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

6 ADVERSE 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 [see Warnings and Precautions (5.2)] Risk of Uterine Malignancy [see Warnings and Precautions (5.4)] Hypertriglyceridemia