Fareston

FARESTON- toremifene citrate tablet
KYOWA KIRIN, INC,

1 INDICATIONS AND USAGE

FARESTON® is 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 FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

3 DOSAGE FORMS AND STRENGTHS

Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.

4 CONTRAINDICATIONS

4.1 Hypersensitivity to the Drug

FARESTON is 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 FARESTON. 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 FARESTON. 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, FARESTON 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 FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology (13.1)]. Long-term use of FARESTON 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 FARESTON. 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 FARESTON 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, FARESTON 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 FARESTON. 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

FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON 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 FARESTON 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 FARESTON (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 FARESTON 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 FARESTON 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)].

* 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).
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 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)	–	–	–

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 FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON 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.