February 10, 2016
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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 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.


In a clinical study in postmenopausal women with primary breast cancer treated with single doses of FASLODEX 15-22 days prior to surgery, there was evidence of increasing down- regulation of ER with increasing dose. 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.



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 FASLODEX given two weeks after the initial dose allows for steady state concentrations to be reached within the first month of dosing.

Table 3: Summary of fulvestrant pharmacokinetic parameters [gMean (CV%)] in postmenopausal advanced breast cancer patients after intramuscular administration 500 mg + AD dosing regimen

  Cmax (ng/mL) Cmin (ng/mL) AUC (ng•hr/mL)
500 mg + AD* Single dose 25.1 (35.3) 16.3 (25.9) 11400 (33.4)
Multiple dose steady state* 28.0 (27.9) 12.2 (21.7) 13100 (23.4)
* additional 500 mg dose given on day 15
** month 3


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.


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.


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 [see DRUG INTERACTIONS].

Clinical Studies

The efficacy of FASLODEX 500 mg versus FASLODEX 250 mg was compared in Study 1. The efficacy of FASLODEX 250 mg was compared to anastrozole in Studies 2 and 3.

Comparison of FASLODEX 500 mg and FASLODEX 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 FASLODEX 500 mg (n=362) with FASLODEX 250 mg (n=374).

FASLODEX 500 mg was administered as two 5 mL injections each containing FASLODEX 250 mg/5mL, one in each buttock, on Days 1, 15, 29 and every 28 (+/- 3) days thereafter. FASLODEX 250 mg was administered as two 5 mL injections (one containing FASLODEX 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 after a minimum follow-up duration of 18 months are summarized in Table 4. The efficacy of FASLODEX 500 mg was compared to that of FASLODEX 250 mg. Figure 4 shows a Kaplan-Meier plot of the Progression Free Survival (PFS) data demonstrating statistically significant superiority of FASLODEX 500 mg vs FASLODEX 250 mg. Figure 5 shows a Kaplan-Meier plot of the Overall Survival (OS) data. There was no statistically significant difference in OS between the two treatment groups.

Table 4: Efficacy Results Study 1: Intent To Treat (ITT) Population

Endpoint Fulvestrant 500 mg
Fulvestrant 250 mg
PFSa Median (months) 6.5 5.4
Hazard Ratiob (95% CIc) 0.80 (0.68-0.94)
p-value 0.006
OSd Died 175 (48.3) 203 (54.3)
Median OS (months) 25.1 22.8
Hazard Ratiob (95% CIc) 0.84 (0.69-1.03)
ORRe (95% CIc) 13.8% (9.7%, 18.8%) (33/240) 14.6% (10.5%, 19.4%) (38/261)
a PFS (Progression Free Survival) = the time between randomization and the earliest of progression or death from any cause.
bHazard ratio < 1 favors FASLODEX 500 mg.
cCI = Confidence Interval
dOS = Overall Survival
e ORR (Objective Response Rate), defined as number (%) of patients with complete response or partial response, was analyzed in the evaluable patients with measurable disease at baseline (fulvestrant 500 mg N=240; fulvestrant 250 mg N=261).

Figure 4 : Kaplan-Meier PFS: Study 1 ITT Population

Kaplan-Meier PFS - Illustration

Figure 5 : Kaplan-Meier OS: Study 1 ITT Popul

Kaplan-Meier Overall survival - Illustration

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Data (Studies 2 and 3)

Efficacy of FASLODEX 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 FASLODEX 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 FASLODEX arm of Study 2 received two separate injections (2 X 2.5 mL), whereas FASLODEX 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 FASLODEX 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 FASLODEX 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.

Table 5: Efficacy Results

Endpoint Study 2

Study 3 (Open-Label)
Anastrozole 1 mg
Anastrozole 1 mg
Objective tumor response
  Number (%) of subjects with CRa + PRb 35 (17.0) 33 (17.0) 45 (20.3) 34 (14.9)
% Difference in Tumor
  Response Rate (FASc -ANAd) 0.0 5.4
  2-sided 95.4% CIe (-6.3, 8.9) (-1.4, 14.8)
Time to progression (TTP)
  Median TTP (days) 165 103 166 156
  Hazard ratiof 0.9 1.0
  2-sided 95.4% CIe (0.7, 1.1) (0.8, 1.2)
Stable Disease for ≥ 24 weeks (%) 26.7 19.1 24.3 30.1
Overall Survival (OS)
  Died n (%) 152 (73.8%) 149 (76.8%) 167 (75.2%) 173 (75.5%)
  Median Survival (days) 844 913 803 736
  Hazard Ratiof (2-sided 95% CIe) 0.98 (0.78, 1.24) 0.97 (0.78, 1.21)
aCR = Complete Response
bPR = Partial Response
dANA = anastrozole
eCI = Confidence Interval
fHazard ratio < 1 favors FASLODEX

There are no efficacy data for the use of FASLODEX in premenopausal women with advanced breast cancer (women with functioning ovaries as evidenced by menstruation and/or premenopausal LH, FSH and estradiol levels).

Last reviewed on RxList: 8/3/2012
This monograph has been modified to include the generic and brand name in many instances.

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