Toremifene Citrate Capsules

Toremifene Citrate is a nonsteroidal selective estrogen receptor modulator (SERM) and a member of the triphenylethylene SERM drug class. Toremifene was approved by the FDA for use in estrogen-receptor positive or receptor-unknown metastatic breast cancer on May 29, 1997. The Orion Corporation has marketed toremifene for breast carcinoma in Finland since 1988. Toremifene is as effective as tamoxifen in treating metastatic breast cancer.

Toremifene is a tamoxifen analog, modified by the addition of a single chloride group. The chloride addition inhibits the formation of DNA adducts, in turn significantly reducing toxicity. Down stream effects of tamoxifen DNA adducts in some cases ultimately induce carcinoma; furthermore, toremifene does not produce detectable DNA adducts or carcinoma in animal models. Unlike tamoxifen, no current literature directly links toremifene to malignant cancers in human.

Toremifene (Acapodene®) is under investigation for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia and for the treatment of multiple side effects of androgen deprivation therapy (ADT) for prostate cancer. Toremifene has been used in men undergoing ADT to alleviate the negative effects of hormonal manipulation. Deleterious side effects of ADT, among others, include gynecomastia, changes in body composition, changes in blood lipids, and osteoporosis. The alleviation of the previously mentioned side effects by toremifene has been reported.

When compared to tamoxifen, toremifene differentially affects biomarkers of hepatic origin. Toremifene has been shown to significantly decrease total cholesterol, decrease LDL cholesterol, decrease triglycerides, increase HDL cholesterol (fig.1 excerpt from), prevent osteoporosis, and reduce the incidence of prostate cancer in men, this improvement in dyslipidemia and osteoporosis has also been demonstrated in women. In one study, toremifene increased high-density lipoprotein (HDL) cholesterol serum concentrations whereas tamoxifen decreased HDL cholesterol serum concentrations. Consequently, toremifene appears to have a more favorable effect on lipid levels than tamoxifen.

In infertile men, toremifene increased total serum testosterone by approximately 45%, and FSH by approximately 64%. Toremifene also significantly improved three semen quality parameters, increasing total sperm count by 38%, total motile sperm by 25%, and total sperm with normal morphology by 42%.

Toremifene acts on the estrogen receptor (ER) and possibly activates transcription indirectly through induction of other transcription factors.

Two subtypes of the estrogen receptor are currently characterized including: ERα and ERβ. At ERα toremifene, due to its alkylaminoethoxyphenyl side chain, most likely opposes estrogen actions (antagonist) and at ERβ stimulates estrogen-like actions (agonist). The production of ERα and ERβ are tissue specific. ERα activity and ERβ polymorphisms have been identified in the pathogenesis of breast cancer and gynecomastia.

The antitumor actions of toremifene are believed to be mainly due to its antagonistic effects at ERα; however, other mechanisms may be involved. Toremifene competes with estrogen for binding sites in cancer cells, thereby blocking the growth-stimulating effects of estrogen in the tumor. Further, toremifene may have additional mechanisms which do not involve estrogen receptors. Toremifene also promotes the production of transforming growth factor beta (TGFβ), an inhibitory growth factor. TGFβ may cause growth retardation and tumor regression by enhancing cell death (apoptosis) and/or arresting cell proliferation. This mechanism of toremifene requires further investigation.

Toremifene may be given without regard to meals. Following oral administration, toremifene is well absorbed and food has no influence on absorption. Peak plasma concentrations are obtained within 3 hours.

For patients with renal impairment no dosage adjustments are needed.

For patients with hepatic impairment no dosage guidelines are available; however, patients may be at increased risk for side effects. The mean elimination half-life of toremifene was increased by less than two-fold in 10 patients with hepatic impairment compared to subjects with normal hepatic function. Safety and efficacy have not been established in patients with hepatic impairment.

Route-Specific Pharmacokinetics:

Toremifene is administered orally. Protein binding is extensive (> 99.5%), primarily to albumin. Toremifene is metabolized (demethylated) by the hepatic P-450 enzyme system primarily via cytochrome P450 3A4 (CYP3A4). CYP1A also plays a minor role in toremifene metabolism. The principal metabolite, N-demethyltoremifene, is also antiestrogenic but has weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2-4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Toremifene also undergoes enterohepatic circulation. The elimination half-lives of toremifene and its principal active metabolite (N-demethyltoremifene) are about 5 days and 6 days, respectively.

According to the manufacturer, toremifene should not be administered during breast-feeding. It is not known whether toremifene is excreted into human milk; however, because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue the drug or to discontinue breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Toremifene is a pregnancy category D drug. Toremifene can cause harm to the fetus if administered to pregnant women and therefore should be used cautiously during pregnancy. Animal data indicate that toremifene can cross the placental barrier. There have been no studies in pregnant women. Women should be instructed to use barrier methods of contraception. If toremifene is used during pregnancy, or if the patient becomes pregnant while receiving toremifene, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

Toremifene should generally not be used to treat patients with a history of thromboembolic disease. Leukocyte and platelet counts should be monitored when using toremifene in patients with leukopenia or thrombocytopenia. Leukopenia and thrombocytopenia have been reported rarely with toremifene therapy. Further, intramuscular injections should be avoided in patients receiving toremifene since IM injections may cause bleeding, bruising, or hematomas.

Use toremifene cautiously in patients with preexisting hypercalcemia. 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.

Toremifene should be used cautiously in patients with hepatic disease. Patients with cirrhosis or hepatic fibrosis had an almost twofold increase in the mean elimination half-life of toremifene compared to patients with normal hepatic function; the pharmacokinetic parameters of N-demethyltoremifene were unchanged in these patients Elevated or prolonged toremifene exposure may increase the risk of side effects, such as prolongation of the QT interval. In patients at increased risk for prolongation of the QT interval, such as those with hepatic disease, obtain electrocardiograms at baseline and as clinically indicated.

There is no indication for the use of toremifene in children.

Use toremifene cautiously in patients with preexisting endometrial hyperplasia or endometrial cancer. In general, patients with preexisting endometrial hyperplasia should not receive long-term toremifene therapy.

Toremifene is contraindicated for use by patients with acquired or congenital long QT syndrome, uncorrected hypokalemia, or uncorrected hypomagnesemia. Correct hypokalemia or hypomagnesemia before toremifene initiation; periodically monitor these electrolytes during therapy. Cautious use of toremifene is advised for patients with congestive heart failure and a history of electrolyte abnormalities. 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. In patients at increased risk of QT prolongation, obtain an electrocardiogram (ECG) at baseline and as clinically indicated. Toremifene prolongs the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. Avoid concomitant use of toremifene with drugs known to prolong the QT interval and with strong CYP3A4 inhibitors.

Toremifene is a pregnancy category D drug. Toremifene can cause harm to the fetus if administered to pregnant women and therefore should be used cautiously during pregnancy. Animal data indicate that toremifene can cross the placental barrier. There have been no studies in pregnant women. Women should be instructed to use barrier methods of contraception. If toremifene is used during pregnancy, or if the patient becomes pregnant while receiving toremifene, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

According to the manufacturer, toremifene should not be administered during breastfeeding. It is not known whether toremifene is excreted into human milk; however, because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue the drug or to discontinue breastfeeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

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.

Coadministration of toremifene and warfarin may result in increased warfarin concentrations, which may increase the INR and increase the risk for bleeding. Toremifene is a weak inhibitor of CYP2C9. Warfarin is a CYP2C9 substrate. Coadminster with caution and with careful monitoring of the INR.

Cytochrome P450 3A4 (CYP3A4) enzyme inducers increase the rate of toremifene metabolism. In a pharmacokinetic study in healthy volunteers, administration of a single dose of toremifene was given following chronic dosing with rifampin. The AUC of toremifene was reduced by 87% and the Cmax was reduced by 55%. The half-life of toremifene was reduced by 44% following rifampin dosing. The effect of rifampin on chronic toremifene therapy is unknown but may lead to a loss of toremifene’s antiestrogen effects. A similar effect may occur with concurrent administration of toremifene and other CYP3A4 inducers such as rifabutin or rifapentine.

Cytochrome P450 3A4 (CYP3A4) enzyme inducers, such as phenytoin (or fosphenytoin), increase the rate of toremifene metabolism. Coadminister these drugs with caution and carefully monitor the patient.

Cytochrome P450 3A4 (CYP3A4) enzyme inducers increase the rate of toremifene metabolism. Examples of CYP3A4 inducers include: bosentan, carbamazepine, barbiturates (e.g., phenobarbital), and St. John’s Wort. Ten patients on either carbamazepine, clonazepam, phenobarbital, or phenytoin and receiving toremifene showed a two-fold increase in clearance and a decrease in the elimination half-life of toremifene (manufacturer product literature).

Aprepitant, fosaprepitant is a moderate inhibitor and an inducer of CYP3A4. Toremifene is a substrate of CYP3A4. Coadminister these drugs with caution. Altered toremifene serum concentrations may occur, leading to either an increased risk of toremifene-related adverse reactions or a risk of decreased toremifene efficacy.

Cytochrome P450 3A4 (CYP3A4) enzyme inducers, such as efavirenz, increase the rate of toremifene metabolism. Coadminister toremifene and efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) with caution and carefully monitor the patient.

Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Examples of CYP3A4 inhibitors include anti-retroviral protease inhibitors, cyclosporine, dalfopristin; quinupristin, danazol, delavirdine, diltiazem, fluoxetine, fluvoxamine, imatinib, STI-571, nicardipine, verapamil, and zafirlukast. This list is not inclusive of all CYP3A4 inhibitors. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain.

Thiazide diuretics and other drugs that decrease renal calcium excretion may increase the risk of hypercalcemia in patients receiving toremifene. Further, administration of calcium salts may also increase the risk of hypercalcemia.

It is unknown if phytoestrogen compounds like black cohosh, Cimicifuga racemosa, potentiate or interfere with the therapeutic activity of selective-estrogen receptor modifier (SERM) therapies like tamoxifen, toremifene, or raloxifene. Since black cohosh may potentially suppress luteinizing hormone (LH) or have estrogen-receptor binding activity, interactions could theoretically occur.  Clinically, black cohosh has been studied in combination with tamoxifen in breast cancer survivors; the data are not conclusive regarding clinical benefit in managing hot flashes in this population. The effects of black cohosh may be dependent on the underlying endogenous estrogen balance and age of the female patient (i.e., pre- versus post-menopausal), and the presence of other health conditions (e.g., pregnancy). Interactions remain primarily theoretical, as clinical documentation of harmful interactions is lacking. It is recommended that patients discuss the use of black cohosh with their practitioner prior to combining therapy with SERMs.

Theoretically, the soy isoflavones may compete with drugs that selectively modulate estrogen receptors. Soy isoflavones should be used with caution in patients taking toremifene.

Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Because of the potential for torsade de pointes (TdP), use of the following drugs with toremifene is contraindicated: astemizole, bepridil, bretylium, cisapride, dofetilide, dronedarone, grepafloxacin, halofantrine, levomethadyl, mesoridazine, pimozide, probucol, sparfloxacin, terfenadine, thioridazine, and ziprasidone.

Coadministration of posaconazole with drugs that are CYP3A4 substrates that also prolong the QT interval, such as toremifene, may result in an elevated plasma concentrations of toremifene and an increased risk for adverse events, including QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Posaconazole in itself can prolong the QT interval. The manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4.

Coadministration of ketoconazole with drugs that are CYP3A4 substrates that also prolong the QT interval, such as toremifene, may result in an elevated plasma concentrations of toremifene and an increased risk for adverse events, including QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ketoconazole in itself can prolong the QT interval. In addition, ketoconazole is a potent inhibitor of CYP3A4. Drugs that are known to prolong that QT interval and are metabolized by CYP3A4 may be contraindicated with ketoconazole. The manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4. Because ketoconazole also is a potent inhibitor of CYP3A4, it would be prudent to follow the same recommendations.

Coadministration of itraconazole with drugs that are CYP3A4 substrates that also prolong the QT interval, such as toremifene, may result in an elevated plasma concentrations of toremifene and an increased risk for adverse events, including QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Itraconazole in itself can prolong the QT interval. In addition, itraconazole is a potent inhibitor of CYP3A4. Drugs that are known to prolong that QT interval and are metabolized by CYP3A4 may be contraindicated with itraconazole. The manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4. Because itraconazole also is a potent inhibitor of CYP3A4, it would be prudent to follow the same recommendations.

Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with toremifene include: abarelix, alfuzosin, apomorphine, amiodarone, arsenic trioxide, aripiprazole, artemether; lumefantrine, asenapine, atomoxetine, azithromycin, bedaquiline, beta-agonists, ofloxacin, ciprofloxacin, chloroquine, chlorpromazine, citalopram, clarithromycin, clozapine, crizotinib, cyclobenzaprine, dasatinib, daunorubicin, degarelix, disopyramide, dolasetron, donepezil, donepezil; memantine, doxorubicin, droperidol, eribulin, erythromycin, escitalopram, ezogabine, fingolimod, flecainide, fluconazole, fluphenazine, gemifloxacin, granisetron, halogenated anesthetics, haloperidol, ibutilide, iloperidone, lapatinib, levofloxacin, lithium, ritonavir, lopinavir; ritonavir, maprotiline, mefloquine, methadone, mifepristone, RU-486, moxifloxacin, nilotinib, norfloxacin, octreotide, olanzapine, ondansetron, paliperidone, pasireotide, pazopanib, systemic pentamidine, perflutren lipid microspheres, perphenazine, primaquine, procainamide, prochlorperazine, propafenone, quetiapine, quinidine  (including dextromethorphan; quinidine), ranolazine, regadenoson, rilpivirine, risperidone, romidepsin, saquinavir, solifenacin, sorafenib, sotalol, sunitinib, tacrolimus, telavancin, telithromycin, tetrabenazine, tolterodine, trazodone, tricyclic antidepressants, trifluoperazine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, and vorinostat.

Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner and should be used with caution and close monitoring with other drugs that may prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.

Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) such as toremifene should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.

Caution is warranted when cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.

Caution is warranted when darunavir; cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; darunavir and cobicistat are CYP3A4 inhibitors.

Caution is warranted when atazanavir; cobicistat is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; atazanavir and cobicistat are CYP3A4 inhibitors.

Caution is warranted when cobicistat; elvitegravir; emtricitabine; tenofovir is administered with toremifene as there is a potential for elevated toremifene concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Toremifene is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.

The co-administration of panobinostat with toremifene is not recommended; QT prolongation has been reported with both agents.

Concurrent administration of toremifene with ombitasvir; paritaprevir; ritonavir may result in elevated toremifene plasma concentrations and subsequent adverse effects such as QT prolongation. Toremifene is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Toremifene and ritonavir have both been associated with QT prolongation; caution and close monitoring are advised if these drugs are administered together.

Concurrent administration of toremifene with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated toremifene plasma concentrations and subsequent adverse effects such as QT prolongation.Toremifene is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Toremifene and ritonavir have both been associated with QT prolongation; caution and close monitoring are advised if these drugs are administered together.

Changes in appetite; changes in menstrual periods; diarrhea; hair loss; headache; nausea, vomiting; tiredness; trouble sleeping; weight loss. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue; breathing problems; chest pain; excessive sweating or intolerance to heat; fast or irregular heartbeat; nervousness; swelling of ankles, feet, or legs; tremors.

Monitor for signs and symptoms of hypothyroidism that could require an upward adjustment of the desiccated thyroid dosage. Signs or symptoms of underdosage or hypothyroidism include constipation, cold intolerance, dry skin (xerosis) or hair, fatigue, impaired intellectual performance or other mental status changes (e.g., depression), deepening of voice, lethargy, weight gain, tongue enlargement, and, eventually, myxedema coma.

Adverse reactions to desiccated thyroid are rare. Adverse reactions usually indicate inappropriate dosage of the hormone. No well-documented evidence from the literature of true allergic or idiosyncratic reactions to thyroid hormone exist.

Transient partial alopecia may occur in children in the first few months of desiccated thyroid treatment, but normal hair growth usually recovers. Alopecia may be due to hyperthyroidism from therapeutic overdosage or to hypothyroidism from therapeutic underdosage.

Many of the signs and symptoms of thyroid hormone imbalance are subtle and insidious. Manifestations of desiccated thyroid excessive dosage or hyperthyroidism include anorexia, diaphoresis, diarrhea, dyspnea, elevated hepatic enzymes, emotional lability, fatigue, fever, flushing, headache, heat intolerance, hyperactivity, appetite stimulation, infertility, irritability, insomnia, menstrual irregularity (e.g., amenorrhea), muscle weakness, muscle cramps, nausea, vomiting, nervousness or anxiety, tremor, and weight loss. The clinician should be alert to constellations of symptoms that gradually worsen over time.

Pseudotumor cerebri has been reported in patients receiving thyroid hormone replacement therapy such as desiccated thyroid. Symptoms such as headache, papilledema, and elevated opening pressures on lumbar puncture may occur within weeks of starting thyroid hormone replacement therapy and must be differentiated from brain metastases, if applicable.

In infants, excessive doses of thyroid hormone preparations such as desiccated thyroid may produce craniosynostosis. Also, undertreatment may result in slowed reduced adult height, and overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature (growth inhibition). Slipped capital femoral epiphysis has been reported in children receiving levothyroxine.

Overtreatment with thyroid hormone such as desiccated thyroid may have adverse cardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias. Symptoms may include palpitations, sinus tachycardia, arrhythmias, hypertension, heart failure, angina, myocardial infarction, and cardiac arrest. Peripheral edema may also occur. Patients with subclinical hyperthyroidism, either from excessive thyroid hormone replacement or other, may also be at an increased risk for atrial fibrillation. One study compared elderly patients (mean age 65 years) with subclinical hyperthyroidism to euthyroid subjects for 2 years; atrial fibrillation was initially recorded in 8 patients and 3 additional patients developed atrial fibrillation during follow-up; the data correspond to a total incidence of atrial fibrillation of 28% in subclinical hyperthyroidism patients compared to 10% in euthyroid subjects. Lower initial doses of desiccated thyroid are advised for patients where compromised integrity of the cardiovascular system, particularly the coronary arteries, is suspected or known such as patients with angina pectoris or the elderly. Also, reduce the dose in such patients if a euthyroid state can only be reached at the expense of an aggravation of the cardiovascular disease. Closely monitor infants for cardiac overload, arrhythmias, and aspiration from avid suckling during the first 2 weeks of thyroid hormone replacement.

Administration of too much desiccated thyroid may lead to osteopenia and osteoporosis. Suppressed serum thyrotropin (TSH) concentrations by use of another thyroid hormone levothyroxine was associated with bone loss and the potential increased risk for osteopenia and the premature development of osteoporosis. Because estrogen plays a protective role against bone loss, this increased risk is thought to be relevant in postmenopausal women receiving prolonged thyroid therapy. In a meta-analysis that pooled study data on the effects of slight over treatment with levothyroxine on pre- and postmenopausal women, a significant reduction in bone mass was observed in the postmenopausal study groups. Pooled study data contained skeletal measurements of the distal forearm, femoral neck, and lumbar spines of postmenopausal women. For all postmenopausal women, a theoretical bone consisting of 11.3% distal forearm, 42% femoral neck, and 46.7% lumbar spine was constructed (n = 317 measurements). Data showed that a postmenopausal woman at an average age of 61.2 years and treated with levothyroxine for 9.93 years (leading to suppressed serum TSH) would have an excess loss of bone mass of 9.02%; corresponding to an excess annual loss of 0.91% after 9.93 years of levothyroxine treatment as compared to healthy postmenopausal women.

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

The most common adverse reactions reported with toremifene therapy are principally due to the antiestrogenic hormonal actions of the drug and typically occur at the beginning of treatment.

The most common general adverse events reported among toremifene recipients include diaphoresis (20%), edema (5%), and hot flashes (35%). Other adverse events events include fatigue, lethargy, dyspnea, and rigors.

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. Tumor flare is often accompanied by hypercalcemia and is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. Tumor flare does not imply failure of treatment or represent tumor progression. Drugs that decrease renal calcium excretion such as thiazide diuretics may increase the risk of hypercalcemia. Closely monitor patients with bone metastases for hypercalcemia during the first weeks of treatment. Discontinue toremifene if hypercalcemia is severe. In clinical trials, < 1% to 3% of patients had hypercalcemia.

Elevated hepatic enzymes (AST) occurred in 5—19% of toremifene recipients. Hyperbilirubinemia occurred in 1—1.5% of patients, and 8—19% had elevated alkaline phosphatase. Jaundice and toxic hepatitis were also reported.

Among toremifene recipients, < 1% to 2% had pulmonary embolism or thrombophlebitis/phlebitis, < 1% to 1.5% had thrombosis, and < 1% to 2% had stroke (CVA) or transient ischemic attack. [28822]

Among toremifene recipients ophthalmic adverse reactions that have been reported in clinical trials include cataracts (10%), xerophthalmia (9%), abnormal visual fields or visual impairment (4%), corneal keratopathy (2%), glaucoma (< 1.5%), and abnormal vision or diplopia (1.5%). Reversible corneal opacification (corneal verticulata) and blurred vision were also reported.

Toremifene prolongs the QTc interval in a dose- and concentration-related manner; no effects on heart rate, PR, and QRS interval duration were noted. Among healthy adults, the percentage of patients with an increase of 60 ms in QTc was 0 with a 20 mg dose, 4.3% with a 80 mg dose, and 89.6% with a 300 mg dose. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene is contraindicated for use by patients with congenital/acquired QT prolongation, uncorrected hypokalemia, or uncorrected hypomagnesemia. Also, cautious use of toremifene is advised for patients with congestive heart failure, hepatic impairment, or electrolyte abnormalities (see Contraindications). Correct hypokalemia or hypomagnesemia before initiating toremifene, and periodically monitor these electrolytes during therapy. Avoid the concurrent use of drugs known to prolong the QT interval and strong CYP3A4 inhibitors (see Drug Interactions). Obtain ECG at baseline and as clinically indicated for patients at increased risk of QT prolongation. In addition to QT prolongation, other adverse reactions included heart failure (1%), myocardial infarction (< 1% to 1%), arrhythmia exacerbation (1.5%), and angina pectoris (< 1%).

Gastrointestinal adverse events reported during toremifene clinical trials include nausea (14%), vomiting (4%), constipation, and anorexia.

Vaginal bleeding (2%) and vaginal discharge (13%) were reported in patients during toremifene clinical trials.

Nervous system or psychiatric adverse events reported during toremifene clinical trials include dizziness (9%), depression, paresis, tremor, vertigo, asthenia, incoordination, and ataxia.

Cardiac adverse events reported during toremifene clinical trials include heart failure (1%), myocardial infarction (< 1% to 1%), arrhythmia (1.5%), and angina (< 1%).

Leukopenia and thrombocytopenia were reported during clinical trials with toremifene.

Skin and soft tissue adverse events reported during toremifene clinical trials include skin discoloration, dermatitis, pruritus, and alopecia.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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