TAMOXIFEN CITRATE, (E)-

Details

Stereochemistry	ACHIRAL
Molecular Formula	C26H29NO.C6H8O7
Molecular Weight	563.6381
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)CC(O)(CC(O)=O)C(O)=O.CC\C(=C(\C1=CC=CC=C1)C2=CC=C(OCCN(C)C)C=C2)C3=CC=CC=C3

InChI

InChIKey=FQZYTYWMLGAPFJ-BTKVJIOYSA-N

InChI=1S/C26H29NO.C6H8O7/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;7-3(8)1-6(13,5(11)12)2-4(9)10/h5-18H,4,19-20H2,1-3H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/b26-25+;

HIDE SMILES / InChI

Molecular Formula	C26H29NO
Molecular Weight	371.5146
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Molecular Formula	C6H8O7
Molecular Weight	192.1235
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017970s054lbl.pdf
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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Estrogen receptor alpha 127 Target ID: CHEMBL206 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23786452	Antagonist 2778	39.0 nM [IC50]
Estrogen receptor beta 110 Target ID: CHEMBL242 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22647217	Antagonist 2778	1660.0 nM [IC50]
Estrogen receptor 75 Target ID: CHEMBL2093866 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15658851	Antagonist 2778	580.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 434 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017970s054lbl.pdf	Primary	Approved 8429	NOLVADEX Approved Use Metastatic 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 Date 1977
Reduction in breast cancer incidence 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017970s054lbl.pdf	Preventing	Approved 8429	NOLVADEX Approved Use Metastatic 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 Date 1977
Ductal carcinoma in situ 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017970s054lbl.pdf	Primary	Approved 8429	NOLVADEX Approved Use Metastatic 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 Date 1977

C_max

Value	Dose	Co-administered	Analyte	Population
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
187 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf	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

AUC

Value	Dose	Co-administered	Analyte	Population
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
4110 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf	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

T_1/2

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 Co-administed with:: etoposide(300 mg orally; day-1 for 3 days) Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/	unhealthy, Median age 50 years n = 16 Health Status: unhealthy Condition: cancer Age Group: Median age 50 years Sex: M+F Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/	Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 1-4) Vomiting (grade 1-4) Dizziness (grade 1-4) Unsteadiness (grade 1-4) Malaise (grade 1-4) Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/
240 mg 1 times / day multiple, oral MTD Dose: 240 mg, 1 times / day Route: oral Route: multiple Dose: 240 mg, 1 times / day Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	Other AEs: Neutropenia, Thrombocytopenia... Other AEs: Neutropenia (grade 4, 10%) Thrombocytopenia (grade 2, 10%) Hemoglobin decreased Serum creatinine increased Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	DLT: Neutropenia, Thrombocytopenia... Disc. AE: Nausea, Vomiting... Other AEs: Serum creatinine increased... Dose limiting toxicities: Neutropenia (grade 4, 22.2%) Thrombocytopenia (grade 4, 22.2%) AEs leading to discontinuation/dose reduction: Nausea (11.1%) Vomiting (11.1%) Anorexia (11.1%) Septicemia (11.1%) Other AEs: Serum creatinine increased (11.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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: https://pubmed.ncbi.nlm.nih.gov/12395333/	unhealthy, Median age 61 years n = 74 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: Median age 61 years Sex: M+F Population Size: 74 Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/	Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 3, 1.3%) Vomiting (grade 3, 1.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/
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: https://pubmed.ncbi.nlm.nih.gov/12395333/	unhealthy, Median age 61 years n = 120 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: Median age 61 years Sex: M+F Population Size: 120 Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/	Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 3, 0.8%) Vomiting (grade 3, 0.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf	unhealthy, adult n = 902 Health Status: unhealthy Condition: breast cancer Age Group: adult Sex: F Population Size: 902 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf	Other AEs: Uterine neoplasms malignant NEC, Stroke... Other AEs: Uterine neoplasms malignant NEC Stroke Pulmonary embolism Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf
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 Co-administed with:: daunorubicin(50 mg/m2 intravenously on days 5, 6 and 7) Sources: https://pubmed.ncbi.nlm.nih.gov/7564501/	unhealthy, median age 50 years n = 3 Health Status: unhealthy Condition: acute leukemia Age Group: median age 50 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/7564501/	Sources: https://pubmed.ncbi.nlm.nih.gov/7564501/
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 3 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	Other AEs: Mental status changes... Other AEs: Mental status changes (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 6 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	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%) Thrombosis venous deep (16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 4 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	Other AEs: Thrombosis venous deep... Other AEs: Thrombosis venous deep (grade 3, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: Vinblastine(1.5 mg/m2 per day intravenous; on days 9-13) Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/	unhealthy, median age 58 years n = 3 Health Status: unhealthy Condition: epithelial tumors Age Group: median age 58 years Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/	Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/
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 Co-administed with:: Vinblastine(1.5 mg/m2 per day intravenous; on days 9-13) Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/	unhealthy, median age 58 years n = 3 Health Status: unhealthy Condition: epithelial tumors Age Group: median age 58 years Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/	DLT: Grand mal seizure... Dose limiting toxicities: Grand mal seizure (33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/
250 mg/m2 multiple, oral (starting) Studied dose Dose: 250 mg/m2 Route: oral Route: multiple Dose: 250 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf	unhealthy Health Status: unhealthy Condition: advanced metastatic cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf	Other AEs: QT interval prolonged... Other AEs: QT interval prolonged Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf
400 mg/m2 multiple, oral (starting) Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf	unhealthy Health Status: unhealthy Condition: advanced metastatic cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf	Other AEs: Tremor, Hyperreflexia... Other AEs: Tremor Hyperreflexia Unsteady gait Dizziness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767 inducer 389	substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478	CYP1A1 349 CYP1A2 1054 CYP3A 191 CYP2C19 991 CYP2B6 664 P-gp 1537 SULT1A1 29 UGT2B7 389 UGT1A4 347 UGT1A3 422 UGT1A1 418 UGT1A8 283 UGT1A9 380 UGT2B17 213 CYP3A5 395 CYP2C8 693	CYP1A2 701 CYP2B6 547 CYP2C8 168 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity	Metabolite
CYP1A2 1692	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	no
CYP3A4 1925	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [EC50 0.178 uM]	norendoxifen 4
CYP2B6 1001	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [EC50 0.187 uM]	norendoxifen 4
CYP2C19 1553	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [EC50 0.3 uM]	norendoxifen 4
CYP2C8 965	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [EC50 0.4 uM]	norendoxifen 4
CYP2C9 1819	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [EC50 0.488 uM]	norendoxifen 4
CYP1A2 1692	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [EC50 0.518 uM]	norendoxifen 4
CYP2C9 1819	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [IC50 0.21 uM]	norendoxifen 4
CYP2C19 1553	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [IC50 0.32 uM]	norendoxifen 4
CYP2C8 965	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=10 Page: -	yes [IC50 2.4 uM]	norendoxifen 4
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0	no
CYP1A1 349	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
CYP1A2 1054	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0	yes
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0	yes
CYP2C8 693	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0	yes
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0	yes
CYP3A4 1737	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
CYP3A5 395	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
SULT1A1 29	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf#page=20 Page: -	yes
UGT1A1 418	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
UGT1A3 422	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
UGT1A4 347	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf#page=20 Page: -	yes
UGT1A8 283	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
UGT1A9 380	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
UGT2B17 213	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866846/pdf/204_2017_Article_2147.pdf#page=7 Page: -	yes
UGT2B7 389	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf#page=20 Page: -	yes
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021807s000_MedR_ClinPharmR.pdf#page=15 Page: 15.0	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
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/25680947/ Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:41774	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:41774
ChemicalBook	CB9438781	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9438781
ZINC	ZINC000001530689	http://zinc15.docking.org/substances/ZINC000001530689
eMolecules	594967	https://www.emolecules.com/cgi-bin/more?vid=594967

PubMed

Title	Date	PubMed
Treatment of supratentorial glioblastoma multiforme with radiotherapy and a combination of BCNU and tamoxifen: a phase II study.	1999	10845393
Ocular toxicity in low-dose tamoxifen: a prospective study.	1999 Dec	10707134
Ultrasound, tamoxifen and endometrial carcinoma.	1999 May	10380310
A clinical trial of intravenous vinorelbine tartrate plus tamoxifen in the treatment of patients with advanced malignant melanoma.	2000 Feb 1	10649251
Benign, borderline, and malignant endometrioid neoplasia arising in endometriosis in association with tamoxifen therapy.	2000 Jul	10907178
Hemolysis of human erythrocytes induced by tamoxifen is related to disruption of membrane structure.	2000 Mar 15	10704919
Occurrence of stroke with tamoxifen in NSABP B-24.	2000 Mar 4	10711957
Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen.	2000 Nov	11194452
Relationships between tamoxifen use, liver fat and body fat distribution in women with breast cancer.	2001 Feb	11410835
Transcriptional activation of heat shock protein 27 gene expression by 17beta-estradiol and modulation by antiestrogens and aryl hydrocarbon receptor agonists.	2001 Feb	11174852
Combination chemotherapy of cisplatin, methotrexate, vinblastine, and high-dose tamoxifen for transitional cell carcinoma.	2001 Jan-Feb	11299831
[132 grams of tamoxifen: ultrasonographic and MRI appearance of endometrial carcinoma].	2001 Nov	11894549
Thromboses after estrogen hormone replacement, progesterone or tamoxifen therapy in patients with elevated blood levels of homocysteine.	2001 Oct	11559956
Comparison of an array of in vitro assays for the assessment of the estrogenic potential of natural and synthetic estrogens, phytoestrogens and xenoestrogens.	2001 Sep 14	11518614
Tamoxifen-related porphyria cutanea tarda.	2002	12180481
Functional analysis of the rat bile salt export pump gene promoter.	2002 Jul	12135489
The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.	2002 Oct	12372848
First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial.	2002 Sep 14	12243915
Effect of tamoxifen on venous thrombosis risk factors in women without cancer: the Breast Cancer Prevention Trial.	2003 Jan	12492585

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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).

Substance Class	Chemical Created by `admin` on `Sat Dec 16 03:01:39 GMT 2023` Edited by `admin` on `Sat Dec 16 03:01:39 GMT 2023`
Record UNII	U7FJP95NF4
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TAMOXIFEN CITRATE, (E)-

Common Name

English

TAMOXIFEN (E)-FORM CITRATE [MI]

Common Name

English

ETHANAMINE, 2-(4-((1E)-1,2-DIPHENYL-1-BUTEN-1-YL)PHENOXY)-N,N-DIMETHYL-, 2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE (1:1)

Systematic Name

English

Code System Code Type Description

PUBCHEM

3033630

Created by admin on Sat Dec 16 03:01:39 GMT 2023 , Edited by admin on Sat Dec 16 03:01:39 GMT 2023

PRIMARY

CAS

76487-65-5

Created by admin on Sat Dec 16 03:01:39 GMT 2023 , Edited by admin on Sat Dec 16 03:01:39 GMT 2023

PRIMARY

MERCK INDEX

m10450

Created by admin on Sat Dec 16 03:01:39 GMT 2023 , Edited by admin on Sat Dec 16 03:01:39 GMT 2023

PRIMARY

Merck Index

FDA UNII

U7FJP95NF4

Created by admin on Sat Dec 16 03:01:39 GMT 2023 , Edited by admin on Sat Dec 16 03:01:39 GMT 2023

PRIMARY

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 Co-administed with:: etoposide(300 mg orally; day-1 for 3 days) Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/	unhealthy, Median age 50 years n = 16 Health Status: unhealthy Condition: cancer Age Group: Median age 50 years Sex: M+F Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/
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 Co-administed with:: etoposide(300 mg orally; day-1 for 3 days) Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/	unhealthy, Median age 50 years n = 16 Health Status: unhealthy Condition: cancer Age Group: Median age 50 years Sex: M+F Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/
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 Co-administed with:: etoposide(300 mg orally; day-1 for 3 days) Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/	unhealthy, Median age 50 years n = 16 Health Status: unhealthy Condition: cancer Age Group: Median age 50 years Sex: M+F Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/
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 Co-administed with:: etoposide(300 mg orally; day-1 for 3 days) Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/	unhealthy, Median age 50 years n = 16 Health Status: unhealthy Condition: cancer Age Group: Median age 50 years Sex: M+F Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/
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 Co-administed with:: etoposide(300 mg orally; day-1 for 3 days) Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/	unhealthy, Median age 50 years n = 16 Health Status: unhealthy Condition: cancer Age Group: Median age 50 years Sex: M+F Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/1358168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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 Co-administed with:: cisplatin(80 mg/m2 intravenous; once weekly) Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/	unhealthy, Median age 53 years n = 3 Health Status: unhealthy Condition: metastatic melanoma Age Group: Median age 53 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/9041168/
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: https://pubmed.ncbi.nlm.nih.gov/12395333/	unhealthy, Median age 61 years n = 74 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: Median age 61 years Sex: M+F Population Size: 74 Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/
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: https://pubmed.ncbi.nlm.nih.gov/12395333/	unhealthy, Median age 61 years n = 74 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: Median age 61 years Sex: M+F Population Size: 74 Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/
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: https://pubmed.ncbi.nlm.nih.gov/12395333/	unhealthy, Median age 61 years n = 120 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: Median age 61 years Sex: M+F Population Size: 120 Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/
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: https://pubmed.ncbi.nlm.nih.gov/12395333/	unhealthy, Median age 61 years n = 120 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: Median age 61 years Sex: M+F Population Size: 120 Sources: https://pubmed.ncbi.nlm.nih.gov/12395333/
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf	unhealthy, adult n = 902 Health Status: unhealthy Condition: breast cancer Age Group: adult Sex: F Population Size: 902 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf	unhealthy, adult n = 902 Health Status: unhealthy Condition: breast cancer Age Group: adult Sex: F Population Size: 902 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf	unhealthy, adult n = 902 Health Status: unhealthy Condition: breast cancer Age Group: adult Sex: F Population Size: 902 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/017970Orig1s052.pdf
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 3 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 6 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 6 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 6 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: temozolomide(75 mg/m2 orally; 6 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/	unhealthy, median age 51 years n = 4 Health Status: unhealthy Condition: high-grade glioma Age Group: median age 51 years Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/21353747/
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 Co-administed with:: Vinblastine(1.5 mg/m2 per day intravenous; on days 9-13) Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/	unhealthy, median age 58 years n = 3 Health Status: unhealthy Condition: epithelial tumors Age Group: median age 58 years Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/1359155/
QT interval prolonged		250 mg/m2 multiple, oral (starting) Studied dose Dose: 250 mg/m2 Route: oral Route: multiple Dose: 250 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf	unhealthy Health Status: unhealthy Condition: advanced metastatic cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf
Dizziness		400 mg/m2 multiple, oral (starting) Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf	unhealthy Health Status: unhealthy Condition: advanced metastatic cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf
Hyperreflexia		400 mg/m2 multiple, oral (starting) Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf	unhealthy Health Status: unhealthy Condition: advanced metastatic cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf
Tremor		400 mg/m2 multiple, oral (starting) Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf	unhealthy Health Status: unhealthy Condition: advanced metastatic cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf
Unsteady gait		400 mg/m2 multiple, oral (starting) Studied dose Dose: 400 mg/m2 Route: oral Route: multiple Dose: 400 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf	unhealthy Health Status: unhealthy Condition: advanced metastatic cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021807lbl.pdf

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