Fulvestrant
Injection · Intramuscular, Intravenous
Uses
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 ) 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.
Dosage and administration
Fulvestrant Injection 500 mg should be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 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 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter. ( 2.2 , 5.2 , 8.6 ) 2.1 Recommended Dose Monotherapy The recommended dose of Fulvestrant Injection is 500 mg to be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter [see Clinical Studies ( 14 )]. Combination Therapy When Fulvestrant Injection is used in combination with palbociclib, abemaciclib, or ribociclib, the recommended dose of Fulvestrant Injection is 500 mg to be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter. When Fulvestrant Injection is used in combination with palbociclib, the recommended dose of palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food. Refer to the Full Prescribing Information for palbociclib. When Fulvestrant Injection is used in combination with abemaciclib, the recommended dose of abemaciclib is 150 mg orally, twice daily. Abemaciclib may be taken with or without food. Refer to the Full Prescribing Information for abemaciclib. When Fulvestrant Injection is used in combination with ribociclib, the recommended dose of ribociclib is 600 mg taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Ribociclib can be taken with or without food. Refer to the Full Prescribing Information for ribociclib. Pre/perimenopausal women treated with the combination of Fulvestrant Injection plus palbociclib, abemaciclib, or ribociclib, should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards [see Clinical Studies ( 14 )]. 2.2 Dose Modification Monotherapy Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter. Fulvestrant Injection has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )]. Combination Therapy When Fulvestrant Injection is used in combination with palbociclib, abemaciclib, or ribociclib, refer to monotherapy dose modification instructions for Fulvestrant Injection. Refer to the Full Prescribing Information of co-administered palbociclib, abemaciclib, or ribociclib, for dose modification guidelines in the event of toxicities, for use with concomitant medications, and other relevant safety information. 2.3 Administration Technique Administer the injection according to the local guidelines for performing large volume intramuscular injections. NOTE: Due to the proximity of the underlying sciatic nerve, caution should be taken if administering Fulvestrant Injection at the dorsogluteal injection site [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )]. The proper method of administration of Fulvestrant Injection for intramuscular use is described in the following instructions. For each single-dose prefilled syringe: Remove glass syringe barrel from tray and check that it is not damaged. Inspect drug product in glass syringe for any visible particulate matter or discoloration prior to use. Discard if particulate matter or discoloration is present. Peel open the safety needle (SafetyGlide TM ) outer packaging. Hold the syringe upright. Twist and remove the Luer tip cap (see Figure 1 ). Figure 1 Do Not Touch the Sterile Syringe Tip (Luer-Lok). Attach the safety needle to the syringe tip (Luer-Lok). Twist needle until firmly seated (see Figure 2 ). Confirm that the needle is locked to the Luer connector before moving or tilting the syringe out of the vertical plane to avoid spillage of syringe contents. Figure 2 For Administration: Pull needle cap straight off needle to avoid damaging needle point. Expel excess gas from the syringe (a small gas bubble may remain). Administer intramuscularly slowly (1-2 minutes/injection) into the buttock (gluteal area). For user convenience, the needle ‘bevel up’ position is orientated to the lever arm, as shown in Figure 3 . Figure 3 After injection, immediately activate the lever arm to deploy the safety shield by applying a single finger stroke to the activation assisted lever arm to push the lever arm completely forward. Listen for a click. Confirm that the safety shield has completely covered the needle (see Figure 4 ). NOTE: Activate away from self and others. Figure 4 Discard the empty syringe into an approved sharps collector in accordance with applicable regulations and institutional policy. Repeat steps 1 through 11 for second syringe. Figure 1 Figure 2 Figure 3 Figure 4 How To Use Fulvestrant Injection For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg recommended dose. SAFETYGLIDE TM INSTRUCTIONS FROM BECTON DICKINSON SafetyGlide TM is a trademark of Becton Dickinson and Company.
Dosage forms and strengths
Fulvestrant Injection, an injection for intramuscular administration, is supplied as 5-mL single-dose prefilled syringes containing 250 mg/5 mL fulvestrant. Fulvestrant Injection, an injection for intramuscular administration, is supplied as 250 mg/5 mL fulvestrant. ( 3 )
Contraindications
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 [see Adverse Reactions ( 6.2 )]. Hypersensitivity. ( 4 )
Warnings and precautions
Risk of Bleeding: Use with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. ( 5.1 ) Increased Exposure in Patients with Hepatic Impairment: Use a 250 mg dose for patients with moderate hepatic impairment. ( 2.2 , 5.2 , 8.6 ) Injection Site Reaction: Use caution while administering Fulvestrant Injection at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) Immunoassay Measurement of Serum Estradiol: Fulvestrant Injection can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels. ( 5.5 ) 5.1 Risk of Bleeding Because Fulvestrant Injection is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. 5.2 Increased Exposure in Patients with Hepatic Impairment The safety and pharmacokinetics of fulvestrant 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 ( 2.2 )]. Fulvestrant has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations ( 8.6 )]. 5.3 Injection Site Reaction Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with fulvestrant injection. Caution should be taken while administering Fulvestrant Injection at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve [see Dosage and Administration ( 2.3 ) and Adverse Reactions ( 6.1 )] . 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, Fulvestrant Injection 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 Fulvestrant Injection and for one year after the last dose [see Use in Specific Populations ( 8.1 ), ( 8.3 ) and Clinical Pharmacology ( 12.1 )]. 5.5 Immunoassay Measurement of Serum Estradiol Due to structural similarity of fulvestrant and estradiol, fulvestrant can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels.
Side effects
The following adverse reactions are discussed in more detail in other sections of the labeling: Risk of Bleeding [see Warnings and Precautions ( 5.1 )] Increased Exposure in Patients with Hepatic Impairment [see Warnings and Precautions ( 5.2 )] Injection Site Reaction [see Warnings and Precautions ( 5.3 )] Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.4 )] The most common adverse reactions occurring in ≥5% of patients receiving fulvestrant 500 mg were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation. ( 6.1 ) Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of fulvestrant patients and were not dose-dependent. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Monotherapy Comparison of Fulvestrant Injection 500 mg and Fulvestrant Injection 250 mg (CONFIRM) The following adverse reactions (ARs) were calculated based on the safety analysis of CONFIRM comparing the administration of fulvestrant 500 mg intramuscularly once a month with fulvestrant 250 mg intramuscularly once a month. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients), and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients), and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from CONFIRM. Table 1: Adverse Reactions in CONFIRM (≥ 5% in Either Treatment Group) 1. Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. Adverse Reactions Fulvestrant 500 mg N=361 % Fulvestrant 250 mg N=374 % Body as a Whole Injection Site Pain 1 12 9 Headache 8 7 Back Pain 8 11 Fatigue 8 6 Pain in Extremity 7 7 Asthenia 6 6 Vascular System Hot Flash 7 6 Digestive System Nausea 10 14 Vomiting 6 6 Anorexia 6 4 Constipation 5 4 Musculoskeletal System Bone Pain 9 8 Arthralgia 8 8 Musculoskeletal Pain 6 3 Respiratory System Cough 5 5 Dyspnea 4 5 In the pooled safety population (N=1127) from clinical trials comparing fulvestrant 500 mg to fulvestrant 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving fulvestrant. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg fulvestrant arms. Comparison of Fulvestrant Injection 500 mg and Anastrozole 1 mg (FALCON) The safety of fulvestrant 500 mg versus anastrozole 1 mg was evaluated in FALCON. The data described below reflect exposure to fulvestrant in 228 out of 460 patients with HR-positive advanced breast cancer in postmenopausal women not previously treated with endocrine therapy who received at least one (1) dose of treatment in FALCON. Permanent discontinuation associated with an adverse reaction occurred in 4 of 228 (1.8%) patients receiving fulvestrant, and in 3 of 232 (1.3%) patients receiving anastrozole. Adverse reactions leading to discontinuation for those patients receiving fulvestrant included drug hypersensitivity (0.9%), injection site hypersensitivity (0.4%), and elevated liver enzymes (0.4%). The most common adverse reactions (≥10%) of any grade reported in patients in the fulvestrant arm were arthralgia, hot flash, fatigue, and nausea. Adverse reactions reported in patients who received fulvestrant in FALCON at an incidence of ≥5% in either treatment arm are listed in Table 2 , and laboratory abnormalities are listed in Table 3 . Table 2: Adverse Reactions in FALCON Adverse Reactions Fulvestrant 500 mg N=228 Anastrozole 1 mg N=232 All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Vascular Disorders Hot flash 11 0 10 0 Gastrointestinal Disorders Nausea 11 0 10 <1 Diarrhea 6 0 6 <1 Musculoskeletal and Connective Tissue Disorders Arthralgia 17 0 10 0 Myalgia 7 0 3 0 Pain in extremity 6 0 4 0 Back pain 9 <1 6 0 General Disorders and Administration Site Conditions Fatigue 11 <1 7 <1 Table 3: Laboratory Abnormalities in FALCON 1 1. In FALCON, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >10% of patients receiving fulvestrant. Grade 3-4 increases were observed in 1%-3% of patients. Laboratory Parameters Fulvestrant 500 mg N=228 Anastrozole 1 mg N=232 All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Alanine aminotransferase increased (ALT) 7 1 3 0 Aspartate aminotransferase increased (AST) 5 1 3 <1 Comparison of Fulvestrant Injection 250 mg and Anastrozole 1 mg in Combined Trials (Studies 0020 and 0021) The most commonly reported adverse reactions in the fulvestrant and anastrozole treatment groups were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea, and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis. Injection site reactions with mild transient pain and inflammation were seen with fulvestrant and occurred in 7% of patients given the single 5 mL injection (Study 0020) and in 27% of patients given the 2 x 2.5 mL injections (Study 0021) in the two clinical trials that compared fulvestrant 250 mg and anastrozole 1 mg.
Drug interactions
There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro , drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP 3A4 inhibitors or inducers [see Clinical Pharmacology ( 12.3 )] . There are no known drug-drug interactions. ( 7 )
Use in specific populations
Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy 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 2-4% and 15-20%, 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. 8.2 Lactation 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 Injection, advise a lactating woman not to breastfeed during treatment with Fulvestrant Injection and for one year after the last 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. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating Fulvestrant Injection. Contraception Females Fulvestrant Injection 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 Injection 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 )]. 8.4 Pediatric Use 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.
Pregnancy
8.1 Pregnancy 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 2-4% and 15-20%, 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.
Pediatric use
8.4 Pediatric Use 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. 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. 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.
Geriatric use
8.5 Geriatric Use 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 in Study 0021 and Study 0020, respectively.
Overdosage
Human experience of overdose with fulvestrant is limited. There are isolated reports of overdose with fulvestrant in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection. The potential toxicity of fulvestrant at these or higher concentrations in cancer patients who may have additional comorbidities is unknown. There is no specific treatment in the event of fulvestrant overdose, and symptoms of overdose are not established. In the event of an overdose, healthcare practitioners should follow general supportive measures and should treat symptomatically.
Description
Fulvestrant Injection for intramuscular administration is an estrogen receptor antagonist. The chemical name is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)- triene-3,17-beta-diol. The molecular formula is C 32 H 47 F 5 O 3 S and its structural formula is: Fulvestrant is a white powder with a molecular weight of 606.77. The solution for injection is a clear, colorless to yellow, viscous liquid. Each injection contains 250 mg fulvestrant in a solution composed of 10% w/v Dehydrated Alcohol, USP and 10% w/v Benzyl Alcohol, NF, as co-solvents, 0.12% w/v Polysorbate 80, NF as a solubilizing agent, 0.06% w/v alpha-Tocopherol, USP as a stabilizing agent, and made up to 100% w/v with Castor Oil, USP as a co-solvent and release rate modifier. Structural Formula
Mechanism of action
12.1 Mechanism of Action Many breast cancers have estrogen receptors (ER) and the growth of these tumors can be stimulated by estrogen. Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner with affinity comparable to that of estradiol and downregulates the ER protein in human breast cancer cells. In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts. Fulvestrant showed no agonist-type effects in in vivo uterotrophic assays in immature or ovariectomized mice and rats. In in vivo studies in immature rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects.
How supplied
Fulvestrant Injection is supplied as two 5 mL clear glass (Type 1) syringes fitted with a removable tip cap, each containing 250 mg per 5 mL of Fulvestrant Injection solution for intramuscular use. Product Code Unit of Sale Strength Each 760105 NDC 63323-715-05 Unit of 2 250 mg per 5 mL (50 mg per mL) NDC 63323-715-01 5 mL Single-Dose Pre-filled Syringe The pre-filled syringes with attached plunger rods are presented in a tray with two pre-packaged safety needles (SafetyGlide ™ ) for connection to the syringes. Discard each syringe after use. If a patient dose requires only one syringe, unused syringe should be stored as directed below. Storage: Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F) [USP Controlled Room Temperature]. Do not freeze. Do not use Fulvestrant Injection if it has been frozen. To protect from light, store in the original carton until time of use.
Storage
Storage: Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F) [USP Controlled Room Temperature]. Do not freeze. Do not use Fulvestrant Injection if it has been frozen. To protect from light, store in the original carton until time of use.
Patient information
Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Monotherapy Risk of Bleeding: Because Fulvestrant Injection 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 ( 5.1 )]. Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with Fulvestrant Injection 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 ( 5.4 ) and Use in Specific Populations ( 8.1 ), ( 8.3 )] . Lactation: Advise women not to breastfeed during treatment with Fulvestrant Injection and for one year after the last dose [see Use in Specific Populations ( 8.2 )] . Combination Therapy When Fulvestrant Injection is used in combination with palbociclib, abemaciclib, or ribociclib, refer to the respective Full Prescribing Information for Patient Counseling Information. Manufactured for: Lake Zurich, IL 60047 www.fresenius-kabi.com/us Made in Austria 451542D Fresenius Kabi Logo
Label text from the FDA structured product label by Fresenius Kabi USA, LLC (revised Jan 31, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Fulvestrant in 22 products
Fulvestrant NDC products (22)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 16729-436 | Fulvestrant 250 mg/5mL Injection | Accord Healthcare Inc. | ANDA |
| 62332-650 | Fulvestrant 50 mg/mL Injection | Alembic Pharmaceuticals Inc. | ANDA |
| 70121-1463 | Fulvestrant 250 mg/5mL Injection, Solution | Amneal Pharmaceuticals LLC | ANDA |
| 70860-211 | Fulvestrant 50 mg/mL Injection, Solution | Athenex Pharmaceutical Division, LLC. | ANDA |
| 83634-203 | Fulvestrant 50 mg/mL Injection, Solution | Avenacy, Inc. | ANDA |
| 68001-522 | Fulvestrant 250 mg/5mL Injection | BluePoint Laboratories | ANDA |
| 68001-484 | Fulvestrant 250 mg/5mL Injection, Solution | BluePoint Laboratories | ANDA |
| 68001-626 | Fulvestrant 50 mg/mL Injection | BluePoint Laboratories. | ANDA |
| 71731-6121 | Fulvestrant 50 mg/mL Injection | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | ANDA |
| 43598-262 | Fulvestrant 50 mg/mL Injection, Solution | Dr.Reddy's Laboratories Inc | ANDA |
| 55150-394 | Fulvestrant 50 mg/mL Injection | Eugia US LLC | ANDA |
| 68462-317 | Fulvestrant 50 mg/mL Injection | GLENMARK PHARMACEUTICALS INC., USA | ANDA |
| 0143-9022 | Fulvestrant 50 mg/mL Injection | Hikma Pharmaceuticals USA Inc. | ANDA |
| 71288-555 | Fulvestrant 50 mg/mL Injection | Meitheal Pharmaceuticals Inc | ANDA |
| 16714-070 | Fulvestrant 50 mg/mL Injection, Solution | Northstar Rx, LLC, | ANDA |
| 25021-471 | Fulvestrant 50 mg/mL Injection, Solution | Sagent Pharmaceuticals | ANDA |
| 0781-9055 | Fulvestrant 50 mg/mL Injection | Sandoz Inc | ANDA |
| 0781-3532 | Fulvestrant 50 mg/mL Injection | Sandoz Inc | ANDA |
| 70700-284 | Fulvestrant 50 mg/mL Injection, Solution | Xiromed, LLC | ANDA |
| 70771-1626 | Fulvestrant 50 mg/mL Injection, Solution | Zydus Lifesciences Limited | ANDA |
| 70710-1688 | Fulvestrant 50 mg/mL Injection, Solution | Zydus Pharmaceuticals USA Inc. | ANDA |
| 63323-715 | Fulvestrant 50 mg/mL Injection, Solution | Fresenius Kabi USA, LLC | NDA |
Fulvestrant recalls
- D-1351-2022 Aug 24, 2022 · Class II · Terminated
Failed Impurities/Degradation Specifications - D-0820-2021 Sep 29, 2021 · Class II · Terminated
Lack of Assurance of Sterility
Frequently asked questions
What is Fulvestrant used for?
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 )…
What are the side effects of Fulvestrant?
The following adverse reactions are discussed in more detail in other sections of the labeling: Risk of Bleeding [see Warnings and Precautions ( 5.1 )] Increased Exposure in Patients with Hepatic Impairment [see Warnings and Precautions ( 5.2 )] Injection Site Reaction [see Warnings and Precautions ( 5.3 )] Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.4 )] The most common adverse… See the full label for the complete list.
Who makes Fulvestrant?
Fulvestrant is listed by 20 labelers in the FDA NDC directory, including Accord Healthcare Inc., Alembic Pharmaceuticals Inc., Amneal Pharmaceuticals LLC, Athenex Pharmaceutical Division, LLC..
Has Fulvestrant been recalled?
The FDA enforcement database lists 2 recalls for Fulvestrant, most recently D-1351-2022 (class ii): Failed Impurities/Degradation Specifications