Drug Use Evaluation of Tamoxifen Focusing on Off-Label Use in a Managed Care Population in Israel

BACKGROUND: Policy development to manage new off-label uses of medications is an issue relevant to health policy stakeholders internationally. Retrospective drug utilization analyses may be useful to identify practice trends in the use of drugs for unapproved (off-label) uses. Since drug use evaluations (DUE) are generally performed for expensive medications or when safety concerns warrant increased scrutiny, patterns of off-label use of inexpensive drugs will probably be undetected. Tamoxifen citrate, an estrogen receptor antagonist, is indicated in Israel exclusively for palliative [sic: meaning adjuvant] treatment of breast cancer. This DUE was motivated by observations that tamoxifen may be used off-label for indications without evidence of safety or efficacy. OBJECTIVES: To assess the extent of off-label prescribing of tamoxifen and ascertain what evidence is available supporting the use of the drug for the off-label indications observed. METHODS: A retrospective DUE of tamoxifen was performed for the 12 months of calendar year 2008 in a 650,000-member HMO in Israel for patients who received at least 1 prescription for tamoxifen. All patients for whom tamoxifen was dispensed in 2008 were identified from pharmacy claims data. The HMOs electronic patient record (EPR) was subsequently queried to identify the diagnoses of patients who received tamoxifen and exclude those patients who had a diagnosis code (ICD-9-CM 174.x or 175.x) for breast cancer. An EPR chart review was also performed to identify and exclude patients who had a diagnosis or treatment of breast cancer that was recorded in free text. For the patients who did not have a diagnosis code or free-text description of breast cancer, the recorded off-label diagnoses and ICD-9-CM codes in the EPR during the visit when tamoxifen was first prescribed were tabulated. A literature search was conducted to collect information supporting the use of tamoxifen for the observed offlabel indications. We defined the use as "supported" if studies were found in PubMed, Cochrane database, or Micromedex that supported the clinical decision to use the drug for the off-label indication. RESULTS: 877 patients were treated with tamoxifen in 2008 of whom 826 (94.2%) had a diagnosis of breast cancer, and 51 patients (5.8%) received the drug from 41 physicians in 7 medical specialty categories for 25 different off-label diagnoses. Of these 25 diagnoses, 33 patients (64.7% of 51 patients with off-label use) received tamoxifen for 8 diagnoses that were associated with some evidence to support their off-label use. Malignant neoplasm of ovary (n = 13) and female infertility (n = 13) were the most commonly recorded indications with some evidence to support off-label use. Of the 13 women treated for infertility, 9 (69.2%) had been treated with clomiphene citrate prior to being treated with tamoxifen, suggesting that some physicians may be experimenting with tamoxifen as second-line treatment. CONCLUSIONS: Tamoxifen was found to be used off-label in only 5.8% of the patients who received the drug in 2008 in this HMO, and only 18 patients (2.1%) received tamoxifen for a diagnosis that did not have some supporting evidence of efficacy. Since off-label prescribing of tamoxifen was found to be relatively rare, this HMO did not impose a prior authorization requirement for this drug and instead added an edit in the EPR to block off-label prescribing by requiring the physician to register a diagnosis of breast cancer.