Faslodex

FASLODEX is indicated for the treatment of:

• •Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, or
• •HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy.

FASLODEX is indicated for the treatment of:

• •HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with ribociclib as initial endocrine based therapy or following disease progression on endocrine therapy.
• •HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy.

• •FASLODEX 500 mg should be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter. (
  2.1 Recommended Dose

  Monotherapy

  The recommended dose of FASLODEX is 500 mg to be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter

  [see Clinical Studies (14)]

  .

  Combination Therapy

  When FASLODEX is used in combination with palbociclib, abemaciclib, or ribociclib, the recommended dose of FASLODEX is 500 mg to be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter.

  When FASLODEX is used in combination with palbociclib, the recommended dose of palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food. Refer to the Full Prescribing Information for palbociclib.

  When FASLODEX is used in combination with abemaciclib, the recommended dose of abemaciclib is 150 mg orally, twice daily. Abemaciclib may be taken with or without food. Refer to the Full Prescribing Information for abemaciclib.

  When FASLODEX is used in combination with ribociclib, the recommended dose of ribociclib is 600 mg taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Ribociclib can be taken with or without food. Refer to the Full Prescribing Information for ribociclib.

  Pre/perimenopausal women treated with the combination of FASLODEX plus palbociclib, abemaciclib, or ribociclib, should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards

  [see Clinical Studies (14)]

  .
  ,
  14 CLINICAL STUDIES

  The efficacy of FASLODEX 500 mg versus FASLODEX 250 mg was compared in CONFIRM. The efficacy of FASLODEX 250 mg was compared to 1 mg anastrozole in Studies 0020 and 0021. The efficacy of FASLODEX 500 mg was compared to 1 mg anastrozole in FALCON. The efficacy of FASLODEX 500 mg in combination with palbociclib 125 mg was compared to FASLODEX 500 mg plus placebo in PALOMA-3. The efficacy of FASLODEX 500 mg in combination with abemaciclib 150 mg was compared to FASLODEX 500 mg plus placebo in MONARCH 2. The efficacy of FASLODEX 500 mg in combination with ribociclib 600 mg was compared to FASLODEX 500 mg plus placebo in MONALEESA-3.

  Monotherapy

  Comparison of FASLODEX 500 mg and FASLODEX 250 mg (CONFIRM)

  A randomized, double-blind, controlled clinical trial (CONFIRM, NCT00099437) 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/5 mL, 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/5 mL 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 years. All patients had ER+ advanced breast cancer. Approximately 30% of subjects had no measurable disease. Approximately 55% of patients had visceral disease.

  Results of CONFIRM are summarized in Table 12. The efficacy of FASLODEX 500 mg was compared to that of FASLODEX 250 mg. Figure 6 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 FASLODEX 500 mg vs. FASLODEX 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 7 shows a Kaplan-Meier plot of the updated OS data.

  Table 12: Efficacy Results in CONFIRM (Intent-To-Treat (ITT) Population)

  Endpoint	FASLODEX 500 mg (N=362)	FASLODEX 250 mg (N=374)
  PFS PFS (Progression Free Survival)=the time between randomization and the earliest of progression or death from any cause. Minimum follow-up duration of 18 months. Median (months)	6.5	5.4
  Hazard RatioHazard Ratio <1 favors FASLODEX 500 mg.(95% CICI=Confidence Interval)	0.80 (0.68-0.94)
  p-value	0.006
  OS OS=Overall Survival Updated Analysis Minimum follow up duration of 50 months. (% patients who died)	261 (72.1%)	293 (78.3%)
  Median OS (months)	26.4	22.3
  Hazard Ratio (95% CI )Not statistically significant as no adjustments were made for multiplicity.	0.81 (0.69-0.96)
  ORR ORR (Objective Response Rate), as 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). Minimum follow-up duration of 18 months.(95% CI )	13.8% (9.7%, 18.8%) (33/240)	14.6% (10.5%, 19.4%) (38/261)

  Figure 6 Kaplan-Meier PFS: CONFIRM ITT Population

  

  Figure 7 Kaplan-Meier OS (Minimum Follow-up Duration of 50 Months): CONFIRM ITT Population

  

  Comparison of FASLODEX 500 mg and Anastrozole 1 mg (FALCON)

  A randomized, double-blind, double-dummy, multi-center study (FALCON, NCT01602380) of FASLODEX 500 mg versus anastrozole 1 mg was conducted in postmenopausal women with ER-positive and/or PgR-positive, HER2-negative locally advanced or metastatic breast cancer who had not previously been treated with any hormonal therapy. A total of 462 patients were randomized 1:1 to receive administration of FASLODEX 500 mg as an intramuscular injection on Days 1, 15, 29, and every 28 (+/- 3) days thereafter or daily administration of 1 mg of anastrozole orally. This study compared the efficacy and safety of FASLODEX 500 mg and anastrozole 1 mg.

  Randomization was stratified by disease setting (locally advanced or metastatic), use of prior chemotherapy for advanced disease, and presence or absence of measurable disease.

  The major efficacy outcome measure of the study was investigator-assessed progression-free survival (PFS) evaluated according to RECIST v.1.1 (Response Evaluation Criteria in Solid Tumors). Key secondary efficacy outcome measures included overall survival (OS), objective response rate (ORR), and duration of response (DoR).

  Patients enrolled in this study had a median age of 63 years (range 36-90). The majority of patients (87%) had metastatic disease at baseline. Fifty-five percent (55%) of patients had visceral metastasis at baseline. A total of 17% of patients had received one prior chemotherapy regimen for advanced disease; 84% of patients had measurable disease. Sites of metastases were as follows: musculoskeletal 59%, lymph nodes 50%, respiratory 40%, liver (including gall bladder) 18%.

  The efficacy results of FALCON are presented in Table 13 and Figure 8.

  Table 13: Efficacy Results in FALCON (Investigator Assessment, ITT Population)

  	FASLODEX 500 mg N=230	Anastrozole 1 mg N=232
  Progression-Free Survival
  Number of PFS Events (%)	143 (62.2%)	166 (71.6%)
  Median PFS (months)	16.6	13.8
  PFS Hazard Ratio (95% CI)	0.797 (0.637 - 0.999)
  p-value	0.049
  Overall Survival Interim OS analysis with 61% of total number of events required for the final OS analysis.
  Number of OS Events	67 (29.1%)	75 (32.3%)
  Median OS (months)	NR	NR
  OS Hazard Ratio (95% CI)	0.874 (0.629 – 1.216)
  Objective Response for Patients with Measurable Disease	N=193	N=196
  Objective Response Rate (%, 95% CI)	46.1% (38.9%, 53.4%)	44.9% (37.8%, 52.1%)
  Median DoR (months)	20.0	13.2
  NR: Not reached

  Figure 8 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, ITT Population) ─ FALCON

  

  Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Data (Studies 0020 and 0021)

  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 0021, NCT00635713; the other predominantly in Europe, Study 0020) 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 years. 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 0021 was a double-blind, randomized trial in 400 postmenopausal women. Study 0020 was an open-label, randomized trial conducted in 451 postmenopausal women. Patients on the FASLODEX arm of Study 0021 received two separate injections (2 x 2.5 mL), whereas FASLODEX patients received a single injection (1 x 5 mL) in Study 0020. 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 14. 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 0021 and 24.4 months in Study 0020.

  Table 14: Efficacy Results in Studies 0020 and 0021 (Objective Response Rate (ORR) and Time to Progression (TTP))

  	Study 0021 (Double-Blind)		Study 0020 (Open-Label)
  Endpoint	FASLODEX 250 mg N=206	Anastrozole 1 mg N=194	FASLODEX 250 mg N=222	Anastrozole 1 mg N=229
  Objective Tumor Response Number (%) of subjects with CRCR=Complete Response+ PRPR=Partial Response	35 (17.0)	33 (17.0)	45 (20.3)	34 (14.9)
  % Difference in Tumor Response Rate (FASFAS=FASLODEX-ANAANA=anastrozole) 2-sided 95.4% CICI=Confidence Interval	0.0 (-6.3, 8.9)		5.4 (-1.4, 14.8)
  Time to Progression (TTP) Median TTP (days)	165	103	166	156
  Hazard RatioHazard Ratio <1 favors FASLODEX 2-sided 95.4% CI	0.9 (0.7, 1.1)		1.0 (0.8, 1.2)
  Stable Disease for ≥24 weeks (%)	26.7	19.1	24.3	30.1
  Overall Survival (OS)
  Died n (%) Median Survival (days)	152 (73.8%) 844	149 (76.8%) 913	167 (75.2%) 803	173 (75.5%) 736
  Hazard Ratio (2-sided 95% CI)	0.98 (0.78, 1.24)		0.97 (0.78, 1.21)

  Combination Therapy

  Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy

  FASLODEX 500 mg in Combination with Palbociclib 125 mg (PALOMA-3)

  PALOMA-3 (NCT-1942135) was an international, randomized, double-blind, parallel group, multi-center study of FASLODEX plus palbociclib versus FASLODEX plus placebo conducted in women with HR-positive, HER2-negative advanced breast cancer, regardless of their menopausal status, whose disease progressed on or after prior endocrine therapy.

  A total of 521 pre/postmenopausal women were randomized 2:1 to FASLODEX plus palbociclib or FASLODEX plus placebo and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal), and presence of visceral metastases. Palbociclib was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Fulvestrant 500 mg was administered as two 5 mL injections each containing fulvestrant 250 mg/5 mL, one in each buttock, on Days 1, 15, 29, and every 28 (+/- 3) days thereafter. Pre/perimenopausal women were enrolled in the study and received the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of PALOMA-3.

  Patients continued to receive assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. The major efficacy outcome of the study was investigator-assessed PFS evaluated according to RECIST v.1.1.

  Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of patients on study were White (74%), all patients had an ECOG PS of 0 or 1, and 80% were postmenopausal. All patients had received prior systemic therapy and 75% of patients had received a previous chemotherapy regimen. Twenty-five percent of patients had received no prior therapy in the metastatic disease setting, 60% had visceral metastases, and 23% had bone only disease.

  The results from the investigator-assessed PFS and final OS data from PALOMA-3 are summarized in Table 15. The relevant Kaplan-Meier plots are shown in Figures 9 and 10, respectively. Consistent PFS results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. After a median follow-up time of 45 months, the final OS results were not statistically significant.

  Table 15: Efficacy Results in PALOMA-3 (Investigator Assessment, ITT Population)

  	FASLODEX plus Palbociclib	FASLODEX plus Placebo
  Progression-Free Survival for ITT	N=347	N=174
  Number of PFS Events (%)	145 (41.8%)	114 (65.5%)
  Median PFS (months) (95% CI)	9.5 (9.2-11.0)	4.6 (3.5-5.6)
  Hazard Ratio (95% CI) and p-value	0.461 (0.360-0.591) p <0.0001
  Objective Response for Patients with Measurable Disease	N=267	N=138
  Objective response rateResponses are based on confirmed responses.(%, 95% CI)	24.6 (19.6-30.2)	10.9 (6.2-17.3)
  Overall Survival for ITT population	N=347	N=174
  Number of OS events (%)	201 (57.9)	109 (62.6)
  Median OS (months) (95% CI)	34.9 (28.8, 40.0)	28.0 (23.6, 34.6)
  Hazard Ratio (95% CI) and p-value	0.814 (0.644, 1.029), p=0.0857Not statistically significant at the pre-specified 2-sided alpha level of 0.047.2-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior endocrine therapy per randomization.
  N=number of patients; PFS=progression-free survival; CI=confidence interval; ITT=Intent-to-Treat; OS=overall survival.

  Figure 9 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, ITT Population) – PALOMA-3

  

  Figure 10 Kaplan-Meier Plot of Overall Survival (ITT Population) ─ PALOMA-3

  

  FASLODEX 500 mg in Combination with Abemaciclib 150 mg (MONARCH 2)

  MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multi-center study conducted in women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy treated with FASLODEX plus abemaciclib versus FASLODEX plus placebo. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). A total of 669 patients received intramuscular injection of FASLODEX 500 mg on Days 1 and 15 of cycle 1 and then on Day 1 of cycle 2 and beyond (28-day cycles), plus abemaciclib or placebo orally twice daily. Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity.

  Patient median age was 60 years (range, 32-91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had

  de novo

  metastatic disease, 27% had bone only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal.

  The efficacy results from the MONARCH 2 study are summarized in Table 16, Figure 11, and Figure 12. PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and endocrine therapy resistance for PFS and OS.

  Table 16: Efficacy Results in MONARCH 2 (Intent-to-Treat Population)

  	FASLODEX plus Abemaciclib	FASLODEX plus Placebo
  Progression-Free Survival (Investigator Assessment)	N=446	N=223
  Number of patients with an event (n, %)	222 (49.8)	157 (70.4)
  Median (months, 95% CI)	16.4 (14.4, 19.3)	9.3 (7.4, 12.7)
  Hazard ratio (95% CI)	0.553 (0.449, 0.681)
  p-valueStratified by disease site (visceral metastases vs. bone-only metastases vs. other) and endocrine therapy resistance (primary resistance vs. secondary resistance)	p<0.0001
  Overall Survival Data from a pre-specified interim analysis (77% of the number of events needed for the planned final analysis) with the p-value compared with the allocated alpha of 0.021.
  Number of deaths (n, %)	211 (47.3)	127 (57.0)
  Median OS in months (95% CI)	46.7 (39.2, 52.2)	37.3 (34.4, 43.2)
  Hazard ratio (95% CI)1	0.757 (0.606, 0.945)
  p-value	p=0.0137
  Objective Response for Patients with Measurable Disease	N=318	N=164
  Objective response rateComplete response + partial response.(n, %)	153 (48.1)	35 (21.3)
  95% CI	42.6, 53.6	15.1, 27.6
  Abbreviations: CI=confidence interval, OS=overall survival.

  Figure 11 Kaplan-Meier Curves of Progression-Free Survival: FASLODEX Plus Abemaciclib versus FASLODEX plus Placebo (MONARCH 2)

  

  Figure 12 Kaplan-Meier Curves of Overall Survival: FASLODEX plus Abemaciclib versus FASLODEX plus Placebo (MONARCH 2)

  

  Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy

  FASLODEX 500 mg in Combination with Ribociclib 600 mg (MONALEESA-3)

  MONALEESA-3 (NCT 02422615) was a randomized double-blind, placebo-controlled study of FASLODEX plus ribociclib versus FASLODEX plus placebo conducted in postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.

  A total of 726 patients were randomized in a 2:1 ratio to receive FASLODEX plus ribociclib or FASLODEX plus placebo and stratified according to the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Fulvestrant 500 mg was administered intramuscularly on Days 1, 15, 29, and once monthly thereafter, with either ribociclib 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

  Patients enrolled in this study had a median age of 63 years (range 31 to 89). Of the patients enrolled, 47% were 65 years and older, including 14% age 75 years and older. The patients enrolled were primarily Caucasian (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First- and second-line patients were enrolled in this study (of which 19% had de novo metastatic disease). Forty-three percent (43%) of patients had received chemotherapy in the adjuvant vs. 13% in the neoadjuvant setting and 59% had received endocrine therapy in the adjuvant vs. 1% in the neoadjuvant setting prior to study entry. Twenty-one percent (21%) of patients had bone-only disease and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.

  The efficacy results from MONALEESA-3 are summarized in Table 17, Figure 13, and Figure 14. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease.

  Abbreviation: NR, not reached

  Table 17: Efficacy Results – MONALEESA-3 (Investigator Assessment, Intent-to-Treat Population)

  	FASLODEX plus Ribociclib	FASLODEX plus Placebo
  Progression-free survival Investigator Assessment	N=484	N=242
  Events (n, %)	210 (43.4%)	151 (62.4%)
  Median (months, 95% CI)	20.5 (18.5, 23.5)	12.8 (10.9, 16.3)
  Hazard Ratio (95% CI)	0.593 (0.480 to 0.732)
  p-valuep-value is obtained from the one-sided log-rank	<0.0001
  Overall Survival	N=484	N=242
  Events (n, %)	167 (34.5%)	108 (44.6%)
  Median (months, 95% CI)	NR (42.5, NR)	40.0 (37.0, NR)
  Hazard Ratio (95% CI)	0.724 (0.568, 0.924)
  p-value	0.00455
  Overall Response Rate Based on confirmed responses	N=379	N=181
  Patients with measurable disease (95% CI)	40.9 (35.9, 45.8)	28.7 (22.1, 35.3)

  Figure 13 Kaplan-Meier Progression Free Survival Curves – MONALEESA-3 (Intent-To-Treat Population, Investigator assessment)

  

  Figure 14 Kaplan-Meier plot of Overall Survival – MONALEESA-3 (Intent -to-Treat Population)

  

  figure_6

  Figure 7

  Figure 8

  Figure 9

  Figure 10

  Figure 11

  Figure 12

  Figure 13

  Figure_14

  )
• •A dose of 250 mg is recommended in patients with moderate hepatic impairment to be administered intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter. (
  2.2 Dose Modification

  Monotherapy

  Hepatic Impairment:

  A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter.

  FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)

  [see Warnings and Precautions (5.2)and Use in Specific Populations (8.6)]

  .

  Combination Therapy

  When FASLODEX is used in combination with palbociclib, abemaciclib, or ribociclib, refer to monotherapy dose modification instructions for FASLODEX.

  Refer to the Full Prescribing Information of co-administered palbociclib, abemaciclib, or ribociclib for dose modification guidelines in the event of toxicities, for use with concomitant medications, and other relevant safety information.
  ,
  5.2 Increased Exposure in Patients with Hepatic Impairment

  The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore, a dose of 250 mg is recommended

  [see Dosage and Administration (2.2)].

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

  [see Use in Specific Populations (8.6)].
  ,
  8.6 Hepatic Impairment

  FASLODEX is metabolized primarily in the liver.

  The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n=7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B), the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p=0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

  A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B)

  [see Dosage and Administration (2.2)and Warnings and Precautions (5.2)].
  )

FASLODEX, an injection for intramuscular administration, is supplied as 5-mL single-dose prefilled syringes containing 250 mg/5 mL fulvestrant.

• •Lactation: Advise not to breastfeed.
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of fulvestrant in human milk, nor of its effects on milk production or breastfed infant. Fulvestrant can be detected in rat milk

  [see Data]

  . Because of the potential for serious adverse reactions in breastfed infants from FASLODEX, advise a lactating woman not to breastfeed during treatment with FASLODEX and for one year after the final dose.

  Data

  Levels of fulvestrant were approximately 12-fold higher in milk than in plasma after exposure of lactating rats to a dose of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. In a study in rats of fulvestrant at 10 mg/kg given twice or 15 mg/kg given once (less than the recommended human dose based on mg/m²) during lactation, offspring survival was slightly reduced.

• •Risk of Bleeding: Use with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.
  5.1 Risk of Bleeding

  Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.
• •Increased Exposure in Patients with Hepatic Impairment: Use a 250 mg dose for patients with moderate hepatic impairment. (
  2.2 Dose Modification

  Monotherapy

  Hepatic Impairment:

  A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter.

  FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)

  [see Warnings and Precautions (5.2)and Use in Specific Populations (8.6)]

  .

  Combination Therapy

  When FASLODEX is used in combination with palbociclib, abemaciclib, or ribociclib, refer to monotherapy dose modification instructions for FASLODEX.

  Refer to the Full Prescribing Information of co-administered palbociclib, abemaciclib, or ribociclib for dose modification guidelines in the event of toxicities, for use with concomitant medications, and other relevant safety information.
  ,
  5.2 Increased Exposure in Patients with Hepatic Impairment

  The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore, a dose of 250 mg is recommended

  [see Dosage and Administration (2.2)].

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

  [see Use in Specific Populations (8.6)].
  ,
  8.6 Hepatic Impairment

  FASLODEX is metabolized primarily in the liver.

  The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n=7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B), the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p=0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

  A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B)

  [see Dosage and Administration (2.2)and Warnings and Precautions (5.2)].
  )
• •Injection Site Reaction: Use caution while administering FASLODEX at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve.
  5.3 Injection Site Reaction

  Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with FASLODEX injection. Caution should be taken while administering FASLODEX at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve

  [see Dosage and Administration (2.3)and Adverse Reactions (6.1)]

  .
• •Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.4 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at daily doses that are significantly less than the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with FASLODEX and for one year after the last dose

  [see Use in Specific Populations (8.1), (8.3)and Clinical Pharmacology (12.1)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology (12.1)]

  . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicity, including skeletal malformations and fetal loss, at daily doses that were 6% and 30% of the maximum recommended human dose based on mg/m², respectively

  [see Data]

  . Advise pregnant women of the potential risk to a fetus.

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Data

  Animal Data

  Administration of fulvestrant to rats prior to and up to implantation caused embryonic loss at daily doses that were 0.6% of the daily maximum recommended human dose based on mg/m². When fulvestrant was administered to pregnant rats during the period of organogenesis, intramuscular doses ≥0.1 mg/kg/day (6% of the human recommended dose based on mg/m²) caused effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on mg/m²) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day. Fulvestrant administered at 2 mg/kg/day caused fetal loss.

  When administered to pregnant rabbits during the period of organogenesis, fulvestrant caused pregnancy loss at an intramuscular dose of 1 mg/kg/day (equivalent to the human dose based on mg/m²). Further, at 0.25 mg/kg/day (30% the human dose based on mg/m²), fulvestrant caused increases in placental weight and post-implantation loss in rabbits. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on mg/m²) when administered during the period of organogenesis.
  , 8.3)
• •Immunoassay Measurement of Serum Estradiol: FASLODEX can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels.
  5.5 Immunoassay Measurement of Serum Estradiol

  Due to structural similarity of fulvestrant and estradiol, FASLODEX can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels.