Tamoxifen: Drug Information

Tamoxifen: Drug information

(For additional information see "Tamoxifen: Patient drug information" and see "Tamoxifen: Pediatric drug information")

For abbreviations and symbols that may be used in Lexicomp (show table) ALERT: US 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.

Brand Names: US Soltamox

Brand Names: Canada Apo-Tamox; Mylan-Tamoxifen; Nolvadex-D; PMS-Tamoxifen; Teva- Tamoxifen

Pharmacologic Category Antineoplastic Agent, Estrogen Receptor Antagonist; Selective Estrogen Receptor Modulator (SERM)

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 for 5 years

Premenopausal women: Duration of treatment is 5 years (Burstein 2010; NCCN Breast Cancer guidelines v.2.2013) Postmenopausal women: Duration of tamoxifen treatment is 2-3 years followed by an aromatase inhibitor (AI) to complete 5 years; may take tamoxifen for the full 5 years (if contraindications or intolerance to AI) or extended therapy: 4.5 to 6 years of tamoxifen followed by 5 years of an AI (Burstein 2010; NCCN Breast Cancer guidelines v.2.2013)

ER-positive early breast cancer: Extended duration: Duration of treatment of 10 years demonstrated a reduced risk of recurrence and mortality (Davies 2012)

Metastatic (males and females): 20-40 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).

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)

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)

Paget’s disease of the breast (risk reduction; with DCIS or without associated cancer): Oral: 20 mg once daily for 5 years (NCCN Breast Cancer Guidelines v.2.2013)

Dosage adjustment for DVT, pulmonary embolism, cerebrovascular accident, or prolonged immobilization: Discontinue tamoxifen (NCCN Breast Cancer Risk Reduction Guidelines v.1.2013)

Dosing: Pediatric

(For additional information see "Tamoxifen: Pediatric drug information") Females: Precocious puberty secondary to McCune-Albright syndrome (off-label use): Oral: A dose of 20 mg daily 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 (Eugster, 2003)

Dosing: Geriatric Refer to adult dosing.

Dosing: Renal Impairment No dosage adjustment provided in manufacturer’s labeling.

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

Dosing: Hepatic Impairment No dosage adjustment provided in manufacturer’s labeling (has not been studied).

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

Generic Equivalent Available (US) May be product dependent

Medication Guide and/or Vaccine Information Statement (VIS) An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication when used in females for breast cancer prevention or treatment of ductal carcinoma in situ:

Soltamox:http://soltamox.com/content/images/Soltamox-Med-Guide.pdf

Administration Administer tablets or oral solution orally with or without food. Use supplied dosing cup for oral solution. Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016). Use 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 Use: Off-Label

Desmoid tumors, progressive or recurrent; Endometrial carcinoma, recurrent, metastatic, or high-risk (endometrioid histologies only); Gynecomastia; Induction of ovulation; Oligospermia; Ovarian cancer, advanced and/or recurrent; Precocious puberty (females) due to McCune-Albright syndrome; Mastalgia; Paget’s disease of the breast (risk reduction; with ER-positive DCIS or without associated cancer)

Medication Safety Issues

Sound-alike/look-alike issues:

Tamoxifen may be confused with pentoxifylline, Tambocor, tamsulosin, temazepam

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 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 breast cancer risk reduction in women at high risk for breast cancer or with ductal carcinoma in situ [DCIS]) 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: [U.S. 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. 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: [U.S. 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 (NCCN Breast Cancer Risk Reduction Guidelines v.1.2013; Sideras, 2010). Weak CYP2D6 inhibitors (eg, venlafaxine, citalopram) have minimal effect on the conversion to endoxifen (Jin, 2005; NCCN Breast Cancer Risk Reduction Guidelines v.1.2013); 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 (NCCN Breast Cancer Guidelines v.2.2013; Visvanathan, 2009).

Other warnings/precautions:

• Risks vs benefits: [U.S. 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.

Metabolism/Transport Effects Substrate of CYP2A6 (minor), CYP2B6 (minor), CYP2C9 (major), CYP2D6 (major), CYP2E1 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C8 (moderate), CYP2C9 (weak)

Drug Interactions

(For additional information: Launch drug interactions program)

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. 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. Risk D: Consider therapy modification

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Risk X: Avoid combination Anastrozole: Tamoxifen may decrease the serum concentration of Anastrozole. Risk D: Consider therapy modification

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Risk D: Consider therapy modification

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Risk D: Consider therapy modification

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. Risk D: 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. Risk X: Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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). Risk D: Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. 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). Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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. Risk D: Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. 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. Risk D: Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Risk D: Consider therapy modification

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

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

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

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. 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. Risk D: Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Risk D: Consider therapy modification

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

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

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Risk C: Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Risk C: 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. Risk X: Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

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

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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. Risk D: Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

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

Food Interactions Grapefruit juice may decrease the metabolism of tamoxifen. Management: Avoid grapefruit juice.

Pregnancy Risk Factor D (show table)

Pregnancy Implications 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.

Breast-Feeding Considerations It is not known if tamoxifen is excreted in breast milk, however, it has been shown to inhibit lactation. Due to the potential for adverse reactions, women taking tamoxifen should not breast-feed.

Dietary Considerations Tablets and oral solution may be taken with or without food. Avoid grapefruit and grapefruit juice.

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); 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)

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 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

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

Time to peak, serum:

Children 2 to 10 years (female): ~8 hours

Adults: ~5 hours

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

Pricing: US Solution (Soltamox Oral)

10 mg/5 mL (150 mL): $688.42

Tablets (Tamoxifen Citrate Oral)

10 mg (60): $113.64

20 mg (30): $113.64

Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single manufacturer of the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for reimbursement or purchasing functions. Pricing data is updated monthly.

International Brand Names Bilem (TH); Citofen (HR); Crisafeno (PY); Cytofen (LK); Cytotam-10 (ET); Diemon (AR); Fenahex (PH); Genox (AU, NZ); Ginarsan (PE); Ginarsan Forte (PE); Gynatam (PH); Gyraxen (PH); Kessar (CL, FR, GR, IT, ZA); Mamofen (IN); Medtax (PH); Moxafen (AE, BH, CY, EG, IL, IQ, IR, JO, KR, KW, LB, LY, OM, SA, SY, YE); Neophedan (ZA); Neophedan-10 (ZW); Nolvadex (AE, AT, AU, BB, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CI, CL, CR, CY, DE, DO, EG, ES, ET, FI, FR, GH, GM, GN, GR, GT, GY, HK, HN, HR, IE, IL, IN, IQ, IR, IT, JM, JO, KE, KR, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, NE, NG, NI, NL, NO, NZ, OM, PA, PK, PL, PR, PT, QA, SA, SC, SD, SE, SG, SL, SN, SR, SV, SY, TN, TR, TT, TW, TZ, UG, VE, VN, YE, ZM, ZW); Nolvadex D (LK, MT); Nolvadex-D (AU, CO, CU, EE, HK, IE, MY, NZ, PY, SG, TH, UY); Novofen (EC, HK, SG, TH, TW); Novofen Forte (BZ, GY, SR); Novofen-D (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Oncotamox (EC); Retaxim (HR); Soltamox (GB); Tadex (FI, TW); Tamec (CH); Tamifen (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Tamifine (VN); Tamizam (BE, LU); Tamofen (CN, DK, FI, HK, ID, IL, QA, TW); Tamofon (AE, JO); Tamona (BD); Tamophar (AE, BH, KW, QA, SA); Tamoplex (KR, PE, PH); Tamorex (KR); Tamosin (AU); Tamoxen (AU, BD); Tamoxi (IL); Tamoxifen-Eurogenerics (LU); Tamoxifen-Hexal (LU); Tamoxifen-ratioparm (LU); Tamoxifen-Teva (HU); Tamoxifen-Zeneca (LU); Tamoxis (LK); Tamoxit (LB); Taxus (EC, PE); Tecnofen (MX); Temolex (BD); Xifen (LK, PH); Zitazonium (CZ, HK, HU, PH, RU)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Adamopoulos DA, Nicopoulou S, Kapolla N, Karamertzanis M, Andreou E. The combination of testosterone undecanoate with tamoxifen citrate enhances the effects of each agent given independently on seminal parameters in men with idiopathic oligozoospermia. Fertil Steril. 1997;67(4):756-762. [PubMed 9093207] 2. Adamopoulos DA, Nicopoulou S, Kapolla N, Vassilopoulos P, Karamertzanis M, Kontogeorgos L. Endocrine effects of testosterone undecanoate as a supplementary treatment to menopausal gonadotropins or tamoxifen citrate in idiopathic oligozoospermia. Fertil Steril. 1995;64(4):818-824. [PubMed 7672156] 3. Adamopoulos DA, Pappa A, Billa E, Nicopoulou S, Koukkou E, Michopoulos J. Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia. Fertil Steril. 2003;80(4):914-920. [PubMed 14556812] 4. Aubert RE, Stanek EJ, Yao J, et al, “Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen With CYP2D6 Inhibitors,” J Clin Oncol, 2009, 27(18S):CRA508 [abstract CRA508 from 2009 ASCO Annual Meeting]. 5. Boccardo F, Rubagotti A, Battaglia M, et al. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol. 2005;23(4):808-815. [PubMed 15681525] 6. 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. [PubMed 11334921] 7. Bratherton DG, Brown CH, Bucha a R, et al, “A Comparison of Two Doses of Tamoxifen (Nolvadex) in Postmenopausal Women With Advanced Breast Cancer: 10 mg bd Versus 20 mg bd,” Br J Cancer, 1984, 50(2):199-205. [PubMed 6380554] 8. Burstein HJ, Prestrud AA, Seidenfeld J, et al, “American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women with Hormone Receptor-Positive Breast Cancer,” J Clin Oncol, 2010, 28(23):3784-96. [PubMed 20625130] 9. Buvat J, Buvat-Herbaut M, Marcolin G, Ardaens-Boulier K. Antiestrogens as treatment of female and male infertilities. Horm Res. 1987;28(2-4):219-229. [PubMed 3331375] 10. 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. [PubMed 7835785] 11. Davies C, Pan H, Godwin J, et al, “Long-Term Effects of Continuing Adjuvant Tamoxifen to 10 Years versus Stopping at 5 Years After Diagnosis of Oestrogen Receptor-Positive Breast Cancer: ATLAS, A Randomized Trial,” Lancet, 2012 [epub ahead of print]. [PubMed 23219286] 12. Dezentje V, Van Blijderveen NJ, Gelderblom H, et al, “Concomitant CYP2D6 Inhibitor Use and Tamoxifen Adherence in Early-Stage Breast Cancer: A Pharmacoepidemiologic Study,” J Clin Oncol, 2009, 27(18S):CRA509 [abstract CRA509 from 2009 ASCO Annual Meeting]. 13. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), “Effects of Chemotherapy and Hormonal Therapy for Early Breast Cancer on Recurrence and 15-Year Survival: An Overview of the Randomised Trials,” Lancet, 2005, 365(9472):1687-717. [PubMed 15894097] 14. 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. [PubMed 18309940] 15. 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. [PubMed 12915825] 16. Fiorica JV, Brunetto VL, Hanjani P, et al, “Phase II trial of Alternating Courses of Megestrol Acetate and Tamoxifen in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study,” Gynecol Oncol, 2004, 92(1):10-4 [PubMed 14751131] 17. Fradet Y, Egerdie B, Andersen M, et al. Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study. Eur Urol. 2007;52(1):106-114. [PubMed 17270340] 18. Goetz MP, Kamal A, and Ames MM, “Tamoxifen Pharmacogenomics: The Role of CYP2D6 as a Predictor of Drug Response,” Clin Pharmacol Ther, 2008, 83(1):160-6. [PubMed 17882159] 19. Hansmann A, Adolph C, Vogel T, et al, “High-Dose Tamoxifen and Sulindac as First-Line Treatment for Desmoid Tumors,” Cancer, 2004, 100(3):612-20. [PubMed 14745880] 20. Hatch KD, Beecham JB, Blessing JA, et al, “Responsiveness of Patients With Advanced Ovarian Carcinoma to Tamoxifen. A Gynecologic Oncology Group Study of Second-Line Therapy in 10 Patients,” Cancer, 1991, 68(2):269-71. [PubMed 2070324] 21. Hochner-Celnikier D, Anteby E, and Yael 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. [PubMed 7726283] 22. Janus N, Launay-Vacher V, Thyss A, et al, “Management of Anticancer Treatment in Patients Under Chronic Dialysis: Results of the Multicentric CANDY (CANcer and DialYsis) Study,” Ann Oncol, 2013, 24(2):501-7. [PubMed 23038759] 23. Jin Y, Desta Z, Stearns V, et al, “CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment,” J Natl Cancer Inst, 2005, 97(1):30-9. [PubMed 15632378] 24. Jordan VC, "Tamoxifen: A Most Unlikely Pioneering Medicine," Nat Rev Drug Discov, 2003, 2(3):205-13. [PubMed 12612646] 25. Jubelirer SJ, “The Management of Menopausal Symptoms in Women With Breast Cancer,” W V Med J, 1995, 91(2):54-6. [PubMed 7610643] 26. Kelly CM, Juurlink DN, Gomes T, et al, “Selective Serotonin Reuptake Inhibitors and Breast Cancer Mortality in Women Receiving Tamoxifen: A Population Based Cohort Study,” BMJ, 2010, 340:c693. [PubMed 20142325] 27. Khatcheressian JL, Wolff AC, Smith TJ, et al, “American Society of Clinical Oncology 2006 Update of the Breast Cancer Follow-Up and Management Guidelines in the Adjuvant Setting,” J Clin Oncol, 2006, 24(31):5091-7. [PubMed 17033037] 28. LiVolsi VA, Salhany KE, and Dowdy YG, “Endocervical Adenocarcinoma in Tamoxifen-Treated Patient,” Am J Obstet Gynecol, 1995, 172(3):1065. [PubMed 7892857] 29. Markman M, Iseminger KA, Hatch KD, et al, “Tamoxifen in Platinum-Refractory Ovarian Cancer: A Gynecologic Oncology Group Ancillary Report,” Gynecol Oncol, 1996, 62(1):4-6. [PubMed 8690289] 30. National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Breast Cancer,” Version 2.2013. Available at http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf 31. National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Breast Cancer Risk Reduction, Version 1.2013.” Available at http://www.nccn.org/professionals/physician_gls/PDF/breast_risk.pdf 32. 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. [PubMed 10819701] 33. Rao GG and Miller DS, “Hormonal Therapy in Epithelial Ovarian Cancer,” Expert Rev Anticancer Ther, 2006, 6(1):43-7. [PubMed 16375643] 34. 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. [PubMed 7752269] 35. Schroth W, Goetz MP, Hamann U, et al, “Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen,” JAMA, 2009, 302(13):1429-36. [PubMed 19809024] 36. Sideras K, Ingle JN, Ames MM, et al, “Coprescription of Tamoxifen and Medications That Inhibit CYP2D6,” J Clin Oncol, 2010, 28(16):2768-76. [PubMed 20439629] 37. Steiner AZ, Terplan M, and Paulson RJ, “Comparison of Tamoxifen and Clomifene Citrate for Ovulation Induction: A Meta-Analysis,” Hum Reprod, 2005, 20(6):1511-5. [PubMed 15845599] 38. Tamoxifen citrate [prescribing information]. Corona, CA: Watson Laboratories; July 2011.

39. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, “Consensus on Infertility Treatment Related to Polycystic Ovary Syndrome,” Fertil Steril, 2008, 89(3):505-22. [PubMed 18243179] 40. Thigpen T, Brady MF, Homesley HD, et al, “Tamoxifen in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study,” J Clin Oncol, 2011, 19(2):364-7. [PubMed 11208827] 41. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016. 42. 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. [PubMed 16446340] 43. Visvanathan K, Chlebowski RT, Hurley P, et al, “American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction,” J Clin Oncol, 2009, 27(19):3235-58. [PubMed 19470930] 44. 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. [PubMed 15545664]

Topic 9972 Version 165.0