Fulvestrant is an intramuscular estrogen-receptor antagonist without any known estrogen agonist effects. It was the first in a class of antiestrogens that works by downregulating the estrogen receptor as opposed to blocking it as with tamoxifen. Fulvestrant has demonstrated potent inhibition of breast cancer cells in vitro and in vivo. In clinical trials, fulvestrant was as effective as anastrozole, an aromatase inhibitor, in postmenopausal women who had received previous hormonal therapy. Fulvestrant is FDA approved in postmenopausal women as monotherapy or in combination with ribociclib for the first-line treatment of hormone receptor (HR)-positive, HER2-negative advanced breast cancer and as monotherapy or in combination with ribociclib for the treatment of HR-positive advanced breast cancer after disease progression following endocrine therapy. It is FDA approved in combination with palbociclib or abemaciclib for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in women after disease progression on endocrine-based therapy. Pregnancy should be avoided during treatment and for 1 year after the last dose of fulvestrant. Fulvestrant can also interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intramuscular Administration
-Fulvestrant is given by intramuscular injection; do not give intravenously.
-Administer the injection according to local guidelines for large volume intramuscular injections.
-Use caution at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve; injection site-related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported.
-Two 250-mg syringes must be administered to receive the full 500-mg dose.
Syringe Preparation:
-Remove perforated patient record label from syringe.
-Peel open the safety needle outer packaging.
-Hold the syringe upright on the ribbed part; with the other hand, disconnect and remove the cap per individual product instructions. Pull the cap off in a straight upward direction.
-Attach the safety needle to the Luer Lock of the syringe.
-Remove the needle sheath and expel excess gas from the syringe (a small gas bubble may remain).
-Storage: If a patient dose requires only one syringe (250 mg), the unused syringe should be stored in the refrigerator (2 to 8 degrees C; 36 to 46 degrees F) in the original carton and protected from light.
Intramuscular injection:
-Administer each 250-mg syringe into the gluteal area of the buttock over 1 to 2 minutes; give each injection in a separate buttock and rotate injection sites.
-After withdrawal of the needle from the patient, push the lever arm completely forward with a single-finger stroke to the activation assisted lever arm, until the needle tip is fully covered.
-Discard the empty syringes into an approved sharps collector.
Gastrointestinal (GI) adverse events associated with fulvestrant have generally been mild and occurred at a similar incidence regardless of dose (250 mg or 500 mg). In a pooled analysis of 2 randomized studies, adverse reactions of the digestive system (not specified) occurred in 52% of fulvestrant-treated patients (n = 423). Nausea is the most commonly reported GI adverse reaction, occurring in 10% to 28% (grade 3 or 4, 1% or less) of patients treated with fulvestrant monotherapy in clinical trials (n = 2,022). Additionally, abdominal pain (12% to 16%; grade 3 or 4, 1% or less), diarrhea (6% to 25%; grade 3 or 4, 1% or less), constipation (4% to 13%), and vomiting (6% to 15%; grade 3 or 4, 2% or less) has been reported in several clinical trials. Mild (grade 1 or 2) stomatitis (including cheilitis, glossitis, glossodynia, oral ulceration, oral pain, and mucosal inflammation) occurred in 10% to 13% of patients treated with fulvestrant plus placebo in 2 randomized clinical trials (n = 395); the incidence of stomatitis in these was increased when fulvestrant was administered in combination with abemaciclib (15%; grade 3, less than 1%) or palbociclib (28%; grade 3, 1%).
Anorexia or decreased appetite has been reported across several clinical trials of patients receiving fulvestrant as monotherapy or in combination with placebo (n = 1,794) (4% to 13%; grade 3, 1% or less); dysgeusia (3%) and weight loss (2%; grade 3, less than 1%) were also reported in patients receiving fulvestrant plus placebo (n = 223) in one randomized clinical trial.
An injection site reaction has been reported in 9% to 12% of patients receiving fulvestrant in 3 randomized clinical trials (n = 1,163), including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy; the risk of more severe injection site-related events may increase when administering fulvestrant at the dorsogluteal injection site due to proximity of the underlying sciatic nerve. Injection site reactions with mild transient pain and inflammation were seen in 7% of patients receiving a single 250-mg injection of fulvestrant (n = 222) in one randomized, open-label trial, and in 27% of patients receiving two 125-mg injections of fulvestrant (n = 206) in another randomized, double-blind clinical trial. Injection site hypersensitivity resulted in a discontinuation of therapy in 0.4% of fulvestrant-treated patients (n = 228) in a separate randomized, double-blind clinical trial.
In postmarketing surveillance, hypersensitivity reactions such as angioedema and urticaria were reported in less than 1% of patients who received intramuscular injections of fulvestrant 250 mg.
Elevated hepatic enzymes with post-baseline increases of 1 grade or more in either AST, ALT, or alkaline phosphatase were observed in greater than 15% (grade 3 or 4, 1% to 2%) of patients receiving fulvestrant in a pooled safety population (n = 1,127) from clinical trials comparing fulvestrant 500 mg to fulvestrant 250 mg; the incidence did not differ between the 250 mg and 500 mg arms. In one randomized, double-blind clinical trial, increased ALT was reported in 7% (grade 3 or 4, 1%) and increased ALT in 5% (grade 3 or 4, 1%) of patients receiving fulvestrant monotherapy (n = 228); post-baseline increases of 1 grade or more were observed in greater than 10% of patients (grade 3 or 4, 1% to 3%). Investigations into increased ALT occurred in 5% (grade 3 or 4, 2% or less) and increased AST in 5% to 7% (grade 3 or 4, 3% or less) of patients with advanced or metastatic breast cancer receiving fulvestrant plus placebo (n = 464) in 2 randomized clinical trials. Increased ALT and AST were separately reported as laboratory findings in 32% to 37% (grade 3, 2% or less) and 25% to 48% (grade 3 or 4, less than 3% to 5%) of patients who received fulvestrant plus placebo (n = 636), respectively, in these trials plus one additional clinical trial with a similar patient population. Increased GGT (49%; grade 3 or 4, 10%) and hypoalbuminemia (8%) have also been reported in patients receiving fulvestrant plus placebo in one clinical trial (n = 241). Hyperbilirubinemia, increased GGT, hepatitis, and hepatic failure have been reported in less than 1% of patients receiving fulvestrant in postmarketing experience. Elevated liver enzymes resulted in a discontinuation of therapy in 0.6% or fewer patients receiving fulvestrant in clinical trials.
In a pooled analysis of 2 randomized studies, adverse reactions of the musculoskeletal system (not specified) occurred in 26% of fulvestrant-treated patients (n = 423). Back pain was reported in 8% to 14% (grade 3 or 4, less than 1%) of patients treated with fulvestrant monotherapy in 3 clinical trials (n = 1,386). Musculoskeletal pain (3% to 6%), myalgia (7%), arthralgia (8% to 17%), arthritis (3%), and bone pain (8% to 16%) were also each reported in one of these 3 trials. The incidence of musculoskeletal effects was similar between the 500-mg and 250-mg doses in available data.
In a pooled analysis of 2 randomized studies, adverse reactions of the respiratory system (not specified) occurred in 39% of fulvestrant-treated patients (n = 423). Specifically, cough was reported in 5% to 15% of breast cancer patients receiving fulvestrant as monotherapy or in combination with placebo in 4 clinical trials (n = 1,622). Dyspnea was reported in 4% to 15% of patients in 3 of these trials (n = 1,399).
Insomnia (7% vs. 9%), depression (6% vs. 7%), and anxiety (5% vs. 4%) were reported with similar frequency in patients with locally advanced or metastatic breast cancer treated with fulvestrant (n = 423) compared with anastrozole (n = 423) in combined results of 2 randomized clinical trials.
Infection including nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, herpes simplex, gastroenteritis, tooth infection, pharyngitis, ocular infection, paronychia, vaginal infection, and respiratory tract infection occurred in 25% to 31% (grade 3, less than 4%) of patients with HR-positive, HER2-negative advanced breast cancer who received fulvestrant plus placebo (n = 636) in 3 randomized, double-blind clinical trials; sepsis occurred in less than 1% of patients. Additionally, pharyngitis occurred in 16%, urinary tract infection in 6%, and a flu-like syndrome in 7% of postmenopausal women with advanced breast cancer who received fulvestrant 250 mg IM injections in a pooled analysis of 2 randomized studies comparing IM fulvestrant (n = 423) with oral anastrozole (n = 423). In this analysis, other urogenital system adverse events (not specified) occurred in 18% of fulvestrant-treated patients.
Hot flashes were reported in 6% to 11% of patients treated with fulvestrant monotherapy (250-mg and 500-mg doses) in 2 clinical trials (n = 963). Additionally, vasodilation (hot flashes) occurred in 18% of fulvestrant-treated patients (n = 423) in a pooled analysis of 2 randomized studies. In this analysis, adverse reactions of the cardiovascular system (not specified), including vasodilation, occurred in 30% of fulvestrant-treated patients.
Peripheral edema was reported in 7% to 9% of breast cancer patients treated with fulvestrant as monotherapy or in combination with placebo in 3 clinical trials (n = 887). In one analysis, metabolic and nutritional disorder adverse events (not specified), including peripheral edema, occurred in 18% of fulvestrant-treated patients.
Generally mild hematologic toxicities have been reported with fulvestrant use. In a pooled analysis of 2 randomized studies, hematologic adverse reactions (not specified) occurred in 14% of fulvestrant-treated patients (n = 423); anemia was reported in 5% of patients. Anemia was also reported in 4% to 40% (grade 3, 2% or less) of patients treated with fulvestrant plus placebo (n = 636) in 3 separate randomized clinical trials, while decreased hemoglobin was reported in 35% (grade 3, 3%) of patients who received fulvestrant plus placebo in one clinical trial (n = 241). Additional hematologic toxicities reported in these trials included decreased WBC from baseline (25% to 33%; grade 3 or 4, 1% or less), decreased lymphocytes from baseline (35% or less; grade 3 or 4, less than 5%), decreased neutrophils from baseline (14% to 30%; grade 3 or 4, less than 5%), decreased platelets from baseline (10% to 15%), neutropenia (2% to 4%; grade 3 or 4, less than 2%), leukopenia (5% or less; grade 3 or 4, 2% or less), thrombocytopenia (less than 3%; grade 3 or 4, less than 1%). Leukopenia has also been reported in less than 1% of patients treated with fulvestrant in postmarketing experience.
Asthenia was reported in 6% of patients with advanced breast cancer who received fulvestrant monotherapy (either 250 mg or 500 mg) in a randomized clinical trial (n = 735). It was reported in 23% of breast cancer patients treated with fulvestrant monotherapy (250 mg; n = 423) in a pooled analysis of 2 other randomized studies compared with 27% of patients who received anastrozole (n = 423). Fatigue has separately been reported in 6% to 11% (grade 3 or 4, less than 1%) of patients receiving fulvestrant monotherapy in 2 clinical trials (n = 963) and in 29% to 32% (grade 3, 1% or less) of patients receiving fulvestrant plus placebo in 2 other randomized, double-blind clinical trials (n = 395).
In a pooled analysis of 2 randomized studies, pain (not specified) was reported in 19% of patients treated with fulvestrant monotherapy (n = 423), including pelvic pain (10%) and chest pain (unspecified) (7%); accidental injury occurred in 5% of these patients and paresthesias in 6%. Pain in the extremities was additionally reported in 6% to 7% of fulvestrant-treated patients in 2 additional clinical trials (n = 963); the incidence was similar in patients treated with both the 250-mg and 500-mg doses.
Fever has been reported in 5% to 6% (grade 3 or 4, less than 1%) of patients treated with fulvestrant monotherapy or fulvestrant plus placebo in 5 randomized clinical trials (n = 1,059).
In postmarketing surveillance, vaginal bleeding was reported in less than 1% of fulvestrant-treated patients, typically within the first 6 weeks of changing from existing hormonal therapy to fulvestrant therapy. Evaluation is suggested if bleeding persists.
In postmarketing surveillance, vertigo was reported in less than 1% of patients who received IM injections of fulvestrant 250 mg.
Venous thromboembolism (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava) occurred in 5% of patients treated with fulvestrant plus abemaciclib (n = 441) compared to 0.9% of patients treated with fulvestrant plus placebo (n = 223) in a randomized, double-blind clinical trial clinical trial. In postmarketing surveillance, thromboembolism was reported in less than 1% of patients who received IM injections of fulvestrant at the 250-mg dose level.
In a combined analysis of 2 randomized studies, dermatologic adverse reactions (not specified) occurred in 22% of fulvestrant-treated patients (n = 423), including rash (7%) and diaphoresis (5%). In 3 separate randomized, placebo-controlled clinical trials, a mild (grade 1 or 2) rash (including maculopapular rash, pruritic rash, erythema, dermatitis, acneiform rash, and toxic skin eruption) was reported in 4% to 7% of patients who received fulvestrant plus placebo (n = 636). Pruritus (6% to 7%) and alopecia (2% to 6%) were also reported.
Grade 1 or 2 increases in creatinine were reported in 74% of patients with advanced breast cancer who received fulvestrant plus placebo (n = 223) compared with 98% (grade 3, 1%) of patients treated with fulvestrant plus abemaciclib (n = 441) in a randomized clinical trial. Increased creatinine was also reported in 33% (grade 3, less than 1%) of patients who received fulvestrant plus placebo (n = 241) compared with 65% (grade 3 or 4, less than 2%) of those treated with fulvestrant plus ribociclib (n = 483) in another randomized clinical trial; decreased serum glucose (hypoglycemia; 18% vs. 23%) and decreased phosphorus (hypophosphatemia; 8% vs. 18%; grade 3 or 4, less than 1% vs. 5%) were also reported in this trial.
Headache was reported in 7% to 15% (grade 3, less than 1%) of patients with breast cancer receiving fulvestrant as monotherapy or in combination with placebo in 3 clinical trials (n = 1,381). Dizziness also occurred in 6% to 8% of fulvestrant-treated patients in 3 other clinical trials (n = 887).
Injection site-related neurologic events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with fulvestrant administration. Fulvestrant is given by intramuscular injection into the gluteal area of the buttock; use caution at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve.
Increased drug exposure has occurred in patients with moderate hepatic disease (Child Pugh class B); a dose reduction is necessary in these patients. The safety and efficacy of fulvestrant have not been established in patients with severe hepatic impairment (Child Pugh class C), however, the safety profile in patients with mild hepatic impairment is similar to that seen in patients with no hepatic impairment.
Because fulvestrant is given intramuscularly (IM), it should not be used or given with caution in patients with underlying coagulopathy, thrombocytopenia, or those receiving anticoagulant therapy. Fulvestrant IM injections may cause bleeding, bruising, or hematomas.
Due to structural similarity, fulvestrant can cause a laboratory test interference with estradiol measurement by immunoassay; this may result in falsely elevated estradiol levels.
The efficacy and safety of fulvestrant have not been established in neonates, infants, children, or adolescents. Once monthly intramuscular injections of fulvestrant 4 mg/kg have been studied in 30 female pediatric patients aged 1 to 8 years with progressive precocious puberty secondary to McCune-Albright Syndrome. Patients treated with fulvestrant experienced a reduction in the rate of bone age advancement over the 12 month study period compared to baseline and a reduction in mean growth velocity Z-score compared to baseline. Of the 23 patients with vaginal bleeding at baseline, 35% experienced cessation of bleeding with fulvestrant therapy. No clinically meaningful changes in median Tanner stage, mean uterine volume, mean ovarian volume, or predicted adult height compared to baseline were observed.
Pregnancy should be avoided by females of reproductive potential during fulvestrant treatment and for at least 1 year after the last dose. Although there are no adequately controlled studies in pregnant women, fulvestrant can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving fulvestrant should be apprised of the potential hazard to the fetus. Administration of fulvestrant 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; nonossification of the odontoid and ventral tubercle of the first cervical vertebra also occurred at this level of exposure. Effects on embryo-fetal development consistent with antiestrogenic activity occurred when fulvestrant was administered to rats during organogenesis at 6% of the recommended human doses based on mg/m2. Fulvestrant increased the incidence of fetal abnormalities in rats (i.e., tarsal flexure of the hind paw) and caused fetal loss at doses equivalent to the human dose based on mg/m2. Pregnancy loss also occurred when fulvestrant was administered to pregnant rabbits during organogenesis at doses equivalent to the human dose on a mg/m2 basis. At lower doses in rabbits (30% of the human dose based on mg/m2), fulvestrant administration during organogenesis caused increases in placental weight, an increased incidence of fetal variations (i.e., backward displacement of the pelvic girdle, 27 pre-sacral vertebrae), and postimplantation loss.
Counsel patients about reproductive risk and contraception requirements during fulvestrant therapy. Fulvestrant can be teratogenic and embryotoxic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during treatment and for at least 1 year after the last dose of fulvestrant. Females of reproductive potential should undergo pregnancy testing within 7 days prior to initiation of fulvestrant. Women who become pregnant while receiving fulvestrant should be apprised of the potential hazard to the fetus. In addition, based on animal data, fulvestrant may cause impairment of fertility or infertility in both males and females of reproductive potential; the effects on fertility were reversible in female rats.
Due to the potential for serious adverse reactions in nursing infants from fulvestrant, advise women to discontinue breast-feeding during treatment and for 1 year after the final dose. It is not known whether fulvestrant is present in human milk, although many drugs are excreted in human milk.
For the treatment of breast cancer:
-for the treatment of hormone receptor (HR)-positive, HER2-negative advanced breast cancer in postmenopausal women who have not previously been treated with endocrine therapy, as monotherapy:
Intramuscular dosage:
Postmenopausal females: 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes. In a randomized, double-blind, placebo-controlled clinical trial (FALCON), the first-line treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with fulvestrant significantly improved progression-free survival (PFS) compared with anastrozole (16.6 months vs. 13.8 months); median overall survival was not reached in either group. The objective response rate was 46.1% with a median duration of 20 months in the fulvestrant arm, compared with 44.9% and a duration of 13.2 months in the anastrozole arm.
-for the treatment of HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy, as monotherapy:
Intramuscular dosage:
Postmenopausal females: 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes. The median progression-free survival (6.5 months vs. 5.4 months) and overall survival (26.4 months vs. 22.3 months) were significantly improved with fulvestrant 500 mg IM compared with fulvestrant 250 mg IM in postmenopausal women with estrogen-receptor positive advanced breast cancer who experienced disease progression following endocrine therapy in a randomized, double-blind, phase 3 study (the CONFIRM study).
-for the first-line treatment of HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy, in combination with ribociclib:
Intramuscular dosage:
Adults: 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes. Administer in combination with ribociclib (600 mg PO once daily, preferably in the morning, on days 1 to 21, followed by 7 days of rest, repeated every 28 days). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Men should also be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. In a randomized, double-blind, clinical trial (MONALEESA-3), treatment with ribociclib plus fulvestrant significantly improved median overall survival (not reached vs. 40 months) as well as median investigator-assessed progression-free survival (PFS) compared with placebo plus fulvestrant in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no or only one line of prior endocrine treatment (20.5 months vs. 12.8 months); the overall response rate in patients with measurable disease was 40.9% versus 28.7%, respectively.
-for the first-line treatment of hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women, in combination with anastrozole*:
Intramuscular dosage:
Postmenopausal females: 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area) over 1 to 2 minutes on day 1, followed by 250 mg intramuscularly every 2 weeks for 2 doses then 250 mg intramuscularly every 4 weeks thereafter in combination with anastrozole (1 mg PO once daily) was evaluated in 2 randomized, open label, phase 3 trials. Treatment was continued until disease progression.
-for the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer after disease progression following endocrine-based therapy, in combination with palbociclib:
Intramuscular dosage:
Adult females: 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area) over 1 to 2 minutes on days 1, 15, 29, and once monthly thereafter in combination with palbociclib (125 mg PO once daily with food for 21 days, followed by 7 days off, repeated every 28 days) until progressive disease or unacceptable toxicity occurs. Premenopausal and perimenopausal women should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists, according to current clinical practice standards. Coadministration of palbociclib with certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind, clinical trial (PALOMA-3), treatment with fulvestrant plus palbociclib significantly improved investigator-assessed progression-free survival compared with fulvestrant plus placebo (9.5 months vs. 4.6 months) in women with HR-positive, HER2-negative advanced breast cancer (regardless of menopausal status) who had previously received endocrine therapy, with a response duration of 9.3 and 7.6 months, respectively. Results were consistent across subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. Median overall survival was 34.9 months in patients treated with palbociclib plus fulvestrant and 28 months in those who received placebo plus fulvestrant. Investigator-assessed confirmed overall response rate was 24.6% in the palbociclib arm compared with 10.9% in the placebo arm.
-for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy, in combination with abemaciclib:
Intramuscular dosage:
Adult females: 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter, in combination with abemaciclib (150 mg PO twice daily) until disease progression or unacceptable toxicity. Give each injection over 1 to 2 minutes. Pre- and perimenopausal women should also be treated with a gonadotropin-releasing hormone agonist according to current clinical practice standards. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with fulvestrant plus abemaciclib significantly improved the primary outcome of median progression-free survival (PFS) compared with fulvestrant plus placebo in a multicenter, randomized clinical trial of women with HR-positive, HER2-negative metastatic breast cancer with disease progression following adjuvant or metastatic endocrine therapy (MONARCH-2) (16.4 months vs. 9.3 months); both arms were also treated with goserelin for at least 4 weeks prior to starting and continuing for the duration of the study. The objective response rate for patients with measurable disease was 48.1% in the abemaciclib arm compared with 21.3% in the placebo arm. An interim analysis after a median follow-up of 47.7 months found that median overall survival was also significantly improved in the abemaciclib arm (46.7 months vs. 37.3 months).
-for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer after disease progression on endocrine therapy, in combination with ribociclib:
Intramuscular dosage:
Adults: 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes. Administer in combination with ribociclib (600 mg PO once daily, preferably in the morning, on days 1 to 21, followed by 7 days of rest, repeated every 28 days). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Men should also be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. In a randomized, double-blind, clinical trial, treatment with ribociclib plus fulvestrant significantly improved investigator-assessed progression-free survival (PFS) compared with placebo plus fulvestrant in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no or only one line of prior endocrine treatment (20.5 months vs. 12.8 months); the overall response rate in patients with measurable disease was 40.9% versus 28.7%, respectively.
-for the treatment of hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer with 1 or more PIK3CA/AKT1/PTEN-alteration following progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy, in combination with capivasertib*:
NOTE: Capivasertib is FDA-approved for the treatment of HR-positive, HER2-negative, locally advanced or metastatic breast cancer with 1 or more PIK3CA/AKT1/PTEN-alteration following progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy, in combination with fulvestrant.
Intramuscular dosage:
Adults: 500 mg IM on days 1, 15, 29 and every 28 days thereafter, in combination with capivasertib (400 mg PO twice daily on days 1 through 4 every 7 days) until disease progression or unacceptable toxicity. Consider adding a luteinizing hormone-releasing hormone (LHRH) agonist for men and for pre- and perimenopausal women according to current clinical practice standards. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind, phase 3 clinical trial (CAPItello-291), treatment with capivasertib plus fulvestrant significantly improved the median progression-free survival (PFS) compared with placebo plus fulvestrant in patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer with eligible PIK3CA/AKT1/PTEN alterations and progression on an aromatase inhibitor (AI) based treatment in the metastatic setting or recurrence on or within 12 months of completing neoadjuvant or adjuvant therapy with an AI (7.3 months vs. 3.1 months). The median objective response rate was 26% versus 8%, respectively (complete response, 2.3% vs. 0%), with a median duration of response of 10.2 months in the fulvestrant arm and 8.6 months in the placebo arm. Overall survival results were immature.
Maximum Dosage Limits:
-Adults
500 mg IM.
-Elderly
500 mg IM.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Child-Pugh A: No dosage adjustment required.
-Child-Pugh B: Administer 250 mg intramuscularly on days 1, 15, 29, and once monthly thereafter.
-Child-Pugh C: Fulvestrant has not been evaluated in patients with severe hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Fluoroestradiol F 18: (Major) Administer fluoroestradiol F 18 before starting fulvestrant; however, do not delay indicated therapy to administer fluoroestradiol F 18. Fulvestrant may block estrogen receptors (ER) for up to 28 weeks and reduce the uptake of fluoroestradiol F 18 and detection of ER-positive lesions.
Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity to the ER receptor comparable to that of estradiol. Many breast cancers have estrogen receptors; the growth of these tumors can be stimulated by estrogen. Fulvestrant downregulates the ER protein in human breast cancer cells. In vitro, fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer cell lines (MCF-7). In vivo, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice; it also inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts. Fulvestrant showed no agonist-type effects in in vivo uterotropic assays in immature or ovariectomized mice and rats. During 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 suggests no peripheral steroidal effects.
There was evidence of increasing down-regulation of ER with increasing fulvestrant dose in a clinical study of postmenopausal women with primary breast cancer who received a single dose of fulvestrant 15 to 22 days prior to surgery. This was associated with a dose-related decrease in the expression of the progesterone receptor, an estrogen-regulated protein. These effects on the ER pathway were also associated with a decrease in Ki67 labeling index, a marker of cell proliferation.
Fulvestrant is given by intramuscular (IM) injection. It is highly (99%) bound to plasma proteins; VLDL, LDL, and HDL lipoprotein fractions appear to be the major binding components. The role of sex hormone-binding globulin could not be determined. The apparent volume of distribution (Vd) at steady-state is approximately 3 to 5 liters. Metabolism of fulvestrant appears to involve combinations of several 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. Cytochrome P450 3A4 is the only P450 isoenzyme involved in fulvestrant oxidation; the relative contribution of P450 and non-P450 routes in vivo is unknown. Identified metabolites are either less active or have a similar activity to fulvestrant in antiestrogen models. After IM injection, the mean clearance (+/- standard deviation) was 690 +/- 226 mL/min with an apparent half-life of 40 days. Fulvestrant is rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%); less than 1% is eliminated renally.
Affected cytochrome P450 isoenzymes (CYP450) or drug transporters: None
Although fulvestrant is metabolized by CYP3A4 in vitro, drug interaction studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.
-Route-Specific Pharmacokinetics
Intramuscular Route
After a single 500-mg dose of fulvestrant, the geometric mean peak plasma concentration (Cmax) was 25.1 ng/mL (CV, 35.3%) and the AUC was 11,400 ng x h/mL (CV, 33.4%); minimum plasma concentrations after a single 500-mg dose were 16.3 ng/mL (CV, 25.9%). The additional dose of fulvestrant given 2 weeks after the initial dose allows for steady-state concentrations to be reached within the first month of dosing. By the 3rd month of administration, the steady-state Cmax is 28 ng/mL (CV, 27.9%), AUC 13,100 ng x h/mL (CV, 23.4%), and Cmin 12.2 ng/mL (CV, 21.7%).
-Special Populations
Hepatic Impairment
Subjects with mild hepatic impairment (Child-Pugh A; n = 7) had comparable mean AUC and clearance values to those with normal hepatic function (n = 7) after a single 100-mg IM dose of fulvestrant. In subjects with moderate hepatic impairment (Child-Pugh B; n = 7), the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function; this was positively correlated with total bilirubin concentration (p = 0.012). Fulvestrant has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Renal Impairment
Due to negligible urinary elimination of fulvestrant, studies in patients with renal impairment were not conducted. In clinical trials of women with advanced breast cancer, fulvestrant concentrations were similar in patients with estimated creatinine clearance (CrCL) as low as 30 mL/min to patients with normal CrCL.
Pediatrics
In a population pharmacokinetic analysis, the geometric mean clearance (CL/F) of fulvestrant (4 mg/kg IM once monthly) in female pediatric patients (n = 30; age, 1 to 8 years) was 32% lower than in adults (444 +/- 165 mL/min). The geometric mean steady-state trough (Cmin) was 4.19 +/- 0.87 ng/mL and the geometric mean steady-state AUC was 3,680 +/- 1,020 ng x h/mL.
Geriatric
Age (range, 33 to 89 years) did not affect the pharmacokinetic profile of fulvestrant in patients with breast cancer.
Gender Differences
Gender did not affect the pharmacokinetic profile of fulvestrant after a single intravenous dose; menopausal status of women also did not affect the pharmacokinetics of fulvestrant. Similarly, there were no differences between men and postmenopausal women after IM administration of fulvestrant.
Ethnic Differences
Race (i.e., Caucasian, Black, Hispanic, or Japanese) did not affect the pharmacokinetics of fulvestrant.