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
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
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
ActionsActions
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
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 03/2011. 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 20MG Tablets (TEVA PHARMACEUTICALS USA): 30/$21.99 or 90/$49.97
Disclaimer
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The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 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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