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Risk Of Bleeding
Increased Exposure In Patients With Hepatic Impairment
The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see DOSAGE AND ADMINISTRATION].
FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations].
Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at daily doses that are significantly less than the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with FASLODEX and for one year after the last dose [see Use in Specific Populations and CLINICAL PHARMACOLOGY].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)
Risk of Bleeding
- Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding disorders, decreased platelet count, or in patients receiving anticoagulants (for example, warfarin) [see WARNINGS AND PRECAUTIONS].
- Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with FASLODEX and for one year after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
- Advise women not to breast-feed during treatment with FASLODEX and for one year after the last dose [see Use in Specific Populations].
Combination Therapy with Palbociclib
See palbociclib full prescribing information for Patient Counseling Information.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenesis studies were conducted in rats and mice. Positive findings were observed in both species. Rats were treated at intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days.
These doses correspond to 0.9-, 1.5-, and 3-fold (in females) and 0.8-, 0.8-, and 2-fold (in males) the systemic exposure [AUC0-30 days] achieved in women receiving the recommended dose of 500 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. Mice were treated at oral doses of 0, 20, 150 and 500 mg/kg/day. These doses correspond to 0, 0.8, 8.4 and 18-fold (in females) and 0.8-, 7.1- and 11.9- fold (in males), the systemic exposure (AUC0-30 days) achieved in women receiving the recommended dose of 500 mg/month. There was an increased incidence of sex cord stromal tumors (both benign and malignant) in the ovary of mice at doses of 150 and 500 mg/kg/day. 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 (0.6% the human recommended dose based on body surface area [BSA in mg/m²]), 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 (0.06% the human dose based on BSA in mg/m²). Restoration of female fertility to values similar to controls was evident following a 29-day withdrawal period after dosing at 2 mg/kg/day (equivalent to the human dose based on BSA in mg/m²). The effects of fulvestrant on the fertility of female rats appear to be consistent with its antiestrogenic 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 1.3-, 1.2- and 3.5-fold the systemic exposure [AUC0-30 days] achieved in women receiving the recommended dose of 500 mg/month.
Use In Specific Populations
Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicity, including skeletal malformations and fetal loss, at daily doses that were 6% and 30% of the maximum recommended human dose based on mg/m², respectively [see Data]. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Administration of fulvestrant to rats prior to and up to implantation caused embryonic loss at daily doses that were 0.6% of the daily maximum recommended human dose based on mg/m². When fulvestrant was administered to pregnant rats during the period of organogenesis, intramuscular doses ≥ 0.1 mg/kg/day (6% of the human recommended dose based on mg/m²) caused effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on mg/m²) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥ 0.1 mg/kg/day. Fulvestrant administered at 2 mg/kg/day caused fetal loss.
When administered to pregnant rabbits during the period of organogenesis, fulvestrant caused pregnancy loss at an intramuscular dose of 1 mg/kg/day (equivalent to the human dose based on mg/m²). Further, at 0.25 mg/kg/day (30% the human dose based on mg/m²), fulvestrant caused increases in placental weight and post-implantation loss in rabbits. 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; 30% the human dose based on mg/m²) when administered during the period of organogenesis.
There is no information regarding the presence of fulvestrant in human milk, nor of its effects on milk production or breast-fed infant. Fulvestrant can be detected in rat milk [see Data]. Because of the potential for serious adverse reactions in breast-fed infants from FASLODEX, advise a lactating woman not to breast-feed during treatment with FASLODEX and for one year after the final dose.
Levels of fulvestrant were approximately 12-fold higher in milk than in plasma after exposure of lactating rats to a dose of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. In a study in rats of fulvestrant at 10 mg/kg given twice or 15 mg/kg given once (less than the recommended human dose based on mg/m²) during lactation, offspring survival was slightly reduced.
Females And Males Of Reproductive Potential
Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating FASLODEX.
FASLODEX can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for one year after the last dose.
Based on animal studies, FASLODEX may impair fertility in females and males of reproductive potential. The effects of fulvestrant on fertility were reversible in female rats [see Nonclinical Toxicology].
Safety and effectiveness in pediatric patients have not been established. A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8).
The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.
Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients' baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.
Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI: -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI: -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known.
Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritus, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died.
The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.
In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0.87) ng/mL and 3680 (1020) ng*hr/mL, respectively.
For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.
FASLODEX is metabolized primarily in the liver.
The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B), the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/9/2016
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