|FDA Approved For:
|Metastatic Breast Cancer: Tamoxifen citrate is effective in the treatment of metastatic breast cancer in women and men… Adjuvant Treatment of Breast Cancer: Tamoxifen citrate is indicated for the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation…Tamoxifen citrate is indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation…Tamoxifen citrate is indicated to reduce the incidence of breast cancer in women at high risk for breast cancer…Tamoxifen citrate is indicated for high-risk women. "High risk" is defined as women at least 35 years of age with a 5-year predicted risk of breast cancer ³1.67%, as calculated by the Gail Model.
|The safety and efficacy of tamoxifen citrate in pediatric patients have not been established.
|A conventional carcinogenesis study in rats (doses of 5, 20, and 35 mg/kg/day for up to 2 years) revealed hepatocellular carcinoma at all doses, and the incidence of these tumors was significantly greater among rats given 20 or 35 mg/kg/day (69%) than those given 5 mg/kg/day (14%). The incidence of these tumors in rats given 5 mg/kg/day (29.5 mg/m2) was significantly greater than in controls. In addition, preliminary data from two independent reports of 6-month studies in rats reveal liver tumors which in one study are classified as malignant. (See WARNINGS .) Endocrine changes in immature and mature mice were investigated in a 13-month study. Granulosa cell ovarian tumors and interstitial cell testicular tumors were found in mice receiving tamoxifen citrate, but not in the controls.
|Although no genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems present, increased levels of DNA adducts have been found in the livers of rats exposed to tamoxifen. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells.
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Adverse reactions to tamoxifen citrate are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients. Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen citrate as compared to placebo. Metastatic Breast Cancer Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen citrate and generally subside rapidly. In patients treated with tamoxifen citrate for metastatic breast cancer, the most frequent adverse reaction to tamoxifen citrate is hot flashes. Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial hair loss, and vaginal dryness. Premenopausal Women TABLE 4 summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared tamoxifen citrate therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. (See Table) Male Breast Cancer Tamoxifen citrate is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of tamoxifen citrate in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported. Adjuvant Breast Cancer In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen citrate 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated in TABLE 5 (mean follow-up of approximately 6.8 years) showing adverse events more common on tamoxifen citrate than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with tamoxifen citrate compared with placebo. All other adverse effects occurred with similar frequency in the two treatment groups, with the exception of thrombotic events, a higher incidence was seen in tamoxifen citrate-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen citrate who had thrombotic events died. (See Table) In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen citrate or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen citrate showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the two treatment groups with the exception of thrombocytopenia where the incidence for tamoxifen citrate was 10% vs. 3% for placebo, an observation of borderline statistical significance. In other adjuvant studies, Toronto and Nolvadex Adjuvant Trial Organization (NATO), women received either tamoxifen citrate or no therapy. In the Toronto study, hot flashes were observed in 29% for tamoxifen citrate versus 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen citrate versus 0.2% for each in the untreated group. Reduction in Breast Cancer Incidence in High Risk Women In the NSABP P-1 Trial, there was an increase in five serious adverse affects in the tamoxifen citrate group: endometrial cancer (33 cases in the tamoxifen citrate group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen citrate group vs. six in the placebo group); deep vein thrombosis (30 cases in the tamoxifen citrate group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen citrate vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen citrate group vs. 483 in the placebo group) and cataract surgery (101 cases in the tamoxifen citrate group vs. 63 in the placebo group) (see WARNINGS and TABLE 2). TABLE 6 presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse events more common on tamoxifen citrate than placebo are shown. (See Table) In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen citrate and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from tamoxifen citrate and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%). In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving tamoxifen citrate and placebo therapy, respectively, withdrew for non-medical reasons. On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on tamoxifen citrate. Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen citrate. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen citrate respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms. Postmarketing Experience Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities and skin rash. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome and bullous pemphigoid have been reported with tamoxifen citrate therapy. )More Information