TOREMIFENE Drug Interactions: What You Need to Know

INTERACTIONS Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving toremifene citrate tablets. ( 7.1 ) Agents that prolong QT should be avoided. ( 7.2 ) Coadministration with a strong CYP3A4 inducer may result in a relevant decrease in toremifene citrate tablets exposure and should be avoided. ( 7.3 ) Coadministration with a strong CYP3A4 inhibitor can result in a relevant increase in toremifene citrate tablets exposure and should be avoided. ( 7.4 ) CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with toremifene citrate tablets should be used with caution and require careful monitoring. ( 7.6 )

7.1 Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving toremifene citrate tablets.

7.2 Agents that Prolong QT The administration of toremifene citrate tablets with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with toremifene citrate tablets be interrupted. If interruption of treatment with toremifene citrate tablets is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated <span class="opacity-50 text-xs">[see Boxed Warning and Warnings and Precautions ( 5.1 )]</span> .

7.3 Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John&apos;s Wort, lower the steady-state concentration of toremifene in serum.

7.4 Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene C max and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene C max and AUC were reduced by 56% and 20%, respectively. The administration of toremifene citrate tablets with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with toremifene citrate tablets be interrupted. If interruption of treatment with toremifene citrate tablets is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval <span class="opacity-50 text-xs">[see Boxed Warning and Warnings and Precautions ( 5.1 )]</span> .

7.5 Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam C max and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam C max and AUC were reduced by less than 20%. Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.

7.6 Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide C max and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide C max and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with toremifene citrate tablets should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).

Hypersensitivity to the drug ( 4.1 ) QT Prolongation, Hypokalemia, Hypomagnesemia ( 4.2 )

4.1 Hypersensitivity to the Drug Toremifene citrate tablets are contraindicated in patients with known hypersensitivity to the drug.

4.2 QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.

AND PRECAUTIONS Prolongation of the QT Interval ( 5.1 ) Hepatotoxicity ( 5.2 ) Hypercalcemia and Tumor Flare ( 5.3 ) Risk of Uterine Malignancy ( 5.4 ) General ( 5.5 )

Laboratory

Tests ( 5.6 ) Pregnancy: Fetal harm may occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking toremifene citrate tablets. ( 5.7 , 8.1 ) Women of Childbearing Potential: Use effective nonhormonal contraception during toremifene citrate tablets therapy. ( 5.8 )

5.1 Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . 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 should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.2 ) ]</span> .

5.2 Hepatotoxicity Hepatotoxicity, both increases in the serum concentration for grade 3 and 4 transaminitis and hyperbilirubinemia, including jaundice, hepatitis, and non-alcoholic fatty liver disease, have also been reported in clinical trials and postmarketing with toremifene citrate tablets. Liver function tests should be performed periodically. [ see Adverse Reactions ( 6.1 ), Post-marketing Experience ( 6.2 ) ]

5.3 Hypercalcemia and Tumor Flare 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 citrate tablets. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, toremifene citrate tablets treatment should be discontinued.

5.4 Risk of Uterine Malignancy Endometrial cancer, endometrial hypertrophy, hyperplasia, and uterine polyps have been reported in some patients treated with toremifene citrate tablets. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [ see Nonclinical Toxicology ( 13.1 ) ]. Long-term use of toremifene citrate tablets has not been established in patients with pre-existing endometrial hyperplasia. All patients should have baseline and annual gynecological examinations. In particular, patients at high risk of endometrial cancer should be closely monitored.

5.5 General Patients with a history of thromboembolic diseases should generally not be treated with toremifene citrate. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using toremifene citrate in patients with leukopenia and thrombocytopenia.

5.6 Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

5.7 Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, toremifene citrate tablets can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women using toremifene citrate tablets. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> .

5.8 Women of Childbearing Potential Toremifene citrate tablets are indicated only in postmenopausal women. However, premenopausal women prescribed toremifene citrate tablets should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.