Class: Antineoplastic Agents
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
Uses for Toremifene Citrate
Palliative treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or estrogen-receptor unknown tumors1 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† 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
Because of demonstrated cross-resistance with tamoxifen, usefulness of toremifene as second-line† endocrine therapy for treatment of metastatic breast cancer refractory to tamoxifen appears to be limited.3 13 14 19
Toremifene Citrate Dosage and Administration
Administer orally without regard to meals.1
Available as toremifene citrate; dosage expressed in terms of toremifene.1
Dosage adjustments not required.10
Dosage adjustments not required.9
Cautions for Toremifene Citrate
Known hypersensitivity to toremifene or any ingredient in the formulation.1
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 serum calcium concentrations periodically during therapy.1
Effects on the Uterus
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
Cardiac failure, MI, arrhythmia, angina pectoris, and edema reported.1
Monitor CBCs periodically during therapy.1
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
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
Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Not labeled for use in children.1
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
Interactions for Toremifene Citrate
Metabolized principally by CYP3A4.1
No formal drug interaction studies to date.1
Drugs Affecting Hepatic Microsomal Enzymes
Drugs Affecting Calcium
Drugs that decrease renal calcium excretion (e.g., thiazide diuretics): Potential pharmacologic interaction (increased risk of hypercalcemia).1
Anticoagulants, oral (e.g., warfarin)
Anticonvulsants (e.g., carbamazepine, clonazepam, phenobarbital, phenytoin)
Antifungals, azoles (e.g., ketoconazole)
Macrolides (e.g., erythromycin)
Decreased peak plasma concentration and AUC of toremifene24
Toremifene Citrate Pharmacokinetics
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 does not appear to affect absorption.1
Plasma Protein Binding
>99.5% (mainly albumin).1
Extensively metabolized, principally via CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo.1
Excreted as metabolites principally in feces, with about 10% excreted in urine over 1 week.1
Toremifene: Approximately 5 days.1
Elimination is slow due to enterohepatic circulation.1
25°C (may be exposed to 15–30°C); protect from heat and light.1
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
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.)
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.
60 mg (of toremifene)
Fareston (with povidone)
AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
Date published: July 01, 2006
Last reviewed: March 01, 2009
Date modified: February 08, 2016
1. GTx, Inc. Fareston (toremifene citrate) tablets prescribing information. Memphis, TN; 2004 Dec.
2. Jordan VC. Alternate antiestrogens and approaches to the prevention of breast cancer. J Cell Biochem. 1995; 22(Suppl):51-7.
3. Wiseman LR, Goa KL. Toremifene: a review of its pharmacological properties and clinical efficacy in the management of advanced breast cancer. Drugs. 1997; 54:141-60. [PubMed 9211086]
4. Pyrhonen S, Valavaara R, Modig H et al. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the Nordic phase III study. Br J Cancer. 1997; 76:270-7. [PubMed 9231932]
5. Gradishar WJ, Jordan VC. Clinical potential of new antiestrogens. J Clin Oncol. 1997; 15:840-52. [IDIS 381300] [PubMed 9053512]
6. Saarto T, Blomqvist C, Ehnholm C et al. Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer. J Clin Oncol. 1996; 14:429-33. [IDIS 362035] [PubMed 8636753]
7. Anon. Schering/Orion Fareston launch awaits resolution of labeling, promotional issues; European toremifene report cites need for long-term toxicity studies. F-D-C Rep. June 9, 1997: 6-7.
8. Tomas E, Kauppila A, Blanco G et al. Comparison between the effects of tamoxifen and toremifene on the uterus in postmenopausal breast cancer patients. Gynecol Oncol. 1995; 59:261-6. [PubMed 7590484]
9. Sotaniemi EA, Anttila MI. Influence of age on toremifene pharmacokinetics. Cancer Chemother Pharmacol. 1997; 40:185-8. [PubMed 9182842]
10. Anttila M, Laakso S, Nylanden P et al. Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function. Clin Pharmacol Ther. 1995; 57:628-35. [IDIS 348949] [PubMed 7781262]
11. Hayes DF, Van Zyl JA, Hacking A et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995; 13:2556-66. [IDIS 356136] [PubMed 7595707]
12. Pyrhonen S, Valavaara R, Vuorinen J et al. High dose toremifene in advanced breast cancer resistant to or relapsed during tamoxifen treatment. Breast Cancer Res Treat. 1994; 29:223-8. [PubMed 8049456]
13. Vogel CL, Shemano I, Schoenfelder J et al. Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer. J Clin Oncol. 1993; 11:345-50. [PubMed 8426212]
14. Stenbygaard LE, Herrstedt J, Thomsen JF et al. Toremifene and tamoxifen in advanced breast cancer: a double-blind cross-over trial. Breast Cancer Res Treat. 1993; 25:57-63. [PubMed 8518408]
15. Gershanovich M, Garin A, Baltina D et al. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Breast Cancer Res Treat. 1997; 45:251-62. [PubMed 9386869]
16. Gylling H, Pyrhonen S, Mantyla E et al. Tamoxifen and toremifene lower serum cholesterol by inhibition of delta 8-cholesterol conversion to lathosterol in women with breast cancer. J Clin Oncol. 1995; 13:2900-5. [IDIS 357160] [PubMed 8523053]
17. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Drug Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 1998 May.
18. Anon. Toremifene and letrozole for advanced breast cancer. Med Lett Drugs Ther. 1998; 40:43-5. [PubMed 9580744]
19. Buzdar AU, Hortobagyi GN. Tamoxifen and toremifene in breast cancer: comparison of safety and efficacy. J Clin Oncol. 1998; 16:348-53. [IDIS 397613] [PubMed 9440763]
20. Mitlak BH, Cohen FJ. In search of optimal long-term female hormone replacement: the potential of selective estrogen receptor modulators. Horm Res. 1997; 155-63.
21. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]
22. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.
23. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.
24. Kivisto KT, Villikka K, Nyman L et al. Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clin Pharmacol Ther. 1998; 64:648-54. [IDIS 416902] [PubMed 9871429]
25. Hamada N, Ogawa Y, Saibara T et al. Toremifene-induced fatty liver and NASH in breast cancer patients with breast-conservation treatment. Int J Oncol. 2000; 17:1119-23. [PubMed 11078796]
26. Pyrhonen S, Ellmen J, Vuorinen J et al. Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer. Breast Cancer Res Treat. 1999; 56:133-43. [PubMed 10573106]
27. Buzdar AU, Hortobagyi GN. Differences in toxicity findings for antiestrogens. J Clin Oncol. 1998; 16:2000.
28. O’Regan RM, Cisneros A, England GM et al. Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on endometrial cancer growth. J Natl Cancer Inst. 1998; 90:1552-8. [PubMed 9790548]
29. Reviewers’ comments (personal observations).
30. Shire, Newport, KY: Personal communication.
31. Holli K. Valavaara R, Blanco G et al. Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer. Finnish Breast Cancer Group. J Clin Oncol. 2000;18:3487-94.
32. Pagani O, Gelber S, Price K et al. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Ann Oncol. 2004;15:1749-59.
33. Price D, Stein B, Sieber P et al. Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J Urol. 2006; 176:965-71. [PubMed 16890670]
34. Bishop J, Murray R, Webster L et al. Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal patients with advanced breast cancer. Cancer Chemother Pharmacol. 1992; 30:174-8. [PubMed 1385761]
More about toremifene
- Other brands: Fareston