TOREMIFENE: 245 Adverse Event Reports & Safety Profile

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 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 7.76. Freely soluble in dimethyl sulphoxide, sparingly soluble in methanol and insoluble in water. Toremifene citrate tablets are available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K 30, and sodium starch glycolate. structure

AND USAGE 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.

AND ADMINISTRATION 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.

REACTIONS 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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 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 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 FAR60 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 (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 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 60 mg (FAR60) 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)].

Adverse Reactions North American Eastern

European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%)

Cardiac Cardiac Failure

2 (1) 1 (<1) - 1 (<1) 2 (1) 3 (1.5)

Myocardial Infarction

2 (1) 3 (1.5) 1 (<1) 2 (1) - 1 (<1) Arrhythmia - - - - 3 (1.5) 1 (<1)

Angina

Pectoris - - 1 (<1) - 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) - - - 5 (3)

Dry Eyes

20 (9) 16 (7.5) - - - - Abnormal Visual Fields 8 (4) 10 (5) - - - 1 (<1)

Corneal Keratopathy

4 (2) 2 (1) - - - - Glaucoma 3 (1.5) 2 (1) 1 (<1) - - 1 (<1) Abnormal - - - - 3 (1.5) - Vision/Diplopia Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) - - 1 (<1) Thrombophlebitis - 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis - 1 (<1) 1 (<1) - 3 (1.5) 4 (2) CVA/TIA 1 (<1) - - 1 (<1) 4 (2) 4 (2)

Elevated Liver

Tests** AST 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17)

Alkaline Phosphatase

41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15)

Bilirubin

3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5)

Hypercalcemia

6 (3) 6 (3) 1 (<1) - - - * 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 dose arms than in the tamoxifen arms. Higher doses of toremifene citrate were also associated with an increase in nausea.

Approximately

4% of patients were withdrawn for toxicity from the high-dose toremifene citrate 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.

6.2 Post-marketing Experience The following adverse reactions were identified during post approval use of toremifene citrate. 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 have been consistent with clinical trial experience. The most frequently reported adverse reactions related to toremifene citrate use since market introduction include hot flash, sweating, nausea, and vaginal discharge. Hepatototoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span> Risk of Uterine Malignancy <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4)]</span> Hypertriglyceridemia

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.

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).