FULVESTRANT MYLAN 250mg / 5ml injection solution in pre-filled syringe medication leaflet

Fulvestrant Mylan 250 mg solution for injection in prefilled syringe

One pre-filled syringe contains 250 mg fulvestrant in 5 ml solution.

Excipients with known effect (per 5 ml)

Ethanol, anhydrous (500 mg)

Benzyl alcohol (500 mg)

Benzyl benzoate (750 mg)

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless to yellow, viscous solution.

Fulvestrant is indicated:

* as monotherapy for the treatment of estrogen receptor positive, locally advanced or metastaticbreast cancer in postmenopausal women:

- not previously treated with endocrine therapy, or

- with disease relapse on or after adjuvant antiestrogen therapy, or disease progression onantiestrogen therapy.

* in combination with palbociclib for the treatment of hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breastcancer in women who have received prior endocrine therapy (see section 5.1).

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

Adult females (including elderly)

The recommended dose is 500 mg at intervals of one month, with an additional 500 mg dose giventwo 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 itsduration, pre/perimenopausal women should be treated with LHRH agonists according to local clinicalpractice.

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 severerenal impairment (creatinine clearance <30 ml/min), and, therefore, caution is recommended in thesepatients (see section 4.4).

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 thesepatients. There are no data in patients with severe hepatic impairment (see sections pct. 4.3, pct. 4.4 and 5.2).

The safety and efficacy of fulvestrant in children from birth to 18 years of age have not beenestablished. Currently available data are described in sections 5.1 and 5.2, but no recommendation ona posology can be made.

Fulvestrant Mylan should be administered as two consecutive 5 ml injections by slow intramuscularinjection (1-2 minutes/injection), one in each buttock (gluteal area).

Caution should be taken if injecting Fulvestrant Mylan at the dorsogluteal site due to the proximity ofthe 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).

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

Fulvestrant should be used with caution in patients with severe renal impairment (creatinine clearanceless than 30 ml/min).

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

Thromboembolic events are commonly observed in women with advanced breast cancer and havebeen observed in clinical studies with fulvestrant (see section 4.8). This should be taken intoconsideration when prescribing fulvestrant to patients at risk.

Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathyhave been reported with fulvestrant injection. Caution should be taken while administering fulvestrantat the dorsogluteal injection site due to the proximity of the underlying sciatic nerve (see sections 4.2and 4.8).

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

The efficacy and safety of fulvestrant (either as monotherapy or in combination with palbociclib) havenot 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 antibodybased-estradiol assays and may result in falsely increased levels of estradiol.

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

Fulvestrant Mylan contains 10% w/v ethanol (alcohol)

This medicine contains 10% w/v ethanol (alcohol) as an excipient, i.e. 500 mg in each 5 ml. Theamount in one treatment dose (i.e. two syringes) of this medicine is equivalent to 25 ml beer or 10 mlwine. The small amount of alcohol in this medicine will not have any noticeable effects.

Fulvestrant Mylan contains benzyl alcohol

This medicinal product contains 500 mg benzyl alcohol in each 5 ml which is equivalent to 100 mg/ml(10% w/v). Benzyl alcohol may cause allergic reactions.

A clinical interaction study with midazolam (substrate of CYP3A4) demonstrated that fulvestrant doesnot inhibit CYP3A4. Clinical interaction studies with rifampicin (inducer of CYP3A4) andketoconazole (inhibitor of CYP3A4) showed no clinically relevant change in fulvestrant clearance.

Dose adjustment is therefore not necessary in patients who are receiving fulvestrant and CYP3A4inhibitors or inducers concomitantly.

Patients of child-bearing potential should use effective contraception during treatment with Fulvestrant

Mylan and for 2 years after the last dose.

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

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

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

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

This section provides information based on all adverse reactions from clinical studies, post-marketingstudies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequentlyreported adverse reactions were injection site reactions, asthenia, nausea, and increased hepaticenzymes (ALT, AST, ALP).

In table 1, the following frequency categories for adverse drug reactions (ADRs) were calculatedbased on the fulvestrant 500 mg treatment group in pooled safety analyses of studies that comparedfulvestrant 500 mg with fulvestrant 250 mg [CONFIRM (Study D6997C00002), FINDER 1 (Study

D6997C00004), FINDER 2 (Study D6997C00006), and NEWEST (Study D6997C00003) studies], orfrom FALCON (Study D699BC00001) alone that compared fulvestrant 500 mg with anastrozole1 mg. Where frequencies differ between the pooled safety analysis and FALCON, the highestfrequency 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 mgtreatment across the pooled dataset (including the studies mentioned above plus FALCON) was 6.5months.

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 groupingadverse reactions are reported in order of decreasing seriousness.

Table 1 Adverse Drug Reactions reported in patients treated with fulvestrantmonotherapy

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, hepatitis f,elevated gamma-GT f

Skin and subcutaneous tissue disorders Very common Rashe

Musculoskeletal and connective tissue Very common Joint and musculoskeletal painddisorders

Common Back paina

Reproductive system and breast disorders Common Vaginal haemorrhagee

Uncommon Vaginal moniliasis f, leukorrhea f

General disorders and administration site Very common Astheniaa, injection site reactionsbconditions Common Neuropathy peripherale, sciaticae

Uncommon Injection site haemorrhage f,injection site haematoma f,neuralgiac,fa Includes adverse drug reactions for which the exact contribution of fulvestrant cannot be assessed due tothe underlying disease.

b The term injection site reactions does not include the terms injection site haemorrhage, injection sitehaematoma, 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 pointestimate. 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.

The descriptions included below are based on the safety analysis set of 228 patients who received atleast 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 andmusculoskeletal 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 andmusculoskeletal pain within the first month of treatment, and 66.2% (43/65) of patients within the first3 months of treatment. No patients reported events that were CTCAE Grade ≥3 or that required a dosereduction, 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 datafrom 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer in therandomised PALOMA3 study (see section 5.1). The most common (≥20%) adverse reactions of anygrade reported in patients receiving fulvestrant in combination with palbociclib were neutropenia,leukopenia, infections, fatigue, nausea, anaemia, stomatitis, diarrhoea, thrombocytopenia andvomiting. 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 and4.8 months in the fulvestrant + placebo arm. Median duration of exposure to palbociclib in thefulvestrant + palbociclib arm was 10.8 months.

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

Fulvestrant + Palbociclib Fulvestrant + placebo

System Organ Class (N=345) (N=172)

Frequency

Preferred Terma All Grades Grade ≥ 3 All Grades Grade ≥ 3n (%) n (%) n (%) n (%)

Very common

Infectionsb 188 (54.5) 19 (5.5) 60 (34.9) 6 (3.5)

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

Very common

Decreased appetite 60 (17.4) 4 (1.2) 18 (10.5) 1 (0.6)

Common

Dysgeusia 27 (7.8) 0 6 (3.5) 0

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

Common

Epistaxis 25 (7.2) 0 4 (2.3) 0

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)

Very common

Alopecia 67 (19.4) NA 11 (6.4) NA

Rashh 63 (18.3) 3 (0.9) 10 (5.8) 0

Common

Dry skin 28 (8.1) 0 3 (1.7) 0

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)

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 applicablea 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.

In patients receiving fulvestrant in combination with palbociclib in the PALOMA3 study, neutropeniaof 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 noreports 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 ofany grade neutropenia was 15 days (range: 13-512 days) and the median duration of Grade ≥3neutropenia was 16 days. Febrile neutropenia has been reported in 3 (0.9%) patients receivingfulvestrant in combination with palbociclib.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Endocrine therapy, anti-estrogens, 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 down-regulation of estrogen receptor protein levels.

Clinical studies in postmenopausal women with primary breast cancer have shown that fulvestrantsignificantly down-regulates ER protein in ER positive tumours compared with placebo. There wasalso a significant decrease in progesterone receptor expression consistent with a lack of intrinsicestrogen agonist effects. It has also been shown that fulvestrant 500 mg downregulates ER and theproliferation marker Ki67, to a greater degree than fulvestrant 250 mg in breast tumours inpostmenopausal neoadjuvant setting.

Clinical efficacy and safety in advanced breast cancer

A Phase 3 clinical study was completed in 736 postmenopausal women with advanced breast cancerwho had disease recurrence on or after adjuvant endocrine therapy or progression following endocrinetherapy for advanced disease. The study included 423 patients whose disease had recurred orprogressed during anti-estrogen therapy (AE subgroup) and 313 patients whose disease had recurredor progressed during aromatase inhibitor therapy (AI subgroup). This study compared the efficacy andsafety of fulvestrant 500 mg (n=362) with fulvestrant 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 studyare summarized in Table 3.

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

Variable Type of Fulvestrant Fulvestrant Comparison between groupsestimate; 500 mg 250 mgtreatment (N=362) (N=374) (Fulvestrant 500 mg/ Fulvestrant 250 mg)comparison Hazard ratio 95% CI p-value

PFS K-M medianin months;hazard ratio

All Patients 6.5 5.5 0.80 0.68, 094 0.006

- AE subgroup (n=423) 8.6 5.8 0.76 0.62, 0.94 0.013

- AI subgroup (n=313) a 5.4 4.1 0.85 0.67, 1.08 0.195

OSb K-M medianin months;hazard ratio

All Patients 26.4 22.3 0.81 0.69, 0.96 0.016 c

- AE subgroup (n=423) 30.6 23.9 0.79 0.63, 0.99 0.038 c

- AI subgroup (n=313)a 24.1 20.8 0.86 0.67, 1.11 0.241 c

Variable Type of Fulvestrant Fulvestrant Comparison between groupsestimate 500 mg 250 mg (Fulvestrant 500 mg/Fulvestrant 250 mg)treatment (N=362) (N=374) Absolute 95% CIcomparison difference in %

ORRd % of patientswith ORabsolutedifference in %

All Patients 13.8 14.6 -0.8 -5.8, 6.3

- AE subgroup (n=296) 18.1 19.1 -1.0 -8.2, 9.3

- AI subgroup (n=205)a 7.3 8.3 -1.0 -5.5, 9.8

CBRe % of patientswith CB;absolutedifference in%

All Patients 45.6 39.6 6.0 -1.1, 13.3

- AE subgroup (n=423) 52.4 45.1 7.3 -2.2, 16.6

- AI subgroup (n=313)a 36.2 32.3 3.9 -6.1, 15.2a Fulvestrant is indicated in patients whose disease had recurred or progressed on an anti-estrogen therapy.

The results in the AI subgroup are inconclusive.

b OS is presented for the final survival analyses at 75 % maturity.c Nominal p-value with no adjustments made for multiplicity between the initial overall survival analyses at 50%maturity and the updated survival analyses at 75% maturity.d ORR was assessed in patients who were evaluable for response at baseline (i.e. those with measurable disease atbaseline: 240 patients in the fulvestrant 500 mg group and 261 patients in the fulvestrant 250 mg group).e Patients with a best objective response of complete response, partial response or stable disease ≥24 weeks.

PFS:Progression-free survival; ORR:Objective response rate; OR:Objective response; CBR:Clinical benefit rate;

CB:Clinical benefit; OS:Overall survival; K-M:Kaplan-Meier; CI:Confidence interval; AI:Aromatase inhibitor;

AE:Anti-estrogen.

A Phase 3, randomised, double-blind, double-dummy, multicentre study of fulvestrant 500 mg versusanastrozole 1 mg was conducted in postmenopausal women with ER-positive and/or PgR-positivelocally advanced or metastatic breast cancer who had not previously been treated with any hormonaltherapy. A total of 462 patients were randomised 1:1 sequentially to receive either fulvestrant 500 mgor anastrozole 1 mg. Randomisation was stratified by disease setting (locally advanced or metastatic),prior chemotherapy for advanced disease, and measurable disease.

The primary efficacy endpoint of the study was investigator assessed progression-free survival (PFS)evaluated according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumours). Key secondaryefficacy endpoints included overall survival (OS) and objective response rate (ORR).

Patients enrolled in this study had a median age of 63 years (range 36-90). The majority of patients(87.0%) had metastatic disease at baseline. Fifty-five percent (55.0%) of patients had visceralmetastasis at baseline. A total of 17.1% of patients received a prior chemotherapy regimen foradvanced disease; 84.2% of patients had measurable disease.

Consistent results were observed across the majority of pre-specified patient subgroups. For thesubgroup of patients with disease limited to non-visceral metastasis (n=208), the HR was 0.592 (95%

CI: 0.419, 0.837) for the fulvestrant arm compared to the anastrozole arm. For the subgroup of patientswith visceral metastasis (n=254), the HR was 0.993 (95% CI: 0.740, 1.331) for the fulvestrant armcompared to the anastrozole arm. The efficacy results of the FALCON study are presented in Table 4and Figure 1.

Table 4 Summary of results of the primary efficacy endpoint (PFS) and key secondaryefficacy endpoints (Investigator Assessment, Intent-To-Treat Population) ─

FALCON study

Fulvestrant Anastrozole500 mg 1 mg(N=230) (N=232)

Progression-Free Survival

Number of PFS Events (%) 143 (62.2%) 166 (71.6%)

PFS Hazard Ratio (95% CI) and p- HR 0.797 (0.637 - 0.999)value p = 0.0486

PFS Median [months (95% CI)] 16.6 (13.8, 21.0) 13.8 (12.0, 16.6)

Number of OS Events* 67 (29.1%) 75 (32.3%)

OS Hazard Ratio (95% CI) and HR 0.875 (0.629 - 1.217)p-value p = 0.4277

ORR** 89 (46.1%) 88 (44.9%)

ORR Odds Ratio (95% CI) and OR 1.074 (0.716 - 1.614)p-value p = 0.7290

Median DoR (months) 20.0 13.2

CBR 180 (78.3%) 172 (74.1%)

CBR Odds Ratio (95% CI) and OR 1.253 (0.815 - 1.932)p-value p = 0.3045

*(31% maturity)-not final OS analysis

**for patients with measurable disease

Figure 1 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment,

Intent-To-Treat Population) ─ FALCON Study

Time from randomisation (months)

Treatment ——— Fulvestrant 500 mg (N=230) - - - - - - Anastrozole 1 mg (N=232)

Number of patients at risk

FUL500 230 187 171 150 124 110 96 81 63 44 24 11 2 0

ANAS1 232 194 162 139 120 102 84 60 45 31 22 10 0 0

Two phase-3 clinical studies were completed in a total of 851 postmenopausal women with advancedbreast cancer who had disease recurrence on or after adjuvant endocrine therapy or progressionfollowing endocrine therapy for advanced disease. Seventy seven percent (77%) of the studypopulation had estrogen receptor positive breast cancer. These studies compared the safety andefficacy of monthly administration of fulvestrant 250 mg versus the daily administration of 1 mganastrozole (aromatase inhibitor). Overall, fulvestrant at the 250 mg monthly dose was at least aseffective as anastrozole in terms of progression free survival, objective response, and time to death.

There were no statistically significant differences in any of these endpoints between the two treatmentgroups. Progression-free survival was the primary endpoint. Combined analysis of both studiesshowed that 83% of patients who received fulvestrant progressed, compared with 85% of patients whoreceived anastrozole. Combined analysis of both studies showed the hazard ratio of fulvestrant 250 mgto anastrozole for progression-free survival was0.95 (95% CI 0.82 to 1.10). The objective response rate for Fulvestrant 250 mg was 19.2% comparedwith 16.5% for anastrozole. The median time to death was 27.4 months for patients treated withfulvestrant and 27.6 months for patients treated with anastrozole. The hazard ratio of fulvestrant250 mg to anastrozole for time to death was 1.01 (95% CI 0.86 to 1.19).

Combination therapy with palbociclib

A Phase 3, international, randomised, double-blind, parallel-group, multicentre study of fulvestrant500 mg plus palbociclib 125 mg versus fulvestrant 500 mg plus placebo was conducted in women with

HR-positive, HER2-negative locally advanced breast cancer not amenable to resection or radiationtherapy with curative intent or metastatic breast cancer, regardless of their menopausal status, whosedisease progressed after prior endocrine therapy in the (neo) adjuvant or metastatic setting.

Probability of PFS

A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 months fromcompletion of adjuvant endocrine therapy on or within 1 month from prior endocrine therapy foradvanced disease, were randomised 2:1 to fulvestrant plus palbociclib or fulvestrant plus placebo andstratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry(pre/peri- versus postmenopausal), and presence of visceral metastases. Pre/perimenopausal womenreceived the LHRH agonist goserelin. Patients with advanced/metastatic, symptomatic, visceralspread, that were at risk of life-threatening complications in the short term (including patients withmassive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over50% liver involvement), were not eligible for enrolment into the study.

Patients continued to receive assigned treatment until objective disease progression, symptomaticdeterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

Crossover between treatment arms was not allowed.

Patients were well matched for baseline demographics and prognostic characteristics between thefulvestrant plus palbociclib arm and the fulvestrant plus placebo arm. The median age of patientsenrolled in this study was 57 years (range 29, 88). In each treatment arm the majority of patients were

White, had documented sensitivity to prior hormonal therapy, and were postmenopausal.

Approximately 20% of patients were pre/perimenopausal. All patients had received prior systemictherapy and most patients in each treatment arm had received a previous chemotherapy regimen fortheir primary diagnosis. More than half (62%) had an ECOG PS of 0, 60% had visceral metastases,and 60% had received more than 1 prior hormonal regimen for their primary diagnosis.

The primary endpoint of the study was investigator-assessed PFS evaluated according to RECIST 1.1.

Supportive PFS analyses were based on an Independent Central Radiology Review. Secondaryendpoints included OR, CBR, overall survival (OS), safety, and time-to-deterioration (TTD) in painendpoint.

The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysisconducted on 82% of the planned PFS events; the results crossed the pre-specified Haybittle-Petoefficacy boundary (α=0.00135), demonstrating a statistically significant prolongation in PFS and aclinically meaningful treatment effect. A more mature update of efficacy data is reported in Table 5.

After a median follow-up time of 45 months, the final OS analysis was performed based on 310 events(60% of randomised patients). A 6.9-month difference in median OS in the palbociclib plus fulvestrantarm compared with the placebo plus fulvestrant arm was observed; this result was not statisticallysignificant at the prespecified significance level of 0.0235 (1-sided). In the placebo plus fulvestrantarm, 15.5% of randomised patients received palbociclib and other CDK inhibitors as post-progressionsubsequent treatments.

The results from the investigator-assessed PFS and final OS data from PALOMA3 study are presentedin Table 5. The relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively.

Table 5 Efficacy results - PALOMA3 study (Investigator assessment, intent-to-treatpopulation)

Updated Analysis(23 October 2015 cut-off)

Fulvestrant plus palbociclib Fulvestrant plus placebo(N=347) (N=174)

Progression-Free Survival

Median [months (95% CI)] 11.2 (9.5, 12.9) 4.6 (3.5, 5.6)

Hazard ratio (95% CI) 0.497 (0.398, 0.620), p <0.000001and p-value

Secondary end points

OR [% (95% CI)] 26.2 (21.7, 31.2) 13.8 (9.0, 19.8)

OR (measurable disease) [% 33.7 (28.1, 39.7) 17.4 (11.5, 24.8)(95% CI)]

CBR [% (95% CI)] 68.0 (62.8, 72.9) 39.7 (32.3, 47.3)

Final overall survival (OS)(13 April 2018 cutoff)

Number of events (%) 201 (57.9) 109 (62.6)

Median [months (95% CI)] 34.9 (28.8, 40.0) 28.0 (23.6, 34.6)

Hazard ratio (95% CI) and p- 0.814 (0.644, 1.029)value† p=0.0429†*

CBR=clinical benefit response; CI=confidence interval; N=number of patients; OR=objective response

Secondary endpoint results are based on confirmed and unconfirmed responses according to RECIST 1.1.

* Not statistically significant.† 1-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to priorendocrine therapy per randomisation.

Figure 2 Kaplan-Meier plot of progression-free survival (investigator assessment, intent-to-treat population) - PALOMA3 study (23 October 2015 cutoff)100 palbociclib+fulvestrant90 placebo+fulvestrant0 2 4 6 8 10 12 14 16 18 20 22

Time (Month)

Number of patients at risk

PAL+FUL 347 276 245 215 189 168 137 69 38 12 2 1

PCB+FUL 174 112 83 62 51 43 29 15 11 4 1

FUL=fulvestrant; PAL=palbociclib; PCB=placebo.

A reduction in the risk of disease progression or death in the fulvestrant plus palbociclib arm wasobserved in all individual patient subgroups defined by stratification factors and baselinecharacteristics. This was evident for pre/perimenopausal women (HR of 0.46 [95% CI: 0.28, 0.75])and postmenopausal women (HR of 0.52 [95% CI: 0.40, 0.66]) and patients with visceral site ofmetastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless of lines of prior therapy in themetastatic setting, whether 0 (HR of 0.59 [95% CI: 0.37, 0.93]), 1 (HR of 0.46 [95% CI: 0.32, 0.64]),2 (HR of 0.48 [95% CI: 0.30, 0.76]), or ≥3 lines (HR of 0.59 [95% CI: 0.28, 1.22]).

Progression-Free Survival Probability (%)

Figure 3. Kaplan-Meier plot of overall survival (intent-to-treat population) - PALOMA3 study(13 April 2018 cutoff)100 palbociclib+fulvestrantplacebo+fulvestrant0 6 12 18 24 30 36 42 48 54

Time (Month)

Number of patients at risk

PAL+FUL 347 321 286 247 209 165 148 126 17

PCB+FUL 174 155 135 115 86 68 57 43 7

FUL=fulvestrant; PAL=palbociclib; PCB=placebo.

Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or withoutvisceral disease are displayed in Table 6.

Table 6 Efficacy results in visceral and non-visceral disease from PALOMA3 study (intent-to-treat population)

Visceral Disease Non-visceral Disease

Fulvestrant plus Fulvestrant plus Fulvestrant plus Fulvestrant pluspalbociclib placebo palbociclib placebo(N=206) (N=105) (N=141) (N=69)

OR [% (95% CI)] 35.0 13.3 13.5 14.5(28.5, 41.9) (7.5, 21.4) (8.3, 20.2) (7.2, 25.0)

TTR*, Median 3.8 5.4 3.7 3.6[months (range)] (3.5, 16.7) (3.5, 16.7) (1.9, 13.7) (3.4, 3.7)

*Response results based on confirmed and unconfirmed responses.

N=number of patients; CI=confidence interval; OR= objective response; TTR=time to first tumour response.

Patient-reported symptoms were assessed using the European Organization for Research and

Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and its Breast Cancer Module(EORTC QLQ-BR23). A total of 335 patients in the fulvestrant plus palbociclib arm and 166 patientsin the fulvestrant plus placebo arm completed the questionnaire at baseline and at least 1 post-baselinevisit.

Time-to-Deterioration was pre-specified as time between baseline and first occurrence of ≥10 pointsincrease from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in asymptom benefit by significantly delaying Time-to-Deterioration in pain symptom compared withfulvestrant plus placebo (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85];p<0.001).

Effects on the postmenopausal endometrium

Preclinical data do not suggest a stimulatory effect of fulvestrant on the postmenopausal endometrium(see section 5.3). A 2-week study in healthy postmenopausal volunteers treated with 20 μg per day

Overall Survival Probability (%)ethinylestradiol showed that pre-treatment with fulvestrant 250 mg resulted in significantly reducedstimulation of the postmenopausal endometrium, compared to pre-treatment with placebo, as judgedby ultrasound measurement of endometrium thickness.

Neoadjuvant treatment for up to 16 weeks in breast cancer patients treated with either fulvestrant500 mg or fulvestrant 250 mg did not result in clinically significant changes in endometrial thickness,indicating a lack of agonist effect. There is no evidence of adverse endometrial effects in the breastcancer patients studied. No data are available regarding endometrial morphology.

In two short-term studies (1 and 12 weeks) in premenopausal patients with benign gynaecologicdisease, no significant differences in endometrial thickness were observed by ultrasound measurementbetween fulvestrant and placebo groups.

Effects on bone

There are no long-term data on the effect of fulvestrant on bone. Neoadjuvant treatment for up to 16weeks in breast cancer patients with either fulvestrant 500 mg or fulvestrant 250 mg did not result inclinically significant changes in serum bone-turnover markers.

Fulvestrant is not indicated for use in children. The European Medicines Agency has waived theobligation to submit the results of studies with fulvestrant in all subsets of the paediatric population inbreast cancer (see section 4.2 for information on paediatric use).

An open-label phase 2 study investigated the safety, efficacy and pharmacokinetics of fulvestrant in30 girls aged 1 to 8 years with Progressive Precocious Puberty associated with McCune Albright

Syndrome (MAS). The paediatric patients received 4 mg/kg monthly intramuscular dose offulvestrant. This 12-month study investigated a range of MAS endpoints and showed a reduction in thefrequency of vaginal bleeding and a reduction in the rate of bone age advancement. The steady-statetrough concentrations of fulvestrant in children in this study were consistent with that in adults (seesection 5.2). There were no new safety concerns arising from this small study, but 5-year data are yetnot available.

After administration of fulvestrant long-acting intramuscular injection, fulvestrant is slowly absorbedand maximum plasma concentrations (Cmax) are reached after about 5 days. Administration offulvestrant 500 mg regimen achieves exposure levels at, or close to, steady state within the first monthof dosing (mean [CV]: AUC 475 [33.4%] ng.days/ml, Cmax 25.1 [35.3%] ng/ml, Cmin16.3 [25.9%] ng/ml, respectively). At steady state, fulvestrant plasma concentrations are maintainedwithin a relatively narrow range with up to an approximately 3-fold difference between maximum andtrough concentrations. After intramuscular administration, the exposure is approximatelydose-proportional in the dose range 50 to 500 mg.

Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution atsteady 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), lowdensity lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major bindingcomponents. No interaction studies were conducted on competitive protein binding. The role of sexhormone-binding globulin (SHBG) has not been determined.

The metabolism of fulvestrant has not been fully evaluated, but involves combinations of a number ofpossible 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 orexhibit similar activity to fulvestrant in anti-estrogen models. Studies using human liver preparationsand recombinant human enzymes indicate that CYP3A4 is the only P450 isoenzyme involved in theoxidation of fulvestrant; however, non-P450 routes appear to be more predominant in vivo. In vitrodata suggest that fulvestrant does not inhibit CYP450 isoenzymes.

Fulvestrant is eliminated mainly in metabolised form. The major route of excretion is via the faeces,with less than 1% being excreted in the urine. Fulvestrant has a high clearance, 11±1.7 ml/min/kg,suggesting a high hepatic extraction ratio. The terminal half-life (t1/2) after intramuscularadministration is governed by the absorption rate and was estimated to be 50 days.

In a population pharmacokinetic analysis of data from phase 3 studies, no difference in fulvestrant’spharmacokinetic profile was detected with regard to age (range 33 to 89 years), weight (40-127 kg) orrace.

Mild to moderate impairment of renal function did not influence the pharmacokinetics of fulvestrant toany clinically relevant extent.

The pharmacokinetics of fulvestrant has been evaluated in a single-dose clinical study conducted inwomen with mild to moderate hepatic impairment (Child-Pugh class A and B). A high dose of ashorter duration intramuscular injection formulation was used. There was up to about 2.5-fold increasein AUC in women with hepatic impairment compared to healthy subjects. In patients administeredfulvestrant, an increase in exposure of this magnitude is expected to be well tolerated. Women withsevere hepatic impairment (Child-Pugh class C) were not evaluated.

The pharmacokinetics of fulvestrant has been evaluated in a clinical study conducted in 30 girls with

Progressive Precocious Puberty associated with McCune Albright Syndrome (see section 5.1). Thepaediatric patients were aged 1 to 8 years and received 4 mg/kg monthly intramuscular dose offulvestrant. The geometric mean (standard deviation) steady state trough concentration (Cmin,ss) and

AUCss was 4.2 (0.9) ng/mL and 3680 (1020) ng*hr/mL, respectively. Although the data collectedwere limited, the steady-state trough concentrations of fulvestrant in children appear to be consistentwith those in adults.

The acute toxicity of fulvestrant is low.

Fulvestrant solution for injection and other formulations of fulvestrant were well tolerated in animalspecies used in multiple dose studies. Local reactions, including myositis and granulomata at theinjection site were attributed to the vehicle but the severity of myositis in rabbits increased withfulvestrant, compared to the saline control. In toxicity studies with multiple intramuscular doses offulvestrant in rats and dogs, the antiestrogenic activity of fulvestrant was responsible for most of theeffects seen, particularly in the female reproductive system, but also in other organs sensitive tohormones in both sexes. Arteritis involving a range of different tissues was seen in some dogs afterchronic (12 months) dosing.

In dog studies following oral and intravenous administration, effects on the cardiovascular system(slight elevations of the S-T segment of the ECG [oral], and sinus arrest in one dog [intravenous])were seen. These occurred at exposure levels higher than in patients (Cmax >15 times) and are likely tobe of limited significance for human safety at the clinical dose.

Fulvestrant showed no genotoxic potential.

Fulvestrant showed effects upon reproduction and embryo/foetal development consistent with itsanti-estrogenic activity, at doses similar to the clinical dose. In rats, a reversible reduction in femalefertility and embryonic survival, dystocia and an increased incidence of foetal abnormalitiesincluding tarsal flexure were observed. Rabbits given fulvestrant failed to maintain pregnancy.

Increases in placental weight and post-implantation loss of foetuses were seen. There was anincreased incidence of foetal variations in rabbits (backwards displacement of the pelvic girdle and27 pre-sacral vertebrae).

A two-year oncogenicity study in rats (intramuscular administration of fulvestrant) showed increasedincidence of ovarian benign granulosa cell tumours in female rats at the high dose, 10 mg/rat/15 daysand an increased incidence of testicular Leydig cell tumours in males. In a two-year mouseoncogenicity study (daily oral administration) there was an increased incidence of ovarian sex cordstromal tumours (both benign and malignant) at doses of 150 and 500 mg/kg/day. At the no-effectlevel for these findings, systemic exposure levels (AUC) were, in rats, approximately 1.5-fold theexpected human exposure levels in females and 0.8-fold in males, and in mice, approximately 0.8-fold the expected human exposure levels in both males and females. Induction of such tumours isconsistent with pharmacology-related endocrine feedback alterations in gonadotropin levels causedby anti-estrogens in cycling animals. Therefore these findings are not considered to be relevant to theuse of fulvestrant in postmenopausal women with advanced breast cancer.

Environmental risk assessment studies have shown that fulvestrant may have potential to causeadverse effects to the aquatic environment (see section 6.6).

Benzyl benzoate

Benzyl alcohol

Ethanol, anhydrous

Castor oil, refined

In the absence of compatibility studies, this medicinal product must not be mixed with othermedicinal products.

2 years

Store and transport refrigerated (2°C - 8°C).

Temperature excursions outside 2°C - 8°C should be limited and not exceeding a 28 day periodwhere the average storage temperature for the product is below 25°C (but above 2°C - 8°C). Aftertemperature excursions, the product should be returned immediately to the recommended storageconditions (store and transport in a refrigerator 2°C - 8°C).

Temperature excursions have a cumulative effect on the product quality and the 28 day time periodmust not be exceeded over the duration of the shelf life of Fulvestrant Mylan (see section 6.3).

Exposure to temperatures below 2°C will not damage the product providing it is not storedbelow -20°C.

Store the pre-filled syringe in the original package in order to protect from light.

The pre-filled syringe presentation consists of:

One clear type 1 glass pre-filled syringe with polypropylene plunger rod, fitted with a tamper-evidentclosure, containing 5 ml Fulvestrant Mylan solution for injection.

A safety needle (BD SafetyGlide) for connection to the barrel is also provided.

Or

Two clear type 1 glass pre-filled syringes with polypropylene plunger rod, fitted with a tamper-evident closure,each containing 5 ml Fulvestrant Mylan solution for injection. Safety needles (BD SafetyGlide) for connectionto each barrel are also provided.

Or

Four clear type 1 glass pre-filled syringes with polypropylene plunger rod, fitted with a tamper-evident closure,each containing 5 ml Fulvestrant Mylan solution for injection. Safety needles (BD SafetyGlide) for connectionto each barrel are also provided.

Or

Six clear type 1 glass pre-filled syringes with polypropylene plunger rod, fitted with a tamper-evident closure,each containing 5 ml Fulvestrant Mylan solution for injection. Safety needles (BD SafetyGlide) for connectionto each barrel are also provided.

Not all pack sizes may be marketed.

Instructions for administration

Administer the injection according to the local guidelines for performing large volume intramuscularinjections.

NOTE: Due to the proximity of the underlying sciatic nerve, caution should be taken if administering

Fulvestrant Mylan at the dorsogluteal injection site (see section 4.4).

Warning - Do not autoclave safety needle (BD SafetyGlide Shielding Hypodermic Needle) before use.

Hands must remain behind the needle at all times during use and disposal.

For each of the two syringes:

* Remove glass syringe barrel from tray and check that it is Figure 1not damaged.

* Peel open the safety needle (SafetyGlide) outer packaging.

* Parenteral solutions must be inspected visually forparticulate matter and discolouration prior toadministration.

* Hold the syringe upright on the ribbed part (C). With theother hand, take hold of the cap (A) and carefully tilt backand forth until the cap disconnects and can be pulled off,do not twist (see Figure 1).

Figure 2

* Remove the cap (A) in a straight upward direction. Tomaintain sterility do not touch the syringe tip (B) (see

Figure 2).

* Attach the safety needle to the Luer-Lok and twist until Figure 3firmly seated (see Figure 3).

* Check that the needle is locked to the Luer connectorbefore moving out of the vertical plane.

* Pull shield straight off needle to avoid damaging needlepoint.

* Transport filled syringe to point of administration.

* Remove needle sheath.

* Expel excess gas from the syringe.

Figure 4

* Administer intramuscularly slowly (1-2 minutes/injection)into the buttock (gluteal area). For user convenience, the needlebevel- up position is oriented to the lever arm (see Figure 4).

* After injection, immediately apply a single-finger stroke to Figure 5the activation assisted lever arm to activate the shieldingmechanism (see Figure 5).

NOTE: Activate away from self and others. Listen for clickand visually confirm needle tip is fully covered.

Pre-filled syringes are for single use only.

This medicine may pose a risk to the aquatic environment. Any unused medicinal product or wastematerial should be disposed of in accordance with local requirements (see section 5.3).

MYLAN S.A.S.117 Allée des Parcs69800 SAINT-PRIEST

FRANCE

EU/1/17/1253/001

EU/1/17/1253/002

EU/1/17/1253/003

EU/1/17/1253/004

Date of first authorisation: 08 january 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.