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Tamoxifen Citrate

Pronunciation

Class: Antineoplastic Agents
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
Brands: Nolvadex

Warning(s)

  • For women with ductal carcinoma in situ (DCIS) and women at high risk for breast cancer: serious and life-threatening events associated with tamoxifen in the risk reduction setting include uterine malignancies, stroke, and pulmonary embolism.a Incidence rates for these events have been estimated from the NSABP P-1 trial (median length of follow-up 6.9 years).a

    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 for placebo).

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

    For pulmonary embolism, the incidence rate per 1000 women-years was 0.75 for tamoxifen versus 0.25 for placebo.a

  • Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer.a

  • The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.a

Introduction

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

Uses for Tamoxifen Citrate

Breast Cancer

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

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Reduction of risk of invasive breast cancer in patients with DCIS following surgery and radiation therapy.a

Palliative treatment of metastatic breast cancer in men and women.128 An alternative to ovarian ablative therapy (oopherectomy or radiation) in premenopausal women.128 133 158 159 160 161 162 163 164 165 166 167 168 169 183

Reduction in the incidence of breast cancer in women at high risk for developing the disease.128 293

Albright’s 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’s syndrome (McCune-Albright syndrome) and precocious puberty.a

Long-term effects not established.a

Tamoxifen Citrate Dosage and Administration

General

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

Administration

Administered orally as a single daily dose or in divided doses; dosages exceeding 20 mg daily should be given in divided doses (morning and evening).128

Initiate therapy during menstruation when used to reduce the incidence of breast cancer in sexually active women.a In women with menstrual irregularity, a negative β-human chorionic gonadotropin test immediately prior to therapy is sufficient.a

Dosage

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

Adults

Breast Cancer
Adjuvant Therapy
Oral

20–40 mg daily.100 102 110 121 128 129 130 194 195 196 205 Current data from clinical studies support 5 years of adjuvant therapy.128 194 195 196 253 254 256 257 291 328

Ductal Carcinoma in Situ
Oral

20 mg daily for 5 years.a

Metastatic Breast Cancer
Oral

20–40 mg daily.128

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

20 mg daily for 5 years.128 270 284 291

Prescribing Limits

Adults

Breast Cancer
Adjuvant Therapy
Oral

No evidence that dosages >20 mg daily are more effective.112 128

Cautions for Tamoxifen Citrate

Contraindications

  • Known hypersensitivity to tamoxifen or any ingredient in the formulation.128

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

  • When used in women with DCIS and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative.a 278 293 309

Warnings/Precautions

Warnings

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

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.) Gynecologic symptoms (i.e., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure) should be promptly evaluated.128 163 183

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

Cardiovascular Effects

Increased incidence of thromboembolic events, including DVT128 293 and pulmonary embolism; 269 270 293 stroke 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

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

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 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

General Precautions

Hematologic Effects

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

Specific Populations

Pregnancy

Category D.128 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether tamoxifen is distributed into milk.128 Discontinue nursing or the drug because of potential risk to nursing infant.128

Pediatric Use

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

Geriatric Use

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

Common Adverse Effects

Hot flashes, vaginal discharge, menstrual irregularities, weight loss.128

Interactions for Tamoxifen Citrate

A substrate of CYP3A, 2C9, 2D6.a

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

Cytotoxic Agents

Increased risk of thromboembolic events.128

Specific Drugs

Drug

Interaction

Comments

Aminoglutethimide

Decreased plasma tamoxifen and N-desmethyltamoxifen concentrations128

Anticoagulants (e.g., warfarin)

Enhanced warfarin effects128 170 171 172

Careful monitoring of PT is recommended128 170 171 172

When used in women with DCIS or at high risk for breast cancer, concomitant use contraindicateda

Bromocriptine

Increased plasma tamoxifen and N-desmethyltamoxifen concentrations128

Cyclosporine

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Diltiazem

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Erythromycin

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Letrozole

Decreased plasma letrozole concentrationsa

Medroxyprogesterone

Decreased plasma N-desmethyltamoxifen concentrations but did not reduce plasma tamoxifen concentrationsa

Nifedipine

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Phenobarbital

Decreased plasma tamoxifen concentrations128

Clinical importance unknown128

Rifampin

Decreased plasma tamoxifen and N-desmethyltamoxifen concentrationsa

Tamoxifen Citrate 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

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.26 28 140 142 143 144 145 146 148 149 150 151 The major metabolite, N-desmethyltamoxifen,128 140 143 144 145 146 148 150 151 has biologic activity similar to that of the parent drug.128

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 female children 2–10 years of age than in women; exposure to N-desmethyltamoxifen in these pediatric patients similar to adults.a

Stability

Storage

Oral

Tablets

Well-closed, light-resistant containers 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

  • 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

  • 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

  • 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.a Necessity of advising pregnant patients of the risk to the fetus.128

  • 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.128

  • Importance of women informing clinicians if they are or plan to breast-feed.128

  • 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.

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

Tamoxifen Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg (of tamoxifen)*

Nolvadex

AstraZeneca

Tamoxifen Citrate Tablets

Aegis, Andrx, Barr, Mylan, Roxane, Teva

20 mg (of tamoxifen)*

Nolvadex

AstraZeneca

Tamoxifen Citrate Tablets

Aegis, Andrx, Barr, Mylan, Roxane, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nolvadex 20MG Tablets (ASTRAZENECA): 30/$120.99 or 60/$239.98

Tamoxifen Citrate 10MG Tablets (MYLAN): 30/$14.99 or 60/$20.98

Tamoxifen Citrate 20MG Tablets (TEVA PHARMACEUTICALS USA): 30/$61.99 or 90/$165.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† 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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