Eur J Clin Pharmacol (2005) 61: 467–469 DOI 10.1007/s00228-005-0954-1
SH O RT CO MM U N IC A T IO N
Elena Balları´ n Æ Luisa Iba´n˜ez Æ Jose´-Angel Herna´ndez Lluı´ s Force Æ Joan-Ramon Laporte
Cyanamide-induced aplastic anemia
Received: 28 January 2005 / Accepted: 4 May 2005 / Published online: 1 July 2005 Springer-Verlag 2005
Abstract Objective: To report a case of aplastic anemia in a patient treated with cyanamide, an alcohol-aversive drug. Case summary: A 67-year-old man was admitted to hospital because of fever and pancytopenia. He had taken cyanamide for 6 months as an alcohol deterrent. No other risk factors for aplastic anemia were identified by interviewing the patient using a structured validated questionnaire. The results of bone-marrow biopsy showed severe aplastic anemia. Cyanamide was discontinued and the patient was treated according to a prespecified treatment protocol. One year after hospital admission, the patient was completely recovered with no need of immunosuppressive therapy. An objective causality assessment revealed that an adverse drug reaction was probable. Discussion: As the efficacy of cyanamide has been questioned, due to the failure of various trials to show any benefit over placebo, its overall benefit/risk ratio should be reconsidered. The complete and rapid hematological recovery after discontinuation of the drug, and the absence of other factors that could explain the condition support the association of the present case of aplastic anemia with cyanamide. The mechanism remains unknown. Aplastic anemia is a rare but potentially serious adverse drug effect of cyanamide treatment. Conclusions: Given the poor evidence on the efficacy of cyanamide and the associated risk of aplastic anemia, its E. Balları´ n (&) Æ L. Iba´n˜ez Æ J.-R. Laporte Fundacio´ Institut Catala` de Farmacologia Servei de Farmacologia Clı´ nica, Hospital Universitari Vall d’Hebron Universitat Auto`noma de Barcelona, P Vall d’Hebron 129-139, 08035 Barcelona, Spain E-mail:
[email protected] Tel.: +34-93-489-4125 Fax: +34-93-489-4109 J.-A. Herna´ndez Hematology Department, Hospital de Mataro´, Mataro´, Spain L. Force Internal Medicine Department, Hospital de Mataro´, Mataro´, Spain
use in reducing alcohol consumption should be reconsidered. Keywords Cyanamide Æ Aplastic anemia Æ Pharmacovigilance Æ Adverse drug reaction
Introduction Cyanamide is an alcohol-sensitizing drug. Like disulfiram, it inhibits the liver enzyme aldehyde dehydrogenase (ALDH), causing an increase in blood acetaldehyde level after ethanol ingestion. Increased concentrations of acetaldehyde cause flushing, tachycardia, tachypnea, feeling of warmth, palpitations, and shortness of breath. Inhibition of ALDH is maximal 1–2 h after cyanamide administration and lasts up to 24 h. The severity and duration of symptoms depend on the dose of the drug and the amount of ethanol in the body. Cyanamide is approved in Austria, Ireland, and Spain. It is used as a conditioning method to help motivate alcoholics to give up drinking. Its efficacy is being questioned because several trials have failed to show any benefit over placebo [1–3]. Various adverse drug effects have been described, such as peripheral neuropathy [4], hepatocyte inclusion bodies [5], liver dysfunction [6], hypoxia with hypotension [7], agranulocytosis [8, 9], and aplastic anemia [10, 11]. We report a case of aplastic anemia in a patient treated with cyanamide.
Case report A 67-year-old man with a history of severe chronic alcoholism, lumbar sympathectomy, and chronic obstructive lung disease was admitted because of fever and pancytopenia. His blood count showed hemoglobin 92 g/l; platelets 114·109/l; leukocytes 0.72·109/l with neutrophil count 4 2
No No Salbutamol, ipratropium, budesonide
a b
Two episodes in the same patient, the second one after inadvertent rechallenge Present case
(PHN), and viral markers were negative. Bone-marrow biopsy revealed that cellularity was lower than 25% with predominance of lymphocytes and plasmatic cells. A diagnosis of severe aplastic anemia was made. He had been taking salbutamol, ipratropium bromide, and budesonide for years as regular medication. He had also taken cyanamide 120 mg/day as an alcoholaversive drug during the 6 months prior to hospital admission. He had not been exposed to pesticides, industrial solvents, or other environmental toxins. Cyanamide was discontinued, and the patient was treated with amikacin and amoxycillin plus clavulanate because of fever. Filgrastim (300 lg per day subcutaneously), cyclosporin A (5 mg/kg per day PO), and methylprednisolone (2 mg/kg per day PO) were initiated. Therapy with lymphoglobulin was not necessary because the blood count began to improve. He was discharged 10 days later. Doses of cyclosporin A and methylprednisolone were progressively tapered off, and the drugs were discontinued 2 months after the diagnosis of aplastic anemia. At 3 months, blood count was hemoglobin 131 g/l; platelets 212·109/l; and leukocytes 7.8·109/l with neutrophil count 4.9·109/l. One year after hospital admission, the patient had completely recovered with no need of immunosuppressive therapy.
Discussion In this case report, the temporal sequence of events—in particular the complete and rapid hematological recovery after discontinuation of the drug, and the lack of underlying concomitant diseases and of exposures to other drugs or chemicals known to be associated with aplastic anemia—supports the association with cyanamide. The patient had also taken salbutamol, ipratropium, and budesonide, which have not been associated with aplastic anemia or pancytopenia [12]. In addition, although these drugs were not discontinued, the patient’s condition improved. Application of the Naranjo probability scale [13] suggests that the causal relationship between exposure to cyanamide and aplastic anemia is probable. The case was reported to the Catalan Centre of Pharmacovigilance in Spain. A search in Medline 1966–2005 and in SIETES 1997– 2005 (Sistema de Informacio´n Esencial en Terape´utica y
Salud http://www.sietes.org, a database including more than 67,000 references related to clinical pharmacology and therapeutics, based on the manual systematic review of 150 medical journals) using the terms cyanamide, calcium carbimide, aplastic anemia, and pancytopenia identified two published case reports of cyanamide-induced aplastic anemia [10, 11]. They described a woman who suffered two episodes of aplastic anemia in an interval of 12 years (Table 1). Cyanamide treatment had only been associated with aplastic anemia in one patient [10, 11]. The Uppsala Database of the WHO International Programme for Drug Monitoring includes no cases of aplastic anemia in patients treated with cyanamide. Among the 222 cases of aplastic anemia assembled by the International Study on Agranulocytosis and Aplastic Anemia [14], no cases had been exposed to cyanamide. In the Barcelona Study, of 230 confirmed cases of aplastic anemia until June 2003, none had been exposed to cyanamide [15]. The dose of cyanamide taken by our patient was higher than the recommended dosage (the recommended dose of cyanamide in Spain is 36–75 mg/day). The duration of exposure ranged from 20 days to 6 months. However, the mechanism of this reaction remains unknown and therefore we do not know whether the amount of the drug taken could have had a role. Within a few weeks after the diagnoses, recovery occurred in all three episodes. This supports a causal relationship between exposure to cyanamide and aplastic anemia. We did not find any robust evidence on the efficacy of cyanamide. It has been evaluated in several small size and short-term clinical trials [16–21]. The clinical trial with the greatest number of patients was a 4-month, doubleblind, cross-over study in which no differences between the placebo and cyanamide-treated patients were seen [1].
Conclusion Our case report adds to the existing evidence supporting a causal relationship between the use of cyanamide and aplastic anemia. Unfortunately, the available evidence does not enable calculating a risk. This risk of uncertain magnitude compares with unproven efficacy of the drug, and hence its use in alcohol dependence should be avoided.
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