Generic Name: TAMOXIFEN CITRATE
Brand Name: Tamoxifen Citrate
- Substance Name(s):
- TAMOXIFEN CITRATE
WARNINGS
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 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 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 postoperative 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. Non-Malignant Effects on the Uterus An increased incidence of endometrial changes including hyperplasia and polyps has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of tamoxifen. There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen. The underlying mechanism may be due to the partial estrogenic effect of tamoxifen. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen. Tamoxifen has been reported to cause menstrual irregularity or amenorrhea. Thromboembolic Effects of Tamoxifen There is evidence of an increased incidence of thromboembolic events, including deep-vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of tamoxifen should be carefully considered in women with a history of thromboembolic events. In a small substudy (N = 81) of the NSABP-1 trial, there appeared to be no benefit to screening women for Factor V Leiden and Prothrombin mutations G20210A as a means to identify those who may not be appropriate candidates for tamoxifen therapy. Data from the NSABP P-1 trial show that participants receiving tamoxifen without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18 tamoxifen, 6 placebo; RR = 3.01, 95% CI: 1.15 to 9.27). Three of the pulmonary emboli, all in the tamoxifen arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age at randomization. Among women receiving tamoxifen, the events appeared between 2 and 60 months (average = 27 months) from the start of treatment. In this same population, a non-statistically significant increase in deep-vein thrombosis (DVT) was seen in the tamoxifen group (30-tamoxifen, 19-placebo; RR = 1.59, 95% CI: 0.86 to 2.98). The same increase in relative risk was seen in women ≤ 49 and in women ≥ 50, although fewer events occurred in younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women on placebo, 5 out of 48 women on tamoxifen) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen). Among women receiving tamoxifen, deep-vein thrombosis events occurred between 2 and 57 months (average = 19 months) from the start of treatment. There was a non-statistically significant increase in stroke among patients randomized to tamoxifen (24 placebo; 34 tamoxifen; RR = 1.42, 95% CI: 0.82 to 2.51). Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen group were categorized as hemorrhagic. Seventeen of the 34 strokes in the tamoxifen group were considered occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the tamoxifen group were fatal. Eighty-eight percent of the strokes occurred in women at least 50 years of age at the time of randomization. Among women receiving tamoxifen, the events occurred between 1 and 63 months (average = 30 months) from the start of treatment. Effects on the Liver: Liver Cancer In the Swedish trial using adjuvant tamoxifen 40 mg/day for 2 to 5 years, 3 cases of liver cancer have been reported in the tamoxifen-treated group vs. 1 case in the observation group (see PRECAUTIONS , Carcinogenesis ). In other clinical trials evaluating tamoxifen, no cases of liver cancer have been reported to date. One case of liver cancer was reported in NSABP P-1 in a participant randomized to tamoxifen. Effects on the Liver: Non-Malignant Effects Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to tamoxifen is uncertain. However, some positive rechallenges and dechallenges have been reported. In the NSABP P-1 trial, few grade 3 to 4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on tamoxifen). Serum lipids were not systematically collected. Other Cancers A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with tamoxifen in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving tamoxifen. Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still uncertain and continues to be evaluated. Effects on the Eye Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving tamoxifen. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving tamoxifen. In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540 tamoxifen; 483 placebo; RR = 1.13, 95% CI: 1.00 to 1.28) was observed. Among these same women, tamoxifen was associated with an increased risk of having cataract surgery (101 tamoxifen; 63 placebo; RR = 1.62, 95% CI: 1.18 to 2.22) (see Table 3 in CLINICAL PHARMACOLOGY ). Among all women on the trial (with or without cataracts at baseline), tamoxifen was associated with an increased risk of having cataract surgery (201 tamoxifen; 129 placebo; RR = 1.58, 95% CI: 1.26 to 1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made. Pregnancy Category D Tamoxifen may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen and should use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2 fold the daily maximum recommended human dose on a mg/m2 basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations. In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4 fold the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1,000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women. However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have been followed long enough (to age 15 to 20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure. There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the potential risks to the fetus including the potential long-term risk of a DES-like syndrome. Reduction in Breast Cancer Incidence in High Risk Women Pregnancy Category D For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient (see PRECAUTIONS, Information for Patients, Reduction in Breast Cancer Incidence in High Risk Women ).
DRUG INTERACTIONS
Drug-Drug Interactions In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown. Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. In the anastrozole adjuvant trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see PRECAUTIONS, Drug Interactions ). Tamoxifen should not be coadministered with anastrozole.
OVERDOSAGE
Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions. Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer patients which specifically determined the maximum tolerated dose of tamoxifen in evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms occurred within 3 to 5 days of beginning tamoxifen and cleared within 2 to 5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after tamoxifen was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to tamoxifen therapy is unknown. Doses given in these patients were all greater than 400 mg/m2 loading dose, followed by maintenance doses of 150 mg/m2 of tamoxifen given twice a day. In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses of 80 mg/m2 of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m2 the minimal loading dose and maintenance doses given at which neurological symptoms and QT changes occurred were at least 6 fold higher in respect to the maximum recommended dose. No specific treatment for overdosage is known; treatment must be symptomatic.
DESCRIPTION
Tamoxifen citrate tablets USP, a nonsteroidal antiestrogen, are for oral administration. Each tablet contains 10 mg or 20 mg tamoxifen (equivalent to 15.2 mg or 30.4 mg, respectively, of tamoxifen citrate). Each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose (monohydrate), magnesium stearate, polyethylene glycol 400, povidone, corn starch, and titanium dioxide. Chemically, tamoxifen is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl)phenoxy]- N,N-dimethylethanamine 2-hydroxy-1,2,3- propanetricarboxylate (1:1). The structural formula, empirical formula, and molecular weight are as follows: C32H37NO8 M.W. 563.62 Tamoxifen citrate has a pKa’ of 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL. Structural formula of tamoxifen
CLINICAL STUDIES
Clinical Studies Metastatic Breast Cancer Premenopausal women (tamoxifen vs. ablation) Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared tamoxifen to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for death (tamoxifen/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving tamoxifen, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during tamoxifen therapy responded to subsequent ovarian ablation. Male breast cancer Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with tamoxifen have shown that tamoxifen is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to tamoxifen which constitutes a 50% objective response rate. Adjuvant Breast Cancer Overview The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10 year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant tamoxifen using doses of 20 to 40 mg/day for 1 to 5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing tamoxifen to no adjuvant therapy and 42% were entered into trials comparing tamoxifen in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease. Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for tamoxifen vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for tamoxifen vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for tamoxifen vs. 64.3% for control (logrank 2p < 0.00001). The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of tamoxifen, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001). Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of tamoxifen on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective. Anastrozole adjuvant ATAC trial – study of anastrozole compared to tamoxifen for adjuvant treatment of early breast cancer An anastrozole adjuvant trial was conducted in 9,366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of these two treatments for 5 years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen therapy alone in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Please refer to CLINICAL PHARMACOLOGY , Special Populations and Drug-Drug Interactions ; PRECAUTIONS, Laboratory Tests ; PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS for safety information from this trial. Please refer to the full prescribing information for anastrozole 1 mg tablets for additional information on this trial. Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p = 0.0127] in the anastrozole arm compared to the tamoxifen arm. Node positive – individual studies Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when tamoxifen was added to adjuvant cytotoxic chemotherapy. In the Hubay study, tamoxifen was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, tamoxifen was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F). In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50 to 59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60 to 70 years, there was a trend toward a beneficial effect of tamoxifen without any clear relationship to estrogen or progesterone receptor status. Three prospective studies (ECOG-1178, Toronto, NATO) using tamoxifen adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit. Node negative – individual studies NSABP B-14, a prospective, double-blind, randomized study, compared tamoxifen to placebo in women with axillary node-negative, estrogen-receptor positive (≥ 10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving tamoxifen. This benefit was apparent both in women under age 50 and in women at or beyond age 50. One additional randomized study (NATO) demonstrated improved disease-free survival for tamoxifen compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of tamoxifen appeared to be independent of estrogen receptor status. Duration of therapy In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. In the NSABP B-14 trial, in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5 year period were offered rerandomization to an additional 5 years of tamoxifen or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of tamoxifen were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of tamoxifen (p = 0.003). Overall survivals were 96% and 94%, respectively (p = 0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit. A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR = 1.27, 95% CI: 0.87 to 1.85). In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant tamoxifen 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5 year tamoxifen group, compared with 74% among corresponding patients in the 2 year treatment group (p = 0.03). Disease-free survival at 10 years was 73% in the 5 year group and 67% in the 2 year group (p = 0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant. Contralateral breast cancer The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving tamoxifen compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with tamoxifen of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving tamoxifen were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of tamoxifen reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group. In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant tamoxifen 40 mg/day for 2 to 5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1,000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization. Ductal Carcinoma in Situ NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of tamoxifen or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast. In this trial 1,804 women were randomized to receive either tamoxifen or placebo for 5 years: 902 women were randomized to tamoxifen citrate 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months. The tamoxifen and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis. For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to tamoxifen (44 cases-tamoxifen, 74 cases-placebo; p = 0.004; relative risk (RR) = 0.57, 95% CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base. Results are shown in Table 1 . For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. Table 1: Major Outcomes of the NSABP B-24 Trial Type of Event Lumpectomy, radiotherapy, and placebo Lumpectomy, radiotherapy, and tamoxifen RR 95% CI limits No. of events Rate per 1,000 women per year No. of events Rate per 1,000 women per year Invasive breast cancer (Primary endpoint) 74 16.73 44 9.60 0.57 0.39 to 0.84 Ipsilateral 47 10.61 27 5.90 0.56 0.33 to 0.91 Contralateral 25 5.64 17 3.71 0.66 0.33 to 1.27 Side undetermined 2 — 0 — — Secondary Endpoints DCIS 56 12.66 41 8.95 0.71 0.46 to 1.08 Ipsilateral 46 10.40 38 8.29 0.71 0.51 to 1.25 Contralateral 10 2.26 3 0.65 0.29 0.05 to 1.13 All Breast Cancer Events 129 29.16 84 18.34 0.63 0.47 to 0.83 All ipsilateral events 96 21.70 65 14.19 0.65 0.47 to 0.91 All contralateral events 37 8.36 20 4.37 0.52 0.29 to 0.92 Deaths 32 28 Uterine Malignancies1 4 9 Endometrial Adenocarcinoma1 4 0.57 8 1.15 Uterine Sarcoma1 0 0.0 1 0.14 Second primary malignancies (other than endometrial and breast) 30 29 Stroke 2 7 Thromboembolic events (DVT, PE) 5 15 1Updated follow-up data (median 8.1 years) Survival was similar in the placebo and tamoxifen groups. At 5 years from study entry, survival was 97% for both groups. Reduction in Breast Cancer Incidence in High Risk Women The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (see INDICATIONS AND USAGE ). Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of tamoxifen, including: endometrial cancer, pulmonary embolus, deep-vein thrombosis, stroke, and cataract formation and surgery (see WARNINGS ). The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5 year predicted risk of breast cancer of ≥ 1.67% was required for entry into the trial. In this trial, 13,388 women of at least 35 years of age were randomized to receive either tamoxifen or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to tamoxifen (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2 . Table 2: Demographic Characteristics of Women in the NSABP P-1 Trial Characteristic Placebo Tamoxifen # % # % Age (yrs.) 35 to 39 184 3 158 2 40 to 49 2,394 36 2,411 37 50 to 59 2,011 31 2,019 31 60 to 69 1,588 24 1,563 24 ≥ 70 393 6 393 6 Age at first live birth (yrs.) Nulliparous 1,202 18 1,205 18 12 to 19 915 14 946 15 20 to 24 2,448 37 2,449 37 25 to 29 1,399 21 1,367 21 ≥ 30 606 9 577 9 Race White 6,333 96 6,323 96 Black 109 2 103 2 Other 128 2 118 2 Age at menarche ≥ 14 1,243 19 1,170 18 12 to 13 3,610 55 3,610 55 ≤ 11 1,717 26 1,764 27 # of first degree relatives with breast cancer 0 1,584 24 1,525 23 1 3,714 57 3,744 57 2+ 1,272 19 1,275 20 Prior hysterectomy No 4,173 63.5 4,018 62.4 Yes 2,397 36.5 2,464 37.7 # of previous breast biopsies 0 2,935 45 2,923 45 1 1,833 28 1,850 28 ≥ 2 1,802 27 1,771 27 History of atypical hyperplasia in the breast No 5,958 91 5,969 91 Yes 612 9 575 9 History of LCIS at entry No 6,165 94 6,135 94 Yes 405 6 409 6 5 year predicted breast cancer risk (%) ≤ 2.00 1,646 25 1,626 25 2.01 to 3.00 2,028 31 2,057 31 3.01 to 5.00 1,787 27 1,707 26 ≥ 5.01 1,109 17 1,162 18 Total 6,570 100.0 6,544 100.0 Results are shown in Table 3 . After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to tamoxifen (86 cases-tamoxifen, 156 cases-placebo; p < 0.00001; relative risk (RR) = 0.56, 95% CI: 0.43 to 0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (≤ 49, 50 to 59, ≥ 60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23 tamoxifen, 35 placebo; RR = 0.66, 95% CI: 0.39 to 1.11). There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61 tamoxifen, 59 placebo; RR = 1.04, 95% CI: 0.73 to 1.49). No overall difference in mortality (53 deaths in tamoxifen group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (4 deaths in tamoxifen group vs. 5 deaths in placebo group). Although there was a non-significant reduction in the number of hip fractures (9 on tamoxifen, 20 on placebo) in the tamoxifen group, the number of wrist fractures was similar in the two treatment groups (69 on tamoxifen, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving tamoxifen. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, tamoxifen was associated with significant bone loss of the lumbar spine and hip in premenopausal women. The risks of tamoxifen therapy include endometrial cancer, DVT, PE, stroke, cataract formation, and cataract surgery (see Table 3 ). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the tamoxifen group vs. 14 in the placebo group (RR = 2.48, 95% CI: 1.27 to 4.92). Deep-vein thrombosis was observed in 30 women receiving tamoxifen vs. 19 in women receiving placebo (RR = 1.59, 95% CI: 0.86 to 2.98). Eighteen cases of pulmonary embolism were observed in the tamoxifen group vs. 6 in the placebo group (RR = 3.01, 95% CI: 1.15 to 9.27). There were 34 strokes on the tamoxifen arm and 24 on the placebo arm (RR = 1.42, 95% CI: 0.82 to 2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking tamoxifen vs. 483 women receiving placebo (RR = 1.13, 95% CI: 1.00 to 1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking tamoxifen vs. 129 women receiving placebo (RR = 1.51, 95% CI: 1.21 to 1.89) (see WARNINGS ). Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing risk factors, for women who developed breast cancer. The 5 year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit (see INDICATIONS AND USAGE ). Table 3. Major Outcomes of the NSABP P-1 Trial TYPE OF EVENT # OF EVENTS RATE/1,000 WOMEN/YEAR 95% CI PLACEBO TAMOXIFEN PLACEBO TAMOXIFEN RR LIMITS Invasive Breast Cancer 156 86 6.49 3.58 0.56 0.43 to 0.72 Age ≤ 49 59 38 6.34 4.11 0.65 0.43 to 0.98 Age 50 to 59 46 25 6.31 3.53 0.56 0.35 to 0.91 Age ≥ 60 51 23 7.17 3.22 0.45 0.27 to 0.74 Risk Factors for Breast Cancer History, LCIS No 140 78 6.23 3.51 0.56 0.43 to 0.74 Yes 16 8 12.73 6.33 0.50 0.21 to 1.17 History, Atypical Hyperplasia No 138 84 6.37 3.89 0.61 0.47 to 0.80 Yes 18 2 8.69 1.05 0.12 0.03 to 0.52 No. First Degree Relatives 0 32 17 5.97 3.26 0.55 0.30 to 0.98 1 80 45 5.81 3.31 0.57 0.40 to 0.82 2 35 18 8.92 4.67 0.52 0.30 to 0.92 ≥ 3 9 6 13.33 7.58 0.57 0.20 to 1.59 5 Year Predicted Breast Cancer Risk (as calculated by the Gail Model) ≤ 2.00% 31 13 5.36 2.26 0.42 0.22 to 0.81 2.01 to 3.00% 39 28 5.25 3.83 0.73 0.45 to 1.18 3.01 to 5.00% 36 26 5.37 4.06 0.76 0.46 to 1.26 ≥ 5.00% 50 19 13.15 4.71 0.36 0.21 to 0.61 DCIS 35 23 1.47 0.97 0.66 0.39 to 1.11 Fractures (protocol-specified sites) 921 761 3.87 3.20 0.61 0.83 to 1.12 Hip 20 9 0.84 0.38 0.45 0.18 to 1.04 Wrist2 74 69 3.11 2.91 0.93 0.67 to 1.29 Total Ischemic Events 59 61 2.47 2.57 1.04 0.71 to 1.51 Myocardial Infarction 27 27 1.13 1.13 1.00 0.57 to 1.78 Fatal 8 7 0.33 0.29 0.88 0.27 to 2.77 Nonfatal 19 20 0.79 0.84 1.06 0.54 to 2.09 Angina3 12 12 0.50 0.50 1.00 0.41 to 2.44 Acute Ischemic Syndrome4 20 22 0.84 0.92 1.11 0.58 to 2.13 Uterine Malignancies (among women with an intact uterus)10 17 57 Endometrial Adenocarcinoma10 17 53 0.71 2.20 Uterine Sarcoma10 0 4 0.0 0.17 Stroke5 24 34 1.00 1.43 1.42 0.82 to 2.51 Transient Ischemic Attack 21 18 0.88 0.75 0.86 0.43 to 1.70 Pulmonary Emboli6 6 18 0.25 0.75 3.01 1.15 to 9.27 Deep-Vein Thrombosis7 19 30 0.79 1.26 1.59 0.86 to 2.98 Cataracts Developing on Study8 483 540 22.51 25.41 1.13 1.00 to 1.28 Underwent Cataract Surgery8 63 101 2.83 4.57 1.62 1.18 to 2.22 Underwent Cataract Surgery9 129 201 5.44 8.56 1.58 1.26 to 1.97 1 Two women had hip and wrist fractures 2 Includes Colles’ and other lower radius fractures 3 Requiring angioplasty or CABG 4 New Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization without surgery 5 Seven cases were fatal; three in the placebo group and four in the tamoxifen group 6 Three cases in the tamoxifen group were fatal 7 All but three cases in each group required hospitalization 8 Based on women without cataracts at baseline (6,230 Placebo, 6,199 Tamoxifen) 9 All women (6,707 Placebo, 6,681 Tamoxifen) 10 Updated long-term follow-up data, (median 6.9 years), from NSABP P-1 study added after cut-off for the other information in this table. Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor size, nodal status, ER status. Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. Table 4: Characteristics of Breast Cancer in NSABP P-1 Trial Staging Parameter Placebo Tamoxifen Total N = 156 N = 86 N = 242 Tumor size: T1 117 60 177 T2 28 20 48 T3 7 3 10 T4 1 2 3 Unknown 3 1 4 Nodal status: Negative 103 56 159 1 to 3 positive nodes 29 14 43 ≥ 4 positive nodes 10 12 22 Unknown 14 4 18 Stage: I 88 47 135 II: node negative 15 9 24 II: node positive 33 22 55 III 6 4 10 IV 21 1 3 Unknown 12 3 15 Estrogen receptor: Positive 115 38 153 Negative 27 36 63 Unknown 14 12 26 1 One participant presented with a suspicious bone scan but did not have documented metastases. She subsequently died of metastatic breast cancer. Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of tamoxifen in reducing breast cancer incidence have been reported. The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and 70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5,408 women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After 46 months of follow-up there were 22 breast cancers in women on placebo and 19 in women on tamoxifen. Although no decrease in breast cancer incidence was observed, there was a trend for reduction in breast cancer among women receiving protocol therapy for at least 1 year (19 placebo, 11 tamoxifen). The small numbers of participants along with the low level of risk in this otherwise healthy group precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of breast cancer. The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT was begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was subsequently extended to a pilot trial to accrue additional participants to further assess the safety of tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986 and 1996; they were selected on the basis of a family history of breast cancer. HRT was used in 40% of participants. In this trial, with a 70 month median follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm) were observed among women on tamoxifen and placebo, respectively. Patients in this trial were younger than those in the NSABP P-1 trial and may have been more likely to develop ER (-) tumors, which are unlikely to be reduced in number by tamoxifen therapy. Although women were selected on the basis of family history and were thought to have a high risk of breast cancer, few events occurred, reducing the statistical power of the study. These factors are potential reasons why the RMT may not have provided an adequate assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer. In these trials, an increased number of cases of deep-vein thrombosis, pulmonary embolus, stroke, and endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency of events was consistent with the safety data observed in the NSABP P-1 trial. McCune-Albright Syndrome A single, uncontrolled multicenter trial of tamoxifen 20 mg once a day was conducted in a heterogenous group of girls with McCune-Albright syndrome and precocious puberty manifested by physical signs of pubertal development, episodes of vaginal bleeding and/or advanced bone age (bone age of at least 12 months beyond chronological age). Twenty-eight female pediatric patients, aged 2 to 10 years, were treated for up to 12 months. Effect of treatment on frequency of vaginal bleeding, bone age advancement, and linear growth rate was assessed relative to prestudy baseline. Tamoxifen treatment was associated with a 50% reduction in frequency of vaginal bleeding episodes by patient or family report (mean annualized frequency of 3.56 episodes at baseline and 1.73 episodes on-treatment). Among the patients who reported vaginal bleeding during the prestudy period, 62% (13 out of 21 patients) reported no bleeding for a 6 month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Not all patients improved on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. Tamoxifen therapy was associated with a reduction in mean rate of increase of bone age. Individual responses with regard to bone age advancement were highly heterogeneous. Linear growth rate was reduced during the course of tamoxifen treatment in a majority of patients (mean change of 1.68 cm/year relative to baseline; change from 7.47 cm/year at baseline to 5.79 cm/year on study). This change was not uniformly seen across all stages of bone maturity; all recorded response failures occurred in patients with bone ages less than 7 years at screening. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen (see BOXED WARNING ), continued monitoring of McCune-Albright patients treated with tamoxifen for long-term uterine effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy in girls have not been established.
HOW SUPPLIED
Tamoxifen citrate tablets USP, 10 mg (base) are white, round, biconvex, film-coated, unscored tablets debossed “93”and “784” and are supplied in: Boxes of 25×30 UD 750 NDC 63739-269-01 Boxes of 25×30 PC 750 NDC 63739-269-03 Boxes of 10×10 UD 100 NDC 63739-269-10 Tamoxifen citrate tablets USP, 20 mg (base) are white to off-white, round, biconvex, film-coated, unscored tablets debossed “93” and “782” . Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container as defined in the USP.
GERIATRIC USE
Geriatric Use In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets. A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger patients (See CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence in High Risk Women ). In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. This subset is too small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were comparable to those of younger women enrolled in this trial. No overall differences in tolerability were observed between older and younger patients.
INDICATIONS AND USAGE
Metastatic Breast Cancer Tamoxifen citrate tablets 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 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 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 1 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. Age 50 or older and any of the following combination of factors: •At least 2 first degree relatives with a history of breast cancer; or •History of 1 breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. Age 55 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. Age 60 or older and: •Five-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-888-838-2872. There are insufficient data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of tamoxifen in these patients. After an assessment of the risk of developing breast cancer, 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. In the NSABP P-1 trial, tamoxifen treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk (see Table 3 in CLINICAL PHARMACOLOGY ).
PEDIATRIC USE
Pediatric Use The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy for girls have not been established. In adults treated with tamoxifen, an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING and CLINICAL PHARMACOLOGY, Clinical Studies, McCune-Albright Syndrome ).
PREGNANCY
Pregnancy Category D Tamoxifen may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen and should use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2 fold the daily maximum recommended human dose on a mg/m2 basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations. In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4 fold the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1,000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women. However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have been followed long enough (to age 15 to 20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure. There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the potential risks to the fetus including the potential long-term risk of a DES-like syndrome.
NUSRING MOTHERS
Nursing Mothers Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of tamoxifen on established milk production is not known. There are no data that address whether tamoxifen is excreted into human milk. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals. However, direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis. It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed.
BOXED WARNING
WARNING For Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast Cancer Serious and life-threatening events associated with tamoxifen in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY, Clinical Studies , Reduction in Breast Cancer Incidence in High Risk Women). Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for tamoxifen vs. 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for tamoxifen vs. 0.4 for placebo)*. For stroke, the incidence rate per 1,000 women-years was 1.43 for tamoxifen vs. 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 women-years was 0.75 for tamoxifen versus 0.25 for placebo**. Some of the strokes, pulmonary emboli, and uterine malignancies were fatal. Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer. The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer. * Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See WARNINGS, Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma . ** See Table 3 under CLINICAL PHARMACOLOGY, Clinical Studies .
INFORMATION FOR PATIENTS
Information for Patients Patients should be instructed to read the Medication Guide supplied as required by law when tamoxifen is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. Reduction in Invasive Breast Cancer and DCIS in Women With DCIS Women with DCIS treated with lumpectomy and radiation therapy who are considering tamoxifen to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with tamoxifen decreased the incidence of invasive breast cancer, but has not been shown to affect survival (see Table 1 in CLINICAL PHARMACOLOGY ). Reduction in Breast Cancer Incidence in High Risk Women Women who are at high risk for breast cancer can consider taking tamoxifen therapy to reduce the incidence of breast cancer. Whether the benefits of treatment are considered to outweigh the risks depends on a woman’s personal health history and on how she weighs the benefits and risks. Tamoxifen therapy to reduce the incidence of breast cancer may therefore not be appropriate for all women at high risk for breast cancer. Women who are considering tamoxifen therapy should consult their health care professional for an assessment of the potential benefits and risks prior to starting therapy for reduction in breast cancer incidence (see Table 3 in CLINICAL PHARMACOLOGY ). Women should understand that tamoxifen reduces the incidence of breast cancer, but may not eliminate risk. Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately 50%. Women who are pregnant or who plan to become pregnant should not take tamoxifen to reduce their risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking tamoxifen and for approximately two months after discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient (see WARNINGS, Pregnancy Category D ). Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled women at a lower risk for breast cancer than those in P-1. Monitoring During Tamoxifen Therapy Women taking or having previously taken tamoxifen should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all care providers, regardless of the reason for evaluation, that they take tamoxifen. Women taking tamoxifen to reduce the incidence of breast cancer should have a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking tamoxifen as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking tamoxifen for the reduction in the incidence of breast cancer. Women taking tamoxifen as treatment for metastatic breast cancer should review this monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation.
DOSAGE AND ADMINISTRATION
For patients with breast cancer, the recommended daily dose is 20 to 40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening). In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit (see CLINICAL PHARMACOLOGY ). In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Ductal Carcinoma in Situ (DCIS) The recommended dose is tamoxifen 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in High Risk Women The recommended dose is tamoxifen 20 mg daily for 5 years. There are no data to support the use of tamoxifen other than for 5 years (see CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence in High Risk Women ).