Chemical: Drug
tamoxifen

Clinical PGx
PGx Research
Overview
Properties
Pathways
Is Related To
Publications
LinkOuts

Prescribing Info (2) Drug Labels (2) Clinical Annotations (20)

Available Prescribing Info

Dosing Guidelines

Annotation of DPWG Guideline for tamoxifen and CYP2D6

last updated 08/10/2011

1. Annotation of DPWG Guideline for tamoxifen and CYP2D6

Summary

For CYP2D6 poor and intermediate metabolizers, consider using aromatase inhibitors for postmenopausal women due to increased risk for relapse of breast cancer with tamoxifen. For intermediate metabolizers, avoid concomitant CYP2D6 inhibitor use.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tamoxifen based on CYP2D6 genotypes [Article:21412232]. For PM and IM genotypes, they recommend considering using aromatase inhibitors for postmenopausal women due to increased risk for relapse of breast cancer with tamoxifen. For IM genotypes, they recommend avoiding concomitant CYP2D6 inhibitor use.

Phenotype (Genotype)	Therapeutic Dose Recommendation	Level of Evidence	Clinical Relevance
PM (two inactive (3-8, 11-16, 19-21, 38, 40, *42) alleles)	Increased risk for relapse of breast cancer. Consider aromatase inhibitor for postmenopausal women.	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x10⁹/l; leucopenia < 1.0x10⁹/l; thrombocytopenia < 25x10⁹/l; life-threatening complications from diarrhea.
IM (two decreased-activity (9, 10, 17, 29, 36, 41) alleles or carrying one active (1, 2, 33, 35) and one inactive (3-8, 11-16, 19-21, 38, 40, 42) allele, or carrying one decreased-activity (9, 10, 17, 29, 36, 41) allele and one inactive (3-8, 11-16, 19-21, 38, 40, 42) allele)	Increased risk for relapse of breast cancer. Avoid concomitant use of CYP2D6 inhibitors. Consider aromatase inhibitor for postmenopausal women.	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x10⁹/l; leucopenia < 1.0x10⁹/l; thrombocytopenia < 25x10⁹/l; life-threatening complications from diarrhea.
UM (a gene duplication in absence of inactive (3-8, 11-16, 19-21, 38, 40, 42) or decreased-activity (9, 10, 17, 29, 36, *41) alleles)	No.	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S).

*See Methods or [Article:18253145] for definition of "good quality."
S: statistically significant difference.

view legend

Annotated Labels

Annotation of FDA Label for tamoxifen and ESR1,ESR2,F2,F5
Annotation of HCSC Label for tamoxifen and CYP2D6,ESR1,ESR2

last updated 01/16/2014

1. Annotation of FDA Label for tamoxifen and ESR1,ESR2,F2,F5

On FDA Biomarker List

Actionable PGx

Summary

Tamoxifen is an anti-estrogen used in the treatment and prevention of breast neoplasms particularly those with estrogen receptor positive breast cancer.

Annotation

Tamoxifen is an anti-estrogen used in the treatment and prevention of breast neoplasms particularly those with estrogen receptor positive breast cancer.

Excerpts from the tamoxifen (Nolvadex) drug label:

Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from NOLVADEX therapy.

The estrogen and progesterone receptor values may help to predict whether adjuvant NOLVADEX therapy is likely to be beneficial. NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant NOLVADEX therapy for breast cancer.

The FDA also highlight factor V Leiden and Prothrombin mutations in their "Table of Pharmacogenomic Biomarkers in Drug Labels", however in the trial mentioned within the drug label there was no benefit of screening for these factors:

When NOLVADEX is coadminstered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of NOLVADEX should be carefully considered in women with a history of thromboembolic events. In a subsmall study (N=81) of the NSABP P-1 trial, there appeared to be no benefit to screening women for Factor V Leiden and Prothrombin mutations G20210A as a means to identify those who may not be appropriate candidates for NOLVADEX therapy.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tamoxifen drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

Breast Neoplasms
- Indications & usage section, Contraindications section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Death
- Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Depression
- Adverse reactions section
- source: PHONT
Hot Flashes
- Adverse reactions section
- source: PHONT
Neoplasms
- Indications & usage section, Contraindications section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Pain
- Warnings section, Adverse reactions section, Precautions section
- source: PHONT
ESR1
- efficacy, Indications & usage section, Precautions section
- source: U.S. Food and Drug Administration
ESR2
- efficacy, Indications & usage section, Precautions section
- source: U.S. Food and Drug Administration
F2
- toxicity, Warnings section
- source: U.S. Food and Drug Administration
F5
- toxicity, Warnings section
- source: U.S. Food and Drug Administration

2. Annotation of HCSC Label for tamoxifen and CYP2D6,ESR1,ESR2

Testing required

Summary

The product monograph for tamoxifen states that it is indicated for treatment of early breast cancer in women with estrogen receptor positive tumors. It also notes that individuals with low CYP2D6 activity (or using CYP2D6 inhibitors) may have reductions in plasma concentrations of the active metabolite of tamoxifen.

Annotation

Excerpts from the tamoxifen product monograph:

MYLAN-TAMOXIFEN (tamoxifen citrate) is indicated for the adjuvant treatment of early breast cancer in women with estrogen receptor positive tumours.

In patients with tumours positive for estrogen receptors, the response rate to endocrine therapy was approximately 56%; and in patients with tumours negative for estrogen receptors, the response rate was about 10%. It was concluded that estrogen receptor assays are useful in predicting the results of endocrine therapy in patients with breast cancer.

MYLAN-TAMOXIFEN is a pro-drug requiring metabolic activation by CYP2D6. Low CYP2D6 activity that occurs in patients harbouring certain CYP2D6 alleles (i.e. *4) or from the chronic use of CYP2D6 inhibitors can lead to persistent reductions in plasma concentrations of an active metabolite of tamoxifen citrate (endoxifen). Reduced efficacy on tamoxifen citrate has been reported with concomitant usage of some selective serotonin reuptake inhibitor (SSRI) antidepressants...Concurrent chronic use of CYP2D6 inhibitors that may affect tamoxifen citrate efficacy should be avoided if possible.

For the complete product monograph text with sections containing pharmacogenetic information highlighted, see the tamoxifen product monograph.

*Disclaimer: The contents of this page have not been endorsed by HCSC and are the sole responsibility of PharmGKB.

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.