Clinical use and control of the dispensing of thalidomide in Brasilia-Federal District, Brazil, from 2001 to 2012.

The use of thalidomide was never discontinued in Brazil where it is prescribed for leprosy type 2 reaction. Babies with birth defects compatible with the thalidomide embryopathy phenotype were born after 1965, an indication that control on drug dispensing and use failed in the country. The article reports data on thalidomide dispensing and clinical uses in the Federal District in 2011/12, when new rules were put into effect, and data on drug dispensing and use obtained ten years earlier. It was found that the number of patients making use of thalidomide declined from 819 in 2001 to 369 in 2011/12. Leprosy accounted for over 70% of prescriptions in both time periods analyzed in this study. In the same time interval, however, use for lupus erythematosus decreased from 13.7 to 4.9%, while that for multiple myeloma increased from 2.9 to 20.3% of all prescriptions. Thalidomide prescription for the remaining approved indications was far less frequent, and so was the use for off label indications that accounted for <1% of prescriptions in 2001 and 2011/12. Registration of prescribing doctors, patients and dispensing units at the state department of health, apparently rendered this control more effective and reliable.

Clinical use and control of the dispensing of thalidomide in Brasilia-Federal District, Brazil, from 2001 to 2012 / Uso clínico e controle sobre a dispensação de talidomida em Brasília-DF, Brasil, de 2001 a 2012

The use of thalidomide was never discontinued in Brazil where it is prescribed for leprosy type 2 reaction. Babies with birth defects compatible with the thalidomide embryopathy phenotype were born after 1965, an indication that control on drug dispensing and use failed in the country. The article reports data on thalidomide dispensing and clinical uses in the Federal District in 2011/12, when new rules were put into effect, and data on drug dispensing and use obtained ten years earlier. It was found that the number of patients making use of thalidomide declined from 819 in 2001 to 369 in 2011/12. Leprosy accounted for over 70% of prescriptions in both time periods analyzed in this study. In the same time interval, however, use for lupus erythematosus decreased from 13.7 to 4.9%, while that for multiple myeloma increased from 2.9 to 20.3% of all prescriptions. Thalidomide prescription for the remaining approved indications was far less frequent, and so was the use for off label indications that accounted for <1% of prescriptions in 2001 and 2011/12. Registration of prescribing doctors, patients and dispensing units at the state department of health, apparently rendered this control more effective and reliable.

O uso da talidomida nunca foi interrompido no Brasil, sendo prescrita para tratar a reação tipo 2 da hanseníase. Crianças com defeitos congênitos compatíveis com o fenótipo da embriopatia causada pela talidomida nasceram após 1965, evidenciando que o controle do uso e da dispensação do medicamento falhou no país. O artigo relata dados sobre a dispensação e usos clínicos da talidomida no Distrito Federal em 2011/12, quando a nova regulamentação passou a vigorar, e dados sobre a dispensação e uso do medicamento 10 anos antes. Os resultados mostraram que o número de pacientes que usaram talidomida decresceu de 819 em 2001 para 369 em 2011/12. A hanseníase foi a indicação clínica para mais de 70% das prescrições nos períodos analisados no estudo. No mesmo período, entretanto, o uso para lupus eritematoso reduziu de 13,7 para 4,9%, enquanto o uso para mieloma múltiplo cresceu de 2.9 para 20,3% de todas as prescrições. A prescrição de talidomida para as outras indicações aprovadas foi muito menor, enquanto para indicações não aprovadas correspondeu a < 1% das prescrições em 2001 e 2011/12. O cadastro dos prescritores, pacientes e unidades dispensadoras na secretaria estadual de saúde, aparentemente tornou esse controle mais eficiente e confiável.

Thalidomide use in the US : experience with pregnancy testing in the S.T.E.P.S. programme.

INTRODUCTION: In 1998, thalidomide (Thalomid), a known human teratogen, was approved by the US FDA for the treatment of erythema nodosum leprosum. To prevent fetal exposure to thalidomide, a restricted distribution risk management programme, the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.), was implemented. All clinicians, pharmacists and patients who prescribe, dispense and receive thalidomide, respectively, are required to enroll in S.T.E.P.S. Sexually active females of childbearing potential must use two methods of birth control before, during and after treatment. These patients must also have a negative pregnancy test within 24 hours before beginning therapy and periodically while on therapy. The objective of this report is to summarise the patterns of thalidomide use and to describe the occurrence of positive pregnancy tests in females of childbearing potential while they were using thalidomide in the S.T.E.P.S. programme in the US. STUDY DESIGN/METHODS: A retrospective review of patients receiving thalidomide within the S.T.E.P.S. programme from September 1998 to 31 December 2004 to determine the occurrence of positive pregnancy tests whilst on treatment. RESULTS: Approximately 124,000 (43% female) patients were registered within the S.T.E.P.S. programme between September 1998 and 31 December 2004. Approximately 6,000 patients were females of childbearing potential, representing 5% of all patients and 11% of all female patients. Between 30 July 2001 and 31 December 2004, >88% of thalidomide use was for oncological conditions. There were 72 females of childbearing potential who had positive pregnancy tests. Sixty-nine of these patients had false positive pregnancy tests. Of the remaining three, one woman was pregnant while on thalidomide. This patient had an initial negative test and received thalidomide. Therapy was stopped when she had a positive pregnancy test. This pregnancy resulted in a miscarriage. Two additional patients were determined to be pregnant before receiving thalidomide. CONCLUSIONS: The S.T.E.P.S. programme is critical to managing the risks of thalidomide-associated teratogenicity. Sustained vigilance among health care providers and patients receiving thalidomide is essential to its continued success. Health care providers should be aware of the occurrence of false-positive pregnancy tests in females of childbearing potential receiving thalidomide.

Thalidomide: 40 years on.

Thalidomide was marketed in the late-1950s as a sedative and tranquilliser of exceptionally low general toxicity, but in 1961 it was implicated separately by Lenz and MacBride as the cause of the epidemic of congenital malformations that had been puzzling the world for some years. It is a very potent teratogen in humans, but in few other mammalian species; damage to the embryo is produced at specific stages of gestation, but the mechanism of embryopathic action is still not understood. Following the withdrawal of the drug worldwide, it was consigned to the history of medical tragedies. In 1965, however, Sheskin discovered that it was effective in treating erythema nodosum leprosum, a distressing complication of leprosy. As the drug is neither an antibiotic nor an analgesic, its action was assumed to be immunosuppressive. In Brazil the drug was used widely with few regulatory controls, since when more than 100 cases of congenital malformation have appeared. Sheskin's discovery led to the experimental use of thalidomide in many other indications thought to possess some immunological component. In some cases, e.g. Behçet's syndrome, graft-versus-host disease and aphthous ulceration in HIV-positive patients, the drug has been shown to possess some efficacy. And there is some evidence that it inhibits the replication of one of the immunodeficiency viruses. The AIDS community in the US has exerted much pressure on the FDA to allow the drug on to the market, although the use of a potent immunosuppressive drug of unknown mechanism in an immunodeficiency condition raises further questions. Thalidomide is not always beneficial; its use is associated with an increased mortality in epidermal necrolysis. In 1991, D'Amato confirmed it possessed antiangiogenic properties and this led to further trials in malignant conditions. Results were mixed, but those in multiple myeloma gave some grounds for optimism. In 1998, the FDA announced its extraordinary decision to grant marketing approval for thalidomide.

S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide.

In July 1998, the US Food and Drug Administration approved the marketing of thalidomide for the treatment of cutaneous manifestations of erythema nodosum leprosum. To ensure that fetal exposure to this teratogenic agent does not occur, the manufacturer has instituted a comprehensive program to control prescribing, dispensing, and use of the drug. This program, known as the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S. [Celgene Corporation, Warren, New Jersey]), is based in part on experience gained with other drugs--specifically isotretinoin and clozapine--that offer important clinical benefits but carry the potential for serious harm. To achieve its goal of the lowest possible incidence of drug-associated teratogenicity, the S.T.E.P.S. program uses a three-pronged approach: (1) controlling access to the drug; (2) educating prescribers, pharmacists, and patients; and (3) monitoring compliance. Clinicians who wish to prescribe thalidomide must be registered in the S.T.E.P.S. Prescriber Registry and agree to prescribe the drug in accordance with S.T.E.P.S. patient eligibility criteria and monitoring procedures. Pharmacies must also register and agree to comply with patient identification and monitoring criteria. Finally, patients receive visual aids, including a videotape, written material, and verbal counseling about the benefits and risks of thalidomide therapy, the importance of not becoming pregnant during therapy, and the types of contraception required (including emergency contraception) and their availability. Women of childbearing potential must agree to undergo pregnancy testing before starting therapy and on a regular schedule during therapy. All patients must agree to complete a confidential survey about their compliance with contraception, testing, and drug therapy. The manufacturer is monitoring survey results and outcome data and is prepared to make whatever modifications to the S.T.E.P.S. program are necessary to ensure its effectiveness. In addition to minimizing the potential risk for fetal harm associated with thalidomide therapy, the S.T.E.P.S. program may provide a model for future cases in which a drug offers compelling benefits but poses profound risks unless its distribution is carefully controlled.

[Thalidomide once more in the spotlight]. / Thalidomide opnieuw in de belangstelling.

Thalidomide was withdrawn from the market in the early sixties because of major teratogenic effects such as reduction defects of the limbs. Since, however, it has been found to be an effective drug in erythema nodosum leprosum. In the United States it was decided in September 1997 to admit thalidomide to the market for this indication, and in South America it has been available for this indication all the time. Thalidomide is also efficacious in other major disorders (e.g. aphtae and ulcers in aids) or its efficacy is being investigated in clinical trials (e.g. autoimmune diseases, other complications in aids). The American Food and Drug Administration has imposed conditions for the use of thalidomide. Users have to sign an informed consent and to take adequate contraceptive measures. Physicians should inform the patients and monitor side effects. Pharmacists should record and control the use.