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 14C Tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.
Special Populations
The effects of age, gender and race on the pharmacokinetics of Tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of Tamoxifen have not been determined.
Pediatric PatientsThe 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 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 4,110 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 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 for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Tamoxifen therapy in 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).
Drug-Drug Interactions
In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl Tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown.
Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced Tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces Tamoxifen and N-desmethyl Tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not Tamoxifen.
In the anastrozole adjuvant trial, coadministration of anastrozole and Tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of Tamoxifen or N-desmethylTamoxifen (see PRECAUTIONS, Drug Interactions). Tamoxifen should not be coadministered with anastrozole.
Clinical Studies
Metastatic Breast Cancer Premenopausal women (Tamoxifen vs. ablation)
Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared Tamoxifen 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/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, 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 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 have shown that Tamoxifen is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to Tamoxifen 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 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 unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing Tamoxifen to no adjuvant therapy and 42% were entered into trials comparing Tamoxifen in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease.
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 Tamoxifen vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for Tamoxifen 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 Tamoxifen vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for Tamoxifen vs. 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 Tamoxifen, 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).
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 Tamoxifen 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.
Anastrozole adjuvant ATAC trial – study of anastrozole compared to Tamoxifen for adjuvant treatment of early breast cancer
An anastrozole adjuvant trial was conducted in 9,366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, Tamoxifen 20 mg daily, or a combination of these two treatments for 5 years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and Tamoxifen did not demonstrate any efficacy benefit when compared with Tamoxifen 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 and Drug-Drug Interactions; PRECAUTIONS, Laboratory Tests; PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS for safety information from this trial. Please refer to the full prescribing information for 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 Tamoxifen arm.
Node positive – individual studies
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 was added to adjuvant cytotoxic chemotherapy. In the Hubay study, Tamoxifen was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, Tamoxifen 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 to 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 adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60 to 70 years, there was a trend toward a beneficial effect of Tamoxifen without any clear relationship to estrogen or progesterone receptor status.
Three prospective studies (ECOG-1178, Toronto, NATO) using Tamoxifen 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.
Node negative – individual studies
NSABP B-14, a prospective, double-blind, randomized study, compared Tamoxifen to placebo in women with axillary node-negative, estrogen-receptor positive (≥ 10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving Tamoxifen. This benefit was apparent both in women under age 50 and in women at or beyond age 50.
One additional randomized study (NATO) demonstrated improved disease-free survival for Tamoxifen compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of Tamoxifen appeared to be independent of estrogen receptor status.
Duration of therapy
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.
In the NSABP B-14 trial, in which patients were randomized to Tamoxifen 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5 year period were offered rerandomization to an additional 5 years of Tamoxifen or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of Tamoxifen were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of Tamoxifen (p = 0.003). Overall survivals were 96% and 94%, respectively (p = 0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit.
A Scottish trial of 5 years of Tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR = 1.27, 95% CI: 0.87 to 1.85).
In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant Tamoxifen 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5 year Tamoxifen group, compared with 74% among corresponding patients in the 2 year treatment group (p = 0.03). Disease-free survival at 10 years was 73% in the 5 year group and 67% in the 2 year group (p = 0.009). Compared with 2 years of Tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant.
Contralateral breast cancer
The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving Tamoxifen compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with Tamoxifen of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving Tamoxifen were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer Tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of Tamoxifen reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the Tamoxifen group.
In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant Tamoxifen 40 mg/day for 2 to 5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on Tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to Tamoxifen 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1,000 patients in the placebo group compared with 5.0 per 1,000 patients in the Tamoxifen group, at 10 years after first randomization.
Ductal Carcinoma in SituNSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of Tamoxifen or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of Tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.
In this trial 1,804 women were randomized to receive either Tamoxifen or placebo for 5 years: 902 women were randomized to Tamoxifen citrate 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months.
The Tamoxifen and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis.
For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to Tamoxifen (44 cases-Tamoxifen, 74 cases-placebo; p = 0.004; relative risk (RR) = 0.57, 95% CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base.
Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and Tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between Tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of Tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of Tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.
Table 1: Major Outcomes of the NSABP B-24 Trial
|
| Type of Event |
Lumpectomy, radiotherapy, and placebo |
Lumpectomy, radiotherapy, and Tamoxifen |
RR |
95% CI limits |
|
No. of events |
Rate per 1,000 women per year |
No. of events |
Rate per 1,000 women per year |
|
|
| Invasive breast cancer (Primary endpoint) |
74 |
16.73 |
44 |
9.60 |
0.57 |
0.39 to 0.84 |
| Ipsilateral |
47 |
10.61 |
27 |
5.90 |
0.56 |
0.33 to 0.91 |
| Contralateral |
25 |
5.64 |
17 |
3.71 |
0.66 |
0.33 to 1.27 |
| Side undetermined |
2 |
-- |
0 |
-- |
-- |
|
| Secondary Endpoints |
|
|
|
|
|
|
| DCIS |
56 |
12.66 |
41 |
8.95 |
0.71 |
0.46 to 1.08 |
| Ipsilateral |
46 |
10.40 |
38 |
8.29 |
0.88 |
0.51 to 1.25 |
| Contralateral |
10 |
2.26 |
3 |
0.65 |
0.29 |
0.05 to 1.13 |
| All Breast Cancer Events |
129 |
29.16 |
84 |
18.34 |
0.63 |
0.47 to 0.83 |
| All ipsilateral events |
96 |
21.70 |
65 |
14.19 |
0.65 |
0.47 to 0.91 |
| All contralateral events |
37 |
8.36 |
20 |
4.37 |
0.52 |
0.29 to 0.92 |
| Deaths |
32 |
|
28 |
|
|
|
| Uterine Malignancies |
4 |
|
9 |
|
|
|
| Endometrial Adenocarcinoma* |
4 |
0.57 |
8 |
1.15 |
|
|
| Uterine Sarcoma* |
0 |
0.0 |
1 |
0.14 |
|
|
| Second primary malignancies (other than endometrial and breast) |
30 |
|
29 |
|
|
|
| Stroke |
2 |
|
7 |
|
|
|
| Thromboembolic events (DVT, PE) |
5 |
|
15 |
|
|
|
Survival was similar in the placebo and Tamoxifen groups. At 5 years from study entry, survival was 97% for both groups.
Reduction in Breast Cancer Incidence in High Risk WomenThe Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of Tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (see INDICATIONS AND USAGE). Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of Tamoxifen, including: endometrial cancer, pulmonary embolus, deep-vein thrombosis, stroke, and cataract formation and surgery (see WARNINGS).
The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5 year predicted risk of breast cancer of ≥ 1.67% was required for entry into the trial.
In this trial, 13,388 women of at least 35 years of age were randomized to receive either Tamoxifen or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to Tamoxifen (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2.
Table 2: Demographic Characteristics of Women in the NSABP P-1 Trial
| Characteristic |
Placebo |
Tamoxifen |
| |
# |
% |
# |
% |
| Age (yrs.) |
| 35 to 39 |
184 |
3 |
158 |
2 |
| 40 to 49 |
2,394 |
36 |
2,411 |
37 |
| 50 to 59 |
2,011 |
31 |
2,019 |
31 |
| 60 to 69 |
1,588 |
24 |
1,563 |
24 |
| ≥ 70 |
393 |
6 |
393 |
6 |
| Age at first live birth (yrs.) |
| Nulliparous |
1,202 |
18 |
1,205 |
18 |
| 12 to 19 |
915 |
14 |
946 |
15 |
| 20 to 24 |
2,448 |
37 |
2,449 |
37 |
| 25 to 29 |
1,399 |
21 |
1,367 |
21 |
| ≥ 30 |
606 |
9 |
577 |
9 |
| Race |
| White |
6,333 |
96 |
6,323 |
96 |
| Black |
109 |
2 |
103 |
2 |
| Other |
128 |
2 |
118 |
2 |
| Age at menarche |
| ≥ 14 |
1,243 |
19 |
1,170 |
18 |
| 12 to 13 |
3,610 |
55 |
3,610 |
55 |
| ≤ 11 |
1,717 |
26 |
1,764 |
27 |
| # of first degree relatives with breast cancer |
| 0 |
1,584 |
24 |
1,525 |
23 |
| 1 |
3,714 |
57 |
3,744 |
57 |
| 2+ |
1,272 |
19 |
1,275 |
20 |
| Prior hysterectomy |
| No |
4,173 |
63.5 |
4,018 |
62.4 |
| Yes |
2,397 |
36.5 |
2,464 |
37.7 |
| # of previous breast biopsies |
| 0 |
2,935 |
45 |
2,923 |
45 |
| 1 |
1,833 |
28 |
1,850 |
28 |
| ≥ 2 |
1,802 |
27 |
1,771 |
27 |
| History of atypical hyperplasia in the breast |
| No |
5,958 |
91 |
5,969 |
91 |
| Yes |
612 |
9 |
575 |
9 |
| History of LCIS at entry |
| No |
6,165 |
94 |
6,135 |
94 |
| Yes |
405 |
6 |
409 |
6 |
| 5 year predicted breast cancer risk (%) |
| ≤ 2.00 |
1,646 |
25 |
1,626 |
25 |
| 2.01 to 3.00 |
2,028 |
31 |
2,057 |
31 |
| 3.01 to 5.00 |
1,787 |
27 |
1,707 |
26 |
| ≥ 5.01 |
1,109 |
17 |
1,162 |
18 |
|
|
|
|
|
| Total |
|
