No

Antineoplastic Agent, Miscellaneous

Treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor (ER) positive or ER unknown tumors

D

Hypersensitivity to toremifene

Hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply treatment failure or represent tumor progression. Institute appropriate measures if hypercalcemia occurs, and if severe, discontinue treatment. Drugs that decrease renal calcium excretion (eg, thiazide diuretics) may increase the risk of hypercalcemia in patients receiving toremifene.

>10%:

Endocrine & metabolic: Vaginal discharge, hot flashes

Gastrointestinal: Nausea, vomiting

Miscellaneous: Diaphoresis

1% to 10%:

Cardiovascular: Thromboembolism: Tamoxifen has been associated with the occurrence of venous thrombosis and pulmonary embolism; arterial thrombosis has also been described in a few case reports; cardiac failure, myocardial infarction, edema

Central nervous system: Dizziness

Endocrine & metabolic: Hypercalcemia may occur in patients with bone metastases; galactorrhea and vitamin deficiency, menstrual irregularities

Genitourinary: Vaginal bleeding or discharge, endometriosis, priapism, possible endometrial cancer

Ocular: Ophthalmologic effects (visual acuity changes, cataracts, or retinopathy), corneal opacities, dry eyes

Theoretically, overdose may be manifested as an increase of antiestrogenic effects such as hot flashes; estrogenic effects such as vaginal bleeding; or nervous system disorders such as vertigo, dizziness, ataxia and nausea

No specific antidote exists and treatment is symptomatic

CYP3A3/4 enzyme substrate

Increased toxicity:

CYP3A4-6 enzyme inhibitors (ketoconazole, erythromycin) inhibit the metabolism of toremifene

Warfarin results in significant enhancement of the anticoagulant effects of warfarin; has been speculated that a decrease in antitumor effect of tamoxifen may also occur due to alterations in the percentage of active tamoxifen metabolites

Nonsteroidal, triphenylethylene derivative. Competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. Nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues; cells accumulate in the G₀ and G₁ phases; therefore, tamoxifen is cytostatic rather than cytocidal.

Absorption: Well absorbed from GI tract

Distribution: V_d: 580 L

Protein binding: Plasma: Extensive, >99.5%, mainly to albumin

Metabolism: Extensively, principally by cytochrome P-450 3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency

Half-life: ~5 days

Time to peak serum concentration: Oral: Within 3 hours

Elimination: Primarily in the feces with about 10% excreted in the urine during a 1-week period

Refer to individual protocols

Dosage adjustment in renal impairment: No dosage adjustment necessary

Dosage adjustment in hepatic impairment: Toremifene is extensively metabolized in the liver and dosage adjustments may be indicated in patients with liver disease; however, no specific guidelines have been developed

Orally, usually as a single daily dose; occasionally in 2 or 3 divided doses

Obtain periodic complete blood counts, calcium levels, and liver function tests. Closely monitor patients with bone metastases for hypercalcemia during the first few weeks of treatment. Leukopenia and thrombocytopenia have been reported rarely; monitor leukocyte and platelet counts during treatment.

Dizziness, anxiety, irritability, insomnia, and depression are common

None reported

No information available to require special precautions

No effects or complications reported

Take as directed, without regard to food. You may experience an initial "flare" of this disease (increased bone pain and hot flashes) which will subside with continued use. You may experience nausea, vomiting, or loss of appetite (frequent mouth care, frequent small meals, chewing gum, or sucking lozenges may help); dizziness (use caution when driving, climbing stairs, or engaging in tasks requiring alertness until response to drug is known); or loss of hair (will grow back). Report vomiting that occurs immediately after taking medication; chest pain, palpitations or swollen extremities; vaginal bleeding, hot flashes, or excessive perspiration; chest pain, unusual coughing, or difficulty breathing; or any changes in vision or dry eyes. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Do not breast-feed.

Increase of bone pain usually indicates a good therapeutic response

Tablet, as citrate: 60 mg

Gams R, "Phase III Trials of Toremifene vs Tamoxifen," Oncology, 1997, 11(5 Suppl 4): 23-8.

Hamm JT, "Phase I and II Studies of Toremifene," Oncology, 1997, 11(5 Suppl 4):19-22.

Holli K, "Evolving Role of Toremifene in the Adjuvant Setting," Oncology, 1997, 11(5 Suppl 4):48-51.

Kangas L, "Review of the Pharmacological Properties of Toremifene," J Steroid Biochem, 1990, 36(3):191-5.

Pyrhönen S, Valavaara R, Modig H, et al, "Comparison of Toremifene and Tamoxifen in Postmenopausal Patients With Advanced Breast Cancer: A Randomized Double-Blind, the "Nordic" Phase III Study," Br J Cancer, 1997, 76(2):270-7.

Williams GM and Jeffrey AM, "Safety Assessment of Tamoxifen and Toremifene," Oncology, 1997, 11(5 Suppl 4):41-7.