|indication=metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors
|indication=metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors
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<!--Contraindications-->
<!--Contraindications-->
|contraindications=* Condition1
|contraindications=* Hypersensitivity to the Drug
FARESTON is contraindicated in patients with known hypersensitivity to the drug.
4.2 QT Prolongation, Hypokalemia, Hypomagnesemia
Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.
<!--Warnings-->
<!--Warnings-->
|warnings=* Description
|warnings=* Prolongation of the QT Interval
Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.
====Precautions====
Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].
* Description
5.2 Hypercalcemia and Tumor Flare
As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued.
<!--Adverse Reactions-->
5.3 Tumorigenicity
Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology (13.1)].
<!--Clinical Trials Experience-->
5.4 General
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions (5.2)]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.
=====Body as a Whole=====
5.5 Laboratory Tests
Periodic complete blood counts, calcium levels, and liver function tests should be obtained.
5.6 Use in Pregnancy
Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
5.7 Women of Childbearing Potential
FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=* Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
=====Cardiovascular=====
6.1 Clinical Trials Experience
Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.
The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.
: [[File:Toremifene Adv Eff 1.png|none|500px]]
Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).
=====Digestive=====
Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.
Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively
: [[File:Toremifene Adv Eff 2.png|none|500px]]
Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.
=====Endocrine=====
The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.
Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.
|postmarketing=* The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.
|drugInteractions=Drugs that Decrease Renal Calcium Excretion
Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON.
7.2 Agents that Prolong QT
The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see BOXED WARNING and Warnings and Precautions (5.1)].
=====Hematologic and Lymphatic=====
7.3 Effect of Strong CYP3A4 Inducers on Toremifene
Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John's Wort, lower the steady-state concentration of toremifene in serum.
7.4 Effect of Strong CYP3A4 Inhibitors on Toremifene
In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.
The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see BOXED WARNING and Warnings and Precautions (5.1)].
7.5 Effect of Toremifene on CYP3A4 Substrates
In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%.
=====Metabolic and Nutritional=====
Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.
7.6 Effect of Toremifene on CYP2C9 Substrates
In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC.
Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).
<!--Use in Specific Populations-->
|FDAPregCat=D
|useInPregnancyFDA=* Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
=====Musculoskeletal=====
In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.
In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInNursing=* It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInPed=* There is no indication for use of FARESTON in pediatric patients.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGeri=* The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC.
The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRace=* The pharmacokinetics of toremifene in patients of different races has not been studied.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.
|useInRenalImpair=* The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.
|useInHepaticImpair=* The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
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|administration=* Oral
|administration=* Oral
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
|monitoring=* Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy.
* Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment
<!--IV Compatibility-->
* leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.
* Periodic complete blood counts, calcium levels, and liver function tests should be obtained.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
<!--Overdosage-->
|overdose====Acute Overdose===
|overdose=* Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
<!--Pharmacology-->
Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.
<!--Drug box 2-->
Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.
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Black Box Warning
WARNING: QT PROLONGATION :
See full prescribing information for complete Boxed Warning.
WARNING: QT PROLONGATION :
FARESTON has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided
Overview
Toremifene is a antineoplasic agent that is FDA approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flashes, sweating, nausea and vaginal discharge.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.
Dosage
The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.
DOSAGE FORMS AND STRENGTHS
Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Toremifene in adult patients.
There is limited information regarding FDA-Labeled Use of Toremifene in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Toremifene in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Toremifene in pediatric patients.
Contraindications
Hypersensitivity to the Drug
FARESTON is contraindicated in patients with known hypersensitivity to the drug.
4.2 QT Prolongation, Hypokalemia, Hypomagnesemia
Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.
Warnings
WARNING: QT PROLONGATION :
See full prescribing information for complete Boxed Warning.
WARNING: QT PROLONGATION :
FARESTON has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided
Prolongation of the QT Interval
Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.
Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].
5.2 Hypercalcemia and Tumor Flare
As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued.
5.3 Tumorigenicity
Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology (13.1)].
5.4 General
Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions (5.2)]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.
5.5 Laboratory Tests
Periodic complete blood counts, calcium levels, and liver function tests should be obtained.
5.6 Use in Pregnancy
Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
5.7 Women of Childbearing Potential
FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
6.1 Clinical Trials Experience
Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.
The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.
Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).
Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.
Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively
Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.
The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.
Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.
Postmarketing Experience
The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.
Drug Interactions
Drugs that Decrease Renal Calcium Excretion
Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON.
7.2 Agents that Prolong QT
The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see BOXED WARNING and Warnings and Precautions (5.1)].
7.3 Effect of Strong CYP3A4 Inducers on Toremifene
Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John's Wort, lower the steady-state concentration of toremifene in serum.
7.4 Effect of Strong CYP3A4 Inhibitors on Toremifene
In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.
The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see BOXED WARNING and Warnings and Precautions (5.1)].
7.5 Effect of Toremifene on CYP3A4 Substrates
In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%.
Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.
7.6 Effect of Toremifene on CYP2C9 Substrates
In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC.
Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).
Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.
Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.
In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Toremifene in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Toremifene during labor and delivery.
Nursing Mothers
It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
There is no indication for use of FARESTON in pediatric patients.
Geriatic Use
The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC.
The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.
Gender
There is no FDA guidance on the use of Toremifene with respect to specific gender populations.
Race
The pharmacokinetics of toremifene in patients of different races has not been studied.
Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.
Renal Impairment
The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.
Hepatic Impairment
The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Toremifene in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Toremifene in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy.
Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment
leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.
Periodic complete blood counts, calcium levels, and liver function tests should be obtained.
IV Compatibility
There is limited information regarding IV Compatibility of Toremifene in the drug label.
Overdosage
Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.
Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.
Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.
Pharmacology
There is limited information regarding Toremifene Pharmacology in the drug label.
