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  • CLASSES

    Cytostatic Anti-estrogens

    DEA CLASS

    Rx

    DESCRIPTION

    Estrogen-receptor antagonist without any known estrogen agonist effects
    Used in postmenopausal women as monotherapy or in combination with ribociclib for first- and second-line treatment of HR-positive, HER2-negative advanced breast cancer, and in combination with palbociclib or abemaciclib in women with HR-positive, HER2-negative advanced or metastatic breast cancer after disease progression following endocrine therapy
    May interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels

    COMMON BRAND NAMES

    FASLODEX

    HOW SUPPLIED

    FASLODEX/Fulvestrant Intramuscular Inj Sol: 1mL, 50mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    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 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.[32947] [58768] Median overall survival was 34.9 months in patients treated with palbociclib plus fulvestrant and 28 months in those who received placebo plus fulvestrant.[63690] Investigator-assessed confirmed overall response rate was 24.6% in the palbociclib arm compared with 10.9% in the placebo arm.[32947] [58768]

    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, 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 first-line treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy, in combination with ribociclib.
    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. 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. 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.[61816] [32947]

    For the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer after disease progression on endocrine therapy, in combination with ribociclib.
    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. 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. 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.

    MAXIMUM DOSAGE

    Adults

    500 mg IM.

    Elderly

    500 mg IM.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    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.[32947] [64577]

    STORAGE

    FASLODEX:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Refrigerate (between 39 and 46 degrees F)
    - See package insert for detailed storage information
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Neurologic events, peripheral neuropathy

    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.[32947]

    Hepatic disease

    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.

    Anticoagulant therapy, coagulopathy, thrombocytopenia

    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.

    Laboratory test interference

    Due to structural similarity, fulvestrant can cause a laboratory test interference with estradiol measurement by immunoassay; this may result in falsely elevated estradiol levels.

    Children, infants, neonates

    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

    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.[32947]

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    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.[32947]

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 0-10.0
    infection / Delayed / 0-4.0
    vomiting / Early / 0-2.0
    leukopenia / Delayed / 0-2.0
    neutropenia / Delayed / 0-2.0
    anemia / Delayed / 0-2.0
    abdominal pain / Early / 0-1.0
    nausea / Early / 0-1.0
    diarrhea / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    weight loss / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    hepatic failure / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    fatigue / Early / 0-1.0
    fever / Early / 0-1.0
    thromboembolism / Delayed / 0-1.0
    hypophosphatemia / Delayed / 0-1.0
    headache / Early / 0-1.0
    thrombosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known

    Moderate

    hot flashes / Early / 6.0-18.0
    hypoglycemia / Early / 0-18.0
    bone pain / Delayed / 0-16.0
    dyspnea / Early / 4.0-15.0
    stomatitis / Delayed / 0-13.0
    constipation / Delayed / 4.0-13.0
    peripheral edema / Delayed / 7.0-9.0
    hypoalbuminemia / Delayed / 0-8.0
    chest pain (unspecified) / Early / 0-7.0
    depression / Delayed / 0-6.0
    hepatitis / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    vaginal bleeding / Delayed / 0-1.0
    oral ulceration / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    neuropathic pain / Delayed / Incidence not known
    ocular infection / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 7.0-27.0
    arthralgia / Delayed / 0-17.0
    pharyngitis / Delayed / 0-16.0
    cough / Delayed / 5.0-15.0
    pelvic pain / Delayed / 0-10.0
    dizziness / Early / 6.0-8.0
    myalgia / Early / 0-7.0
    insomnia / Early / 0-7.0
    pruritus / Rapid / 0-7.0
    musculoskeletal pain / Early / 0-6.0
    paresthesias / Delayed / 0-6.0
    alopecia / Delayed / 0-6.0
    anxiety / Delayed / 0-5.0
    diaphoresis / Early / 0-5.0
    dysgeusia / Early / 0-3.0
    urticaria / Rapid / 0-1.0
    vertigo / Early / 0-1.0
    cheilitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    influenza / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.[32947]

    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.

    MECHANISM OF ACTION

    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.[32947]
     
    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.[32947]

    PHARMACOKINETICS

    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.[32947]
     
    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.[32947]

    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%).[32947]