Tamoxifen

Pronunciation

(ta MOKS i fen)

U.S. Brand Names

Nolvadex®

Synonyms

ICI-46474; NSC-180973; TAM; Tamoxifen Citrate

Generic Available

Yes

Canadian Brand Names

Apo-Tamox®; Gen-Tamoxifen; Nolvadex®; Nolvadex®-D; Novo-Tamoxifen; PMS-Tamoxifen; Tamofen®

Use

Palliative or adjunctive treatment of advanced breast cancer; reduce the incidence of breast cancer in women at high risk; reduce risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS); metastatic female and male breast cancer; treatment of melanoma, desmoid tumors

Use - Unlabeled/Investigational

Treatment of mastalgia, gynecomastia, pancreatic carcinoma; induction of ovulation; treatment of precocious puberty in females, secondary to McCune-Albright syndrome

Pregnancy Risk Factor

Pregnancy Implications

There are no adequate and well-controlled studies in pregnant women. For sexually-active women of childbearing age, initiate during menstruation (negative

-hCG immediately prior to initiation in women with irregular cycles). Pregnancy should be avoided for 2 months after treatment has been discontinued.

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to tamoxifen or any component of the formulation; concurrent warfarin therapy (when used for cancer risk reduction); pregnancy

Warnings/Precautions

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. An increased incidence of thromboembolic events has been associated with use for breast cancer; risk may increase with chemotherapy addition; use caution in individuals with a history of thromboembolic events. Use with caution in patients with leukopenia, thrombocytopenia, or hyperlipidemias; ovulation may be induced; decreased visual acuity, retinopathy, corneal changes, and increased incidence of cataracts have been reported. Hypercalcemia has occurred in patients with bone metastasis. Significant bone loss of the lumbar spine and hip was associated with use in premenopausal women. Liver abnormalities such as cholestasis, hepatitis, and hepatic necrosis have occurred; hepatocellular carcinomas have been reported in some studies, relationship to treatment is unclear. Endometrial hyperplasia and polyps have occurred. Increased risk of uterine or endometrial cancer; monitor.

Adverse Reactions

Note: Differences in the frequency of some adverse events may be related to use for a specific indication.

Frequency not defined: Depression, dizziness, headache, hypercalcemia, lightheadedness, peripheral edema, pruritus vulvae, taste disturbance, vaginal dryness

>10%:

Cardiovascular: Fluid retention (32%)

Central nervous system: Mood changes (up to 12%; may include depression)

Dermatologic: Skin changes (19%)

Endocrine & metabolic: Hot flashes (3% to 80%), weight loss (23%)

Gastrointestinal: Nausea (26%)

Genitourinary: Vaginal bleeding (up to 23%), vaginal discharge (30% to 55%), menstrual irregularities (25%)

Neuromuscular & skeletal: Bone pain, tumor pain, and local disease flare (including increase in lesion size and erythema) during treatment of metastatic breast cancer (generally resolves with continuation)

1% to 10%:

Dermatologic: Alopecia (<1% to 5%)

Gastrointestinal: Constipation (up to 4%)

Hematologic: Thrombocytopenia (<1% to 2%)

Hepatic: SGOT increased (2%), serum bilirubin increased (2%)

Renal: Serum creatinine increased (up to 2%)

Miscellaneous: Infection/sepsis (up to 6%), allergic reaction (up to 3%)

<1% (Limited to important or life-threatening): Angioedema, bullous pemphigoid, deep vein thrombosis, erythema multiforme, hypersensitivity reactions, hypertriglyceridemia, interstitial pneumonitis, pancreatitis, phlebitis, pulmonary embolism, rash, retinopathy (optic disc swelling, retinal hemorrhage, visual impairment associated with doses >200 mg/day), Stevens-Johnson syndrome

Postmarketing and/or case reports: Headache, impotence (males), loss of libido (males)

Overdosage/Toxicology

Symptoms of overdose include hypercalcemia and edema. Provide general supportive care.

Drug Interactions

Substrate of CYP2A6 (minor), 2B6 (minor), 2C8/9 (major), 2D6 (major), 2E1 (minor), 3A4 (major); Inhibits CYP2B6 (weak), 2C8/9 (weak), 3A4 (weak)

Allopurinol: Concurrent use may result in exacerbation of allopurinol-induced hepatotoxicity.

Cyclosporine: Concurrent use may result in an increase in cyclosporine serum levels.

CYP2C8/9 inducers: May decrease the levels/effects of tamoxifen. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of tamoxifen. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP2D6 inhibitors: May increase the levels/effects of tamoxifen. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of tamoxifen. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of tamoxifen. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Letrozole: Serum levels may be reduced by tamoxifen.

Warfarin: Concomitant use is contraindicated when used for risk reduction; results in significant enhancement of the anticoagulant effects of warfarin

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Avoid black cohosh, dong quai in estrogen-dependent tumors.

Stability

Store at room temperature of 20°C to 25°C (68°F to 77°F).

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

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:

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)

Prevention (high-risk females): 20 mg/day for 5 years

DCIS (females): 20 mg once daily for 5 years

Note: Higher dosages (up to 700 mg/day) have been investigated for use in modulation of multidrug resistance (MDR), but are not routinely used in clinical practice

Induction of ovulation (unlabeled use): 5-40 mg twice daily for 4 days

Monitoring Parameters

Monitor WBC and platelet counts, serum calcium, LFTs; abnormal vaginal bleeding

Test Interactions

T4 elevations (which may be explained by increases in thyroid-binding globulin) have been reported; not accompanied by clinical hyperthyroidism

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by 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) during therapy. You should schedule an annual ophthalmic examination is 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 or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Notify prescriber if menstrual irregularities or vaginal bleeding occur. Report unusual bleeding or bruising, severe weakness, sedation, mental changes, swelling or pain in calves, respiratory difficulty, or any vision changes. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures. Do not breast-feed.

Nursing Implications

Increase of bone pain usually indicates a good therapeutic response

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

Oncology: Emetic Potential

Low (10% to 30%)

Dosage Forms

Tablet, as citrate: 10 mg, 20 mg

References

Allan SG, Rodger A, Smyth JF, et al, "Tamoxifen as Primary Treatment of Breast Cancer in Elderly or Frail Patients: A Practical Management," Br Med J [Clin Res] , 1985, 290:358.

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.

Buckley MM and Goa KL, "Tamoxifen. A Reappraisal of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use," Drugs , 1989, 37(4):451-90.

Catherino WH and Jordan VC, "A Risk-Benefit Assessment of Tamoxifen Therapy," Drug Saf , 1993, 8(5):381-97.

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.

Cutuli B, Petit JC, Fricker JP et al, "Thromboembolic Accidents in Postmenopausal Patients Treated by Tamoxifen and Adjuvant Treatment: Frequency, Risk Factors, and Prevention," Bull Cancer , 1995, 82(1):51-6.

Cuzick J, Allen D, Baum M, et al, "Long Term Effects of Tamoxifen: Biological Effects of Tamoxifen Working Party," Eur J Cancer , 1992, 29A(1):15-21.

Dew JE and Eden JA, "Gynaecological Complications of Women Treated With Tamoxifen for Breast Cancer," Aust N Z J Obstet Gynaecol , 1995, 35(2):198-200.

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.

Fernando IN and Tobias JS, "Priapism in Patient on Tamoxifen," Lancet , 1989, 1(8635):436.

Folk JJ, Mazur MT, Eddy GL, et al, "Secretory Endometrial Adenocarcinoma in a Patient on Tamoxifen for Breast Cancer: A Report of a Case," Gynecol Oncol , 1995, 58(1):133-5.

Gelmann EP, "Tamoxifen for the Treatment of Malignancies Other Than Breast and Endometrial Carcinoma," Semin Oncol , 1997, 24(1 Suppl 1):1-65, 1-70.

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: Toxicities and Drug Resistance During Treatment and Prevention of Breast Cancer," Annu Rev Pharmacol Toxicol , 1995, 35:195-211.

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.

Nease RF Jr and Ross JM, "The Decision to Enter a Randomized Trial of Tamoxifen for the Prevention of Breast Cancer in Healthy Women: An Analysis of the Tradeoffs," Am J Med , 1995, 99(2):180-9.

Pandya KJ, Raubertas RF, Flynn PJ, et al, "Oral Clonidine in Postmenopausal Patients With Breast cancer Experiencing Tamoxife-induced Hot Flashes: A University of Rochester Cancer Center Community Clinical Oncology Program Study," Ann Intern Med , 2000, 132:788-93.

Parry BR, "Radiation Recall Induced by Tamoxifen," Lancet , 1992, 340(8810):49.

Pratt DS, Knox TA, and Erban J, "Tamoxifen-Induced Steatohepatitis," Ann Intern Med , 1995, 123(3):236.

Rabinowicz AL, Hinton DR, Dyck P, et al, "High-Dose Tamoxifen in Treatment of Brain Tumors: Interaction With Antiepileptic Drugs," Epilepsia , 1995, 36(5):513-5.

Ritchie LD and Grant SM, "Tamoxifen-Warfarin Interaction: The Aberdeen Hospitals Drug File," BMJ , 1989, 298(6682):1253.

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.

Rutqvist LE, "Long-Term Toxicity of Tamoxifen," Recent Results Cancer Res , 1993, 127:257-66.

Spooner D and Evans BD, "Tamoxifen and Life-Threatening Hypercalcaemia," Lancet , 1979, 2(8139):413-4.

Taylor SG, Gelman RS, Falkson G, et al, "Combination Chemotherapy Compared to Tamoxifen as Initial Therapy for Stage IV Breast Cancer in Elderly Women," Ann Intern Med , 1986, 104:455-61.

Wogan GN, "Review of the Toxicology of Tamoxifen," Semin Oncol , 1997, 24(1 Suppl 1):1-87, 1-97.

International Brand Names

Apo-Tamox® (CA, SG, TR); Asta Medica Tamoxifeno® (BR); Bilem® (RO, RU); Crisafeno® (AR); Diemon® (AR); Ebefen® (AT); Emblon® (GB); Farmifeno® (AR); Genox® (AU, NZ); Gen-Tamoxifen (CA); Ginarsan® (AR); Gynatam® (TH); Jenoxifen® (DE); Kessar® (AT, CH, CL, DE, FR, IT); Ledertam® (IT); Mamofen® (IN); Mandofen® (DE); Merck-Tamoxifen® (BE); Neophedan® (ZA); Nolgen® (IE, RO); Nolvadex® (AR, AT, AU, BD, BE, BG, BR, CA, CH, CL, CY, CZ, DE, EC, EG, ES, FI, FR, GB, HK, HR, ID, IE, IL, IN, IT, JO, KW, LB, LU, MT, MX, NL, NO, NZ, PL, PT, RO, RU, SE, SG, SI, SY, TH, TR, YU, ZA); Nolvadex®-D (CA); Nolvafen-D® (TR); Nolvafen® (TR); Nomafen® (IT); Nourytam® (DE); Novadex® (AT); Novofen® (CY, EC, HK, TH); Novo-Tamoxifen (CA); Oestrifen® (GB); Oncotam® (FR); Oxeprax® (ES); PMS-Tamoxifen (CA); Prosanil® (CL); P&U Tamoxifen® (BR); Retaxim® (SI); Rolap® (AR); Sinmaren® (ES); Soltamox® (GB); Tadex® (FI, TR); Tamax® (AT); Tamec® (CH); Tamexin® (FI); Tamifen® (CZ, HK, RU); Tamizam® (BE, LU); Tamodex® (TR); Tamofen® (AR, BR, CA, CN, FI, GB, HK, ID, IE, IL, IN, NZ, PL, RU, SG, TH); Tamofène® (FR); Tamokadin® (DE); Tamoneprin® (RO); Tamooex® (BR); Tamopham® (DE); Tamoplex® (BE, HK, ID, TH, TR); Tamosin® (AU); Tamox 1A Pharma® (DE); Tamox AbZ® (DE); Tamoxan® (PT); Tamoxasta® (DE); Tamox® (BR, IE); Tamoxen® (AU, IL); Tamoxene® (IT); Tamox-GRY® (DE); Tamoxifen Abic-Teva® (TH); Tamoxifen AL® (DE); Tamoxifen Arcana® (AT); Tamoxifen Austropharm® (AT); Tamoxifen beta® (DE); Tamoxifen Big® (IT); Tamoxifen-biosyn® (DE); Tamoxifen® (BR, CO, CZ, GB, NO, PL, RO, RU, TR, YU); Tamoxifen cell pharm® (DE); Tamoxifen Citrate® (RU); Tamoxifen.d.a.v.i.d® (DE); Tamoxifen Ebewe® (AT, CZ, ID); Tamoxifen-Ebewe® (PL); Tamoxifen Ebewe® (RU, TH, YU); Tamoxifene BIG (IT); Tamoxifen-Eurogenerics® (LU); Tamoxifen Farmos® (CH); Tamoxifen GEA® (SE); Tamoxifen Heumann® (DE); Tamoxifen Hexal® (DE, HR); Tamoxifen-Hexal® (LU); Tamoxifen Hexal® (PL); Tamoxifen medac® (DE); Tamoxifen NC® (DE); Tamoxifen NM® (DK); Tamoxifen NM Pharma® (SE); Tamoxifen Nordic® (SE); Tamoxifeno Bayvit® (ES); Tamoxifeno Biocrom® (AR); Tamoxifeno Biotenk® (AR); Tamoxifeno® (BR, CL, CO); Tamoxifeno Cinfa® (ES); Tamoxifeno Dosa® (AR); Tamoxifeno Edigen® (ES); Tamoxifeno Elfar® (ES); Tamoxifeno Farmitalia® (ES); Tamoxifeno Ferrer Farma® (ES); Tamoxifeno Filaxis® (AR); Tamoxifeno Funk® (ES); Tamoxifeno Gador® (AR, TR); Tamoxifeno Labinca® (AR); Tamoxifeno Lazar® (AR); Tamoxifeno Lepori® (ES); Tamoxifeno R® (AR); Tamoxifeno Ratiopharm® (ES); Tamoxifeno Vegal® (ES); Tamoxifeno Verifarma® (AR); Tamoxifeno Veris® (ES); Tamoxifen-ratioparm® (BE, LU); Tamoxifen-ratiopharm® (AT, CZ, DE, RU); Tamoxifen-Teva® (HU, TR); tamoxifen von ct® (DE); Tamoxifen-Zeneca® (LU); Tamoxi® (IL); Tamoximerck® (DE); Tamoxin® (BR); Tamoxis® (AR); Tamoxistad® (DE); Tamox-Puren® (DE); Tamox-TEVA® (DE); Taxfeno® (AR); Taxofen® (BR); Taxus® [tabs] (CL, CO, MX); Tecnofen® [tabs] (MX); Tecnotax® (BR); Trimetrox® (AR); Tuosomin® (TH); Virtamox® (IT); Zemide® (DE); Zitazonium® (BD, CZ, EG, HU, RO, RU, SY, TH)

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