Professional Drug Information > Fareston

Toremifene (Systemic)

VA CLASSIFICATION
Primary: AN500

Commonly used brand name(s): Fareston.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Accepted

Carcinoma, breast (treatment)—Toremifene is indicated for treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor–positive or unknown tumors ^{01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Nonsteroidal triphenylethylene derivative ^{01}.
Molecular weight—
    Toremifene citrate: 598.1 ^{01}

pKa—
    8 ^{01}

Solubility
    Water solubility at 37 °C is 0.63 mg per mL (mg/mL) and solubility in hydrochloric acid at 37 °C is 0.38 mg/mL ^{01}.

Mechanism of action/Effect:

Toremifene binds to estrogen receptors. Its effects are mainly antiestrogenic (as indicated by a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women), but it also has some estrogenic effects (as indicated by a decrease in serum gonadotropin [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] concentrations). The antitumor effect in breast cancer is thought to be related primarily to its antiestrogenic effects (i.e., competition with estrogen for binding sites in the cancer), thereby blocking the growth-stimulating effects of estrogen in the tumor. ^{01}

Absorption:

Well absorbed; not affected by food ^{01}.

Distribution:

Apparent volume of distribution is 580 liters ^{01}.

Protein binding:

Very high (more than 99.5%), mainly to albumin ^{01}.

Biotransformation:

Hepatic, extensive, mainly by cytochrome CYP3A4 to N-demethyltoremifene, which has antiestrogenic effects but weak in vivo antitumor activity ^{01}.

Half-life:


Distribution:

Mean, about 4 hours ^{01}.



Elimination:

Toremifene: About 5 days ^{01}.

N-demethyltoremifene: 6 days ^{01}.

Deaminohydroxy toremifene: 4 days ^{01}.

Note: Enterohepatic recirculation contributes to the slow elimination of toremifene ^{01}.



Note: Mean total clearance of toremifene is approximately 5 liters per hour ^{01}.


Time to peak concentration:

Plasma—Within 3 hours ^{01}.

Note: Time to steady-state concentrations is about 4 to 6 weeks ^{01}. Serum concentrations of N-demethyltoremifene, the main metabolite, are two to four times higher than those of toremifene at steady state ^{01}.
Pharmacokinetics are linear after single oral doses of 10 to 680 mg; with multiple doses, dose proportionality occurs for doses of 10 to 400 mg ^{01}.


Elimination:
    Fecal, as metabolites ^{01}.
    Renal, about 10% within 1 week ^{01}.


Precautions to Consider

Carcinogenicity

Studies in rats at doses of 0.12 to 12 mg per kg of body weight per day (mg/kg per day) (about .01 to 1.5 times the daily maximum recommended human dose [MRHD] on a mg per square meter of body surface area [mg/m ²] basis) for up to 2 years did not find evidence of carcinogenicity ^{01}. Studies in mice given doses of 1 to 30 mg/kg per day (about .07 to 2 times the daily MRHD on a mg/m ² basis) for up to 2 years showed increased incidence of ovarian and testicular tumors, and an increased incidence of osteoma and osteosarcoma; the significance is uncertain because toremifene is predominantly estrogenic, rather than antiestrogenic, in mice ^{01}.

Some patients treated with toremifene have developed endometrial cancer, but because of other factors present (short duration of treatment, prior antiestrogen therapy, premalignant conditions) a direct causal relationship has not been established ^{01}.

Mutagenicity

Toremifene has not been found to be mutagenic in in vitro tests (Ames and Escherichia coli bacterial tests). It is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). Use of ³²P post-labeling in liver DNA from rats given toremifene produced no detectable adduct formation compared with tamoxifen at similar doses. In addition, in a study in cultured human lymphocytes, adducting activity of toremifene (detected using ³²P post-labeling) was approximately one sixth that of tamoxifen at approximately equipotent concentrations. In a study in salmon sperm, adducting activity of toremifene (detected using ³²P post-labeling) was one sixth and one fourth that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold that of tamoxifen based on human area under the plasma concentration–time curve (AUC) in serum at recommended clinical doses. ^{01}

Pregnancy/Reproduction
Fertility—
Studies in male and female rats at doses of 25 and 0.14 mg per kg of body weight per day (mg/kg per day) (about 3.5 times and .02 the daily MRHD on a mg/m ² basis) or higher, respectively, found impairment of fertility and conception. At these doses, atrophy of seminal vesicles and prostate were seen in males and sperm counts, fertility indices, and conception rates were reduced. In females, fertility and reproductive indices were reduced markedly with increased pre- and postimplantation loss. Reproductive indices were also depressed in offspring of treated rats. Studies in dogs showed that doses of 3 mg/kg per day (about 1.5 times the daily MRHD on a mg/m ² basis) or higher for 16 weeks produced ovarian atrophy. Studies in monkeys for 52 weeks at doses of 1 mg/kg per day (about one fourth of the daily MRHD on a mg/m ² basis) or higher found cystic ovaries and reduction in endometrial stromal cellularity. ^{01}

Pregnancy—
Studies in humans have not been done ^{01}.

Studies in rats at doses of 1 mg/kg per day (about one fourth of the daily MRHD on a mg/m ² basis) or higher given during the period of organogenesis found toremifene to be embryotoxic and fetotoxic, as indicated by 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). Fetal anomalies may be the result of maternal toxicity. Toremifene crosses the placenta and accumulates in the rodent fetus. ^{01}

In rodent models of fetal reproductive tract development, toremifene inhibits uterine development in female pups in a manner similar to that of diethylstilbestrol and tamoxifen, although the clinical relevance of these effects is unknown ^{01}.

Studies in rabbits at doses of 1.25 mg/kg per day and 2.5 mg/kg per day (about one third and two thirds of the daily MRHD on a mg/m ² basis) found embryotoxicity and fetotoxicity, respectively. Fetal anomalies included incomplete ossification and anencephaly. ^{01}

Women who are or may become pregnant should be advised of the potential risks to the fetus or the risk for loss of the pregnancy ^{01}.

FDA Pregnancy Category D ^{01}.

Breast-feeding

It is not known whether toremifene is distributed into breast milk. However, it is distributed into the milk of lactating rats. ^{01}

Geriatrics


The median ages in controlled clinical trials of toremifene ranged from 60 to 66 years; no age-related differences in efficacy or safety were noted ^{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants, coumarin-derivative    (concurrent use may result in an increased prothrombin time ^{01})


» Cytochrome P450 3A4 enzyme inducers, such as:
Carbamazepine
Phenobarbital
Phenytoin    (may increase the rate of metabolism of toremifene, leading to lower steady-state serum concentrations ^{01})


Cytochrome P450 CYP3A4-6 inhibitors, such as:
Erythromycin and similar macrolides
Ketoconazole and similar antimycotics    (theoretically may inhibit metabolism of toremifene; this interaction has not been studied ^{01})


Medications that decrease renal excretion of calcium, such as
Diuretics, thiazide    (risk of hypercalcemia may be increased ^{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase values, serum, and
Aspartate aminotransferase (AST [SGOT]) values, serum, and
Bilirubin concentrations, serum    (may be increased; dose-related ^{01})


Calcium    (serum concentrations may be increased infrequently, usually in patients with bone metastases ^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Thromboembolic disease, history of    (use of toremifene is generally not recommended ^{01})


Risk-benefit should be considered when the following medical problems exist
Bone metastases    (close monitoring for hypercalcemia is recommended during the first weeks of toremifene therapy ^{01})


» Endometrial hyperplasia, pre-existing    (long-term use is not recommended ^{01})


Leukopenia or
Thrombocytopenia    (since leukopenia and thrombocytopenia have been reported rarely during treatment with toremifene, monitoring of leukocyte and platelet counts is recommended ^{01})


Sensitivity to toremifene^{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Calcium concentrations, serum    (recommended at periodic intervals during treatment ^{01})


Complete blood count    (recommended at periodic intervals during treatment ^{01})


Hepatic function tests    (recommended at periodic intervals during treatment ^{01})




Side/Adverse Effects

Note: Side/adverse effects are mostly related to the antiestrogenic hormonal effects of toremifene and usually occur at the beginning of treatment ^{01}.
Some patients have developed endometrial cancer, but because of other factors present (short duration of treatment, prior antiestrogen therapy, premalignant conditions) a direct causal relationship with toremifene therapy has not been established ^{01}.
Leukopenia and thrombocytopenia have been reported but have not been attributed definitely to toremifene ^{01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hepatotoxicity^{01} —usually asymptomatic

Note: Hepatotoxicity usually consists of elevated hepatic enzyme and bilirubin levels. However, jaundice has been seen rarely. ^{01}


Incidence less frequent
    
Endometrial hyperplasia^{01} (change in vaginal discharge; pain or feeling of pressure in pelvis; vaginal bleeding)
    
hypercalcemia^{01} (confusion; increased urination; loss of appetite; unusual tiredness)
    
ocular toxicity, including abnormal visual fields, cataracts, corneal keratopathy, glaucoma^{01} (blurred vision; changes in vision)—may be asymptomatic initially

Note: Endometrial hyperplasia of the uterus has also been seen in monkeys following doses of 1 mg per kg of body weight (mg/kg) (about one fourth of the daily maximum recommended human dose [MRHD] on a mg per square meter of body surface area [mg/m ²] basis) or higher for 52 weeks, and in dogs following doses of 3 mg/kg (about 1.4 times the daily MRHD on a mg/m ² basis) or higher for 16 weeks ^{01}.
Hypercalcemia may occur in some patients, usually those with bone metastases, during the first weeks of treatment ^{01}.


Incidence rare
    
Cardiac failure^{01} (swelling of feet or lower legs)
    
myocardial infarction^{01} (chest pain)
    
pulmonary embolus^{01} (shortness of breath)
    
thrombophlebitis or thrombosis^{01} (pain or swelling in legs)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Hot flashes^{01} (sudden sweating and feelings of warmth)
    
nausea^{01}

Note: Nausea is dose-related ^{01}.


Incidence less frequent
    
Dizziness^{01}
    
dry eyes^{01}
    
tumor flare (bone pain)
    
vomiting^{01}

Note: “Tumor flair,” a transient increase in bone or tumor pain (characterized by diffuse musculoskeletal pain and erythema with increased size of tumor lesions) may occur during the first few weeks after initiation of therapy. It is often accompanied by hypercalcemia. This temporary “tumor flair” subsequently regresses and does not imply treatment failure or tumor progression. ^{01}






Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Dizziness^{01}
    
headache^{01}
    
nausea and/or vomiting


Note: The symptoms listed above have been reported with administration of a daily dose of 680 mg for 5 days; they appeared in two of five healthy subjects during the third day of treatment and disappeared within 2 days after withdrawal of the medication ^{01}. In a study in postmenopausal breast cancer patients, a dose of 400 mg per square meter of body surface area per day caused similar symptoms, as well as reversible hallucinations and ataxia in one patient ^{01}.
Theoretical symptoms of toremifene overdose include antiestrogenic effects such as hot flashes, estrogenic effects such as vaginal bleeding, or nervous system disorders such as vertigo, dizziness, ataxia, or nausea ^{01}.


Treatment of overdose
Treatment is symptomatic ^{01}.

There is no specific antidote ^{01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Toremifene (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to toremifene

Pregnancy—Risk of miscarriage, death of the fetus, and birth defects; telling physician immediately if pregnancy is suspected
Other medications, especially anticoagulants (coumarin-derivative), carbamazepine, phenobarbital, or phenytoin
Other medical problems, especially endometrial hyperplasia or history of thromboembolic disease

Proper use of this medication

» Proper dosing

» Proper storage


Side/adverse effects
Possible increased risk of endometrial carcinoma

Signs of potential side effects, especially endometrial hyperplasia, hypercalcemia, ocular toxicity, cardiac failure, myocardial infarction, pulmonary embolus, and thrombophlebitis or thrombosis

Asymptomatic side effects including hepatotoxicity and ocular toxicity


General Dosing Information
If hypercalcemia occurs, appropriate measures should be taken. If it is severe, toremifene should be discontinued ^{01}.


Oral Dosage Forms

TOREMIFENE CITRATE TABLETS

Note: The dosing and strengths available are expressed in terms of toremifene base (not the salt) ^{01}.


Usual adult dose
Breast carcinoma
Oral, 60 mg (base) once a day ^{01}.


Usual geriatric dose
See Usual adult dose ^{01}.

Strength(s) usually available
U.S.—


60 mg (base) (Rx) [Fareston (lactose)]

Packaging and storage:
Store at 25 °C (77 °F). Protect from light. ^{01}

Developed: 03/23/1998

References

1. Fareston package insert (Schering—US), Rev 1/97, Rec 12/97.
   

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