Toremifene 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 torsades 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. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors.
Breast cancer, metastatic: Postmenopausal women: Oral: 60 mg once daily, continue until disease progression.
Desmoid tumors (aggressive fibromatosis) (off-label use): Oral: 180 mg once daily until disease progression or unacceptable toxicity (Fiore 2015). Additional data may be necessary to further define the role of toremifene in this condition.
There are no dosage adjustments listed in the manufacturer’s labeling. However, pharmacokinetics in patients with renal impairment are similar to those in patients with normal renal function and dosage adjustment is unlikely to be necessary.
There are no dosage adjustments provided in the manufacturer’s labeling. However, hepatic impairment increases the half-life of toremifene.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Fareston: 60 mg
Generic: 60 mg
Yes
Administer with or without food.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).
Breast cancer, metastatic: Treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown tumors
Desmoid tumors (aggressive fibromatosis)
Toremifene may be confused with ospemifene, raloxifene
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Diaphoresis (20%)
Endocrine & metabolic: Hot flash (35%)
Gastrointestinal: Nausea (14%)
Genitourinary: Vaginal discharge (13%)
Hepatic: Increased serum alkaline phosphatase (8% to 19%), increased serum AST (5% to 19%)
1% to 10%:
Cardiovascular: Edema (5%), cardiac arrhythmia (≤2%), cerebrovascular accident (≤2%), local thrombophlebitis (≤2%), pulmonary embolism (≤2%), thrombosis (≤2%), transient ischemic attacks (≤2%), cardiac failure (≤1%), myocardial infarction (≤1%)
Central nervous system: Dizziness (9%)
Endocrine & metabolic: Hypercalcemia (≤3%)
Gastrointestinal: Vomiting (4%)
Genitourinary: Vaginal hemorrhage (2%)
Hepatic: Increased serum bilirubin (1% to 2%)
Ophthalmic: Cataract (≤10%), xerophthalmia (≤9%), visual field defect (≤4%), corneal disease (≤2%), glaucoma (≤2%), visual disturbance (≤2%), diplopia (≤2%)
<1%, postmarketing, and/or case reports: Alopecia, angina pectoris, anorexia, arthritis, ataxia, blurred vision, constipation, corneal opacity (reversible; including corneal verticulata), depression, dermatitis, dyspnea, endometrial carcinoma, endometrial hyperplasia, fatigue, hepatotoxicity (including hepatitis, nonalcoholic fatty liver disease), jaundice, lethargy, leukopenia, paresis, polyp (uterine), prolonged QT interval on ECG, pruritus, rigors, skin discoloration, thrombocytopenia, toxic hepatitis, tremor, tumor flare, vertigo, weakness
Known hypersensitivity to toremifene or any component of the formulation; congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, uncorrected hypomagnesemia
Concerns related to adverse effects:
• Bone marrow suppression: Leukopenia and thrombocytopenia have been reported rarely; monitor leukocyte and platelet counts in patients with leukopenia and thrombocytopenia.
• Hepatotoxicity: Grades 3 and 4 transaminase increases and hyperbilirubinemia have been reported, including jaundice, hepatitis, and non-alcoholic fatty liver disease. Monitor liver function tests periodically.
• Hypercalcemia: May occur during the first weeks of treatment in breast cancer patients with bone metastases; monitor closely for hypercalcemia. Institute appropriate measures if hypercalcemia occurs; discontinue treatment if severe. Medications that decrease renal calcium excretion (eg, thiazide diuretics) may increase the risk of hypercalcemia in patients receiving toremifene.
• QT prolongation: [US Boxed Warning]: May prolong the QT interval; QTc prolongation is dose-dependent and concentration-dependent. QT prolongation may lead to a form of ventricular tachycardia called torsades de pointes, which may result in syncope, seizure and/or sudden death. Use is contraindicated in patients with congenital or acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. Avoid use with other medications known to prolong the QT interval and with strong CYP3A4 inhibitors. If concurrent use with QT prolonging agents cannot be avoided, interrupt treatment with toremifene. Use with caution in patients with heart failure, hepatic impairment, or electrolyte abnormalities. Monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Obtain ECG at baseline and as clinically indicated in patients at risk for QT prolongation.
• Tumor flare: May occur during the first weeks of treatment in breast cancer patients with bone metastases. Tumor flare consists of diffuse musculoskeletal pain and erythema with initial increased size of tumor lesions (which later regress). It is often accompanied by hypercalcemia and does not imply treatment failure or represent tumor progression.
• Uterine malignancy: Endometrial cancer, hypertrophy, hyperplasia, and uterine polyps have been reported. Long-term use of toremifene in patients with pre-existing endometrial hyperplasia has not been established. Baseline and annual gynecological exams are recommended in all patients; closely monitor patients who are at high risk for endometrial cancer.
Disease-related concerns:
• Hepatic impairment: The half-life of toremifene is increased (less than 2-fold) in patients with hepatic impairment (cirrhosis and fibrosis), although the pharmacokinetics of N-demethyltoremifene (a metabolite with weak antitumor potency) were unchanged.
• Thromboembolic disease: Avoid use in patients with a history of thromboembolic disease.
Concurrent drug therapy issues:
• Drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Substrate of CYP1A2 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy
Azithromycin (Systemic): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Chloroquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Clofazimine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Toremifene may increase the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Toremifene. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Toremifene. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Toremifene. CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Toremifene. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Toremifene. Management: Use of toremifene with strong CYP3A4 inhibitors should be avoided if possible. If coadministration is necessary, monitor for increased toremifene toxicities, including QTc interval prolongation. Risk D: Consider therapy modification
Dabrafenib: Toremifene may enhance the QTc-prolonging effect of Dabrafenib. Dabrafenib may decrease the serum concentration of Toremifene. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Also monitor for reduced toremifene efficacy. Risk C: Monitor therapy
Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fluoroestradiol F18: Estrogen Receptor Antagonists may diminish the diagnostic effect of Fluoroestradiol F18. Management: Image patients with fluoroestradiol F-18 prior to starting systemic endocrine therapies that block the estrogen receptor. Use of fluoroestradiol F-18 should not delay indicated treatment. Risk D: Consider therapy modification
Fluorouracil Products: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gadobenate Dimeglumine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Grapefruit Juice: May increase the serum concentration of Toremifene. Risk X: Avoid combination
Halofantrine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Haloperidol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Inotuzumab Ozogamicin: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination
Lofexidine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Midostaurin: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ondansetron: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ospemifene: Selective Estrogen Receptor Modulators may enhance the adverse/toxic effect of Ospemifene. Ospemifene may also enhance adverse/toxic effects of other Selective Estrogen Receptor Modulators. Selective Estrogen Receptor Modulators may diminish the therapeutic effect of Ospemifene. Ospemifene may also diminish the therapeutic effects of other Selective Estrogen Receptor Modulators. Risk X: Avoid combination
Pentamidine (Systemic): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Piperaquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Piperaquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination
Probucol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Probucol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Toremifene. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Toremifene. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Quinolone Antibiotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): Toremifene may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase the serum concentration of Toremifene. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Toremifene may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Toremifene. Management: Avoid concomitant use of toremifene and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, monitor patients for toremifene toxicities including QTc prolongation and TdP. Risk D: Consider therapy modification
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Sugammadex: Toremifene may diminish the therapeutic effect of Sugammadex. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May enhance the hypercalcemic effect of Toremifene. Risk C: Monitor therapy
Grapefruit juice may increase toremifene levels. Management: Avoid grapefruit juice.
Toremifene is only approved for use in postmenopausal women; however, if prescribed in premenopausal women, effective nonhormonal contraception should be used.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to toremifene may cause fetal harm.
It is not known if toremifene is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.
Avoid grapefruit juice.
CBC with differential (periodically), electrolytes (magnesium and potassium prior to and periodically during treatment; calcium periodically), hepatic function tests (periodically). Obtain ECG (baseline and periodically during treatment) in patients at risk for QT prolongation. In patients with bone metastases, monitor closely for hypercalcemia during the first few weeks of treatment. Baseline and annual gynecological exams (patients at high risk for endometrial cancer should be closely monitored). Signs/symptoms of uterine disorders (bleeding, discharge, pelvic pain/pressure).
Nonsteroidal, triphenylethylene derivative with potent antiestrogenic properties (also has estrogenic effects). Competitively binds to estrogen receptors on tumors and inhibits the growth stimulating effects of estrogen.
Absorption: Well absorbed
Distribution: Vd: 580 L
Protein binding, plasma: >99.5%, primarily to albumin
Metabolism: Extensively hepatic, principally by CYP3A4 to N-demethyltoremifene (a weak antiestrogen)
Bioavailability: Not affected by food
Half-life elimination: Toremifene: ~5 days, ~7 days (females > 60 years); N-demethyltoremifene: 6 days
Time to peak, serum: ≤3 hours
Excretion: Primarily feces; urine (~10%) during a 1-week period
Hepatic function impairment: The mean elimination half-life was increased by less than 2-fold in patients with cirrhosis or fibrosis.
Older adult: Elimination half-life prolonged and Vd increased (457 vs 627 L) observed in elderly women.
Tablets (Fareston Oral)
60 mg (per each): $52.00
Tablets (Toremifene Citrate Oral)
60 mg (per each): $45.83
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