Serious and life-threatening events from the use of tamoxifen include uterine malignancies, stroke, and pulmonary embolism. Fatal cases of each type of event have occurred.
Incidence rates per 1,000 woman-years for these events were estimated from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial in women at high risk for breast cancer:
Endometrial adenocarcinoma: 2.20 for tamoxifen versus 0.71 for placebo
Uterine sarcoma: 0.17 for tamoxifen versus 0.04 for placebo
Stroke: 1.43 for tamoxifen versus 1.00 for placebo.
Pulmonary embolism: 0.75 for tamoxifen versus 0.25 for placebo
Discuss the potential benefits of tamoxifen versus the potential risks of these serious events with women at high risk for breast cancer and women with ductal carcinoma in situ (DCIS) considering tamoxifen to reduce the risk of developing breast cancer. For most patients already diagnosed with breast cancer, the benefits of tamoxifen outweigh its risks.
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, risk reduction (pre- and postmenopausal high-risk females): Oral: 20 mg once daily for 5 years.
Breast cancer, treatment: Oral:
Adjuvant therapy: 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.
Ductal carcinoma in situ (DCIS) (females), to reduce the risk for invasive breast cancer: 20 mg once daily for 5 years.
Metastatic: 20 mg once daily. Although the manufacturer's labeling recommends dosing of 20 to 40 mg daily (with doses >20 mg administered in 2 divided doses), 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).
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 males with prostate cancer receiving bicalutamide. Use has also been reported in patients with idiopathic gynecomastia.
Idiopathic male infertility (off label use): Oral: 20 to 30 mg once daily for 3 to 6 months, then proceed to assisted reproductive therapy if pregnancy has not been achieved (Chua 2013; Colpi 2018).
Induction of ovulation (in breast cancer patients) (off-label use): Oral: 60 mg daily starting on the second or third day of the menstrual cycle (in combination with low-dose follicle-stimulating hormone [FSH]), and continued until the day of hCG administration (Oktay 2005).
Mastalgia, severe (off-label use): Oral: 10 mg once daily for 3 months; may consider further treatment if relapse occurs (Fentiman 1988).
Ovarian cancer, advanced and/or recurrent (off-label use): Oral: 20 mg twice daily (Hatch 1991; Markman 1996).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
Chronic dialysis: No dosage adjustment necessary (Janus 2013).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(For additional information see "Tamoxifen: Pediatric drug information")
McCune-Albright syndrome; precocious puberty: Limited data available: Children 2 to 10 years: Oral: 20 mg once daily; dosing based on a trial of 25 girls ≤10 years of age (range: 2.9 to 10.9 years) who received treatment for 1 year; frequency of vaginal bleeding episodes were decreased; growth velocity was significantly decreased prior to pretreatment rates as was skeletal maturation; ovarian and uterine volumes were increased; further studies are needed (Eugester 2003)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling (not studied).
Chronic dialysis: No dosage adjustment necessary based on experience in adult patients (Janus 2013).
There are no dosage adjustments provided in the manufacturer’s labeling; the effect of hepatic dysfunction on tamoxifen pharmacokinetics has not been determined.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Soltamox: 10 mg/5 mL (150 mL) [sugar free; contains alcohol, usp, propylene glycol; licorice flavor]
Soltamox: 10 mg/5 mL (150 mL) [sugar free; contains alcohol, usp, propylene glycol; licorice-aniseed flavor]
Generic: 10 mg, 20 mg
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Nolvadex D: 20 mg
Generic: 10 mg, 20 mg
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:
Oral: Administer tablets or oral solution orally with or without food. Use supplied dosing cup for oral solution.
Oral: Administer tablets or oral solution with or without food; use supplied dosing cup for oral solution.
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).
Breast cancer, risk reduction: Risk reduction in females at high risk: To reduce the incidence of breast cancer in adult females at high risk for breast cancer
Breast cancer, treatment:
Adjuvant treatment: Adjuvant treatment of adult patients with early stage estrogen receptor-positive breast cancer; to reduce the incidence of contralateral breast cancer in adult patients when used as adjuvant therapy for the treatment of breast cancer
Ductal carcinoma in situ: To reduce the risk of invasive breast cancer in adult females with ductal carcinoma in situ (following breast surgery and radiation)
Metastatic breast cancer: Treatment of adult patients with estrogen receptor-positive metastatic breast cancer
Desmoid tumors, progressive or recurrent; Endometrial carcinoma, recurrent, metastatic, or high-risk (endometrioid histologies only); Gynecomastia; Idiopathic male infertility; Induction of ovulation (in breast cancer patients); Mastalgia, severe; Ovarian cancer, advanced and/or recurrent
Tamoxifen may be confused with pentoxifylline, raloxifene, Tambocor, tamsulosin, temazepam, toremifene
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Hot flashes commonly occur and can drastically affect the quality of life in females taking tamoxifen. Because many females will take tamoxifen for more than 5 years for the treatment or prevention of breast cancer, the risk of nonadherence or discontinuation related to this condition should be considered (Ref). Females who associate tamoxifen treatment with hot flashes are 3 to 4 times more likely to report severe symptoms (Ref). Severity of symptoms decline during the last 2 years of treatment and within 3 to 6 months after tamoxifen therapy is discontinued (Ref).
Mechanism: Non-dose-related; exact mechanism unknown; thought to be due to antiestrogen effects in the CNS affecting the regulation of core body temperature (Ref).
Onset: Varied; occurrence and severity increase over the first 3 months of therapy and remain consistent throughout therapy with highest rates (over 90%) in the first 2 years (Ref).
• Obesity (Ref)
• Smoking, caffeine, and alcohol (Ref)
• Depression and anxiety (Ref)
• Being employed (Ref)
• Previous chemotherapy (Ref)
Ocular effects (including corneal deposits, cataract, epithelial keratopathy, macular edema, maculopathy, optic neuritis, retinal thrombosis, retinopathy, and vision color changes) have been reported in patients taking tamoxifen (Ref). An increased need for cataract surgery has also been reported (Ref).
Mechanism: Dose and time-related; retinal toxicity may occur due to axonal degeneration or a mechanism related to binding polar lipids resulting in drug-lipid accumulation (Ref). Chloride channel blockage in the lens has been proposed as the mechanism for cataract induction (Ref).
• Long duration of therapy (Ref).
• While extremely high doses (240 to 320 mg/day) have been linked to ocular toxicity, doses ranging from 20 to 40 mg/day are also associated with visual function abnormalities and ocular effects (Ref)
Serious and life-threatening thromboembolic events (some fatal) have occurred with tamoxifen, including cerebrovascular accident (stroke), deep vein thrombosis (DVT), and pulmonary embolism (PE). Risk normalized after discontinuation of therapy (Ref).
Mechanism: Dose-related; not clearly understood; proposed that estrogenic effects increase the risk. Influences anticoagulant proteins, such as antithrombin, protein S, and protein C similar to postmenopausal estrogen (Ref).
Onset: Delayed; PE events occurred at an average of 27 months after tamoxifen initiation (range: 2 to 60 months). DVT occurred at an average of 19 months (range: 2 to 57 months). Stroke occurred at an average of 30 months (range: 1 to 63 months).
• Coadministration with chemotherapy
• Doses ≥20 mg/day (Ref)
• Age >49 years (Ref)
• First 24 months of use (Ref)
• High BMI (≥25 kg/m2) (Ref)
• History of surgery, fracture, and immobilization (Ref)
• Factor V Leiden mutations (Ref)
• Smoking (Ref)
• Personal history/family history of venous thromboembolism (Ref)
• Elevated blood pressure or cholesterol (Ref)
Uterine malignancies have been reported with tamoxifen, including fatal cases of endometrial carcinoma and uterine carcinoma (sarcoma). The increased risk of endometrial cancer continues during therapy with tamoxifen but decreases after treatment discontinuation (Ref).
Mechanism: Dose- and time-related; in postmenopausal uterine and endometrial tissue, the estrogenic effects of tamoxifen are associated with endometrial polyp formation, endometrial hyperplasia, and uterine fibroids which lead to increased risk of endometrial carcinoma and uterine sarcoma (Ref). Other mechanisms related to biomolecular pathways and signaling pathways have been suggested (Ref).
Onset: Delayed; endometrial carcinoma has been reported as early as 6 months after initiation to 6 years after discontinuing tamoxifen (Ref). Uterine sarcomas have been reported to develop a median of 6 to 9 years after initiation of tamoxifen, with a case developing 20 years after initiation of therapy (Ref).
• Cumulative dose (Ref)
• Prior estrogen replacement therapy (Ref)
• Obesity (Ref)
• History of endometrial abnormalities (Ref)
• Duration of therapy of ≥2 years (Ref)
• Postmenopausal females, especially those without hysterectomy and >49 years of age (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Cardiovascular: Flushing (33%), hypertension (11%), peripheral edema (11%), vasodilation (41%)
Dermatologic: Skin changes (6% to 19%), skin rash (13%)
Endocrine & metabolic: Amenorrhea (16%), fluid retention (32%), hot flash (19% to 80% [placebo: 8% to 68%]), weight loss (23%)
Gastrointestinal: Nausea (5% to 26%), nausea and vomiting (12%)
Genitourinary: Irregular menses (13% to 25%), vaginal discharge (12% to 55%), vaginal hemorrhage (6% to 23%)
Hematologic & oncologic: Lymphedema (11%)
Nervous system: Depression (2% to 12%), fatigue, mood changes (12% to 18%), pain (3% to 16%)
Neuromuscular & skeletal: Arthralgia (11%), arthritis (14%), asthenia
Respiratory: Pharyngitis (14%)
1% to 10%:
Cardiovascular: Chest pain (5%), deep vein thrombosis (≤2% [placebo: 0.2% to 0.3%]), edema (4%), ischemic heart disease (3%), venous thromboembolism (5%)
Dermatologic: Alopecia (5%), diaphoresis (6%)
Endocrine & metabolic: Hypercholesterolemia (3%), infrequent uterine bleeding (9%), menstrual disease (6%), ovarian cyst (3%), weight gain (9%)
Gastrointestinal: Abdominal cramps (1%), abdominal pain (9%), anorexia (1%), constipation (4% to 8%), diarrhea (7%), dyspepsia (6%)
Genitourinary: Leukorrhea (9%), mastalgia (6%), urinary tract infection (10%), vaginitis (5%), vulvovaginitis (5%)
Hematologic & oncologic: Anemia (5%), neoplasm (5%; second primary), thrombocytopenia (2% to 10%)
Hepatic: Increased serum aspartate aminotransferase (5%), increased serum bilirubin (2%)
Hypersensitivity: Hypersensitivity reaction (3%)
Infection: Infection, sepsis
Nervous system: Anxiety (6%), dizziness (8%), headache (8%), insomnia (9%), paresthesia (5%)
Neuromuscular & skeletal: Arthropathy (5%), back pain (10%), bone fracture (7%; premenopausal increased risk) (Kyvernitakis 2018), musculoskeletal pain (3%), myalgia (5%), ostealgia (6%), osteoporosis (7%)
Ophthalmic: Cataract (8% [placebo: 7%])
Renal: Increased serum creatinine (2%)
Respiratory: Bronchitis (5%), cough (4% to 9%), dyspnea (8%), flu-like symptoms (6%), sinusitis (5%), throat irritation (oral solution: 5%)
Miscellaneous: Cyst (5%)
Cardiovascular: Cerebrovascular accident (Fisher 2005; Lai 2017), pulmonary embolism (placebo: 0.09% to 0.2%), superficial thrombophlebitis
Hematologic & oncologic: Endometrial carcinoma (Cohen 1996; Fisher 2005)
Hepatic: Hepatic neoplasm
Cardiovascular: Portal vein thrombosis (Hsu 2015), retinal thrombosis (Demirci 2019; Onder 2013)
Dermatologic: Bullous pemphigoid, cutaneous lupus erythematosus (Andrew 2014), erythema multiforme, night sweats (Day 2001; Moon 2017), pruritus vulvae (Day 2001), Stevens-Johnson syndrome, toxic epidermal necrolysis (Madabhavi 2015)
Endocrine & metabolic: Decreased libido (Morales 2004; Mourits 2002), hypercalcemia (Legha 1981; Nikolic-Tomasevic 2001), hyperglycemia (Hozumi 1997; Kim 2014), hypertriglyceridemia (Liu 2003; Singh 2016), loss of libido (males) (Pemmaraju 2012; Wibowo 2016)
Gastrointestinal: Cholestasis (Blackburn 1984), dysgeusia (Schiffman 2018), pancreatitis (Singh 2016; Tey 2019)
Genitourinary: Dyspareunia (Mourits 2002), endometrial hyperplasia (Cheng 1997; Lindahl 2008), endometrial polyps (Cohen 1996; Neven 1998), endometriosis (Kraft 2006), impotence (Pemmaraju 2012), vaginal dryness (Mortimer 1999; Mourits 2002)
Hematologic & oncologic: Agranulocytosis (Ching 1992; Herrscher 2020), leukopenia, malignant neoplasm of ovary (Cohen 1996; Ohara 2002), malignant neoplasm of uterus (Kloos 2002; Yildirim 2005), neutropenia (Herrscher 2020), pancytopenia (Mitani 2006), tumor flare (during treatment of metastatic breast cancer; generally resolves with continuation; includes increased lesion size and erythema) (Mulvenna 1999; Plotkin 1978), tumor lysis syndrome (Cech 1986), uterine carcinoma (sarcoma), uterine fibroids (Polin 2008)
Hepatic: Hepatic necrosis (Ching 1992; Storen 2000), hepatitis (Oien 1999; Pinto 1995), liver steatosis (Roy 2019; Saphner 2009)
Hypersensitivity: Angioedema (Bork 2017; Rousset-Jablonski 2009)
Nervous system: Tumor pain (during treatment of metastatic breast cancer; generally resolves with continuation) (Mulvenna 1999)
Neuromuscular & skeletal: Subacute cutaneous lupus erythematosus (Andrew 2014)
Ophthalmic: Corneal deposits (Muftuoglu 2006; Tarafdar 2012), epithelial keratopathy (Noureddin 1999; Pavlidis 1992), macular edema (Murray 1998; Zafeiropoulos 2014), maculopathy (Bommireddy 2016; Srikantia 2010), optic neuritis (Colley 2004; Noureddin 1999), retinal hole without detachment (macula hole) (Cronin 2005), retinal pigment changes (Noureddin 1999), retinopathy (Georgalas 2013; Wang 2015), vision color changes (Eisner 2011; Salomao 2007)
Respiratory: Eosinophilic pneumonitis (Kwon 2019), interstitial pneumonitis (Ahmed 2016), pulmonary fibrosis (Bentzen 1996), pulmonary injury (Etori 2017)
Known hypersensitivity (eg, angioedema, serious skin reactions) 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 risk reduction of invasive breast cancer after treatment of ductal carcinoma in situ [DCIS]).
Canadian labeling: Additional contraindications (not in the US labeling): History of stroke or at increased risk for developing endometrial cancer (when used in the prevention setting [not approved indication]); pregnancy.
• 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 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: Hypercholesterolemia and postmarketing cases of hyperlipidemias have been reported. Periodic monitoring of cholesterol and triglycerides may be indicated in patients with preexisting hyperlipidemias.
• 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 tamoxifen if hypercalcemia is severe.
Concurrent drug therapy issues:
• Selective serotonin reuptake inhibitors (SSRI): Concomitant use with select SSRIs may result in decreased tamoxifen efficacy. Strong CYP2D6 inhibitors (eg, fluoxetine, paroxetine) 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).
• 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).
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP, 1997; Shehab, 2009).
Substrate of CYP2A6 (minor), CYP2B6 (minor), CYP2C9 (minor), CYP2D6 (major), CYP2E1 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C9 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Anastrozole: Tamoxifen may decrease the serum concentration of Anastrozole. Risk X: Avoid combination
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: 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. Risk C: 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 to the use of moderate CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with reduced clinical effectiveness of tamoxifen. 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. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tamoxifen. Risk C: 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. Risk X: Avoid combination
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Fluoroestradiol F18: Estrogen Receptor Antagonists may diminish the diagnostic effect of Fluoroestradiol F18. Management: Image patients with fluoroestradiol F-18 prior to starting systemic endocrine therapies that block the estrogen receptor. Use of fluoroestradiol F-18 should not delay indicated treatment. Risk D: Consider therapy modification
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
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
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Letrozole: Tamoxifen may decrease the serum concentration of Letrozole. Risk C: Monitor therapy
Mipomersen: Tamoxifen may enhance the hepatotoxic effect of Mipomersen. 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
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). Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: 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. Risk D: Consider therapy modification
TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase the serum concentration of TOLBUTamide. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Tamoxifen may increase the serum concentration of Vitamin K Antagonists. Risk X: Avoid combination
Grapefruit juice may decrease the metabolism of tamoxifen. Management: Monitor for increased effects/toxicity with concomitant use.
Evaluate pregnancy status prior to use in patients who may become pregnant. Treatment should be initiated during menstruation or immediately after a negative pregnancy test.
Patients who may become pregnant should use effective nonhormonal contraception or barrier contraceptives during tamoxifen therapy. Recommendations for how long contraception should continue once tamoxifen is discontinued vary. The US product labeling recommends contraception be continued for 2 months following the last tamoxifen dose; other sources suggest contraception be continued for 3 to 6 months (ESMO [Lambertini 2020]; ESMO [Peccatori 2013]) or longer (Nolvadex-D Canadian product monograph).
Tamoxifen may induce ovulation (Steiner 2005) or cause menstrual cycle irregularities. Based on animal data, tamoxifen may impair embryo implantation in patients who may become pregnant, but may not reliably cause infertility, even if menstrual cycles are irregular.
Use of tamoxifen has been considered for the treatment of idiopathic male infertility; however, benefits may be limited (ASRM [Schlegel 2021]; Colpi 2018).
Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to tamoxifen may cause fetal harm. However, available data are insufficient to establish a causal relationship; no pattern of birth defects has been observed, and the long-term effects of tamoxifen on development are not known (Braems 2011; Buonomo 2020; Schuurman 2019). There have been reports of vaginal bleeding, birth defects, spontaneous abortions and fetal death following use in pregnancy. Tamoxifen use during pregnancy may have a potential long-term risk to the fetus of a diethylstilbestrol (DES)-like syndrome (based on animal data).
The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy; the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). Use of tamoxifen during pregnancy is contraindicated (ESMO [Peccatori 2013]).
A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).
Tamoxifen is present in breast milk (Peccatori 2020).
The presence of tamoxifen in breast milk was evaluated in a breastfeeding woman diagnosed with breast cancer. Breast milk samples were collected prior to the first dose and over the next 23 days of therapy (total 39 samples). Tamoxifen was present in breast milk after the first dose and concentrations significantly increased over 3 weeks. The N-desmethyl tamoxifen metabolite was detected in breast milk by day 6 and concentrations also increased over time. Two other active metabolites were also present. Tamoxifen concentrations in the maternal plasma were not evaluated and steady state concentrations were likely not reached; therefore, breast milk concentrations may have continued to rise. Authors of the study concluded clinically significant concentrations of tamoxifen are likely present in breast milk (Peccatori 2020).
Tamoxifen has been shown to inhibit early postpartum milk production; effects on established milk production is not known. Breastfeeding during tamoxifen therapy is contraindicated by some guidelines (ABM [Johnson 2020]). Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 3 months following the last tamoxifen dose.
CBC with platelets, serum calcium, liver function tests; triglycerides and cholesterol (in patients with preexisting hyperlipidemias); INR and PT (in patients on vitamin K antagonists); pregnancy test (prior to treatment in females of reproductive potential); monitor for and promptly evaluate abnormal vaginal bleeding, menstrual irregularities, changes in vaginal discharge, or pelvic pain/pressure; breast exam (baseline and routine), gynecologic exam (baseline and annually, continuing after discontinuation of therapy), mammogram (baseline and routine); signs/symptoms of thromboembolism (eg, stroke, DVT [leg swelling, tenderness], or PE [shortness of breath]); ophthalmic exam (if vision problem or cataracts); bone mineral density (premenopausal women). Monitor adherence.
Tamoxifen is a selective estrogen receptor modulator (SERM) that 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: Widely distributed to most tissues, particularly tissues that inhibit estrogen receptors (Perry 2012)
Protein binding: Highly protein bound (Perry 2012)
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
Bioavailability: Tamoxifen oral solution is bioequivalent to tamoxifen tablets
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: ~65% (primarily fecal); <30% as unchanged drug and unconjugated metabolites
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
Solution (Soltamox Oral)
10 mg/5 mL (per mL): $5.54
Tablets (Tamoxifen Citrate Oral)
10 mg (per each): $1.89
20 mg (per each): $3.79
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