4.1. Therapeutic indications

Fulvestrant 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.

4.2. Posology and method of administration

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 fulvestrant 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 fulvestrant plus palbociclib, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.

Special population

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, fulvestrant 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 fulvestrant 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

Fulvestrant 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 fulvestrant at the dorsogluteal site due to the proximity of the underlying sciatic nerve.

For detailed instructions for administration, see section 6.6.

4.3. Contraindications

• 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).

4.4. Special warnings and precautions for use

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

Fulvestrant 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, fulvestrant 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 trials with fulvestrant (see section 4.8). This should be taken into consideration when prescribing fulvestrant to patients at risk.

Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with fulvestrant injection. Caution should be taken while administering fulvestrant 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 fulvestrant (either as monotherapy or in combination with palbociclib) have not been studied in patients with critical visceral disease.

When fulvestrant 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

This medicinal product contains 500 mg of alcohol (ethanol) in each injection which is equivalent to 100 mg/ ml (10% w/v). The amount in each injection of this medicine is equivalent to 13 ml beer or 5 ml wine.

A dose of 500 mg of this medicine (two syringes) administered to an adult women weighing 70 kg would result in exposure to 14.3 mg / kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 2.4 mg /100 ml (see Appendix I of report EMA/CHMP/43486/2018).

For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/ 100 ml.

Co-administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects.

Benzyl alcohol

This medicinal product contains benzyl alcohol as an excipient which may cause allergic reactions.

Paediatric population

Fulvestrant 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).

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

Fulvestrant 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 fulvestrant, 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 fulvestrant. 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 fulvestrant on fertility in humans has not been studied.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

Monotherapy

This section provides information based on all adverse reactions from clinical trials, post-marketing studies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequently reported adverse reactions are 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 fulvestrant 500 mg treatment group in pooled safety analyses of studies that compared fulvestrant 500 mg with fulvestrant 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 fulvestrant 500 mg with anastrozole 1 mg. Where frequencies differ between the pooled safety analysis and FALCON, the highest frequency is presented. The frequencies in the following table 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 fulvestrant 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 failurecf, 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

Asthenia, 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 fulvestrant cannot be assessed due to the underlying disease.

b The term injection site reactions does not include the terms injection site haemorrhage and 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 fulvestrant 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, anaemia, infections, 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

Fulvestrant + palbociclib

(N=345)

Fulvestrant + placebo

(N=172)

Frequency

Preferred Terma

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)

0

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)

0

0

Uncommon

Febrile neutropenia

3 (0.9)

3 (0.9)

0

0

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)

0

6 (3.5)

0

Eye disorders

Common

Lacrimation increased

25 (7.2)

0

2 (1.2)

0

Vision blurred

24 (7.0)

0

3 (1.7)

0

Dry eye

15 (4.3)

0

3 (1.7)

0

Respiratory, thoracic and mediastinal disorders

Common

Epistaxis

25 (7.2)

0

4 (2.3)

0

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)

0

Diarrhoea

94 (27.2)

0

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)

N/A

11 (6.4)

N/A

Rashh

63 (18.3)

3 (0.9)

10 (5.8)

0

Common

Dry skin

28 (8.1)

0

3 (1.7)

0

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)

0

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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