Label: TAMOXIFEN CITRATE tablet

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 to 183 ng/mL) for tamoxifen and 336 ng/mL (range 148 to 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 to 183 ng/mL) and 353 ng/mL (range 152 to 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 tamoxifen citrate tablets given twice a day vs. a 20 mg tamoxifen citrate tablet given once daily, the 20 mg tamoxifen citrate tablet was bioequivalent to the 10 mg tamoxifen citrate 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.

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-desmethyl tamoxifen (see PRECAUTIONS: Drug Interactions). Tamoxifen should not be coadministered with anastrozole.

Clinical Studies

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 citrate tablets are 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 citrate tablet therapy.

Adjuvant Treatment of Breast Cancer

Tamoxifen citrate tablets are 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 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 citrate tablet therapy is likely to be beneficial.

Tamoxifen citrate tablets reduce the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen citrate tablet 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). The decision regarding therapy with tamoxifen citrate tablets for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen citrate tablet therapy.

Current data from clinical trials support 5 years of adjuvant tamoxifen citrate tablet 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 citrate tablets on overall or breast cancer-related mortality (see BOXED WARNING).

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, two or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or

•

At least two first-degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy; or

•

LCIS

Age 40 or older and any of the following combination of factors:

•

One first-degree relative with a history of breast cancer, two or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or

•

At least two 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 two 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 two first-degree relatives with a history of breast cancer; or

•

History of one 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 two 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 two breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older.

Age 60 or older and:

•

5 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. Healthcare Professionals can obtain a Gail Model Risk Assessment Tool by dialing Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

There are insufficient data available regarding the effect of tamoxifen citrate tablets 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 citrate tablets for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen citrate tablet therapy. In the NSABP P-1 trial, tamoxifen citrate tablet treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk (see CLINICAL PHARMACOLOGY: Table 3).

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

Tamoxifen citrate tablets are contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus.

Effects in Metastatic Breast Cancer Patients

As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued.

Effects on the Uterus

Non-Malignant Effects on the Uterus

An increased incidence of endometrial changes including hyperplasia and polyps have 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 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 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 (seven out of 25 women on placebo, five 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 seven were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and four of unknown etiology. Among these strokes three strokes in the placebo group and four 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, three cases of liver cancer have been reported in the tamoxifen-treated group vs. one 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 six 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 CLINICAL PHARMACOLOGY: Table 3). 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

Reduction in Breast Cancer Incidence in High Risk Women

General

Decreases in platelet counts, usually to 50,000 to 100,000/mm3, infrequently lower, have been occasionally reported in patients taking tamoxifen for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to tamoxifen 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 tamoxifen; this can sometimes be severe.

In the NSABP P-1 trial, six women on tamoxifen and two on placebo experienced grade 3 to 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 tamoxifen 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 tamoxifen (9% vs. 3.5%, respectively).

Drug Interactions

When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended.

In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (see CONTRAINDICATIONS).

There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen.

Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. 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 tamoxifen with concomitant phenobarbital exhibited a steady-state serum level of tamoxifen lower than that observed for other patients (i.e., 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 ten 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, tamoxifen should not be administered with anastrozole (see CLINICAL PHARMACOLOGY: Drug-Drug Interactions).

Drug/Laboratory Testing Interactions

During post-marketing 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 tamoxifen.

In the post-marketing experience with tamoxifen, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with preexisting hyperlipidemias (see ADVERSE REACTIONS: Post-Marketing Experience).

Carcinogenesis

A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about 1-, 3- and 7-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 9-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, 2- and 5-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 2 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 to 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

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.

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).

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 ten 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.

Metastatic Breast Cancer

Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen and generally subside rapidly.

In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction to tamoxifen 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 tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.

Male Breast Cancer

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

Adjuvant Breast Cancer

In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen 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 tamoxifen than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with tamoxifen compared with placebo. All other adverse effects occurred with similar frequency in the two treatment groups, with the exception of thrombotic events; a higher incidence was seen in tamoxifen-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen who had thrombotic events died.

In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen 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 tamoxifen was 10% vs. 3% for placebo, an observation of borderline statistical significance.

In other adjuvant studies, Toronto and Nolvadex Adjuvant Trial Organization (NATO), women received either tamoxifen or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group.

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 tamoxifen.

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 tamoxifen group: endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen group vs. six in the placebo group); deep vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group) and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group) (see WARNINGS and CLINICAL PHARMACOLOGY: Table 3).

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

In the NSABP P-1 trial, 15% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from tamoxifen and placebo therapy, respectively: Hot Flashes 3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%).

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

On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on tamoxifen. Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen 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

Post-Marketing 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 tamoxifen 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 tamoxifen (see PRECAUTIONS: Drug/Laboratory Testing Interactions).

Ductal Carcinoma in Situ (DCIS)

The recommended dose is tamoxifen citrate tablet 20 mg daily for 5 years.

Reduction in Breast Cancer Incidence in High Risk Women

The recommended dose is tamoxifen citrate tablets 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).