Tamoxifen

L02B - Hormone antagonists and related agents ATC L02BA01 Small molecule approved 1977 Oral Prodrug Black-box warning

Active form: N-Desmethyltamoxifen.

JFDA label: Tamocit - 10mg tablets

⚠ Black-Box Warning

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

Mechanism of Action

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.

Indications

Approved

Breast cancer

Off-label

Desmoid tumors, progressive or recurrent
Endometrial carcinoma, recurrent, metastatic, or high-risk (endometrioid histologies only)
Gynecomastia
Induction of ovulation
Mastalgia, severe
Oligospermia
Ovarian cancer, advanced and/or recurrent
Precocious puberty (females) due to McCune-Albright syndrome

Contraindications

Source: Curated · Lexicomp

History of deep vein thrombosis or pulmonary embolism — relative CI Absolute
Known hypersensitivity to tamoxifen or any component of the formulation Absolute
Pregnancy (teratogenic; embryotoxic) Absolute
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]) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (15)

Very Common flushing · hypertension · peripheral edema · Vasodilatation

Common angina pectoris · Chest pain · deep vein thrombosis · edema · ischemic heart disease · myocardial infarction · venous thrombosis

Not Known Cerebrovascular accident · phlebitis (including superficial) · pulmonary embolism · thrombosis (retinal vein)

Nervous system disorders (10)

Very Common depression · Mood changes · pain

Common anxiety · dizziness · fatigue · headache · Insomnia · paresthesia

Not Known Tumor pain (during treatment of metastatic breast cancer; generally resolves with continuation)

Hepatobiliary disorders (5)

Common Increased serum AST · increased serum bilirubin

Not Known Hepatic necrosis · hepatitis · liver steatosis

Renal and urinary disorders (12)

Very Common Vaginal discharge · vaginal hemorrhage

Common Increased serum creatinine · leukorrhea · mastalgia · Urinary tract infection · vaginitis · vulvovaginitis

Not Known Endometrial hyperplasia · endometrial polyps · endometriosis · vaginal dryness

Blood and lymphatic system disorders (8)

Very Common Lymphedema

Common anemia · breast neoplasm · neoplasm · Thrombocytopenia

Not Known Endometrial carcinoma · tumor flare (during treatment of metastatic breast cancer; generally resolves with continuation; includes increased lesion size and erythema) · uterine fibroids

Immune system disorders (1)

Common Hypersensitivity reaction

Metabolism and nutrition disorders (11)

Very Common amenorrhea · fluid retention · Hot flash · menstrual disease · weight loss

Common hypercholesterolemia · Oligomenorrhea · ovarian cyst · weight gain

Not Known Hypercalcemia · hyperlipidemia

Gastrointestinal disorders (10)

Very Common Nausea · vomiting

Common abdominal cramps · Abdominal pain · anorexia · constipation · diarrhea · dyspepsia

Not Known Cholestasis · dysgeusia

Skin and subcutaneous tissue disorders (5)

Very Common Skin changes · skin rash

Common alopecia · Diaphoresis

Not Known Pruritus vulvae

Musculoskeletal and connective tissue disorders (10)

Very Common arthralgia · arthritis · Weakness

Common arthropathy · Back pain · bone fracture · musculoskeletal pain · myalgia · ostealgia · osteoporosis

Eye disorders (3)

Common Cataract

Not Known Corneal changes · retinopathy

Infections and infestations (2)

Common Infection · sepsis

General disorders and administration site conditions (1)

Common Cyst

Respiratory, thoracic and mediastinal disorders (7)

Very Common Pharyngitis

Common bronchitis · Cough · dyspnea · flu-like symptoms · sinusitis · throat irritation

Dosing

Source: Lexicomp

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 postmenopa

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

Refer to adult dosing.

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).

Warnings & Precautions

Source: Lexicomp

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

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

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

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.

Pregnancy & Lactation

Pregnancy

FDA category D Teratogenic

Avoid

Generally classified D or X depending on reference. Avoid in pregnancy. Effective contraception required during treatment and for 2 months after stopping

Lactation

Avoid

It is not known if tamoxifen is present in breast milk; however, it has been shown to inhibit lactation. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	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)

Clinical pearl

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)

Chemistry & Properties

Formula	C26H29NO
Molecular weight	371.52 g/mol
IUPAC name	2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine
CAS	10540-29-1
PubChem CID	2733526
InChIKey	`NKANXQFJJICGDU-QPLCGJKRSA-N`
logP	6.0 (XLogP 7.1)
Polar surface area	12.47 Å²
H-bond acceptors / donors	2 / 0
Drug-likeness (QED)	0.45
Lipinski violations	1

SMILES

CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB 0.92)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	Ki 0.8999999999999998 µM
CYP2B6	Substrate	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	IC₅₀ 14.299999999999986 µM
CYP2C9	Substrate	—
CYP2D6	Inhibitor	—
CYP2D6	Substrate	IC₅₀ 13.699999999999996 µM
CYP3A4	Inhibitor	—
CYP3A4	Substrate	Ki 0.20000000000000004 µM

Receptor binding (top 3)

Target	Action	Affinity
Estrogen receptor-α (ESR1)	Agonist	pKi 7.8
Estrogen receptor-β (ESR2)	Agonist	pKi 7.2
GPER (GPER1)	Agonist	pKi 6.0

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)OATP1B3 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abiraterone	major
Amiodarone	major
Amisulpride	major
Anagrelide	major
Anisindione	major
Arsenic trioxide	major
Bedaquiline	major
Bepridil	major
Bupropion	major
Cabozantinib	major
Carfilzomib	major
Celecoxib	major
Ceritinib	major
Chloroquine	major
Cimetidine	major
Cinacalcet	major
Cisapride	major
Citalopram	major
Clozapine	major
Colchicine	major
Crizotinib	major
Dacomitinib	major
Dalfopristin	major
Darifenacin	major
Dexfenfluramine	major
Dextropropoxyphene	major
Dicoumarol	major
Diphenhydramine	major
Disopyramide	major
Dofetilide	major
Dolasetron	major
Dronedarone	major
Droperidol	major
Duloxetine	major
Edoxaban	major
Efavirenz	major
Eliglustat	major
Escitalopram	major
Fedratinib	major
Fenfluramine	major

Showing 40 of 100+.

Registered Products (11)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
TAMOXIFEN EBEWE TABS	Tablet 10 mg	30 tab	Sabbagh Drug Store	3.180
Medotamifen TAB	Tablet 10 mg	30 tab	Al Hilal Drug Store	3.580
NOVOFEN 10 TABS	Tablet 10 mg	30 tab	JAWEDA INT. DRUD STORE	3.670
Tamocit -	Tablet 10 mg	30 tab pack varies	AL-RAM PHARMA.INDUS.CO.LTD/JORDAN	3.990
NOVOFEN 20 TABS	Tablet 20 mg	30 tab	JAWEDA INT. DRUD STORE	5.860
Medotamifen DS TAB	Tablet 20 mg	30 tab pack varies	Al Hilal Drug Store	6.350
Tamocit -20mg tablets	Tablet 20 mg	30 tab	AL-RAM PHARMA.INDUS.CO.LTD/JORDAN	7.500
Nolvadex D Tablet	Tablet 20 mg	30 tab	Shawi & Rushedat Drug Store	7.660
Tamocit -	Tablet 10 mg	500 tab pack varies	AL-RAM PHARMA.INDUS.CO.LTD/JORDAN	57.860
Tamocit -	Tablet 10 mg	1000 tab pack varies	AL-RAM PHARMA.INDUS.CO.LTD/JORDAN	113.050
Medotamifen DS TAB	Tablet 20 mg	1000 tab pack varies	Al Hilal Drug Store	179.850