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FARESTON®
(toremifene citrate)
Tablets
1E Rev 12/2004
DESCRIPTION
FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.
FARESTON is a nonsteroidal antiestrogen. 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 C26H28CINO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL.
FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.
CLINICAL PHARMACOLOGY
Special Populations:
CLINICAL STUDIES
Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. 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. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S.
Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table).
| Study | North American | Eastern European | Nordic | |||
|---|---|---|---|---|---|---|
1CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval | ||||||
| Treatment Group | FAR60 | TAM20 | FAR60 | TAM40 | FAR60 | TAM40 |
| No. Patients | 221 | 215 | 157 | 149 | 214 | 201 |
| Responses | ||||||
| CR1 + PR2 | 14+33 | 11+30 | 7+25 | 3+28 | 19+48 | 19+56 |
| RR3 (CR + PR)% | 21.3 | 19.1 | 20.4 | 20.8 | 31.3 | 37.3 |
| Difference in RR 95% CI4 for | 2.2 | -0.4 | -6.0 | |||
| Difference in RR | -5.8 to 10.2 | -9.5 to 8.6 | -15.1 to 3.1 | |||
| Time to Progression (TTP) | ||||||
| Median TTP (mo.) | 5.6 | 5.8 | 4.9 | 5.0 | 7.3 | 10.2 |
| Hazard Ratio (TAM/FAR) 95% CI4 for | 1.01 | 1.02 | 0.80 | |||
| Hazard Ratio (%) | 0.81 to 1.26 | 0.79 to 1.31 | 0.64 to 1.00 | |||
| Survival (S) | ||||||
| Median S (mo.) | 33.6 | 34.0 | 25.4 | 23.4 | 33.0 | 38.7 |
| Hazard Ratio (TAM/FAR) 95% CI4 for | 0.94 | 0.96 | 0.94 | |||
| Hazard Ratio (%) | 0.74 to 1.24 | 0.72 to 1.28 | 0.73 to 1.22 | |||
The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).
INDICATION AND USAGE
FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.
CONTRAINDICATIONS
FARESTON is contraindicated in patients with known hypersensitivity to the drug.
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
Adverse drug reactions are principally due to the antiestrogenic hor-monal 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 events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).
Serious adverse events occurring in patients receiving FARESTON in the three major trials are uled in the table below.
* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. | ||||||||||||
** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal). | ||||||||||||
| Adverse Events | North American | Eastern European | Nordic | |||||||||
| FAR60 n=221(%) | TAM20 n=215(%) | FAR60 n=157(%) | TAM40 n=149(%) | FAR60 n=214(%) | TAM40 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** | ||||||||||||
| SGOT | 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 events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.
In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. 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.
OVERDOSAGE
Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.
Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.
Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.
DOSAGE AND ADMINISTRATION
The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.
HOW SUPPLIED
FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. FARESTON Tablets are identified with TO 60 embossed on one side. FARESTON Tablets are available as:
NDC 11399-005-30 bottles of 30
NDC 11399-005-01 bottles of 100
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.
Distributed by GTx, Inc.
Memphis, TN 38163, USA
Product covered by Orion Product Patents and related patent numbers.
© 2004 GTx, Inc.
All rights reserved.
1E Rev. 12/2004