Toremifene

Uses

Toremifene is a first generation nonsteroidal selective estrogen receptor modulator used to treat certain breast cancers.

For the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer.

Toremifene is also used to associated treatment for these conditions: Desmoid Tumors, Metastatic Breast Cancer

How Toremifene works

Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 and therefore, may elevate toremifene serum levels.
• Take with or without food.

[Moderate] GENERALLY AVOID: Coadministration with grapefruit juice may theoretically increase the plasma concentrations of toremifene.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism by certain compounds present in grapefruit.

Because toremifene is associated with dose- and concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

GENERALLY AVOID: Due to their estrogenic effect, isoflavones present in soy such as genistein and daidzein may stimulate breast tumor growth and antagonize the antiproliferative action of toremifene.

Supportive data are derived primarily from in vitro and animal studies.

In vitro, low concentrations of these phytoestrogens have been found to promote DNA synthesis and reverse the inhibitory effect of tamoxifen on oestrogen-dependent breast cancer cell proliferation.

In contrast, high concentrations of genistein greater than 10 microM

It is not known if these high concentrations are normally achieved in humans.

Plasma concentrations below 4 microM

These concentrations are comparable to the low plasma concentrations associated with tumor stimulation reported in animals.

In a study of 155 female breast cancer survivors with substantially bothersome hot flashes, a product containing 50 mg of soy isoflavones (40% to 45% genistein; 40% to 45% daidzein; 10% to 20% glycitein) taken three times a day was found to be no more effective than placebo in reducing hot flashes.

No toxicity or recurrence of breast cancer was reported during the 9-week study period.

MANAGEMENT: Until more information is available, patients treated with toremifene should consider avoiding the consumption of grapefruit juice and soy-containing products.

Patients should be advised to contact their physician if they experience vaginal bleeding or potential signs of blood clots such as chest pain, shortness of breath, sudden loss of vision, and pain, redness or swelling in an extremity.

Patients should seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Toremifene Drug Interaction

Major: venlafaxine, atazanavirModerate: oxcarbazepineUnknown: isotretinoin, amphetamine / dextroamphetamine, exemestane, liothyronine, estradiol / testosterone, dextroamphetamine, cabergoline, omega-3 polyunsaturated fatty acids, eszopiclone, pregabalin, emtricitabine / tenofovir, acetaminophen / codeine

Toremifene Disease Interaction

Major: QT prolongationModerate: endometrial hyperplasia, hepatotoxicity, thromboembolism

Volume of Distribution

• 580 L

Elimination Route

Well absorbed

Half Life

5 days

Clearance

• 5 L/h

Elimination Route

Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency.

Innovators Monograph

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