AHFS Class:

• Estrogen Agonists-Antagonists 68:16.12

Generic Name(s):

• Toremifene Citrate

Toremifene, a nonsteroidal estrogen agonist-antagonist, is an antineoplastic agent.1,3

Breast Cancer

Adjuvant Therapy for Early-stage Breast Cancer

The use of toremifene as adjuvant therapy for early-stage breast cancer† is being investigated.31,32 Results to date from 2 large randomized trials suggest that toremifene has similar efficacy and toxicity as tamoxifen for the adjuvant treatment of node-positive breast cancer in postmenopausal women.31,32

Therapy for Metastatic Breast Cancer

Toremifene is used in the palliative treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or estrogen receptor-unknown tumors.1,21 Currently, toremifene has been studied in women only, and efficacy of the drug in the treatment of advanced breast cancer in men† has not been demonstrated.29,30 Use of toremifene is not recommended for the treatment of estrogen receptor-negative breast tumors.5,7

The current indication for toremifene in the palliative treatment of breast cancer is based principally on the results of 3 prospective, randomized, controlled studies involving 1157 postmenopausal women with estrogen receptor-positive or estrogen receptor-unknown metastatic breast cancer.1,4,11,15 In these comparative studies, patients were randomly assigned to receive toremifene or tamoxifen,1,4,11,15 and, in 2 of the 3 trials, patients receiving toremifene were assigned to usual-dose (60 mg daily) or high-dose (200 or 240 mg daily) therapy.11,15

The results of these large comparative studies show that toremifene is as effective as tamoxifen for the treatment of estrogen receptor-positive or estrogen receptor-unknown metastatic breast cancer in postmenopausal women.1,4,11,15 In 2 studies, patients receiving toremifene (60 mg daily) or tamoxifen (20 mg daily in one study and 40 mg daily in the other study) had similar objective response rates (21.3 versus 19.1% and 20.4 versus 20.8%, respectively) and median time to progression of disease (5.6 versus 5.8 months and 4.9 versus 5 months, respectively).1,11,15 In a third study, objective response rates were similar (31.3 versus 37.3%) in patients receiving toremifene 60 mg daily or tamoxifen 40 mg daily, but the median time to progression of disease was shorter for toremifene compared with tamoxifen (7.3 versus 10.2 months).4 Median survival was similar among patients receiving toremifene (60 mg daily) compared with those receiving tamoxifen 20 mg daily (33.6 versus 34 months) in one study or tamoxifen 40 mg daily (25.4 versus 23.4 months, 33 versus 38.7 months) in the other 2 studies.1,4,15

Similar toxicity was observed for patients receiving toremifene (at usual doses) or tamoxifen in these randomized trials.1,3 Similar efficacy but greater toxicity was observed in patients receiving high dosages (200 or 240 mg daily) of toremifene.1,11,15 Greater frequency of nausea and elevation in serum AST (SGOT) concentration occurred in patients receiving high-dose toremifene, and 4% of these patients discontinued the drug because of adverse effects.1

Analysis of data from each study and analysis of pooled data from all 3 pivotal randomized trials demonstrate that toremifene and tamoxifen have similar efficacy and toxicity for the treatment of advanced estrogen receptor-positive or estrogen receptor-unknown breast cancer in postmenopausal women.1,26 Further study is needed to determine and/or clarify other potential effects of long-term therapy with toremifene, including beneficial effects (e.g., reduction in serum lipid concentrations and decrease in cardiovascular risk, increase in bone mineral density and decreased risk of osteopenia and osteoporosis) as well as detrimental effects (e.g., risk of endometrial cancer).3,19 Until further data are available, it is not known whether toremifene offers a therapeutic advantage over tamoxifen for the treatment of advanced breast cancer in eligible patients.18,19,27,29,30

Although occasional responses to higher dosages of toremifene (120-240 mg daily) have been reported in postmenopausal women with metastatic breast cancer refractory to tamoxifen therapy†, 3,12,13 cross-resistance between toremifene and tamoxifen has been demonstrated, and the usefulness of toremifene as second-line endocrine therapy for such disease appears to be limited.3,13,14,19

Prostate Cancer

The use of toremifene as a preventative agent for prostate cancer† is being investigated.33 In a randomized, placebo-controlled, phase II study, the incidence of prostate cancer at 1 year was lower in men who received toremifene rather than placebo for high-grade prostatic intraepithelial neoplasia.33 A phase III trial is under way to further evaluate the use of toremifene as preventive therapy in men at high risk for developing prostate cancer.33

Administration

Toremifene citrate is administered orally.1 Food does not affect the absorption of toremifene, and the drug may be administered without regard to meals.1

Dosage

Dosage of toremifene citrate is expressed in terms of toremifene.1

Breast Cancer

For the palliative treatment of estrogen receptor-positive or estrogen receptor-unknown tumors in postmenopausal women with advanced or metastatic breast cancer, the usual dosage of toremifene is 60 mg once daily.1 Treatment generally is continued until disease progression occurs; the median duration of treatment in 3 large randomized trials was 5 months.1

Dosage Modification for Toxicity and Contraindications to Continued Therapy

Adverse effects requiring discontinuance of therapy, including pulmonary embolism, myocardial infarction, ischemic attack, thrombophlebitis, nausea and vomiting, anorexia, fatigue, depression, lethargy, and arthritis, occurred in approximately 1% of patients receiving toremifene 60 mg daily in clinical trials.1

Musculoskeletal Toxicity

If hypercalcemia occurs during toremifene therapy, appropriate treatment should be initiated; if hypercalcemia is severe, the drug should be discontinued.1

Dosage in Renal and Hepatic Impairment

Because only minimal amounts of toremifene (about 10%) are excreted in urine, and because the pharmacokinetics of toremifene citrate and N -demethyltoremifene, an active metabolite of the drug, are not altered in patients with renal impairment, dosage adjustment is not necessary in such patients.1,10

Toremifene is extensively metabolized in the liver, and the drug is eliminated more slowly in patients with hepatic impairment (e.g., cirrhosis or fibrosis).1,10 In patients with hepatic impairment, toremifene should be used with caution and liver function should be monitored carefully; although the manufacturer makes no specific recommendation, reduction of toremifene dosage may be necessary.1,10

Similar toxicity was observed for patients receiving toremifene (at usual doses) or tamoxifen in large randomized trials; high-dose toremifene caused greater toxicity without any added benefit.1,3 Adverse effects of toremifene mainly result from the antiestrogenic actions of the drug and usually occur early in the course of therapy.1 Adverse effects requiring discontinuance of toremifene, including pulmonary embolism, myocardial infarction, ischemic attack, thrombophlebitis, nausea and vomiting, anorexia, fatigue, depression, lethargy, and arthritis, occurred in approximately 1% of patients.1

Unless otherwise stated, incidence data for adverse effects are based on data from 3 randomized comparative trials involving a total of 592 postmenopausal women receiving toremifene 60 mg daily for metastatic breast cancer.1 In one of these randomized trials, the North American Study, 221 patients received toremifene 60 mg daily and 215 patients received tamoxifen 20 mg daily.1 In the other 2 randomized trials (the Eastern European and Nordic studies), patients received toremifene 60 mg daily (157 and 214 patients, respectively) or tamoxifen 40 mg daily (149 and 201 patients, respectively).1

Cardiovascular Effects

Discontinuance of therapy because of adverse cardiovascular effects, including pulmonary embolism, myocardial infarction, ischemic attack, and thrombophlebitis, has occurred in patients receiving toremifene.1

Thromboembolic Events

Pulmonary embolism was reported in up to 2% of patients receiving toremifene in clinical trials, and thrombosis was reported in up to 1.5% of patients.1 Cerebrovascular accident (or transient ischemic attack) and thrombophlebitis each were reported in up to 2% of patients.1

Myocardial infarction and cardiac failure each occurred in up to 1% of patients.1 Angina pectoris was reported in less than 1% of patients receiving toremifene in clinical trials.1

Vasomotor Symptoms

Vasomotor symptoms (i.e., hot flushes [flashes]), one of the most common adverse effects reported in women receiving toremifene, were reported in 35% of patients receiving the drug in the North American Study.1

Effects on Lipoproteins

Limited data indicate that toremifene, like tamoxifen, reduces serum concentrations of total cholesterol and low-density lipoprotein (LDL)-cholesterol.3,6,16

Other Cardiovascular Effects

Edema was reported in 5% of patients receiving toremifene in the North American Study.1 Arrhythmias were reported in up to 1.5% of patients receiving toremifene.1

Hepatic Effects

Elevated serum alkaline phosphatase concentration (exceeding 200 IU/L) was reported in 19% of patients receiving toremifene in the North American Study.1 In the same study, elevated serum AST (SGOT) concentration (exceeding 100 IU/L) occurred in 5% of patients, and elevated serum bilirubin concentration (exceeding 2 mg/dL) occurred in 1.5% of patients.1 Using the WHO definition, grade 1 elevations (1.25 times the upper level of normal) in serum alkaline phosphatase, AST, and bilirubin concentrations were reported in 10 and 8%, 19 and 15%, and 1% of patients receiving toremifene in the Eastern European and Nordic studies, respectively.1 A higher incidence of elevated serum AST concentration was reported in patients receiving high-dose toremifene.1

Jaundice also has been reported in patients receiving toremifene.1 Discontinuance of therapy secondary to abnormal liver function test results or toxic hepatitis was reported in patients receiving high-dose toremifene.1 Fatty liver and nonalcoholic steatohepatitis have been reported in patients receiving long-term therapy with toremifene at a higher than recommended dosage (i.e., 80 mg daily).25

GI Effects

Nausea and vomiting were reported in 14 and 4%, respectively, of patients receiving toremifene in the North American Study.1 Discontinuance of therapy because of nausea and vomiting or anorexia has been reported in patients receiving toremifene.1 A higher incidence of nausea was reported in patients receiving high-dose toremifene, and such therapy was discontinued in a patient experiencing a syndrome consisting of nausea, sweating, and tremor.1 Constipation also has been reported in patients receiving toremifene.1

Genitourinary Effects

Vaginal discharge and vaginal bleeding were reported in 13 and 2%, respectively, of patients receiving toremifene in the North American Study.1 Endometrial hyperplasia and endometrial cancer have been reported in women receiving toremifene.1

Ocular Effects

Ophthalmic examinations were performed during the study and biannually for patients enrolled in the North American Study.1 Among these patients, cataracts and dry eyes were reported in 10 and 9%, respectively, of those receiving toremifene; abnormal visual fields, corneal keratopathy, and glaucoma were reported in 4, 2, and 1.5%, respectively, of patients receiving toremifene.1 No cases of retinopathy were observed in patients receiving toremifene or tamoxifen in the North American Study.1 Abnormal vision/diplopia occurred in up to 1.5% of patients receiving toremifene.1 Reversible corneal opacity (corneal verticulata) has been reported in patients receiving toremifene.1 A case of blurry vision resulting in discontinuance of therapy was reported in a patient receiving high-dose toremifene.1

Musculoskeletal Effects

As with other antiestrogens (e.g., tamoxifen), hypercalcemia and tumor flare may occur during initial toremifene therapy in patients with bone metastases.1 Tumor flare, which often is accompanied by hypercalcemia, 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

Hypercalcemia, in some cases severe, may occur during initial toremifene therapy in patients with metastatic breast cancer who have bone metastases.1 Hypercalcemia was reported in up to 3% of patients receiving toremifene in clinical trials.1 Discontinuance of therapy because of severe hypercalcemia has been reported in patients receiving high-dose toremifene.1 If hypercalcemia occurs during toremifene therapy, appropriate treatment should be initiated; if hypercalcemia is severe, the drug should be discontinued.1

Arthritis has been reported and cited as a reason for discontinuance of therapy in patients receiving toremifene.1

Nervous System Effects

Dizziness was reported in 9% of patients receiving toremifene in the North American Study.1 Depression has been reported and cited as a reason for discontinuance of therapy in patients receiving usual or high doses of toremifene.1 Dizziness, incoordination, and ataxia each were reported as leading to discontinuance of treatment in at least one patient receiving high-dose toremifene.1 Paresis, tremor, and vertigo also have been reported in patients receiving toremifene.1

Dermatologic Effects

Sweating was reported in 20% of patients receiving toremifene in the North American Study.1 Skin discoloration, dermatitis, alopecia, and pruritus have been reported in patients receiving toremifene.1 Diffuse dermatitis leading to discontinuance of therapy was reported in a patient receiving high-dose toremifene.1

Hematologic Effects

Leukopenia and thrombocytopenia rarely have been reported in patients receiving toremifene.1

Other Adverse Effects

Other adverse effects reported in patients receiving toremifene include dyspnea, rigors, and asthenia.1 Fatigue and lethargy have been reported and cited as reasons for discontinuance of therapy in patients receiving high-dose toremifene.1 High-dose toremifene therapy was discontinued in a patient experiencing a syndrome consisting of nausea, sweating, and tremor.1

Precautions and Contraindications

Because of the risk of thrombotic events, including pulmonary embolism and thrombosis, the manufacturer generally does not recommend use of toremifene in patients with a history of thromboembolic disorders.1

Long-term tamoxifen therapy has been associated with an increased risk of uterine cancer, including endometrial cancer,8 and endometrial cancer and endometrial hyperplasia have been reported in patients receiving toremifene.1,30 Because of the risk of endometrial cancer associated with tamoxifen and toremifene, a tamoxifen analog, patients should be monitored carefully for uterine disorders.8,29,30 The manufacturer generally does not recommend long-term therapy with the drug in patients with preexisting endometrial hyperplasia.1,30 Women receiving toremifene or women with a history of having received toremifene who report abnormal vaginal bleeding should be evaluated promptly.29 Women receiving or who have received toremifene should receive routine gynecologic care and should be advised to report promptly any abnormal gynecologic symptoms, such as menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain/pressure, to their clinician.1,29

Patients with bone metastases should be monitored closely for hypercalcemia for several weeks following initiation of toremifene therapy; such patients should be informed about the typical manifestations of hypercalcemia and instructed to report promptly any symptoms to their clinician.1

Complete blood cell counts, serum calcium concentration, and liver function tests should be measured periodically in patients receiving toremifene.1 Leukocyte and platelet counts should be monitored carefully during toremifene therapy in patients with leukopenia and thrombocytopenia.1

Patients complaining of visual changes or abnormalities during toremifene therapy should be assessed carefully for possible ocular toxicity.1

Toremifene is contraindicated in patients with known hypersensitivity to the drug.1

Pediatric Precautions

Toremifene is not labeled for use in children.1

Geriatric Precautions

While safety and efficacy of toremifene in geriatric patients have not been established specifically, the median age of women in large randomized trials of toremifene for the treatment of advanced breast cancer was 60-66 years.1 No age-related differences in the safety or efficacy of toremifene have been observed to date.1 Although the volume of distribution was increased and elimination of the drug was prolonged in elderly women, no change in the clearance of toremifene was observed.1,9 Dosage adjustment based solely on age does not appear to be necessary in geriatric patients; however, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.9

Mutagenicity and Carcinogenicity

Mutagenicity

In vitro tests (Ames test and E. coli bacterial tests) have not shown toremifene to be mutagenic.1 However, the drug has been shown to be clastogenic both in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).1

Carcinogenicity

The potential carcinogenicity of toremifene in humans has not been fully established; endometrial cancer has been reported in patients receiving toremifene. 1

Evidence of carcinogenicity was not observed in rats receiving toremifene 0.12-12 mg/kg daily (about 1/100 to 1.5 times the daily maximum recommended human dosage on a mg/m² basis) for up to 2 years.1 Administration of toremifene 1-30 mg/kg daily (about 1/15 to 2 times the daily maximum recommended human dosage on a mg/m² basis) for up to 2 years in mice resulted in an increased incidence of ovarian and testicular tumors, osteoma, and osteosarcoma.1 However, because of the mostly estrogenic effect of toremifene in mice and the different role of estrogens in mice, the clinical importance of these findings is uncertain.1 An increased incidence of ovarian and testicular tumors in mice also has been observed with other human antiestrogenic agents that have mainly estrogenic activity in mice.1

Uterine Cancer

Long-term tamoxifen therapy has been associated with an increased risk of uterine cancer, including endometrial cancer.8 Toremifene had estrogenic effects on the uterus similar to those elicited by tamoxifen (e.g., increase in endometrial thickness) in postmenopausal women with breast cancer,8 and toremifene and tamoxifen showed similar effects on stimulating the growth of endometrial tumors in athymic mice.28 Endometrial cancer and endometrial hyperplasia have been reported in patients receiving toremifene.1 Further study is needed to fully establish the comparative risk of endometrial cancer associated with long-term use of toremifene or tamoxifen.1,19,27 Endometrial hyperplasia was observed in monkeys following 52 weeks of treatment with toremifene at doses of at least 1 mg/kg and in dogs following 16 weeks of toremifene at doses of at least 3 mg/kg (about one-fourth and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m² basis).1

Liver Cancer

The risk of liver cancer in patients receiving toremifene or tamoxifen has not been fully established.2,19 Using equivalent concentrations of the drugs, toremifene showed about one-fourth and one-sixth of the DNA adducting activity of tamoxifen following activation by human and rat microsomal systems, respectively, in salmon sperm; however, when administered at the recommended doses in humans, exposure to toremifene is 4 times that of tamoxifen based on area under the concentration-time curve.1 At approximately equipotent concentrations, toremifene demonstrated about one-sixth of the adducting activity of tamoxifen in cultured human lymphocytes.1 In contrast to tamoxifen, no significant levels of DNA adducts were detected in the livers of rats exposed to similar doses of toremifene.1 Because an increase in the risk of hepatocellular cancer has not been demonstrated to date in patients receiving tamoxifen, the clinical importance of the relative carcinogenicity of toremifene and tamoxifen in rats is not known.19,27,29,30

Pregnancy, Fertility, and Lactation

Pregnancy

Toremifene can cause fetal toxicity when administered to pregnant women,1 but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.22,23

Embryotoxicity and fetotoxicity were demonstrated in rabbits receiving toremifene doses of at least 1.25 mg/kg and 2.5 mg/kg daily (approximately one-third and two-thirds, respectively, the daily maximum recommended human dosage on a mg/m² basis); fetal anomalies included incomplete ossification and anencephaly.1 In reproduction studies in rats using toremifene dosages of at least 1 mg/kg daily (about one-fourth the daily maximum recommended human dosage on a mg/m² basis) administered during the period of organogenesis, toremifene was embryotoxic and fetotoxic, resulting in intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies (including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema).1 Fetal anomalies may have occurred as a consequence of maternal toxicity.1 Toremifene has been shown to cross the placenta and accumulate in the fetus in rodents.1

In models of fetal reproductive tract development in rodents, toremifene caused inhibition of uterine development in female pups in a manner similar to tamoxifen and diethylstilbestrol (DES; no longer commercially available in the US); the clinical importance of this finding is not known.1

There are no adequate and well-controlled studies using toremifene in pregnant women.1 Toremifene is labeled for use in postmenopausal women.1 Toremifene should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.22,30 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus and the potential risk for loss of the pregnancy.1,30

Fertility

Studies in monkeys, dogs, and rats have revealed evidence of impaired fertility associated with toremifene.1

Cystic ovaries and reduced endometrial stromal cellularity were observed in monkeys receiving toremifene dosages of at least 1 mg/kg daily (about one-fourth the maximum daily recommended human dosage on a mg/m² basis) for 52 weeks.1 Ovarian atrophy occurred in dogs receiving toremifene dosages of at least 3 mg/kg daily (about 1.5 times the daily maximum recommended human dosage on a mg/m² basis) for 16 weeks.1

In reproduction studies in rats, toremifene dosages of at least 25 mg/kg daily in males or at least 0.14 mg/kg daily in females (about 3.5 times and 1/50, respectively, the daily maximum recommended human dosage on a mg/m² basis) resulted in impaired fertility and conception.1 In male rats, decreases in sperm counts, fertility index, and conception rate associated with atrophy of the seminal vesicles and prostate were observed; in female rats, indices of fertility and reproduction were markedly reduced, and increased rates of preimplantation and postimplantation loss were observed.1 Impaired fertility also was observed in the offspring of rats receiving toremifene.1

Lactation

It is not known if toremifene is distributed into milk in humans; however, the drug is distributed into milk in rats.1,30 Because of the potential for serious adverse reactions to toremifene in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.30

Formal studies of drug interactions with toremifene have not been performed to date.1

Anticoagulants

Like other triphenylethylene-derivative antiestrogens (e.g., tamoxifen), toremifene may cause an increase in prothrombin time in patients receiving coumarin-type anticoagulants (e.g., warfarin); if these agents must be used concomitantly, careful monitoring of prothrombin time is advised, and dosage adjustment of the anticoagulant may be necessary.1,29,30

Drugs Affecting Hepatic Microsomal Enzymes

Because toremifene is extensively metabolized by the liver, principally by the cytochrome P-450 isoenzyme 3A4, agents that affect CYP3A4 isoenzymes may alter the metabolism of the drug.1 The clinical importance of this interaction has not been fully established, but dosage adjustment of toremifene may be necessary.1,10,24

Concomitant use of known CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) may decrease serum concentrations of toremifene, and an increase in the dosage of toremifene may be necessary.1,10,24 In 10 patients receiving concomitant anticonvulsants (carbamazepine, clonazepam, phenobarbital, or phenytoin), a twofold increase in clearance and a decrease in the elimination half-life of toremifene were observed.1 In a crossover study of 9 healthy male individuals receiving placebo or rifampin 600 mg orally for 5 days prior to a single 120-mg dose of toremifene, administration of rifampin caused decreases of 87% in the area under the plasma concentration-time curve (AUC), 55% in the peak plasma concentration, and 44% in the elimination half-life of toremifene; the peak plasma concentration of its active metabolite, N -demethyltoremifene, was increased by 48%, while its AUC and elimination half-life were decreased by 80 and 41%, respectively.24

Concomitant use of CYP3A4-6 inhibitors (e.g., ketoconazole and similar antimycotic agents, erythromycin and similar macrolides) may inhibit the metabolism and possibly increase serum concentrations of toremifene.1,29,30 This interaction has not been studied and its clinical importance is not known.1

Other Drugs

Concomitant use of agents that decrease renal calcium excretion (e.g., thiazide diuretics) may increase the risk of hypercalcemia associated with toremifene therapy.1

Acute Toxicity

Pathogenesis

Limited information is available on the acute toxicity of toremifene.1 The acute lethal dose of toremifene in humans is not known.30 In rats, single oral doses of toremifene of at least 1000 mg/kg (about 150 times the maximum recommended human dose on a mg/m² basis) caused gastric atony and dilatation leading to interference with digestion, adrenal enlargement, and death.1

Manifestations

Overdosage of toremifene would be expected to produce symptoms related to the drug's antiestrogenic effects (e.g., hot flushes [flashes]), estrogenic effects (e.g., vaginal bleeding), and nervous system toxicity (e.g., vertigo, dizziness, ataxia, nausea).1

In healthy individuals receiving toremifene 680 mg daily for 5 days, vertigo, headache, and dizziness were observed.1 Symptoms occurred in 2 of 5 individuals during the third day of treatment and disappeared within 2 days of discontinuance of the drug.1 Immediate concomitant alterations in clinical chemistry parameters were not observed.1 Administration of toremifene 400 mg/m² daily in postmenopausal women with breast cancer resulted in dose-limiting nausea, vomiting, and dizziness; reversible hallucinations and ataxia also were reported in one patient.1,34

Treatment

There is no specific antidote for toremifene overdosage, and symptomatic treatment should be initiated.1

Pharmacology

Toremifene, a nonsteroidal triphenylethylene-derivative, is an estrogen agonist-antagonist.1,3

Toremifene is structurally and pharmacologically related to tamoxifen, and the drugs also have been referred to as antiestrogens since they previously were thought to be devoid of clinically important estrogen agonist activity.1,20 However, like tamoxifen, toremifene exhibits both estrogen agonist and antagonist (antiestrogen) activity, and the pharmacologic profiles of the 2 drugs are similar.1,3,19 This estrogen agonist and antagonist activity also is shared by several agents with differing chemical structure and pharmacologic activity, such as raloxifene and clomiphene.2,5,20

The degree of antiestrogenic and/or estrogenic effect of toremifene is influenced by factors such as duration of treatment, target organ, gender, and species; nonsteroidal triphenylethylene derivatives, such as toremifene, generally have a stronger antiestrogenic effect in humans and rats and a mainly estrogenic effect in mice.1 Toremifene acts as an estrogen antagonist on breast tissue.1 The antiestrogenic activity of toremifene is demonstrated by a decrease in the estradiol-induced cornification index, which has been observed in some postmenopausal women receiving the drug.1 Toremifene has weak estrogen-like effects in several sites, including endometrium, bone, and lipids.3 The estrogenic activity of toremifene has been demonstrated by decreases in serum gonadotropin (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) concentrations.1

Toremifene differs from tamoxifen by chlorination of the ethyl side chain, which reduces its antiestrogenic potency and antitumor potency;2,5 further study is needed to establish the comparative risk of carcinogenicity (e.g., uterine cancer, hepatocellular cancer) associated with these agents.2,3,18

Effects on the Breast

The principal mechanism of toremifene in breast cancer is thought to involve its antiestrogenic effect through competitive binding of the drug to estrogen receptors in the cancer, thus blocking tumor growth stimulated by estrogen.1,3 In rats, toremifene has been shown to cause regression of dimethylbenzanthracene-induced mammary tumors.1 In addition, toremifene may inhibit tumor growth through other mechanisms, such as induction of apoptosis and regulation of oncogene expression and growth factors.3

Effects on Lipoproteins

Limited data indicate that toremifene, like tamoxifen, reduces serum concentrations of total cholesterol and low-density lipoprotein (LDL)-cholesterol.3,6,16 Although toremifene increased serum concentrations of high-density lipoprotein (HDL)-cholesterol in one study,6 no effect was observed in another study;16 HDL-cholesterol concentrations appear to be marginally affected by tamoxifen.3,6 Long-term studies are needed to determine the effects of toremifene on serum cholesterol concentrations and cardiovascular risk.3,6,16,19

Effects on Bone

The effect of toremifene on bone density and risk of osteoporosis or osteopenia has not been established.7,19

Effects on the Uterus

Like tamoxifen, toremifene has estrogenic effects on the uterus (i.e., increase in endometrial thickness), and endometrial cancer has been reported in patients receiving toremifene.1,8

Pharmacokinetics

Absorption

Toremifene is well absorbed following oral administration.1 Absorption of the drug is not affected by food.1 Peak plasma concentrations of toremifene are achieved within 3 hours following oral administration of the drug.1 Toremifene undergoes enterohepatic circulation.1 Toremifene displays linear pharmacokinetics after single oral doses of 10-680 mg and dose proportionality after multiple doses of 10-400 mg.1 Steady-state concentrations of the drug are reached after 4-6 weeks of daily toremifene administration.1

Distribution

The apparent volume of distribution of toremifene is 580 L.1 The drug binds extensively (greater than 99.5%) to serum proteins, principally albumin.1 It is not known if toremifene is distributed into milk in humans; however, the drug is distributed into milk in rats.1 Toremifene has been shown to cross the placenta and accumulate in the fetus in rodents.1

Elimination

Plasma concentrations of toremifene appear to decline in a biphasic manner, with a mean distribution half-life of about 4 hours and a mean elimination half-life of about 5 days.1 The mean total clearance of toremifene is approximately 5 L/hour.1

Toremifene is extensively metabolized in the liver.1,3 The drug is metabolized mainly by cytochrome P-450 isoenzyme 3A4 to N -demethyltoremifene, which is antiestrogenic but has weak antitumor potency in vivo.1 At steady state, serum concentrations of N -demethyltoremifene are 2-4 times higher than those of toremifene.1 The elimination half-lives of N -demethyltoremifene and (deaminohydroxy) toremifene (another major metabolite) are reported to be 6 and 4 days, respectively.1

Toremifene is predominantly excreted in feces as metabolites, with about 10% of an administered dose excreted in urine during a 1-week period.1 Toremifene undergoes enterohepatic circulation, which contributes to its slow elimination.1

The pharmacokinetics of toremifene citrate and N -demethyltoremifene are not altered in patients with renal impairment.1,10 The elimination of toremifene is affected by hepatic dysfunction; in 10 patients with hepatic impairment secondary to cirrhosis or fibrosis, the mean elimination half-life of toremifene was increased by less than twofold compared with that in individuals with normal hepatic function.1,10 No effect on the pharmacokinetics of N -demethyltoremifene was observed in patients with hepatic impairment.1,10

Increases in the elimination half-life (7.2 versus 4.2 days) and the volume of distribution (627 versus 457 L) compared with values observed in healthy young males were reported in geriatric female patients receiving a single 120-mg dose of toremifene under fasting conditions; however, clearance and area under the plasma concentration-time curve were not altered.1,9

The pharmacokinetics of toremifene have not been evaluated separately by race; 86% of the patients in the North American study were white.1

Chemistry and Stability

Chemistry

Toremifene, a nonsteroidal estrogen agonist-antagonist, is an antineoplastic agent.1 Toremifene differs from tamoxifen by chlorination of the ethyl side chain, which reduces its antiestrogenic potency.

Toremifene citrate has a pK_a of 8.1 At 37°C, the drug is very slightly soluble in water (0.63 mg/mL) or 0.02 N hydrochloric acid (0.38 mg/mL).1 Toremifene is commercially available as tablets containing 88.5 mg of toremifene citrate, which is equivalent to 60 mg of toremifene.1

Stability

Commercially available toremifene citrate tablets should be stored at a controlled room temperature of 25°C and protected from light but may be exposed to temperatures ranging from 15-30°C.1

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. GTx. Fareston^® (toremifene citrate) tablets prescribing information. Memphis, TN; 2004 Dec.

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29. Reviewers' comments (personal observations).

30. Shire, Newport, KY: Personal communication.

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