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|Trade names||Fareston, others|
|Synonyms||(Z)-Toremifene; 4-Chlorotamoxifen; Acapodene; CCRIS-8745; FC-1157; FC-1157a; GTx-006; NK-622; NSC-613680|
|Drug class||Selective estrogen receptor modulator|
|Metabolites||N-Desmethyltoremifene; 4-Hydroxytoremifene; Ospemifene|
Toremifene: 5–6 days|
Metabolites: 4–21 days
|Excretion||Feces: 70% (as metabolites)|
|Chemical and physical data|
|Molar mass||405.959 g/mol|
|3D model (JSmol)|
Side effects of toremifene include hot flashes, sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. It can also cause blood clots, irregular heartbeat, cataracts, visual disturbances, elevated liver enzymes, endometrial hyperplasia, and endometrial cancer. High blood calcium levels can occur in women with bone metastases.
The drug is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist–antagonist of the estrogen receptor (ER), the biological target of estrogens like estradiol. It has estrogenic effects in bone, the liver, and the uterus and antiestrogenic effects in the breasts. It is a triphenylethylene derivative and is closely related to tamoxifen.
Toremifene was introduced for medical use in 1997. It was the first antiestrogen to be introduced since tamoxifen in 1978. It is not available as a generic medication in the United States.
Toremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors. This is its only approved use in the United States. It shows equivalent effectiveness to tamoxifen for this indication. Toremifene has been found to be effective in the treatment of breast pain and may be a better drug than tamoxifen for this indication.
The side effects of toremifene are similar to those of tamoxifen. The most common side effect is hot flashes. Other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. In women with bone metastases, hypercalcemia may occur. Toremifene has a small risk of thromboembolic events. Cataracts, vision changes, and elevation of liver enzymes have been reported. The drug prolongs the QT interval and hence has a risk of potentially fatal dysrhythmias. The risk of dysrhythmias can be reduced by avoiding use in patients with hypokalemia, hypomagnesemia, pre-existing QT prolongation, and in those taking other QT-prolonging drugs. Because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer.
Toremifene is a competitive ligand of the estrogen receptor and has mixed agonistic and antagonistic actions in a tissue-selective manner. It has estrogenic activity in bone, partial estrogenic activity in the uterus and liver, and pure antiestrogenic activity in the breasts. The drug is very similar to tamoxifen and shares most of its properties. There are some indications that it may be safer than tamoxifen as it is not a hepatocarcinogen in animals and may have less potential for genotoxicity. However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of toremifene has been somewhat limited.
The bioavailability of toremifene has not been precisely determined but is known to be good. The drug is more than 99% bound to plasma proteins. It is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation. The metabolites of toremifene include N-desmethyltoremifene and 4-hydroxytoremifene and are less active than toremifene itself. Ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene. Toremifene and 4-hydroxytoremifene have a very long elimination half-life of 5 to 6 days, while N-desmethyltoremifene has an even longer elimination half-life of 6 to 21 days and ospemifene has an elimination half-life of 4 days. The long elimination half-lives of toremifene and its metabolites can be attributed to enterohepatic recirculation. Toremifene is eliminated 70% in the feces, as metabolites.
Unlike tamoxifen, toremifene is not a prodrug and does not depend on metabolism by CYP2D6 for bioactivation; hence, it may be preferable to tamoxifen in CYP2D6 poor metabolizers or in patients who are taking a drug that inhibits CYP2D6.
Toremifene, also known as 4-chlorotamoxifen, is a derivative of triphenylethylene and a close analogue of tamoxifen. It is also closely related to afimoxifene (4-hydroxytamoxifen) and ospemifene (deaminohydroxytoremifene).
Toremifene is marketed widely throughout the world and is available in the United States, the United Kingdom, Ireland, many other European countries, South Africa, Australia, New Zealand, and elsewhere throughout the world.
In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008
An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009, and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.
Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.