TOREMIFENE CITRATE

Toremifene citrate tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. Toremifene citrate tablets are an estrogen agonist/antagonist. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: and the molecular formula is C 26 H 28 ClNO • C 6 H 8 O 7 . The molecular weight of toremifene citrate is 598.10. The pK a is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCl at 37˚C is 0.38 mg/mL. Toremifene citrate tablets are available only as tablets for oral administration. Inactive ingredients: sodium starch glycolate, lactose monohydrate, copovidone, silicified microcrystalline cellulose, magnesium stearate, and purified water. structure.jpg

Toremifene citrate tablets are an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. Toremifene citrate tablets are an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

The dosage of toremifene citrate tablets is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. 60 mg once daily, orally ( 2 )

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Most common adverse reactions are hot flashes, sweating, nausea and vaginal discharge. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of toremifene citrate tablets and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study TOR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving toremifene citrate tablets (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse reactions occurring in at least 1% of patients receiving toremifene citrate tablets in the three major trials are listed in the table below. Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving toremifene citrate tablets 60 mg (TOR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies ( 14 )]. * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. **Elevated defined as follows: North American Study: AST>100 IU/L; alkaline phosphatase>200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin - WHO Grade 1 (1.25 times the upper limit of normal). Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. The incidence of AST elevations was greater in the 200 and 240 mg toremifene citrate tablets dose arms than in the tamoxifen arms. Higher doses of toremifene citrate tablets were also associated with an increase in nausea. Approximately 4% of patients were withdrawn for toxicity from the high-dose toremifene citrate tablets treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. Table 1.jpg 6.2 Post-marketing Experience The following adverse reactions were identified during post approval use of toremifene citrate tablets . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported during post approval use of toremifene citrate tablets have been consistent with clinical trial experience. The most frequently reported adverse reactions related to toremifene citrate tablets use since market introduction include hot flash, sweating, nausea, and vaginal discharge. Hepatotoxicity [ see Warnings and Precautions ( 5.2 ) ] Risk of Uterine Malignancy [ see Warnings and Precautions ( 5.4 ) ] Hypertriglyceridemia

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 [see Boxed Warning and Warnings and Precautions ( 5.1 )] . 7.3 Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John'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 [see Boxed Warning and Warnings and Precautions ( 5.1 )] . 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).

16 HOW SUPPLIED/STORAGE AND HANDLING Toremifene citrate tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are white to off-white, round, flat beveled edge tablet with “TO” on one side and plain on the reverse. Toremifene citrate tablets are available as: NDC 64980-404-03 bottles of 30 Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature.] Protect from heat and light.