Fulvestrant
- Treatment for hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
- The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter.
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 slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter.
- Fulvestrant has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)
- Because fulvestrant is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.

# 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.
- Fulvestrant has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

# Use in Pregnancy
- Based on its mechanism of action and findings in animals, fulvestrant can cause fetal harm when administered to a pregnant woman.
- Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area.
- There are no adequate and well-controlled studies in pregnant women using fulvestrant. Women of childbearing potential should be advised not to become pregnant while receiving fulvestrant.
- If fulvestrant is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Comparison of fulvestrant 500 mg and fulvestrant 250 mg
- The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared fulvestrant 500 mg with fulvestrant 250 mg. 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 the controlled clinical trial Study 1 comparing the administration of fulvestrant 500 mg intramuscularly once a month with fulvestrant 250 mg intramuscularly once a month.
- 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 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3)
- The most commonly reported adverse reactions in the fulvestrant and anastrozole treatment groups, regardless of the investigators assessment of causality, 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 (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2).
- Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of fulvestrant 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.
Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with fulvestrant. If bleeding persists, further evaluation should be considered.
Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).
- In studies in female rats at intramuscular doses  0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as 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 BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses  0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis.
- Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. 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 BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.
- 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 ); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 ). 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, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to 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 (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.
- A dose of fulvestrant 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B)

# Administration Technique
- The proper method of administration of fulvestrant for intramuscular use is described in the instructions that follow:
- Remove glass syringe barrel from tray and check that it is not damaged.
- Remove perforated patient record label from syringe.
- Peel open the safety needle outer packaging.
- Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap (see Figure 1).
- Twist to lock the needle to the luer connector.
- Remove needle sheath.
- Remove excess gas from the syringe (a small gas bubble may remain).
- Administer intramuscularly slowly in the buttock.
- Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered (see Figure 2).
- Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector.
- Repeat steps 1 through 10 for second syringe.
How To Use fulvestrant
For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg recommended dose.
- 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 uterotropic 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.
- 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 as inactive ingredients: 10% w/v Alcohol, USP, 10% w/v benzyl alcohol, NF, and 15% w/v benzyl benzoate, USP, as co-solvents, and made up to 100% w/v with Castor Oil, USP as a co-solvent and release rate modifier.
- The single dose and multiple dose PK parameters for the 500 mg dosing regimen with an additional dose (AD) at Day 15 are reported in Table 3. The additional dose of fulvestrant given two weeks after the initial dose allows for steady state concentrations to be reached within the first month of dosing.

# Distribution
- The apparent volume of distribution at steady state is approximately 3 to 5 L/kg.
- This suggests that distribution is largely extravascular. Fulvestrant 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, if any, could not be determined.

# Metabolism
- Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of 14C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a number of 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. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models.
- Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.

# Excretion
- Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).
- After an intramuscular injection of 250 mg, the clearance (Mean  SD) was 690  226 mL/min with an apparent half-life about 40 days.

# Special Populations
- In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).
- Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and women or between premenopausal and postmenopausal women. Similarly, there were no differences between men and postmenopausal women after intramuscular administration.
- In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women were similar to those obtained in non-Japanese patients.

# Drug-Drug Interactions
- There are no known drug-drug interactions. Fulvestrant does not significantly inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, and studies of co-administration of fulvestrant with midazolam indicate that therapeutic doses of fulvestrant have no inhibitory effects on CYP 3A4 or alter blood levels of drug metabolized by that enzyme. Although fulvestrant is partly metabolized by CYP 3A4, a clinical study with rifampin, an inducer of CYP 3A4, showed no effect on the pharmacokinetics of fulvestrant. Also results from a healthy volunteer study with ketoconazole, a potent inhibitor of CYP3A4, indicated that ketoconazole had no effect on the pharmacokinetics of fulvestrant and dosage adjustment is not necessary in patients co-prescribed CYP 3A4 inhibitors or inducers.
- A two-year carcinogenesis study was conducted in female and male rats, at intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days.
- These doses correspond to 0.9-, 1.5-, and 3-fold (in females) and 0.8-, 0.8-, and 2-fold (in males) the systemic exposure  achieved in women receiving the recommended dose of 500 mg/month. An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/30 days, respectively. In addition, a two year carcinogenicity study was conducted in female and male mice at orally administered doses of 0, 20, 150 and 500 mg/kg/day.
- These doses correspond to 0, 0.8, 8.4 and 18 -fold (in females) and 0, 0.8, 7.1 and 11.9  fold (in males), the systemic exposure (AUC0-30 days) achieved in women receiving the recommended dose of 500 mg/month. There was an increased incidence of sex cord stromal tumors (both benign and malignant) in the ovary at doses of 150 and 500 mg/kg/day. Induction of such tumors is consistent with the pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an antiestrogen.
- Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests with and without the addition of a mammalian liver metabolic activation factor (bacterial mutation assay in strains of Salmonella typhimurium and Escherichia coli, in vitro cytogenetics study in human lymphocytes, mammalian cell mutation assay in mouse lymphoma cells and in vivo micronucleus test in rat).
- In female rats, fulvestrant administered at doses  0.01 mg/kg/day (0.6% the human recommended dose based on body surface area ), for 2 weeks prior to and for 1 week following mating, caused a reduction in fertility and embryonic survival. No adverse effects on female fertility and embryonic survival were evident in female animals dosed at 0.001 mg/kg/day (0.06% the human dose based on BSA). Restoration of female fertility to values similar to controls was evident following a 29-day withdrawal period after dosing at 2 mg/kg/day (equivalent to the human dose based on BSA). The effects of fulvestrant on the fertility of female rats appear to be consistent with its antiestrogenic activity. The potential effects of fulvestrant on the fertility of male animals were not studied but, in a 6-month toxicology study, male rats treated with intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant showed a loss of spermatozoa from the seminiferous tubules, seminiferous tubular atrophy, and degenerative changes in the epididymides. Changes in the testes and epididymides had not recovered 20 weeks after cessation of dosing. These fulvestrant doses correspond to 1.3-, 1.2- and 3.5-fold the systemic exposure  achieved in women receiving the recommended dose of 500 mg/month.
- Comparison of fulvestrant 500 mg and fulvestrant 250 mg (Study 1)
- A Phase 3 randomized, double-blind, controlled clinical trial (Study 1) was completed in 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease. This trial compared the efficacy and safety of fulvestrant 500 mg (n=362) with fulvestrant 250 mg (n=374).
- Fulvestrant 500 mg was administered as two 5 mL injections each containing fulvestrant 250 mg/5mL, one in each buttock, on Days 1, 15, 29 and every 28 (+/- 3) days thereafter. Fulvestrant 250 mg was administered as two 5 mL injections (one containing fulvestrant 250 mg/5mL injection plus one placebo injection), one in each buttock, on Days 1, 15 (2 placebo injections only), 29 and every 28 (+/- 3) days thereafter.
- The median age of study participants was 61. All patients had ER+ advanced breast cancer. Approximately 30% of subjects had no measurable disease. Approximately 55% of patients had visceral disease.
- Results of Study 1 are summarized in Table 4. The efficacy of fulvestrant 500 mg was compared to that of fulvestrant 250 mg. Figure 4 shows a Kaplan-Meier plot of the Progression Free Survival (PFS) data after a minimum follow-up duration of 18 months demonstrating statistically significant superiority of fulvestrant 500 mg vs fulvestrant 250 mg. In the initial Overall Survival (OS) analysis after a minimum follow-up duration of 18 months, there was no statistically significant difference in OS between the two treatment groups. After a minimum follow-up duration of 50 months, an updated OS analysis was performed. Figure 5 shows a Kaplan-Meier plot of the updated OS data.
Comparison of fulvestrant 250 mg and Anastrozole 1 mg in Combined Data (Studies 2 and 3)
- Efficacy of fulvestrant was established by comparison to the selective aromatase inhibitor anastrozole in two randomized, controlled clinical trials (one conducted in North America, Study 2; the other predominantly in Europe, Study 3) in postmenopausal women with locally advanced or metastatic breast cancer. All patients had progressed after previous therapy with an antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting.
- The median age of study participants was 64. 81.6% of patients had ER+ and/or PgR+ tumors. Patients with ER- /PgR- or unknown tumors were required to have demonstrated a prior response to endocrine therapy. Sites of metastases occurred as follows: visceral only 18.2%; viscera  liver involvement 23.0%; lung involvement 28.1%; bone only 19.7%; soft tissue only 5.2%; skin and soft tissue 18.7%.
- In both trials, eligible patients with measurable and/or evaluable disease were randomized to receive either fulvestrant 250 mg intramuscularly once a month (28 days + 3 days) or anastrozole 1 mg orally once a day. All patients were assessed monthly for the first three months and every three months thereafter. Study 2 was a double-blind, randomized trial in 400 postmenopausal women. Study 3 was an open-label, randomized trial conducted in 451 postmenopausal women. Patients on the fulvestrant arm of Study 2 received two separate injections (2 X 2.5 mL), whereas fulvestrant patients received a single injection (1 X 5 mL) in Study 3. In both trials, patients were initially randomized to a 125 mg per month dose as well, but interim analysis showed a very low response rate, and low dose groups were dropped.
- Results of the trials, after a minimum follow-up duration of 14.6 months, are summarized in Table 5. The effectiveness of fulvestrant 250 mg was determined by comparing Objective Response Rate (ORR) and Time to Progression (TTP) results to anastrozole 1 mg, the active control. The two studies ruled out (by one-sided 97.7% confidence limit) inferiority of fulvestrant to anastrozole of 6.3% and 1.4% in terms of ORR. There was no statistically significant difference in overall survival (OS) between the two treatment groups after a follow-up duration of 28.2 months in Study 2 and 24.4 months in Study 3.
- There are no efficacy data for the use of fulvestrant in premenopausal women with advanced breast cancer (women with functioning ovaries as evidenced by menstruation and/or premenopausal LH, FSH and estradiol levels).
- NDC 0310072010
- The syringes are presented in a tray with polystyrene plunger rod and safety needles  for connection to the barrel.
- TO PROTECT FROM LIGHT, STORE IN THE ORIGINAL CARTON UNTIL TIME OF USE.
Women of childbearing potential should be advised not to become pregnant while receiving fulvestrant. fulvestrant can cause fetal harm when administered to a pregnant woman.

# Blood Disorders
Because fulvestrant 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)
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