Tamoxifen

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

Pharmaceuticals -> Antibiotics

1.02e-03 g/L

2.6 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Estrogen Antagonists

Pharmaceuticals

Hormones and antihormones

96-98 °C

MP: 72-74 °C from methanol. /Cis-Form base/

MP: 126-128 °C; C32-H37-N-08; ICI-47699 /Cis-Form citrate/

97 °C

8.48

8.71

10

196.9 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID8021301]

197.1 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

195.96 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H302 (58.3%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P263, P264, P270, P273, P280, P301+P317, P318, P319, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 12 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

REACH registered substance: Tamoxifen (EC: 234-118-0)

Ethanamine, 2-4-(1Z)-1,2-diphenyl-1-butenylphenoxy-N,N-dimethyl-: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tamoxifen citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /tamoxifen citrate/

National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Tamoxifen (10540-29-1) is listed as known to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s167tamo.pdf]

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/

For more Disposal Methods (Complete) data for TAMOXIFEN (8 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/

For more Preventive Measures (Complete) data for TAMOXIFEN (19 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

Concomitant use of Aminoglutethimide may decrease plasma concentrations of tamoxifen and N-desmethyl tamoxifen.

Concomitant use coumarin-derivatived anticoagulants, may result in significant increase in anticoagulant effect; use is contraindicated in women for reducing the risk of breast cancer in high-risk women and women with ductal carcinoma in situ (DCIS).

Concomitant use of bromocriptine may increase serum levels of tamoxifen and N-desmethyl tamoxifen.

Concomitant use of cytotoxic agents may result in increased risk of thromboembolic events.

For more Interactions (Complete) data for TAMOXIFEN (12 total), please visit the HSDB record page.

Tamoxifen has been associated with rare instances of idiosyncratic, clinically apparent liver injury, typically arising within the first six months of treatment and having variable presentations with cholestatic, mixed or hepatocellular pattern of enzyme elevations. Immunoallergic features (fever, rash, eosinophilia) are uncommon, as are autoantibodies. Some instances have been severe with signs of hepatic failure, but most cases are self-limited.

Similar to many cancer treatments, tamoxifen is associated with a range of adverse effects, although severe or fatal outcomes are rare. Common adverse effects observed in the treatment include hot flashes, irregular periods, and vaginal discharge. Other frequently reported adverse effects include peripheral edema, hypertension, mood changes, pain, depression, skin changes, skin rashes, nausea, vomiting, weakness, arthritis, arthralgia, lymphedema, and pharyngitis. Less common adverse effects include insomnia, dizziness, headache, weight gain, abdominal pain, diarrhea, indigestion, urinary tract infections, thrombocytopenia, back pain, alopecia, ostealgia, and cataracts. Given the wide range of potential adverse effects, patients should discuss any adverse effects they experience with their healthcare provider.

When a single oral dose of 20 mg is given, the average peak plasma concentration (Cmax) is 40 ng/mL which occurred approximately 5 hours after dosing (Tmax). The Cmax of N-desmethyl tamoxifen is 15 ng/mL. Steady-state concentrations for tamoxifen is achieved in 4 weeks, while steady-state concentrations for N-desmethyl tamoxifen is achieved in 8 weeks.

IDENTIFICATION: Tamoxifen is an anti-estrogenic non-steroidal drug. Indications: Treatment of advanced breast cancer and adjuvant treatment of early breast cancer. Treatment of anovulatory infertility. HUMAN EXPOSURE: Main risks and target organs: Adverse effects in therapeutic use are usually mild. They include effects caused by antagonism of endogenous oestrogens: hot flushes, non-specific gastrointestinal effects (nausea and vomiting), central nervous system effects, and rare ocular effects. Adverse hematological effects have been reported, also isolated cases of death from peliosis hepatis and from hyperlipidemia. In the treatment of breast cancer, hypercalcemia and tumor flare can occur. Summary of clinical effects: Anti-estrogenic effects in women treated with tamoxifen include vasomotor symptoms (hot flushes), vaginal bleeding and (in premenopausal women) irregular menses, and pruritus vulvae. Nausea and vomiting can occur. Dizziness, lethargy, depression, irritability and cerebellar dysfunction have been described. Reversible retinopathy with macular edema has been reported after high cumulative doses, and corneal changes can occur. Thrombocytopenia or leukopenia have been associated with tamoxifen treatment. Thromboembolism, which may be due to the disease rather than the treatment, has been recorded in women given tamoxifen for breast cancer. Contraindications: Pregnancy is an absolute contraindication because of the anti-estrogenic effects. Routes of entry: Oral: Usual route of entry Absorption by route of exposure: Peak concentrations occur 4-7 hr after oral dosing. Peak concentrations after single oral dose are about 40 u/l. Distribution by route of exposure: Tamoxifen is more than 99% protein-bound in serum, predominantly to albumin. In patients with breast cancer, concentrations of tamoxifen and its metabolites in pleural, pericardial and peritoneal effusion fluid are between 20 and 100% of those in serum, but only trace amounts enter the cerebrospinal fluid. Concentrations in breast cancer tissue exceed those in serum. The volume of distribution is 50-60 l/kg. Biological half-life by route of exposure: The elimination is biphasic, with an initial half-life of around 7 hr and a terminal half-life of 7-11 days. Metabolism: Tamoxifen citrate undergoes extensive hepatic metabolism to: 1-(4-ethanolyloxyphenyl)-1,2-diphenylbut-1-ene (the primary alcohol), N-desmethyl tamoxifen, 4-hydroxy tamoxifen, 4-hydroxy-N-desmethyl tamoxifenn and N-desdimethyl tamoxifen Elimination by route of exposure: The major excretory route is via the bile as metabolites and enterohepatic recirculation occurs. Less than 1% is excreted in the urine. Mode of action: Toxicodynamics: The adverse effects observed are due mainly to its anti-estrogen effect, as Tamoxifen and certain of its metabolites antagonise the effects of estrogens in estrogen sensitive tissues. Pharmacodynamics: Tamoxifen and several of its metabolites (particularly 4-hydroxytamoxifen) bind to nuclear estrogen receptors in estrogen sensitive tissues, and also to a microsomal protein termed the anti-estrogen binding site. Tamoxifen interferes with the physiological sequence by which estrogen binds to its receptor, is translocated in the nucleus and then activates messenger RNA synthesis. Although the tamoxifen receptor complex is transported in the nucleus in the same way as estrogen receptor complex, it fails to activate synthesis of mRNA. Carcinogenicity: A case-control study showed a significantly increased relative risk of carcinoma of the uterus in women previously treated with tamoxifen and who had previously had radiotherapy involving the uterus. The study showed an increase in relative risk with tamoxifen treatment alone which was not statistically significant. Teratogenicity: Studies in neonatal male and female mice at relative doses 10 times higher than those used in humans have shown genital tract abnormalities. Interactions: Tamoxifen potentiates the anticoagulant effect of warfarin, and this interaction can be life-threatening. Main adverse effects: Adverse effects are usually mild. Thrombocytopenia, leukopenia, thromboembolism, peliosis hepatis and hyperlipidaemia have been mentioned in case reports. Severe hypercalcemia can occur rarely when treatment is started in patients with metastases to bone. Chronic poisoning: Ingestion: Retinal damage and keratitis have been reported in patients after large cumulative doses of tamoxifen, for more than 1 year, though sometimes with smaller doses. There seems to be correlation between long term tamoxifen administration and endometrial proliferation. Neurological: CNS: A case of depression, syncope, and incoordination has been described during therapy with 10 mg twice daily. The symptoms resolved when tamoxifen was discontinued and reappeared when treatment was restarted. Gastrointestinal: Nausea and vomiting occur with therapeutic doses in some patients, and are anticipated in overdosage. Hepatic: A fatal case of peliosis hepatis has been reported in a woman treated with tamoxifen for 2 years after mastectomy for carcinoma. Urinary: Other: A case of persistent nocturnal priapism has been reported. Endocrine and reproductive systems: The anti-estrogenic effects of tamoxifen in premenopausal women receiving therapeutic doses can cause irregular menses. Anti-estrogenic adverse effects in women treated with tamoxifen include vasomotor symptoms and vaginal bleeding and pruritus vulvae. Eye, ear, nose, throat: local effects: Treatment has been associated with retinal and corneal changes. Hematological: Thromboembolism may be more common in patients treated with tamoxifen, though this is not certain, as patients with cancer are at increased risk anyway. A small reduction in antithrombin III concentration was noted in a study of 11 postmenopausal women treated with tamoxifen, but it was clinically insignificant, and no significant reduction was seen in a group of premenopausal women. Thrombocytopenia and leukopenia can occur during therapy, but are not usually severe. One case of severe myelosuppression has been reported. Fluid and electrolyte disturbances: Severe hypercalcemia, associated with increased bone resorption, has been noted when patients with bony metastases commenced therapy. Others: Severe hyperlipidemia is occasionally seen, and has been ascribed to an estrogenic effect. Special risks: Pregnancy, breast feeding and enzyme deficiencies. ANIMAL/PLANT STUDIES: In some animal species, estrogenic agonist effects become manifest at dosages equivalent to 10-100 times the human therapeutic dose. Mutagenicity: Tamoxifen is believed not to be mutagenic. /Tamoxifen citrate/

Signs and Symptoms of Overdose

Tamoxifen is a nonsteroidal agent that binds to estrogen receptors (ER), inducing a conformational change in the receptor. This results in a blockage or change in the expression of estrogen dependent genes. 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.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

/HUMAN EXPOSURE STUDIES/ In one study to determine the maximum tolerated dose of tamoxifen, acute neurotoxicity, manifested by tremor, hyperreflexia, unsteady gait, and dizziness, occurred in patients with advanced (metastatic) carcinoma who were receiving very high dosages of tamoxifen (i.e., loading doses exceeding 400 mg/sq m followed by maintenance dosages of 150 mg/sq m given twice daily) to reverse multiple-drug resistance. These adverse effects occurred within 3-5 days of initiating tamoxifen therapy and disappeared 2-5 days after discontinuance of the drug. No permanent neurologic sequelae were reported in these patients. Although a causal relationship to tamoxifen has not been established, seizures were reported in at least one of these patients several days after discontinuance of the drug and disappearance of adverse nervous system effects. In patients receiving loading doses exceeding 250 mg/sq m followed by maintenance doses of 80 mg/sq m administered twice daily, prolongation of the QT interval was reported.

/SIGNS AND SYMPTOMS/ Thinning and/or partial loss of hair occurs infrequently in patients receiving tamoxifen for metastatic breast cancer. Erythema multiforme, Stevens-Johnson syndrome, and bullous pemphigoid have been reported rarely in patients receiving tamoxifen. Skin changes have occurred in patients receiving tamoxifen as adjuvant therapy for breast cancer.

/SIGNS AND SYMPTOMS/ Serious, life-threatening or fatal events associated with tamoxifen used for reduction in the incidence of breast cancer (i.e., women at high risk for breast cancer and women with ductal carcinoma in situ) include endometrial cancer, uterine sarcoma, stroke, and pulmonary embolism.

/CASE REPORTS/ The fourth case of heterologous mesodermal tumour of the uterine corpus, that developed, years following tamoxifen therapy for breast cancer in a postmenopausal woman with no previous pelvic irradiation, is presented with coincidental endometriosis and endometrial intraepithelial carcinoma.

For more Human Toxicity Excerpts (Complete) data for TAMOXIFEN (12 total), please visit the HSDB record page.

Tamoxifen

Group 1: Carcinogenic to humans

Volume 66: (1996) Some Pharmaceutical Drugs

2012

2008

NB There is "evidence suggesting lack of carcinogenicity" for tamoxifen in humans and cancer of the female breast. An inverse association has been observed between tamoxifen and cancer of the female breast.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

tamoxifen

Nolvadex®

Antineoplastic agents

6

most-DILI-concern

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tamoxifen citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /tamoxifen citrate/

L02BA01

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

L02BA01

Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies.

Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth. Tamoxifen has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β.

Tamoxifen is a nonsteroidal agent with potent antiestrogenic properties. The antiestrogen effects may be related to tamoxifen's ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen competes with estradiol for estrogen receptor protein in cytosols derived from human breast adenocarcinomas. Tamoxifen has been shown to inhibit the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. Tamoxifen appears to exert its antitumor effects by binding the estrogen receptors in this rat model.

Tamoxifen may induce ovulation in anovulatory women, stimulating release of gonadotropin-releasing hormone from the hypothalamus, which in turn stimulates release of pituitary gonadotropins. In oligospermic males, tamoxifen increases serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estrogen.

Tamoxifen is an antiestrogen frequently used in the treatment of breast cancer and is currently being assessed as a prophylactic for those at high risk of developing tumors. We have found that tamoxifen and its derivatives are high-affinity blockers of specific chloride channels. This blockade appears to be independent of the interaction of tamoxifen with the estrogen receptor and therefore reflects an alternative cellular target. One of the clinical side effects of tamoxifen is impaired vision and cataract. Chloride channels in the lens of the eye were shown to be essential for maintaining normal lens hydration and transmittance. These channels were blocked by tamoxifen and, in organ culture, tamoxifen led to lens opacity associated with cataracts at clinically relevant concentrations. These data suggest a molecular mechanism by which tamoxifen can cause cataract formation and have implications for the clinical use of tamoxifen and related antiestrogens.

The terminal elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 14 days.

Limited data suggest that tamoxifen has a distribution half-life of 7-14 hours and an elimination half-life of about 5-7 days (range: 3-21 days). The elimination half-life of N-desmethyltamoxifen, the major metabolite, is estimated to be 9-14 days.

Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide. Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides.

Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in plasma. N-desmethyl tamoxifen activity is similar to tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P450 CYP3A, CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein.

Tamoxifen is rapidly and extensively metabolized, principally by demethylation and to a small degree by subsequent deamination and also by hydroxylation. Initial studies suggested that 4-hydroxytamoxifen (metabolite B) was the major metabolite of the drug, but subsequent studies using improved assay methodologies have shown that 4-hydroxytamoxifen is a minor metabolite and that the major metabolite is N-desmethyltamoxifen (metabolite X). The biologic activity of N-desmethyltamoxifen appears to be similar to that of tamoxifen. N-Desmethyltamoxifen undergoes demethylation to form N,N-desdimethyltamoxifen (metabolite Z) which undergoes subsequent deamination to form the primary alcohol metabolite (metabolite Y). Both 4-hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. 3,4-Dihydroxytamoxifen and an unidentified metabolite (metabolite E) also have been detected in plasma in small amounts. With continuous administration of tamoxifen, serum concentrations of N-desmethyltamoxifen are generally about 1-2 times those of unchanged tamoxifen, while those of N,N-desdimethyltamoxifen are about 20-40% those of unchanged tamoxifen and those of the primary alcohol metabolite are about 5-25% those of unchanged tamoxifen; concentrations of the hydroxylated metabolites and metabolite E appear to be less than 5% of those of unchanged tamoxifen.

Several metabolites of tamoxifen, including 4-hydroxy-N-desmethyltamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, the primary alcohol, and N-desdimethyltamoxifen were identified and their concn determined in fluids and feces from patients receiving chronic tamoxifen treatment. The biological samples investigated were serum, pleural, pericardial and peritoneal effusions, cerebrospinal fluid, saliva, bile, feces, and urine. In serum, tamoxifen itself, and the metabolites N-desmethyltamoxifen and N-desdimethyltamoxifen were the prevailing species, but significant amounts of the metabolites the primary alcohol, 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen were also detected. About 3 hr after drug intake tamoxifen as well as, N-desmethyltamoxifen, an N-desdimethyltamoxifen) showed a peak in serum. This may be explained by efficient metabolism of the metabolite precursor before being distributed to peripheral compartments. Upon drug withdrawal all metabolites showed first-order elimination curves which paralleled that of tamoxifen suggesting that their rate of elimination exceeded that of tamoxifen and that the serum levels are production rate limited. The protein binding of tamoxifen and its major serum metabolites (the primary alcohol, N-desmethyltamoxifen, N-desdimethyltamoxifen) was determined and found to be higher than 98%. Albumin was the predominant carrier for tamoxifen in human plasma. The concn of tamoxifen and its metabolites in pleural, pericardial, and peritoneal effusions equalled those detected in serum, corresponding to an effusion/serum ratio between 0.2 and 1. Only trace amounts of tamoxifen and metabolite N-desmethyltamoxifen were detected in cerebrospinal fluid (CSF/serum ratio less than 0.02). In saliva, concn of tamoxifen and N-desmethyltamoxifen exceeded the amounts of free drug in serum, suggesting active transport or trapping of these compounds in the salivary gland. Bile and urine were rich in the hydroxylated, conjugated metabolites (the primary alcohol, 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, whereas in feces unconjugated metabolite B and tamoxifen were the predominating species.

The amount of tamoxifen, N-desmethyltamoxifen (metabolite X), N-desdimethyltamoxifen (metabolite Z), and hydroxylated metabolites (trans-1(4-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene, 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen) were determined in brain metastases from breast cancer patients and in the surrounding brain tissues. Specimens were collected from the breast cancer patients who received tamoxifen for 7-180 days and with the last dose taken within 28 hr before surgical removal of the tumour. The concn of tamoxifen and its metabolites were up to 46 fold higher in the brain metastatic tumour and brain tissue than in serum. Metabolite N-desmethyltamoxifen was the most abundant species followed by tamoxifen and metabolite N-desdimethyltamoxifen. Small but significant amounts of the hydroxylated metabolites, trans-1(4-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene, 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen were detected in most specimens. The ratios between the concn of tamoxifen and various metabolites were similar in tumour, brain and serum. This is the first report on the distribution of tamoxifen and metabolites into human brain and brain tumour, and the data form a basis for further investigation into the therapeutic effects of tamoxifen on brain metastases from breast cancer.

Tamoxifen has known human metabolites that include 3-Hydroxytamoxifen, N-Desmethyltamoxifen, 4'-Hydroxytamoxifen, 4-Hydroxytamoxifen, Tamoxifen N-glucuronide, and alpha-Hydroxytamoxifen.

094ZI81Y45

TAMOXIFEN

Established Pharmacologic Class [EPC] - Estrogen Agonist/Antagonist

Mechanisms of Action [MoA] - Selective Estrogen Receptor Modulators

Tamoxifen is an Estrogen Agonist/Antagonist. The mechanism of action of tamoxifen is as a Selective Estrogen Receptor Modulator.

Compounds which inhibit or antagonize the action or biosynthesis of estrogenic compounds.

Antineoplastic agents that are used to treat hormone-sensitive tumors. Hormone-sensitive tumors may be hormone-dependent, hormone-responsive, or both. A hormone-dependent tumor regresses on removal of the hormonal stimulus, by surgery or pharmacological block. Hormone-responsive tumors may regress when pharmacologic amounts of hormones are administered regardless of whether previous signs of hormone sensitivity were observed. The major hormone-responsive cancers include carcinomas of the breast, prostate, and endometrium; lymphomas; and certain leukemias. (From AMA Drug Evaluations Annual 1994, p2079)

A structurally diverse group of compounds distinguished from ESTROGENS by their ability to bind and activate ESTROGEN RECEPTORS but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the ENDOMETRIUM or second generation based on their patterns of tissue specificity. (Horm Res 1997;48:155-63)

Agents that inhibit BONE RESORPTION and/or favor BONE MINERALIZATION and BONE REGENERATION. They are used to heal BONE FRACTURES and to treat METABOLIC BONE DISEASES such as OSTEOPOROSIS.

An oral dose of 20mg reaches a Cmax of 40ng/mL with a Tmax of 5 hours. The metabolite N-desmethyltamoxifen reaches a Cmax of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a Css of 120ng/mL and a Css of 336ng/mL.

Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% in the feces.

The volume of distribution of tamoxifen is approximately 50-60L/kg.

The clearance of tamoxifen was 189mL/min in a study of six postmenopausal women.

Tamoxifen appears to be absorbed slowly following oral administration, with peak serum concentrations generally occurring about 3-6 hours after a single dose. The extent of absorption in humans has not been adequately determined, but limited data from animal studies suggest that the drug is well absorbed. Data from animal studies also suggest that tamoxifen and/or its metabolites undergo extensive enterohepatic circulation.

Following oral administration, peak serum tamoxifen concentrations average about 17 ng/mL after a single 10-mg dose, about 40 ng/mL after a single 20-mg dose, and 65-70 ng/mL after a single 40-mg dose; however, there is considerable interindividual variation in serum tamoxifen concentrations attained after single doses and at steady state with continuous dosing.

THERAP CAT: Antiestrogen; antineoplastic (hormonal)

MEDICATION

Use (kg; approx.) in Germany (2009): >1000

Tamoxifen is indicated for the treatment of metastatic breast cancer in women and men and ductal carcinoma in Situ.

Tamoxifen is synthesized from appropriately substituted desoxybenzoin by an alkanol preparation by using standard methods and an olefinic link generated by an acid-catalyzed elimination reaction. Isomers are generated from this process in approximately a 1:1 ratio of Z (trans) and E (cis). These isomers can be separated by fractional crystallization to give the main functional (Z) form of tamoxifen.