Toremifene (Monograph)

Brand name: Fareston
Drug class: Estrogen Agonists-Antagonists
- Antiestrogens
VA class: AN500
Chemical name: 2-Hydroxy-1,2,3-propanetricarboxylate (1:1) (Z)-2-[4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
Molecular formula: C₂₆H₂₈ClNO•C₆H₈O₇
CAS number: 89778-27-8

Medically reviewed by Drugs.com on Oct 6, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a nonsteroidal estrogen agonist-antagonist that is structurally and pharmacologically related to tamoxifen.^{1 3 19 20}

Uses for Toremifene

Breast Cancer

Palliative treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or estrogen-receptor unknown tumors^{1 4 11 15 21} (designated an orphan drug by FDA for this use).¹⁷ Not recommended for treatment of estrogen-receptor negative breast tumors.^{5 7} Similar efficacy and toxicity as tamoxifen.^{1 3 4 11 15 26} Not known whether toremifene offers a therapeutic advantage over tamoxifen for the treatment of advanced breast cancer in eligible patients.^{18 19 27}

Under investigation for use as adjuvant therapy^{† [off-label]} for early-stage breast cancer in node-positive postmenopausal women.^{31 32} Results from trials to date suggest similar efficacy and toxicity as tamoxifen.^{31 32}

Efficacy in treatment of advanced breast cancer in men^{† [off-label]} not demonstrated.^{29 30}

Because of demonstrated cross-resistance with tamoxifen, usefulness of toremifene as second-line^{† [off-label]} endocrine therapy for treatment of metastatic breast cancer refractory to tamoxifen appears to be limited.^{3 13 14 19}

Prostate Cancer

Under investigation as a preventive agent for prostate cancer^{† [off-label]} in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer.³³

Related/similar drugs

Enhertu, Kisqali, Ibrance, Arimidex, Femara, Verzenio, Xeloda

Toremifene Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.¹

Dosage

Available as toremifene citrate; dosage expressed in terms of toremifene.¹

Adults

Breast Cancer

Oral

60 mg once daily for metastatic breast cancer.¹ Continue therapy until disease progression occurs; in clinical studies, therapy was continued for a median duration of 5 months.¹

Prescribing Limits

Adults

Breast Cancer

Oral

Higher dosages (200 or 240 mg daily) associated with greater toxicity but provide no additional benefit in metastatic breast cancer.^{1 11 15}

Special Populations

Hepatic Impairment

Use with caution and monitor liver function carefully.¹⁰ Dosage reduction may be necessary.¹⁰

Renal Impairment

Dosage adjustments not required.¹⁰

Geriatric Patients

Dosage adjustments not required.⁹

Cautions for Toremifene

Contraindications

• Known hypersensitivity to toremifene or any ingredient in the formulation.¹

Warnings/Precautions

Warnings

Hypercalcemia and Tumor Flare

Hypercalcemia and tumor flare reported (usually during the first weeks of therapy) in patients with metastatic breast cancer who have bone metastases.¹ Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increase and then regression in the size of tumor lesions; tumor flare does not represent tumor progression or imply failure of treatment.¹

Monitor patients with bone metastases closely for hypercalcemia during first weeks of therapy.¹ If hypercalcemia occurs, institute appropriate measures; if severe, discontinue toremifene.¹

Monitor serum calcium concentrations periodically during therapy.¹

Effects on the Uterus

Endometrial hyperplasia and endometrial cancer reported.^{1 30} Long-term therapy not recommended in patients with preexisting endometrial hyperplasia.^{1 30}

Monitor carefully for uterine disorders.^{8 29 30} Gynecologic symptoms (i.e., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure) should be promptly evaluated.^{1 29} (See Advice to Patients.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹ Embryotoxicity and fetotoxicity demonstrated in animals.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard and potential loss of pregnancy.¹

General Precautions

Cardiovascular Effects

Pulmonary embolism, thrombophlebitis, thrombosis, cerebrovascular accident, and TIA reported.¹ Use not recommended in patients with history of thromboembolic disorders.¹

Cardiac failure, MI, arrhythmia, angina pectoris, and edema reported.¹

Hematologic Effects

Leukopenia and thrombocytopenia reported rarely;¹ monitor leukocyte and platelet counts in patients with leukopenia and thrombocytopenia.¹

Monitor CBCs periodically during therapy.¹

Hepatic Effects

Increased hepatic enzyme concentrations (e.g., AST, alkaline phosphatase, bilirubin) and jaundice reported.¹ Fatty liver and nonalcoholic steatohepatitis reported following long-term therapy with higher than recommended dosage (i.e., 80 mg daily).²⁵

Obtain liver function tests periodically during therapy.¹

Ocular Effects

Cataracts, dry eyes, abnormal visual fields, corneal keratopathy, glaucoma, abnormal vision/diplopia, and corneal opacity (corneal verticulata) reported.¹ Blurred vision reported following therapy with higher than recommended dosages (i.e., 200 or 240 mg daily).¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 30} Discontinue nursing or the drug.³⁰

Pediatric Use

Not labeled for use in children.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults,¹ but increased sensitivity cannot be ruled out.⁹

Hepatic Impairment

Decreased clearance in patients with hepatic impairment (i.e., cirrhosis, fibrosis).^{1 10} (See Elimination: Special Populations, under Pharmacokinetics.) Use with caution and monitor liver function carefully.¹⁰ Dosage reduction may be necessary.¹⁰

Common Adverse Effects

Hot flushes (flashes), sweating, nausea, vaginal discharge, dizziness, edema, vomiting, vaginal bleeding.¹

Drug Interactions

Metabolized principally by CYP3A4.¹

No formal drug interaction studies to date.¹

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4-6: Potential pharmacokinetic interaction (increased toremifene concentrations).^{1 29 30} Clinical importance unknown.¹

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased toremifene concentrations).^{1 10 24}

Drugs Affecting Calcium

Drugs that decrease renal calcium excretion (e.g., thiazide diuretics): Potential pharmacologic interaction (increased risk of hypercalcemia).¹

Specific Drugs

Toremifene Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak plasma concentration usually attained within 3 hours.¹

Steady-state concentrations are reached in about 4–6 weeks.¹

Food

Food does not appear to affect absorption.¹

Distribution

Extent

Crosses the placenta and accumulates in the fetus in rodents.¹ Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

>99.5% (mainly albumin).¹

Special Populations

Increased toremifene volume of distribution in geriatric female patients; however, no change in AUC.^{1 9}

Elimination

Metabolism

Extensively metabolized, principally via CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo.¹

Elimination Route

Excreted as metabolites principally in feces, with about 10% excreted in urine over 1 week.¹

Half-life

Toremifene: Approximately 5 days.¹

N-demethyltoremifene: 6 days.¹ Deaminohydroxy toremifene: 4 days.¹

Elimination is slow due to enterohepatic circulation.¹

Special Populations

Increased toremifene elimination half-life in patients with hepatic impairment (i.e., cirrhosis, fibrosis).^{1 10}

Pharmacokinetics are not altered in patients with renal impairment.^{1 10}

Increased toremifene elimination half-life in geriatric female patients; however, no change in clearance.^{1 9}

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C); protect from heat and light.¹

Actions

• Acts as an estrogen antagonist on breast tissue and as a weak estrogen agonist on endometrium, bone, and lipids.^{1 3}

• In breast cancer, competitively binds to estrogen receptors and blocks tumor growth stimulated by estrogen.^{1 3} Also may inhibit tumor growth through other mechanisms (e.g., induction of apoptosis, regulation of oncogene expression and growth factors).³

• Decreases total and LDL-cholesterol concentrations.^{3 6 16}

• Acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects on the endometrium.¹

Advice to Patients

• Importance of receiving routine gynecologic care and of immediately informing clinician if any new breast lumps or abnormal gynecologic symptoms, including menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain/pressure occur.^{1 29}

• Importance of informing patients with bone metastases about the typical manifestations of hypercalcemia and instructing patients to report promptly any symptoms to their clinician.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹ Necessity for clinicians to advise women to avoid pregnancy during therapy and to advise pregnant women of risk to the fetus and of potential loss of pregnancy.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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