Toremifene Citrate

TOREMIFENE CITRATE — toremifene citrate tablet
Rising Pharmaceuticals, Inc.

WARNING: QT PROLONGATION

TOREMIFENE CITRATE TABLETS have been shown to prolong the QTc interval in a dose- and concentration-related manner [see Clinical Pharmacolog y (12.2)]. 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 not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [ see Warnings and Precautions (5.1) ].

1 INDICATIONS 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.

2 DOSAGE AND ADMINISTRATION

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

3 DOSAGE FORMS AND STRENGTHS

Tablet is white to off-white, round, flat beveled edge tablet with “TO” on one side and plain on the reverse.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

5.1 Prolongation of the QT Interval

Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2)]. 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 [see Drug Interactions (7.2) and Clinical Pharmacology (12.2 ) ].

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 [see Warnings and Precautions (5.2)]. 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/m2 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 [see Use in Specific Populations (8.1)].

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.

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.

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)].

Adverse Reactions North American Eastern European Nordic
TOR60 TAM20 TOR60 TAM40 TOR60 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 Vision/Diplopia 3 (1.5)
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 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.

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