Oral Reduction of breast cancer incidence in women at high risk
Adult: 20 mg daily for 5 years.
Oral Breast cancer
Adult: Usual dose: 20 mg daily, given as a single dose or in 2 divided doses. Doses of up to 40 mg daily may be given in advanced or metastatic cases; however, no additional clinical benefit has been demonstrated.
Oral Anovulatory infertility
Adult: In women with regular menstruation, but with anovular cycles: Initially, 20 mg daily given on days 2-5 of the menstrual cycle. If initial treatment course is unsuccessful, doses may be increased during subsequent menstrual periods to 40 mg then to 80 mg daily. In women with irregular menstruation: Initial course may begin on any day; if there is no response, a subsequent treatment course may start 45 days later with the dose increased to 40 mg then to 80 mg daily. If patient responds with menstruation, then the next course is started on the 2nd day of the cycle.
Special Patient Group
Pharmacogenomics:
Tamoxifen is metabolised by CYP2D6 enzyme into 4-hydroxytamoxifen and further to endoxifen (metabolite with higher potency than the parent drug). Genetic polymorphism of CYP2D6 gene may affect the efficacy of tamoxifen. CYP2D6 genotyping test may be considered prior to initiation of therapy.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of January 2018:
Phenotype and Genotype
Implications
Recommendations
CYP2D6 ultrarapid metaboliser
Carriers of duplications of functional alleles e.g. *1/*1xN,
*1/*2xN, *2/*2xN
Therapeutic endoxifen levels.
Avoid concomitant use with moderate to strong CYP2D6
inhibitors. No dose adjustment needed.
CYP2D6 normal metaboliser
Carriers of 2 normal function alleles or 1 normal
function and 1 decreased function allele e.g. *1/*1, *1/*2, *1/*9, *1/*41,
*2/*2
Therapeutic endoxifen levels.
Avoid concomitant use with moderate to strong CYP2D6
inhibitors. No dose adjustment needed.
CYP2D6 intermediate metaboliser
Carriers of 1 decreased function and 1 non-functional
allele e.g. *4/*10, *4/*41, *5/*9
Patient may have lower endoxifen concentration and may
have higher risk of breast cancer recurrence, event-free and recurrence-free
survival.
Consider aromatase inhibitor therapy in postmenopausal
women; or aromatase inhibitor with ovarian function suppression therapy in
premenopausal women. If contraindicated to aromatase inhibitor, may consider
increasing tamoxifen dose to 40 mg daily. Avoid concomitant use with CYPD26
strong to weak inhibitors.
CYP2D6 poor metaboliser
Carriers of non-functional alleles e.g. *3/*4,
*4/*4, *5/*5, *5/*6
Patient may have lower endoxifen concentration and may
have higher risk of breast cancer recurrence, event-free and recurrence-free
survival.
Recommend aromatase inhibitor therapy in
postmenopausal women; or aromatase inhibitor with ovarian function suppression
therapy in premenopausal women. If contraindicated to aromatase inhibitor, may
increase tamoxifen dose to 40 mg daily.
Administration
May be taken with or without food.
Contraindications
History of DVT or pulmonary embolism (when used for treatment of infertility, and risk reduction of breast cancer in high-risk women). Pregnancy and lactation. Concurrent use with anastrozole. Concomitant coumarin-type anticoagulant therapy (when used in risk reduction of breast cancer in high-risk women).
Special Precautions
Patient with risk factors for thromboembolic events (e.g. family history of venous thrombosis, smoking, obesity); pre-menopausal women. Patient undergoing major surgery or prolonged immobility (refer to detailed product guideline for recommendations on dosing interruption or discontinuation). CYP2D6 intermediate and poor metabolisers.
Adverse Reactions
Significant: Bone marrow suppression (e.g. thrombocytopenia, leucopenia, neutropenia, pancytopenia); hepatocellular carcinoma, elevated transaminases; ocular effects (e.g. retinal vein thrombosis, retinopathy, corneal changes, colour perception changes, cataracts); changes in bone mineral density, hypercholesterolaemia, hyperlipidaemia, hypercalcaemia; local disease flare, increased bone and tumour pain; abnormal gynaecological symptoms (e.g. endometrial hyperplasia, polyps, endometriosis, uterine fibroids, ovarian cysts, amenorrhoea, menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure). Rarely, radiation recall (reversible). Blood and lymphatic system disorders: Anaemia. General disorders and administration site conditions: Fatigue, asthenia. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, constipation, dysgeusia. Immune system disorders: Hypersensitivity reactions. Investigations: Increased triglycerides. Metabolism and nutrition disorders: Fluid retention. Musculoskeletal and connective tissue disorders: Myalgia, leg cramp, arthralgia. Nervous system disorders: Headache, light-headedness, dizziness, paraesthesia, ischaemic cerebrovascular events. Psychiatric disorders: Mood disturbances, depression. Reproductive system and breast disorders: Pruritus vulvae. Respiratory, thoracic and mediastinal disorders: Pharyngitis. Skin and subcutaneous tissue disorders: Rash, alopecia. Vascular disorders: Hot flushes, hypertension. Potentially Fatal: Thromboembolic events (e.g. stroke, DVT, pulmonary embolism), uterine malignancies (e.g. endometrial adenocarcinoma, uterine sarcoma), severe hepatic abnormalities (e.g. fatty liver, cholestasis, hepatitis, hepatic necrosis).
This drug may cause visual disturbances, light-headedness, and fatigue; if affected, do not drive or operate machinery.
Monitoring Parameters
Evaluate pregnancy status, and calculate patient’s risk for developing breast cancer according to local guidelines (for the reduction of cases in women at high risk) before treatment initiation. May consider CYP2D6 gene testing prior therapy. Monitor CBC with platelets, serum Ca, LFTs, triglycerides and cholesterol (in patient with hyperlipidaemia) periodically; abnormal gynaecologic symptoms (e.g. abnormal vaginal bleeding, menstrual irregularities, pelvic pain or pressure); bone mineral density (particularly in premenopausal women); signs and symptoms of DVT and pulmonary embolism. Perform breast and gynaecologic exams, and mammogram at baseline and routinely thereafter; ophthalmic exam as necessary.
Increased risk of thromboembolic events with cytotoxic agents. May decrease plasma concentrations with CYP3A4 inducers (e.g. rifampicin, aminoglutethimide). Diminished therapeutic efficacy with CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, cinacalcet, bupropion, quinidine). Increased serum concentration with bromocriptine. Effectiveness of tamoxifen may be reduced by hormone replacement therapy or oral hormonal contraceptives. May reduce the plasma levels of letrozole. Potentially Fatal: Significantly increased effect of coumarin anticoagulants (e.g. warfarin).
Food Interaction
May decrease metabolism with grapefruit juice.
Lab Interference
May cause an elevation in T4 not accompanied by clinical hyperthyroidism. May cause variations with vagina smear karyopyknotic index and Pap smear estrogen effects
Action
Description: Mechanism of Action: Tamoxifen, a non-steroidal triphenylethylene derivative, produces a nuclear complex by competitively binding to estrogen receptors on tumours and other tissue targets, thus reducing DNA synthesis and inhibiting estrogen effects. It is cytostatic rather than cytocidal due to the accumulation of cells in G0 and G1 phases. Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration: 4-7 hours. Distribution: Widely distributed into most tissues (particularly those that inhibit estrogen receptors). Plasma protein binding: >99% mainly to albumin. Metabolism: Extensively metabolised in the liver via demethylation by CYP3A4/5 to N-desmethyltamoxifen (major) and hydroxylation by CYP2D6 to 4-hydroxytamoxifen (minor), which are both further metabolised to 4-hydroxy-N-desmethyltamoxifen (endoxifen). Excretion: Mainly via faeces (approx 65% as polar conjugates; <30% as unchanged drug and unconjugated metabolites); urine (small amounts). Elimination half-life: Approx 5-7 days (tamoxifen); approx 14 days (N-desmethyltamoxifen).
Chemical Structure
Tamoxifen Source: National Center for Biotechnology Information. PubChem Database. Tamoxifen, CID=2733526, https://pubchem.ncbi.nlm.nih.gov/compound/Tamoxifen (accessed on Jan. 23, 2020)
Storage
Tab: Store below 30°C. Protect from light. Oral solution: Store between 20-25°C. Do not freeze or refrigerate. Protect from light. Follow applicable procedures for receiving, handling, administration, and disposal.
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