Tamoxifen


Generic Medicine Info
Indications and Dosage
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
Genotype  Implications  Therapeutic 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).
Patient Counseling Information
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.
Overdosage
Symptoms: Acute neurotoxicity (e.g. dizziness, tremor, hyperreflexia, unsteady gait), QT prolongation. Management: Symptomatic treatment.
Drug Interactions
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: 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

Chemical Structure Image
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.
ATC Classification
L02BA01 - tamoxifen ; Belongs to the class of anti-estrogens. Used in treatment of neoplastic diseases.
References
Goetz MP, Sangkuhl K, Guchelaar HJ et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. CPIC Guidelines. 2018;00(00):1-8. doi: 10.1002/cpt.1007. Accessed 06/11/2020

Annotation of CPIC Guideline for Tamoxifen and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 06/11/2020.

Annotation of HCSC Label for Tamoxifen and CYP2D6, ESR1, ESR2. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 06/11/2020.

Anon. CYP2D6 – Tamoxifen (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 10/11/2020.

Anon. Tamoxifen. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 05/11/2020.

Anon. Tamoxifen. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/11/2020.

Buckingham R (ed). Tamoxifen Citrate. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/11/2020.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 06/11/2020.

Joint Formulary Committee. Tamoxifen. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/11/2020.

Novaldex (AstraZeneca). MHRA. https://products.mhra.gov.uk/. Accessed 05/11/2020.

Novaldex D (AstraZeneca UK Limited). MHRA. https://products.mhra.gov.uk/. Accessed 05/11/2020.

Novaldex-D Tablets (AstraZeneca Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 05/11/2020.

Soltamox Liquid (Fortovia Therapeutics Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 05/11/2020.

Tamoxen Tablets (Meyer Pharmaceuticals Limited). MIMS Hong Kong. http://www.mims.com/hongkong. Accessed 09/11/2020.

Tamoxifen 40 mg Film-Coated Tablets (Wockhardt UK Limited). MHRA. https://products.mhra.gov.uk/. Accessed 05/11/2020.

Tamoxifen Citrate Tablet, Film Coated (Aurobindo Pharma Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 05/11/2020.

Tamoxifen Rosemont 10mg/5ml Oral Solution (Rosemont Pharmaceuticals Ltd). MHRA. https://products.mhra.gov.uk/. Accessed 05/11/2020.

Disclaimer: This information is independently developed by MIMS based on Tamoxifen from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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