Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C26H29NO.ClH |
| Molecular Weight | 407.976 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.CC\C(C1=CC=CC=C1)=C(/C2=CC=CC=C2)C3=CC=C(OCCN(C)C)C=C3
InChI
InChIKey=FTDBIGNROSSDTJ-OQKDUQJOSA-N
InChI=1S/C26H29NO.ClH/c1-4-25(21-11-7-5-8-12-21)26(22-13-9-6-10-14-22)23-15-17-24(18-16-23)28-20-19-27(2)3;/h5-18H,4,19-20H2,1-3H3;1H/b26-25-;
DescriptionCurator's Comment: description was created based on several sources, including
https://www.drugbank.ca/drugs/DB00675 | https://www.ncbi.nlm.nih.gov/pubmed/18316672 | https://www.ncbi.nlm.nih.gov/pubmed/2021551 | https://www.drugs.com/tamoxifen.html | http://reference.medscape.com/drug/soltamox-tamoxifen-342183
Curator's Comment: description was created based on several sources, including
https://www.drugbank.ca/drugs/DB00675 | https://www.ncbi.nlm.nih.gov/pubmed/18316672 | https://www.ncbi.nlm.nih.gov/pubmed/2021551 | https://www.drugs.com/tamoxifen.html | http://reference.medscape.com/drug/soltamox-tamoxifen-342183
Tamoxifen (brand name Nolvadex), is selective estrogen receptor modulators (SERM) with tissue-specific activities for the treatment and prevention of estrogen receptor positive breast cancer. Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor (ER). It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen (4-OHT) (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have 30–100 times more affinity with the ER than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the ER. In breast tissue, 4-OHT acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited. Tamoxifen has 7% and 6% of the affinity of estradiol for the ERα and ERβ, respectively, whereas 4-OHT has 178% and 338% of the affinity of estradiol for the ERα and ERβ. The prolonged binding of tamoxifen to the nuclear chromatin of these results in reduced DNA polymerase activity, impaired thymidine utilization, blockade of estradiol uptake, and decreased estrogen response. It is likely that tamoxifen interacts with other coactivators or corepressors in the tissue and binds with different estrogen receptors, ER-alpha or ER-beta, producing both estrogenic and antiestrogenic effects. Tamoxifen is currently used for the treatment of both early and advanced estrogen receptor (ER)-positive (ER+) breast cancer in pre- and post-menopausal women. Additionally, it is the most common hormone treatment for male breast cancer. Patients with variant forms of the gene CYP2D6 (also called simply 2D6) may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites. Tamoxifen is used as a research tool to trigger tissue-specific gene expression in many conditional expression constructs in genetically modified animals including a version of the Cre-Lox recombination technique. Tamoxifen has been shown to be effective in the treatment of mania in patients with bipolar disorder by blocking protein kinase C (PKC), an enzyme that regulates neuron activity in the brain. Researchers believe PKC is over-active during the mania in bipolar patients.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL206 |
39.0 nM [IC50] | ||
Target ID: CHEMBL242 |
1660.0 nM [IC50] | ||
Target ID: CHEMBL2093866 |
580.0 nM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | NOLVADEX Approved UseMetastatic Breast Cancer Tamoxifen citrate tablets are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy. Adjuvant Treatment of Breast Cancer Tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate tablets are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial. Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer. Ductal Carcinoma in Situ (DCIS) In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Reduction in Breast Cancer Incidence in High Risk Women Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label). Tamoxifen citrate tablets are indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5 year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. Examples of combinations of factors predicting a 5 year risk ≥ 1.67% are: Age 35 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or •At least 2 first degree relatives with a history of breast cancer, and a personal history of at least 1 breast biopsy; or •LCIS Age 40 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or •At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or •One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. Age 45 or older and any of the following combination of factors: •At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or •One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. Age 50 or older and any of the following combination of factors: •At least 2 first degree relatives with a history of breast cancer; or •History of 1 breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. Age 55 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. Age 60 or older and: •Five-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-888-838-2872. There are insufficient data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of tamoxifen in these patients. After an assessment of the risk of developing breast cancer, the decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. In the NSABP P-1 trial, tamoxifen treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk (see Table 3 in CLINICAL PHARMACOLOGY ). Launch Date1977 |
|||
| Preventing | NOLVADEX Approved UseMetastatic Breast Cancer Tamoxifen citrate tablets are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy. Adjuvant Treatment of Breast Cancer Tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate tablets are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial. Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer. Ductal Carcinoma in Situ (DCIS) In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Reduction in Breast Cancer Incidence in High Risk Women Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label). Tamoxifen citrate tablets are indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5 year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. Examples of combinations of factors predicting a 5 year risk ≥ 1.67% are: Age 35 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or •At least 2 first degree relatives with a history of breast cancer, and a personal history of at least 1 breast biopsy; or •LCIS Age 40 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or •At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or •One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. Age 45 or older and any of the following combination of factors: •At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or •One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. Age 50 or older and any of the following combination of factors: •At least 2 first degree relatives with a history of breast cancer; or •History of 1 breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. Age 55 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. Age 60 or older and: •Five-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-888-838-2872. There are insufficient data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of tamoxifen in these patients. After an assessment of the risk of developing breast cancer, the decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. In the NSABP P-1 trial, tamoxifen treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk (see Table 3 in CLINICAL PHARMACOLOGY ). Launch Date1977 |
|||
| Primary | NOLVADEX Approved UseMetastatic Breast Cancer Tamoxifen citrate tablets are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy. Adjuvant Treatment of Breast Cancer Tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate tablets are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial. Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer. Ductal Carcinoma in Situ (DCIS) In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Reduction in Breast Cancer Incidence in High Risk Women Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label). Tamoxifen citrate tablets are indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5 year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. Examples of combinations of factors predicting a 5 year risk ≥ 1.67% are: Age 35 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or •At least 2 first degree relatives with a history of breast cancer, and a personal history of at least 1 breast biopsy; or •LCIS Age 40 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or •At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or •One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. Age 45 or older and any of the following combination of factors: •At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or •One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. Age 50 or older and any of the following combination of factors: •At least 2 first degree relatives with a history of breast cancer; or •History of 1 breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. Age 55 or older and any of the following combination of factors: •One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or •History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. Age 60 or older and: •Five-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model. For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-888-838-2872. There are insufficient data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of tamoxifen in these patients. After an assessment of the risk of developing breast cancer, the decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. In the NSABP P-1 trial, tamoxifen treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk (see Table 3 in CLINICAL PHARMACOLOGY ). Launch Date1977 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
187 ng/mL |
20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
TAMOXIFEN plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE food status: UNKNOWN |
|
63.6 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8740091 |
30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered: |
TAMOXIFEN blood | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
4110 ng × h/mL |
20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
TAMOXIFEN plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE food status: UNKNOWN |
|
3370.1 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8740091 |
30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered: |
TAMOXIFEN blood | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
209.8 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8740091 |
30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered: |
TAMOXIFEN blood | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
240 mg 3 times / day multiple, oral MTD Dose: 240 mg, 3 times / day Route: oral Route: multiple Dose: 240 mg, 3 times / day Sources: |
unhealthy, Median age 50 years Health Status: unhealthy Age Group: Median age 50 years Sex: M+F Sources: |
Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 1-4) Sources: Vomiting (grade 1-4) Dizziness (grade 1-4) Unsteadiness (grade 1-4) Malaise (grade 1-4) |
240 mg 1 times / day multiple, oral MTD Dose: 240 mg, 1 times / day Route: oral Route: multiple Dose: 240 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
Other AEs: Neutropenia, Thrombocytopenia... Other AEs: Neutropenia (grade 4, 10%) Sources: Thrombocytopenia (grade 2, 10%) Hemoglobin decreased Serum creatinine increased |
280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
DLT: Neutropenia, Thrombocytopenia... Disc. AE: Nausea, Vomiting... Other AEs: Serum creatinine increased... Dose limiting toxicities: Neutropenia (grade 4, 22.2%) AEs leading toThrombocytopenia (grade 4, 22.2%) discontinuation/dose reduction: Nausea (11.1%) Other AEs:Vomiting (11.1%) Anorexia (11.1%) Septicemia (11.1%) Serum creatinine increased (11.1%) Sources: |
30 mg 2 times / day multiple, oral Studied dose Dose: 30 mg, 2 times / day Route: oral Route: multiple Dose: 30 mg, 2 times / day Sources: |
unhealthy, Median age 61 years Health Status: unhealthy Age Group: Median age 61 years Sex: M+F Sources: |
Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 3, 1.3%) Sources: Vomiting (grade 3, 1.3%) |
60 mg 2 times / day multiple, oral Studied dose Dose: 60 mg, 2 times / day Route: oral Route: multiple Dose: 60 mg, 2 times / day Sources: |
unhealthy, Median age 61 years Health Status: unhealthy Age Group: Median age 61 years Sex: M+F Sources: |
Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 3, 0.8%) Sources: Vomiting (grade 3, 0.8%) |
10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: F Sources: |
Other AEs: Uterine neoplasms malignant NEC, Stroke... Other AEs: Uterine neoplasms malignant NEC Sources: Stroke Pulmonary embolism |
700 mg 1 times / day multiple, oral Highest studied dose Dose: 700 mg, 1 times / day Route: oral Route: multiple Dose: 700 mg, 1 times / day Sources: |
unhealthy, median age 50 years Health Status: unhealthy Age Group: median age 50 years Sex: M+F Sources: |
|
100 mg/m2 2 times / day multiple, oral MTD Dose: 100 mg/m2, 2 times / day Route: oral Route: multiple Dose: 100 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
Other AEs: Mental status changes... |
125 mg/m2 2 times / day multiple, oral Studied dose Dose: 125 mg/m2, 2 times / day Route: oral Route: multiple Dose: 125 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
DLT: Thrombocytopenia... Other AEs: QT interval prolonged, Thrombosis venous deep... Dose limiting toxicities: Thrombocytopenia (grade 4, 16.7%) Other AEs:QT interval prolonged (16.7%) Sources: Thrombosis venous deep (16.7%) |
75 mg/m2 2 times / day multiple, oral Studied dose Dose: 75 mg/m2, 2 times / day Route: oral Route: multiple Dose: 75 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
Other AEs: Thrombosis venous deep... |
680 mg/m2 1 times / day single, oral Highest studied dose Dose: 680 mg/m2, 1 times / day Route: oral Route: single Dose: 680 mg/m2, 1 times / day Sources: |
unhealthy, median age 58 years Health Status: unhealthy Age Group: median age 58 years Sources: |
|
230 mg/m2 2 times / day multiple, oral Studied dose Dose: 230 mg/m2, 2 times / day Route: oral Route: multiple Dose: 230 mg/m2, 2 times / day Sources: |
unhealthy, median age 58 years Health Status: unhealthy Age Group: median age 58 years Sources: |
DLT: Grand mal seizure... |
250 mg/m2 multiple, oral Studied dose Dose: 250 mg/m2 Route: oral Route: multiple Dose: 250 mg/m2 Sources: |
unhealthy Health Status: unhealthy Sources: |
Other AEs: QT interval prolonged... Other AEs: QT interval prolonged Sources: |
400 mg/m2 multiple, oral Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: |
unhealthy Health Status: unhealthy Sources: |
Other AEs: Tremor, Hyperreflexia... Other AEs: Tremor Sources: Hyperreflexia Unsteady gait Dizziness |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Dizziness | grade 1-4 | 240 mg 3 times / day multiple, oral MTD Dose: 240 mg, 3 times / day Route: oral Route: multiple Dose: 240 mg, 3 times / day Sources: |
unhealthy, Median age 50 years Health Status: unhealthy Age Group: Median age 50 years Sex: M+F Sources: |
| Malaise | grade 1-4 | 240 mg 3 times / day multiple, oral MTD Dose: 240 mg, 3 times / day Route: oral Route: multiple Dose: 240 mg, 3 times / day Sources: |
unhealthy, Median age 50 years Health Status: unhealthy Age Group: Median age 50 years Sex: M+F Sources: |
| Nausea | grade 1-4 | 240 mg 3 times / day multiple, oral MTD Dose: 240 mg, 3 times / day Route: oral Route: multiple Dose: 240 mg, 3 times / day Sources: |
unhealthy, Median age 50 years Health Status: unhealthy Age Group: Median age 50 years Sex: M+F Sources: |
| Unsteadiness | grade 1-4 | 240 mg 3 times / day multiple, oral MTD Dose: 240 mg, 3 times / day Route: oral Route: multiple Dose: 240 mg, 3 times / day Sources: |
unhealthy, Median age 50 years Health Status: unhealthy Age Group: Median age 50 years Sex: M+F Sources: |
| Vomiting | grade 1-4 | 240 mg 3 times / day multiple, oral MTD Dose: 240 mg, 3 times / day Route: oral Route: multiple Dose: 240 mg, 3 times / day Sources: |
unhealthy, Median age 50 years Health Status: unhealthy Age Group: Median age 50 years Sex: M+F Sources: |
| Hemoglobin decreased | 240 mg 1 times / day multiple, oral MTD Dose: 240 mg, 1 times / day Route: oral Route: multiple Dose: 240 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
|
| Serum creatinine increased | 240 mg 1 times / day multiple, oral MTD Dose: 240 mg, 1 times / day Route: oral Route: multiple Dose: 240 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
|
| Thrombocytopenia | grade 2, 10% | 240 mg 1 times / day multiple, oral MTD Dose: 240 mg, 1 times / day Route: oral Route: multiple Dose: 240 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Neutropenia | grade 4, 10% | 240 mg 1 times / day multiple, oral MTD Dose: 240 mg, 1 times / day Route: oral Route: multiple Dose: 240 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Serum creatinine increased | 11.1% | 280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Anorexia | 11.1% Disc. AE |
280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Nausea | 11.1% Disc. AE |
280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Septicemia | 11.1% Disc. AE |
280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Vomiting | 11.1% Disc. AE |
280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Neutropenia | grade 4, 22.2% DLT, Disc. AE |
280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Thrombocytopenia | grade 4, 22.2% DLT, Disc. AE |
280 mg 1 times / day multiple, oral Studied dose Dose: 280 mg, 1 times / day Route: oral Route: multiple Dose: 280 mg, 1 times / day Sources: |
unhealthy, Median age 53 years Health Status: unhealthy Age Group: Median age 53 years Sex: M+F Sources: |
| Nausea | grade 3, 1.3% | 30 mg 2 times / day multiple, oral Studied dose Dose: 30 mg, 2 times / day Route: oral Route: multiple Dose: 30 mg, 2 times / day Sources: |
unhealthy, Median age 61 years Health Status: unhealthy Age Group: Median age 61 years Sex: M+F Sources: |
| Vomiting | grade 3, 1.3% | 30 mg 2 times / day multiple, oral Studied dose Dose: 30 mg, 2 times / day Route: oral Route: multiple Dose: 30 mg, 2 times / day Sources: |
unhealthy, Median age 61 years Health Status: unhealthy Age Group: Median age 61 years Sex: M+F Sources: |
| Nausea | grade 3, 0.8% | 60 mg 2 times / day multiple, oral Studied dose Dose: 60 mg, 2 times / day Route: oral Route: multiple Dose: 60 mg, 2 times / day Sources: |
unhealthy, Median age 61 years Health Status: unhealthy Age Group: Median age 61 years Sex: M+F Sources: |
| Vomiting | grade 3, 0.8% | 60 mg 2 times / day multiple, oral Studied dose Dose: 60 mg, 2 times / day Route: oral Route: multiple Dose: 60 mg, 2 times / day Sources: |
unhealthy, Median age 61 years Health Status: unhealthy Age Group: Median age 61 years Sex: M+F Sources: |
| Pulmonary embolism | 10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: F Sources: |
|
| Stroke | 10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: F Sources: |
|
| Uterine neoplasms malignant NEC | 10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: F Sources: |
|
| Mental status changes | grade 3, 33.3% | 100 mg/m2 2 times / day multiple, oral MTD Dose: 100 mg/m2, 2 times / day Route: oral Route: multiple Dose: 100 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
| QT interval prolonged | 16.7% | 125 mg/m2 2 times / day multiple, oral Studied dose Dose: 125 mg/m2, 2 times / day Route: oral Route: multiple Dose: 125 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
| Thrombosis venous deep | 16.7% | 125 mg/m2 2 times / day multiple, oral Studied dose Dose: 125 mg/m2, 2 times / day Route: oral Route: multiple Dose: 125 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
| Thrombocytopenia | grade 4, 16.7% DLT |
125 mg/m2 2 times / day multiple, oral Studied dose Dose: 125 mg/m2, 2 times / day Route: oral Route: multiple Dose: 125 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
| Thrombosis venous deep | grade 3, 25% | 75 mg/m2 2 times / day multiple, oral Studied dose Dose: 75 mg/m2, 2 times / day Route: oral Route: multiple Dose: 75 mg/m2, 2 times / day Sources: |
unhealthy, median age 51 years Health Status: unhealthy Age Group: median age 51 years Sex: M+F Sources: |
| Grand mal seizure | 33.3% DLT |
230 mg/m2 2 times / day multiple, oral Studied dose Dose: 230 mg/m2, 2 times / day Route: oral Route: multiple Dose: 230 mg/m2, 2 times / day Sources: |
unhealthy, median age 58 years Health Status: unhealthy Age Group: median age 58 years Sources: |
| QT interval prolonged | 250 mg/m2 multiple, oral Studied dose Dose: 250 mg/m2 Route: oral Route: multiple Dose: 250 mg/m2 Sources: |
unhealthy Health Status: unhealthy Sources: |
|
| Dizziness | 400 mg/m2 multiple, oral Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: |
unhealthy Health Status: unhealthy Sources: |
|
| Hyperreflexia | 400 mg/m2 multiple, oral Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: |
unhealthy Health Status: unhealthy Sources: |
|
| Tremor | 400 mg/m2 multiple, oral Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: |
unhealthy Health Status: unhealthy Sources: |
|
| Unsteady gait | 400 mg/m2 multiple, oral Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: |
unhealthy Health Status: unhealthy Sources: |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no | ||||
| no | ||||
| no | ||||
| yes [EC50 0.178 uM] | ||||
| yes [EC50 0.187 uM] | ||||
| yes [EC50 0.3 uM] | ||||
| yes [EC50 0.4 uM] | ||||
| yes [EC50 0.488 uM] | ||||
| yes [EC50 0.518 uM] | ||||
| yes [IC50 0.21 uM] | ||||
| yes [IC50 0.32 uM] | ||||
| yes [IC50 2.4 uM] | ||||
| yes |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | unknown (co-administration study) Comment: Although concomitant administration of CYP2D6 inhibitors reduces the plasma concentration of endoxifen, a potent metabolite, the clinical significance is not well established [see Drug Interactions (7.4)]. The mean steady-state endoxifen plasma concentration in patients taking CYP2D6 inhibitors was significantly reduced compared to those not taking concomitant CYP2D6 inhibitors (14.8 ± 10.6 versus 26.7 ± 15.4 ng/mL). The mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors was 31.4 ± 14.7 ng/mL compared to 8.8 ± 3.5 ng/mL in CYP2D6 normal metabolizers receiving potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) with tamoxifen. The plasma levels of endoxifen in CYP2D6 normal metabolizers taking potent CYP2D6 inhibitors were similar to the levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors (8.8 versus 7.2 ng/mL). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0 |
Tox targets
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
Page: - |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Cirrhosis with steatohepatitis after adjuvant tamoxifen. | 1999 Jan 2 |
|
| The association between tamoxifen and the development of hepatocellular carcinoma: case report and literature review. | 1999 Jun |
|
| Ultrasound, tamoxifen and endometrial carcinoma. | 1999 May |
|
| Bezafibrate for tamoxifen-induced non-alcoholic steatohepatitis. | 1999 May 22 |
|
| The Italian Tamoxifen Prevention Trial. | 1999 Oct |
|
| Non-alcoholic steatohepatitis. | 1999 Oct 9 |
|
| The relationship of tamoxifen with dementia, depression, and dependence in activities of daily living in elderly nursing home residents. | 2000 |
|
| A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review. | 2000 |
|
| Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. | 2000 Apr 15 |
|
| Toremifene-induced fatty liver and NASH in breast cancer patients with breast-conservation treatment. | 2000 Dec |
|
| Proteinase inhibitor 9, an inhibitor of granzyme B-mediated apoptosis, is a primary estrogen-inducible gene in human liver cells. | 2000 Feb 25 |
|
| Tamoxifen-induced transient multifocal hepatic fatty infiltration. | 2000 Jan |
|
| Hemolysis of human erythrocytes induced by tamoxifen is related to disruption of membrane structure. | 2000 Mar 15 |
|
| Occurrence of stroke with tamoxifen in NSABP B-24. | 2000 Mar 4 |
|
| Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes. | 2000 May |
|
| Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients. | 2000 Nov-Dec |
|
| Cell response endpoints enhance sensitivity of the immature mouse uterotropic assay. | 2001 May-Jun |
|
| [132 grams of tamoxifen: ultrasonographic and MRI appearance of endometrial carcinoma]. | 2001 Nov |
|
| First do no harm: extending the debate on the provision of preventive tamoxifen. | 2001 Nov 2 |
|
| Modulation by estrogens and xenoestrogens of recombinant human neuronal nicotinic receptors. | 2001 Nov 2 |
|
| Tamoxifen-based treatment induces clinically meaningful responses in multiple myeloma patients with relapsing disease after autotransplantation. | 2001 Nov-Dec |
|
| Tamoxifen-induced cirrhotic process. | 2001 Nov-Dec |
|
| Thromboses after estrogen hormone replacement, progesterone or tamoxifen therapy in patients with elevated blood levels of homocysteine. | 2001 Oct |
|
| Tamoxifen-related porphyria cutanea tarda. | 2002 |
|
| Endometrial disorders in 406 breast cancer patients on tamoxifen: the case for less intensive monitoring. | 2002 Feb 10 |
|
| [A case of locally recurrent breast cancer in which phlebothrombosis of the right leg after hormonal therapy using a high dose of toremifene citrate]. | 2002 Jan |
|
| Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. | 2002 Jul |
|
| Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites. | 2002 Oct |
|
| Chemoimmunohormonal therapy with carmustine, dacarbazine, cisplatin, tamoxifen, and interferon for metastatic melanoma: a prospective phase II study. | 2002 Oct |
|
| Molecular identification of P-glycoprotein: a role in lens circulation? | 2002 Sep |
|
| First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. | 2002 Sep 14 |
|
| Serum leptin levels are associated with tamoxifen-induced hepatic steatosis. | 2003 |
|
| Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. | 2003 Apr |
|
| Tamoxifen induces apoptosis in Fas+ tumor cells by upregulating the expression of Fas ligand. | 2003 Apr |
|
| Effects of a diphenyl ether-type herbicide, chlornitrofen, and its amino derivative on androgen and estrogen receptor activities. | 2003 Apr |
|
| Comparison of the reporter gene assay for ER-alpha antagonists with the immature rat uterotrophic assay of 10 chemicals. | 2003 Apr 30 |
|
| Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 actions in human breast cancer cells. | 2003 Feb |
|
| Inhibition of TNF-alpha-induced RANTES expression in human hepatocyte-derived cells by fibrates, the hypolipidemic drugs. | 2003 Feb |
|
| Extensive pelvic endometriosis with malignant change in tamoxifen-treated postmenopausal women. | 2003 May-Jun |
Patents
Sample Use Guides
For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than
20 mg per day should be given in divided doses (morning and evening).
Route of Administration:
Oral
HELNalpha and HELNbeta two human cervix adenocarcinoma cell lines derived from HeLa cells stably transfected with the reporter gene ERE-betaGlob-Luc-SVNeo and the expression plasmids ERalpha or ERbeta respectively, were used to quantify the antiestrogenic and estrogenic effects of Tamoxifen. These cells were routinely cultivated in DMEM phenol red free, supplemented with 5% sFBS, 2 mM glutamine, 1% penicillin/streptomycin, 1 mg/mL Geneticin, and 0.5 mkg/mL puromycin to ensure appropriate antibiotic selection. For the assay, cells were trypsinized from the maintenance flask with phenol red free trypsin (0.05%)-EDTA (0.02%) (HyClone, Logan, UT) and seeded in an opaque 96-well plate (Nunc) at a density of 7.5 x 10^4 cells/well in a final volume of 100 mkL of assay medium (DMEM, phenol red free, supplemented with 3% sFBS, 2 mM glutamine, and penicillin/streptomycin). Five hours later, cells were adherent. Serial dilutions of Tamoxifen or DMSO as diluent control were then added in the presence of a fixed concentration of 17beta-estradiol (10^-10 M in HELNalpha and 10^-9 M in HELNbeta) to triplicate microcultures. Faslodex (Tocris, 10^-8 M) was used as a baseline indicator. Cells were incubated for 20 h at 37 °C in a 5% CO2 humidified incubator before being processed for luciferase determination. Medium was aspirated and 100 mkL of a 1:1 mixture of LucLite (Perkin-Elmer, Life Science, Boston, MA)/assay medium was added to each well. Plates were then sealed with a Topseal and left in the dark for 10 min before luminescence activity was determined by counting the plates for 6 s in a beta-TopCount (Packard Instrument Company, Meriden, CT).
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ACTIVE MOIETY
SUBSTANCE RECORD
