherapy upon pre-menopausal breast cancer patients. Ann Oncol 1990; 1: 30-35. Meakin JW, Allt WEC, Beale FA, et al. Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast. Can Med Assoc J 1979; 120: 1221-31. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000

women.

Lancet 1992; 339: 1-15; 71-85.

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