TAMOXIFEN CITRATE

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 citrate 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 citrate vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for tamoxifen citrate vs 0.4 for placebo)*. For stroke, the incidence rate per 1,000 women-years was 1.43 for tamoxifen citrate vs 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 women-years was 0.75 for tamoxifen citrate 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 citrate to reduce their risk of developing breast cancer. The benefits of tamoxifen citrate 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 .

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 citrate. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen citrate 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 citrate treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen citrate. Most uterine malignancies seen in association with tamoxifen citrate 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 citrate 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 citrate 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 citrate 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 citrate 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 citrate group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen citrate group occurred in asymptomatic women. Among women receiving tamoxifen citrate 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 citrate. 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 citrate 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 citrate 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 1B 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 citrate (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 citrate (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and one 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 citrate, 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 one patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen citrate in five other NSABP clinical trials. Any patient receiving or who has previously received tamoxifen citrate who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received tamoxifen citrate 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 citrate 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 have been reported in association with tamoxifen citrate treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of tamoxifen citrate. There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen citrate. The underlying mechanism may be due to the partial estrogenic effect of tamoxifen citrate. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen citrate. Tamoxifen citrate has been reported to cause menstrual irregularity or amenorrhea. Thromboembolic Effects of Tamoxifen Citrate: There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen citrate therapy. When tamoxifen citrate is coadminstered 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 citrate should be carefully considered in women with a history of thromboembolic events. In a small substudy (N=81) of the NSABP P-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 citrate therapy. Data from the NSABP P-1 trial show that participants receiving tamoxifen citrate without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-tamoxifen citrate, 6-placebo, RR=3.01, 95% CI: 1.15 to 9.27). Three of the pulmonary emboli, all in the tamoxifen citrate 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 citrate, 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 citrate group (30-tamoxifen citrate, 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 citrate) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen citrate). Among women receiving tamoxifen citrate, 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 citrate (24-Placebo; 34-tamoxifen citrate; 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 citrate group were categorized as hemorrhagic. Seventeen of the 34 strokes in the tamoxifen citrate 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 citrate 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 citrate, 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 citrate 40 mg/day for 2 to 5 years, 3 cases of liver cancer have been reported in the tamoxifen citrate-treated group vs. 1 case in the observation group (See PRECAUTIONS- Carcinogenesis ). In other clinical trials evaluating tamoxifen citrate, 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 citrate. Effects on the liver: Non-malignant effects: Tamoxifen citrate 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 citrate 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 citrate). 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 citrate 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 citrate. Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen citrate 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 citrate. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving tamoxifen citrate. In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540-tamoxifen citrate; 483-placebo; RR=1.13, 95% CI: 1.00 to 1.28) was observed. Among these same women, tamoxifen citrate was associated with an increased risk of having cataract surgery (101-tamoxifen citrate; 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 citrate was associated with an increased risk of having cataract surgery (201-tamoxifen citrate; 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: Tamoxifen citrate may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen citrate or within 2 months of discontinuing tamoxifen citrate 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/m 2 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/m 2 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 1000 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: For sexually active women of child-bearing potential, tamoxifen citrate 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 ).

CONTRAINDICATIONS 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.

OVERDOSAGE Signs observed at the highest doses following studies to determine LD 50 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/m 2 loading dose, followed by maintenance doses of 150 mg/m 2 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/m 2 loading dose, followed by maintenance doses of 80 mg/m 2 of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m 2 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.