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, 2024. Written by ASHP.

Introduction

A nonsteroidal estrogen agonist-antagonist; an antineoplastic agent.

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. Also reduces the occurrence of contralateral breast cancer in these women.

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).

Metastatic Breast Cancer

Palliative treatment of metastatic breast cancer in women. An alternative to ovarian ablative therapy (oophorectomy or radiation) in premenopausal women. Patients with estrogen receptor-positive tumors are more likely to respond.

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. Base decision regarding use on an individualized assessment of potential benefits and risks of therapy.

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. Base decision regarding use on an individualized assessment of potential benefits and risks of preventive therapy.

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).

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

Breast Cancer in Men

Palliative treatment of metastatic breast cancer in men.

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.

The high frequency of hormone receptors in tumors of men may explain the high response rate of male breast carcinoma to endocrine therapy. Treatment to date has been similar to that for women with breast cancer; however, experience in men is very limited.

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).

Exposure to endoxifen (major active metabolite of tamoxifen) is strongly associated with CYP2D6 metabolizer phenotype, and low endoxifen concentrations are associated with increased risk for disease recurrence in women receiving adjuvant tamoxifen therapy for breast cancer; however, the validity of CYP2D6 metabolizer phenotype as a predictor of the outcome of tamoxifen therapy is controversial.

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, 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). 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.

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.

Long-term effects beyond one year not established. (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).

Administer without regard to meals.

Dosage

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

Adults

Breast Cancer

Adjuvant Therapy

Oral

Usually 20 mg daily, although dosages of 20–40 mg daily have been used. In several clinical studies, no evidence indicating that dosages >20 mg daily are necessary.

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. (See Pharmacogenomic Considerations for Tamoxifen Therapy of Breast Cancer under Uses.)

Optimum duration of adjuvant therapy generally is 5 years; however, continuation of adjuvant therapy for an additional 5 years (for a total of 10 years) may be considered based on menopausal status. 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.

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. 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.

Metastatic Breast Cancer

Oral

20–40 mg daily. Usual initial dosage is 20 mg daily.

Ductal Carcinoma in Situ

Oral

20 mg daily for 5 years.

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

Oral

20 mg daily for 5 years.

Breast Cancer in Men

Oral

Metastatic breast cancer: 20–40 mg daily.

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

Prescribing Limits

Adults

Breast Cancer

Adjuvant Therapy

Oral

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

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

Cautions for Tamoxifen

Contraindications

• Known hypersensitivity to tamoxifen or any ingredient in the formulation.

• When used in women with DCIS and women at high risk for breast cancer, history of DVT or pulmonary embolism.

• When used in women with DCIS and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative.

Warnings/Precautions

Warnings

Effects on the Uterus

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

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

Menstrual irregularities and amenorrhea also reported.

Thromboembolic Effects

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

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

Other Warnings and Precautions

Hypercalcemia

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

Hepatic Effects

Liver cancer reported.

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.

Manufacturer recommends periodic monitoring of liver function tests.

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.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. 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. (See Advice to Patients.)

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

Hematologic Effects

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

Hyperlipidemia

Lipoprotein abnormalities (e.g., hypertriglyceridemia, marked hyperlipoproteinemia ) reported infrequently. Periodic monitoring of serum triglycerides and cholesterol recommended in patients with preexisting hyperlipidemia.

Infertility

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

Common Adverse Effects

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

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).

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

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Possible decreased plasma concentrations of endoxifen; data regarding effects on tamoxifen efficacy are inconclusive. Some experts make recommendations regarding concomitant use based on CYP2D6 genotyping (see Table 1). 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.

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

Drugs Metabolized by Hepatic Microsomal Enzymes

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

Cytotoxic Agents

Increased risk of thromboembolic events.

Specific Drugs

Tamoxifen Pharmacokinetics

Absorption

Bioavailability

Absorbed slowly following oral administration; peak serum concentrations of tamoxifen occur about 3–6 hours after a single dose.

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

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

Food

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

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.

Distribution

Extent

Not fully characterized.

Not known whether tamoxifen is distributed into milk.

Elimination

Metabolism

Rapidly and extensively metabolized in the liver, principally by demethylation and hydroxylation.

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). Formation of N-desmethyltamoxifen accounts for approximately 92% of the metabolism of the parent drug.

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. Several other metabolites also identified.

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.

N-Desmethyltamoxifen has biologic activity similar to that of the parent drug. 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.

Elimination Route

Excreted principally in feces as polar conjugates.

Half-life

Tamoxifen: 5–7 days.

N-Desmethyltamoxifen: 9–14 days.

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.

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. Individuals with low CYP2D6 activity have lower serum endoxifen concentrations, but studies evaluating association with breast cancer recurrence have been inconclusive. (See Pharmacogenomic Considerations for Tamoxifen Therapy of Breast Cancer under Uses.)

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

Stability

Storage

Oral

Solution

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

Tablets

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

Actions

• Acts as an estrogen antagonist on breast tissue and in the CNS and as an estrogen agonist on endometrium, bone, and lipids.

• In breast epithelial tissue, increases production of inhibitory factors and decreases production of stimulatory factors that influence breast cell growth.

• Reduces bone resorption and bone turnover.

• Decreases total and LDL-cholesterol concentrations. Less favorably, decreases HDL-cholesterol concentrations and increases triglyceride concentrations.

• Acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects on the endometrium.

Advice to Patients

• Risk of uterine malignancies (endometrial carcinoma, uterine sarcoma), which may be fatal. 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.

• Importance of informing clinician of any changes in vision.

• Risk of thromboembolic events (DVT, PE, stroke), which may be fatal. Importance of immediately informing clinician of unexplained shortness of breath or leg swelling/tenderness.

• Importance of periodic monitoring, including liver function test monitoring and blood counts.

• 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.

• Advise patients with DCIS that tamoxifen may decrease the incidence of invasive breast cancer, but has not been shown to affect survival.

• Importance of women informing clinicians immediately if they are or plan to become pregnant; importance of avoiding pregnancy during therapy; importance of using effective nonhormonal contraception while receiving tamoxifen and for 2 months after discontinuing the drug. Necessity of advising pregnant patients of the risk to the fetus.

• Importance of advising women of childbearing potential that tamoxifen does not reliably cause infertility, even in the presence of menstrual irregularity.

• Risk of liver cancer and hepatic abnormalities.

• Importance of reading the medication guide; the guide is for women using tamoxifen to lower their risk of breast cancer or with DCIS.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements.

• Importance of women informing clinicians if they plan to breast-feed. Importance of advising women to discontinue nursing during therapy and for 3 months after discontinuance of the drug.

• Importance of informing patients of other important precautionary information. (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

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Frequently asked questions

• How do you relieve joint pain associated with tamoxifen or Aromasin?
• Is it common to lose hair AFTER stopping tamoxifen?

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