tamoxifen (Novaldex, Soltamox)
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Introduction
Tradename: Novaldex.
Indications
- adjuvant therapy for breast cancer
- reduces the breast cancer mortality for 15 years after diagnosis[17]
- prevention of breast cancer in high-risk women (age 40-60) with strong family history or atypical cells on breast biopsy (see risk factors for breast cancer & management ...)
- ovarian cancer[21]
- endometrial cancer[21]
* Hypothetical benefits:
- decreased bone loss
- less cognitive impairment
- diminished cardiovascular risk
Benefit/risk
- 22 high-risk women needed to be treated with tamoxifen for 5 years to prevent 1 breast cancer over 20 years[7]
Dosage
- 10 mg PO BID or 20 mg QD post-menopausal women
- 20 mg PO BID or 40 mg QD pre-menopausal women
- duration of therapy
- survival benefit for up to 10 years of therapy in women with estrogen receptor positive breast cancer[17]
Tabs: 10 mg., Liquid (Soltamox)
Pharmacokinetics
- well absorbed orally
- metabolized by cyt P450 2D6 to active metabolite endoxifen & 4-hydroxytamoxifen[10][14][23]
- slowly metabolized in the liver by cyt P450 3A4 to several metabolites
- eliminated in the bile & feces
- elimination 1/2life is approximately 4 days for the parent compound & 10 days for active metabolites
elimination via liver
1/2life = 4 days
Monitor
- complete blood count (CBC)
- liver function tests periodically[13]
- eye exam at baseline & every 2 years
- annual gynecologic examination (risk of endometrial cancer)[20]
Adverse effects
- common (> 10%)
- nausea (mild)/vomiting
- weight gain
- flushing
- bone & tumor pain & local disease flare shortly after initiation of therapy (subsides rapidly)
- rash
- hepatotoxicity
- myelosuppression
- transient thrombocytopenia (24%)
- transient leukopenia less common
- anemia not common
- less common (1-10%)
- menstrual irregularities, lightheadedness, depression, dizziness, headache, lassitude, confusion, weakness, vaginal bleeding or discharge, endometriosis, hypercalcemia may occur in patients with bone metastases, galactorrhea, priapism
- other
- hot flashes
- decreased libido
- headache
- spot bleeding in females
- muscle weakness
- thromboembolism (1-2%)
- deep vein thrombosis (DVT)
- pulmonary embolism (PE)
- screening for Factor V Leiden & prothrombin G20210->A mutations does NOT predict risk[12]
- endometrial cancer
- relative risk 1.5; absolute risk 0.001/year > 55 years[6]
- combined risk for thromboembolism & endometrial cancer ~1% vs 10% reduction in mortality for elderly women with breast cancer treated with tamoxifen[18]
- ophthalmologic effects
- estrogen-dependent gynecologic problems*[11]
- endometrial hyperplasia (2.0)
- edometrial polys (2.0)
- endometriosis (2.0)
- leiomyomas (1.3)
- ovarian cysts in premenopausal women (1.5)
- increased likelihood of procedures
- currettage (2.0)
- hysterectomy (1.7)
- bilateral oophorectomy (1.6)
- hysteroscopy {postmoneopausal} (3.5)
- laparoscopy {postmenopausal} (2.2)
- 30% recurrence of breast cancer within 15 years[15]
* (relative risk)
Drug interactions
- anticoagulants
- any drug that inhibits cyt P450 3A4 may increase levels of tamoxifen
- any drug that induces cyt P450 3A4 may diminish levels of tamoxifen
- drugs that inhibit cyt P450 2D6 may inhibit effectiveness of tamoxifen[10]:
- bupropion inhibits effectiveness of tamoxifen[20]
- paroxetine inhibits effectiveness of tamoxifen[14][20]
- fluoxetine inhibits effectiveness of tamoxifen[20]
- other SSRIs probably do not inhibit effectiveness of tamoxifen[14]
Test interactions
- increase in serum Ca+2 & serum T4
Laboratory
- CYP2D6 genotyping
- poor metabolizers may require increase in dose or a switch to an aromatase inhibitor[23]
- see ARUP consult[16]
Mechanism of action
- non-steroidal estrogen antagonist & partial agonist
- binds to estrogen receptors in hormonally-sensitive tissue blocking estrogen growth stimulation & mRNA synthesis
More general terms
- aromatic compound
- ether
- amine
- protein kinase inhibitor
- antineoplastic endocrine agent
- estrogen antagonist
More specific terms
Additional terms
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ internal Medicine Alert 20(22):169-171, 1998
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Northern California Kaiser Permanente Videoconference, Nov. 11, 1999
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ 6.0 6.1 Journal Watch 20(20):164, 2000 Bergman et al, Lancet 356:881, 2000
- ↑ 7.0 7.1 Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Prescriber's Letter 9(9):50 2002
- ↑ Prescriber's Letter 10(11):65 2003
- ↑ 10.0 10.1 10.2 Prescriber's Letter 11(1):3 2004
- ↑ 11.0 11.1 Journal Watch 25(13):107, 2005 Chalas E, Costantino JP, Wickerham DL, Wolmark N, Lewis GC, Bergman C, Runowicz CD. Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial. Am J Obstet Gynecol. 2005 Apr;192(4):1230-7; discussion 1237-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15846210
- ↑ 12.0 12.1 Abramson N, Costantino JP, Garber JE, Berliner N, Wickerham DL, Wolmark N. Effect of Factor V Leiden and prothrombin G20210-->A mutations on thromboembolic risk in the national surgical adjuvant breast and bowel project breast cancer prevention trial. J Natl Cancer Inst. 2006 Jul 5;98(13):904-10. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16818854
- ↑ 13.0 13.1 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 14.0 14.1 14.2 14.3 Kelly CM et al Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010 Feb 8;340:c693. doi:http://dx.doi.org/ 10.1136/bmj.c693 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20142325
- ↑ 15.0 15.1 Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
- ↑ 16.0 16.1 ARUP Consult: CYP2D6 Genotyping - Tamoxifen deprecated reference
- ↑ 17.0 17.1 17.2 Davies C 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 randomised trial. The Lancet, Early Online Publication, 5 December 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23219286 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61963-1/abstract
Powles TJ Extended adjuvant tamoxifen for breast cancer-a new era? The Lancet, Early Online Publication, 5 December 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23219287 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62038-8/fulltext - ↑ 18.0 18.1 Davies C, Godwin J, Gray R, et al. Early Breast Cancer Trialists' Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378:771-784 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21802721
- ↑ 19.0 19.1 Physician's First Watch, April 16, 2013 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org
Nelson HD et al Use of Medications to Reduce Risk for Primary Breast Cancer: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 16 April 2013;158(8):604-614 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23588749 <Internet> http://annals.org/article.aspx?articleid=1676456 - ↑ 20.0 20.1 20.2 20.3 20.4 Medical Knowledge Self Assessment Program (MKSAP) 16, 18, 19. American College of Physicians, Philadelphia 2012, 2018, 2021.
- ↑ 21.0 21.1 21.2 Deprecated Reference
- ↑ Cuzick J et al Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology, Early Online Publication, 11 December 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25497694 <Internet> http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2971171-4/fulltext
Chlebowski RT IBIS-I tamoxifen update: maturity brings questions. The Lancet Oncology, Early Online Publication, 11 December 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25497695 <Internet> http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2971184-2/fulltext - ↑ 23.0 23.1 23.2 Kuznar W Guidance Issued for Tamoxifen Based on CYP2D6 Genotyping. Poor metabolizers may require increase in dose or a switch to an aromatase inhibitor. MedPage Today. ASCO Reading Room 03.20.2018 https://www.medpagetoday.com/reading-room/asco/breast-cancer/71868
Goetz MP, Sangkuhl K, Guchelaar HJ, et al Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy Clin Pharmacol Ther. 2018 Jan 31 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29385237 - ↑ American College of Obstetricians and Gynecologists. ACOG committee opinion no. 601: tamoxifen and uterine cancer. Obstet Gynecol 2014 Jun; 123:1394 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24848920
- ↑ 25.0 25.1 Brooks M Tamoxifen Ups Risk of Uterine Disease, Endometrial Cancer. Medscape, Dec 1, 2022 https://www.medscape.com/viewarticle/984846
Ryu KJ, Kim MS, Lee JY et al Risk of Endometrial Polyps, Hyperplasia, Carcinoma, and Uterine Cancer After Tamoxifen Treatment in Premenopausal Women With Breast Cancer. JAMA Netw Open. 2022;5(11):e2243951. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36441547 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799011
Database
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2733526
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5376
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2733525
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=23672
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3032583