VA Class:AN500

AHFS Class:

• Estrogen Agonists-Antagonists 68:16.12

Generic Name(s):

• Tamoxifen Citrate

Chemical Name:

• 2-Hydroxy-1,2,3-propanetricarboxylate-( Z )-2-[4-(1,2-diphyl-1-butenyl)phenoxy]- N , N dimethyl ethanamine

Molecular Formula:

• C₂₆H₂₉NO•C₆H₈O₇

Tamoxifen, a triphenylethylene-derivative, nonsteroidal estrogen agonist-antagonist, is an antineoplastic agent.

Breast Cancer

Adjuvant Therapy

Tamoxifen is used as an adjunct to surgery and radiation therapy for the treatment of breast cancer in women with positive or negative axillary lymph nodes.110,121,128,130,133,136,194,195,196,198,204,205,253,254,258,396 Adjuvant tamoxifen therapy reduces the occurrence of contralateral breast cancer in premenopausal or postmenopausal women with breast cancer.128,253,254,258,396

Systematic overviews of randomized clinical studies evaluating the effects of adjuvant tamoxifen therapy for early breast cancer have been conducted at regular intervals and have shown increases in 10-year survival and disease-free survival rates in patients receiving tamoxifen 20-40 mg daily for 1-5 years or longer (median 2 years).128,253,254,255,364 Among women with estrogen receptor-positive or estrogen receptor-unknown breast cancer and positive nodes who received about 5 years of tamoxifen therapy, overall survival at 10 years was 61.4% compared with 50.5% for patients who did not receive tamoxifen.128,253 Among women with estrogen receptor-positive or estrogen receptor-unknown breast cancer and negative nodes who received about 5 years of tamoxifen therapy, overall survival at 10 years was 78.9% compared with 73.3% for patients who did not receive tamoxifen.128,253 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.128,253,254 Greater reductions in disease recurrence and mortality were observed in patients with estrogen receptor-positive or estrogen receptor-unknown tumors than those with estrogen receptor-negative tumors.128,364,365 The reduction in disease recurrence and mortality was greater in those studies that used tamoxifen for about 5 years rather than shorter periods.128,253 There was no indication that dosages exceeding 20 mg daily were more effective.128,253 About 5 years of tamoxifen therapy generally reduced the rate of recurrence by one-third to one-half throughout the initial 10 years and reduced disease mortality by approximately one-third throughout the initial 15 years in women with estrogen receptor-positive breast cancer.365,366 Absolute risk reductions were independent of progesterone receptor status, patient age, axillary lymph node status, or use of chemotherapy.365

Data from 2 large randomized phase 3 clinical studies (Adjuvant Tamoxifen: Longer Against Shorter [ATLAS] and Adjuvant Tamoxifen—To Offer More? [aTTom]) indicate that extended adjuvant tamoxifen therapy for 10 years further reduces the risk of breast cancer mortality and recurrence.332,333,335 In these studies, women who received adjuvant therapy with tamoxifen for 5 years were randomized to discontinue tamoxifen or to continue the drug for an additional 5 years (for a total of 10 years of adjuvant tamoxifen therapy).333,335 In the ATLAS study, extended adjuvant tamoxifen therapy reduced the risk of breast cancer mortality or recurrence by 3 or 10%, respectively, during years 5-9 and by 29 or 25%, respectively, beyond 10 years in women with estrogen receptor-positive breast cancer.335 In the aTTom trial, similar reductions in breast cancer mortality and recurrence were observed in women with estrogen receptor-positive or estrogen receptor-unknown breast cancer who received extended adjuvant tamoxifen therapy.333 Endometrial cancer occurred more frequently in patients who received extended adjuvant tamoxifen therapy compared with those who received 5 years of therapy in the ATLAS (3.1 versus 1.6% cumulative risk) and aTTom (2.9 versus 1.3% incidence) studies;332,335,338 an increased risk of pulmonary embolism also was observed in those receiving extended therapy.332,335

Because the risk for breast cancer recurrence following 5 years of therapy is low in patients with small tumors and/or node-negative disease compared with those with large tumors and/or node-positive disease, the magnitude of benefit derived from extended therapy is expected to be lower in patients with lower-stage disease.332 Experts previously recommended an optimum duration of adjuvant tamoxifen therapy of 5 years in premenopausal women with hormone receptor-positive breast cancer, and a minimum of 5 years of adjuvant endocrine therapy (i.e., aromatase inhibitor or tamoxifen followed by an aromatase inhibitor for a total of at least 5 years) in those who are postmenopausal.332 Based on current evidence, the American Society of Clinical Oncology (ASCO) and other experts recommend continuation of initial adjuvant tamoxifen therapy for an additional 5 years (for a total of 10 years) in premenopausal or perimenopausal women and, in postmenopausal women who received 5 years of initial adjuvant tamoxifen therapy, an option of continuing tamoxifen or switching to an aromatase inhibitor for an additional 5 years (for a total of 10 years).332,338 The potential benefits of extended adjuvant endocrine therapy and drug cost, adverse effects, and risks associated with an extended duration of therapy also should be considered.332,338

Tamoxifen is used as an adjunct to surgery and radiation therapy in the treatment of breast cancer in women with negative axillary lymph nodes.110,121,128,130,133,194,195,196,198,204,205,253,254 Several controlled studies have demonstrated an improvement in disease-free survival for women with node-negative breast cancer who received adjuvant therapy with tamoxifen110,121,195,196,205,253,254 or combination chemotherapy194,195,208,209,210,253,254 compared with no therapy until relapse.136,194,196,253,254 Adjuvant therapy with tamoxifen has been associated with reductions in tumor recurrence at both local and distant sites, including reductions in new primary tumors in the contralateral breast, with a relatively low incidence of clinically important adverse effects.194,196 Data indicate that adjuvant therapy with tamoxifen or combination chemotherapy generally reduces the rate of recurrence by one-fourth to one-third,110,194,196,198,201,253,254 although the reduction in absolute risk of recurrence appears to be relatively modest (e.g., 4-15%).194,201,204,206 Although all patients with node-negative breast cancer are at some risk for recurrence, patients with tumors smaller than 0.5 cm in diameter have a favorable prognosis, and the clinical benefit of adjuvant systemic therapy in these patients is minimal;338,368 adjuvant systemic therapy generally is not recommended in such patients, but some experts state that use of adjuvant endocrine therapy with or without sequential combination chemotherapy in patients with node-negative disease should be individualized based on consideration of the risk of recurrent disease without such adjuvant therapy, the expected reduction in risk and improvement in quality of life with such adjuvant therapy, and the potential adverse effects of such therapy.338 For patients with large tumors (exceeding 0.5 cm in diameter) and node-negative, hormone receptor-positive disease, ASCO and other experts state that the decision regarding use of adjuvant endocrine therapy with or without sequential combination chemotherapy may be guided by prognostic tools, such as the recurrence score based on 21-gene assay results, to predict the absolute benefits of combination chemotherapy in addition to adjuvant endocrine therapy.338,367,369

Tamoxifen also is used as an adjunct to surgery and radiation therapy in the treatment of breast cancer in women with positive axillary lymph nodes.100,101,102,110,111,112,113,116,121,128,129,133,134,250,253,258 Numerous studies have shown that adjuvant therapy with tamoxifen alone increases disease-free survival in postmenopausal women whose tumors contain hormone receptors and who have positive axillary lymph nodes.100,101,102,110,111,112,113,116,129,136,250,253,258 The therapeutic benefit of tamoxifen alone may correlate with increasing quantity of hormone receptors in the tumor and may be greatest in patients with 4 or more positive nodes.112 Tamoxifen also has been used in conjunction with combination chemotherapy as adjuvant therapy following surgery in patients with positive nodes.114,115,122,127,129,135,253,254,258,338 Several studies indicate that disease-free survival in postmenopausal women with hormone receptor-containing tumors and positive nodes is greater following adjuvant therapy consisting of sequential tamoxifen and combination chemotherapy than following adjuvant therapy consisting of combination chemotherapy alone,113,114,115,124,127,129,135,253,254,258 but some data suggest that the benefit may be limited to the subgroup of patients with 4 or more positive nodes.129,135 Although the addition of combination chemotherapy to standard endocrine therapy is recommended in most patients with hormone receptor-positive tumors and positive nodes, some experts state that prognostic tools, such as the recurrence score based on 21-gene assay results, may be used to guide the decision to add adjuvant chemotherapy to endocrine therapy in certain patients with early-stage hormone receptor-positive breast cancer with 1-3 positive ipsilateral nodes.338

Combination Therapy with Ovarian Suppression

Endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) has been used in combination with ovarian suppression† as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer in several open-label phase 3 studies.10010,10011,10013,10023,10026

In the Suppression of Ovarian Function Trial (SOFT), 3066 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, tamoxifen 20 mg daily and ovarian suppression, or exemestane 25 mg daily and ovarian suppression.10010 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10010 Approximately one-half (53%) of patients enrolled in the study had received prior adjuvant chemotherapy.10010 The primary analysis involved comparison of tamoxifen and ovarian suppression with tamoxifen alone.10010 At a median follow-up of 8 years, disease-free survival and overall survival were prolonged, without a reduction in distant recurrences, in women receiving tamoxifen and ovarian suppression compared with those receiving tamoxifen alone; a disease-free survival benefit and a reduction in distant recurrences were observed, without an overall survival benefit, in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen alone.10012 (See Table 1.)

Subgroup analysis in the SOFT study suggested that the relative clinical benefits of the 3 treatments generally were similar regardless of prior use of adjuvant chemotherapy; however, no difference in disease-free survival was observed with the addition of ovarian suppression to tamoxifen therapy in patients at lower risk of breast cancer recurrence (i.e., older age, node-negative disease, low-grade tumor, smaller tumor size) who had not required prior adjuvant chemotherapy.10010,10012,10017 The absolute benefit of combined endocrine and ovarian suppression therapy was greater in higher-risk patients who had received adjuvant chemotherapy.10012 The absolute difference in 8-year disease-free survival rates between women receiving exemestane and ovarian suppression and those receiving tamoxifen alone was greater in women at higher risk of breast cancer recurrence (i.e., younger age, larger or high-grade tumor, lymph node involvement10010,10012 ) who had received prior adjuvant chemotherapy (9%) compared with those in the lower-risk cohort (5.2%).10012 The absolute difference in 8-year disease-free survival rates between women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone also was greater in women in the higher-risk cohort (5.3%) compared with those in the lower-risk cohort (3.2%).10012

A combined analysis of the SOFT study and the Tamoxifen and Exemestane Trial (TEXT) included data for 4690 premenopausal women with hormone receptor-positive operable breast cancer who were randomized to receive ovarian suppression and either exemestane 25 mg daily or tamoxifen 20 mg daily for 5 years.10011 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10011 In patients who received adjuvant chemotherapy in the TEXT study, triptorelin was initiated concomitantly with chemotherapy.10011 Approximately one-half (57.4%) of patients in the combined analysis received adjuvant chemotherapy.10011 A 5-year disease-free survival benefit and higher 5-year rates of freedom from breast cancer and freedom from distant recurrence were observed in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression.10011 Beneficial effects of combined exemestane and ovarian suppression therapy on disease-free survival and distant recurrences were maintained at 8 years.10012 (See Table 2.) Musculoskeletal symptoms (89.9 versus 77.8%) and osteoporosis (42.2 versus 27.9%) occurred more frequently in exemestane-treated patients compared with tamoxifen-treated patients.10012

In the HOBOE study, 1065 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, letrozole 2.5 mg daily, or letrozole 2.5 mg daily in combination with zoledronic acid 4 mg IV every 6 months; all patients received ovarian suppression with triptorelin 3.75 mg by IM injection every 4 weeks for 5 years or until the age of 55 years.10026 The majority (62.6%) of patients had received prior neoadjuvant or adjuvant chemotherapy.10026 At a median follow-up of approximately 5.3 years, a substantial disease-free survival benefit was observed in women receiving letrozole in combination with zoledronic acid and ovarian suppression (hazard ratio of 0.52, which corresponded to an absolute improvement in disease-free survival of 7.9%) but not in those receiving letrozole and ovarian suppression (hazard ratio of 0.72 with a 95% confidence interval of 0.48-1.07), compared with women receiving tamoxifen and ovarian suppression.10026 No difference in overall survival was observed among the 3 treatment groups.10026 However, at the time of the analysis, only 81% of the number of events required for final analysis had occurred.10026 Among patients receiving either letrozole or tamoxifen in combination with ovarian suppression, hypercholesterolemia (30.4 versus 20.3%), arthralgia (44.5 versus 22%), bone pain (29 versus 15.3%), insomnia (8.1 versus 4.2%), sensory neuropathy (13 versus 7.7%), and vaginal dryness ( 20.8 versus 11.7%) occurred more frequently in those receiving letrozole, while endometrial abnormalities (3 versus 6.8%) occurred more frequently in those receiving tamoxifen.10026

In the E-3193/INT-0142 study, 345 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive tamoxifen 20 mg daily with or without ovarian suppression for 5 years.10013 Ovarian suppression therapy could be achieved with goserelin 3.6 mg implanted subcutaneously every 4 weeks, leuprolide acetate 3.75 mg by IM injection every 4 weeks, bilateral oophorectomy, or bilateral ovarian irradiation.10013 Patients enrolled in the study had baseline characteristics associated with lower risk of breast cancer recurrence (i.e., node-negative disease, tumor size of 3 cm or less, no prior adjuvant chemotherapy, median age 45 years).10013,10017 At a median follow-up of approximately 9.9 years, results of this study were consistent with those of the SOFT study, demonstrating no difference in disease-free or overall survival between lower-risk women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone; however, interpretation of the results is limited by failure to meet the accrual goal of 1600 patients for superiority testing.10013,10017 In this study, the addition of ovarian suppression to tamoxifen therapy was associated with increased menopausal symptoms, decreased sexual function, increased breast cancer-specific symptoms, and lower quality of life during the first 3 years of therapy.10013

Based on current evidence,10010,10011,10012,10013,10023,10026 use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression as adjuvant therapy may be considered a reasonable choice (accepted) in premenopausal women with early-stage hormone receptor-positive breast cancer at higher risk of disease recurrence (i.e., younger age, larger or high-grade tumor, increased risk of lymph node involvement) and those who received prior adjuvant chemotherapy.10028 ASCO states that the duration of adjuvant gonadotropin-releasing hormone (GnRH) agonist therapy should not exceed 5 years, since the toxicity of long-term (e.g., beyond 5 years) use of GnRH agonist-induced ovarian suppression has not been determined and comparative data for alternative treatment durations are lacking.10017,10018 Although inconsistent estrogen suppression may occur in premenopausal women receiving combined ovarian suppression and endocrine therapy, routine monitoring of serum estradiol concentrations is not recommended since there is insufficient evidence to support specific monitoring guidelines and validated estradiol assays are not widely available;10016,10017,10020,10025 however, ASCO recommends monitoring for physiologic changes that would suggest recovery of ovarian function.10017 ASCO states that clinicians should consider recurrence risk, adverse effects, patient preference, quality of life, consequences for childbearing, and the potential for ambiguity regarding the status of ovarian function (e.g., in women with chemotherapy-induced amenorrhea, hysterectomy-induced amenorrhea, incomplete ovarian suppression, or noncompliance with ovarian suppression therapy) when considering the addition of ovarian suppression therapy to adjuvant endocrine therapy.10017,10018

Metastatic Breast Cancer

Tamoxifen is used in the palliative treatment of metastatic breast cancer in women.128,396

Selective estrogen receptor modulators (i.e., tamoxifen, toremifene) have been used for many years and are still considered an appropriate treatment option for postmenopausal women with hormone receptor-positive metastatic breast cancer;338,395 however, results of randomized clinical studies indicate that aromatase inhibitors are modestly more effective than tamoxifen in such patients.338,392,393,394 A randomized, open-label phase 3 study comparing tamoxifen with exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer demonstrated similar progression-free survival and overall survival outcomes in both treatment groups;338,392 however, findings from a meta-analysis of randomized controlled studies suggested a modest, but significant, survival benefit favoring aromatase inhibitors over other endocrine therapies (hazard ratio of 0.9; 95% confidence interval: 0.84-0.97).395 Tamoxifen and aromatase inhibitors were both well tolerated in clinical trials; however, thromboembolic events and vaginal bleeding occurred more frequently in patients receiving tamoxifen.393,394,395 Based on current evidence and because of the favorable toxicity profile, ASCO recommends aromatase inhibitors as initial endocrine therapy in postmenopausal women with metastatic hormone receptor-positive breast cancer.336

Tamoxifen also is used in the palliative treatment of metastatic breast cancer in premenopausal women as an alternative to ovarian ablative therapy (oophorectomy or radiation).128,133,158,159,160,161,162,163,164,165,166,167,168,169,183 Patients with tumors containing estrogen receptors are more likely to respond to tamoxifen therapy than those with estrogen receptor-negative tumors.128,158,163,166 While objective response rate, time to treatment failure (relapse or progression), and overall survival appear to be similar in premenopausal women receiving tamoxifen or ovarian ablative therapy,128,161,162,163,166,183 current data and experience are inadequate to establish therapeutic equivalence.128 Some premenopausal women with disease progression during tamoxifen therapy subsequently respond to ovarian ablation.128,158,159,160,161,163 While some evidence suggests that an initial response to tamoxifen may be associated with a greater likelihood of subsequent response to ablative therapy following disease progression,158,160,163,167,183 failure to respond initially to tamoxifen does not preclude the possibility of subsequent response to ovarian ablation (i.e., some premenopausal women not responding initially to tamoxifen subsequently have responded to ablation).160,161,163,164,169,183

Reduction in the Incidence of Invasive Breast Cancer in Women with Ductal Carcinoma in Situ

Tamoxifen is used to reduce the risk of invasive breast cancer following surgery and radiation therapy in women with ductal carcinoma in situ (DCIS).128,396 The decision regarding use of tamoxifen to reduce the risk of invasive breast cancer in women with DCIS should be based on an individualized assessment of the benefits versus risks of such therapy.128 Current evidence suggests a duration of 5 years of tamoxifen therapy.128,338

The current indication for tamoxifen is based principally on the results of a randomized, double-blind, placebo-controlled clinical trial (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-24) in women undergoing surgery and radiation therapy for the treatment of DCIS.128 The primary measure of efficacy was reduced incidence of invasive breast cancer in the ipsilateral or contralateral breast.128 More than 80% of tumors were 1 cm or less in diameter, not palpable, and detected by mammography alone.128 Most patients (over 60%) were postmenopausal, 16% had positive surgical margins, and approximately 50% of tumors contained comedo necrosis.128 In this trial, 1804 women were randomized to receive tamoxifen (10 mg twice daily) or placebo for 5 years.128 Data available as of December 31, 1998, for 1798 women at a median follow-up of 74 months showed a 43% reduction in the incidence of invasive breast cancer in women receiving tamoxifen compared with those receiving placebo (44 versus 74 cases, respectively).128 At 5 years following study enrollment, survival was 97% in both treatment groups.128

Reduction in the Incidence of Breast Cancer in Women at High Risk

Tamoxifen is used to reduce the incidence of breast cancer in women at high risk for developing the disease.128,250,293,396

ASCO considers use of tamoxifen an option for reducing the risk of invasive breast cancer in premenopausal or postmenopausal women 35 years of age or older who are considered at high risk for developing breast cancer (i.e., 5-year projected risk of 1.67% or greater based on the calculated score derived from the Gail risk model).337 In addition, ASCO considers use of tamoxifen an option for reducing the risk of invasive breast cancer in premenopausal or postmenopausal women 35 years of age or older with a history of lobular carcinoma in situ (LCIS),337 since these women are at increased risk for developing invasive breast cancer in both the affected and contralateral breast.337,371 (See Risk Assessment under Breast Cancer: Reduction in the Incidence of Breast Cancer in Women at High Risk, in Uses.)

Clinical Trials

The current indication for use of tamoxifen in reduction of the incidence of breast cancer is based principally on the results of the Breast Cancer Prevention Trial (BCPT; also known as the NSABP P-1 trial), a double-blind, randomized, placebo-controlled clinical trial conducted in the US, which was stopped early because of the clear evidence of a reduction in the incidence of invasive breast cancer among women at high risk for the disease who received tamoxifen therapy.269,293

Tamoxifen has been shown to decrease the incidence of breast cancer among women at high risk for developing the disease and is considered an alternative to prophylactic bilateral mastectomy (typically total mastectomy accompanied by breast reconstruction), which generally is reserved for women with exceptionally high risk of developing breast cancer.239,276,289 The reduction in the incidence of a second primary cancer in the contralateral breast in women with early breast cancer who received adjuvant therapy with tamoxifen provided the rationale for the study of the drug in the primary prevention of breast cancer.271,272,277 No effect of tamoxifen on overall or breast cancer-related mortality was observed in this study.128

In the BCPT, 13,388 women 35 years of age and older who were at high risk for developing breast cancer were randomized to receive either tamoxifen 10 mg twice daily or placebo twice daily for 5 years.128,270,293 Data available as of January 31, 1998, for 13,114 women at a median follow-up of 4.2 years showed a 44% reduction in the incidence of invasive breast cancer in women receiving tamoxifen versus placebo (86 versus 156 cases, respectively);128 data available as of March 31, 1998, for 13,175 women at a median follow-up of 4.6 years showed a 49% reduction in the incidence of invasive breast cancer among women receiving tamoxifen (89 cases) compared with those receiving placebo (175 cases);293 and data available as of March 31, 2005, for 13,207 women at a mean follow-up of 6 years showed a 43% reduction in the incidence of invasive breast cancer among women who received tamoxifen compared with those who received placebo.370,371 Reductions in the incidence of invasive breast cancer were observed in all age groups (35-49, 50-59, and 60 years of age and older), in women with or without LCIS, and in women at each risk level specified in the study;128,293,370 however, the reduction in the incidence of invasive breast cancer was substantial (75%) in those with a history of atypical hyperplasia.370,371 According to characteristics of the breast tumors that developed in women during the study, use of tamoxifen decreased the incidence of small, estrogen receptor-positive tumors but did not affect the incidence of estrogen receptor-negative or larger (exceeding 2 cm in diameter at the time of diagnosis) tumors.128,293 According to data available as of March 31, 2005, 23 participants in the study had died of breast cancer (12 in the tamoxifen group, 11 in the placebo group).370 A 37% reduction in the incidence of noninvasive breast cancer (DCIS and LCIS) also was observed among women who received tamoxifen compared with those who received placebo according to data available as of March 31, 2005.370

Tamoxifen therapy is associated with an increased risk of serious adverse effects, including uterine malignancies (see Cautions: Mutagenicity and Carcinogenicity), pulmonary embolism, deep-vein thrombosis, and stroke (see Cautions: Cardiovascular Effects).269,277,293,330 In the BCPT, the risk of these adverse effects was increased particularly among tamoxifen-treated women who were 50 years of age or older.239,269,290,293

Secondary objectives of the BCPT included study of the effects of tamoxifen on the incidence of ischemic heart disease (see Pharmacology: Effects on Lipoproteins) and bone fractures (see Pharmacology: Effects on Bone).128,269,277,278,279,280,281,293 No difference in the incidence of ischemic events was observed among women receiving tamoxifen or placebo.128,293,370 Data available as of March 31, 2005, showed a 29% reduction in the incidence of osteoporotic fractures in women 50 years of age or older at study entry who received tamoxifen compared with those who received placebo.370

About 39% of the participants in the BCPT were women 35-49 years of age, 31% were 50-59 years of age, and 30% were 60 years of age or older.293 Despite efforts to enroll members of minority groups in the trial, only about 4% of participants represented minority groups (e.g., African American, Asian American, Hispanic),269,293 and the generalizability of the study results, including the size of the treatment effect as well as the risk of adverse effects, to these populations is uncertain.289,293,305,306,307,270

Additional clinical trials investigating the use of 5 or 8 years of tamoxifen therapy for the prevention of breast cancer were conducted in other countries, including the UK and Italy.272,273,372,373,374 Following completion of a pilot study in the UK involving 2494 women (Royal Marsden Hospital study), 7154 women at high risk of breast cancer were enrolled in a tamoxifen chemoprevention study (International Breast Cancer Intervention Study [IBIS-I]).279,285,297,372,373 In 1992, recruitment of women 35 years of age or older who had undergone a hysterectomy was begun for a tamoxifen chemoprevention trial in Milan, Italy (Italian Tamoxifen Prevention study);279,294,374 following enrollment and randomization of 5408 women, recruitment was terminated earlier than planned because of the large number of women dropping out of the study and concerns regarding the adverse effects of tamoxifen.294

In contrast to the findings of the BCPT, a reduction in the incidence of breast cancer among women who received tamoxifen compared with those who received placebo was not observed in the Royal Marsden Hospital and Italian Tamoxifen Prevention studies at a median follow-up of approximately 13 and 9 years, respectively;294,295,371,372,374 however, tamoxifen reduced the incidence of invasive estrogen receptor-positive tumors by 39% in the Royal Marsden Hospital study, particularly during the posttreatment period (reduction of 52%).371,372 In the Royal Marsden Hospital study, the posttreatment reduction in the incidence of invasive estrogen receptor-positive tumors did not differ according to menopausal status or concomitant use of hormone replacement therapy.372 The interaction of several factors may have contributed to the differing outcomes of the European studies of tamoxifen for the prevention of breast cancer compared with the results of the BCPT, including smaller sample size, differing study populations (e.g., fewer older women in the UK and Italian studies than in the BCPT), and differences in the degree of risk of developing breast cancer among study populations (e.g., lower risk of developing breast cancer among participants in the Italian study compared with those in the BCPT).128,293,294,295,296,297,304,371 Consistent with findings from the BCPT, an increased incidence of deep-vein thrombosis, pulmonary embolism, stroke, and endometrial cancer has been observed in patients receiving tamoxifen versus placebo in these trials.128,294,295

Analysis of data from the IBIS-I study at a median follow-up of 16 years showed a 28% reduction in the incidence of breast cancer in patients who received tamoxifen compared with those who received placebo in the 10 years following initiation of therapy; a slightly greater reduction (31%) was observed in subsequent years.373 Consistent with findings from the BCPT, use of tamoxifen reduced the incidence of DCIS or invasive estrogen receptor-positive breast cancer by 35 or 34%, respectively, compared with placebo but did not affect the incidence of invasive estrogen receptor-negative tumors.373 The preventive effects of tamoxifen did not differ according to age, but reduced benefit was observed in women who used concomitant hormone replacement therapy during the 5-year treatment period.373 Increased incidences of deep-vein thrombosis during the initial 10 years and nonmelanoma skin cancers were observed in patients who received tamoxifen compared with those who received placebo.373

Tamoxifen also has been compared with raloxifene in a double-blind, randomized, phase 3 study (Study of Tamoxifen and Raloxifene [STAR]; also known as the NSABP P-2 study).375,376,391 Patients enrolled in this study were randomized to receive either tamoxifen (20 mg daily) or raloxifene (60 mg daily) for a maximum of 5 years.371,376 Analysis of the data at an average follow-up of approximately 4 years (47 months) showed that tamoxifen and raloxifene were equivalent in efficacy in lowering the risk of invasive breast cancer.371,376 Although the comparison did not reach statistical significance, there were fewer cases of noninvasive breast cancer in women receiving tamoxifen than in those receiving raloxifene (1.51 per 1000 in the tamoxifen group versus 2.11 per 1000 in the raloxifene group; risk ratio of 1.4).371,376 In contrast to these findings, longer-term follow-up (approximately 7 years) showed that tamoxifen had a greater effect than raloxifene in lowering the risk of invasive breast cancer, while the between-treatment difference in risk of noninvasive breast cancer was smaller than that observed at the time of the initial analysis.371,391 The updated analysis showed a 24% reduction in raloxifene efficacy in lowering the risk of invasive breast cancer compared with tamoxifen.371,391 Although raloxifene remained as effective as tamoxifen in lowering the risk of invasive breast cancer in women with LCIS (risk ratio of 1.13), the drug was less effective than tamoxifen in women with atypical hyperplasia (risk ratio of 1.48).371 Noninvasive breast cancer was reported slightly (risk ratio of 1.22), but not significantly, more frequently in those receiving raloxifene compared with those receiving tamoxifen at approximately 7 years' follow-up.371,391

In the STAR study, use of tamoxifen was associated with a higher risk of thromboembolic events than use of raloxifene, but rates of myocardial infarction, severe angina, or acute ischemic syndrome did not differ between the tamoxifen and raloxifene groups.376 Rates of fracture were essentially identical in the tamoxifen and raloxifene groups.376 Fewer cataracts were reported in the raloxifene group than in the tamoxifen group.376 Between-treatment differences in adverse effects mostly remained similar over approximately 7 years' follow-up.391 No differences in overall physical, mental health, or depressive symptoms were observed among women receiving either tamoxifen or raloxifene.375,376 However, women receiving tamoxifen reported more bladder-control (e.g., urinary incontinence) problems, gynecologic problems, and leg cramps.375 At the time of the initial analysis, endometrial cancer was reported more frequently in women receiving tamoxifen compared with those receiving raloxifene, but the difference was not statistically significant;376 however, an increase in the risk of endometrial cancer and endometrial hyperplasia was observed in patients receiving tamoxifen compared with those receiving raloxifene at approximately 7 years.391

Risk Assessment

Benefit of tamoxifen for the primary prevention of breast cancer currently has been demonstrated only for women at high risk of developing breast cancer.269,299,308 Women are advised to consult with a health-care professional to determine their risk of developing breast cancer, and formal risk assessment by an oncology expert should be considered before the initiation of tamoxifen therapy.269,270 The National Cancer Institute (NCI) and NSABP have developed a computer-based tool that will help women consult with health-care providers regarding their personal risk and benefit for tamoxifen therapy.269,270,302,303 Examples of profiles that define a woman as being at high risk for developing breast cancer are included in the prescribing information for tamoxifen.128

In the BCPT, women 60 years of age and older were eligible for enrollment based on age alone because the risk of breast cancer increases with increasing age.269,293 Women 35 years of age or older who had been diagnosed with LCIS were eligible for the study based on that diagnosis alone.270,293 Other women 35-59 years of age were eligible to participate in the study if they had a 5-year predicted risk of breast cancer scored as 1.67% or greater according to calculations with a statistical model known as the Gail model, which considers a combination of risk factors including number of first-degree relatives (i.e., mother, sister, daughter) diagnosed with breast cancer, number of breast biopsies, presence or absence of atypical hyperplasia on breast biopsy, age at menarche (i.e., first menstrual period), and either nulliparity or age at first live birth.128,269,293,309

The following profiles are examples predicting a 5-year risk of 1.67% or greater according to the Gail model; although these examples are arranged in ascending order by age, they do not necessarily represent ascending order of risk :128,303

• Age 35 years or older, one first-degree relative with a history of breast cancer, a personal history of 2 or more benign breast biopsies, and a personal history of a breast biopsy showing atypical hyperplasia
• Age 35 years or older, at least 2 first-degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy
• Age 35 years or older and LCIS
• Age 40 years or older, one first-degree relative with a history of breast cancer, a personal history of 2 or more benign breast biopsies, age at first live birth 25 years or older, and age at menarche 11 years or younger
• Age 40 years or older, at least 2 first-degree relatives with a history of breast cancer, and age at first live birth 19 years or younger
• Age 40 years or older, one first-degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia
• Age 45 years or older, at least 2 first-degree relatives with a history of breast cancer, and age at first live birth 24 years or younger
• Age 45 years or older, one first-degree relative with a history of breast cancer, a personal history of a benign breast biopsy, age at menarche 11 years or younger, and age at first live birth 20 years or older
• Age 50 years or older, at least 2 first-degree relatives with a history of breast cancer
• Age 50 years or older, history of one breast biopsy showing atypical hyperplasia, age at first live birth 30 years or older, and age at menarche 11 years or younger
• Age 50 years or older, history of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 years or older
• Age 55 years or older, one first-degree relative with a history of breast cancer, a personal history of a benign breast biopsy, and age at menarche 11 years or younger
• Age 55 years or older, history of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 years or older
• Age 60 years or older, 5-year predicted breast cancer risk of at least 1.67% according to the Gail model

Although each of the above profiles represents a 5-year predicted breast cancer risk of at least 1.67%, the absolute risk for these profiles varies (including both low and high risk scores) and must be calculated using the Gail model.128,303 Because the degree of risk differs according to the specific values applied to each variable in the Gail model and the combination of these individual risk factors, calculation of the 5-year predicted absolute risk for breast cancer provides the best estimate of risk to be used in judging possible benefit of tamoxifen therapy.128 In the BCPT, 25% of the women had a 5-year predicted breast cancer risk of 2% or less, 57.6% had a risk of 2.01-5%, and 17.4% had a risk of 5% or greater.293 Health-care professionals can request a Gail Model Risk Assessment Tool from the manufacturer128 or access a calculator based on the Gail model on the National Cancer Institute's website ([Web]).

For women 60 years of age or older, no additional risk factors were required for participation in the BCPT.303 However, a woman 50 years of age or older must consider other factors before choosing to take tamoxifen (e.g., whether she has had a hysterectomy).271,303 For women in the BCPT, particularly those 50 years of age or older, tamoxifen increased the risk of uterine malignancies (see Uterine Cancer in Cautions: Mutagenicity and Carcinogenicity), pulmonary embolism, deep-vein thrombosis, and stroke (see Cautions: Cardiovascular Effects). 128,239,269,290,293 Following assessment of the risk of developing breast cancer, the decision regarding use of tamoxifen for reduction in the incidence of breast cancer should be based on an individual assessment of the benefits versus risks of tamoxifen therapy.128 (See Benefit Versus Risk under Breast Cancer: Reduction in the Incidence of Breast Cancer in Women at High Risk, in Uses.)

Although other criteria may identify women at high risk for the development of breast cancer, the benefit of tamoxifen therapy in these groups is unknown. Women with BRCA1 or BRCA2 genetic mutations are known to be at high risk for developing breast cancer, but data regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations are insufficient to support recommendations regarding tamoxifen use.128 Some evidence suggests that plasma insulin-like growth factor I (IGF-I) concentrations may be useful in identifying premenopausal women who are at high risk of breast cancer,286,287 but additional studies are needed to confirm this correlation and establish the benefit of tamoxifen therapy in such women.286

Benefit Versus Risk

The benefit of tamoxifen as preventive therapy must be weighed against the risks associated with its use, and such treatment may not be appropriate in some women despite a high risk of breast cancer.269,271,299,308 The decision to initiate tamoxifen therapy for the prevention of breast cancer is complex and must be individualized.269,271,293,303

Some experts state that for women with a life expectancy of less than 10 years, the benefit of tamoxifen as preventive therapy is likely minimal.371

Women with risk factors for thrombosis, including hypertension, diabetes mellitus, smoking, and/or obesity, must consider that tamoxifen increases the risk of serious thrombosis.270

Women with BRCA1 or BRCA2 genetic mutations, which place them at high risk for developing breast cancer, have been proposed as candidates for tamoxifen preventive therapy,293 but data regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations are insufficient to support recommendations regarding tamoxifen use.128 One small study showed that breast tumors arising in women with the BRCA1 mutation were less likely to be estrogen receptor-positive and thus may be less likely to respond to tamoxifen preventive therapy.299,300,301 Anonymous blood samples taken from 288 participants in the BCPT who developed invasive breast cancer were analyzed retrospectively to determine the incidence of breast cancer in women with BRCA1 or BRCA2 mutations who received tamoxifen compared with those who received placebo.377 The analysis indicated that tamoxifen use was associated with a reduction in breast cancer incidence in those with BRCA2 mutation but not in those with BRCA1 mutation.377 However, interpretation of the data are limited because only 19 of the samples (6.6%) were from patients with BRCA1 or BRCA2 mutations377 and because this question was not included in the initial design of the study.239,270,289,293,302 Further evidence is needed to establish the effect of tamoxifen therapy on the prevention of breast cancer in this population.299,300

Because of the small number (about 4%) of minority participants (e.g., African American, Asian American, Hispanic)269,293 in the BCPT, the generalizability of the study results, including the size of the treatment effect as well as the risk of adverse effects, to these populations is uncertain.289,293,305,306,307

Although tamoxifen therapy may reduce the incidence of breast cancer in women at high risk, it does not replace the need for clinical surveillance, and regular breast examination and screening with mammography are advised in such patients.269

Duration of Therapy

The optimum duration of therapy with tamoxifen for the prevention of breast cancer has not been established; however, experts recommend a duration of 5 years.337,371

Male Breast Cancer

Tamoxifen is used in the palliative treatment of metastatic breast cancer in men.104,128,229,231,233,236,237,238,252,378,396 Breast cancer is a relatively rare disease in men and accounts only for about 0.5-1% of all breast cancers in the US.104,226,227,228,229,230,231,232,233,238,251 Cancer of the male breast appears to be biologically similar to the disease in women;228,230 however, centrally located lesions predominate in men, and tumors in males usually contain a higher frequency of hormone receptors than in females.228,229,231,237,238 Since the therapeutic benefit of tamoxifen may correlate with increasing quantity of hormone receptors in the tumor,104,230,235 the high frequency of hormone receptors in men230,237,251,252 may explain the high response rate of male breast carcinoma to endocrine therapy.228 Treatment to date has been similar to that for women with breast cancer;226,229,231,233,238 however, experience in men is very limited.226,228,229,231,251

Combined results of several studies and published case reports showed an objective response (complete and partial) rate of about 50% in males with advanced (metastatic) breast cancer treated with tamoxifen.104,105,128,226,251 In addition to that in the breast, tumor regression is apparent in affected bone, soft tissue, liver, and lungs.104,226 Some experts consider tamoxifen the first-line hormonal therapy in males with estrogen receptor-containing tumors and positive nodes.228,229,231 Since limited evidence suggests that objective response rates may be similar in males receiving tamoxifen or testicular ablative therapy105,226,230 and drug therapy may be accepted better,105,226,230,232,233,235,238 tamoxifen is rapidly replacing orchiectomy in the palliative treatment of advanced breast cancer when estrogen receptors are present.226,228,230,235,239,253 Male breast cancer that progresses during tamoxifen therapy subsequently may respond to testicular ablation.232,233,252 Tamoxifen alone or in conjunction with combination chemotherapy also is used as an adjunct to surgery in the treatment of breast cancer in men with positive axillary lymph nodes†.226,227,228,230,231,236,237,251,378 Limited data indicate that disease-free 5-year survival is greater in males receiving adjuvant tamoxifen therapy compared with those not receiving the drug.226,227,230 Although randomized, controlled trials would be needed to evaluate systematically the role of tamoxifen in systemic adjuvant therapy in men with breast cancer, it is unlikely that such studies can be performed because of the rarity of this condition.105,226,227,230,235,253

Pharmacogenomic Considerations for Tamoxifen Therapy

Cytochrome P-450 Isoenzyme 2D6 Polymorphism

Studies indicate that exposure to endoxifen, the major active metabolite of tamoxifen, is strongly associated with cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer phenotype,339,349,354,355,359,360,383,396 and low endoxifen concentrations have been associated with an increased risk for disease recurrence in women receiving adjuvant tamoxifen therapy for breast cancer;339,355,359 however, the validity of CYP2D6 metabolizer phenotype as a predictor of the outcome of tamoxifen therapy is controversial.339,348,351,353,360,384,396

Although tamoxifen is metabolized by multiple CYP isoenzymes, CYP2D6 is the principal isoenzyme responsible for formation of the active metabolites endoxifen (4-hydroxy- N -desmethyltamoxifen) and 4-hydroxytamoxifen.339,346,347,348,352 (See Pharmacokinetics: Elimination.) Activity of the CYP2D6 isoenzyme is under genetic control and is subject to individual variation; the CYP2D6 gene is highly polymorphic.339,348 Interindividual variability in systemic exposure to endoxifen is partially (approximately 30-53%) explained by CYP2D6 polymorphism.339,355,359,383

The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy assigns the following metabolizer phenotypes and activity scores based on genotype; the activity score is the sum of activity score values assigned to each CYP2D6 allele, where 0 = no function and 1 = normal function.339 Individuals who lack functional alleles of the CYP2D6 gene have an activity score of 0 and are described as poor metabolizers; those with one decreased-function allele and one inactive allele have an activity score of 0.5 and are intermediate metabolizers; those with 2 decreased-function alleles or one normal-function allele and one inactive allele have an activity score of 1 and may be variably described as normal or intermediate metabolizers; those with 2 normal-function alleles or one normal-function allele and one decreased-function allele have an activity score of 2 or 1.5, respectively, and are normal metabolizers; and those who carry a duplicate or amplified gene have an activity score exceeding 2 and are ultrarapid metabolizers.339,348 The CYP2D6*4 allele (null activity) and CYP2D6*10 allele (reduced activity) are the most common variations reported in Caucasians and individuals of Asian ancestry, respectively, although variation exists in prevalence among various Asian populations.348,350 The ultrarapid metabolizer phenotype is more common in patients from Arabic and North African countries than in individuals of European ancestry.359

Results from several studies demonstrated an approximately twofold to threefold higher risk of breast cancer recurrence in women with the CYP2D6 poor-metabolizer phenotype who received adjuvant tamoxifen therapy compared to those with the normal-metabolizer phenotype.339,388,389,390

In a secondary analysis of the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) study, postmenopausal women with the poor-metabolizer phenotype (2 inactive alleles) who received adjuvant tamoxifen therapy for 5 years had a substantially higher risk of disease recurrence or death compared with extensive metabolizers (those who lacked inactive or decreased-function alleles) (odds ratio of 2.45; 95% confidence interval of 1.05-5.73); a trend toward higher risk of disease recurrence or death was observed in women with one inactive allele (i.e., poor/intermediate metabolizer, poor/extensive metabolizer) compared with extensive metabolizers (odds ratio of 1.67; 95% confidence interval of 0.95-2.93).358,360 However, among patients who received sequential therapy with tamoxifen for 2 years followed by anastrozole for 3 years, CYP2D6 metabolizer phenotypes were not associated with increased risk of disease recurrence or death, suggesting that the risk of these events in patients with reduced CYP2D6 metabolic activity was negated by sequential use with another active drug that is not metabolized by CYP2D6.358,360

In contrast to these findings, an association between CYP2D6 metabolizer phenotype and disease recurrence in postmenopausal women who received adjuvant tamoxifen therapy for 5 years was not demonstrated in secondary analyses of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group 1-98 (BIG 1-98) studies;356,357,360 however, limitations of these studies include potential genotype errors (e.g., genotyping from somatic rather than germline tissue) and analysis of DNA samples for only a small proportion of study participants.360,361,362

A nested case-control study from the BCPT and STAR studies also failed to demonstrate an association between CYP2D6 metabolizer phenotype and breast cancer incidence in women 50 years of age or older who received tamoxifen therapy for the primary prevention of breast cancer for a duration of up to 5 years.337,352

A meta-analysis conducted by the International Tamoxifen Pharmacogenomics Consortium (ITPC), which combined data from 12 clinical trials in 4973 tamoxifen-treated patients worldwide, found an increased risk of disease recurrence in CYP2D6 poor metabolizers; however, this risk was observed only when strict inclusion criteria were used (i.e., postmenopausal women with estrogen receptor-positive breast cancer receiving adjuvant tamoxifen therapy at a dosage of 20 mg daily for 5 years).339,360 In addition, a systematic review of 38 studies investigating associations between CYP2D6 genetic variation and survival outcomes after tamoxifen treatment found that 53% of the studies reported at least one statistically significant association between CYP2D6 genetic variation and survival; studies that used comprehensive genotyping panels were more likely to report such an association.384 Numerical, but not statistically significant, associations were observed based on the source of DNA for genotyping.384 Other study limitations (e.g., retrospective design, inadequate statistical power, use of convenience samples, differences in outcome definitions and phenotype classification, noncompliance with therapy, use of CYP2D6 inhibitors or chemotherapy, duration of follow-up) might have contributed to the discrepant findings reported to date.360,384

In a clinical study evaluating CYP2D6 genotype-guided dosing, an increase in tamoxifen dosage from 20 mg daily to 40 mg daily in patients with poor or intermediate metabolizer phenotype increased endoxifen concentrations.354 Following 4 months of therapy at the 40-mg daily dosage, endoxifen concentrations in intermediate metabolizers were similar to those in extensive metabolizers receiving a standard tamoxifen dosage (20 mg daily); although endoxifen concentrations also increased in poor metabolizers following dosage escalation, the concentrations remained significantly lower than those achieved in extensive metabolizers receiving the standard dosage or in intermediate metabolizers receiving the genotype-guided dosage.354 Clinically meaningful increases in adverse effects or decreases in quality of life were not observed in those receiving genotype-guided dosing.354

Although some experts do not recommend use of CYP2D6 genotyping to guide treatment decisions in patients with hormone receptor-positive breast cancer based on current levels of evidence,338 CPIC and other experts recommend that postmenopausal women with CYP2D6 poor-, intermediate-, or normal/intermediate-metabolizer phenotypes (activity scores of 0-1) receive adjuvant endocrine therapy with an alternative agent such as an aromatase inhibitor and that premenopausal women with these phenotypes receive an aromatase inhibitor plus ovarian ablation.339,384 If use of an aromatase inhibitor is contraindicated, CPIC and these experts state that an increased tamoxifen dosage of 40 mg daily may be considered; however, suboptimal concentrations of endoxifen may be achieved in patients with a CYP2D6 poor-metabolizer phenotype despite dosage adjustment.339,354,384 The safety of tamoxifen dosages exceeding 40 mg daily in patients with the poor-metabolizer phenotype has not been established.354

Application of CYP2D6 genotyping as a tool to aid in treatment decisions has important limitations and should not substitute for appropriate clinical judgment and patient management.339 The potential for other patient characteristics, such as menopausal status, to influence the utility of CYP2D6 genotyping for optimizing tamoxifen therapy has not been adequately studied to date.348,384

Other Polymorphic Cytochrome P-450 Isoenzymes

Although some data suggest a direct relationship between CYP2C19 polymorphism and endoxifen plasma concentrations and survival, analysis of data from the ITPC data set failed to confirm a clinically meaningful association between CYP2C19 genomic variants and disease recurrence in women who received adjuvant tamoxifen therapy for breast cancer.339,347 Therefore, CPIC and some other experts state that a clinical role for CYP2C19 polymorphisms in guiding tamoxifen treatment decisions has not been established.339,347 Pharmacogenetic variation in other CYP isoenzymes (e.g., 2C9, 3A4, and 3A5) appears to have only a small effect on endoxifen exposure.339,383

Other Uses

Tamoxifen has been used to stimulate ovulation† in appropriately selected anovulatory women desiring pregnancy, especially in those with oligomenorrhea or amenorrhea who were previously receiving oral contraceptives. Limited data suggest that tamoxifen therapy may be useful for the management of some types of mastalgia† (e.g., cyclical), but additional studies are needed to evaluate the efficacy, safety, and dosage of the drug for this condition.125,126 Tamoxifen also has been used to reduce the frequency of vaginal bleeding episodes and to reduce the rate of increase in bone age in girls with Albright syndrome† (also known as McCune-Albright syndrome) and precocious puberty; however, the effects of tamoxifen beyond one year of treatment in these patients have not been established.128 (See Cautions: Pediatric Precautions.)

Administration

Tamoxifen citrate is administered orally without regard to meals.128,396 Dosages exceeding 20 mg daily should be given in divided doses (morning and evening).128,227,230,232,233,252,396

Dosage

Dosage of tamoxifen citrate is expressed in terms of tamoxifen.

Breast Cancer

Adjuvant Therapy

When tamoxifen is used as an adjunct to surgery and radiation therapy in the treatment of breast cancer, the usual dosage of the drug is 20 mg daily, although dosages of 20-40 mg daily have been used.100,102,110,121,128,129,130,194,195,196,205,396,10010,10011,10013,10026 In more recent clinical studies evaluating adjuvant endocrine therapy regimens, tamoxifen 20 mg daily has been used as the standard for comparison.10010,10011,10013,10026 In several clinical studies of adjuvant tamoxifen therapy, there was no evidence that dosages exceeding 20 mg daily are necessary.112,128,396 However, if tamoxifen is used as adjuvant therapy in patients with cytochrome P-450 isoenzyme 2D6 (CYP2D6) poor-, intermediate-, or normal/intermediate-metabolizer phenotypes (activity scores of 0-1), some experts state that a dosage of 40 mg daily may be considered, since a dosage of 20 mg daily may result in suboptimal concentrations of the active metabolite endoxifen.339,354,384 Although endoxifen concentrations may remain suboptimal in patients with the poor-metabolizer phenotype despite such dosage adjustment,339,354,384 the safety of tamoxifen dosages exceeding 40 mg daily in these patients has not been established.354 (See Cytochrome P-450 Isoenzyme 2D6 Polymorphism under Breast Cancer: Pharmacogenomic Considerations for Tamoxifen Therapy, in Uses.) The optimum duration of adjuvant tamoxifen therapy is 5 years in most patients; however, continuation of adjuvant therapy for an additional 5 years (for a total of 10 years) may be considered in women with early-stage hormone receptor-positive breast cancer based on their menopausal status.332,338 (See Adjuvant Therapy under Uses: Breast Cancer.) The magnitude of benefit of extended therapy (i.e., beyond 5 years) with tamoxifen is expected to be lower in women with small tumors and/or node-negative disease.332

When tamoxifen has been used in combination with ovarian suppression† as adjuvant therapy in premenopausal women† with early-stage hormone receptor-positive breast cancer, tamoxifen has been administered at a dosage of 20 mg once daily for 5 years.10010,10011,10012,10013,10026 In clinical studies, ovarian suppression was achieved with goserelin 3.6 mg implanted subcutaneously every 4 weeks, leuprolide acetate 3.75 mg by IM injection every 4 weeks, triptorelin 3.75 mg by IM injection every 4 weeks, or surgical or radiation ablation.10010,10011,10012,10013,10023,10026

Metastatic Breast Cancer

For the treatment of metastatic breast cancer in women, the usual dosage of tamoxifen is 20-40 mg daily.128,396 Because there does not appear to be any significant difference in response rates with the two dosages, most clinicians believe that 20 mg daily usually should be used initially. If an objective response to the drug occurs, it usually is evident within 4-10 weeks; however, several months of therapy may be required before an objective response occurs in patients with bone metastases.

Reduction in the Incidence of Invasive Breast Cancer in Women with Ductal Carcinoma in Situ

For reduction in the incidence of invasive breast cancer in women with ductal carcinoma in situ (DCIS), the recommended dosage of tamoxifen is 20 mg daily for 5 years.128,396

Reduction in the Incidence of Breast Cancer in Women at High Risk

For reduction in the incidence of breast cancer in women at high risk, the recommended dosage of tamoxifen is 20 mg daily.128,396 Experts recommend a 5-year duration of tamoxifen therapy for the prevention of breast cancer in women at high risk of the disease.337,371

Male Breast Cancer

For the treatment of metastatic breast cancer in men, the usual dosage of tamoxifen is 20-40 mg daily.128,396 When tamoxifen alone or in combination with radiation therapy was used as an adjunct to surgery† in the treatment of breast cancer in men, a tamoxifen dosage of 20 mg daily was used.227,231 The optimum duration of adjuvant tamoxifen therapy has not been established; however, some clinicians suggest a similar duration of therapy in men as in women (i.e., 5-10 years).227,378 Decisions about the duration of adjuvant tamoxifen therapy may be individualized, as they are for women, based on risk of disease recurrence and adverse effects.378

Other Uses

To stimulate ovulation†, 5-40 mg of tamoxifen has been administered twice daily for 4 days.

The manufacturer states that the adverse effect profile of tamoxifen in breast cancer patients generally appears to be similar for men and women.128 Adverse effects of tamoxifen citrate usually are relatively mild and rarely severe enough to necessitate discontinuance of the drug in patients with breast cancer.128 Tamoxifen usually is well tolerated in male patients with breast cancer.128 In the Breast Cancer Prevention Trial (BCPT), 15% of women receiving tamoxifen withdrew from the trial for medical reasons (e.g., hot flushes, vaginal discharge) compared with 9.7% of women receiving placebo.128

Tamoxifen therapy is associated with increased risk of serious adverse effects, including uterine cancer, pulmonary embolism, deep-vein thrombosis, and stroke in women receiving the drug for reduction in the incidence of breast cancer (i.e., women at high risk for breast cancer or women with ductal carcinoma in situ).269,277,293,330 In the BCPT, the risk of these adverse effects was increased particularly among tamoxifen-treated women who were 50 years of age or older.239,269,290,293

Cardiovascular Effects

Adverse cardiovascular effects of tamoxifen include thrombotic and venous thromboembolic events such as stroke, pulmonary embolism, and deep-vein thrombosis.269,293

Thromboembolic Events

In the BCPT, women without a history of pulmonary emboli receiving tamoxifen had an approximately threefold increase in the risk of developing a pulmonary embolism (18 versus 6 cases; incidence rate of 0.75 versus 0.25 per 1000 women-years) compared with those receiving placebo.128,269,270,293 Three women in the study, all of whom were receiving tamoxifen, died of pulmonary embolism.128,270,293 Of the cases of pulmonary embolism, 87% occurred in women at least 50 years of age at the time of randomization; among women receiving tamoxifen in the BCPT, episodes of pulmonary embolism occurred on average at 27 months (range: 2-60 months) following initiation of therapy with the drug.128

Although the difference was not significant, the risk of deep-vein thrombosis was increased (relative risk of 1.6) among women receiving tamoxifen versus placebo in the BCPT (35 versus 22 cases according to data available as of March 31, 1998).128,293 A similar increase in relative risk of deep-vein thrombosis was observed in women 49 years of age and younger as in women 50 years of age or older, although fewer events occurred in younger women.128 Women who had thromboembolic events were at risk for a second related event (7 of 25 women receiving placebo and 5 of 48 women receiving tamoxifen according to data available as of January 31, 1998).128 Among women receiving tamoxifen in the BCPT, episodes of deep-vein thrombosis occurred on average at 19 months (range: 2-57 months) following initiation of therapy with the drug.128 Thrombotic events, including deep-vein thrombosis,342 pulmonary embolism,342 and superficial phlebitis,342 also have been reported in 1.7% of women receiving tamoxifen as adjuvant therapy for the treatment of breast cancer;128,342,258 at least 2 deaths have occurred in patients with breast cancer who had thrombotic events during tamoxifen therapy.342 Clotting factor abnormalities have been observed with prolonged tamoxifen therapy at usual dosages, and antithrombin III, fibrinogen, and platelet counts have been decreased minimally; the relationship, if any, of such changes to thromboembolic phenomena is unclear.258,261 Results of a small substudy of the BCPT suggested that screening patients for factor V Leiden and prothrombin G20210A mutations would not be beneficial in identifying patients who should not receive tamoxifen.128

Although the difference was not significant, an increase in the incidence of stroke was observed in women receiving tamoxifen (38 events) versus placebo (24 events) in the BCPT (relative risk of 1.59 and 95% confidence interval of 0.93-2.77 according to data available as of March 31, 1998).293 Hemorrhagic strokes accounted for 10 of 38 (26%) or 6 of 24 (25%) strokes in women receiving tamoxifen or placebo, respectively.293 Occlusive strokes accounted for 21 of 38 (55%) or 14 of 24 (58%) strokes in women receiving tamoxifen or placebo, respectively.293 Among women receiving tamoxifen or placebo, 7 of 38 (18%) or 4 of 24 (17%) strokes, respectively, were of unknown etiology.293 Fatal stroke occurred in 4 women receiving tamoxifen and in 3 women receiving placebo.128,293 Among women experiencing stroke, 88% occurred in women 50 years of age or older at the time of randomization.128 Among women receiving tamoxifen in the BCPT, episodes of stroke occurred on average at 30 months (range: 1-63 months) following initiation of therapy with the drug.128

In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, venous thromboembolic events and ischemic cerebrovascular events were reported more frequently in women receiving adjuvant therapy with tamoxifen compared with those receiving anastrozole (5 versus 3% and 3 versus 2%, respectively).128

Vasomotor Symptoms

In clinical studies, vasomotor symptoms (i.e., hot flushes [flashes]) occur more frequently in patients receiving tamoxifen than in those receiving placebo.128 Hot flushes are one of the most common adverse effects reported in women receiving tamoxifen for the treatment128 or prevention128,270,273,293 of breast cancer. In the BCPT, hot flushes occurred in 80% of women receiving tamoxifen compared with 68% of those receiving placebo.128,293 In addition, more women who were receiving tamoxifen versus placebo reported severe hot flushes (45 versus 28%).128,293 Withdrawal from the trial because of hot flushes occurred more frequently among women receiving tamoxifen versus placebo (3.1 versus 1.5%).128 In the ATAC trial, hot flushes were reported more frequently in women receiving adjuvant therapy with tamoxifen compared with those receiving anastrozole (41 versus 36%).128 In some patients, clonidine may ameliorate tamoxifen-induced hot flushes.258,260

Effects on Lipoproteins

Hyperlipidemias have been reported in patients receiving tamoxifen.128 Hypertriglyceridemia has been reported in patients with breast cancer receiving tamoxifen and may be severe, particularly in patients with a known history of elevated triglyceride levels, such as those associated with familial hypertriglyceridemia.324,325 Although tamoxifen-induced hypertriglyceridemia may respond to withdrawal of the drug or treatment with lipid-lowering agents, at least one patient developed fulminant pancreatitis and subsequently died.324,325 Periodic monitoring of plasma triglyceride concentrations is advised in patients with preexisting hyperlipidemias during the entire duration of tamoxifen therapy since onset of hypertriglyceridemia may be delayed.324,325

Potentially beneficial estrogenic effects, including decreased total and low-density lipoprotein concentrations and decreased cardiovascular morbidity and mortality (particularly in postmenopausal women), also have been observed in women receiving prolonged tamoxifen therapy.258,263,264 (See Pharmacology: Effects on Lipoproteins.)

Other Cardiovascular Effects

Fluid retention has been reported in women receiving tamoxifen as adjuvant therapy for breast cancer.128 Edema has also been reported in women with metastatic breast cancer receiving tamoxifen.128

Genitourinary and Renal Effects

Vaginal discharge128 and menstrual irregularities128 occur more frequently in patients receiving tamoxifen than in those receiving placebo.128 Vaginal discharge, occurring in 55%, was one of the most common adverse effects reported among women receiving tamoxifen for the primary prevention of breast cancer in the BCPT.128,270,273,293 In addition, more women who were receiving tamoxifen versus placebo reported vaginal discharge that was moderately, quite a bit, or extremely bothersome (29 versus 13%).293 Withdrawal from the trial because of vaginal discharge occurred more frequently among women receiving tamoxifen versus placebo (0.5 versus 0.1%).128 Vaginal bleeding may occur with tamoxifen therapy.128 In the ATAC trial, vaginal bleeding and vaginal discharge were reported more frequently in women receiving tamoxifen compared with those receiving anastrozole (10 versus 5% and 13 versus 4%, respectively).128 Vaginal dryness and pruritus vulvae have been reported infrequently in women receiving tamoxifen for metastatic breast cancer.128 Amenorrhea also has been reported in women receiving tamoxifen.128

An increased incidence of endometrial changes, including hyperplasia and polyps, has been associated with tamoxifen therapy.128 The underlying mechanism of these changes appears to be related to the estrogenic properties of tamoxifen.128 Endometriosis and uterine fibroids, possibly resulting from tamoxifen's partial estrogenic activity, have been reported rarely in women receiving tamoxifen.128 In addition, ovarian cysts have been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen.128 An increased incidence of uterine fibroids (in premenopausal and postmenopausal women) and benign ovarian cysts (in premenopausal women) also was noted in women receiving tamoxifen in a study for the prevention of breast cancer.273

Loss of libido and impotence have been reported in some male patients and resulted in discontinuance of tamoxifen therapy.128 In oligospermic men who were receiving tamoxifen therapy, increased lutropin (luteinizing hormone, LH), follitropin (follicle-stimulating hormone, FSH), testosterone, and estrogen concentrations were reported.128 Priapism has been reported in at least one patient receiving tamoxifen.213,239

Increased serum BUN and/or creatinine also has been reported in patients receiving tamoxifen as adjuvant therapy for breast cancer.128

Musculoskeletal Effects

Musculoskeletal pain and bone pain have been reported in patients with breast cancer receiving tamoxifen.128 Increased bone and tumor pain or flare have occurred with tamoxifen therapy for metastatic breast cancer and are sometimes associated with a good tumor response.128 Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may demonstrate sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions, and/or development of new lesions.128 If bone pain and disease flare occur, they are usually apparent shortly after initiation of tamoxifen therapy and generally subside rapidly.128 Management of tamoxifen-related flare includes supportive care and possibly interruption of treatment with the drug, with subsequent reinstitution of therapy at a reduced dosage (i.e., 5-10 mg daily) and gradual increases to the usual dosa in some cases, prednisone may be added concomitantly for 1-2 weeks.

Hypercalcemia, in some cases life-threatening, may occur during initial tamoxifen therapy in patients with metastatic breast cancer who have bone metastases.128,129 Periodic determination of serum calcium concentrations should be performed during initial therapy in these patients (e.g., once or twice weekly during the first 2-3 weeks of therapy) and appropriate treatment initiated if hypercalcemia occurs. If hypercalcemia is severe, the drug should be discontinued.128,129 Following appropriate management of hypercalcemia, tamoxifen therapy may be reinstituted with caution and careful monitoring, at a reduced dosage or concomitantly with a low dosage of prednisone.

A potentially beneficial estrogenic effect of prolonged tamoxifen therapy is preservation of bone mineral density (BMD) of the lumbar spine in postmenopausal women.258,265,266,267 (See Pharmacology: Effects on Bone.) Results of a substudy of the ATAC trial indicated that at 12 and 24 months postmenopausal women receiving adjuvant therapy with tamoxifen had a mean increase from baseline in both lumbar spine and total hip BMD, whereas those receiving anastrozole had a mean decrease from baseline in both lumbar spine and total hip bone BMD.128 In the ATAC trial, fractures of the spine, hip, or wrist were reported in 4% of patients receiving anastrozole compared with 3% of those receiving tamoxifen.128

Joint symptoms also were reported more frequently in patients receiving anastrozole compared with those receiving tamoxifen (36 versus 29%) in the ATAC trial.128

Ocular Effects

Tamoxifen rarely has been associated with ocular toxicity.277 Retinopathy, corneal opacities, and decreased visual acuity have occurred in patients receiving extremely high dosages (e.g., 180-320 mg daily) of tamoxifen for longer than 1 year.118,120,189 Ocular effects such as visual disturbances, decrement in color vision perception, corneal changes, cataracts, need for cataract surgery, optic neuritis, retinal vein thrombosis, intraretinal crystals, posterior subcapsular opacities, and/or retinopathy have also been reported in patients receiving recommended dosages of the drug.128,190,191,192,193,258,268,326 A slightly increased rate of developing cataracts and a greater risk of developing cataracts and undergoing cataract surgery were observed in women receiving tamoxifen in the BCPT.128,293

Hepatic Effects

Changes in hepatic enzyme concentrations (e.g., increased serum AST [SGOT] or ALT [SGPT] concentrations) and increased bilirubin and/or alkaline phosphatase concentrations have been reported in patients receiving tamoxifen therapy.128 Rarely, more severe hepatic abnormalities, including fatty changes in the liver, cholestasis, hepatitis, hepatic necrosis, and death, have occurred.128 A causal relationship of these adverse hepatic effects to tamoxifen has not been established; however, following rechallenge with tamoxifen, adverse hepatic effects occurred in some patients.128

GI Effects

Adverse GI effects of tamoxifen, including nausea, anorexia, distaste for food, and abdominal cramps, have been reported in patients with breast cancer.128

Nervous System Effects

Mood disturbances have been reported in patients with breast cancer receiving tamoxifen.396 Adverse nervous system effects reported in patients receiving tamoxifen for metastatic breast cancer include dizziness, lightheadedness, headache, fatigue, and mental depression.128

Hematologic Effects

Thrombocytopenia (platelet counts of 50,000-100,000/mm³ and, infrequently, lower) occasionally has occurred in patients receiving tamoxifen for the treatment of breast cancer;128 however, platelet counts returned to normal even though tamoxifen therapy was continued. Hemorrhagic episodes have occurred rarely in patients with severe thrombocytopenia.128 Neutropenia, pancytopenia, and leukopenia (sometimes associated with anemia and/or thrombocytopenia) also have been reported and may be severe.128 A causal relationship of the drug to some of these hematologic reactions has not been established.128

Purpuric vasculitis, which was unresponsive to prednisone 25 mg daily but resolved completely following drug withdrawal, has been reported in at least one patient receiving tamoxifen.212

Dermatologic Effects

Thinning and/or partial loss of hair occurs infrequently in patients receiving tamoxifen for metastatic breast cancer.128 Erythema multiforme, Stevens-Johnson syndrome, and bullous pemphigoid have been reported rarely in patients receiving tamoxifen.128 Skin changes have occurred in patients receiving tamoxifen as adjuvant therapy for breast cancer.128

Other Adverse Effects

Other adverse effects reported in patients receiving tamoxifen as adjuvant therapy for breast cancer or for metastatic breast cancer include weight loss, fatigue,128 and cough.128 Hypersensitivity reactions, including angioedema, have been reported rarely in patients receiving tamoxifen, sometimes more than one year following initiation of therapy.128 Interstitial pneumonitis also has been reported rarely in patients receiving the drug.128

Tamoxifen oral solution may cause mild throat irritation.396

Precautions and Contraindications

Serious, life-threatening or fatal events associated with tamoxifen used for reduction in the incidence of breast cancer (i.e., women at high risk for breast cancer and women with ductal carcinoma in situ [DCIS]) include endometrial cancer, uterine sarcoma, stroke, and pulmonary embolism.128,330 Healthcare providers should discuss the potential benefits versus risks of tamoxifen therapy with women considering use of the drug to potentially reduce their risk of developing breast cancer.128,330

Because of the increased risk of thromboembolic events associated with tamoxifen therapy in the BCPT, tamoxifen for reduction in the incidence of breast cancer is contraindicated in women with a history of deep-vein thrombosis or pulmonary embolism.128,278,293,396 Use of tamoxifen to reduce the incidence of breast cancer also is contraindicated in women who require anticoagulant therapy with a coumarin derivative.128,309,396 Women receiving or who have received tamoxifen should promptly seek medical attention for symptoms of unexplained shortness of breath or leg swelling/tenderness.128

Use of tamoxifen is associated with an increased incidence of uterine malignancies.128,330 (See Cautions: Mutagenicity and Carcinogenicity.) Women receiving tamoxifen or women with a history of having received tamoxifen who report abnormal vaginal bleeding should be evaluated promptly.128,330 Women receiving or who have received tamoxifen should receive routine gynecologic care and should be advised to report promptly any abnormal gynecologic symptoms, such as menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain/pressure, to their physician.128,163,183,330

Women receiving or who have received tamoxifen also should seek prompt medical attention for new breast lumps.128 Women should inform all care providers, regardless of the reason for evaluation, that they are receiving tamoxifen therapy.128

Women receiving tamoxifen to reduce the incidence of breast cancer should receive clinical evaluation including a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy with the drug.128 Such clinical evaluation should be repeated at regular intervals during tamoxifen therapy.128 The same type of clinical evaluation should be followed for women receiving tamoxifen as adjuvant therapy for breast cancer.128 Women receiving tamoxifen for the treatment of metastatic breast cancer should review this clinical monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation.128

The manufacturer states that tamoxifen should be used with caution in patients with leukopenia and thrombocytopenia, and periodic complete blood counts, including platelet counts, should be performed in patients receiving the drug.128 The manufacturer also states that periodic liver function tests should be obtained.128

Because of infrequent reports of lipoprotein abnormalities in patients receiving tamoxifen,128,185,186,187,188 including cases of hypertriglyceridemia324,325 and marked hyperlipoproteinemia,185,186,187 periodic monitoring of serum triglycerides and cholesterol is recommended during tamoxifen therapy in patients with a preexisting hyperlipoproteinemia.128,324 However, potentially beneficial estrogenic effects on lipoproteins (e.g., decreased total and low-density lipoproteins concentrations) also may occur.258,263

Patients complaining of visual changes or abnormalities during tamoxifen therapy should be assessed carefully for possible ocular toxicity.128,190,191,192,193,258,268 Women receiving or who have received tamoxifen should seek prompt medical attention for changes in vision.128

Women who are at high risk of developing breast cancer may consider tamoxifen therapy to reduce the incidence of breast cancer.128 Women who are considering use of tamoxifen for reduction in the incidence of breast cancer should consult a health-care professional to assess their risk of breast cancer and weigh the potential benefits and risks of therapy.128 Women should be informed and understand that while tamoxifen therapy may reduce the incidence of breast cancer, it may not eliminate risk of the disease.128 Those electing to receive tamoxifen therapy should be advised to read the medication guide for tamoxifen prior to initiating therapy with the drug and each time the prescription is renewed.128 In the BCPT, tamoxifen decreased the incidence of small, estrogen receptor-positive tumors, but did not alter the incidence of larger (exceeding 2 cm in diameter) or estrogen receptor-negative breast tumors.128 In other clinical trials that were smaller than the BCPT and enrolled women at a lower risk for breast cancer, no difference in the number of cases of breast cancer was observed in women receiving tamoxifen or placebo.128 In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately 50%.128

Women who are pregnant or who plan to become pregnant should not use tamoxifen to reduce the risk of breast cancer.128 (See Cautions: Pregnancy, Fertility, and Lactation.)

Women with DCIS who are considering use of tamoxifen to reduce the risk of invasive breast cancer following surgery and radiation therapy should consult a health-care professional to assess the potential benefits and risks of therapy, since tamoxifen has been shown to reduce the incidence of invasive breast cancer but has not been shown to improve survival.128 Those electing to receive tamoxifen therapy should be advised to read the medication guide for tamoxifen prior to initiating therapy with the drug and each time the prescription is renewed.128

Tamoxifen is contraindicated in patients with known hypersensitivity to the drug or other ingredients in the formulation.128,396

Pediatric Precautions

Tamoxifen has been used for the treatment of Albright syndrome† (also known as McCune-Albright syndrome) and precocious puberty in girls 2-10 years of a however, the effects of tamoxifen beyond one year of treatment in these patients have not been established.128 In a noncomparative study, 28 girls 2-10 years of age with Albright syndrome and precocious puberty (manifested by physical signs of pubertal development, episodes of vaginal bleeding, and/or advanced bone age) received tamoxifen 20 mg once daily for up to 12 months.128 Tamoxifen therapy was associated with a 50% reduction in frequency of vaginal bleeding episodes and reductions in bone age maturation and linear growth velocity.128 An increase in mean uterine volume was observed following 6 months of therapy, with doubling of uterine volume observed after one year of therapy; however, a casual relationship to the drug has not been established.128 Because tamoxifen has been associated with an increased incidence of endometrial and uterine malignancies in adults, the manufacturer recommends continued monitoring for long-term uterine effects in pediatric patients receiving tamoxifen for the treatment of Albright syndrome.128

In animal studies, direct exposure of neonatal mice and rats to tamoxifen resulted in lesions in the female reproductive tract (similar to those observed with diethylstilbestrol in humans) and functional defects of the male reproductive tract (e.g., testicular atrophy, arrest of spermatogenesis).396

Geriatric Precautions

In the BCPT, 16% of the study participants were 65 years of age or older and 6% were at least 70 years of age.128 Reductions in the incidence of breast cancer were observed in women receiving tamoxifen across all age groups.128 Across all other outcomes, the results in the subset of women 65 years of age or older reflect the results observed in the subset of women at least 50 years of age.128 In this trial, the risk of serious adverse effects (e.g., endometrial cancer, pulmonary embolism, deep-vein thrombosis, stroke) was greatest in women 50 years of age and older.239,269,290,293

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 study evaluating tamoxifen in patients with DCIS, 23% of the study participants were 65 years of age or older and 10% were at least 70 years of age.128 Because invasive breast cancer occurred in relatively few tamoxifen- or placebo-treated women 65 years of age or older, the results were insufficient to determine whether geriatric patients respond differently than younger adults for this outcome.128 Across all other outcomes, no overall differences were observed between geriatric patients and younger adults.128 In this study, no overall differences in safety were observed between geriatric patients and younger adults.128

Mutagenicity and Carcinogenicity

Mutagenicity

No evidence of tamoxifen-induced mutagenicity was observed in various in vivo and in vitro tests with prokaryotic and eukaryotic test systems in the presence of drug metabolizing systems.128 However, increased levels of DNA adducts have been found in cultured human lymphocytes and the livers of rats exposed to tamoxifen.128 Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell lines (MCL-5).128 Thus, tamoxifen is potentially genotoxic in animals and in humans.128

Carcinogenicity

Tamoxifen is carcinogenic in animals and humans.128

Uterine Cancer

In athymic mice, tamoxifen has stimulated the growth of certain endometrial tumors.177 An increased incidence of uterine sarcoma,330 endometrial cancer,128,173,174,175,240,258,293 and endometrial changes including hyperplasia128,178,258,259 and polyps128,178,240 has been reported in women receiving tamoxifen. The incidence and pattern of this increase is related to the estrogenic activity of tamoxifen.128,258 Some evidence suggests that prior exposure to hormone replacement therapy may contribute to the development of endometrial cancer and may be a confounding factor in determining the effect of tamoxifen therapy on the uterus.239,277,289,298

An increased incidence of uterine cancer, sometimes fatal, has been reported in women receiving tamoxifen.128,330 Most uterine malignancies associated with tamoxifen therapy are classified as adenocarcinoma of the endometrium; however, rare uterine sarcomas, including malignant mixed mullerian tumors, also have been reported.128,330

Uterine sarcoma has been reported more frequently among women receiving long-term therapy (i.e., exceeding 2 years) with tamoxifen than among women not receiving the drug.128,330 Among women enrolled in the BCPT, uterine sarcomas were reported in 4 women receiving tamoxifen versus one of the women receiving placebo (an incidence of 0.17 and 0.04 per 1000 women-years, respectively).128,330 Uterine sarcoma generally is associated with more advanced disease at the time of diagnosis, poorer prognosis, and shorter survival.128,330

Long-term (i.e., exceeding 2 years) tamoxifen therapy has been associated with an increased risk (3.1-7.5 times that in untreated women) of developing endometrial cancer.128,173,176,258,298,330 In a large controlled study of adjuvant tamoxifen therapy (40 mg daily for 2-5 years) in women with early breast carcinoma, the relative risk of developing endometrial cancers associated with tamoxifen therapy was 5.6 times that of the control group (23 of 1372 tamoxifen-treated women and 4 of 1357 women in the control group developed cancers of the uterus).173 After approximately 6.8 years of follow-up in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 study, 15 of 1419 women randomized to receive tamoxifen 20 mg daily for 5 years developed uterine cancer; 2 of 1424 women who were receiving placebo initially, but who subsequently received tamoxifen for recurrent breast carcinoma, also developed uterine cancer.298 The relative risk of endometrial cancer in the tamoxifen-treated women was 7.5; 298 most of the uterine cancers in tamoxifen-treated patients with breast cancer were diagnosed at an early stage, but deaths resulting from uterine cancer associated with tamoxifen therapy for the treatment of breast cancer have been reported.298

Women receiving tamoxifen for the prevention of breast cancer in the Breast Cancer Prevention Trial (BCPT) had an approximately 3.1 times greater risk of developing an endometrial adenocarcinoma than women receiving placebo (53 versus 17 cases or an incidence of 2.2 versus 0.71 per 1000 women-years at a median follow-up of 6.9 years).128,330 The increased risk of developing endometrial cancer in women receiving tamoxifen for the prevention of breast cancer occurred predominantly in women 50 years of age or older at the time of randomization (relative risk of 4.5 according to data available as of January 31, 1998; relative risk of 4.01 according to data available as of March 31, 1998).128,293 According to age at the time of diagnosis of endometrial cancer, increase in risk of endometrial cancer was similar for women 49 years of age or younger (relative risk of 2.21) and women 50 years of age or older (relative risk of 2.5), although fewer cases of endometrial cancer occurred in younger women.128 Among women receiving tamoxifen in the BCPT, endometrial cancer was diagnosed on average at 32 months (range: 1-61 months) following initiation of therapy with the drug.128

All but one of the women in the BCPT who developed endometrial cancer (a study participant receiving placebo who subsequently died of endometrial cancer) had early-stage disease that could be treated effectively with surgery (i.e., hysterectomy) with or without postoperative radiation therapy.128,270,293,307 The distribution according to stage of endometrial cancer (according to FIGO) was similar among women receiving tamoxifen or placebo.128

Approximately 37% of the participants receiving tamoxifen or placebo in the BCPT had undergone a hysterectomy prior to enrollment in the study and therefore were not at risk for the development of endometrial cancer.270,293 For women in the BCPT who had an intact uterus, endometrial sampling (i.e., examination of cells from the lining of the uterus) did not alter the rate of detection of endometrial cancer; currently, no data suggest that routine endometrial sampling in asymptomatic women receiving tamoxifen to reduce the incidence of breast cancer would be beneficial. Endometrial cancer often is associated with clinical manifestations, such as abnormal vaginal bleeding or pelvic pain.270,289 About 88% of cases of endometrial cancer diagnosed in tamoxifen-treated women in the BCPT were associated with symptoms.128,342

Endometrial hyperplasia can be a premalignant change.258 In one study of postmenopausal women receiving tamoxifen for the prevention of breast cancer, 16% developed atypical hyperplasia while no cases occurred in those receiving placebo;258,259,274 8% of women receiving tamoxifen had an endometrial polyp compared with 2% of those receiving placebo.274 These findings were based on screening of a randomized cohort of women from the study who had not been screened before the initiation of therapy, and some of the women also were receiving hormone replacement therapy as permitted by the study protocol.274 Optimal management of women who develop endometrial changes during tamoxifen therapy remains to be elucidated; the value of progestins in reversing such hyperplasia is not established nor are their effects on breast cancer in tamoxifen-treated women adequately studied.258 Screening and management of women who develop endometrial hyperplasia during tamoxifen therapy should be individualized, weighing the risks and benefits of continued therapy with the drug.258

Endometriosis also has been reported.180 In addition, variations in the karyopyknotic index on vaginal smears128 and varying degrees of estrogenic effects on the Papanicolaou test128 also have been reported in postmenopausal women receiving the drug. Patients receiving or having previously received tamoxifen should undergo routine gynecologic examinations, and they should be advised to report promptly any menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain/pressure to their clinician; the cause of such effects should be evaluated promptly.128,163,183

Liver Cancer

In rats given 5, 20, or 35 mg/kg of tamoxifen daily (approximately 1, 3, or 7 times, respectively, the maximum recommended human dosage on a mg/m² basis) for up to 2 years, hepatocellular carcinoma occurred at all dosages.128,204,244 The incidence of this carcinoma in rats receiving 20 or 35 mg/kg daily (69%) was substantially greater than that in those given 5 mg/kg daily (14%), and the incidence in rats given 5 mg/kg daily was substantially greater than that in controls.128,204 In rats given 45 mg/kg of tamoxifen daily (approximately 9 times the maximum recommended human dosage on a mg/m² basis), hepatocellular neoplasms were evident at 3-6 months.128

In a study of women with breast cancer receiving tamoxifen (40 mg daily) or no adjuvant endocrine therapy for 2-5 years, 3 cases of liver cancer were reported in women receiving tamoxifen versus 1 case in the control group.128 One case of liver cancer was reported among women receiving tamoxifen in the BCPT.128

Other Cancers

Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in mice receiving trans and racemic formulations of the drug for 13-15 months at dosages of 5, 20, or 50 mg/kg daily (approximately 0.5, 2, or 5 times, respectively, the maximum recommended human dosage on a mg/m² basis);119,128 however, the relevance of these findings to humans is not known.119

Data from the NSABP B-14 study did not reveal an increased incidence of carcinomas other than uterine carcinomas.128 However, several second primary tumors occurring at sites other than the endometrium have been reported in clinical studies;128 it currently is not known whether an increased risk of these carcinomas is associated with tamoxifen therapy, and additional studies are needed to evaluate the risk of this carcinogenicity.128 Tamoxifen therapy has been associated with a reduced incidence of second primary breast carcinomas.128,173,176,183,184

Pregnancy, Fertility, and Lactation

Pregnancy

Tamoxifen may cause fetal harm when administered to pregnant women.128 Effects on reproductive function are expected from the antiestrogenic properties of the drug.128 In reproduction studies in rats using tamoxifen dosages equal to or less than the human dosage, nonteratogenic developmental skeletal changes were observed and were found to be reversible.128 In fertility studies in rats and teratology studies in rabbits using dosages at or below those used in humans, a lower incidence of egg implantation and a higher incidence of fetal death or retarded in utero growth were observed, reportedly with slower learning behavior in some rat offspring compared with historical controls, although this latter effect is not clearly established.128 No teratogenic effects were observed in monkeys receiving tamoxifen during the period of organogenesis or the last half of pregnancy; although the dosage employed was high enough to terminate pregnancy in some of the animals, those that maintained pregnancy delivered offspring without evidence of teratogenicity.128 In reproduction studies in rats using tamoxifen dosages 0.002-2.4 times the maximum recommended dosages in humans on a mg/m² basis, changes in both male and female similar to those caused by estradiol, ethynylestradiol, and diethylstilbestrol (DES) (no longer commercially available in the US) were observed.128 Although the clinical importance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those observed in young women who were exposed to DES in utero;128 such women have a greater risk (1 in 1000) of developing clear-cell adenocarcinoma of the vagina or cervix.128 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.128 However, only a small number of young women have been exposed to tamoxifen in utero;128 of these, a smaller number have been followed long enough (15-20 years) to determine whether vaginal or cervical neoplasia could occur as a result of exposure to tamoxifen.128

There are no adequate and well-controlled studies using tamoxifen in pregnant women.128 There have been reports of spontaneous abortions, birth defects, fetal deaths, and vaginal bleeding.128 Women should not become pregnant while receiving tamoxifen or within 2 months after discontinuance of therapy with the drug,119,128,243 and those of childbearing potential should use an effective barrier or other nonhormonal method of contraception during tamoxifen therapy and for approximately 2 months after the drug has been discontinued.128,396 When tamoxifen is administered during pregnancy or if the patient becomes pregnant while receiving the drug or within approximately 2 months after discontinuance of therapy with tamoxifen, the patient should be informed of the potential hazard to the fetus, including the possible long-term risk of a DES-like syndrome.128

Pregnancy testing should be performed prior to initiation of tamoxifen therapy in women of childbearing potential.396 Alternatively, for sexually active women of childbearing potential who are receiving tamoxifen for reduction in the incidence of breast cancer, therapy with the drug should be initiated during menstruation.128 In women with menstrual irregularity, pregnancy testing with a negative β-human chorionic gonadotropin (β-HCG) test result should be confirmed immediately prior to the initiation of tamoxifen therapy.128

Fertility

Marked reductions in fertility and reproductive indices, as well as death of all fetuses, have been observed in reproduction studies in rats receiving tamoxifen.128 Based on results of animal studies, tamoxifen may impair embryo implantation in females of reproductive potential, but does not reliably cause infertility.396 Women receiving the drug should be advised that tamoxifen does not always cause infertility, even in the presence of menstrual irregularity.128,396

Lactation

It is not known if tamoxifen is distributed into milk.128 Direct exposure (not via breast milk) of neonatal mice and rat pups to tamoxifen has resulted in adverse reproductive tract effects (i.e., lesions in female pups that are similar to those observed in humans after intrauterine DES exposure; functional defects, including testicular atrophy and arrested spermatogenesis, in male pups).128

Because of the potential for serious adverse reactions to tamoxifen in nursing infants, a decision should be made whether to discontinue nursing during tamoxifen therapy and for 3 months after the last dose or to discontinue the drug, taking into account the importance of the drug to the woman.128,396 In 2 placebo-controlled trials, inhibition of early postpartum milk production was observed in women who received tamoxifen within 24 hours of delivery for a duration of 5-18 days.128 The effect of tamoxifen on established milk production is not known.128

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of tamoxifen with inhibitors of cytochrome P-450 (CYP) isoenzyme 2D6 (e.g., bupropion, fluoxetine, paroxetine, quinidine) may result in decreased plasma concentrations of the active metabolite 4-hydroxy- N -desmethyltamoxifen (also known as endoxifen).338,339,351,384,385 (See Drug Interactions: Selective Serotonin-Reuptake Inhibitors.) However, studies investigating the effect of CYP2D6 inhibitors on tamoxifen efficacy have had substantial limitations and are inconclusive, as they have resulted in contradictory findings.348,385,396 Some experts recommend avoiding concomitant use of tamoxifen and weak, moderate, or potent CYP2D6 inhibitors in patients with a CYP2D6 intermediate- or normal/intermediate-metabolizer phenotype; these experts recommend that moderate or potent CYP2D6 inhibitors also be avoided in patients with CYP2D6 normal- or ultrarapid-metabolizer phenotype and that alternative adjuvant endocrine therapies (rather than tamoxifen) be used in patients with poor-metabolizer phenotype.339 (See Cytochrome P-450 Isoenzyme 2D6 Polymorphism under Breast Cancer: Pharmacogenomic Considerations for Tamoxifen Therapy, in Uses.) However, the role of CYP2D6 genotype testing in patients receiving tamoxifen remains controversial, and other experts make recommendations that are not dependent on genotyping results.334,338,385 Because the effect of CYP2D6-mediated interactions on long-term clinical outcomes of tamoxifen therapy is uncertain, these experts state that it is reasonable to avoid concomitant use of CYP2D6 inhibitors, particularly those with moderate or potent inhibitory activity, when possible in patients receiving tamoxifen.334,338,384,385

Concomitant use of tamoxifen and drugs that induce CYP isoenzymes (e.g., phenobarbital, phenytoin, aminoglutethimide [no longer commercially available in the US]) may reduce plasma concentrations of tamoxifen and endoxifen.128,385 (See Drug Interactions: Other Drugs.) However, the clinical importance of this interaction has not been established.385 Nonetheless, some clinicians suggest that use of agents with the potential to induce multiple isoenzymes and transporters (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort [ Hypericum perforatum ]) should be avoided in patients receiving tamoxifen.385

Anticoagulants

Tamoxifen has been reported to potentiate the hypoprothrombinemic effect of warfarin.128,170,171,172,396 In patients stabilized on warfarin therapy, substantial prolongations in prothrombin time have occurred within several days to weeks after initiation of tamoxifen therapy;170,171 overt signs of bleeding (e.g., hematemesis, hematuria, subdural hematoma, intraocular hemorrhage) also have occurred during concomitant therapy with the drugs.170,171,172 While the mechanism for this interaction currently is not known,170,171 tamoxifen and coumarin-derivative anticoagulants should be used concomitantly with caution.128,170,171,172 If the drugs are used concomitantly, the patient and prothrombin time should be monitored closely and dosage of the anticoagulant adjusted accordingly.128,170,171,396

Aromatase Inhibitors

Concomitant use of selective estrogen receptor modulators (e.g., tamoxifen) and aromatase inhibitors (e.g., anastrozole, exemestane, letrozole) is not recommended based on pharmacokinetic and clinical considerations.128,343,344,396 Data from a subprotocol of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial indicate that concomitant use of tamoxifen and anastrozole does not affect the pharmacokinetics of tamoxifen or N -desmethyltamoxifen.128,345 The mean plasma anastrozole concentration was reduced by an average of 27% in patients receiving tamoxifen and anastrozole versus anastrozole alone,128 but analysis of blood samples from a different subprotocol of the ATAC trial demonstrated similar degrees of suppression of plasma estradiol concentrations for anastrozole alone and in combination with tamoxifen.345 Although the clinical importance of this pharmacokinetic interaction is uncertain,345 combination therapy did not demonstrate greater efficacy as adjuvant therapy for breast cancer than use of tamoxifen alone.128,345 When tamoxifen was used concomitantly with letrozole, the plasma letrozole concentration was reduced by 37%.128

Selective Serotonin-Reuptake Inhibitors

Substantial decreases in plasma concentrations of endoxifen have been observed in patients receiving concomitant therapy with tamoxifen and a selective serotonin-reuptake inhibitor (SSRI) with potent CYP2D6 inhibitory activity (i.e., paroxetine, fluoxetine).348,351,384,385,396 However, studies investigating the effect of SSRIs on tamoxifen efficacy have been inconclusive.334,348,385 SSRIs with moderate or potent CYP2D6 inhibitory activity should be avoided in patients receiving tamoxifen; if therapy with an antidepressant is required, use of an SSRI or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) with little or no inhibitory effect on CYP2D6 (e.g., citalopram, escitalopram, venlafaxine, desvenlafaxine) would be preferred.334,338,339,384,385 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Other Drugs

Concomitant use of rifampin and tamoxifen reportedly has decreased systemic exposure to tamoxifen and endoxifen by 84-86 and 70%, respectively.128,385,396 Following administration of aminoglutethimide (no longer commercially available in the US) in patients receiving tamoxifen therapy, systemic exposure to tamoxifen and endoxifen were decreased by 73 and 93%, respectively, while concentrations of other metabolites generally were reduced by about 50%; endoxifen concentrations were undetectable in 3 of 6 patients.385,386,396 Endoxifen concentrations also were markedly lower than predicted following initiation of tamoxifen therapy in a patient with CYP2D6 extensive-metabolizer phenotype who was receiving phenytoin.385,387 In at least one patient receiving tamoxifen and phenobarbital concomitantly, serum tamoxifen concentrations were decreased by about 80%.128 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

The effect of tamoxifen on the metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide, and other drugs that require mixed function oxidases for activation, is unknown.128

In vitro, erythromycin, cyclosporine, nifedipine, and diltiazem competitively inhibited formation of N -desmethyltamoxifen; however, the clinical importance of these interactions is unknown.128 Serum tamoxifen and N -desmethyltamoxifen concentrations reportedly were increased in patients receiving bromocriptine and tamoxifen concomitantly.128 Serum concentrations of N -desmethyltamoxifen, but not those of tamoxifen, are decreased in patients receiving medroxyprogesterone and tamoxifen concomitantly.128,396

An increased risk of thromboembolic events has been observed in patients receiving tamoxifen concomitantly with cytotoxic drugs.128

Laboratory Test Interferences

Estrogen-Receptor Determinations

Because the elimination of tamoxifen and its principal metabolites is prolonged, false-negative estrogen-receptor determinations might result if the determination is performed too soon after discontinuance of tamoxifen therapy.137,145 To avoid this possibility it is recommended that estrogen-receptor determinations be delayed for 4-6 weeks after discontinuance of the drug.137,145

Thyroid Function Tests

Increased serum thyroxine concentrations, which were not accompanied by signs and symptoms of clinical hyperthyroidism and may be explained by increases in thyroxine-binding globulin, have occurred in a few postmenopausal women receiving tamoxifen.128

Acute Toxicity

Manifestations

In studies to determine the acute lethal dose of tamoxifen, respiratory difficulties and seizures were reported in animals receiving very high doses of tamoxifen.128 There currently is no information available on overdosage of tamoxifen in humans.128

In one study to determine the maximum tolerated dose of tamoxifen, acute neurotoxicity, manifested by tremor, hyperreflexia, unsteady gait, and dizziness, occurred in patients with advanced (metastatic) carcinoma who were receiving very high dosages of tamoxifen (i.e., loading doses exceeding 400 mg/m² followed by maintenance dosages of 150 mg/m² given twice daily) to reverse multiple-drug resistance.128 These adverse effects occurred within 3-5 days of initiating tamoxifen therapy and disappeared 2-5 days after discontinuance of the drug.128 No permanent neurologic sequelae were reported in these patients.128 Although a causal relationship to tamoxifen has not been established, seizures were reported in at least one of these patients several days after discontinuance of the drug and disappearance of adverse nervous system effects.128 In patients receiving loading doses exceeding 250 mg/m² followed by maintenance doses of 80 mg/m² administered twice daily, prolongation of the QT interval was reported.128 In one female patient who had a body surface area of 1.5 m², the minimal loading and maintenance doses of the drug at which neurological symptoms and prolongation of the QT interval occurred were at least sixfold higher than the maximum recommended dose.128

Treatment

The manufacturer recommends no specific treatment for tamoxifen overdosage and states that treatment should be symptomatic.128

Pharmacology

Tamoxifen citrate, a nonsteroidal antiestrogen, is a triphenylethylene derivative with both estrogen antagonist (antiestrogen) and agonist (estrogen-like) activity.128,311 Tamoxifen acts as an estrogen antagonist on breast tissue and in the CNS and as an estrogen agonist on endometrium, bone, and lipids.311 The precise mechanism(s) of action of the drug is not known. Tamoxifen and at least several of its metabolites compete with estradiol for binding to cytoplasmic estrogen receptors in tissues such as breast, uterus, vagina, anterior pituitary, and tumors containing high concentrations of estrogen receptors.

Effects on the Breast

The competition of tamoxifen and at least several of its metabolites with estradiol for binding to cytoplasmic estrogen receptors in breast tissue is thought to contribute to its protective effect against the development of breast cancer.128,277,278,311 Although the tamoxifen-receptor and metabolite-receptor complexes are translocated to the nucleus, binding to nuclear chromatin appears to occur in an atypical manner and persists for longer periods of time than the estrogen-receptor complexes. DNA synthesis and estrogen responses are thus markedly reduced. Contrary to a previous hypothesis, a study in rats demonstrated that tamoxifen does not interfere with replenishment of cytoplasmic estrogen receptors. The in vivo antiestrogenic and antitumor effects of tamoxifen appear to result from the combined actions of unchanged drug and several of the identified metabolites, but their relative contribution remains to be fully elucidated.145,150,152,153,154,155,156,157

Tamoxifen also appears to oppose the proliferative effects of estrogen on breast epithelium by increasing production of inhibitory factors (e.g., transforming growth factor [TGF]-β) and decreasing production of stimulatory factors (e.g., TGF-α, insulin-like growth factor-1) that influence breast cell growth.271,286,287,323

Effects on Bone

In vitro and animal studies show that tamoxifen acts as an estrogen agonist on bone.312,313,314,315 Results of an in vitro study show that tamoxifen inhibits the resorbing activity of osteoclasts.312 In oophorectomized rats, tamoxifen prevented increased bone resorption and bone loss.313,314,315 In humans, tamoxifen reduces bone resorption and decreases bone turnover as manifested by reductions in serum and urine concentrations of bone turnover markers (e.g., alkaline phosphatase, osteocalcin) and increases in bone mineral density.265,266,267,316 Tamoxifen appears to act mainly on sites of trabecular bone, such as the lumbar spine, and seems to have little effect on cortical bone (e.g., radial bone).265,316,317

Healthy postmenopausal women receiving tamoxifen 20 mg daily for 2 years experienced a small increase in mean bone mineral density of the lumbar spine compared with those receiving placebo; no effect of tamoxifen was observed on bone mineral density of the proximal femur.316 In studies of postmenopausal women receiving long-term treatment (i.e., at least 2 years) with tamoxifen as adjuvant therapy for early-stage breast cancer, tamoxifen preserved bone mass in the lumbar spine.265,266,267 In the Breast Cancer Prevention Trial (BCPT), women receiving tamoxifen had fewer fractures of the hip than those receiving placebo (12 versus 22 cases, respectively),293 but the difference was not significant, and the total number of fractures identified as most likely to be associated with osteoporosis (hip, wrist, and spine) was similar (111 versus 137 cases, respectively); because of the small number of fracture events overall, no definitive conclusions could be drawn from this study regarding the effect of tamoxifen on the rate of fractures.128,293

Some evidence suggests that the effects of tamoxifen on bone mineral density depend on menopausal status.128,275 In a pilot trial conducted in the UK for the prevention of breast cancer, postmenopausal women receiving tamoxifen had an increase in bone mineral density of the lumbar spine and hip compared with those receiving placebo; in contrast, premenopausal women receiving tamoxifen had loss of bone mineral density in the lumbar spine and hip, which may increase the risk of osteoporosis and fracture, compared with those receiving placebo.275 Similarly, subgroup analysis of data from the BCPT showed no evidence of bone loss at the lumbar spine and hip in tamoxifen-treated postmenopausal women, but tamoxifen was associated with substantial bone loss at the lumbar spine and hip in premenopausal women.128 Additional studies and long-term follow-up are needed to confirm the effects of tamoxifen on bone loss in premenopausal women.289 Although clinicians generally recommend evaluation and treatment of osteoporosis in postmenopausal women only,289 some experts propose investigation of preventive measures for osteoporosis (e.g., bisphosphonates, hormone replacement therapy) in premenopausal women receiving tamoxifen for the prevention and treatment of breast cancer.275,289 Further study is needed to evaluate the long-term effects of tamoxifen on bone mineral density and risk of osteoporosis and fracture in healthy women.275,277,293

Further study is needed to establish the potentially beneficial effects of tamoxifen on bone density and risk of osteoporosis; although it may be considered in the risk-benefit analysis of tamoxifen for the prevention and/or treatment of breast cancer, this effect alone is not an indication for tamoxifen therapy.307

Effects on Lipoproteins

Tamoxifen, like estrogens, favorably affects serum cholesterol by decreasing total and low-density lipoprotein (LDL)-cholesterol concentrations.318,319,320 Less favorably, tamoxifen appears to moderately decrease high-density lipoprotein (HDL)-cholesterol concentrations and increase triglyceride concentrations.318,319,320

Results of studies to determine whether favorable alterations in serum lipoproteins induced by tamoxifen result in reduced risk of cardiovascular events have been inconsistent.263,264,293,321,322 In a large randomized trial conducted in Scotland, postmenopausal women who received adjuvant therapy with tamoxifen for a 5-year period immediately following mastectomy for operable breast cancer had fewer fatal myocardial infarctions than patients who received tamoxifen for a minimum of 6 weeks upon first recurrence of breast cancer.263 In the Stockholm study, retrospective analysis showed that postmenopausal women with early-stage breast cancer who received adjuvant therapy with tamoxifen had less cardiac morbidity than those who received placebo; the reduction in cardiac morbidity was greater for women receiving tamoxifen for a longer duration (i.e., 5 versus 2 years).264 Findings from the NSABP protocol B-14 suggested a trend toward reduced mortality from coronary heart disease among women with node-negative, estrogen receptor-positive breast cancer receiving 5 years of therapy with tamoxifen versus placebo, but the difference between the groups was not significant.322 Although a 20% reduction in mortality from cardiovascular events was projected for women receiving tamoxifen in the BCPT, the incidence of fatal and nonfatal myocardial infarctions was similar among women receiving tamoxifen or placebo;128,277,293 the number of events of severe angina or acute ischemic syndrome also did not differ between the groups.128,293 Because of the age distribution of women in the BCPT (about 30% were 60 years of age or older), some experts have questioned whether the sample size of women at risk for myocardial infarction would be sufficient to detect a positive effect of tamoxifen on cardiovascular disease.281,283

Further study and longer follow-up are needed to establish the effect of tamoxifen on serum lipoprotein concentrations and cardiovascular morbidity/mortality;239,264,283,289,293,322 although it may be considered in the risk-benefit analysis of tamoxifen for the prevention and/or treatment of breast cancer, this effect alone is not an indication for tamoxifen therapy.307

Effects on the Uterus

Tamoxifen acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects on the endometrium.311 (See Cautions: Mutagenicity and Carcinogenicity.)

Other Effects

Following short-term administration in anovulatory women, tamoxifen may induce ovulation by stimulating the release of the hypothalamic gonadotropin-releasing factor with a resulting increase in secretion of pituitary gonadotropin.

Pharmacokinetics

Absorption

Tamoxifen appears to be absorbed slowly following oral administration, with peak serum concentrations generally occurring about 3-6 hours after a single dose.137,138,139,140,141 The extent of absorption in humans has not been adequately determined, but limited data from animal studies suggest that the drug is well absorbed.142 Data from animal studies also suggest that tamoxifen and/or its metabolites undergo extensive enterohepatic circulation.142 Tamoxifen oral solution and tablets are bioequivalent when administered under fasting conditions.396 Bioavailability of the oral solution is similar under fed and fasting conditions.396

Following oral administration, peak serum tamoxifen concentrations average about 17 ng/mL after a single 10-mg dose,141 about 40 ng/mL after a single 20-mg dose,139 and 65-70 ng/mL after a single 40-mg dose;140 however, there is considerable interindividual variation in serum tamoxifen concentrations attained after single doses and at steady state with continuous dosing.137,139,140,141,143 Following a single oral dose of tamoxifen, peak serum concentrations of N -desmethyltamoxifen, the major metabolite of the drug, generally range from about 15-50% those of unchanged tamoxifen;137,139,140,143 however, with continuous dosing, steady-state serum concentrations of N -desmethyltamoxifen generally range from about 1-2 times those of unchanged tamoxifen.137,140,143,144,145,146,150 Following continuous administration in patients receiving oral tamoxifen 10 mg twice daily for 3 months, steady-state plasma concentrations of tamoxifen and N -desmethyltamoxifen average about 120 ng/mL (range: 67-183 ng/mL) and 336 ng/mL (range: 148-654 ng/mL), respectively.128 Steady-state serum concentrations of tamoxifen are generally attained after 3-4 weeks of continuous dosing,128,137,140,143,145 while those of N -desmethyltamoxifen are generally attained after 3-8 weeks of continuous dosing.128,137,140,145 Steady-state serum concentrations can be attained more rapidly with a loading-dose regimen, but there is no therapeutic advantage with such a regimen.137,147 In a 3-month crossover study, the steady-state oral bioavailability of 20-mg tamoxifen tablets (administered once daily) was similar to that of 10-mg tablets (administered twice daily).128,239

In 27 girls 2-10 years of age receiving tamoxifen (20 mg once daily) for the treatment of Albright syndrome, the average steady-state peak plasma concentration of tamoxifen was achieved approximately 8 hours following administration.128 Systemic exposure to N -desmethyltamoxifen was comparable between pediatric patients and adults.128

Distribution

Distribution of tamoxifen and its metabolites into human body tissues and fluids has not been fully characterized.26,144 In a study in a limited number of women given radiolabeled tamoxifen prior to hysterectomy, concentrations of radioactivity in uterine tissues were greater than those in serum 4-96 hours after the drug was given; highest uterine concentrations of radioactivity were present in the endometrium.26 Tamoxifen metabolites are distributed into bile in animals.142 Distribution of tamoxifen and its principal metabolites in the cytosol of human breast tumor tissue generally appears to parallel the relative concentrations present in serum, although cytosol concentrations may exhibit even greater interindividual variation than serum concentrations.143,144

It is not known if tamoxifen is distributed into milk.128

Elimination

Limited data suggest that tamoxifen has a distribution half-life of 7-14 hours28,137,140 and an elimination half-life of about 5-7 days (range: 3-21 days).28,128,137,139,145 The elimination half-life of N -desmethyltamoxifen, the major metabolite, is estimated to be approximately 14 days.128,139,145,379

Tamoxifen is rapidly and extensively metabolized in the liver,26,28,140,142,143,144,145,146,148,149,150,151,380 principally by demethylation and hydroxylation.140,143,144,145,146,148,149,150,151,339,380,381 Although multiple cytochrome P-450 (CYP) isoenzymes, including 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4/5, are involved in the metabolism of tamoxifen, the principal metabolic pathway involves demethylation of the parent drug, mediated mainly by CYP3A4/5, to form N -desmethyltamoxifen, followed by CYP2D6-mediated hydroxylation to form 4-hydroxy- N -desmethyltamoxifen (also known as endoxifen).339,347,380 N -Desmethyltamoxifen also undergoes CYP3A4/5-mediated demethylation to form N,N -didesmethyltamoxifen.149,150,151,152,347,380 Formation of N -desmethyltamoxifen accounts for approximately 92% of the metabolism of the parent drug.347,381 Tamoxifen also is metabolized to a lesser extent (approximately 7%) by CYP isoenzymes, mainly CYP2D6, to form 4-hydroxytamoxifen, which undergoes further metabolism to form endoxifen and polar conjugates.339,347,380,381 Other metabolites, including metabolite E, 4-hydroxy- N,N -didesmethyltamoxifen (norendoxifen), and tamoxifen bisphenol, also have been identified.382 Tamoxifen and its metabolites also are metabolized by multiple uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes and to a lesser extent by sulfotransferases (mainly SULT1A1) to form glucuronide and sulfate conjugates, respectively.339,348,380,381

Tamoxifen and its metabolites exhibit a range of affinities and effects (antagonistic or agonistic) at estrogen receptors.339,379,382 Whereas unchanged tamoxifen is a weak antiestrogen, both endoxifen and 4-hydroxytamoxifen are potent antiestrogens, exhibiting 100-fold greater affinity for estrogen receptors and 30- to 100-fold greater suppression of estrogen-dependent cell proliferation compared with tamoxifen; because plasma concentrations of endoxifen are up to tenfold higher than those of 4-hydroxytamoxifen, endoxifen is considered the major active metabolite of tamoxifen.339,348,349,350,379,381,383,384 The biologic activity of the metabolite N -desmethyltamoxifen appears to be similar to that of tamoxifen.128,379 Both interindividual and intraindividual variation in concentrations of tamoxifen and its metabolites have been observed.339 With continuous administration of tamoxifen, serum concentrations of N -desmethyltamoxifen are generally about 1-2 times those of unchanged tamoxifen,128,137,140,143,144,145,146,150,355,379,380 while those of N,N -desdimethyltamoxifen are about 20-40% of those of unchanged tamoxifen;143,146 concentrations of the hydroxylated metabolites and metabolite E appear to be less than 5% of those of unchanged tamoxifen.143,144,146,151

Studies indicate that endoxifen exposure is strongly associated with CYP2D6 metabolizer phenotype, but genetic polymorphism of CYP2D6 explains only part (approximately 30-53%) of the observed variability in endoxifen concentrations.339,349,354,355,359,360,383 Individuals with low CYP2D6 activity (from CYP2D6 polymorphism or concomitant use with a potent CYP2D6 inhibitor) exhibit substantially lower serum concentrations of endoxifen; however, studies evaluating the effect of these pharmacogenomic factors and drug interactions on breast cancer recurrence have been inconclusive.334,339,348,355,396 (See Cytochrome P-450 Isoenzyme 2D6 Polymorphism under Breast Cancer: Pharmacogenomic Considerations for Tamoxifen Therapy, in Uses.)

The excretory fate of tamoxifen and its metabolites has not been well characterized.28,145 Following oral administration of a 20-mg dose of radiolabeled tamoxifen in women, approximately 65% of the administered dose was excreted in feces over a 2-week period, mainly as polar conjugates; unchanged tamoxifen and unconjugated metabolites accounted for less than 30% of the fecal radioactivity.128 Unchanged tamoxifen and N -desmethyltamoxifen have been detected in urine in small amounts.146 In animals, tamoxifen and/or its metabolites appear to undergo extensive enterohepatic circulation and are excreted in feces and urine as glucuronides, other conjugates, and unidentified polar metabolites.142

In 27 girls 2-10 years of age receiving tamoxifen (20 mg once daily) for the treatment of Albright syndrome, clearance of the drug adjusted for body weight was approximately 2.3-fold higher than clearance in women with breast cancer; among those 2-6 or 7-10 years of age, clearance was increased by 2.6- or 1.9-fold, respectively.128

The effects of age, gender, race, and hepatic impairment on the pharmacokinetics of tamoxifen have not been established.128

Chemistry and Stability

Chemistry

Tamoxifen is a triphenylethylene-derivative, nonsteroidal estrogen agonist-antagonist that is structurally related to clomiphene. Like clomiphene and toremifene, tamoxifen previously was referred to as an antiestrogen because it was thought to be devoid of clinically important estrogen agonist activity. However, like these drugs and raloxifene, tamoxifen exhibits both estrogen agonist and antagonist activity, although the overall pharmacologic profiles of the drugs differ.

Tamoxifen citrate occurs as a fine, white crystalline powder and has a solubility of 0.5 mg/mL in water at 37°C and is very slightly soluble in alcohol. The drug has a pK_a of 8.85.

Stability

Commercially available tamoxifen tablets should be protected from light and stored in well-closed containers at controlled room temperature (20-25°C).

Commercially available tamoxifen oral solution should be protected from light and stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.396 The oral solution should not be frozen or refrigerated.396 Any unused portions of the oral solution should be discarded 3 months after first opening the bottle.396

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Only references cited for selected revisions after 1984 are available electronically.

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