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  • CLASSES

    Cytostatic Anti-estrogens
    Selective Estrogen Receptor Modulators/SERMS

    BOXED WARNING

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, electrolyte imbalance, females, geriatric, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Toremifene is contraindicated for use by patients with acquired or congenital long QT syndrome, uncorrected hypokalemia, or uncorrected hypomagnesemia. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner, which can result in ventricular tachycardia and Torsade de pointes (TdP); TdP can cause syncope, seizures, and/or death. In patients at increased risk of QT prolongation, obtain an electrocardiogram (ECG) at baseline and as clinically indicated. Correct hypokalemia or hypomagnesemia before toremifene initiation; periodically monitor these electrolytes during therapy. The manufacturer of toremifene recommends cautious use in patients with congestive heart failure and a history of electrolyte imbalance. Use toremifene with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. Avoid concomitant use of toremifene with drugs known to prolong the QT interval and with strong CYP3A4 inhibitors.

    DEA CLASS

    Rx

    DESCRIPTION

    Nonsteroidal antiestrogen therapy
    Used for metastatic breast cancer in postmenopausal women
    Contraindicated in patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia; most common adverse reactions are hot flashes, sweating, nausea and vaginal discharge

    COMMON BRAND NAMES

    Fareston

    HOW SUPPLIED

    Fareston Oral Tab: 60mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive tumors or with tumors of unknown estrogen-receptor status.
    NOTE: The FDA has designated toremifene as an orphan drug for the treatment of metastatic breast cancer.
    Oral dosage
    Adult females

    60 mg PO once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In 2 randomized clinical trials, treatment with toremifene 60 mg (n = 378) resulted in similar response rates, time to progression (TTP), and overall survival (OS) compared with tamoxifen 20 mg (n = 215) or tamoxifen 40 mg (n = 149). In a separate clinical trial, tamoxifen (n = 201) had a higher response rate compared with toremifene (n = 214); however, this difference was not statistically significant. Treatment with higher doses of toremifene (200 mg or 240 mg) did not result in significant improvements in TTP or OS.

    MAXIMUM DOSAGE

    Adults

    60 mg PO once daily.

    Geriatric

    60 mg PO once daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage adjustments are not recommended.

    Renal Impairment

    Dosage adjustments are not recommended.

    ADMINISTRATION

    Oral Administration

    May be given without regard to meals.

    STORAGE

    Fareston:
    - Protect from extreme heat
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, electrolyte imbalance, females, geriatric, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Toremifene is contraindicated for use by patients with acquired or congenital long QT syndrome, uncorrected hypokalemia, or uncorrected hypomagnesemia. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner, which can result in ventricular tachycardia and Torsade de pointes (TdP); TdP can cause syncope, seizures, and/or death. In patients at increased risk of QT prolongation, obtain an electrocardiogram (ECG) at baseline and as clinically indicated. Correct hypokalemia or hypomagnesemia before toremifene initiation; periodically monitor these electrolytes during therapy. The manufacturer of toremifene recommends cautious use in patients with congestive heart failure and a history of electrolyte imbalance. Use toremifene with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. Avoid concomitant use of toremifene with drugs known to prolong the QT interval and with strong CYP3A4 inhibitors.

    Thromboembolic disease

    Toremifene should generally not be used to treat patients with a history of thromboembolic disease.

    Hypercalcemia

    Use toremifene cautiously in patients with pre-existing hypercalcemia; medications that decrease renal calcium excretion (e.g., thiazide diuretics) may increase the risk of hypercalcemia. Periodically monitor serum calcium levels; patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment. 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 toremifene. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, toremifene therapy should be discontinued.

    Hepatic disease, hepatitis, hepatotoxicity

    Toremifene should be used cautiously in patients with pre-existing hepatic disease; hepatotoxicity and hepatitis have been reported with toremifene treatment. Periodically monitor liver function tests during treatment. Because hepatic disease may also increase the risk for QT prolongation, monitor ECGs at baseline and as clinically indicated during toremifene therapy.

    Endometrial cancer, endometrial hyperplasia

    Use toremifene cautiously in patients with preexisting endometrial hyperplasia or a history of endometrial cancer. The long-term use of toremifene has not been established in patients with pre-existing endometrial hyperplasia. All patients should have baseline and annual gynecological examinations; patients at high risk for endometrial cancer should be closely monitored. Endometrial cancer, endometrial hypertrophy, hyperplasia, and uterine polyps have been reported in some patients treated with toremifene.

    Leukopenia, thrombocytopenia

    Monitor leukocyte and platelet counts in patients with leukopenia or thrombocytopenia receiving treatment with toremifene. Leukopenia and thrombocytopenia have been reported rarely with toremifene therapy.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during toremifene treatment; toremifene is FDA pregnancy category D. Although there are no adequately controlled studies in pregnant women, toremifene can cause increased pregnancy loss and fetal malformation when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving toremifene should be apprised of the potential hazard to the fetus. In animal studies, toremifene crossed the placenta and caused embryo-fetal toxicities at maternal doses that were lower than the FDA-recommended human dose on a mg/m2 basis. In rat studies, administration to pregnant rats during organogenesis at exposures of approximately 6% of that achieved with the recommended human dose increased preimplantation loss, increased resorptions, reduced fetal weight, and increased fetal anomalies (e.g., malformation of limbs, incomplete ossification, misshapen bones, rib/spine abnormalities, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema); maternal toxicity may have contributed. Similar effects occurred in rabbits that received toremifene at exposures of approximately 40% of the expected human exposure at the recommended dose. Additionally, in rodent models of fetal reproductive tract development, toremifene inhibited uterine development in female pups similar to the effects seen with diethylstilbestrol (DES) and tamoxifen; the clinical relevance of these changes is unknown.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during toremifene treatment. Toremifene can be teratogenic if taken by the mother during pregnancy. Toremifene is only indicated in postmenopausal women. However, premenopausal females of reproductive potential should avoid pregnancy and use effective nonhormonal contraception during treatment with toremifene. Females of reproductive potential should undergo pregnancy testing prior to initiation of toremifene. Women who become pregnant while receiving toremifene should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of toremifene on human fertility, male and female infertility has been observed in animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from toremifene, advise women to discontinue breast-feeding during treatment. It is not known whether toremifene is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 0-4.0
    stroke / Early / 0-2.0
    pulmonary embolism / Delayed / 0-2.0
    thrombosis / Delayed / 0-1.5
    arrhythmia exacerbation / Early / 0-1.5
    heart failure / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    corneal opacification / Delayed / Incidence not known

    Moderate

    QT prolongation / Rapid / 0-89.6
    hot flashes / Early / 0-35.0
    elevated hepatic enzymes / Delayed / 5.0-19.0
    cataracts / Delayed / 0-10.0
    edema / Delayed / 0-5.0
    hypercalcemia / Delayed / 0-3.0
    phlebitis / Rapid / 0-2.0
    keratopathy / Delayed / 0-2.0
    vaginal bleeding / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 1.0-1.5
    angina / Early / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    dyspnea / Early / Incidence not known
    erythema / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    constipation / Delayed / Incidence not known
    endometrial hyperplasia / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    paresis / Delayed / Incidence not known
    depression / Delayed / Incidence not known

    Mild

    diaphoresis / Early / 0-20.0
    nausea / Early / 0-14.0
    vaginal discharge / Delayed / 0-13.0
    xerophthalmia / Early / 0-9.0
    dizziness / Early / 0-9.0
    vomiting / Early / 0-2.0
    diplopia / Early / 0-1.5
    lethargy / Early / 0-1.0
    fatigue / Early / 0-1.0
    musculoskeletal pain / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    tremor / Early / Incidence not known
    vertigo / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Acetaminophen; Butalbital; Caffeine: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Albuterol: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Alfuzosin: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg.
    Amiodarone: (Major) The concomitant use of amiodarone and toremifene should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amobarbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with toremifene. Clarithromycin is associated with an established risk for QT prolongation and TdP, while toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with toremifene. Clarithromycin is associated with an established risk for QT prolongation and TdP, while toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Amprenavir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Examples of CYP3A4 inhibitors include anti-retroviral protease inhibitors. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include toremifene.
    Apomorphine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include apomorphine. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2-10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if toremifene and aprepitant, fosaprepitant are used concurrently and monitor for an increase in toremifene-related adverse effects for several days after administration of a multi-day aprepitant regimen. Toremifene is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of toremifene. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Aripiprazole should be used cautiously and with close monitoring with toremifene.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is necessary, use with caution.
    Artemether; Lumefantrine: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as toremifene, coadministration may result in additive QT prolongation and should be avoided. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is necessary, use with caution. Consider ECG monitoring if toremifene must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Atazanavir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as atazanavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as atazanavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include toremifene.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Azithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with azithromycin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cases of QT prolongation and TdP have been reported with the post-marketing use of azithromycin.
    Barbiturates: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with toremifene. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include toremifene.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include toremifene.
    Boceprevir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Examples of CYP3A4 inhibitors include anti-retroviral protease inhibitors. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Bosentan: (Moderate) Bosentan is a cytochrome P450 3A4 enzyme inducer and may increase the rate of toremifene metabolism.
    Brigatinib: (Moderate) Monitor for decreased efficacy of toremifene if coadministration with brigatinib is necessary. Toremifene is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of toremifene may decrease.
    Budesonide; Formoterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Buprenorphine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration may further increase the risk of QT prolongation and TdP.
    Buprenorphine; Naloxone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration may further increase the risk of QT prolongation and TdP.
    Butabarbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Carbamazepine: (Major) Cytochrome P450 3A4 enzyme inducers, including carbamazepine, may increase the rate of toremifene metabolism.
    Ceritinib: (Major) Avoid coadministration of ceritinib with toremifene due to increased toremifene exposure. If coadministration is unavoidable, monitor for toremifene-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Toremifene is primarily metabolized by CYP3A4 and has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Chloroquine: (Major) Chloroquine administration is associated with an increased risk of QT prolongation and torsades de pointes (TdP). The need to coadminister chloroquine with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits and should be avoided when possible. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is necessary, use with caution
    Chlorpromazine: (Major) Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine. Agents that prolong the QT interval could lead to torsade de pointes when combined with a phenothiazine, and therefore are generally not recommended for combined use. Drugs with a possible risk for QT prolongation and TdP that should be used with caution with chlorpromazine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with ciprofloxacin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ciprofloxacin has been associated with a possible risk for QT prolongation and TdP.
    Cisapride: (Severe) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Because of the potential for torsade de pointes (TdP), use of cisapride with toremifene is contraindicated.
    Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with citalopram include toremifene.
    Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with toremifene. Clarithromycin is associated with an established risk for QT prolongation and TdP, while toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Class IA Antiarrhythmics: (Major) Class IA Antiarrhythmics (disopyramide, procainamide, and quinidine) should be used cautiously with toremifene. Class IA Antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP) and toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Clomipramine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clonazepam: (Major) Cytochrome P450 3A4 enzyme inducers, such as clonazepam, increase the rate of toremifene metabolism. Ten patients on either carbamazepine, clonazepam, phenobarbital, or phenytoin and receiving toremifene showed a two-fold increase in clearance and a decrease in the elimination half-life of toremifene. Use this combination with caution.
    Clozapine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include clozapine.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Codeine; Phenylephrine; Promethazine: (Major) Coadministration may result in additive effects on the QT interval. Promethazine carries a possible risk of QT prolongation; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is required, use caution and close clinical monitoring.
    Codeine; Promethazine: (Major) Coadministration may result in additive effects on the QT interval. Promethazine carries a possible risk of QT prolongation; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is required, use caution and close clinical monitoring.
    Conjugated Estrogens: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Conjugated Estrogens; Bazedoxifene: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Conjugated Estrogens; Medroxyprogesterone: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with toremifene. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Cyclobenzaprine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include cyclobenzaprine. Cyclobenzaprine is structurally similar to tricyclic antidepressants. Tricyclic antidepressants have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage settings).
    Cyclosporine: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, including cyclosporine.
    Dalfopristin; Quinupristin: (Minor) Cytochrome P450 3A4 enzyme inhibitors, such as streptogramins, may decrease the rate of toremifene metabolism.
    Danazol: (Moderate) Cytochrome P450 3A4 enzyme inhibitors, such as danazol, decrease the rate of toremifene metabolism.
    Darunavir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Examples of CYP3A4 inhibitors include anti-retroviral protease inhibitors. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Examples of CYP3A4 inhibitors include anti-retroviral protease inhibitors. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as ritonavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain. In addition, both ritonavir and toremifene are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Dasatinib: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include dasatinib. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval).
    Daunorubicin: (Major) Daunorubicin should be used cautiously with toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Acute cardiotoxicity can occur during the administration of daunorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include degarelix.
    Delavirdine: (Minor) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as delavirdine.
    Desipramine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Avoid coadministration of deutetrabenazine with toremifene. If combination use cannot be avoided, patients should be closely monitored for QT prolongation. For patients taking a deutetrabenazine dosage more than 24 mg/day with toremifene, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Dextromethorphan; Promethazine: (Major) Coadministration may result in additive effects on the QT interval. Promethazine carries a possible risk of QT prolongation; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is required, use caution and close clinical monitoring.
    Dienogest; Estradiol valerate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Diethylstilbestrol, DES: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Diltiazem: (Minor) Cytochrome P450 3A4 enzyme inhibitors decrease the rate of toremifene metabolism.
    Dofetilide: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Because of the potential for TdP, concurrent use is contraindicated.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and toremifene should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Concurrent use may increase risk for QT prolongation.
    Dolutegravir; Rilpivirine: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include toremifene.Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include toremifene.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include toremifene.
    Doxepin: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Doxorubicin: (Major) Toremifene should be used cautiously with doxorubicin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with toremifene is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; toremifene is a weak inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Severe) Concurrent use of toremifene and dronedarone is contraindicated. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Drospirenone; Estradiol: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Drospirenone; Ethinyl Estradiol: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and toremifene may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz.Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner. In addition, efavirenz (a CYP3A4 inducer) may increase the rate of toremifene metabolism.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and toremifene may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz.Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner. In addition, efavirenz (a CYP3A4 inducer) may increase the rate of toremifene metabolism.
    Elbasvir; Grazoprevir: (Moderate) Administering toremifene with elbasvir; grazoprevir may result in elevated toremifene plasma concentrations. Toremifene is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include toremifene.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include toremifene.Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include toremifene.Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of toremifene if coadministration with enzalutamide is necessary. Toremifene is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers lower the steady-state concentration of toremifene in serum.
    Epirubicin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with epirubicin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with eribulin include toremifene.
    Erythromycin: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include erythromycin.
    Erythromycin; Sulfisoxazole: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include erythromycin.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as toremifene, should be done with caution and close monitoring.
    Ester local anesthetics: (Major) Avoid the concomitant use of toremifene with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Local anesthetics have been associated with a possible risk for QT prolongation and TdP based on varying levels of documentation. Interruption of toremifene receipt is recommended if treatment with local anesthetics is required. If interruption of toremifene receipt is not possible, closely monitor the patient for prolongation of the QT interval. In patients at increased risk of QT prolongation, obtain electrocardiograms at baseline and as clinically indicated.
    Esterified Estrogens: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Esterified Estrogens; Methyltestosterone: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol Cypionate; Medroxyprogesterone: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol; Levonorgestrel: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol; Norethindrone: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol; Norgestimate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estrogens: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estropipate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Desogestrel: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Etonogestrel: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Levonorgestrel: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norelgestromin: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norgestimate: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norgestrel: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ezogabine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include ezogabine.
    Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with flecainide. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include fluconazole.
    Fluoxetine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including toremifene. In addition, the metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, including fluoxetine. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including toremifene. In addition, the metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, including fluoxetine. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain. (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with olanzapine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Fluphenazine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include fluphenazine.
    Fluticasone; Salmeterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and toremifene. Use of toremifene with other drugs known to prolong the QT interval should be avoided when possible. If combination use cannot be avoided, patients should be closely monitored for QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. In addition, toremifene is a primary substrate of CYP3A4 and fluvoxamine is a moderate CYP3A4 inhibitor. In theory, fluvoxamine may reduce the metabolism of toremifene.
    Formoterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fosamprenavir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as fosamprenavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as toremifene. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with gemifloxacin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with toremifene due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Glycopyrrolate; Formoterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Toremifene should be used cautiously and with close monitoring with goserelin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include granisetron.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with toremifene. Halogenated anesthetics can prolong the QT interval and toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Haloperidol: (Major) QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval, including toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Hydantoins: (Major) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including toremifene, leading to reduced efficacy of the concomitant medication.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and toremifene. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include toremifene.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Use caution and close monitoring during concurrent administration.
    Idarubicin: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used with caution and close monitoring with other drugs that may prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Imatinib: (Minor) Cytochrome P450 3A4 enzyme inhibitors, such as imatinib, decrease the rate of toremifene metabolism. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Imipramine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indinavir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as indinavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with toremifene due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with toremifene may result in increased serum concentrations of toremifene. Toremifene is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Cytochrome P450 3A4 (CYP3A4) enzyme inducers increase the rate of toremifene metabolism. In a pharmacokinetic study in healthy volunteers, administration of a single dose of toremifene was given following chronic dosing with rifampin. The AUC of toremifene was reduced by 87% and the Cmax was reduced by 55%. The half-life of toremifene was reduced by 44% following rifampin dosing. The effect of rifampin on chronic toremifene therapy is unknown but may lead to a loss of toremifene's antiestrogen effects. A similar effect may occur with concurrent administration of toremifene and other CYP3A4 inducers such as rifabutin or rifapentine.
    Isoniazid, INH; Rifampin: (Major) Cytochrome P450 3A4 (CYP3A4) enzyme inducers increase the rate of toremifene metabolism. In a pharmacokinetic study in healthy volunteers, administration of a single dose of toremifene was given following chronic dosing with rifampin. The AUC of toremifene was reduced by 87% and the Cmax was reduced by 55%. The half-life of toremifene was reduced by 44% following rifampin dosing. The effect of rifampin on chronic toremifene therapy is unknown but may lead to a loss of toremifene's antiestrogen effects. A similar effect may occur with concurrent administration of toremifene and other CYP3A4 inducers such as rifabutin or rifapentine.
    Itraconazole: (Major) Avoid concurrent administration of itraconazole and toremifene due to the potential for additive effects on the QT interval and increased exposure to toremifene. If use of itraconazole is required, temporarily interrupt toremifene therapy. If toremifene therapy cannot be interrupted, and use of these drugs together is unavoidable, closely monitor for prolongation of the QT interval. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Itraconazole can also prolong the QT interval. Use of these drugs together may increase the risk for QT prolongation. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with toremifene (a CYP3A4 substrate) may result in elevated toremifene plasma concentrations and an increased risk for adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ketoconazole: (Major) Avoid concurrent administration of ketoconazole and toremifene due to the potential for additive effects on the QT interval and increased exposure to toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ketoconazole can also prolong the QT interval. Use of these drugs together may increase the risk for QT prolongation. In addition, ketoconazole (a potent inhibitor of CYP3A4) may inhibit the metabolism of toremifene (a CYP3A4 substrate); concurrent use could result in increased toremifene systemic concentrations. If use of ketoconazole is required, temporarily interrupt toremifene therapy. If toremifene therapy cannot be interrupted, and use of these drugs together is unavoidable, closely monitor patient for prolongation of the QT interval. In one study involving 18 healthy subjects, coadministration of ketoconazole (200 mg twice daily) with toremifene (80 mg daily) resulted in a 1.4-fold and 2.9-fold increase in toremifene Cmax and AUC.
    Lapatinib: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include lapatinib.
    Lenvatinib: (Major) Toremifene should be used cautiously and with close monitoring with lenvatinib. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Lesinurad: (Moderate) Use lesinurad and toremifene together with caution; toremifene may increase the systemic exposure of lesinurad. Toremifene is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate. In addition, lesinurad may decrease the systemic exposure and therapeutic efficacy of toremifene; monitor for potential reduction in efficacy. Toremifene is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and toremifene together with caution; toremifene may increase the systemic exposure of lesinurad. Toremifene is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate. In addition, lesinurad may decrease the systemic exposure and therapeutic efficacy of toremifene; monitor for potential reduction in efficacy. Toremifene is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include toremifene.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include toremifene.
    Levalbuterol: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) Concurrent use of toremifene and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with toremifene. Lithium has been associated with QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Long-acting beta-agonists: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like toremifene, should be used cautiously and with close monitoring with loperamide.
    Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like toremifene, should be used cautiously and with close monitoring with loperamide.
    Lopinavir; Ritonavir: (Major) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as ritonavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain. In addition, both ritonavir and toremifene are associated with QT prolongation; concomitant use increases the risk of QT prolongation. (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include lopinavir; ritonavir. In addition, metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as lopinavir; ritonavir.
    Maprotiline: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include maprotiline. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include mefloquine.
    Meperidine; Promethazine: (Major) Coadministration may result in additive effects on the QT interval. Promethazine carries a possible risk of QT prolongation; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is required, use caution and close clinical monitoring.
    Mephobarbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Mesoridazine: (Severe) Avoid the concomitant use of toremifene with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Mesoridazine has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP) and is contraindicated for use with toremifene.
    Mestranol; Norethindrone: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently.
    Metaproterenol: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with methadone include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Methohexital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include toremifene.
    Midostaurin: (Major) The concomitant use of midostaurin and toremifene may lead to additive QT interval prolongation. Obtain ECG at baseline and monitor ECG and serum electrolytes during toremifene therapy in patients at increased risk of QT prolongation; correct hypokalemia and hypomagnesemia prior to starting toremifene. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Toremifene prolongs the QTc interval in a dose- and concentration-related manner.
    Mifepristone, RU-486: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), mifepristone and toremifene should be used together cautiously. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Use of toremifene with other drugs known to prolong the QT interval should be avoided. If combination use cannot be avoided, patients should be closely monitored for QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Major) Avoid the concomitant use of mitotane with toremifene due to decreased toremifene exposure and possible decreases in efficacy. Mitotane is a strong CYP3A4 inducer and toremifene is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of toremifene. In a pharmacokinetic study in healthy volunteers, administration of a single dose of toremifene was given following chronic dosing with another strong CYP3A inducer, rifampin. The AUC of toremifene was reduced by 87% and the Cmax was reduced by 55%. The half-life of toremifene was reduced by 44% following rifampin dosing.
    Moxifloxacin: (Major) Concurrent use of toremifene and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nelfinavir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as nelfinavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Nicardipine: (Minor) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Nicardipine inhibits this isoenzyme and may decrease the metabolism of toremifen.
    Nilotinib: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as toremifene is not advised; nilotinib prolongs the QT interval. If coadministration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with norfloxacin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Administer octreotide cautiously in patients receiving drugs that prolong the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with octreotide include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with ofloxacin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with olanzapine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Olodaterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as ritonavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain. In addition, both ritonavir and toremifene are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Ondansetron: (Major) Avoid coadministration of ondansetron with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osimertinib: (Major) Avoid coadministration of osimertinib with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner
    Oxaliplatin: (Major) Avoid coadministration of toremifene with oxaliplatin due to the additive risk of QT prolongation. If concomitant use is unavoidable, monitor electrolytes and ECGs for QT prolongation; correct electrolyte abnormalities prior to administration of oxaliplatin. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include toremifene.
    Pasireotide: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with pasireotide as coadministration may have additive effects on the prolongation of the QT interval.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be avoided with pazopanib include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Pentobarbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Perphenazine: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include perphenazine.
    Perphenazine; Amitriptyline: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include perphenazine.
    Phenobarbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Phenylephrine; Promethazine: (Major) Coadministration may result in additive effects on the QT interval. Promethazine carries a possible risk of QT prolongation; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is required, use caution and close clinical monitoring.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of toremifene with pimozide is contraindicated.
    Pirbuterol: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Posaconazole: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include posaconazole.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include toremifene.
    Primidone: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Prochlorperazine: (Minor) Phenothiazines have been reported to prolong the QT interval. Concurrent use of drugs that are associated with a possible risk for QT prolongation and torsade de pointes (TdP) with prochlorperazine should be approached with caution. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with prochlorperazine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Promethazine: (Major) Coadministration may result in additive effects on the QT interval. Promethazine carries a possible risk of QT prolongation; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is required, use caution and close clinical monitoring.
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering toremifene with propafenone Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Protriptyline: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with quetiapine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Quinine: (Major) Concurrent use of quinine and toremifene should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Regadenoson: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include regadenoson.
    Ribociclib: (Major) Avoid coadministration of ribociclib with toremifene due to an increased risk for QT prolongation. Systemic exposure of toremifene may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and toremifene is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with toremifene due to an increased risk for QT prolongation. Systemic exposure of toremifene may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and toremifene is a CYP3A4 substrate.
    Rifabutin: (Major) Concurrent administration of a rifamycin with toremifene may lead to decreased antiestrogen effects due to hepatic enzyme induction by the rifamycin.
    Rifampin: (Major) Cytochrome P450 3A4 (CYP3A4) enzyme inducers increase the rate of toremifene metabolism. In a pharmacokinetic study in healthy volunteers, administration of a single dose of toremifene was given following chronic dosing with rifampin. The AUC of toremifene was reduced by 87% and the Cmax was reduced by 55%. The half-life of toremifene was reduced by 44% following rifampin dosing. The effect of rifampin on chronic toremifene therapy is unknown but may lead to a loss of toremifene's antiestrogen effects. A similar effect may occur with concurrent administration of toremifene and other CYP3A4 inducers such as rifabutin or rifapentine.
    Rifapentine: (Moderate) Concurrent administration of rifapentine with toremifene may lead to decreased antiestrogen effects due to hepatic enzyme induction by rifapentine.
    Rilpivirine: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include toremifene.Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Risperidone: (Major) Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes; however, data are currently lacking to establish causality in association with torsades de pointes (TdP). Reports of QT prolongation and torsades de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Since risperidone may prolong the QT interval, it should be used cautiously with other agents also known to have this effect, taking into account the patient's underlying disease state(s) and additional potential risk factors. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with risperidone include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Ritonavir: (Major) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as ritonavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain. In addition, both ritonavir and toremifene are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with romidepsin include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Salmeterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Saquinavir: (Major) Avoid the concomitant use of toremifene with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Saquinavir boosted with ritonavir has also been associated with a possible risk for QT prolongation and TdP. Interruption of toremifene therapy is recommended if treatment with saquinavir/ritonavir is required. If interruption of toremifene therapy is not possible, closely monitor the patient for prolongation of the QT interval by obtaining electrocardiograms at baseline and as clinically indicated. Additionally, saquinavir/ritonavir may inhibit the CYP3A4 metabolism of toremifene.
    Secobarbital: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Sertraline: (Major) There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include toremifene.
    Short-acting beta-agonists: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with toremifene. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Sorafenib: (Major) Sorafenib has been associated with QT prolongation. If sorafenib and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with sorafenib include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Use caution and close monitoring during concurrent administration.
    Soy Isoflavones: (Major) Theoretically, the soy isoflavones may compete with drugs that selectively modulate estrogen receptors. The soy isoflavones have a diphenolic structure similar to that of the potent synthetic and natural estrogens. All isoflavones are competitive ligands of in vitro estrogen receptor assays and appear to function as selective estrogen receptor modifiers (SERMs). Soy isoflavones should be used with caution in patients taking selective estrogen receptor modulators (SERMs, e.g., raloxifene, tamoxifen, or toremifene), as not much is known about how soy might influence side effects or therapeutic efficacy of the SERMs.
    Sparfloxacin: (Severe) Avoid the concomitant use of toremifene with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects; toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Sparfloxacin has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP) and is contraindicated for use with toremifene.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort is a cytochrome P450 3A4 enzyme inducers and may increase the rate of toremifene metabolism.
    Streptogramins: (Minor) Cytochrome P450 3A4 enzyme inhibitors, such as streptogramins, may decrease the rate of toremifene metabolism.
    Sugammadex: (Minor) Toremifene has a relatively high binding affinity for sugammadex and could displace vecuronium or rocuronium from the complex with sugammadex. The recovery to train of four (TOF) ratio to 0.9 could therefore be delayed in patients who have received toremifene on the same day of surgery.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include toremifene.
    Sunitinib: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include sunitinib.
    Tacrolimus: (Major) Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen and toremifene due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Telaprevir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Examples of CYP3A4 inhibitors include anti-retroviral protease inhibitors. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with toremifene. Telavancin has been associated with QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Telithromycin: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include telithromycin.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and toremifene is necessary, as the systemic exposure of toremifene may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of toremifene; consider increasing the dose of toremifene if necessary. Toremifene is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbutaline: (Minor) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Thiazide diuretics: (Moderate) Thiazide diuretics and other drugs that decrease renal calcium excretion may increase the risk of hypercalcemia in patients receiving toremifene.
    Thiopental: (Major) Barbiturates induce CYP3A4 and will increase the rate of toremifene metabolism, potentially leading to decreased clinical effectiveness.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Because of the potential for TdP, thioridazine is contraindicated with toremifene.
    Tiotropium; Olodaterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tipranavir: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Examples of CYP3A4 inhibitors include anti-retroviral protease inhibitors. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.
    Tizanidine: (Major) Toremifene should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with toremifene. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trandolapril; Verapamil: (Minor) Coadministration of toremifene and verapamil may result in increased exposure to toremifene. Toremifene is a CYP3A4 substrate; verapamil inhibits CYP3A4.
    Trazodone: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Tricyclic antidepressants: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with trifluoperazine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trimipramine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used cautiously and with close monitoring with tricyclic antidepressants (TCAs). TCAs share pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include toremifene.
    Umeclidinium; Vilanterol: (Moderate) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with toremifene include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    Vardenafil: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vardenafil include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Venlafaxine: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include venlafaxine.
    Verapamil: (Minor) Coadministration of toremifene and verapamil may result in increased exposure to toremifene. Toremifene is a CYP3A4 substrate; verapamil inhibits CYP3A4.
    Vincristine Liposomal: (Major) Toremifene inhibits P-glycoprotein (P-gp), which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents; vincristine is a P-gp substrate. Use caution if coadministration is necessary and monitor for vincristine toxicity, as exposure may be increased.
    Vincristine: (Major) Toremifene inhibits P-glycoprotein (P-gp), which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents; vincristine is a P-gp substrate. Use caution if coadministration is necessary and monitor for vincristine toxicity, as exposure may be increased.
    Voriconazole: (Major) Avoid concurrent administration of voriconazole and toremifene due to the potential for additive effects on the QT interval and increased exposure to toremifene. If use of voriconazole is required, temporarily interrupt toremifene therapy. If toremifene therapy cannot be interrupted, and use of these drugs together is unavoidable, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes, cardiac arrest, and sudden death. Use of these drugs together may increase the risk for QT prolongation. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with toremifene (a CYP3A4 substrate) may result in elevated toremifene plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Vorinostat: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with toremifene.
    Warfarin: (Moderate) Coadministration of toremifene and warfarin may result in increased warfarin concentrations, which may increase the INR and increase the risk for bleeding. Toremifene is a weak inhibitor of CYP2C9. Warfarin is a CYP2C9 substrate. Coadminster with caution and with careful monitoring of the INR.
    Zafirlukast: (Minor) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Zafirlukast inhibits this isoenzyme and may decrease the metabolism of toremifen.
    Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including toremifene.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during toremifene treatment; toremifene is FDA pregnancy category D. Although there are no adequately controlled studies in pregnant women, toremifene can cause increased pregnancy loss and fetal malformation when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving toremifene should be apprised of the potential hazard to the fetus. In animal studies, toremifene crossed the placenta and caused embryo-fetal toxicities at maternal doses that were lower than the FDA-recommended human dose on a mg/m2 basis. In rat studies, administration to pregnant rats during organogenesis at exposures of approximately 6% of that achieved with the recommended human dose increased preimplantation loss, increased resorptions, reduced fetal weight, and increased fetal anomalies (e.g., malformation of limbs, incomplete ossification, misshapen bones, rib/spine abnormalities, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema); maternal toxicity may have contributed. Similar effects occurred in rabbits that received toremifene at exposures of approximately 40% of the expected human exposure at the recommended dose. Additionally, in rodent models of fetal reproductive tract development, toremifene inhibited uterine development in female pups similar to the effects seen with diethylstilbestrol (DES) and tamoxifen; the clinical relevance of these changes is unknown.

    Due to the potential for serious adverse reactions in nursing infants from toremifene, advise women to discontinue breast-feeding during treatment. It is not known whether toremifene is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Toremifene is a nonsteroidal triphenylethylene derivative that competes with estrogen for binding sites in cancer cells, thereby blocking the growth-stimulating effects of estrogen in the tumor; additional mechanisms which do not involve estrogen receptors may also be involved. Toremifene also promotes the production of transforming growth factor beta (TGF beta), an inhibitory growth factor. Transforming growth factor beta may cause growth retardation and tumor regression by enhancing cell death (apoptosis) and/or arresting cell proliferation. In some postmenopausal women, toremifene causes a decrease in the estradiol-induced vaginal cornification index, indicative of its antiestrogenic activity; however, it also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

    PHARMACOKINETICS

    Toremifene is administered orally. It is greater than 99.5% protein bound, primarily to albumin; the volume of distribution (Vd) is 580 L. The plasma concentration time profile of toremifene declines biexponentially after absorption, with a mean distribution half-life of approximately 4 hours, and an elimination half-life of approximately 5 days. The elimination half-life of the major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 days and 4 days, respectively. The mean total clearance of toremifene was approximately 5 L/hour. Elimination is slow, in part because of enterohepatic circulation. Toremifene is primarily eliminated in the feces, with about 10% in the urine during a 1-week period.
     
    Affected cytochrome P450 (CYP) isoenzymes: CYP2C9, CYP3A4
    Toremifene is extensively metabolized, primarily by CYP3A4, to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency; serum concentrations of the primarily metabolite, N-demethyltoremifene, are 2 to 4 times higher than toremifene at steady state. Coadministration with a strong CYP3A4 inhibitor (ketoconazole) increased the Cmax and AUC of toremifene by 1.4-fold and 2.9-fold, respectively; the Cmax and AUC of N-demethyltoremifene were reduced by 56% and 20%, respectively. Toremifene is also a weak inhibitor of CYP2C9. Coadministration with toremifene increased the Cmax and AUC of tolbutamide, a CYP2C9 substrate, by less than 30%; a reduction of similar magnitude was observed for the Cmax and AUC of hydroxytolbutamide and carboxytolbutamide.
     
    Autoinduction of CYP3A4 by toremifene also likely occurs; however, this is unlikely to result in clinically relevant changes in the exposure of sensitive CYP3A4 substrates. After multiple doses, plasma exposure of toremifene was approximately 14% lower on day 17 compared to day 5 (n = 20); exposure to N-demethyltoremifene was approximately 80% higher on day 17 compared to day 5. Coadministration of toremifene (steady-state) with midazolam (a CYP3A4 substrate) on day 6 did not result in relevant increases in the Cmax or AUC of midazolam and alpha-hydroxymidazolam. After coadministration on day 18 of toremifene, the Cmax and AUC of midazolam and alpha-hydroxymidazolam were decreased by less than 20%.

    Oral Route

    Following oral administration, toremifene is well absorbed; food does not influence absorption. Peak plasma concentrations are obtained within 3 hours (Tmax). The pharmacokinetics of toremifene are linear after a single oral dose (range, 10 mg to 680 mg); after multiple dosing, dose proportionality was observed for doses ranging from 10 mg to 400 mg. Steady-state concentrations were reached in approximately 4 to 6 weeks.