FULVESTRANT injection, solution

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

FULVESTRANT (UNII: 22X328QOC4) (FULVESTRANT - UNII:22X328QOC4)

Available from:

Athenex Pharmaceutical Division, LLC.

Administration route:

INTRAMUSCULAR

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Monotherapy Fulvestrant injection is indicated for the treatment of: - Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, or - HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. Combination Therapy Fulvestrant injection is indicated for the treatment of: - HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with ribociclib as initial endocrine based therapy or following disease progression on endocrine therapy. - HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy. Fulvestrant injection is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with fulvestrant injection [see Adverse Reactions ( 6.2)]. Risk Summary Based on findings from animal studies and its mechanism of action, fulvestrant injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)] . 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/m 2 , 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 to 4% and 15 to 20%, respectively. Data Animal Data 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/m 2 . 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/m 2 ) 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/m 2 ) 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/m 2 ). Further, at 0.25 mg/kg/day (30% the human dose based on mg/m 2 ), 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/m 2 ) when administered during the period of organogenesis. Risk Summary There is no information regarding the presence of fulvestrant in human milk, nor of its effects on milk production or breastfed infant. Fulvestrant can be detected in rat milk [see Data] . Because of the potential for serious adverse reactions in breastfed infants from fulvestrant, advise a lactating woman not to breastfeed during treatment with fulvestrant injection and for one year after the final dose. Data 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/m 2 ) during lactation, offspring survival was slightly reduced. Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating fulvestrant injection. Contraception Females Fulvestrant can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] . Advise females of reproductive potential to use effective contraception during treatment and for one year after the last dose. Infertility Based on animal studies, fulvestrant may impair fertility in females and males of reproductive potential. The effects of fulvestrant on fertility were reversible in female rats [see Nonclinical Toxicology ( 13.1)] . 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 fulvestrant 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 fulvestrant injection. These included injection site reactions (inflammation, pain, hematoma, pruritus, rash), abdominal pain, contusion, tachycardia, hot flash, extremity pain, and vomiting. Nine (30%) patients reported an SAE, none of which were considered related to fulvestrant injection. No patients discontinued study treatment due to an AE and no patients died. Pharmacokinetics 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 (C min,ss ) and AUC ss was 4.19 (0.87) ng/mL and 3680 (1020) ng*hr/mL, respectively. For fulvestrant 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 fulvestrant injection in Study 0021 and Study 0020, respectively. Fulvestrant 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). Fulvestrant injection has not been studied in patients with severe hepatic impairment (Child-Pugh class C). A dose of fulvestrant 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration ( 2.2) and Warnings and Precautions ( 5.2)] . 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.

Product summary:

Fulvestrant Injection is supplied as follows: Fulvestrant injection is supplied as two 5 mL clear neutral glass (Type 1) barrels, each containing 250 mg per 5 mL of fulvestrant injection solution for intramuscular injection and is NOT fitted with a tamper evident closure. The single-dose prefilled syringes are presented in a tray with polystyrene plunger rod and safety needles (SafetyGlide™) for connection to the barrel. The solution for injection is a clear, colorless to yellow, viscous liquid. Discard each syringe after use. If a patient dose requires only one syringe, unused syringe should be stored as directed below. Storage Conditions REFRIGERATE, 2° to 8°C (36° to 46°F). TO PROTECT FROM LIGHT, STORE IN THE ORIGINAL CARTON UNTIL TIME OF USE.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

FULVESTRANT- FULVESTRANT INJECTION, SOLUTION
ATHENEX PHARMACEUTICAL DIVISION, LLC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
FULVESTRANT INJECTION
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
FULVESTRANT INJECTION.
FULVESTRANT INJECTION, FOR INTRAMUSCULAR USE
INITIAL U.S. APPROVAL: 2002
INDICATIONS AND USAGE
Fulvestrant injection is an estrogen receptor antagonist indicated for
the treatment of:
Hormone receptor (HR)-positive, human epidermal growth factor receptor
2 (HER2)-negative advanced
breast cancer in postmenopausal women not previously treated with
endocrine therapy. ( 1)
HR-positive advanced breast cancer in postmenopausal women with
disease progression following
endocrine therapy. ( 1)
HR-positive, HER2-negative advanced or metastatic breast cancer in
postmenopausal women in
combination with ribociclib, as initial endocrine based therapy or
following disease progression on
endocrine therapy. ( 1)
HR-positive, HER2-negative advanced or metastatic breast cancer in
combination with palbociclib or
abemaciclib in women with disease progression after endocrine therapy.
( 1)
DOSAGE AND ADMINISTRATION
Fulvestrant injection 500 mg should be administered intramuscularly
into the buttocks (gluteal area)
slowly (1 to 2 minutes per injection) as two 5 mL injections, one in
each buttock, on Days 1, 15, 29, and
once monthly thereafter. ( 2.1, 14)
A dose of 250 mg is recommended in patients with moderate hepatic
impairment to be administered
intramuscularly into the buttock (gluteal area) slowly (1 to 2
minutes) as one 5 mL injection on Days 1,
15, 29, and once monthly thereafter. ( 2.2, 5.2, 8.6)
DOSAGE FORMS AND STRENGTHS
Fulvestrant injection, an injection for intramuscular administration,
is supplied as 250 mg per 5 mL
fulvestrant. ( 3)
CONTRAINDICATIONS
Hypersensitivity. ( 4)
WARNINGS AND PRECAUTIONS
Risk of Bleeding: Use with caution in patients with bleeding
diatheses, thrombocytopenia, or
anticoagulant use. ( 5.1)
Increased