Tamoxifen (Monograph)

Drug class: Estrogen Agonists-Antagonists
VA class: AN500
Chemical name: 2-Hydroxy-1,2,3-propanetricarboxylate-(Z)-2-[4-(1,2-diphyl-1-butenyl)phenoxy]-N,Ndimethyl ethanamine
Molecular formula: C₂₆H₂₉NO•C₆H₈O₇
CAS number: 54965-24-1

Medically reviewed by Drugs.com on Oct 25, 2023. Written by ASHP.

Warning

Serious and life-threatening events associated with tamoxifen in the risk reduction setting include uterine malignancies, stroke, and pulmonary embolism.¹²⁸ Incidence rates for these events have been estimated from the Breast Cancer Prevention Trial (BCPT; also known as the National Surgical Adjuvant Breast and Bowel Project [NSABP] P-1 trial) (median length of follow-up 6.9 years).¹²⁸

Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1000 women-years of 2.2 for tamoxifen versus 0.71 for placebo) and uterine sarcoma (incidence rate per 1000 women-years of 0.17 for tamoxifen versus 0.04 for placebo).¹²⁸

For stroke, the incidence rate per 1000 women-years was 1.43 for tamoxifen versus 1 for placebo.¹²⁸

For pulmonary embolism, the incidence rate per 1000 women-years was 0.75 for tamoxifen versus 0.25 for placebo.¹²⁸
Discuss potential benefits versus potential risks of these serious, sometimes fatal, events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer.¹²⁸
The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.¹²⁸

Introduction

A nonsteroidal estrogen agonist-antagonist; an antineoplastic agent.¹²⁸

Uses for Tamoxifen

Adjuvant Therapy of Breast Cancer

An adjuvant to surgery and radiation therapy for the treatment of breast cancer in women with negative or positive axillary lymph nodes.¹¹⁰ ¹²¹ ¹²⁸ ¹³⁰ ¹³³ ¹³⁶ ¹⁹⁴ ¹⁹⁵ ¹⁹⁶ ¹⁹⁸ ²⁰⁴ ²⁰⁵ ²⁵³ ²⁵⁴ ²⁵⁸ ³⁹⁶ Also reduces the occurrence of contralateral breast cancer in these women.¹²⁸ ²⁵³ ²⁵⁴ ²⁵⁸

Use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression^{† [off-label]} as adjuvant therapy in premenopausal women^{† [off-label]} with early-stage hormone receptor-positive breast cancer may be considered a reasonable choice (accepted).¹⁰⁰¹⁰ ¹⁰⁰¹¹ ¹⁰⁰¹² ¹⁰⁰¹³ ¹⁰⁰²⁶ ¹⁰⁰²⁸

Metastatic Breast Cancer

Palliative treatment of metastatic breast cancer in women.¹²⁸ ³⁹⁶ An alternative to ovarian ablative therapy (oophorectomy or radiation) in premenopausal women.¹²⁸ ¹³³ ¹⁵⁸ ¹⁵⁹ ¹⁶⁰ ¹⁶¹ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁶⁵ ¹⁶⁶ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁸³ Patients with estrogen receptor-positive tumors are more likely to respond.¹²⁸ ¹⁵⁸ ¹⁶³ ¹⁶⁶

Reduction in Risk of Invasive Breast Cancer in Patients with DCIS

Reduction of risk of invasive breast cancer in patients with DCIS following surgery and radiation therapy.¹²⁸ ³⁹⁶ Base decision regarding use on an individualized assessment of potential benefits and risks of therapy.¹²⁸

Reduction in Incidence of Breast Cancer in Women at High Risk

Reduction in the incidence of breast cancer in women at high risk for developing the disease.¹²⁸ ²⁵⁰ ²⁹³ ³⁹⁶ Base decision regarding use on an individualized assessment of potential benefits and risks of preventive therapy.²⁶⁹ ²⁷¹ ²⁹⁹ ³⁰⁸

ASCO considers tamoxifen an option in premenopausal or postmenopausal women ≥35 years of age with either a 5-year projected risk for developing breast cancer of ≥1.67% (based on Gail risk model) or a history of lobular carcinoma in situ (LCIS).³³⁷

Data regarding effect on breast cancer incidence in women with inherited mutations (e.g., BRCA1, BRCA2) are insufficient to support recommendations regarding tamoxifen use.¹²⁸

Breast Cancer in Men

Palliative treatment of metastatic breast cancer in men.¹⁰⁴ ¹²⁸ ²²⁹ ²³¹ ²³³ ²³⁶ ²³⁷ ²³⁸ ²⁵² ³⁷⁸ ³⁹⁶

Adjunct to surgery in the treatment of breast cancer in men with positive axillary lymph nodes^{† [off-label]}; used alone or in conjunction with combination chemotherapy.²²⁶ ²²⁷ ²²⁸ ²³⁰ ²³¹ ²³⁶ ²³⁷ ²⁵¹ ³⁷⁸

The high frequency of hormone receptors in tumors of 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

Pharmacogenomic Considerations for Tamoxifen Therapy of Breast Cancer

Variations in genes responsible for tamoxifen metabolism may affect treatment decision (e.g., alternative drug or dosage requirement).³³⁹ ³⁸⁴

Exposure to endoxifen (major active metabolite of tamoxifen) is strongly associated with CYP2D6 metabolizer phenotype,³³⁹ ³⁴⁹ ³⁵⁴ ³⁵⁵ ³⁵⁹ ³⁶⁰ ³⁸³ ³⁹⁶ and low endoxifen concentrations are associated with 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 some experts do not recommend use of CYP2D6 genotyping to guide treatment decisions in patients with hormone receptor-positive breast cancer based on available evidence,³³⁸ the Clinical Pharmacogenetics Implementation Consortium (CPIC) and other experts recommend that women with CYP2D6 poor-, intermediate-, or normal/intermediate-metabolizer phenotypes (activity scores of 0–1) receive adjuvant endocrine therapy with an alternative agent (e.g., aromatase inhibitor in postmenopausal women; aromatase inhibitor plus ovarian suppression in premenopausal women).³³⁹ ³⁸⁴ If an aromatase inhibitor is contraindicated, CPIC and these experts state that an increased tamoxifen dosage of 40 mg daily may be considered, but endoxifen concentrations may still be suboptimal in those with a CYP2D6 poor-metabolizer phenotype.³³⁹ ³⁵⁴ ³⁸⁴

Albright Syndrome

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^{† [off-label]} (also known as McCune-Albright syndrome) and precocious puberty.¹²⁸

Long-term effects beyond one year not established.¹²⁸ (See Pediatric Use under Cautions.)

Tamoxifen Dosage and Administration

General

Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

Administration

Oral Administration

Administer orally as a single daily dose or in divided doses; administer dosages >20 mg daily in divided doses (morning and evening).¹²⁸ ³⁹⁶

Administer without regard to meals.¹²⁸ ³⁹⁶

Dosage

Available as tamoxifen citrate; dosage expressed in terms of tamoxifen.¹²⁸

Adults

Breast Cancer

Adjuvant Therapy

Oral

Usually 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 In several clinical studies, no evidence indicating that dosages >20 mg daily are necessary.¹¹² ¹²⁸ ³⁹⁶

Patients with CYP2D6 poor-, intermediate-, or normal/intermediate-metabolizer phenotypes (activity scores of 0–1): Some experts state that 40 mg daily may be considered.³³⁹ ³⁵⁴ ³⁸⁴ (See Pharmacogenomic Considerations for Tamoxifen Therapy of Breast Cancer under Uses.)

Optimum duration of adjuvant therapy generally is 5 years;¹²⁸ ¹⁹⁴ ¹⁹⁵ ¹⁹⁶ ²⁵³ ²⁵⁴ ²⁵⁶ ²⁵⁷ ²⁹¹ ³²⁸ however, continuation of adjuvant therapy for an additional 5 years (for a total of 10 years) may be considered based on menopausal status.³³² ³³⁸ Magnitude of benefit of extended tamoxifen therapy (i.e., >5 years) expected to be lower in women with small tumors and/or node-negative disease.³³²

Dosage of 20 mg once daily for 5 years has been used in combination with ovarian suppression^{† [off-label]} as adjuvant therapy in premenopausal women^† with early-stage hormone receptor-positive breast cancer.¹⁰⁰¹⁰ ¹⁰⁰¹¹ ¹⁰⁰¹² ¹⁰⁰¹³ ¹⁰⁰²⁶ Ovarian suppression achieved with goserelin 3.6 mg implanted sub-Q 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

Oral

20–40 mg daily.¹²⁸ ³⁹⁶ ^a Usual initial dosage is 20 mg daily.^a

Ductal Carcinoma in Situ

Oral

20 mg daily for 5 years.¹²⁸ ³⁹⁶

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

Oral

20 mg daily for 5 years.¹²⁸ ²⁷⁰ ²⁸⁴ ²⁹¹ ³⁹⁶

Breast Cancer in Men

Oral

Metastatic breast cancer: 20–40 mg daily.¹²⁸ ³⁹⁶ ^a

Adjunct to surgery^†: 20 mg daily has been used.²²⁷ ²³¹ Optimum duration of therapy not established; however, some clinicians suggest a similar duration in men as in women (i.e., 5–10 years).²²⁷ ³⁷⁸ Individualize decisions about duration of therapy (as in women) based on risk of disease recurrence and adverse effects.³⁷⁸

Prescribing Limits

Adults

Breast Cancer

Adjuvant Therapy

Oral

In several studies, no evidence that dosages >20 mg daily are more effective.¹¹² ¹²⁸ ³⁹⁶

Safety of dosages >40 mg daily in patients with CYP2D6 poor-metabolizer phenotype not established,³⁵⁴ even though concentrations of endoxifen (major active metabolite) may remain suboptimal.³³⁹ ³⁵⁴ ³⁸⁴

Cautions for Tamoxifen

Contraindications

Known hypersensitivity to tamoxifen or any ingredient in the formulation.¹²⁸ ³⁹⁶
When used in women with DCIS and women at high risk for breast cancer, history of DVT or pulmonary embolism.¹²⁸ ²⁷⁸ ²⁹³ ³⁹⁶
When used in women with DCIS and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative.¹²⁸ ³⁰⁹ ³⁹⁶

Warnings/Precautions

Warnings

Effects on the Uterus

Increased incidence of uterine malignancies, sometimes fatal, reported.¹²⁸ ³³⁰ Most uterine malignancies have been classified as adenocarcinoma of the endometrium; rare uterine sarcomas also reported.¹²⁸ ³³⁰ (See Boxed Warning.) Uterine sarcoma generally associated with more advanced disease at the time of diagnosis, poorer prognosis, and shorter survival.¹²⁸ ³³⁰ Promptly evaluate gynecologic symptoms (i.e., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure).¹²⁸ ¹⁶³ ¹⁸³ ³³⁰

Endometrial changes, including hyperplasias and polyps, endometriosis, and uterine fibroids reported.¹²⁸ ¹⁸⁰ ²⁵⁸ ²⁵⁹ ²⁷⁴ Ovarian cysts reported in a small number of premenopausal women with advanced breast cancer.¹²⁸

Menstrual irregularities and amenorrhea also reported.¹²⁸

Thromboembolic Effects

Increased incidence of thromboembolic events, including DVT¹²⁸ ²⁹³ and pulmonary embolism;¹²⁸ ²⁶⁹ ²⁷⁰ ²⁹³ stroke¹²⁸ ²⁹³ also reported.¹²⁸ ²⁶⁹ ²⁷⁷ ²⁹³ Some cases of stroke and pulmonary emboli have been fatal.¹²⁸ (See Boxed Warning.) Concomitant use with chemotherapy may increase incidence of these events.¹²⁸

Screening patients for factor V Leiden and prothrombin G20210A mutations does not appear to aid in identifying those who should not receive tamoxifen.¹²⁸

Other Warnings and Precautions

Hypercalcemia

Hypercalcemia reported in patients with metastatic breast cancer who have bone metastases.¹²⁸ ¹²⁹ If hypercalcemia occurs, take appropriate measures; if severe, discontinue tamoxifen.¹²⁸ ¹²⁹

Hepatic Effects

Liver cancer reported.¹²⁸

Changes in AST, ALT, bilirubin and/or alkaline phosphatase concentrations reported; severe hepatic abnormalities including fatty changes in the liver, cholestasis, hepatitis, and hepatic necrosis (some fatal) reported rarely.¹²⁸

Manufacturer recommends periodic monitoring of liver function tests.¹²⁸

Ocular Effects

Visual disturbances, decrement in color vision perception, corneal changes, cataracts, optic neuritis, retinal vein thrombosis, intraretinal crystals, posterior subcapsular opacities, and/or retinopathy reported.¹²⁸ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ²⁵⁸ ²⁶⁸ ³²⁶

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹²⁸ ³⁹⁶ If inadvertently used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard, including possible long-term risk of a diethylstilbestrol-like syndrome.¹²⁸ (See Advice to Patients.)

Test for pregnancy status prior to initiating therapy in women of childbearing potential.³⁹⁶ Alternatively, when used to reduce the incidence of breast cancer in sexually active women, initiate therapy during menstruation.¹²⁸ In women with menstrual irregularity, a negative β-human chorionic gonadotropin test immediately prior to therapy is sufficient.¹²⁸

Hematologic Effects

Thrombocytopenia, neutropenia, pancytopenia, and leukopenia reported; caution in patients with leukopenia or thrombocytopenia.¹²⁸ Periodic CBCs, including platelet count, recommended.¹²⁸

Hyperlipidemia

Lipoprotein abnormalities (e.g., hypertriglyceridemia,³²⁴ ³²⁵ marked hyperlipoproteinemia¹⁸⁵ ¹⁸⁶ ¹⁸⁷ ) reported infrequently.¹²⁸ ¹⁸⁵ ¹⁸⁶ ¹⁸⁷ ¹⁸⁸ Periodic monitoring of serum triglycerides and cholesterol recommended in patients with preexisting hyperlipidemia.¹²⁸ ³²⁴

Infertility

May impair embryo implantation in females of reproductive potential, but does not reliably cause infertility.³⁹⁶ Marked reductions in fertility and reproductive indices, as well as death of all fetuses, reported in rats receiving tamoxifen.¹²⁸ (See Advice to Patients.)

Specific Populations

Pregnancy

May cause fetal harm.¹²⁸ ³⁹⁶ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether tamoxifen is distributed into milk.¹²⁸ Because of potential risk to nursing infant, discontinue nursing during therapy and for 3 months after the last dose or discontinue the drug.¹²⁸ ³⁹⁶ May decrease early postpartum milk production.¹²⁸

Pediatric Use

Safety and efficacy in girls 2–10 years of age with Albright syndrome and precocious puberty not studied beyond 1 year.¹²⁸ Increased uterine volume reported but long-term effects not established; continued monitoring recommended.¹²⁸ (See Special Populations under Pharmacokinetics.)

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) reported in neonatal rodents.³⁹⁶

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹²⁸

Common Adverse Effects

Hot flushes (flashes), mood disturbances, vaginal discharge, vaginal bleeding, menstrual irregularities, nausea, fluid retention, weight loss.¹²⁸ ³⁹⁶

Drug Interactions

Metabolized by multiple CYP isoenzymes (e.g., 1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5), but principal pathway involves demethylation by CYP3A4/5, then hydroxylation by CYP2D6, to form major active metabolite (endoxifen).³³⁹ ³⁴⁷ ³⁸⁰

Tamoxifen and its metabolites also metabolized by multiple uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes and to a lesser extent by sulfotransferases (mainly SULT1A1).³³⁹ ³⁴⁸ ³⁸⁰ ³⁸¹

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Possible decreased plasma concentrations of endoxifen;³³⁹ ³⁵¹ ³⁸⁴ ³⁸⁵ data regarding effects on tamoxifen efficacy are inconclusive.³⁴⁸ ³⁸⁵ ³⁹⁶ Some experts make recommendations regarding concomitant use based on CYP2D6 genotyping (see Table 1).³³⁹ Other experts (whose recommendations do not depend on genotype testing) state that it is reasonable to avoid concomitant use of CYP2D6 inhibitors, particularly moderate or potent inhibitors, when possible in patients receiving tamoxifen.³³⁴ ³³⁸ ³⁸⁴ ³⁸⁵

CPIC Recommendations Regarding Concomitant Use of Tamoxifen and CYP2D6 Inhibitors339
CYP2D6 Metabolizer Phenotype	Recommendation
Poor	Alternative adjuvant endocrine therapy (rather than tamoxifen) recommended
Intermediate	Avoid concomitant use of weak, moderate, or potent CYP2D6 inhibitors
Normal/intermediate	Avoid concomitant use of weak, moderate, or potent CYP2D6 inhibitors
Normal	Avoid concomitant use of moderate or potent CYP2D6 inhibitors
Ultrarapid	Avoid concomitant use of moderate or potent CYP2D6 inhibitors

CYP inducers: Possible decreased plasma concentrations of tamoxifen and endoxifen.¹²⁸ ³⁸⁵ Clinical importance not established.³⁸⁵ Nonetheless, some clinicians suggest avoiding concomitant use of agents that induce multiple isoenzymes and transporters.³⁸⁵

Drugs Metabolized by Hepatic Microsomal Enzymes

Effect of tamoxifen on drugs that require mixed function oxidases for activation unknown.¹²⁸

Cytotoxic Agents

Increased risk of thromboembolic events.¹²⁸

Specific Drugs

Drug	Interaction	Comments
Aminoglutethimide (no longer commercially available in US)	Decreased exposure to tamoxifen, endoxifen, and other metabolites; endoxifen concentrations undetectable in some patients¹²⁸ ³⁸⁵ ³⁸⁶ ³⁹⁶	Clinical importance unknown³⁸⁵ Some clinicians suggest avoiding concomitant use³⁸⁵
Anticoagulants (e.g., warfarin)	Enhanced warfarin effects¹²⁸ ¹⁷⁰ ¹⁷¹ ¹⁷² ³⁹⁶	Careful monitoring of PT is recommended¹²⁸ ¹⁷⁰ ¹⁷¹ ¹⁷² ³⁹⁶ When used in women with DCIS or at high risk for breast cancer, concomitant use contraindicated¹²⁸
Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)	CYP inducers: Possible decreased plasma concentrations of tamoxifen and endoxifen¹²⁸ ³⁸⁵ Phenobarbital: Decreased serum tamoxifen concentrations reported¹²⁸ Phenytoin: Low endoxifen concentrations reported³⁸⁵ ³⁸⁷	Clinical importance not established³⁸⁵ Inducers of multiple CYP enzymes/transporters: Some clinicians suggest avoiding concomitant use³⁸⁵
Antimycobacterial agents (rifabutin, rifampin, rifapentine)	Possible decreased plasma concentrations of tamoxifen and endoxifen¹²⁸ ³⁸⁵ Rifampin: Decreased tamoxifen and endoxifen exposure¹²⁸ ³⁸⁵ ³⁹⁶	Clinical importance unknown³⁸⁵ Some clinicians suggest avoiding concomitant use³⁸⁵
Aromatase inhibitors (e.g., anastrozole, exemestane, letrozole)	Anastrozole: Decreased plasma anastrozole concentrations,¹²⁸ but estradiol suppression similar with or without concomitant tamoxifen;³⁴⁵ efficacy of the combination regimen as adjuvant therapy not superior to that of tamoxifen alone¹²⁸ ³⁴⁵ Letrozole: Decreased plasma letrozole concentrations¹²⁸	Clinical importance of pharmacokinetic interaction unknown³⁴⁵ Concomitant use not recommended¹²⁸ ³⁴³ ³⁴⁴ ³⁹⁶
Bromocriptine	Increased plasma tamoxifen and N-desmethyltamoxifen concentrations¹²⁸
Bupropion	Potent CYP2D6 inhibition may decrease plasma endoxifen concentrations ³³⁹ ³⁵¹ ³⁸⁴ ³⁸⁵	Clinical importance unknown³⁴⁸ ³⁸⁵ Some experts recommend avoiding concomitant use³³⁴ ³³⁸ ³³⁹ ³⁸⁴ ³⁸⁵
Cyclosporine	Competitively inhibited formation of N-desmethyltamoxifen in vitro¹²⁸	Clinical importance unknown¹²⁸
Diltiazem	Competitively inhibited formation of N-desmethyltamoxifen in vitro¹²⁸	Clinical importance unknown¹²⁸
Erythromycin	Competitively inhibited formation of N-desmethyltamoxifen in vitro¹²⁸	Clinical importance unknown¹²⁸
Medroxyprogesterone	Decreased plasma N-desmethyltamoxifen concentrations but did not reduce plasma tamoxifen concentrations¹²⁸ ³⁹⁶
Nifedipine	Competitively inhibited formation of N-desmethyltamoxifen in vitro¹²⁸	Clinical importance unknown¹²⁸
Quinidine	Potent CYP2D6 inhibition may decrease plasma endoxifen concentrations ³³⁹ ³⁵¹ ³⁸⁴ ³⁸⁵	Clinical importance unknown³⁴⁸ ³⁸⁵ Some experts recommend avoiding concomitant use³³⁴ ³³⁸ ³³⁹ ³⁸⁴ ³⁸⁵
SSRIs (e.g., fluoxetine, paroxetine)	Potent CYP2D6 inhibitors: Decreased plasma concentrations of endoxifen³⁴⁸ ³⁵¹ ³⁸⁴ ³⁸⁵ ³⁹⁶	Clinical importance unknown³³⁴ ³⁴⁸ ³⁸⁵ Moderate or potent CYP2D6 inhibitors: Some experts recommend avoiding concomitant use; if an antidepressant is required, use an SSRI or SNRI with little or no CYP2D6 inhibitory potential (e.g., citalopram, escitalopram, venlafaxine, desvenlafaxine)³³⁴ ³³⁸ ³³⁹ ³⁸⁴ ³⁸⁵
St. John's wort (Hypericum perforatum)	Possible decreased plasma concentrations of tamoxifen and endoxifen³⁸⁵	Clinical importance unknown³⁸⁵ Some clinicians suggest avoiding concomitant use³⁸⁵

Tamoxifen Pharmacokinetics

Absorption

Bioavailability

Absorbed slowly following oral administration; peak serum concentrations of tamoxifen occur about 3–6 hours after a single dose.¹²⁸ ¹³⁷ ¹³⁸ ¹³⁹ ¹⁴⁰ ¹⁴¹

Animal studies suggest tamoxifen and/or its metabolites undergo extensive enterohepatic circulation.¹⁴²

Oral solution and tablets are bioequivalent when administered under fasting conditions.³⁹⁶

Food

Bioavailability of oral solution is similar under fed or fasting conditions.³⁹⁶

Plasma Concentrations

Steady-state concentrations of tamoxifen are attained after 3–4 weeks and those of N-desmethyltamoxifen, an active metabolite, are attained after 3–8 weeks.¹²⁸ ¹³⁷ ¹⁴⁰ ¹⁴³ ¹⁴⁵

Distribution

Extent

Not fully characterized.¹²⁸

Not known whether tamoxifen is distributed into milk.¹²⁸

Elimination

Metabolism

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

Multiple CYP isoenzymes (e.g., 1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5) contribute to metabolism, but the principal 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 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 is further metabolized to form endoxifen and polar conjugates.³³⁹ ³⁴⁷ ³⁸⁰ ³⁸¹ Several other metabolites also identified.¹⁴⁹ ¹⁵⁰ ¹⁵¹ ¹⁵² ³⁴⁷ ³⁸⁰ ³⁸²

Tamoxifen and its metabolites also are metabolized by multiple UGT isoenzymes and to a lesser extent by sulfotransferases (mainly SULT1A1) to form glucuronide and sulfate conjugates, respectively.³³⁹ ³⁴⁸ ³⁸⁰ ³⁸¹

N-Desmethyltamoxifen has biologic activity similar to that of the parent drug.¹²⁸ ³⁷⁹ Endoxifen and 4-hydroxytamoxifen exhibit 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.³³⁹ ³⁴⁸ ³⁴⁹ ³⁵⁰ ³⁷⁹ ³⁸¹ ³⁸³ ³⁸⁴

Elimination Route

Excreted principally in feces as polar conjugates.¹²⁸

Half-life

Tamoxifen: 5–7 days.²⁸ ¹³⁷ ¹³⁹ ¹⁴⁵

N-Desmethyltamoxifen: 9–14 days.¹²⁸ ¹³⁹ ¹⁴⁵

Special Populations

Clearance higher in girls 2–10 years of age than in women; exposure to N-desmethyltamoxifen in these pediatric patients similar to adults.¹²⁸

CYP2D6 metabolizer phenotype: Endoxifen exposure is strongly associated with CYP2D6 metabolizer phenotype, but genetic polymorphism of CYP2D6 explains only about 30–53% of the observed variability in endoxifen concentrations.³³⁹ ³⁴⁹ ³⁵⁴ ³⁵⁵ ³⁵⁹ ³⁶⁰ ³⁸³ Individuals with low CYP2D6 activity have lower serum endoxifen concentrations, but studies evaluating association with breast cancer recurrence have been inconclusive.³³⁴ ³³⁹ ³⁴⁸ ³⁵⁵ ³⁹⁶ (See Pharmacogenomic Considerations for Tamoxifen Therapy of Breast Cancer under Uses.)

Effects of age, gender, race, and hepatic impairment on tamoxifen pharmacokinetics not established.¹²⁸

Stability

Storage

Oral

Solution

Original container at 20–25°C (may be exposed to 15–30°C); protect from light.³⁹⁶ Do not freeze or refrigerate.³⁹⁶ Discard any unused portion 3 months after first opening the bottle.³⁹⁶

Tablets

Well-closed, light-resistant containers at 20–25°C.¹²⁸

Actions

Acts as an estrogen antagonist on breast tissue and in the CNS and as an estrogen agonist on endometrium, bone, and lipids.³¹¹
In breast epithelial tissue, increases production of inhibitory factors and decreases production of stimulatory factors that influence breast cell growth.²⁷¹ ²⁸⁶ ²⁸⁷ ³²³
Reduces bone resorption and bone turnover.²⁶⁵ ²⁶⁶ ²⁶⁷ ³¹⁶
Decreases total and LDL-cholesterol concentrations.³¹⁸ ³¹⁹ ³²⁰ Less favorably, decreases HDL-cholesterol concentrations and increases triglyceride concentrations.³¹⁸ ³¹⁹ ³²⁰
Acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects on the endometrium.³¹¹

Advice to Patients

Risk of uterine malignancies (endometrial carcinoma, uterine sarcoma), which may be fatal.³⁹⁶ Importance of receiving routine gynecologic care and of immediately informing clinician if any new breast lumps or abnormal gynecologic symptoms, including abnormal vaginal bleeding, change in vaginal discharge, menstrual irregularities, or pelvic pain/pressure, occur.¹²⁸ ¹⁶³ ¹⁸³
Importance of informing clinician of any changes in vision.¹²⁸ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ²⁵⁸ ²⁶⁸
Risk of thromboembolic events (DVT, PE, stroke), which may be fatal.³⁹⁶ Importance of immediately informing clinician of unexplained shortness of breath or leg swelling/tenderness.¹²⁸
Importance of periodic monitoring, including liver function test monitoring and blood counts.¹²⁸
Advise patients at high risk of breast cancer that tamoxifen may decrease the incidence of breast cancer, but may not eliminate the risk of the disease.¹²⁸
Advise patients with DCIS that tamoxifen may decrease the incidence of invasive breast cancer, but has not been shown to affect survival.¹²⁸
Importance of women informing clinicians immediately if they are or plan to become pregnant; importance of avoiding pregnancy during therapy;¹¹⁹ ¹²⁸ ²⁴³ importance of using effective nonhormonal contraception while receiving tamoxifen and for 2 months after discontinuing the drug.¹²⁸ ³⁹⁶ Necessity of advising pregnant patients of the risk to the fetus.¹²⁸
Importance of advising women of childbearing potential that tamoxifen does not reliably cause infertility, even in the presence of menstrual irregularity.¹²⁸ ³⁹⁶
Risk of liver cancer and hepatic abnormalities.³⁹⁶
Importance of reading the medication guide; the guide is for women using tamoxifen to lower their risk of breast cancer or with DCIS.¹²⁸
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements.¹²⁸ ³⁸⁵
Importance of women informing clinicians if they plan to breast-feed.¹²⁸ Importance of advising women to discontinue nursing during therapy and for 3 months after discontinuance of the drug.³⁹⁶
Importance of informing patients of other important precautionary information.¹²⁸ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Tamoxifen Citrate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	10 mg (of tamoxifen) per 5 mL	Soltamox	Fortovia
	Tablets	10 mg (of tamoxifen)*	Tamoxifen Citrate Tablets
		20 mg (of tamoxifen)*	Tamoxifen Citrate Tablets
	Tablets, film-coated	10 mg (of tamoxifen)*	Tamoxifen Citrate Tablets
		20 mg (of tamoxifen)*	Tamoxifen Citrate Tablets

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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

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345. The ATAC Trialists’ Group. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the ‘Arimidex^TM and Tamoxifen Alone or in Combination’ (ATAC) trial. Br J Cancer. 2001; 85:317-24. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2364083&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/11487258?dopt=AbstractPlus

346. Thota K, Prasad K, Basaveswara Rao MV. Detection of Cytochrome P450 Polymorphisms in Breast Cancer Patients May Impact on Tamoxifen Therapy. Asian Pac J Cancer Prev. 2018; 19:343-350. http://www.ncbi.nlm.nih.gov/pubmed/29479969?dopt=AbstractPlus

347. Damkier P, Kjærsgaard A, Barker KA et al. CYP2C19*2 and CYP2C19*17 variants and effect of tamoxifen on breast cancer recurrence: Analysis of the International Tamoxifen Pharmacogenomics Consortium dataset. Sci Rep. 2017; 7:7727. http://www.ncbi.nlm.nih.gov/pubmed/28798474?dopt=AbstractPlus

348. Cronin-Fenton DP, Damkier P. Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics. Adv Pharmacol. 2018; 83:65-91. http://www.ncbi.nlm.nih.gov/pubmed/29801584?dopt=AbstractPlus

349. Klopp-Schulze L, Joerger M, Wicha SG et al. Exploiting Pharmacokinetic Models of Tamoxifen and Endoxifen to Identify Factors Causing Subtherapeutic Concentrations in Breast Cancer Patients. Clin Pharmacokinet. 2018; 57:229-242. http://www.ncbi.nlm.nih.gov/pubmed/28540639?dopt=AbstractPlus

350. Nakamura T, Toshimoto K, Lee W et al. Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen. CPT Pharmacometrics Syst Pharmacol. 2018; 7:474-482. http://www.ncbi.nlm.nih.gov/pubmed/29920987?dopt=AbstractPlus

351. Del Re M, Rofi E, Citi V et al. Should CYP2D6 be genotyped when treating with tamoxifen?. Pharmacogenomics. 2016; 17:1967-1969. http://www.ncbi.nlm.nih.gov/pubmed/27883289?dopt=AbstractPlus

352. Goetz MP, Schaid DJ, Wickerham DL et al. Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention: results from the NSABP P1 and P2 clinical trials. Clin Cancer Res. 2011; 17:6944-51. http://www.ncbi.nlm.nih.gov/pubmed/21880792?dopt=AbstractPlus

353. Damkier P. Don't think twice it's all right: tamoxifen and CYP2D6 genotyping in the treatment of breast cancer patients. Pharmacogenomics. 2017; 18:753-754. http://www.ncbi.nlm.nih.gov/pubmed/28592184?dopt=AbstractPlus

354. Hertz DL, Deal A, Ibrahim JG et al. Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity. Oncologist. 2016; 21:795-803. http://www.ncbi.nlm.nih.gov/pubmed/27226358?dopt=AbstractPlus

355. Madlensky L, Natarajan L, Tchu S et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011; 89:718-25. http://www.ncbi.nlm.nih.gov/pubmed/21430657?dopt=AbstractPlus

356. Regan MM, Leyland-Jones B, Bouzyk M et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst. 2012; 104:441-51. http://www.ncbi.nlm.nih.gov/pubmed/22395644?dopt=AbstractPlus

357. Rae JM, Drury S, Hayes DF et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012; 104:452-60. http://www.ncbi.nlm.nih.gov/pubmed/22395643?dopt=AbstractPlus

358. Goetz MP, Suman VJ, Hoskin TL et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013; 19:500-7. http://www.ncbi.nlm.nih.gov/pubmed/23213055?dopt=AbstractPlus

359. Saladores P, Mürdter T, Eccles D et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J. 2015; 15:84-94. http://www.ncbi.nlm.nih.gov/pubmed/25091503?dopt=AbstractPlus

360. Province MA, Goetz MP, Brauch H et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther. 2014; 95:216-27. http://www.ncbi.nlm.nih.gov/pubmed/24060820?dopt=AbstractPlus

361. Brauch H, Schroth W, Goetz MP et al. Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. J Clin Oncol. 2013; 31:176-80. http://www.ncbi.nlm.nih.gov/pubmed/23091108?dopt=AbstractPlus

362. Nakamura Y, Ratain MJ, Cox NJ et al. Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst. 2012; 104:1264; author reply 1266-8. http://www.ncbi.nlm.nih.gov/pubmed/22851270?dopt=AbstractPlus

363. Swain SM, Wilson JW, Mamounas EP et al. Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst. 2004; 96:516-23. http://www.ncbi.nlm.nih.gov/pubmed/15069113?dopt=AbstractPlus

364. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20; 365:1687-717. http://www.ncbi.nlm.nih.gov/pubmed/15894097?dopt=AbstractPlus

365. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011; 378:771-84. http://www.ncbi.nlm.nih.gov/pubmed/21802721?dopt=AbstractPlus

366. Tremont A, Lu J, Cole JT. Endocrine Therapy for Early Breast Cancer: Updated Review. Ochsner J. 2017; 17:405-411. http://www.ncbi.nlm.nih.gov/pubmed/29230126?dopt=AbstractPlus

367. Sparano JA, Gray RJ, Makower DF et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2018; 379:111-121. http://www.ncbi.nlm.nih.gov/pubmed/29860917?dopt=AbstractPlus

368. Henry NL, Somerfield MR, Abramson VG et al. Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: American Society of Clinical Oncology Endorsement of Cancer Care Ontario Guideline Recommendations. J Clin Oncol. 2016; 34:2303-11. http://www.ncbi.nlm.nih.gov/pubmed/27001586?dopt=AbstractPlus

369. Krop I, Ismaila N, Andre F et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 2017; 35:2838-2847. http://www.ncbi.nlm.nih.gov/pubmed/28692382?dopt=AbstractPlus

370. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005; 97:1652-62. http://www.ncbi.nlm.nih.gov/pubmed/16288118?dopt=AbstractPlus

371. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology (NCCN Guidelines): breast cancer risk reduction. Version 1.2019.

372. Powles TJ, Ashley S, Tidy A et al. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007; 99:283-90. http://www.ncbi.nlm.nih.gov/pubmed/17312305?dopt=AbstractPlus

373. Cuzick J, Sestak I, Cawthorn S et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015; 16:67-75. http://www.ncbi.nlm.nih.gov/pubmed/25497694?dopt=AbstractPlus

374. Veronesi U, Maisonneuve P, Rotmensz N et al. Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst. 2007; 99:727-37. http://www.ncbi.nlm.nih.gov/pubmed/17470740?dopt=AbstractPlus

375. Land SR, Wickerham DL, Costantino JP et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006; 295:2742-51. http://www.ncbi.nlm.nih.gov/pubmed/16754728?dopt=AbstractPlus

376. Vogel VG, Costantino JP, Wickerham DL et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006; 295:2727-41. http://www.ncbi.nlm.nih.gov/pubmed/16754727?dopt=AbstractPlus

377. King MC, Wieand S, Hale K et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001; 286:2251-6. http://www.ncbi.nlm.nih.gov/pubmed/11710890?dopt=AbstractPlus

378. Giordano SH. Breast Cancer in Men. N Engl J Med. 2018; 378:2311-2320. http://www.ncbi.nlm.nih.gov/pubmed/29897847?dopt=AbstractPlus

379. Johnson MD, Zuo H, Lee KH et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004; 85:151-9. http://www.ncbi.nlm.nih.gov/pubmed/15111773?dopt=AbstractPlus

380. Kiyotani K, Mushiroda T, Nakamura Y et al. Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters. Drug Metab Pharmacokinet. 2012; 27:122-31. http://www.ncbi.nlm.nih.gov/pubmed/22041137?dopt=AbstractPlus

381. Klein DJ, Thorn CF, Desta Z et al. PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics. 2013; 23:643-7. http://www.ncbi.nlm.nih.gov/pubmed/23962908?dopt=AbstractPlus

382. Johänning J, Kröner P, Thomas M et al. The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes. Arch Toxicol. 2018; 92:1099-1112. http://www.ncbi.nlm.nih.gov/pubmed/29285606?dopt=AbstractPlus

383. de Vries Schultink AH, Zwart W, Linn SC et al. Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen. Clin Pharmacokinet. 2015; 54:797-810. http://www.ncbi.nlm.nih.gov/pubmed/25940823?dopt=AbstractPlus

384. Drögemöller BI, Wright GEB, Shih J et al. CYP2D6 as a treatment decision aid for ER-positive non-metastatic breast cancer patients: a systematic review with accompanying clinical practice guidelines. Breast Cancer Res Treat. 2018; http://www.ncbi.nlm.nih.gov/pubmed/30411242?dopt=AbstractPlus

385. Hansten PD. The Underrated Risks of Tamoxifen Drug Interactions. Eur J Drug Metab Pharmacokinet. 2018; 43:495-508. http://www.ncbi.nlm.nih.gov/pubmed/29637493?dopt=AbstractPlus

386. Lien EA, Anker G, Lønning PE et al. Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. Cancer Res. 1990; 50:5851-7. http://www.ncbi.nlm.nih.gov/pubmed/2393854?dopt=AbstractPlus

387. Gryn SE, Teft WA, Kim RB. Profound reduction in the tamoxifen active metabolite endoxifen in a patient on phenytoin for epilepsy compared with a CYP2D6 genotype matched cohort. Pharmacogenet Genomics. 2014; 24:367-9. http://www.ncbi.nlm.nih.gov/pubmed/24915025?dopt=AbstractPlus

388. Schroth W, Goetz MP, Hamann U et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009; 302:1429-36. http://www.ncbi.nlm.nih.gov/pubmed/19809024?dopt=AbstractPlus

389. Goetz MP, Rae JM, Suman VJ et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005; 23:9312-8. http://www.ncbi.nlm.nih.gov/pubmed/16361630?dopt=AbstractPlus

390. Schroth W, Antoniadou L, Fritz P et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007; 25:5187-93. http://www.ncbi.nlm.nih.gov/pubmed/18024866?dopt=AbstractPlus

391. Vogel VG, Costantino JP, Wickerham DL et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila). 2010; 3:696-706. http://www.ncbi.nlm.nih.gov/pubmed/20404000?dopt=AbstractPlus

392. Paridaens RJ, Dirix LY, Beex LV et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008; 26:4883-90. http://www.ncbi.nlm.nih.gov/pubmed/18794551?dopt=AbstractPlus

393. Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000; 18:3758-67. http://www.ncbi.nlm.nih.gov/pubmed/11078488?dopt=AbstractPlus

394. Bonneterre J, Thürlimann B, Robertson JF et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000; 18:3748-57. http://www.ncbi.nlm.nih.gov/pubmed/11078487?dopt=AbstractPlus

395. Gibson L, Lawrence D, Dawson C et al. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev. 2009; :CD003370. http://www.ncbi.nlm.nih.gov/pubmed/19821307?dopt=AbstractPlus

396. Fortovia Therapeutics. Soltamox (tamoxifen citrate) oral solution prescribing information. Raleigh, NC; 2019 Jun.

10010. Francis PA, Regan MM, Fleming GF et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015; 372:436-46. http://www.ncbi.nlm.nih.gov/pubmed/25495490?dopt=AbstractPlus

10011. Pagani O, Regan MM, Walley BA et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014; 371:107-18. http://www.ncbi.nlm.nih.gov/pubmed/24881463?dopt=AbstractPlus

10012. Francis PA, Pagani O, Fleming GF et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med. 2018; 379:122-137. http://www.ncbi.nlm.nih.gov/pubmed/29863451?dopt=AbstractPlus

10013. Tevaarwerk AJ, Wang M, Zhao F et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2014; 32:3948-58. http://www.ncbi.nlm.nih.gov/pubmed/25349302?dopt=AbstractPlus

10016. Pan K, Bosserman LD, Chlebowski RT. Ovarian Suppression in Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. J Clin Oncol. 2019; 37:858-861. http://www.ncbi.nlm.nih.gov/pubmed/30742565?dopt=AbstractPlus

10017. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. J Clin Oncol. 2016; 34:1689-701. http://www.ncbi.nlm.nih.gov/pubmed/26884586?dopt=AbstractPlus

10018. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol. 2019; 37:423-438. http://www.ncbi.nlm.nih.gov/pubmed/30452337?dopt=AbstractPlus

10020. Dowsett M, Lønning PE, Davidson NE. Incomplete Estrogen Suppression With Gonadotropin-Releasing Hormone Agonists May Reduce Clinical Efficacy in Premenopausal Women With Early Breast Cancer. J Clin Oncol. 2016; 34:1580-3. http://www.ncbi.nlm.nih.gov/pubmed/26729430?dopt=AbstractPlus

10023. Gnant M, Mlineritsch B, Stoeger H et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011; 12:631-41. http://www.ncbi.nlm.nih.gov/pubmed/21641868?dopt=AbstractPlus

10024. Gnant M, Mlineritsch B, Stoeger H et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol. 2015; 26:313-20. http://www.ncbi.nlm.nih.gov/pubmed/25403582?dopt=AbstractPlus

10025. Bellet M, Gray KP, Francis PA et al. Twelve-Month Estrogen Levels in Premenopausal Women With Hormone Receptor-Positive Breast Cancer Receiving Adjuvant Triptorelin Plus Exemestane or Tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy. J Clin Oncol. 2016; 34:1584-93. http://www.ncbi.nlm.nih.gov/pubmed/26729437?dopt=AbstractPlus

10026. Perrone F, De Laurentiis M, De Placido S et al. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. Eur J Cancer. 2019; 118:178-186. http://www.ncbi.nlm.nih.gov/pubmed/31164265?dopt=AbstractPlus

10027. Chlebowski RT, Pan K, Col NF. Ovarian suppression in combination endocrine adjuvant therapy in premenopausal women with early breast cancer. Breast Cancer Res Treat. 2017; 161:185-190. http://www.ncbi.nlm.nih.gov/pubmed/27785653?dopt=AbstractPlus

10028. AHFS final determination of medical acceptance: Off-label use of endocrine therapy in combination with ovarian suppression for the adjuvant treatment of early-stage hormone receptor-positive breast cancer in premenopausal women. Published January 4, 2021.

a. AHFS drug information. McEvoy GK, ed. Tamoxifen citrate. Bethesda, MD: American Society of Health-System Pharmacists; Updated 2019. From AHFS DI website (www.ahfsdruginformation.com).

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