fulvestrant: prescribing information – dosing, contraindications, interactions, side effects

Faslodex is indicated:
- as monotherapy for the treatment of estrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women:
- not previously treated with endocrine therapy, or
- with disease relapse on or after adjuvant antiestrogen therapy, or disease progression on antiestrogen therapy.
- in combination with palbociclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in women who have received prior endocrine therapy (see section 5.1).

In pre- or perimenopausal women, the combination treatment with palbociclib should be combined with a luteinizing hormone releasing hormone (LHRH) agonist.

Posology
Adult females (including Elderly)
The recommended dose is 500 mg at intervals of one month, with an additional 500 mg dose given two weeks after the initial dose.

When Faslodex is used in combination with palbociclib, please also refer to the Summary of Product Characteristics of palbociclib.

Prior to the start of treatment with the combination of Faslodex plus palbociclib, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.

Special populations
Renal impairment
No dose adjustments are recommended for patients with mild to moderate renal impairment (creatinine clearance 30 ml/min). Safety and efficacy have not been evaluated in patients with severe renal impairment (creatinine clearance <30 ml/min), and, therefore, caution is recommended in these patients (see section 4.4).

Hepatic impairment
No dose adjustments are recommended for patients with mild to moderate hepatic impairment.
However, as fulvestrant exposure may be increased, Faslodex should be used with caution in these patients. There are no data in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).

Paediatric population
The safety and efficacy of Faslodex in children from birth to 18 years of age have not been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration
Faslodex should be administered as two consecutive 5 ml injections by slow intramuscular injection (1-2 minutes/injection), one in each buttock (gluteal area).

Caution should be taken if injecting Faslodex at the dorsogluteal site due to the proximity of the underlying sciatic nerve.

For detailed instructions for administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy and lactation (see section 4.6).
Severe hepatic impairment (see sections 4.4 and 5.2).

Summary of the safety profile
Monotherapy
This section provides information based on all adverse reactions from clinical studies, post-marketing studies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequently reported adverse reactions were injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).

In Table 1, the following frequency categories for adverse drug reactions (ADRs) were calculated based on the Faslodex 500 mg treatment group in pooled safety analyses of studies that compared Faslodex 500 mg with Faslodex 250 mg [CONFIRM (Study D6997C00002), FINDER 1 (Study D6997C00004), FINDER 2 (Study D6997C00006), and NEWEST (Study D6997C00003) studies], or from FALCON (Study D699BC00001) alone that compared Faslodex 500 mg with anastrozole 1 mg.
Where frequencies differ between the pooled safety analysis and FALCON, the highest frequency is presented. The frequencies in Table 1 were based on all reported adverse drug reactions, regardless of the investigator assessment of causality. The median duration of fulvestrant 500 mg treatment across the pooled dataset (including the studies mentioned above plus FALCON) was 6.5 months.

Tabulated list of adverse reactions
Adverse reactions listed below are classified according to frequency and System Organ Class (SOC).
Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100). Within each frequency grouping adverse reactions are reported in order of decreasing seriousness.

Table 1
Adverse Drug Reactions reported in patients treated with Faslodex monotherapy

Adverse reactions by system organ class and frequency
Infections and infestations
Common
Urinary tract infections
Blood and lymphatic system disorders
Common
Reduced platelet counte
Immune system disorders
Very common
Hypersensitivity reactionse

Uncommon
Anaphylactic reactions
Metabolism and nutrition disorders
Common
Anorexiaa
Nervous system disorders
Common
Headache
Vascular disorders
Very common
Hot flushese
Common
Venous thromboembolisma
Gastrointestinal disorders
Very common
Nausea
Common
Vomiting, diarrhoea
Hepatobiliary disorders
Very common
Elevated hepatic enzymes (ALT, AST,
ALP)a
Common
Elevated bilirubina
Uncommon
Hepatic failurec, f, hepatitisf, elevated gamma-GTf
Skin and subcutaneous tissue disorders
Very common
Rashe
Musculoskeletal and connective tissue disorders
Very common
Joint and musculoskeletal paind

Common
Back paina
Reproductive system and breast disorders
Common
Vaginal haemorrhagee
Uncommon
Vaginal moniliasisf, leukorrheaf
General disorders and administration site conditions
Very common
Astheniaa, injection site reactionsb
Common
Neuropathy peripherale, sciaticae
Uncommon
Injection site haemorrhagef, injection site haematomaf, neuralgiac,f

a
Includes adverse drug reactions for which the exact contribution of Faslodex cannot be assessed due to the underlying disease.
b
The term injection site reactions does not include the terms injection site haemorrhage, injection site haematoma, sciatica, neuralgia and neuropathy peripheral.
c
The event was not observed in major clinical studies (CONFIRM, FINDER 1, FINDER 2, NEWEST). The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate.
This is calculated as 3/560 (where 560 is the number of patients in the major clinical studies), which equates to a frequency category of ‘uncommon’.
d
Includes: arthralgia, and less frequently musculoskeletal pain, myalgia and pain in extremity.
e
Frequency category differs between pooled safety dataset and FALCON.
f
ADR was not observed in FALCON.

Description of selected adverse reactions

The descriptions included below are based on the safety analysis set of 228 patients who received at least one (1) dose of fulvestrant and 232 patients who received at least one (1) dose of anastrozole, respectively in the Phase 3 FALCON study.

Joint and musculoskeletal pain
In the FALCON study, the number of patients who reported an adverse reaction of joint and musculoskeletal pain was 65 (31.2%) and 48 (24.1%) for fulvestrant and anastrozole arms, respectively. Of the 65 patients in the Faslodex arm, 40% (26/65) of patients reported joint and musculoskeletal pain within the first month of treatment, and 66.2% (43/65) of patients within the first 3 months of treatment. No patients reported events that were CTCAE Grade ≥3 or that required a dose reduction, dose interruption, or discontinued treatment due to these adverse reactions.

Combination therapy with palbociclib
The overall safety profile of fulvestrant when used in combination with palbociclib is based on data from 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer in the randomised PALOMA3 study (see section 5.1). The most common (≥20%) adverse reactions of any grade reported in patients receiving fulvestrant in combination with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anaemia, stomatitis, diarrhoea, thrombocytopenia and vomiting. The most common (≥2%) Grade ≥3 adverse reactions were neutropenia, leukopenia, infections, anaemia, AST increased, thrombocytopenia, and fatigue.

Table 2 reports the adverse reactions from PALOMA3.
Median duration of exposure to fulvestrant was 11.2 months in the fulvestrant + palbociclib arm and 4.8 months in the fulvestrant + placebo arm. Median duration of exposure to palbociclib in the fulvestrant + palbociclib arm was 10.8 months.

Table 2
Adverse reactions based on PALOMA3 Study (N=517)

System Organ Class
Frequency
Preferred Terma
Faslodex + Palbociclib
(N=345)
Faslodex + placebo
(N=172)
All Grades n (%)
Grade ≥ 3 n (%)
All Grades n (%)
Grade ≥ 3 n (%)
Infections and infestations
Very common

Infectionsb
188 (54.5)
19 (5.5)
60 (34.9)
6 (3.5)
Blood and lymphatic system disorders
Very common

Neutropeniac
290 (84.1)
240 (69.6)
6 (3.5)
Leukopeniad
207 (60.0)
132 (38.3)
9 (5.2)
1 (0.6)
Anaemiae
109 (31.6)
15 (4.3)
24 (14.0)
4 (2.3)
Thrombocytopeniaf
88 (25.5)
10 (2.9)

Uncommon

Febrile neutropenia
3 (0.9)
3 (0.9)
Metabolism and nutrition disorders
Very common

Decreased appetite
60 (17.4)
4 (1.2)
18 (10.5)
1 (0.6)
Nervous system disorders
Common

Dysgeusia
27 (7.8)
6 (3.5)
Eye disorders
Common

Lacrimation increased
25 (7.2)
2 (1.2)
Vision blurred
24 (7.0)
3 (1.7)
Dry eye
15 (4.3)
3 (1.7)
Respiratory, thoracic and mediastinal disorders
Common

Epistaxis
25 (7.2)
4 (2.3)
Gastrointestinal disorders
Very common

Nausea
124 (35.9)
2 (0.6)
53 (30.8)
1 (0.6)
Stomatitisg
104 (30.1)
3 (0.9)
24 (14.0)
Diarrhoea
94 (27.2)
35 (20.3)
2 (1.2)
Vomiting
75 (21.7)
2 (0.6)
28 (16.3)
1 (0.6)
Skin and subcutaneous tissue disorders
Very common

Alopecia
67 (19.4)
NA
11 (6.4)
NA
Rashh
63 (18.3)
3 (0.9)
10 (5.8)
Common

Dry skin
28 (8.1)
3 (1.7)
General disorders and administration site conditions
Very common

Fatigue
152 (44.1)
9 (2.6)
54 (31.4)
2 (1.2)
Pyrexia
47 (13.6)
1 (0.3)
10 (5.8)
Common

Asthenia
27 (7.8)
1 (0.3)
13 (7.6)
2 (1.2)
Investigations
Very common

AST increased
40 (11.6)
11 (3.2)
13 (7.6)
4 (2.3)
Common

ALT increased
30 (8.7)
7 (2.0)
10 (5.8)
1 (0.6)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; N/n=number of patients; NA=Not applicable a Preferred Terms (PTs) are listed according to MedDRA 17.1.
b Infections includes all PTs that are part of the System Organ Class Infections and infestations.
c Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.
d Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.
e Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.
f Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.

g Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.
h Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.

Description of selected adverse reactions
Neutropenia
In patients receiving fulvestrant in combination with palbociclib in the PALOMA3 study, neutropenia of any grade was reported in 290 (84.1%) patients, with Grade 3 neutropenia being reported in 200 (58.0%) patients, and Grade 4 neutropenia being reported in 40 (11.6%) patients. In the fulvestrant + placebo arm (n=172), neutropenia of any grade was reported in 6 (3.5%) patients. There were no reports of Grade 3 and 4 neutropenia in the fulvestrant + placebo arm.

In patients receiving fulvestrant in combination with palbociclib, the median time to first episode of any grade neutropenia was 15 days (range: 13-512 days) and the median duration of Grade ≥3 neutropenia was 16 days. Febrile neutropenia has been reported in 3 (0.9%) patients receiving fulvestrant in combination with palbociclib.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Faslodex should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).

Faslodex should be used with caution in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Due to the intramuscular route of administration, Faslodex should be used with caution if treating patients with bleeding diatheses, thrombocytopenia or those taking anticoagulant treatment.

Thromboembolic events are commonly observed in women with advanced breast cancer and have been observed in clinical studies with Faslodex (see section 4.8). This should be taken into consideration when prescribing Faslodex to patients at risk.

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 sections 4.2 and 4.8).

There are no long-term data on the effect of fulvestrant on bone. Due to the mechanism of action of fulvestrant, there is a potential risk of osteoporosis.

The efficacy and safety of Faslodex (either as monotherapy or in combination with palbociclib) have not been studied in patients with critical visceral disease.

When Faslodex is combined with palbociclib, please also refer to the Summary of Product Characteristics of palbociclib.

Interference with estradiol antibody assays
Due to the structural similarity of fulvestrant and estradiol, fulvestrant may interfere with antibody based-estradiol assays and may result in falsely increased levels of estradiol.

Ethanol
Faslodex contains 10% w/v ethanol (alcohol) as an excipient, i.e. up to 500 mg per injection, equivalent to 12 ml beer or 5 ml wine. This may be harmful for those suffering from alcoholism and should be taken into account in high risk groups such as patients with liver disease and epilepsy.

Benzyl alcohol
Faslodex contains benzyl alcohol as an excipient which may cause allergic reactions.

Paediatric population
Faslodex is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).

A clinical interaction study with midazolam (substrate of CYP3A4) demonstrated that fulvestrant does not inhibit CYP3A4. Clinical interaction studies with rifampicin (inducer of CYP3A4) and ketoconazole (inhibitor of CYP3A4) showed no clinically relevant change in fulvestrant clearance.
Dose adjustment is therefore not necessary in patients who are receiving fulvestrant and CYP3A4 inhibitors or inducers concomitantly.

Women of childbearing potential
Patients of childbearing potential should use effective contraception during treatment with Faslodex and for 2 years after the last dose.

Pregnancy
Faslodex is contraindicated in pregnancy (see section 4.3). Fulvestrant has been shown to cross the placenta after single intramuscular doses in rat and rabbit. Studies in animals have shown reproductive toxicity including an increased incidence of foetal abnormalities and deaths (see section 5.3). If pregnancy occurs while taking Faslodex, the patient must be informed of the potential hazard to the foetus and potential risk for loss of pregnancy.

Breast-feeding
Breast-feeding must be discontinued during treatment with Faslodex. Fulvestrant is excreted in milk in lactating rats. It is not known whether fulvestrant is excreted in human milk. Considering the potential for serious adverse reactions due to fulvestrant in breast-fed infants, use during lactation is contraindicated (see section 4.3).

Fertility
The effects of Faslodex on fertility in humans has not been studied.

Faslodex has no or negligible influence on the ability to drive or use machines. However, since asthenia has been reported very commonly with Faslodex, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery.

There are isolated reports of overdose with Faslodex in humans. If overdose occurs, symptomatic supportive treatment is recommended. Animal studies suggest that no effects other than those related directly or indirectly to antiestrogenic activity were evident with higher doses of fulvestrant (see section 5.3).

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Endocrine therapy, Antiestrogens, ATC code: L02BA03

Mechanism of action and pharmacodynamic effects
Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol.
Fulvestrant blocks the trophic actions of estrogens without any partial agonist (estrogen-like) activity.
The mechanism of action is associated with downregulation of estrogen receptor protein levels.
Clinical studies in postmenopausal women with primary breast cancer have shown that fulvestrant significantly downregulates ER protein in ER positive tumours compared with placebo. There was also a significant decrease in progesterone receptor expression consistent with a lack of intrinsic estrogen agonist effects. It has also been shown that fulvestrant 500 mg downregulates ER and the proliferation marker Ki67, to a greater degree than fulvestrant 250 mg in breast tumours in postmenopausal neoadjuvant setting.

Clinical efficacy and safety in advanced breast cancer

Monotherapy
A Phase 3 clinical study 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. The study included 423 patients whose disease had recurred or progressed during antiestrogen therapy (AE subgroup) and 313 patients whose disease had recurred or progressed during aromatase inhibitor therapy (AI subgroup). This study compared the efficacy and

safety of Faslodex 500 mg (n=362) with Faslodex 250 mg (n=374). Progression-free survival (PFS) was the primary endpoint; key secondary efficacy endpoints included objective response rate (ORR), clinical benefit rate (CBR) and overall survival (OS). Efficacy results for the CONFIRM study are summarized in Table 3.

Table 3
Summary of results of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the CONFIRM study

Variable
Type of estimate;
treatment comparison
Faslodex
500 mg
(N=362)
Faslodex
250 mg
(N=374)
Comparison between groups
(Faslodex 500 mg/Faslodex 250 mg)
Hazard ratio
95% CI p-value
PFS

K-M median in months;
hazard ratio

All Patients

Absorption
After administration of Faslodex long-acting intramuscular injection, fulvestrant is slowly absorbed and maximum plasma concentrations (Cmax) are reached after about 5 days. Administration of Faslodex 500 mg regimen achieves exposure levels at, or close to, steady state within the first month of dosing (mean [CV]: AUC 475 [33.4%] ng.days/ml, Cmax 25.1 [35.3%] ng/ml, Cmin 16.3 [25.9%] ng/ml, respectively). At steady state, fulvestrant plasma concentrations are maintained within a relatively narrow range with up to an approximately 3-fold difference between maximum and trough concentrations. After intramuscular administration, the exposure is approximately dose-proportional in the dose range 50 to 500 mg.

Distribution
Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution at steady state (Vdss) of approximately 3 to 5 l/kg suggests that distribution is largely extravascular.
Fulvestrant is highly (99%) bound to plasma proteins. Very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major binding components. No interaction studies were conducted on competitive protein binding. The role of sex hormone-binding globulin (SHBG) has not been determined.

Biotransformation
The metabolism of fulvestrant has not been fully evaluated, but involves combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids. Identified metabolites (includes 17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronide 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 CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant; however, non-P450 routes appear to be more predominant in vivo. In vitro data suggest that fulvestrant does not inhibit CYP450 isoenzymes.

Elimination