10 mg Tablets:

Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen.

20 mg Tablets:

Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.

Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

Chemically, NOLVADEX 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 and empirical formulas are:

Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 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.

Absorption and Distribution:

Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg NOLVADEX tablets given twice a day vs. a 20 mg NOLVADEX tablet given once daily, the 20 mg NOLVADEX tablet was bioequivalent to the 10 mg NOLVADEX tablets.

Metabolism:

Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.

Excretion:

Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

Special Populations:

The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.

Clinical Studies

Metastatic Breast Cancer:

NOLVADEX is effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, NOLVADEX 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 NOLVADEX therapy.

Adjuvant Treatment of Breast Cancer:

NOLVADEX is indicated for the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some NOLVADEX adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes.

NOLVADEX is 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 NOLVADEX therapy is likely to be beneficial.

NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant NOLVADEX therapy for breast cancer.

Ductal Carcinoma in Situ (DCIS):

In women with DCIS, following breast surgery and radiation, NOLVADEX is indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with NOLVADEX for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of NOLVADEX therapy.

Current data from clinical trials support five years of adjuvant NOLVADEX therapy for patients with breast cancer.

Reduction in Breast Cancer Incidence in High Risk Women:

NOLVADEX is 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).

NOLVADEX is 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:

Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS:

NOLVADEX is 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 NOLVADEX. If hypercalcemia does occur, appropriate measures should be taken and, if severe, NOLVADEX should be discontinued.

Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma:

An increased incidence of uterine malignancies has been reported in association with NOLVADEX treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of NOLVADEX. Most uterine malignancies seen in association with NOLVADEX 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 NOLVADEX 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 NOLVADEX 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: 1.27-4.92). The 33 cases in participants receiving NOLVADEX 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 NOLVADEX 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: 1.78-13.16). 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: 0.28-2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants ≤ 49 randomized to NOLVADEX compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-12.0). For women ≥ 50 at the time of diagnosis, there were 29 cases among participants randomized to NOLVADEX compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the NOLVADEX group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the NOLVADEX group occurred in asymptomatic women. Among women receiving NOLVADEX 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 NOLVADEX. 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 NOLVADEX 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 NOLVADEX 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 NOLVADEX (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 NOLVADEX (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 NOLVADEX, 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 NOLVADEX in five other NSABP clinical trials.

Any patient receiving or who has previously received NOLVADEX who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received NOLVADEX should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, eg, 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 NOLVADEX 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 NOLVADEX treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of NOLVADEX.

There have been a few reports of endometriosis and uterine fibroids in women receiving NOLVADEX. The underlying mechanism may be due to the partial estrogenic effect of NOLVADEX. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with NOLVADEX.

NOLVADEX has been reported to cause menstrual irregularity or amenorrhea.

Thromboembolic Effects of NOLVADEX:

There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during NOLVADEX therapy. When NOLVADEX 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 NOLVADEX should be carefully considered in women with a history of thromboembolic events. In a subsmall study (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 NOLVADEX therapy.

Data from the NSABP P-1 trial show that participants receiving NOLVADEX without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-NOLVADEX, 6-placebo, RR=3.01, 95% CI: 1.15- 9.27). Three of the pulmonary emboli, all in the NOLVADEX 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 NOLVADEX, 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 NOLVADEX group (30-NOLVADEX, 19-placebo; RR=1.59, 95% CI: 0.86-2.98). 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 NOLVADEX) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on NOLVADEX). Among women receiving NOLVADEX, 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 NOLVADEX (24-Placebo; 34-NOLVADEX; RR=1.42; 95% CI 0.82-2.51). Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the NOLVADEX group were categorized as hemorrhagic. Seventeen of the 34 strokes in the NOLVADEX 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 NOLVADEX 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 NOLVADEX, 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 NOLVADEX 40 mg/day for 2-5 years, 3 cases of liver cancer have been reported in the NOLVADEX-treated group vs. 1 case in the observation group (See PRECAUTIONS- Carcinogenesis). In other clinical trials evaluating NOLVADEX, 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 NOLVADEX.

Effects on the liver: Non-malignant effects:

NOLVADEX 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 NOLVADEX is uncertain. However, some positive rechallenges and dechallenges have been reported.

In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on NOLVADEX). 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 NOLVADEX in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving NOLVADEX. Whether an increased risk for other (non-uterine) cancers is associated with NOLVADEX 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 NOLVADEX. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving NOLVADEX.

In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540-NOLVADEX; 483-placebo; RR=1.13, 95% CI: 1.00-1.28) was observed. Among these same women, NOLVADEX was associated with an increased risk of having cataract surgery (101-NOLVADEX; 63-placebo; RR=1.62, 95% CI 1.18-2.22) (See Table 3 in CLINICAL PHARMACOLOGY). Among all women on the trial (with or without cataracts at baseline), NOLVADEX was associated with an increased risk of having cataract surgery (201-NOLVADEX; 129-placebo; RR=1.58, 95% CI 1.26-1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made.

Pregnancy Category D:

NOLVADEX may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking NOLVADEX or within 2 months of discontinuing NOLVADEX 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 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 15-20) 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, NOLVADEX 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).

General:

Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been occasionally reported in patients taking NOLVADEX for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to NOLVADEX therapy. Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving NOLVADEX; this can sometimes be severe.

In the NSABP P-1 trial, 6 women on NOLVADEX and 2 on placebo experienced grade 3-4 drops in platelet counts (≤50,000/mm3).

Information for Patients:

Patients should be instructed to read the Medication Guide supplied as required by law when NOLVADEX is dispensed. The complete text of the Medication Guide is reprinted at the end of this document.

Laboratory Tests:

Periodic complete blood counts, including platelet counts, and periodic liver function tests should be obtained.

During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving NOLVADEX (9% versus 3.5%, respectively).

Drug Interactions:

When NOLVADEX 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 NOLVADEX.

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. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect.

One patient receiving NOLVADEX with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (ie, 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.

Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen.

Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, NOLVADEX should not be administered with anastrozole (see CLINICAL PHARMACOLOGY – Drug-Drug Interactions section).

Drug/Laboratory Testing Interactions:

During postmarketing surveillance, T4 elevations were reported for a few postmenopausal patients which may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism.

Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been infrequently seen in postmenopausal patients given NOLVADEX.

In the postmarketing experience with NOLVADEX, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with pre-existing hyperlipidemias (See ADVERSE REACTIONS-Postmarketing experience section).

Carcinogenesis:

A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years) revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months.

Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the daily recommended human dose on a mg/m2 basis).

Mutagenesis:

No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells.

Impairment of Fertility:

Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose on a mg/m2 basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum recommended human dose on a mg/m2 basis) when female rats were dosed from days 7-17 of pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-fold the daily maximum recommended human dose on a mg/m2 basis). There were no teratogenic changes in either rats or rabbits.

Pregnancy Category D:

See WARNINGS.

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 NOLVADEX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from NOLVADEX, women taking NOLVADEX should not breast feed.

Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS

It is not known if NOLVADEX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from NOLVADEX, women taking NOLVADEX should not breast feed.

Pediatric Use:

The safety and efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of NOLVADEX therapy for girls have not been established. In adults treated with NOLVADEX, 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 subsection).

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 NOLVADEX 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 section).

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 NOLVADEX 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.

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 NOLVADEX and generally subside rapidly.

In patients treated with NOLVADEX for metastatic breast cancer, the most frequent adverse reaction to NOLVADEX is hot flashes.

Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial hair loss, and vaginal dryness.

Premenopausal Women:

The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared NOLVADEX therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.

Male Breast Cancer:

NOLVADEX is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of NOLVADEX in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported.

Adjuvant Breast Cancer:

In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of NOLVADEX 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on NOLVADEX than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with NOLVADEX compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen in NOLVADEX-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with NOLVADEX who had thrombotic events died.

In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, NOLVADEX or placebo was administered for 2 years to women following mastectomy. When compared to placebo, NOLVADEX showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia where the incidence for NOLVADEX was 10% vs. 3% for placebo, an observation of borderline statistical significance.

In other adjuvant studies, Toronto and NOLVADEX Adjuvant Trial Organization (NATO), women received either NOLVADEX or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for NOLVADEX vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for NOLVADEX vs. 0.2% for each in the untreated group.

Anastrozole Adjuvant Trial — Study of Anastrozole compared to NOLVADEX for Adjuvant Treatment of Early Breast Cancer

See CLINICAL PHARMACOLOGY - Clinical Studies. At a median follow-up of 33 months, the combination of anastrozole and NOLVADEX did not demonstrate any efficacy benefit when compared to NOLVADEX therapy given alone, in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and NOLVADEX 20 mg, respectively.

Adverse events occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in the following table.

Certain adverse events and combinations of adverse events were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see the following table).

Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving NOLVADEX. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving NOLVADEX [209 (7%)]. Patients receiving anastrozole had a decrease in hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving NOLVADEX.

Patients receiving NOLVADEX had a decrease in hypercholesterolemia (108 [3.5%]) compared to patients receiving anastrozole (278 [9%]). Angina pectoris was reported in 71 [2.3%] patients in the anastrozole arm and 51 [1.6%] patients in the NOLVADEX arm; myocardial infarction was reported in 37 [1.2%] patients in the anastrozole arm and in 34 [1.1%] patients in the NOLVADEX arm.

Results from the adjuvant trial bone substudy, at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving NOLVADEX had a mean increase in both lumbar spine and total hip BMD compared to baseline.

Ductal Carcinoma in Situ (DCIS):

The type and frequency of adverse events in the NSABP B-24 trial were consistent with those observed in the other adjuvant trials conducted with NOLVADEX.

Reduction in Breast Cancer Incidence in High Risk Women:

In the NSABP P-1 Trial, there was an increase in five serious adverse effects in the NOLVADEX group: endometrial cancer (33 cases in the NOLVADEX group vs. 14 in the placebo group); pulmonary embolism (18 cases in the NOLVADEX group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the NOLVADEX group vs. 19 in the placebo group); stroke (34 cases in the NOLVADEX group vs. 24 in the placebo group); cataract formation (540 cases in the NOLVADEX group vs. 483 in the placebo group) and cataract surgery (101 cases in the NOLVADEX group vs. 63 in the placebo group) (See WARNINGS and Table 3 in CLINICAL PHARMACOLOGY).

The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse events more common on NOLVADEX than placebo are shown.

In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving NOLVADEX and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from NOLVADEX and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%).

In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving NOLVADEX and placebo therapy, respectively withdrew for non-medical reasons.

On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on NOLVADEX. Severe hot flashes occurred in 28% of women on placebo and 45% of women on NOLVADEX. Vaginal discharge occurred in 35% and 55% of women on placebo and NOLVADEX respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms.

Pediatric Patients - McCune-Albright Syndrome:

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 NOLVADEX (see BOXED WARNING), continued monitoring of McCune-Albright patients treated with NOLVADEX for long-term effects is recommended. The safety and efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of NOLVADEX therapy in girls have not been established.

Postmarketing experience:

Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with NOLVADEX therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of NOLVADEX (see PRECAUTIONS- Drug/Laboratory Testing Interactions section).

Ductal Carcinoma in Situ (DCIS):

The recommended dose is NOLVADEX 20 mg daily for 5 years.

Reduction in Breast Cancer Incidence in High Risk Women:

The recommended dose is NOLVADEX 20 mg daily for 5 years. There are no data to support the use of NOLVADEX other than for 5 years (See CLINICAL PHARMACOLOGY-Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women).

Storage:

Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in a well-closed, light-resistant container.