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Tamoxifen

Medically reviewed on Sep 10, 2018

Pronunciation

See also: Kisqali

(ta MOKS i fen)

Index Terms

  • ICI-46474
  • Nolvadex
  • Tamoxifen Citras
  • Tamoxifen Citrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral:

Soltamox: 10 mg/5 mL (150 mL) [sugar free; contains alcohol, usp, propylene glycol; licorice-aniseed flavor]

Tablet, Oral:

Generic: 10 mg, 20 mg

Brand Names: U.S.

  • Soltamox

Pharmacologic Category

  • Antineoplastic Agent, Estrogen Receptor Antagonist
  • Selective Estrogen Receptor Modulator (SERM)

Pharmacology

Tamoxifen 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.

Absorption

Well absorbed

Distribution

High concentrations found in uterus, endometrial and breast tissue

Metabolism

Hepatic; via CYP2D6 to 4-hydroxytamoxifen and via CYP3A4/5 to N-desmethyl-tamoxifen. Each is then further metabolized into endoxifen (4-hydroxy-tamoxifen via CYP3A4/5 and N-desmethyl-tamoxifen via CYP2D6); both 4-hydroxy-tamoxifen and endoxifen are 30- to 100-fold more potent than tamoxifen

Excretion

Feces (26% to 51%); urine (9% to 13%)

Clearance: Higher (~2.3 fold) in female pediatric patients (2 to 10 years) compared to adult breast cancer patients; within pediatric population, clearance faster in children 2 to 6 years compared to older children

Time to Peak

Serum: Children 2 to 10 years (female): ~8 hours; Adults: ~5 hours

Half-Life Elimination

Tamoxifen: ~5 to 7 days; N-desmethyl tamoxifen: ~14 days

Protein Binding

99%

Use: Labeled Indications

Breast cancer: Treatment of metastatic (female and male) breast cancer; adjuvant treatment of breast cancer after primary treatment with surgery and radiation; reduce risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery and radiation; reduce the incidence of breast cancer in women at high risk (eg, women ≥35 years with a 5 year predicted risk of breast cancer ≥1.67% as calculated by the Gail Model)

Off Label Uses

Desmoid tumors, progressive or recurrent

Data from a study evaluating the use of tamoxifen (in combination with sulindac) suggests that tamoxifen may be beneficial for the treatment of this condition [Hansmann 2004]. Additional data may be necessary to further define the role of tamoxifen in this condition.

Endometrial carcinoma, recurrent, metastatic, or high-risk (endometrioid histologies only)

Data from two phase II trials in patients with advanced or recurrent endometrial carcinoma supports the use of tamoxifen for the treatment of this condition [Thigpen 2001], [ Fiorica 2004]. Additional trials may be necessary to further define the role of tamoxifen in this condition.

Gynecomastia

Tamoxifen has been demonstrated to have a significant role in the treatment of primary or secondary gynecomastia.

Induction of ovulation

A metaanalysis of trials evaluating the utility of tamoxifen (or clomiphene citrate) for ovulation induction demonstrated that tamoxifen and clomiphene are equally efficacious for this use [Steiner 2005]. Additional trials may be necessary to further define the role of tamoxifen in this condition.

Mastalgia, severe

Data from a small controlled trial suggests that tamoxifen may be beneficial for the treatment of severe mastalgia [Fentiman 1988]. Additional trials are necessary to further define the role of tamoxifen in this condition.

Oligospermia

In the most successful study, in which improved pregnancy rates were observed, the mean sperm count at baseline in tamoxifen plus testosterone-treated men exceeded 20 million/mL, the typical threshold below which men are considered to be oligospermic. Other trials of combination tamoxifen and testosterone have demonstrated improvements in seminal parameters. In contrast, several small studies with tamoxifen alone found minimal or no benefits on seminal parameters, hormonal parameters, or pregnancy rates. Thus, any improvements observed with tamoxifen therapy may be dependent on or the direct result of concurrent use with testosterone. The potential for tamoxifen to improve pregnancy rates remains to be proven in men with severe oligospermia, who are least likely to achieve conception without intervention.

Ovarian cancer, advanced and/or recurrent

Data from two studies evaluating the use of tamoxifen for the treatment of advanced ovarian cancer suggest that tamoxifen may be beneficial for the treatment of this condition [Hatch 1991], [Markman 1996]. Additional trials may be necessary to further define the role of tamoxifen in this condition.

Precocious puberty (females) due to McCune-Albright syndrome

Data from a multicenter trial in females with precocious puberty due to McCune-Albright syndrome supports the use of tamoxifen for the treatment of this condition [Eugster 2003]. Additional trials may be necessary to further define the role of tamoxifen in this condition.

Contraindications

Known 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 breast cancer risk reduction in women at high risk for breast cancer or with ductal carcinoma in situ [DCIS])

Dosing: Adult

Note: For the treatment of breast cancer, patients receiving both tamoxifen and chemotherapy should receive treatment sequentially, with tamoxifen following completion of chemotherapy.

Breast cancer treatment: Oral:

Adjuvant therapy (females): 20 mg once daily

Duration of therapy: The American Society of Clinical Oncology (ASCO) guidelines for Adjuvant Endocrine Therapy of Hormone-Receptor Positive Breast Cancer (Focused Update) recommend the following durations of therapy based on menopausal status (Burstein 2014):

Pre- or perimenopausal at endocrine therapy initiation: Tamoxifen for an initial duration of 5 years; if pre- or perimenopausal (or status cannot be determined) after 5 years of therapy, may continue tamoxifen for a total duration of 10 years. If postmenopausal after 5 years of tamoxifen therapy, may continue tamoxifen for a total duration of 10 years, or switch to an aromatase inhibitor (AI) for up to a total duration of 10 years of endocrine therapy.

Postmenopausal at endocrine therapy initiation: Tamoxifen for a total duration of 10 years or tamoxifen for an initial duration of 5 years, followed by an AI for up to 5 years (for a total duration of 10 years of endocrine therapy) or tamoxifen for 2 to 3 years, followed by an AI for up to 5 years (for a total duration of 7 to 8 years of endocrine therapy) or an AI for 5 years

Metastatic (males and females): 20 to 40 mg daily (doses >20 mg should be given in 2 divided doses). Note: Although the FDA-approved labeling recommends dosing up to 40 mg daily, clinical benefit has not been demonstrated with doses above 20 mg daily (Bratherton 1984).

Guideline recommendations: The American Society of Clinical Oncology (ASCO) guidelines for Endocrine Therapy for Hormone-Receptor Positive Metastatic Breast Cancer recommend the following based on menopausal status (Rugo 2016):

Premenopausal: Tamoxifen (in combination with ovarian suppression) may be offered as first-line therapy in patients with no prior endocrine therapy or in those who have received prior treatment with ovarian suppression and an AI; tamoxifen (with continued ovarian suppression) may also be offered as second-line therapy. Tamoxifen alone may be considered, but combination therapy is preferred.

Postmenopausal: Tamoxifen may be offered as second-line therapy in patients with no prior endocrine therapy. In patients who have received prior endocrine therapy with tamoxifen, tamoxifen may be offered first- or second-line in patients with late relapse (>12 months since adjuvant therapy). In patients who have received prior endocrine therapy with an AI, tamoxifen may be offered as first- or second-line therapy.

Duration of therapy: Continue tamoxifen treatment until documented disease progression (documented by imaging, clinical examination, or disease-related symptoms).

Ductal carcinoma in situ (DCIS) (females), to reduce the risk for invasive breast cancer: 20 mg once daily for 5 years

Breast cancer risk reduction (pre- and postmenopausal high-risk females): Oral: 20 mg once daily for 5 years

Endometrial carcinoma, recurrent, metastatic, or high-risk (endometrioid histologies only) (off-label use): Oral:

Monotherapy: 20 mg twice daily until disease progression or unacceptable toxicity (Thigpen 2001)

Combination therapy: 20 mg twice daily for 3 weeks (alternating with megestrol acetate every 3 weeks); continue alternating until disease progression or unacceptable toxicity) (Fiorica 2004)

Gynecomastia (off-label use): Oral: 20 mg once daily for up to 12 months (Boccardo 2005; Fradet 2007). The majority of published experiences have been in adult men with prostate cancer receiving bicalutamide. Use has also been reported in patients with idiopathic gynecomastia.

Induction of ovulation (off-label use): Oral: 20 mg once daily (range: 20-80 mg once daily) for 5 days (Steiner 2005)

Mastalgia, severe (off-label use): Oral: 10 mg once daily for 3 months; may consider further treatment if relapse occurs (Fentiman 1988). Additional trials are necessary to further define the role of tamoxifen in the treatment of this condition.

Oligospermia (off-label use): Oral: 10 mg twice daily (Adamopoulos 1995; Adamopoulos 1997; Adamopoulos 2003; Buvat 1987); most effective when used in combination with testosterone (Adamopoulos 2003). The treatment period in clinical trials was up to 18 months (Buvat 1987). Although doses of 10 to 40 mg/day have been used, increasing dose after 6 months from 10 mg twice daily to 20 mg twice daily did not increase sperm count (Buvat 1987).

Ovarian cancer, advanced and/or recurrent (off-label use): Oral: 20 mg twice daily (Hatch 1991; Markman 1996)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Precocious puberty secondary to McCune-Albright syndrome (off-label use): Females: Oral: A dose of 20 mg daily has been reported in patients 2 to 10 years of age; safety and efficacy have not been established for treatment of longer than 1 year duration (Eugster 2003)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Chronic dialysis: No dosage adjustment necessary (Janus 2013).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Extemporaneously Prepared

A 0.5 mg/mL oral suspension may be prepared with tablets. Place two 10 mg tablets into 40 mL purified water and let stand ~2 to 5 minutes. Stir until tablets are completely disintegrated (dispersion time for each 10 mg tablet is ~2 to 5 minutes). Administer immediately after preparation. To ensure the full dose is administered, rinse glass several times with water and administer residue.

Lam MS, "Extemporaneous Compounding of Oral Liquid Dosage Formulations and Alternative Drug Delivery Methods for Anticancer Drugs," Pharmacotherapy, 2011, 31(2):164-92.21275495

Administration

Administer tablets or oral solution orally with or without food. Use supplied dosing cup for oral solution.

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Storage

Oral solution: Store at ≤25°C (77°F); do not freeze or refrigerate. Protect from light. Discard opened bottle after 3 months.

Tablets: Store at 20°C to 25°C (68°F to 77°F). Protect from light; avoid excessive heat.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Anastrozole: Tamoxifen may decrease the serum concentration of Anastrozole. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Bexarotene (Systemic): May decrease the serum concentration of Tamoxifen. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (eg, warfarin, phenytoin) should be avoided when possible. Monitor therapy

Chloroquine: Tamoxifen may enhance the adverse/toxic effect of Chloroquine. Specifically, concomitant use of tamoxifen and chloroquine may increase the risk of retinal toxicity. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

CYP2D6 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Strong) may decrease the serum concentration of Tamoxifen. Management: Consider alternatives to concomitant use of strong CYP3A4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Hydroxychloroquine: Tamoxifen may enhance the adverse/toxic effect of Hydroxychloroquine. Specifically, concomitant use of tamoxifen and hydroxychloroquine may increase the risk of retinal toxicity. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Letrozole: Tamoxifen may decrease the serum concentration of Letrozole. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mipomersen: Tamoxifen may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Ospemifene: Selective Estrogen Receptor Modulators may enhance the adverse/toxic effect of Ospemifene. Ospemifene may also enhance adverse/toxic effects of other Selective Estrogen Receptor Modulators. Selective Estrogen Receptor Modulators may diminish the therapeutic effect of Ospemifene. Ospemifene may also diminish the therapeutic effects of other Selective Estrogen Receptor Modulators. Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

QuiNINE: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ribociclib: May increase the serum concentration of Tamoxifen. Management: Concurrent use of ribociclib with tamoxifen is not indicated. Use of this combination may increase the effects and toxicities of tamoxifen. Consider therapy modification

Rifamycin Derivatives: May increase the metabolism of Tamoxifen. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tamoxifen may increase the serum concentration of Vitamin K Antagonists. Avoid combination

Test Interactions

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

Adverse Reactions

>10%:

Cardiovascular: Vasodilatation (41%), flushing (33%), hypertension (11%), peripheral edema (11%)

Central nervous system: Mood changes (12% to 18%), pain (3% to 16%), depression (2% to 12%)

Dermatologic: Skin changes (6% to 19%), skin rash (13%)

Endocrine & metabolic: Hot flash (3% to 80%), fluid retention (32%), menstrual disease (6% to 25%), weight loss (23%), amenorrhea (16%)

Gastrointestinal: Nausea (5% to 26%), vomiting (12%)

Genitourinary: Vaginal discharge (13% to 55%), vaginal hemorrhage (2% to 23%)

Hematologic & oncologic: Lymphedema (11%)

Neuromuscular & skeletal: Weakness (18%), arthritis (14%), arthralgia (11%)

Respiratory: Pharyngitis (14%)

1% to 10%:

Cardiovascular: Chest pain (5%), venous thrombosis (5%), edema (4%), ischemic heart disease (3%), angina pectoris (2%), deep vein thrombosis (≤2%), myocardial infarction (1%)

Central nervous system: Insomnia (9%), dizziness (8%), headache (8%), anxiety (6%), paresthesia (5%), fatigue (4%)

Dermatologic: Diaphoresis (6%), alopecia (≤5%)

Endocrine & metabolic: Oligomenorrhea (9%), weight gain (9%), hypercholesterolemia (4%), ovarian cyst (3%)

Gastrointestinal: Abdominal pain (9%), constipation (4% to 8%), diarrhea (7%), dyspepsia (6%), abdominal cramps (1%), anorexia (1%)

Genitourinary: Urinary tract infection (10%), leukorrhea (9%), mastalgia (6%), vaginitis (5%), vulvovaginitis (5%)

Hematologic & oncologic: Thrombocytopenia (≤10%), anemia (5%), breast neoplasm (5%), neoplasm (5%; second primary)

Hepatic: Increased serum AST (5%), increased serum bilirubin (2%)

Hypersensitivity: Hypersensitivity reaction (3%)

Infection: Infection (≤9%), sepsis (≤9%)

Neuromuscular & skeletal: Back pain (10%), ostealgia (6% to 10%), bone fracture (7%), osteoporosis (7%), arthropathy (5%), myalgia (5%), musculoskeletal pain (3%)

Ophthalmic: Cataract (7%)

Renal: Increased serum creatinine (≤2%)

Respiratory: Cough (4% to 9%), dyspnea (8%), flu-like symptoms (6%), bronchitis (5%), sinusitis (5%), throat irritation (oral solution: 5%)

Miscellaneous: Cyst (5%)

Frequency not defined:

Cardiovascular: Cerebrovascular accident, phlebitis (including superficial), pulmonary embolism, thrombosis (retinal vein)

Central nervous system: Tumor pain (during treatment of metastatic breast cancer; generally resolves with continuation)

Dermatologic: Pruritus vulvae

Endocrine & metabolic: Hypercalcemia, hyperlipidemia

Gastrointestinal: Cholestasis, dysgeusia

Genitourinary: Endometrial hyperplasia, endometrial polyps, endometriosis, vaginal dryness

Hematologic & oncologic: Endometrial carcinoma, tumor flare (during treatment of metastatic breast cancer; generally resolves with continuation; includes increased lesion size and erythema), uterine fibroids

Hepatic: Hepatic necrosis, hepatitis, liver steatosis

Ophthalmic: Corneal changes, retinopathy

<1%, postmarketing, and/or case reports: Angioedema, bullous pemphigoid, erythema multiforme, hypertriglyceridemia, impotence, interstitial pneumonitis, loss of libido (males), pancreatitis, Stevens-Johnson syndrome, vision color changes

ALERT: U.S. Boxed Warning

Ductal carcinoma in situ/women at high risk for breast cancer:

Serious and life-threatening events associated with tamoxifen in the risk-reduction setting (women at high risk for cancer and women with ductal carcinoma in situ [DCIS]) include uterine malignancies, stroke, and pulmonary embolism (PE). Incidence rates for these events were estimated from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial. Uterine malignancies consist of endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.2 for tamoxifen versus 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for tamoxifen versus 0.4 for placebo) (updated long-term follow-up data [median length of follow-up is 6.9 years] from NSABP P-1 study). For stroke, the incidence rate per 1,000 women-years was 1.43 for tamoxifen versus 1 for placebo. For PE, the incidence rate per 1,000 women-years was 0.75 for tamoxifen versus 0.25 for placebo.

Some of the strokes, PE, and uterine malignancies were fatal. 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 risks of developing breast cancer. The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.

Warnings/Precautions

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: [US Boxed Warning]: Tamoxifen use for breast cancer risk reduction in women at high-risk for breast cancer and in women with ductal carcinoma in situ (DCIS) is associated with an increased incidence of uterine or endometrial cancers (some fatal). Endometrial hyperplasia, polyps, endometriosis, uterine fibroids, and ovarian cysts have occurred. Amenorrhea and menstrual irregularities have been reported with tamoxifen use. Monitor and promptly evaluate any report of abnormal vaginal bleeding.

• Hepatotoxicity: Liver abnormalities such as cholestasis, fatty liver, hepatitis, and hepatic necrosis have occurred (some fatal). 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.

• Thromboembolic events: [US Boxed Warning]: Serious and life-threatening events (some fatal), including stroke and pulmonary emboli have occurred at an incidence greater than placebo during use for breast cancer risk reduction in women at high-risk for breast cancer and in women with DCIS; 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. An increased incidence of thromboembolic events has been associated with use; 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 dependent 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 hyperlipidemias 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 some patients with bone metastasis, hypercalcemia has occurred, usually within a few weeks of therapy initiation. Institute appropriate hypercalcemia management; discontinue if severe.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Decreased efficacy and an increased risk of breast cancer recurrence has been reported with concurrent moderate or strong CYP2D6 inhibitors (Aubert 2009; Dezentje 2009).

• Selective serotonin reuptake inhibitors (SSRI): Concomitant use with select SSRIs may result in decreased tamoxifen efficacy. Strong CYP2D6 inhibitors (eg, fluoxetine, paroxetine) and moderate CYP2D6 inhibitors (eg, sertraline) are reported to interfere with transformation to the active metabolite endoxifen; when possible, select alternative medications with minimal or no impact on endoxifen levels (Sideras 2010). Weak CYP2D6 inhibitors (eg, venlafaxine, citalopram) have minimal effect on the conversion to endoxifen (Jin 2005); escitalopram is also a weak CYP2D6 inhibitor. In a retrospective analysis of breast cancer patients taking tamoxifen and SSRIs, concomitant use of paroxetine and tamoxifen was associated with an increased risk of death due to breast cancer (Kelly 2010).

Special populations:

• CYP2D6 poor metabolizers: Lower plasma concentrations of endoxifen (active metabolite) have been observed in patients with reduced CYP2D6 activity (Jin, 2005; Schroth, 2009) and may be associated with reduced efficacy, although data is conflicting. Routine CYP2D6 testing is not recommended at this time in order to determine optimal endocrine therapy (Visvanathan 2009).

Other warnings/precautions:

• Risks vs benefits: [US Boxed Warning]: In women already diagnosed with breast cancer, the benefits of tamoxifen treatment outweigh risks; evaluate risks versus benefits (and discuss with patients) when used for breast cancer risk reduction.

Monitoring Parameters

CBC with platelets, serum calcium, LFTs; triglycerides and cholesterol (in patients with pre-existing hyperlipidemias); INR and PT (in patients on vitamin K antagonists); pregnancy test (prior to treatment in females of reproductive potential); monitor for abnormal vaginal bleeding; breast and gynecologic exams (baseline and routine), mammogram (baseline and routine); signs/symptoms of DVT (leg swelling, tenderness) or PE (shortness of breath); ophthalmic exam (if vision problem or cataracts); bone mineral density (premenopausal women)

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal reproduction studies have demonstrated fetal adverse effects and fetal loss. 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 β-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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hot flashes, nausea, vomiting, weight loss, weight gain, loss of strength and energy, back pain, bone pain, dizziness, muscle pain, or joint pain. Have patient report immediately to prescriber signs of infection, signs of high calcium (weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), swelling of arms or legs, burning or numbness feeling, pelvic pain or pressure, menstrual changes, abnormal vaginal bleeding, vaginal discharge, vision changes, lump in breast, breast soreness or pain, decreased libido, sexual dysfunction, depression, skin changes, severe headache, painful urination, signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood), amenorrhea, or signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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