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Tamoxifen Citrate




Tamoxifen Citrate Tablets, a nonsterodial antiestrogen, are for oral administration and contain 15.2 mg of Tamoxifen Citrate (equivalent to 10 mg of tamoxifen). In addition, each tablet contains as inactive ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

Chemically, Tamoxifen Citrate 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- hydorxy-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 37oC is 0.5 mg/mL and in 0.02 N HCl at 37oC, it is 0.2 mg/mL.

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Tamoxifen Citrate is a nonsteroidal agent which 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 dimethylbezanthracene (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. It is also recognized that tamoxifen displays estrogenic like effects on several sites including the endometrium, bone and lipids.

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

Tamoxifen is extensively metabolized after oral administration. Studies in women reviewing 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 was excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

N-desmethyl tamoxifen was the major metabolite found in patients plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma.

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 for N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for three months of 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 three 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.

Clinical Studies: The Early Breast Cancer Trialists Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985 and again in 1990. In 1992, 10-year outcome data were reported for 29,892 women in 40 randomized trials of adjuvant tamoxifen using doses of 20-40 mg/day for 1-5+ years (median 2 years). Fifty-one percent were entered into trials comparing tamoxifen to no adjuvant therapy and 49% were entered into trials of tamoxifen in combination with chemotherapy vs. the same chemotherapy alone. Twenty-nine percent were < 50 years of age and 71% were >/= to 50 years. Fifty-seven percent were node-positive and 43% were node-negative. Fifty percent of the tumors were estrogen receptor (ER) positive (>/= to 10 fmol/mg), 18% were ER poor (< 10 fmol/mg), and 32% were ER unknown.

The overall recurrence-free survival at 10 years of follow-up was 51.2% for tamoxifen versus 44.7% for control (logrank 2p < 0.00001). Overall survival at 10 years was 58.8% for tamoxifen versus 52.6% for control (logrank 2p < 0.000001). Both the absolute risk of relapse and the absolute benefit of treatment with tamoxifen were greater in women with positive nodes than in women with negative nodes. In women with positive nodes, 10-year recurrence-free survival was 41.9% for tamoxifen versus 33.1% for control (logrank 1p < 0.0002). Ten-year survival was 50.4% for tamoxifen vs. 42.2% for control (lorank 1p < 0.00001). In women with negative nodes, recurrence-free survival was 68.1% for tamoxifen vs. 63.1% for control (logrank 1p < 0.00001). Survival at 10 years was 74.5% for tamoxifen vs. 71.0% for control (logrank 1p = 0.0002).

The reduction in the annual odds of recurrence with tamoxifen was 12% in women < 50 years of age versus 29% in women >/= to 50 years. Similarly, the reduction in the annual odds of death was 6% versus 20%. The reduction in the annual odds of recurrence with tamoxifen was significantly greater in aer positive (32%) than in ER poor (13%) tumor(1p < 0.00001). The reduction in recurrence and mortality was greater in those studies which used tamoxifen for longer (>/= to 2 years) rather than shorter (< 2 years) periods. There was no indication that doses greater than 20 mg per day were more effective.

Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when Tamoxifen Citrate was added to adjuvant cytotoxic chemotherapy. In the Hubay study, Tamoxifen Citrate was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, Tamoxifen Citrate was added to melphalan [L- phenylalanine mustard (P)] and fluorouracil (F).

In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50-59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward averse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60-70 years, there was a trend toward a beneficial effect of Tamoxifen Citrate without any clear relationship to estrogen or progesterone receptor status.

Three prospective studies (ECOG-1178, Toronto, NATO) using Tamoxifen Citrate adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.

One prospective, double-blind, randomized study (NSABP B-14) demonstrated a significant improvement in disease-free survival for Tamoxifen Citrate compared to placebo when used adjuvantly following total mastectomy and axillary dissection or segmental resection, axillary dissection, and breast radiation in women with axillary node-negative breast cancer whose tumors were estrogen receptor positive (>/= 10 fmol/mg cytosol protein). The benefit was apparent in both women under age 50 and those aged 50 years or more. One additional randomized study (NATO) demonstrated improved disease-free survival for Tamoxifen Citrate compared to no adjuvant therapy following total mastectomy and axillary dissection to postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of Tamoxifen Citrate appeared to be independent of estrogen receptor status.

Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared Tamoxifen Citrate to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the three studies, the hazard ratio for death (Tamoxifen Citrate/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving Tamoxifen Citrate. However, the data from the randomized studies do not suggest an adverse effect. A limited number of premenopausal patients with disease progression during Tamoxifen Citrate therapy responded to subsequent ovarian ablation.

In a large randomized trial in Sweden of adjuvant Tamoxifen Citrate 40 mg/day for 2-5 years, the incidence of second primary breast tumors was reduced in the tamoxifen arm (p < 0.05). In the NSABP B-14 trial in which patients were randomized to Tamoxifen Citrate 20 mg/day for 5 years versus placebo, the incidence of second primary breast cancers is also reduced.

Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with Tamoxifen Citrate have shown that Tamoxifen Citrate is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to Tamoxifen Citrate which constitutes a 50% objective response rate.

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Adjuvant Therapy: 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. Data are insufficient to predict which women are most likely to benefit and to determine if Tamoxifen Citrate Tablets provide any benefit in women with tumors less than 1 cm.

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 Citrate adjuvant studies, most of the benefit to date has been in the subgroup with 4 or more positive axillary nodes.

The estrogen and progesterone receptor values may help to predict whether adjuvant Tamoxifen Citrate therapy is likely to be beneficial.

Therapy for Advanced Disease: 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 therapy with Tamoxifen Citrate Tablets.

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Tamoxifen Citrate Tablets are contraindicated in patients with known hypersensitivity to the drug.

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Visual disturbance including corneal changes, cataracts and retinopathy have been reported in patients receiving Tamoxifen Citrate Tablets.

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

An increased incidence of edometrial changes including hyperplasia, polyps, and endometrial cancer has been reported in association with treatment with Tamoxifen Citrate Tablets. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of Tamoxifen Citrate Tablets. Any patients receiving or having previously received Tamoxifen Citrate Tablets who report abnormal vaginal bleeding should be promptly evaluated.

In a large randomized trial in Sweden of adjuvant Tamoxifen Citrate 40 mg/day for 2-5 years, an increased incidence of uterine cancer was noted. Twenty three of 1,372 patients randomized to receive Tamoxifen Citrate versus 4 of 1,357 patients randomized to the observation group developed cancer of the uterus [RR = 5.6 (1.9-16.2), p< 0.001]. One of the patients with cancer of the uterus who was randomized to receive Tamoxifen Citrate never took the drug. After approximately 6.8 years of follow-up in the ongoing NSABP B-14 trial, 15 of 1,419 women randomized to receive Tramoxifen Citrate 20 mg/day for 5 years developed uterine cancer and 2 of the 1,424 women randomized to receive placebo, and who subsequently were treated with Tamoxifen Citrate, also developed uterine cancer. Most of the uterine cancers were diagnosed at an early stage, but deaths from uterine cancer have been reported. Patients receiving Tamoxifen Citrate should have routine gynecological care and they should promptly inform their physician if they experience any menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain or pressure.

Tamoxifen Citrate Tablets have been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to Tamoxifen Citrate Tablets is uncertain. However, some positive rechallenges and dechallenges have been reported.

In the Swedish trial using adjuvant Tamoxifen Citrate 40 mg/day for 2-5 years, 3 cases of liver cancer have been reported in the Tamoxifen Citrate-treated group versus 1 case in the observation group. In other clinical trials evaluating tamoxifen, no other cases of liver cancer have been reported to date.

Data from the NSABP B-14. study show no increase in other (non-uterine) cancers among patients receiving Tamoxifen Citrate Tablets. However, a number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with Tamoxifen Citrate Tablets in clinical trials. Whether an increased risk for other (non-uterine) cancers is associated with Tamoxifen Citrate Tablets is still uncertain and continues to be evaluated.

Pregnancy Category D: Tamoxifen Citrate Tablets may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking Tamoxifen Citrate Tablets and should use barrier or nonhormonal contraceptive measures if sexually active. 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 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 malformation.

In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.3 to 2.4-fold the human maximum recommended 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 adenomas, 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 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.

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

Information for patients: Women taking or having previously taken Tamoxifen Citrate Tablets should be instructed to report abnormal vaginal bleeding which should be promptly investigated.

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

Drug Interactions: When Tamoxifen Citrate Trablets are 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.

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

Tamoxifen, N-desmethyl tamoxifen and 4-Hydroxtamoxifen have been found to be potent inhibitors of hepatic cytochrome p-450 mixed function oxidases. 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.

One patient receiving Tamoxifen Citrate Tablets 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.

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

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 Tamoxifen Citrate Tablets.

In postmarketing experience with Tamoxifen Citrate Tablets, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with pre-existing hyperlipidemias.

Carcinogenesis: A conventional carcinogenesis study in rats (doses of 5,20, and 35 mg/kg/day for up to 2 years) revealed hepatocellular carcinoma at all doses, and the incidence of these tumors was significantly greater among rats given 20 or 35 mg/kg/day (69%) than those given 5 mg/kg/day (14%). The incidence of these tumors in rats given 5 mg/kg/day (29.5 mg/m2) was significantly greater than in controls.

In addition, preliminary data from 2 independent reports of 6-month studies in rats reveal liver tumors which in one study are classified as malignant. (See WARNINGS)

Endocrine changes in immature and mature mice were investigated in a 13-month study. Granulosa cell ovarian tumors and interstital cell testicular tumors were found in mice receiving Tamoxifen Citrate, but not in the controls.

Mutagenesis: Although 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 present,increased levels of DNA adducts have been found in the liver of rats exposed to tamoxifen. Tamoxifen has also 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: Fertility in female rats was decreased following administration of 0.04 mg/kg for two weeks prior to mating through day 7 of pregnancy. There was a decreased number of implantations, and all fetuses were found dead.

Following administration to rats of 0.16 mg/kg from days 7-17 of pregnancy, there were increased numbers of fetal deaths. Administration of 0.125 mg/kg to rabbits during days 6-18 of pregnancy resulted in abortion or premature delivery. Fetal deaths occurred at higher doses. There were no teratogenic changes in either rat or rabbit segment II studies. Several pregnant marmosets were dosed with 10 mg/kg/day either 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. Rats given 0.16 mg/kg from day 17 of pregnancy to 1 day before weaning demonstrated increased numbers of dead pups at parturition. It was reported that some rat pups showed slower learning behavior, but this did not achieve statistial significance in one study, and in another study where significance was reported, this was obtained by comparing dosed animals with controls of another study.

The recommended daily human dose of 20-40 mg corresponds to 0.4-0.8 mg/kg for an average 50 kg woman.

Pregnancy Category D: See WARNINGS.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Tamoxifen Citrate Tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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Adverse reactions to Tamoxifen Citrate Tablets are relatively mild and rarely severe enough to require discontinuation of treatment. If adverse reactions are severe, it is sometimes possible to control them by a simple reduction of dosage without loss of control of the disease.

In patients treated with Tamoxifen Citrate Tablets for metastatic breast cancer, the most frequent adverse reactions to Tamoxifen Citrate Tablets are hot flashes and nausea and/or vomiting. These may occur in up to one-fourth of patients.

Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities and skin rash. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment.

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, bone pain or disease flare are seen shortly after starting Tamoxifen Citrate Tablets and generally subside rapidly.

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 hairloss, and vaginal dryness.

Tamoxifen Citrate Tablets have been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to Tamoxifen Citrate Tablets is uncertain. However, some positive rechallenges and dechallenges have been reported.

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

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

In the ongoing NSABP study B-14, women with axillary nodenegative breast cancer were randomized to 5 years of Tamoxifen Citrate 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years). The incidence of hot flashes (64% vs 48%), vaginal discharge (30% v 15%), and irregular menses (25% v 19%) were higher with Tamoxifen Citrate compared with placebo. All other adverse effects occurred with similar frequency in the two treatment groups, with the exception of thrombotic events, which although rare, were more common with Tamoxifen Citrate than with placebo. Two of the patients treated with Tamoxifen Citrate who had thrombotic events died.

NSABP B-14 Study

                                       % of Women

                           Tamoxifen Citrate    Placebo

Adverse Effect                  (n=1424)        (n=1440)

Hot Flashes 63.9 47.6 Weight Gain (>5%) 38.1 40.1 Fluid Retention 32.4 29.7 Vaginal Discharge 29.6 15.2 Nausea 25.7 23.9 Irregular Menses 24.6 18.8 Weight Loss (>5%) 22.6 18.0 Skin Changes 18.7 15.3 Increased BUN 18.1 20.2 Diarrhea 11.2 14.0 Increased SGOT 4.8 2.8 Increased Alkaline Phosphatase 3.0 4.6 Vomiting 2.1 1.7 Increased Bilirubin 1.8 1.2 Increased Creatinine 1.7 1.0 Thrombocytopenia* 1.5 1.2 Leukopenia** 0.4 1.1 Thrombotic Events Deep Vein Thrombosis 0.8 0.3 Pulmonary Embolism 0.4 0.1 Superficial Phlebitis 0.3 0.0
*Defined as a platelet count of <100,000/mm3 **Defined as a white blood cell count of <3000/mm3
In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, Tamoxifen Citrate or placebo was administered for 2 years to women following mastectomy. When compared to placebo, Tamoxifen Citrate showed a significantly higher incidence of hot flashes (19% versus 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 Citrate was 10% versus 3% for placebo, an observation of borderline statistical significance.

The other adverse reactions reported equally in the ECOG study for Tamoxifen Citrate and placebo include abnormal renal function tests, fatigue, dyspnea, anorexia, cough, and abdominal cramps. A relationship of these reactions to the administration of Tamoxifen Citrate has not been demonstrated since the frequency was not significantly different from that reported in placebo treated women.

In other adjuvant studies, Toronto and NOLVADEX Adjuvant Trial Organization (NATO), women received either Tamoxifen Citrate or no therapy. In the Toronto Study, hot flashes and nausea and/or vomiting were observed in 29% and 19% of patients, respectively, for Tamoxifen Citrate versus 1% and 0% in the untreated group. In the NATO trial, hot flashes, nausea and/or vomiting and vaginal bleeding were reported in 2.8%, 2.1% and 2.0% of women, respectively, for Tamoxifen Citrate versus 0.2% for each in the untreated group.

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 Citrate therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.

                            Tamoxifen Citrate   Ovarian Ablation

                               All Effects         All Effects

                                Number of           Number of

                                Women (%)           Women (%)

Adverse Reaction* n=104 n=100
Flush 34 (32.7) 46 (46) Amenorrhea 17 (16.3) 69 (69) Altered Menses 13 (12.5) 5 (5) Oligomenorrhea 9 (8.7) 1 (1) Bone Pain 6 (5.7) 6 (6) Menstrual Disorder 6 (5.7) 4 (4) Nausea 5 (4.8) 4 (4) Cough/Coughing 4 (3.8) 1 (1) Edema 4 (3.8) 1 (1) Fatigue 4 (3.8) 1 (1) Musculoskeletal Pain 3 (2.8) 0 (0) Pain 3 (2.8) 4 (4) Ovarian Cyst(s) 3 (2.8) 2 (2) Depression 2 (1.9) 2 (2) Abdominal Cramps 1 (1) 2 (2) Anorexia 1 (1) 2 (2)
*Some women had more than one adverse reaction.
Tamoxifen Citrate is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of Tamoxifen Citrate 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.

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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 Citrate 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 3-5 days of beginning Tamoxifen Citrate and cleared within 2-5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after Tamoxifen Citrate was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to Tamoxifen Citrate 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.

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In women and men with metastatic breast cancer, one or two 10 mg tablets are administered twice a day (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 (see CLINICAL PHARMACOLOGY). In B-14, the ongoing NSABP adjuvant study in women, one 10 mg Tamoxifen Citrate Tablet is being given twice a day for five years. In the EBCTCG 1990 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for two years or longer than in those that used tamoxifen for less than two years. There was no indication that doses greater than 20 mg per day were more effective. The optimal duration of adjuvant therapy is not known.

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Tablets containing tamoxifen as the citrate in an amount equivalent to 10 mg of tamoxifen (round, biconvex, uncoated, white tablet identified with "446" on one side and "barr" debossed on the other side) are supplied in bottles of 60 tablets and 250 tablets.

Store at controlled room temperature, 20o-25oC (68o-77oF) [see USP]. NDC 0555-0446.

POMONA, NY 10970

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