TAMOXIFEN CITRATE TABLETS, USP

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. 0.04 for placebo)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.. For stroke, the incidence rate per 1,000 women-years was 1.43 for tamoxifen vs. 1.00 for placeboSee Table 3 under CLINICAL PHARMACOLOGY: Clinical Studies.. For pulmonary embolism, the incidence rate per 1,000 women-years was 0.75 for tamoxifen vs. 0.25 for placebo.

Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.

Healthcare 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.

Tamoxifen Citrate Tablets USP, a non-steroidal antiestrogen, are for oral administration. Tamoxifen citrate tablets are available as:

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.

Each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate.

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 and molecular 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.

Tamoxifen citrate is a non-steroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.

In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.

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 tablet given once daily, the 20 mg tamoxifen citrate tablet was bioequivalent to the 10 mg tamoxifen citrate tablets.

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.

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.

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.

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 C_max 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.

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.

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 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 tamoxifen therapy is likely to be beneficial.

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

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 five years of adjuvant tamoxifen therapy for patients with breast cancer.

Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label).

Tamoxifen citrate tablets are indicated only for high risk women. "High risk" is defined as women at least 35 years of age with a 5 year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model.

Examples of combinations of factors predicting a 5 year risk ≥ 1.67% are:

Age 35 or older and any of the following combination of factors:

• One first-degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or
• At least 2 first-degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy; or
• LCIS

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

• One first-degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or
• At least 2 first-degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or
• One first-degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia.

Age 45 or older and any of the following combination of factors:

• At least 2 first-degree relatives with a history of breast cancer and age at first live birth 24 or younger; or
• One first-degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more.

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 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 2 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 1-877-446-3679 (1-877-4-INFO-RX).

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).

Tamoxifen citrate tablets are contraindicated in patients with known hypersensitivity to the drug or any of its ingredients.

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.

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.

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.

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 (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.

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.

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.

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.

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.

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, 6 women on tamoxifen and 2 on placebo experienced grade 3 to 4 drops in platelet counts (≤ 50,000/mm³).

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

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% versus 3.5%, respectively).

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 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, tamoxifen should not be administered with anastrozole (see CLINICAL PHARMACOLOGY: Drug-drug 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 section).

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).

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.

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 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.

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.

The safety and efficacy of tamoxifen 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 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).

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 of 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 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.

Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients.

Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen as compared to placebo.

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.

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.

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.

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 2 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.

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.

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. 6 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 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 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.

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 section).

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.

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.

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

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).

10 mg Tamoxifen Citrate Tablets, USP are available containing tamoxifen as the citrate in an amount equivalent to 10 mg of tamoxifen. The tablets are white, unscored, round tablets debossed with M on one side of the tablet and 144 on the other side. They are available as follows:

NDC 0378-0144-91
bottles of 60 tablets
NDC 0378-0144-05
bottles of 500 tablets

20 mg Tamoxifen Citrate Tablets, USP are available containing tamoxifen as the citrate in an amount equivalent to 20 mg of tamoxifen. The tablets are white to off-white, unscored, round tablets debossed with M on one side of the tablet and 274 on the other side. They are available as follows:

NDC 0378-0274-93
bottles of 30 tablets
NDC 0378-0274-01
bottles of 100 tablets
NDC 0378-0274-25
bottles of 250 tablets

Tamoxifen Citrate Tablets, USP

Written for women who use tamoxifen to lower their high chance of getting breast cancer or who have ductal carcinoma in situ (DCIS)

This Medication Guide discusses only the use of tamoxifen to lower the chance of getting breast cancer in high risk women and in women treated for DCIS.

People taking tamoxifen to treat breast cancer have different benefits and different decisions to make than high risk women or women with ductal carcinoma in situ (DCIS) taking tamoxifen to reduce the chance of getting breast cancer. If you already have breast cancer, talk with your doctor about how the benefits of treating breast cancer with tamoxifen compare to the risks that are described in this document.

Why should I read this Medication Guide?

This guide has information to help you decide whether to use tamoxifen to lower your chance of getting breast cancer.

You and your doctor should talk about whether the possible benefit of tamoxifen in lowering your high chance of getting breast cancer is greater than its possible risks. Your doctor has a special computer program or hand-held calculator to tell if you are in the high risk group. If you have DCIS and have been treated with surgery and radiation therapy, your doctor may prescribe tamoxifen to decrease your chance of getting invasive (spreading) breast cancer.

Read this guide carefully before you start tamoxifen. It is important to read the information you get each time you get more medicine. There may be something new. This guide does not tell you everything about tamoxifen and does not take the place of talking with your doctor.

Only you and your doctor can determine if tamoxifen is right for you.

What is the most important information I should know about using tamoxifen to reduce the chance of getting breast cancer?

Tamoxifen is a prescription medicine that is like estrogen (female hormone) in some ways and different in other ways. In the breast, tamoxifen can block estrogen's effects. Because it does this, tamoxifen may block the growth of breast cancers that need estrogen to grow (cancers that are estrogen- or progesterone-receptor positive).

Tamoxifen can lower the chance of getting breast cancer in women with a higher than normal chance of getting breast cancer in the next five years (high risk women) and women with DCIS. Because high risk women don't have cancer yet, it is important to think carefully about whether the possible benefit of tamoxifen in lowering the chance of getting breast cancer is greater than its possible risks.

This Medication Guide reviews the risks and benefits of using tamoxifen to reduce the chance of getting breast cancer in high risk women and women with DCIS. This guide does not discuss the special benefits and decisions for people who already have breast cancer.

Why do women and men use tamoxifen?

Tamoxifen has more than one use. Tamoxifen is used:

• to lower the chance of getting breast cancer in women with a higher than normal chance of getting breast cancer in the next 5 years (high risk women).
• to lower the chance of getting invasive (spreading) breast cancer in women who had surgery and radiation for ductal carcinoma in situ (DCIS). DCIS means the cancer is only inside the milk ducts.
• to treat breast cancer in women after they have finished early treatment. Early treatment can include surgery, radiation, and chemotherapy. Tamoxifen may keep the cancer from spreading to others parts of the body. It may also reduce the woman's chance of getting a new breast cancer.
• in women and men, to treat breast cancer that has spread to other parts of the body (metastatic breast cancer).

This guide talks only about using tamoxifen to lower the chance of getting breast cancer (#1 and #2 above).

What are the benefits of tamoxifen to lower the chance of getting breast cancer in high risk women and in women treated for DCIS?

A large US study looked at high risk women and compared the ones who took tamoxifen for 5 years with others who took a pill without tamoxifen (placebo). High risk women were defined as women who have a 1.7% or greater chance of getting breast cancer in the next 5 years, based on a special computer program. In this study:

• Out of every 1,000 high risk women who took a placebo, each year about 7 got breast cancer.
• Out of every 1,000 high risk women who took tamoxifen, each year about 4 got breast cancer.

The study showed that on average, high risk women who took tamoxifen lowered their chances of getting breast cancer by 44%, from 7 in 1,000 to 4 in 1,000.

Another US study looked at women with DCIS and compared those who took tamoxifen for 5 years with others who took a placebo. In this study:

• Out of every 1,000 women with DCIS who took a placebo, each year about 17 got breast cancer.
• Out of every 1,000 women with DCIS who took tamoxifen, each year about 10 got breast cancer.

The study showed that on average, women with DCIS who took tamoxifen lowered their chances of getting invasive (spreading) breast cancer by 43%, from 17 in 1,000 to 10 in 1,000.

These studies do not mean that taking tamoxifen will lower your personal chance of getting breast cancer. We do not know what the benefits will be for any one woman who takes tamoxifen to reduce her chance of getting breast cancer.

What are the risks of tamoxifen?

In the studies described under "What are the benefits of tamoxifen?", the high risk women who took tamoxifen got certain side effects at a higher rate than those who took a placebo. Some of these side effects can cause death.

In one study, in women who still had their uterus

• Out of every 1,000 women who took a placebo, each year 1 got endometrial cancer (cancer of the lining of the uterus) and none got uterine sarcoma (cancer of the body of the uterus).
• Out of every 1,000 women who took tamoxifen, each year 2 got endometrial cancer and fewer than 1 got uterine sarcoma.

These results show that, on average, in high risk women who still had their uterus, tamoxifen doubled the chance of getting endometrial cancer from 1 in 1,000 to 2 in 1,000, and it increased the chance of getting uterine sarcoma. This does not mean that taking tamoxifen will double your personal chance of getting endometrial cancer or increase your chance of getting uterine sarcoma. We do not know what this risk will be for any one woman. The risk is different for women who no longer have their uterus.

For all women in this study, taking tamoxifen increased the risk of having a blood clot in their lungs or veins, or of having a stroke. In some cases, women died from these effects.

Tamoxifen increased the risk of getting cataracts (clouding of the lens of the eye) or needing cataract surgery. (See "What are the possible side effects of tamoxifen?" for more details about side effects.)

What don't we know about taking tamoxifen to reduce the chance of getting breast cancer?

We don't know

• if tamoxifen lowers the chance of getting breast cancer in women who have abnormal breast cancer genes (BRCA1 and BRCA2)
• if taking tamoxifen for 5 years reduces the number of breast cancers a woman will get in her lifetime or if it only delays some breast cancers
• if tamoxifen helps a woman live longer
• the effects of taking tamoxifen with hormone replacement therapy (HRT), birth control pills, or androgens (male hormones)
• the benefits of taking tamoxifen if you are less than 35 years old

Studies are being done to learn more about the long-term benefits and risks of using tamoxifen to reduce the chance of getting breast cancer.

What are the possible side effects of tamoxifen?

The most common side effect of tamoxifen is hot flashes. This is not a sign of a serious problem.

The next most common side effect is vaginal discharge. If the discharge is bloody, it could be a sign of a serious problem. [See "Changes in the lining (endometrium) or body of your uterus" below.]

Less common but serious side effects of tamoxifen are uled below. These can occur at any time. Call your doctor right away if you have any signs of side effects uled below:

• Changes in the lining (endometrium) or body of your uterus. These changes may mean serious problems are starting, including cancer of the uterus. The signs of changes in the uterus are:
  • -Vaginal bleeding or bloody discharge that could be a rusty or brown color. You should call your doctor even if only a small amount of bleeding occurs.
  • -Change in your monthly bleeding, such as in the amount or timing of bleeding or increased clotting.
  • -Pain or pressure in your pelvis (below your belly button).
• Blood clots in your veins or lungs. These can cause serious problems, including death. You may get clots up to 2 to 3 months after you stop taking tamoxifen. The signs of blood clots are:
  • -sudden chest pain, shortness of breath, coughing up blood
  • -pain, tenderness, or swelling in one or both of your legs
• Stroke. Stroke can cause serious medical problems, including death. The signs of stroke are:
  • -sudden weakness, tingling, or numbness in your face, arm or leg, especially on one side of your body
  • -sudden confusion, trouble speaking or understanding
  • -sudden trouble seeing in one or both eyes
  • -sudden trouble walking, dizziness, loss of balance or coordination
  • -sudden severe headache with no known cause
• Cataracts or increased chance of needing cataract surgery. The sign of these problems is slow blurring of your vision.
• Liver problems, including jaundice. The signs of liver problems include lack of appetite and yellowing of your skin or whites of your eyes.

These are not all the possible side effects of tamoxifen. For a complete ul, ask your doctor or pharmacist.

Who should not take tamoxifen?

Do not take tamoxifen for any reason if you

• Are pregnant or plan to become pregnant while taking tamoxifen or during the 2 months after you stop taking tamoxifen. Tamoxifen may harm your unborn baby. It takes about 2 months to clear tamoxifen from your body. To be sure you are not pregnant, you can start taking tamoxifen while you are having your menstrual period. Or, you can take a pregnancy test to be sure you are not pregnant before you begin.
• Are breast-feeding. We do not know if tamoxifen can pass through your milk and harm your baby.
• Have had an allergic reaction to tamoxifen or to any of its inactive ingredients.

If you get pregnant while taking tamoxifen, stop taking it right away and contact your doctor. Tamoxifen may harm your unborn baby.

Do not take tamoxifen to lower your chance of getting breast cancer if

• You ever had a blood clot that needed medical treatment.
• You are taking medicines to thin your blood, like warfarin, (also called Coumadin^®Coumadin^® is a registered trademark of Bristol-Myers Squibb Pharmaceuticals.).
• Your ability to move around is limited for most of your waking hours.
• You are at risk for blood clots. Your doctor can tell you if you are at high risk for blood clots.
• You do not have a higher than normal chance of getting breast cancer. Your doctor can tell you if you are a high risk woman.

How should I take tamoxifen?

• Swallow the tablet(s) whole, with water or another non-alcoholic liquid. You can take tamoxifen with or without food. Take your medicine every day. It may be easier to remember if you take it at the same time each day.
• If you forget a dose, take it when you remember, then take the next dose as usual. If it is almost time for your next dose or you remember at your next dose, do not take extra tablets to make up the missed dose.
• Take tamoxifen for 5 years, unless your doctor tells you otherwise.

What should I avoid while taking tamoxifen?

• Do not become pregnant while taking tamoxifen or for 2 months after you stop. Tamoxifen can stop hormonal birth control methods from working. Hormonal methods include birth control pills, patches, injections, rings and implants. Therefore, while taking tamoxifen, use birth control methods that don't use hormones, such as condoms, diaphragms with spermicide, or plain IUDs. If you get pregnant, stop taking tamoxifen right away and call your doctor.
• Do not breast-feed. We do not know if tamoxifen can pass through your milk and if it can harm the baby.

What should I do while taking tamoxifen?

• Have regular gynecology check-ups ("female exams"), breast exams and mammograms. Your doctor will tell you how often. These will check for signs of breast cancer and cancer of the endometrium (lining of the uterus). Because tamoxifen does not prevent all breast cancers, and you may get other types of cancers, you need these exams to find any cancers as early as possible.
• Because tamoxifen can cause serious side effects, pay close attention to your body. Signs you should look for are uled in "What are the possible side effects of tamoxifen?"
• Tell all of the doctors that you see that you are taking tamoxifen.
• Tell your doctor right away if you have any new breast lumps.

General information about the safe and effective use of tamoxifen

Medicines are sometimes prescribed for purposes other than those uled in a Medication Guide. Your doctor has prescribed tamoxifen only for you. Do not give it to other people, even if they have a similar condition, because it may harm them. Do not use it for a condition for which it was not prescribed.

This Medication Guide is a summary of information about tamoxifen for women who use tamoxifen to lower their high chance of getting breast cancer or who have DCIS. If you want more information about tamoxifen, ask your doctor or pharmacist. They can give you information about tamoxifen that is written for health professionals. For more information about tamoxifen or breast cancer, please call 1-877-446-3679 (1-877-4-INFO-RX).

Ingredients: tamoxifen citrate, anhydrous lactose, colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate.

This Medication Guide has been approved by the US Food and Drug Administration.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REVISED JANUARY 2007
MG:TAMOX:R2