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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.
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.
Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady-state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg NOLVADEX tablets given twice a day vs. a 20 mg NOLVADEX tablet given once daily, the 20 mg NOLVADEX tablet was bioequivalent to the 10 mg NOLVADEX tablets.
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. 2
Excretion: Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.
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 NOLVADEX 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 (Css, max) and AUC were of 187 ng/mL and 4110 ng hr/mL, respectively, and Css, 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 (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9 year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between pediatric and adult patients. The safety and efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of NOLVADEX therapy in girls have not been established. In adults treated with NOLVADEX, an increase in the incidence of uterine malignancies, stroke, and pulmonary embolism has been noted (see BOXED WARNING).
In vitro studies showed that erythromycin, cyclosporin, nifedipine, and diltiazem competitively inhibited the formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown. Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. 3 In the anastrozole adjuvant trial, co-administration of anastrozole and NOLVADEX 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). NOLVADEX should not be co-administered with anastrozole.
Premenopausal Women (NOLVADEX vs. Ablation): Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared NOLVADEX 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 (NOLVADEX/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 NOLVADEX, 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 NOLVADEX 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 NOLVADEX have shown that NOLVADEX is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to NOLVADEX 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 NOLVADEX using doses of 20-40 mg/day for 1-5+ 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 unknown. Among 29,441 patients with ER-positive or unknown breast cancer, 58% were entered into trials comparing NOLVADEX to no adjuvant therapy and 42% were entered into trials comparing NOLVADEX in combination with chemotherapy vs. the same chemotherapy alone.
Among these patients, 54% had node-positive disease and 46% had node negative disease. 4
Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for NOLVADEX vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for NOLVADEX vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for NOLVADEX vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for NOLVADEX versus 64.3% for control (logrank 2p < 0.00001).
The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of NOLVADEX, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001).
The benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of NOLVADEX on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective.
An anastrozole adjuvant trial was conducted in 9366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, NOLVADEX 20 mg daily, or a combination of these two treatments for five years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and NOLVADEX did not demonstrate any efficacy benefit when compared with NOLVADEX therapy alone in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial.
Please refer to CLINICAL PHARMACOLOGY-Special Populations-Drug-Drug Interactions, PRECAUTIONS-Laboratory Tests, PRECAUTIONS-Drug Interactions and ADVERSE REACTIONS sections for safety information from this trial.
Please refer to the full prescribing information for ARIMIDEX® (anastrozole) 1 mg Tablets for additional information on this trial.
Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the anastrozole arm compared to the NOLVADEX arm.
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