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Toremifene

Pronunciation

(tore EM i feen)

Index Terms

  • FC1157a
  • Toremifene Citrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Fareston: 60 mg

Brand Names: U.S.

  • Fareston

Pharmacologic Category

  • Antineoplastic Agent, Estrogen Receptor Antagonist
  • Selective Estrogen Receptor Modulator (SERM)

Pharmacology

Nonsteroidal, triphenylethylene derivative with potent antiestrogenic properties (also has estrogenic effects). Competitively binds to estrogen receptors on tumors and inhibits the growth stimulating effects of estrogen.

Absorption

Well absorbed

Distribution

Vd: 580 L

Metabolism

Extensively hepatic, principally by CYP3A4 to N-demethyltoremifene (a weak antiestrogen)

Excretion

Primarily feces; urine (~10%) during a 1-week period

Time to Peak

Serum: ≤3 hours

Half-Life Elimination

Toremifene: ~5 days, ~7 days (females > 60 years); N-demethyltoremifene: 6 days

Protein Binding

Plasma: >99.5%, primarily to albumin

Special Populations: Hepatic Function Impairment

The mean elimination half-life was increased by less than 2-fold in patients with cirrhosis or fibrosis.

Special Populations: Elderly

Elimination half-life prolonged and Vd increased (457 vs 627 L) observed in elderly women.

Use: Labeled Indications

Breast cancer, metastatic: Treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown tumors

Off Label Uses

Desmoid tumors (aggressive fibromatosis)

Data from a retrospective review supports the use of toremifene for the treatment of desmoid tumors [Fiore 2015]. Data from a limited number of patients studied (case reports) also suggests that toremifene may be beneficial for the treatment of desmoid tumors [Brooks 1992]. Additional data may be necessary to further define the role of toremifene in this condition.

Contraindications

Known hypersensitivity to toremifene or any component of the formulation; congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, uncorrected hypomagnesemia

Dosing: Adult

Breast cancer, metastatic: Postmenopausal women: Oral: 60 mg once daily, continue until disease progression.

Desmoid tumors (aggressive fibromatosis) (off-label use): Oral: 180 mg once daily until disease progression or unacceptable toxicity (Fiore 2015). Additional data may be necessary to further define the role of toremifene in this condition.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments listed in the manufacturer’s labeling. However, pharmacokinetics in patients with renal impairment are similar to those in patients with normal renal function and dosage adjustment is unlikely to be necessary.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. However, hepatic impairment increases the half-life of toremifene.

Administration

Administer with or without food.

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); protect from heat. Protect from light.

Drug Interactions

Amifampridine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Bilastine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Buprenorphine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Toremifene. Avoid combination

CYP3A4 Inhibitors (Strong): May enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Grapefruit Juice: May increase the serum concentration of Toremifene. Avoid combination

Hydroxychloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Indapamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Mizolastine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Ospemifene: Selective Estrogen Receptor Modulators may enhance the adverse/toxic effect of Ospemifene. Ospemifene may also enhance adverse/toxic effects of other Selective Estrogen Receptor Modulators. Selective Estrogen Receptor Modulators may diminish the therapeutic effect of Ospemifene. Ospemifene may also diminish the therapeutic effects of other Selective Estrogen Receptor Modulators. Avoid combination

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Probucol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Promazine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

QTc-Prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of other QTc-Prolonging Agents (Highest Risk). Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Sugammadex: Toremifene may diminish the therapeutic effect of Sugammadex. Monitor therapy

Teneligliptin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the hypercalcemic effect of Toremifene. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Vitamin K Antagonists (eg, warfarin): Toremifene may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Xipamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Adverse Reactions

>10%:

Dermatologic: Diaphoresis (20%)

Endocrine & metabolic: Hot flash (35%)

Gastrointestinal: Nausea (14%)

Genitourinary: Vaginal discharge (13%)

Hepatic: Increased serum alkaline phosphatase (8% to 19%), increased serum AST (5% to 19%)

1% to 10%:

Cardiovascular: Edema (5%), cardiac arrhythmia (≤2%), cerebrovascular accident (≤2%), local thrombophlebitis (≤2%), pulmonary embolism (≤2%), thrombosis (≤2%), transient ischemic attacks (≤2%), cardiac failure (≤1%), myocardial infarction (≤1%)

Central nervous system: Dizziness (9%)

Endocrine & metabolic: Hypercalcemia (≤3%)

Gastrointestinal: Vomiting (4%)

Genitourinary: Vaginal hemorrhage (2%)

Hepatic: Increased serum bilirubin (1% to 2%)

Ophthalmic: Cataract (≤10%), xerophthalmia (≤9%), visual field defect (≤4%), corneal disease (≤2%), glaucoma (≤2%), visual disturbance (≤2%), diplopia (≤2%)

<1% (Limited to important or life-threatening): Alopecia, angina pectoris, anorexia, arthritis, ataxia, blurred vision, constipation, corneal opacity (reversible; including corneal verticulata), depression, dermatitis, dyspnea, endometrial carcinoma, endometrial hyperplasia, fatigue, hepatotoxicity (including hepatitis, nonalcoholic fatty liver disease), jaundice, lethargy, leukopenia, paresis, polyp (uterine), prolonged Q-T interval on ECG, pruritus, rigors, skin discoloration, thrombocytopenia, toxic hepatitis, tremor, tumor flare, vertigo, weakness

ALERT: U.S. Boxed Warning

QT prolongation:

Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsades de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia, or uncorrected hypomagnesemia. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Leukopenia and thrombocytopenia have been reported rarely; monitor leukocyte and platelet counts in patients with leukopenia and thrombocytopenia.

• Hepatotoxicity: Grades 3 and 4 transaminase increases and hyperbilirubinemia have been reported, including jaundice, hepatitis, and non-alcoholic fatty liver disease. Monitor liver function tests periodically.

• Hypercalcemia: May occur during the first weeks of treatment in breast cancer patients with bone metastases; monitor closely for hypercalcemia. Institute appropriate measures if hypercalcemia occurs; discontinue treatment if severe. Medications that decrease renal calcium excretion (eg, thiazide diuretics) may increase the risk of hypercalcemia in patients receiving toremifene.

• QT prolongation: [US Boxed Warning]: May prolong the QT interval; QTc prolongation is dose-dependent and concentration-dependent. QT prolongation may lead to a form of ventricular tachycardia called torsades de pointes, which may result in syncope, seizure and/or sudden death. Use is contraindicated in patients with congenital or acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. Avoid use with other medications known to prolong the QT interval and with strong CYP3A4 inhibitors. If concurrent use with QT prolonging agents cannot be avoided, interrupt treatment with toremifene. Use with caution in patients with heart failure, hepatic impairment, or electrolyte abnormalities. Monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Obtain ECG at baseline and as clinically indicated in patients at risk for QT prolongation.

• Tumor flare: May occur during the first weeks of treatment in breast cancer patients with bone metastases. Tumor flare consists of diffuse musculoskeletal pain and erythema with initial increased size of tumor lesions (which later regress). It is often accompanied by hypercalcemia and does not imply treatment failure or represent tumor progression.

• Uterine malignancy: Endometrial cancer, hypertrophy, hyperplasia, and uterine polyps have been reported. Long-term use of toremifene in patients with pre-existing endometrial hyperplasia has not been established. Baseline and annual gynecological exams are recommended in all patients; closely monitor patients who are at high risk for endometrial cancer.

Disease-related concerns:

• Hepatic impairment: The half-life of toremifene is increased (less than 2-fold) in patients with hepatic impairment (cirrhosis and fibrosis), although the pharmacokinetics of N-demethyltoremifene (a metabolite with weak antitumor potency) were unchanged.

• Thromboembolic disease: Avoid use in patients with a history of thromboembolic disease.

Concurrent drug therapy issues:

• Drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

CBC with differential (periodically), electrolytes (magnesium and potassium prior to and periodically during treatment; calcium periodically), hepatic function tests (periodically). Obtain ECG (baseline and periodically during treatment) in patients at risk for QT prolongation. In patients with bone metastases, monitor closely for hypercalcemia during the first few weeks of treatment. Baseline and annual gynecological exams (patients at high risk for endometrial cancer should be closely monitored). Signs/symptoms of uterine disorders (bleeding, discharge, pelvic pain/pressure).

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, may cause fetal harm if administered during pregnancy. Toremifene is only approved for use in postmenopausal women; however, if prescribed in premenopausal women, effective non-hormonal contraception should be used.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hot flashes, nausea, vomiting, lack of appetite, sweating a lot, or dry eyes. Have patient report immediately to prescriber signs of high calcium (weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), tachycardia, abnormal heartbeat, severe dizziness, passing out, vision changes, chills, pharyngitis, muscle pain, seizures, pelvic pain or pressure, bruising, bleeding, vaginal discharge, or abnormal vaginal bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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