Toremifene Citrate

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
Brands: Fareston

Introduction

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

Uses for Toremifene Citrate

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† 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† not demonstrated.^{29 30}

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}

Prostate Cancer

Under investigation as a preventive agent for prostate cancer† in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer.³³

Toremifene Citrate 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 Citrate

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

Interactions for Toremifene Citrate

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

Drug	Interaction	Comments
Anticoagulants, oral (e.g., warfarin)	Possible increased PT1 29 30	Monitor PT; adjust anticoagulant dosage if necessary1 29 30
Anticonvulsants (e.g., carbamazepine, clonazepam, phenobarbital, phenytoin)	Possible decreased toremifene concentrations (due to increased clearance and decreased elimination half-life of toremifene)1 10 24	Increase toremifene dosage if necessary1 10 24
Antifungals, azoles (e.g., ketoconazole)	Possible increased toremifene concentrations1 29 30	Adjust toremifene dosage if necessary1 10 24
Macrolides (e.g., erythromycin)	Possible increased toremifene concentrations1 29 30	Adjust toremifene dosage if necessary1 10 24
Rifampin	Decreased peak plasma concentration and AUC of toremifene24	Increase toremifene dosage if necessary1 10 24

Toremifene Citrate 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

ActionsActions

• 
  

  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.

Toremifene Citrate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	60 mg (of toremifene)	Fareston (with povidone)	GTx

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Fareston 60MG Tablets (GTX): 30/$580.02 or 90/$1725.87

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions March 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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]

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