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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
Sound-alike/look-alike issues:
Tamoxifen may be confused with pentoxifylline, Tambocor™
Pronunciation
(ta MOKS i fen)
U.S. Brand Names
Index Terms
Generic Available
Yes: Tablet
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of metastatic (female and male) breast cancer; adjuvant treatment of breast cancer; reduce risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS); reduce the incidence of breast cancer in women at high risk
Use: Unlabeled/Investigational
Treatment of mastalgia, gynecomastia, melanoma and desmoid tumors; induction of ovulation; treatment of precocious puberty in females, secondary to McCune-Albright syndrome
Restrictions
An FDA-approved medication guide must be distributed when dispensing the outpatient prescription (new or refill) to females for breast cancer prevention or treatment of ductal carcinoma in situ where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies have demonstrated fetal adverse effects and fetal loss. There are no adequate and well-controlled studies in pregnant women. There have been reports of vaginal bleeding, birth defects and fetal loss in pregnant women. Tamoxifen use during pregnancy may have a potential long term risk to the fetus of a DES-like syndrome. For sexually-active women of childbearing age, initiate during menstruation (negative ?-hCG immediately prior to initiation in women with irregular cycles). Tamoxifen may induce ovulation. Barrier or nonhormonal contraceptives are recommended. Pregnancy should be avoided during treatment and for 2 months after treatment has been discontinued.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known if tamoxifen is excreted in breast milk, however, it has been shown to inhibit lactation. Reproductive tract defects were observed in neonatal rodents following exposure to tamoxifen. Due to the potential for adverse reactions, women taking tamoxifen should not breast-feed.
Contraindications
Hypersensitivity to tamoxifen or any component of the formulation; concurrent warfarin therapy or history of deep vein thrombosis or pulmonary embolism (when tamoxifen is used for cancer risk reduction)
Warnings/Precautions
Boxed warnings:
• Serious and life-threatening events: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: Thrombocytopenia and/or leukopenia may occur; neutropenia and pancytopenia have been reported rarely. Although the relationship to tamoxifen therapy is uncertain, rare hemorrhagic episodes have occurred in patients with significant thrombocytopenia.
• Gynecologic effects/malignancies: Endometrial hyperplasia, polyps, endometriosis, uterine fibroids, and ovarian cysts have occurred. May increase risk of uterine or endometrial cancer; monitor. Amenorrhea and menstrual irregularities have been reported with tamoxifen use.
• Hepatotoxicity: Liver abnormalities such as cholestasis, fatty liver, hepatitis, and hepatic necrosis have occurred. Hepatocellular carcinomas have been reported in some studies; relationship to treatment is unclear.
• Ocular effects: Decreased visual acuity, retinal vein thrombosis, retinopathy, corneal changes, color perception changes and increased incidence of cataracts (and the need for cataract surgery) have been reported.
• Serious and life-threatening events: [U.S. Boxed Warning]: Serious and life-threatening events (including stroke, pulmonary emboli, and uterine malignancy) have occurred at an incidence greater than placebo during use for cancer risk reduction; these events are rare, but require consideration in risk:benefit evaluation. In patients already diagnosed with breast cancer, the benefits of tamoxifen use are greater than the risks.
• Thromboembolic events: An increased incidence of thromboembolic events, including DVT and pulmonary embolism, has been associated with use for breast cancer; risk is increased with concomitant chemotherapy; use with caution in individuals with a history of thromboembolic events.
Disease-related concerns:
• Bone mineral density: Tamoxifen use may be associated with changes in bone mineral density (BMD) and the effects may be dependant upon menstrual status. In postmenopausal women, tamoxifen use is associated with a protective effect on bone mineral density (BMD), preventing loss of BMD which lasts over the 5-year treatment period. In premenopausal women, a decline (from baseline) in BMD mineral density has been observed in women who continued to menstruate; may be associated with an increased risk of fractures.
• Hyperlipidemia: Use with caution in patients with hyperlipidemias; infrequent postmarketing cases of hyperlipemias have been reported.
• Metastatic breast cancer: Local disease flare and increased bone and tumor pain may occur; may be associated with (good) tumor response; onset is shortly after therapy initiation and usually resolves rapidly. In patients with bone metastasis, hypercalcemia has occurred usually within a few weeks of therapy initiation. Institute appropriate hypercalcemia management; discontinue if severe.
Adverse Reactions
>10%:
Cardiovascular: Flushing (33% to 41%), hypertension (11%), peripheral edema (11%)
Central nervous system: Pain (3% to 16%), mood changes (12% to 18%), depression (2% to 12%)
Dermatologic: Skin changes (6% to 19%), rash (13%)
Endocrine & metabolic: Hot flashes (3% to 80%), fluid retention (32%), altered menses (13% to 25%), amenorrhea (16%)
Gastrointestinal: Nausea (5% to 26%), weight loss (23%)
Genitourinary: Vaginal bleeding (2% to 23%), vaginal discharge (13% to 55%)
Neuromuscular & skeletal: Weakness (19%), arthritis (14%), arthralgia (11%)
Respiratory: Pharyngitis (14%)
1% to 10%:
Cardiovascular: Chest pain (5%), venous thrombotic events (5%), edema (4%), cardiovascular ischemia (3%), cerebrovascular ischemia (3%), angina (2%), deep venous thrombus (?2%), MI (1%)
Central nervous system: Insomnia (9%), dizziness (8%), headache (8%), anxiety (6%), fatigue (4%)
Dermatologic: Alopecia (<1% to 5%)
Endocrine & metabolic: Oligomenorrhea (9%), breast pain (6%), menstrual disorder (6%), breast neoplasm (5%), hypercholesterolemia (4%)
Gastrointestinal: Abdominal pain (9%), weight gain (9%), constipation (4% to 8%), diarrhea (7%), dyspepsia (6%), throat irritation (oral solution 5%), abdominal cramps (1%), anorexia (1%)
Genitourinary: Urinary tract infection (10%), leukorrhea (9%), vaginal hemorrhage (6%), vaginitis (5%), ovarian cyst (3%)
Hematologic: Thrombocytopenia (?10%), anemia (5%)
Hepatic: AST increased (5%), serum bilirubin increased (2%)
Neuromuscular & skeletal: Back pain (10%), bone pain (6% to 10%), osteoporosis (7%), fracture (7%), arthrosis (5%), myalgia (5%), paresthesia (5%), musculoskeletal pain (3%)
Ocular: Cataract (7%)
Renal: Serum creatinine increased (?2%)
Respiratory: Cough (4% to 9%), dyspnea (8%), bronchitis (5%), sinusitis (5%)
Miscellaneous: Infection/sepsis (?9%), diaphoresis (6%), flu-like syndrome (6%), allergic reaction (3%)
<1%, infrequent, or frequency not defined: Cholestasis, corneal changes, endometriosis, endometrial cancer, endometrial hyperplasia, endometrial polyps, fatty liver, hepatic necrosis, hepatitis, hypercalcemia, hyperlipidemia, lightheadedness, phlebitis, pruritus vulvae, pulmonary embolism, retinal vein thrombosis, retinopathy, second primary tumors, stroke, superficial phlebitis, taste disturbances, tumor pain and local disease flare (including increase in lesion size and erythema) during treatment of metastatic breast cancer (generally resolves with continuation), uterine fibroids, vaginal dryness
Postmarketing and/or case reports: Angioedema, bullous pemphigoid, erythema multiforme, hypersensitivity reactions, hypertriglyceridemia, impotence (males), interstitial pneumonitis, loss of libido (males), pancreatitis, Stevens-Johnson syndrome, visual color perception changes
Metabolism/Transport Effects
Substrate of CYP2A6 (minor), 2B6 (minor), 2C9 (major), 2D6 (major), 2E1 (minor), 3A4 (major); Inhibits CYP2B6 (weak), 2C8 (moderate), 2C9 (weak), 3A4 (weak), p-glycoprotein
Drug Interactions
Aminoglutethimide: May increase the metabolism of Tamoxifen. Risk D: Consider therapy modification
Anastrozole: Tamoxifen may decrease the serum concentration of Anastrozole. Risk D: Consider therapy modification
Coumarin Derivatives: Tamoxifen may increase the serum concentration of Coumarin Derivatives. Risk X: Avoid combination
CYP2C8 Substrates (High risk with Highly Effective Inhibitors): CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates (High risk with Highly Effective Inhibitors). Risk C: Monitor therapy
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inducers). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Letrozole: Tamoxifen may decrease the serum concentration of Letrozole. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Tamoxifen. Risk C: Monitor therapy
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid black cohosh, dong quai in estrogen-dependent tumors. Avoid St John's wort (may decrease levels/effects of tamoxifen).
Storage
Solution: Store at room temperature at or below 25°C (77°F); do not refrigerate or freeze. Protect from light. Use within 3 months of opening.
Tablet: Store at room temperature of 20°C to 25°C (68°F to 77°F). Protect from light.
Mechanism of Action
Competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects; nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues; cells accumulate in the G0 and G1 phases; therefore, tamoxifen is cytostatic rather than cytocidal.
Pharmacodynamics/Kinetics
Absorption: Well absorbed; tablet and oral solution are bioequivalent
Distribution: High concentrations found in uterus, endometrial and breast tissue
Protein binding: 99%
Metabolism: Hepatic (via CYP3A4) to major metabolites, N-desmethyl tamoxifen (major) and 4-hydroxytamoxifen (minor), and a tamoxifen derivative (minor); undergoes enterohepatic recirculation
Half-life elimination: Distribution: 7-14 hours; Elimination: 5-7 days; Metabolites: 14 days
Time to peak, serum: 5 hours
Excretion: Feces (26% to 51%); urine (9% to 13%)
Dosage
Oral (refer to individual protocols):
Children: Female: Precocious puberty and McCune-Albright syndrome (unlabeled use): A dose of 20 mg/day has been reported in patients 2-10 years of age; safety and efficacy have not been established for treatment of longer than 1 year duration
Adults:
Breast cancer treatment:
Metastatic (males and females) or adjuvant therapy (females): 20-40 mg/day; daily doses >20 mg should be given in 2 divided doses (morning and evening); doses >20 mg/day are not more effective in adjuvant therapy
DCIS (females): 20 mg once daily for 5 years
Breast cancer risk reduction (pre- and postmenopausal high-risk females): 20 mg/day for 5 years
Induction of ovulation (unlabeled use): 5-40 mg twice daily for 4 days
Dosage: Combination Regimens
Breast cancer: Tamoxifen-Epirubicin
Melanoma:
CCDT (Melanoma)
Dartmouth Regimen
Administration: Oral
Administer once or twice daily. Doses >20 mg/day should be given in divided doses.
Monitoring Parameters
CBC with platelets, serum calcium, LFTs; triglycerides and cholesterol (in patients with pre-existing hyperlipemias); abnormal vaginal bleeding; breast and gynecologic exams (baseline and routine), mammogram (baseline and routine)
Test Interactions
T4 elevations (which may be explained by increases in thyroid-binding globulin) have been reported; not accompanied by clinical hyperthyroidism
Patient Education
Do not take any new medication during therapy without consulting prescriber. Take exactly as directed. It is important to maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake and adequate nutrition (small frequent meals may help). You should schedule an annual ophthalmic examination, gynecological exam, and mammogram if this medication is used long-term. You may experience hot flashes, hair loss, loss of libido (these will subside when treatment is completed). Bone pain may indicate a good therapeutic responses (consult prescriber for mild analgesics). May cause nausea, vomiting, loss of appetite (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); hot flashes (a cool room or cool compresses may help). Notify prescriber if menstrual irregularities, vaginal bleeding, or intolerable hot flashes occur. Report unusual bleeding or bruising; severe weakness or unusual fatigue; CNS changes (depression, mood changes); swelling or pain in calves; respiratory difficulty; vision changes; or other adverse effects. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication and for 2 months after treatment is discontinued; consult prescriber for appropriate barrier or nonhormonal contraceptive measures. Do not breast-feed.
Geriatric Considerations
Studies have shown tamoxifen to be effective in the treatment of primary breast cancer in elderly women. Comparative studies with other antineoplastic agents in elderly women with breast cancer had more favorable survival rates with tamoxifen. Initiation of hormone therapy rather than chemotherapy is justified for elderly patients with metastatic breast cancer who are responsive. Reduction of mortality and recurrence was greater in those studies that used tamoxifen for ?2 years than those that use it for <2 years.
Additional Information
Oral clonidine is being studied for the treatment of tamoxifen-induced “hot flashes.” The tumor flare reaction may indicate a good therapeutic response, and is often considered a good prognostic factor.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness, drowsiness, or confusion
Mental Health: Effects on Psychiatric Treatment
May cause leukopenia; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Use caution in presence of leukopenia, thrombocytopenia, or hyperlipidemia or history of thrombolytic events. Assess potential for interactions with other pharmacological agents and herbal products patient may be taking (increased or decreased levels/effects of tamoxifen or other drugs administered concurrently). Assess results of CBC and platelet counts, therapeutic effectiveness (eg, complaints of bone pain may be an indication of a good therapeutic effectiveness in metastatic breast cancer patients and will usually subside as treatment continues), and adverse reactions (eg, flushing, fluid retention, hot flashes, vaginal bleeding or discharge, constipation, rash, mood changes). Teach patient proper use, possible side effects/appropriate interventions (eg, periodic ophthalmic evaluations and annual gynecological exams and mammogram with long-term use), and adverse symptoms to report.
Oncology: Emetic Potential
Low (10% to 30%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, oral:
Soltamox™: 10 mg/5 mL (150 mL) [sugar free; licorice flavor] [DSC]
Tablet: 10 mg, 20 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Nolvadex)
10 mg (60): $114.79
20 mg (60): $220.37
Tablets (Tamoxifen Citrate)
20 mg (30): $21.99
References
Boostanfar R, Jain JK, Mishell DR Jr, et al, “A Prospective Randomized Trial Comparing Clomiphene Citrate With Tamoxifen Citrate for Ovulation Induction,” Fertil Steril, 2001, 75(5):1024-6.
Cohen I, Altaras MM, Lew S, et al, “Ovarian Endometrioid Carcinoma and Endometriosis Developing in a Postmenopausal Breast Cancer Patient During Tamoxifen Therapy: A Case Report and Review of the Literature,” Gynecol Oncol, 1994, 55(3 Pt 1):443-7.
Eastell R, Adams JE, Coleman RE, et al, “Effect of Anastrozole on Bone Mineral Density: 5-Year Results From the Anastrozole, Tamoxifen, Alone or in Combination Trial 18233230,” J Clin Oncol, 2008, 26(7):1051-7.
Eugster EA, Rubin SD, Reiter EO, et al, “Tamoxifen Treatment for Precocious Puberty in McCune-Albright Syndrome: A Multicenter Trial,” J Pediatr, 2003, 143(1):60-6.
Hochner-Celnikier D, Anteby E, and Yagel S, “Ovarian Cysts in Tamoxifen-Treated Premenopausal Women With Breast Cancer - A Management Dilemma,” Am J Obstet Gynecol, 1995, 172(4 Pt 1):1323-4.
Jordan VC, "Tamoxifen: A Most Unlikely Pioneering Medicine," Nat Rev Drug Discov, 2003, 2(3):205-13.
Jubelirer SJ, “The Management of Menopausal Symptoms in Women With Breast Cancer,” W V Med J, 1995, 91(2):54-6.
LiVolsi VA, Salhany KE, and Dowdy YG, “Endocervical Adenocarcinoma in Tamoxifen-Treated Patient,” Am J Obstet Gynecol, 1995, 172(3):1065.
National Comprehensive Cancer Network (NCCN), “Clinical Practice Guidelines in Oncology™: Breast Cancer Risk Reduction, Version 1.2008.” Accessible at http://www.nccn.org/professionals/physician_gls/PDF/breast_risk.pdf
Pandya KJ, Raubertas RF, Flynn PJ, et al, “Oral Clonidine in Postmenopausal Patients With Breast Cancer Experiencing Tamoxifen-Induced Hot Flashes: A University of Rochester Cancer Center Community Clinical Oncology Program Study,” Ann Intern Med, 2000, 132:788-93.
Rutqvist LE, Johansson H, Signomklao T, et al, “Adjuvant Tamoxifen Therapy for Early Stage Breast Cancer and Second Primary Malignancies. Stockholm Breast Cancer Study Group,” J Natl Cancer Inst, 1995, 87(9):645-51.
Vehmanen L, Elomaa I, Blomqvist C, et al, “Tamoxifen Treatment After Adjuvant Chemotherapy Has Opposite Effects on Bone Mineral Density in Premenopausal Patients Depending on Menstrual Status,” J Clin Oncol, 2006, 24(4):675-80.
Winer EP, Hudis C, Burstein HJ, et al, “American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors as Adjuvant Therapy for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Status Report 2004,” J Clin Oncol, 2005, 23(3):619-29.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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