Faslodex
Faslodex - General Information
Faslodex is a drug treatment of hormone receptor-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor.
Pharmacology of Faslodex
Faslodex for intramuscular administration is an estrogen receptor antagonist without known agonist effects.
Faslodex for patients
Faslodex Interactions
Fulvestrant is metabolized by CYP 3A4 in vitro. Clinical studies of the effect of strong CYP 3A4 inhibitors on the pharmacokinetics of fulvestrant have not been performed.
Carcinogenesis, Mutagenesis and Impairment of Fertility
A two-year carcinogenesis study was conducted in female and male rats, at intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days. These doses correspond to approximately 1-, 3-, and 5-fold (in females) and 1.3-, 1.3-, and 1.6-fold (in males) the systemic exposure [AUC0-30 days]] achieved in women receiving the recommended dose of 250 mg/month. An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/30 days, respectively. Induction of such tumors is consistent with the pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an antiestrogen.
Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests with and without the addition of a mammalian liver metabolic activation factor (bacterial mutation assay in strains of Salmonella typhimurium and Escherichia coli, in vitro cytogenetics study in human lymphocytes, mammalian cell mutation assay in mouse lymphoma cells and in vivo micronucleus test in rat.
In female rats, fulvestrant administered at doses > 0.01 mg/kg/day (approximately one-hundredth of the human recommended dose based on body surface area [BSA], for 2 weeks prior to and for 1 week following mating, caused a reduction in fertility and embryonic survival. No adverse effects on female fertility and embryonic survival were evident in female animals dosed at 0.001 mg/kg/day (approximately one-thousandth of the human dose based on BSA). Restoration of female fertility to values similar to controls was evident following a 29-day withdrawal period after dosing at 2 mg/kg/day (twice the human dose based on BSA). The effects of fulvestrant on the fertility of female rats appear to be consistent with its anti-estrogenic activity. The potential effects of fulvestrant on the fertility of male animals were not studied but in a 6-month toxicology study, male rats treated with intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant showed a loss of spermatozoa from the seminiferous tubules, seminiferous tubular atrophy, and degenerative changes in the epididymides. Changes in the testes and epididymides had not recovered 20 weeks after cessation of dosing. These fulvestrant doses correspond to approximately 2-, 3-, and 3-fold the systemic exposure [AUC0-30 days] achieved in women.
Pregnancy
Pregnancy Category D:.
In studies in female rats at doses > 0.01 mg/kg/day (IM; approximately one-hundredth of the human recommended dose based on body surface area [BSA]), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo/fetal development consistent with its anti-estrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day IM; twice the human dose on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses > 0.1 mg/kg/day IM (approximately one-tenth of the human dose on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed with 1 mg/kg/day fulvestrant IM (twice the human dose on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (about one-half the human dose on BSA), increases in placental weight and post-implantation loss were observed but, there were no observed effects on fetal development. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day IM; one-half the human dose on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.
Nursing Mothers
Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. It is not known if fulvestrant is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from FASLODEX in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.
Pediatric Use
The safety and efficacy of FASLODEX in pediatric patients have not been established.
Geriatric Use
When tumor response was considered by age, objective responses were seen in 24% and 22% of patients under 65 years of age and in 16% and 11% of patients 65 years of age and older, who were treated with FASLODEX in the European and North American trials, respectively.
Faslodex Contraindications
FASLODEX is contraindicated in pregnant women, and in patients with a known hypersensitivity to the drug or to any of its components.
Additional information about Faslodex
Faslodex Indication: For the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
Mechanism Of Action: Faslodex binds to estrogen receptors present in cancer cells and achieves its anti-estrogen effects through two separate mechanisms. First, when fulvestrant binds to the receptors, estrogen is crowded out and is no longer able to bind to these receptors. Second, fulvestrant degrades the estrogen receptors to which it is bound. Both of these mechanisms prevent cancer cells from accessing sufficient amounts of estrogen needed for growth and replication.
Drug Interactions: Not Available
Food Interactions: Not Available
Generic Name: Fulvestrant
Synonyms: ICI 182,780
Drug Category: Antineoplastic Agents
Drug Type: Small Molecule; Approved; Investigational
Other Brand Names containing Fulvestrant: Faslodex;
Absorption: Not Available
Toxicity (Overdose): There is no clinical experience with overdosage in humans.
Protein Binding: 99%
Biotransformation: Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.
Half Life: 40 days
Dosage Forms of Faslodex: Solution Intramuscular
Chemical IUPAC Name: (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
Chemical Formula: C32H47F5O3S
Fulvestrant on Wikipedia: https://en.wikipedia.org/wiki/Fulvestrant
Organisms Affected: Humans and other mammals
