Tamoxifen: uses, appearance and warnings

Metastatic Breast Cancer: Tamoxifen citrate tablets, USP are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy. Adjuvant Treatment of Breast Cancer: Tamoxifen citrate tablets, USP are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate tablets, USP are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial. Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer. Ductal Carcinoma in Situ (DCIS): In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Reduction in Breast Cancer Incidence in High Risk Women: Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label). Tamoxifen citrate tablets are indicated only 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 ≥1.67%, as calculated by the Gail Model. Examples of combinations of factors predicting a 5-year risk ≥1.67% are: Age 35 or older and any of the following combination of factors: One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or At least 2 first degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy; or LCIS Age 40 or older and any of the following combination of factors: One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. Age 45 or older and any of the following combination of factors: At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. …

Tamoxifen Citrate Tablets, USP are available as: 10 mg: Containing 15.2 mg tamoxifen citrate USP, an amount equivalent to 10 mg of tamoxifen. White, round, unscored, biconvex tablet. Debossed with "2232" on one side and " WPI " on the other side. Available in bottles of: Unit-of-use 60 Tablets NDC 0591-2472-60 Unit-of-use 180 Tablets NDC 0591-2472-18 20 mg: Containing 30.4 mg tamoxifen citrate USP, an amount equivalent to 20 mg of tamoxifen. White, round, unscored, biconvex tablet. Debossed with " 2233" on one side and " WPI" on the other side. Available in bottles of: Unit-of-use 30 Tablets NDC 0591-2473-30 Unit-of-use 90 Tablets NDC 0591-2473-19 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container. Keep this and all medications out of the reach of children. For more information about tamoxifen citrate, call 1-888-838-2872. Brands listed are the trademarks of their respective owners. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. B 5/2025

Tamoxifen citrate tablets are contraindicated in patients with known hypersensitivity to the drug or any of its ingredients. Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS: Tamoxifen citrate tablets are contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep-vein thrombosis or pulmonary embolus.

Effects in Metastatic Breast Cancer Patients: As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued. Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma: An increased incidence of uterine malignancies has been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥2 years) of tamoxifen citrate than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. In the NSABP P-1 trial, among participants randomized to tamoxifen there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27 to 4.92). The 33 cases in participants receiving tamoxifen were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on tamoxifen citrate and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR=4.50, 95% CI: 1.78 to 13.16). Among women ≤49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR=0.94, 95% CI: 0.28 to 2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants ≤49 randomized to tamoxifen compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4 to 12.0). For women ≥50 at the time of diagnosis, there were 29 cases among participants randomized to tamoxifen compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3 to 4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the tamoxifen group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen group occurred in asymptomatic women. Among women receiving tamoxifen the events appeared between 1 and 61 months (average=32 months) from the start of treatment. In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking tamoxifen. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. Of the patients receiving tamoxifen who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage IB cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Some patients received post-operative radiation therapy in addition to surgery. Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and 1 patient randomized to placebo (FIGO 1A); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the 1 patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in 5 other NSABP clinical trials. Any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received tamoxifen should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure. In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen to reduce the incidence of breast cancer would be beneficial. …

Adverse reactions to tamoxifen 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 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 and generally subside rapidly. …

When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended. In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (see CONTRAINDICATIONS ). There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen. Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. …