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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 8134-8136 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.5881
Incidence of Cancer in Individuals Receiving Chronic Zopiclone or Eszopiclone Requires Prospective StudyDepartment of Oncology, HIV Medicine, and Immunology, The Chelsea & Westminster Hospital, London, United Kingdom To the Editor: Although initially promoted as superior to benzodiazepines in terms of daytime sedation, dependence, and withdrawal, zopiclone, eszopiclone, zolpidem, and zalepon, the so-called non-benzodiazepine Z drugs, have not demonstrated consistent benefits over benzodiazepines for either effectiveness or safety.1-3 Zopiclone, a cyclopyrrolone, has been prescribed and routinely available in the United Kingdom since 1989. In December 2004, its S-(+)-enantiomer eszopiclone was approved by the United States Food and Drug Administration with a chronic use label that included reducing sleep latency and improving sleep maintenance. Interestingly, a large section of the label was devoted to discussion of carcinogenicity and mutagenesis.4 The label reported that in a carcinogenicity study in Sprague-Dawley rats in which racemic zopiclone or high-dose eszopiclone was given in the diet, an increase in mammary-gland adenocarcinomas in females and an increase in thyroid-gland follicular-cell adenomas and carcinomas in males were seen, at the highest dose of 100 mg/kg/d. While this is considerably above a typical human daily dose, the mechanism for this increase in mammary tumors is unknown. The thyroid tumors are thought to increase levels of thyroid stimulating hormone via a mechanism not thought to be relevant to humans. In a carcinogenicity study in B6C3F1 mice, in which racemic zopiclone was given in the diet, an increase in pulmonary carcinomas and adenomas, skin fibromas, and sarcomas were observed, though once again, the relevance to humans of these data are questioned. In addition, eszopiclone was positive in mice lymphoma chromosomal aberration assays and a metabolite was positive in the Chinese hamster ovary cell and human lymphocyte chromosomal aberration assays. To further investigate this, we studied the incidence of cancer following a prescription for zopiclone, in patients infected with HIV type 1 (HIV-1). Since 1989, a total of 9,035 HIV-1 infected individuals have been followed at the Chelsea and Westminster Hospital. Of these, 1,513 (16.7%) have been diagnosed with any cancer, the incidence of which was significantly higher in the pre-highly active antiretroviral therapy (HAART) attenders (Table 1). HAART has reduced the incidence of cancer by suppressing HIV viremia and improving immune parameters.5,6
From the entire cohort, 606 individuals (6.7%) have been prescribed at least 2 weeks of zopiclone. A total of 32 (5.3%) of these patients have subsequently been diagnosed with cancer at least 3 months after exposure to zopiclone and of these, 11 were diagnosed during the HAART era. The cancers were Kaposi's sarcoma (n = 19) and non-Hodgkin's lymphoma (n = 10), as expected for an HIV positive cohort. In addition, there was one case of each of primary cerebral lymphoma, invasive anal carcinoma, and disseminated non–small-cell lung cancer with a highly unusual case of direct pericardial infiltration, which led to the patient's death. This 57-year old man, a smoker, had a CD4 count of 415 cells/mm3, an HIV-1 viral load of 7390 copies/mL, no prior AIDS defining illnesses, and was receiving zidovudine plus lamivudine and nevirapine. He rapidly developed a T4N2M0 (pericardial effusion) tumor and received supportive care only (performance status of 4). As expected, the incidence of cancer per 1,000 patient years increases with lower CD4 counts (rate ratio of 1.57; 95% CI 1.33 to 1.84; P < .001; Table 2) and results are similar when the pre- and post-HAART attenders are separated.
Recent events concerning drug safety have culminated in the withdrawal of rofecoxib (Vioxx) and antegren (Tysabri) from the market in North America.7,8 Such occurrences have highlighted the requirement for stringent regulation concerning the safety of drugs, and the separation of organizations that oversee safety from those that approve new medications. This assumes increased importance when the drug is to be used in the primary care setting and chronic exposure to millions of individuals may occur and the disease to be treated is not life threatening (sleep can be considered a derivative of a disease, not a disease itself9). We describe a small uncontrolled data set in which 32 cancers have occurred following prescription of zopiclone to 606 HIV-1 infected individuals. While these data are uncontrolled, the label for eszopiclone contains significant warnings regarding carciginogenicity and mutagenesis. While many zopiclone prescriptions may have been written in the community and not recorded in our database (thus we may have underestimated the true effect of the drug), we suggest that further studies be undertaken to prospectively identify drug associated problems in individuals at risk. As cancers in immunocompetent people may take decades to develop,10 this work highlights an important avenue of future prospective research. Author's Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Holbrook AM, Crowther R, Lotter A, et al: Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 162:225-233, 2000 2. Busto UE, Sproule BA, Knight K, et al: Use of prescription and nonprescription hypnotics in a Canadian elderly population. Can J Clin Pharmacol 8:213-221, 2001[Medline]
3. Wagner AK, Zhang F, Soumerai SB, et al: Benzodiazepine use and hip fractures in the elderly: Who is at greatest risk? Arch Intern Med 164:1567-1572, 2004 4. www.sepracor.com: Label for eszopiclone (Lunesta). Sepracor, Marlborough, MA 5. Portsmouth S, Stebbing J, Gill J, et al: A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. Aids 17:F17-22, 2003[CrossRef][Medline]
6. Stebbing J, Gazzard B, Mandalia S, et al: Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 22:2177-2183, 2004
7. Psaty BM, Furberg CD: COX-2 inhibitors–lessons in drug safety. N Engl J Med 352:1133-1135, 2005
8. Okie S: What ails the FDA? N Engl J Med 352:1063-1066, 2005 9. Edinger JD, Fins AI, Glenn DM, et al: Insomnia and the eye of the beholder: Are there clinical markers of objective sleep disturbances among adults with and without insomnia complaints? J Consult Clin Psychol 68:586-593, 2000[CrossRef][Medline] 10. Stebbing J, Bower M: What can oncologists learn from HIV? Lancet Oncol 4:438-445, 2003[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
