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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
    leukopenia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    dyspnea / Early / Incidence not known
    erythema / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / 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
    fatigue / Early / 0-1.0
    lethargy / Early / 0-1.0
    musculoskeletal pain / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    tremor / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known

    DRUG INTERACTIONS

    Albuterol: (Minor) Use toremifene and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Use toremifene and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Major) Avoid coadministration of alfuzosin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Based on electrophysiology studies performed by the manufacturer, alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid coadministration of amiodarone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation; although the frequency of torsade de pointes (TdP) is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Amitriptyline: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to 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) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of clarithromycin with toremifene if possible due to the risk of increased toremifene exposure resulting in additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with toremifene if possible due to the risk of increased toremifene exposure resulting in additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Anagrelide: (Major) Avoid coadministration of anagrelide with toremifene due to the risk of additive QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Apalutamide: (Major) Avoid coadministration of apalutamide with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Apomorphine: (Major) Avoid coadministration of apomorphine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Limited data indicate that QT prolongation is possible with apomorphine administration, although the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Arformoterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Avoid coadministration of aripiprazole with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole as well as following overdose.
    Arsenic Trioxide: (Major) Avoid coadministration of arsenic trioxide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, frequently monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Artemether; Lumefantrine: (Major) Avoid coadministration of artemether with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Artemether; lumefantrine is also associated with prolongation of the QT interval. (Major) Avoid coadministration of lumefantrine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Asenapine: (Major) Avoid coadministration of asenapine with toremifene due to the risk of additive QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Asenapine has also been associated with QT prolongation.
    Atazanavir: (Major) Avoid coadministration of atazanavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%. (Major) Avoid coadministration of cobicistat with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Atomoxetine: (Major) Avoid coadministration of atomoxetine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval has also occurred during therapeutic use of atomoxetine as well as following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of phenobarbital with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Azithromycin: (Major) Avoid coadministration of azithromycin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval and torsade de pointes (TdP) have also been spontaneously reported during azithromycin in postmarketing surveillance.
    Bedaquiline: (Major) Avoid coadministration of bedaquiline with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Bedaquiline has also been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of phenobarbital with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of metronidazole with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of metronidazole with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Budesonide; Formoterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Avoid coadministration of buprenorphine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Buprenorphine has also 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.
    Buprenorphine; Naloxone: (Major) Avoid coadministration of buprenorphine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Buprenorphine has also 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.
    Carbamazepine: (Major) Avoid coadministration of carbamazepine with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Ceritinib: (Major) Avoid coadministration of ceritinib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. An interruption of therapy or dose adjustment of ceritinib may be necessary for QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Concentration-dependent QT prolongation has also been reported with ceritinib.
    Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Chloroquine: (Major) Avoid coadministration of chloroquine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Chloroquine is also associated with a risk of dose-dependent QT prolongation and torsade de pointes (TdP); fatalities have been reported.
    Chlorpromazine: (Major) Avoid coadministration of chlorpromazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Major) Avoid coadministration of ciprofloxacin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsade de pointes (TdP), use of toremifene with cisapride is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Citalopram: (Major) Avoid coadministration of citalopram with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Citalopram also causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin with toremifene if possible due to the risk of increased toremifene exposure resulting in additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Clomipramine: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Avoid coadministration of clozapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Treatment with clozapine has also been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Major) Avoid coadministration of cobicistat with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of promethazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Avoid coadministration of promethazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Conivaptan: (Major) Avoid coadministration of conivaptan with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    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) Avoid coadministration of crizotinib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. An interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary if QT prolongation occurs. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Darunavir: (Major) Avoid coadministration of darunavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%. (Major) Avoid coadministration of darunavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%. (Major) Avoid coadministration of darunavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Dasatinib: (Major) Avoid coadministration of dasatinib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Degarelix: (Major) Avoid coadministration of degarelix with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QTc interval has also been reported with the use of degarelix.
    Delavirdine: (Major) Avoid coadministration of delavirdine with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Desipramine: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to 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 possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. For patients taking a daily dose of deutetrabenazine greater than 24 mg, assess the QTc interval before and after increasing the dose of either deutetrabenazine or toremifene. Clinically relevant QTc prolongation may occur with deutetrabenazine. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Dexamethasone: (Major) Avoid coadministration of dexamethasone with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and dexamethasone is a CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of promethazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of quinidine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
    Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with toremifene is necessary. Diclofenac is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    Diclofenac; Misoprostol: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with toremifene is necessary. Diclofenac is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    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.
    Disopyramide: (Major) Avoid coadministration of disopyramide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP). Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Dofetilide: (Severe) Because of the potential for torsade de pointes (TdP), use of toremifene with dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Dolasetron: (Major) Avoid coadministration of dolasetron with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Dolasetron has also been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of rilpivirine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Donepezil: (Major) Avoid coadministration of donepezil with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Donepezil; Memantine: (Major) Avoid coadministration of donepezil with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Doxepin: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronabinol: (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) Because of the potential for torsade de pointes (TdP), use of toremifene with dronedarone is contraindicated. Both drugs are 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) Avoid coadministration of droperidol with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Droperidol administration is also associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    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) Avoid coadministration of efavirenz with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of efavirenz with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of efavirenz with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Eliglustat: (Major) Avoid coadministration of eliglustat with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Eliglustat is also predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of rilpivirine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of rilpivirine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and toremifene due to the potential for additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Encorafenib is associated with dose-dependent prolongation of the QT interval. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Enzalutamide: (Major) Avoid coadministration of enzalutamide with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Eribulin: (Major) Avoid coadministration of eribulin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Avoid coadministration of erythromycin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of erythromycin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Escitalopram: (Major) Avoid coadministration of escitalopram with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Escitalopram has also been associated with a risk of QT prolongation and torsade de pointes (TdP).
    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; Ferrous bisglycinate: (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.
    Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if coadministration with toremifene is necessary. Etravirine is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    Ezogabine: (Major) Avoid coadministration of ezogabine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ezogabine has been associated with QT prolongation.
    Fingolimod: (Major) Avoid coadministration of fingolimod with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. 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 torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. 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.
    Flecainide: (Major) Avoid coadministration of flecainide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (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 that have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as toremifene, is contraindicated. Fluconazole has been associated with QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Fluoxetine: (Major) Avoid coadministration of fluoxetine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of fluoxetine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine. (Major) Avoid coadministration of olanzapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Use toremifene and fluphenazine together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) Avoid coadministration of fluvoxamine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported during fluvoxamine post-marketing use.
    Formoterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Major) Avoid coadministration of fosamprenavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Foscarnet: (Major) Avoid coadministration of foscarnet with toremifene due to the risk of additive QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Fosphenytoin: (Major) Avoid coadministration of fosphenytoin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene. Phenytoin concentrations may also increase, as phenytoin is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    Gemifloxacin: (Major) Avoid coadministration of gemifloxacin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, obtain an ECG and serum electrolytes prior to starting therapy and closely monitor during treatment; correct hypokalemia or hypomagnesemia. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Glasdegib: (Major) Avoid coadministration of glasdegib with toremifene due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with electrolyte monitoring and increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Glyburide: (Moderate) Monitor blood glycose in patients receiving concomitant treatment with glyburide and toremifene. Glyburide is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor. Toremifene may increase glyburide exposure and decrease blood glucose concentrations.
    Glyburide; Metformin: (Moderate) Monitor blood glycose in patients receiving concomitant treatment with glyburide and toremifene. Glyburide is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor. Toremifene may increase glyburide exposure and decrease blood glucose concentrations.
    Glycopyrrolate; Formoterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Major) Avoid coadministration of goserelin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. 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) Avoid coadministration of granisetron with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Granisetron has also been associated with QT prolongation.
    Grapefruit juice: (Major) Instruct patients to avoid grapefruit juice while receiving toremifene due to increased plasma concentrations of toremifene which may result in QT prolongation. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Halogenated Anesthetics: (Major) Avoid coadministration of halogenated anesthetics with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of haloperidol with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Prolongation of the QT interval 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. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Histrelin: (Major) Avoid coadministration of histrelin with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes, correcting any electrolyte abnormalities. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    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) Avoid coadministration of hydroxyzine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
    Ibutilide: (Major) Avoid coadministration of ibutilide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Ibutilide administration can cause QT prolongation and torsade 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. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Idelalisib: (Major) Avoid coadministration of idelalisib with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Iloperidone: (Major) Avoid coadministration of iloperidone with toremifene due to the risk of additive QT prolongation. Iloperidone has been associated with QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Imipramine: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to 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) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Major) Avoid coadministration of indinavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    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 closely monitor during treatment. Correct hypokalemia or hypomagnesemia prior to administration of toremifene. Inotuzumab has been associated with QT interval prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of rifampin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of rifampin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Itraconazole: (Major) Avoid coadministration of itraconazole with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Itraconazole is a strong CYP3A4 inhibitor that has also been associated with prolongation of the QT interval.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with toremifene due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ketoconazole is a strong CYP3A4 inhibitor that has also been associated with prolongation of the QT interval.
    Lapatinib: (Major) Avoid coadministration of lapatinib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner; ventricular arrhythmias and torsade de pointes (TdP) have been reported with lapatinib use in postmarketing experience.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with toremifene due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Letermovir: (Moderate) An increase in the plasma concentration of toremifene may occur if given with letermovir. Avoid coadministration in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. If both letermovir and cyclosporine must be continued, it is recommended that therapy with toremifene be interrupted. If interruption of treatment is not possible and all 3 drugs must be given together, patients should be closely monitored for prolongation of the QT interval. Toremifene is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of toremifene with another strong CYP3A4 inhibitor increased toremifene maximum plasma concentration (Cmax) and exposure (AUC) by 1.4- and 2.9-fold, respectively. The Cmax and AUC of toremifene metabolite (N-demethyltoremifene) were reduced by 56% and 20%, respectively.
    Leuprolide: (Major) Avoid coadministration of leuprolide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (Minor) Use toremifene and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Major) Avoid coadministration of levofloxacin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Levofloxacin has also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Major) Avoid coadministration of lithium with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of lofexidine with toremifene due to the potential for additive QT prolongation. Monitor ECG and electrolytes if coadministration cannot be avoided. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Long-acting beta-agonists: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Major) Avoid coadministration of loperamide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. At high doses, loperamide has also been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Major) Avoid coadministration of loperamide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. At high doses, loperamide has also been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of conivaptan with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%. (Major) Avoid coadministration of ritonavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as toremifene. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Maprotiline: (Major) Avoid coadministration of maprotiline with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Maprotiline has also 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 torsade de pointes (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) Avoid coadministration of mefloquine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine; Promethazine: (Major) Avoid coadministration of promethazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Mephobarbital: (Major) Avoid coadministration of mephobarbital with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of 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) Use toremifene and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) Avoid coadministration of methadone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation. If toremifene is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2C9 substrate that is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). 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. Toremifene is a weak CYP2C9 inhibitor that has also been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration with weak CYP2C9 inhibitors like toremifene can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If toremifene is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Metronidazole: (Major) Avoid coadministration of metronidazole with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Avoid coadministration of midostaurin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Avoid coadministration of mifepristone with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Mifepristone is a strong CYP3A4 inhibitor that has also been associated with dose-dependent prolongation of the QT interval. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mirtazapine: (Major) Avoid coadministration of mirtazapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner. Torsade de pointes (TdP) has also been reported during postmarketing use of mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid coadministration of mitotane with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Moxifloxacin: (Major) Avoid coadministration of moxifloxacin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nateglinide: (Moderate) Monitor blood glucose in patients receiving concomitant treatment with nateglinide and toremifene. Nateglinide is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor. Toremifene may increase nateglinide exposure and decrease blood glucose concentrations.
    Nefazodone: (Major) Avoid coadministration of nefazodone with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Nelfinavir: (Major) Avoid coadministration of nelfinavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Nilotinib: (Major) Avoid coadministration of nilotinib with toremifene due to the risk of additive QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Norfloxacin: (Major) Avoid coadministration of norfloxacin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to 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) Avoid coadministration of octreotide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Arrhythmias, sinus bradycardia, and conduction disturbances have also occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (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.
    Ofloxacin: (Major) Avoid coadministration of ofloxacin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Avoid coadministration of olanzapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    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
    Ospemifene: (Moderate) Monitor for an increase is ospemifene-related adverse reactions if coadministration with toremifene is necessary. Ospemifene is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience.
    Paliperidone: (Major) Avoid coadministration of paliperidone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Paliperidone has also been associated with QT prolongation.
    Panobinostat: (Major) Coadministration of panobinostat with toremifene is not recommended due to the risk of additive QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval has also been reported with panobinostat.
    Pasireotide: (Major) Avoid coadministration of pasireotide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval has also occurred with pasireotide therapy at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Pazopanib has also been reported to prolong the QT interval.
    Pentamidine: (Major) Avoid coadministration of systemic pentamidine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Systemic administration of pentamidine has also been associated with QT prolongation.
    Perphenazine: (Minor) Use toremifene and perphenazine together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Perphenazine; Amitriptyline: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Use toremifene and perphenazine together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Phenobarbital: (Major) Avoid coadministration of phenobarbital with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of promethazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of phenytoin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene. Phenytoin concentrations may also increase, as phenytoin is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    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) Coadministration of toremifene with pimozide is contraindicated because of the potential for torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Pirbuterol: (Minor) Use toremifene and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Posaconazole: (Severe) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as toremifene, is contraindicated. Posaconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP). Toremifene is a CYP3A4 substrate that has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Primaquine: (Major) Avoid coadministration of primaquine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Primaquine may also cause QT prolongation.
    Primidone: (Major) Avoid coadministration of primidone with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Procainamide: (Major) Avoid coadministration of procainamide with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Minor) Use toremifene and prochlorperazine together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Promethazine: (Major) Avoid coadministration of promethazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of propafenone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Protriptyline: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to 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) Avoid coadministration of quetiapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Avoid coadministration of quinidine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
    Quinine: (Major) Avoid coadministration of quinine with toremifene due to the risk of additive QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Quinine has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Major) Avoid coadministration of ranolazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner. 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.
    Ribociclib: (Major) Avoid coadministration of ribociclib with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Rifabutin: (Major) Avoid coadministration of rifabutin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Rifampin: (Major) Avoid coadministration of rifampin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Rilpivirine: (Major) Avoid coadministration of rilpivirine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Risperidone: (Major) Avoid coadministration of risperidone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Risperidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP), primarily in the setting of overdose.
    Ritonavir: (Major) Avoid coadministration of ritonavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Romidepsin: (Major) Avoid coadministration of romidepsin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Romidepsin has also been reported to prolong the QT interval.
    Salmeterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Severe) Coadministration of saquinavir and toremifene is contraindicated due to the risk of QT prolongation. Saquinavir is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Sertraline: (Major) Avoid coadministration of sertraline and 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. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Short-acting beta-agonists: (Minor) Use toremifene and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Solifenacin: (Major) Avoid coadministration of solifenacin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner. Torsade de pointes (TdP) has also been reported with postmarketing use of solifenacin, although causality was not determined.
    Sorafenib: (Major) Avoid coadministration of sorafenib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Avoid coadministration of sotalol with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Sotalol administration is also associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    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.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of St. John's Wort with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    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.
    Sunitinib: (Major) Avoid coadministration of sunitinib 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. Sunitinib can also cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP).
    Tacrolimus: (Major) Avoid coadministration of tacrolimus with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tacrolimus also causes QT prolongation.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. 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.
    Telavancin: (Major) Avoid coadministration of telavancin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Telavancin has also been associated with QT prolongation.
    Telithromycin: (Major) Avoid coadministration of telithromycin with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and telithromycin is a strong CYP3A4 inhibitor that is also associated with QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Terbutaline: (Minor) Use toremifene and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine with toremifene due to the risk of additive QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Thiazide diuretics: (Moderate) Monitor serum calcium levels in patients receiving concomitant treatment with toremifene and thiazide diuretics. Thiazide diuretics decrease renal calcium excretion and may increase the risk of hypercalcemia in patients receiving toremifene.
    Thioridazine: (Severe) Because of the potential for torsade de pointes (TdP), use of toremifene with thioridazine is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and TdP. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Tiotropium; Olodaterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Major) Avoid coadministration of tipranavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Tolterodine: (Major) Avoid coadministration of tolterodine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Torsemide: (Moderate) Monitor for an increase in torsemide-related adverse reactions including diuretic effect and blood pressure if coadministration with toremifene is necessary; adjust the dose of torsemide if necessary. Torsemide is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    Trazodone: (Major) Avoid coadministration of trazodone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Trazodone can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP).
    Tricyclic antidepressants: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to 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) Use toremifene and trifluoperazine together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trimipramine: (Major) Avoid coadministration of tricyclic antidepressants with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to 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) Avoid coadministration of triptorelin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. 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.
    Umeclidinium; Vilanterol: (Moderate) Use toremifene and long-acting beta agonists together with caution due to the risk of QT prolongation. The manufacturer of toremifene recommends avoiding toremifene with other drugs that prolong the QT, if possible. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with toremifene due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Both drugs can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.
    Vardenafil: (Major) Avoid coadministration of vardenafil with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses.
    Vemurafenib: (Major) Avoid coadministration of vemurafenib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Vemurafenib has also been associated with QT prolongation.
    Venlafaxine: (Major) Avoid coadministration of venlafaxine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Voriconazole: (Major) Avoid coadministration of voriconazole with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Vorinostat: (Major) Avoid coadministration of vorinostat with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Vorinostat therapy is also associated with a risk of QT prolongation.
    Warfarin: (Moderate) Monitor the PT/INR and watch for signs of bleeding if coadministration of warfarin with toremifene is necessary. Warfarin is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
    Ziprasidone: (Severe) 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, including toremifene. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner and medications with a known potential to prolong the QT interval, including ziprasidone, should be avoided with toremifene therapy.

    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.