tamoxifen 40 MG Oral Tablet

INDICATIONS AND USAGE 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 ).

DOSAGE AND ADMINISTRATION 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. Ductal Carcinoma in Situ (DCIS): The recommended dose is tamoxifen citrate tablets 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 ).

WARNINGS AND PRECAUTIONS Uterine malignancies: Promptly evaluate abnormal vaginal bleeding in a woman with current or past tamoxifen use. ( 5.1 ) Thromboembolic events: Risk increases with coadministered chemotherapy. For treatment of breast cancer, consider risks and benefits in patients with a history of thromboembolic events. ( 5.2 ) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) Effects on the liver: Liver cancer and liver abnormalities, some fatal, have occurred. Perform periodic liver function testing. ( 5.4 , 5.9 ) 5.1 Endometrial Cancer, Uterine Sarcoma, and Other Effects on the Uterus Endometrial Cancer and Uterine Sarcoma An increased incidence of uterine malignancies (endometrial adenocarcinoma and uterine sarcoma), including fatal cases, has been reported with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen with tamoxifen are classified as adenocarcinoma of the endometrium; however, uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. Uterine sarcoma was generally associated with a higher FIGO stage (III/IV) at diagnosis, poor prognosis, and short survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥2 years) of tamoxifen than non-users. Promptly evaluate any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding. Patients receiving or who have previously received tamoxifen should have annual gynecological examinations. Advise patients to promptly inform a healthcare provider if they experience any abnormal gynecological symptoms (e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure). There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen is beneficial. In a review of long-term data (median length of total follow-up was 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and uterine sarcomas was increased in women taking tamoxifen. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and 1 patient randomized to placebo (FIGO IA); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the 1 patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in 5 other NSABP clinical trials. In the NSABP P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women who had not undergone hysterectomy. Non-Malignant Effects on the Uterus An increased incidence of endometrial changes including hyperplasia and polyps has been reported with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the partial estrogenic effect of tamoxifen. There have been reports of endometriosis and uterine fibroids in women receiving tamoxifen. Ovarian cysts have also been observed in premenopausal patients with advanced breast cancer who have been treated with tamoxifen. Tamoxifen has been reported to cause menstrual irregularity or amenorrhea. 5.2 Thromboembolic Events There is an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there is a further increase in the risk of thromboembolic events. For treatment of breast cancer, carefully consider the risks and benefits of tamoxifen in women with a history of thromboembolic events. For women with DCIS and for the reduction in breast cancer incidence in women at high risk, tamoxifen is contraindicated in women who require concomitant warfarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus. Advise patients to seek medical attention immediately if signs or symptoms of a thromboembolic event occur. Data from the NSABP P-1 trial in women at high risk for breast cancer show that participants receiving tamoxifen without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (events: 18 tamoxifen, 6 placebo; incidence rate per 1,000 women-years: 0.75 tamoxifen versus 0.25 placebo; RR = 3.01, 95% CI: 1.15 to 9.27) [see Clinical Studies (14.4) ]. 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, PE events occurred 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; relative risk (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 thromboembolic event and treatment related complications (0/25 on placebo, 4/48 on tamoxifen). Among women receiving tamoxifen, DVT events occurred between 2 and 57 months (average = 19 months) from the start of treatment. In a small substudy (N = 81) of the NSABP-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. In the NSABP P-1 trial, there was an increase in stroke among women randomized to tamoxifen compared to women randomized to placebo (events: 24 placebo; 34 tamoxifen; incidence rate per 1,000 women-years: 1.43 tamoxifen versus 1.00 placebo; 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. Three 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 stroke events occurred between 1 and 63 months (average = 30 months) from the start of treatment. 5.3 Embryo-Fetal Toxicity Tamoxifen can cause fetal harm when administered to a pregnant woman. There a

CONTRAINDICATIONS SOLTAMOX is contraindicated in patients with known hypersensitivity (e.g., angioedema, serious skin reactions) to tamoxifen or any other SOLTAMOX ingredient [see Adverse Reactions (6.2) ] . SOLTAMOX is contraindicated in patients who require concomitant warfarin therapy or have a history of deep vein thrombosis or pulmonary embolus if the indication for treatment is either reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS [see Warnings and Precautions (5.2) and Drug Interactions (7.2) ]. Known hypersensitivity to tamoxifen or any other SOLTAMOX ingredient ( 4 ) In patients who require concomitant warfarin therapy or have a history of deep vein thrombosis or pulmonary embolus, if the indication for treatment is either reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS ( 4 )

CLINICAL PHARMACOLOGY Tamoxifen citrate is a nonsteroidal 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. 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 14 C 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. Pediatric Patients: The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of tamoxifen citrate in treating McCune-Albright Syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data. In pediatric patients, an average steady state peak plasma concentration (C ss , max ) and AUC were of 187 ng/mL and 4110 ng hr/mL, respectively, and C ss , max occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2 to 6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7 to 10.9 year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of tamoxifen citrate 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 citrate therapy in girls have not been established. In adults treated with tamoxifen citrate an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING ). Drug-Drug Interactions: In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K 1 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, co-administration of anastrozole and tamoxifen citrate 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-desmethyltamoxifen (see PRECAUTIONS -Drug Interactions ). Tamoxifen citrate should not be co-administered with anastrozole. Clinical Studies Metastatic Breast Cancer: Premenopausal Women (Tamoxifen Citrate vs. Ablation): 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 3 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, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during tamoxifen citrate therapy responded to subsequent ovarian ablation. Male Breast Cancer: 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. Adjuvant Breast Cancer: Overview: The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant tamoxifen citrate using doses of 20 to 40 mg/day for 1 to 5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER