Fulvestrant Mylan

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Fulvestrant Mylan 250 mg solution for injection in prefilled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
 
Clear, colourless to yellow, viscous solution. 
 
 
4. CLINICAL PARTICULARS 
 
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. 
 



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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, 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 Mylan 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 Mylan 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 studies 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. 
 



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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. 
 
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). 
 
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. The 
amount in one treatment dose (i.e. two syringes) of this medicine is equivalent to 25 ml beer or 10 ml 
wine. 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. 
 
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 child-bearing potential should use effective contraception during treatment with Fulvestrant 
Mylan 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. 



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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 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 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 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 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 



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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 
disorders 

Very common  Joint and musculoskeletal paind 

 Common Back paina 
Reproductive system and breast disorders Common Vaginal haemorrhagee 
 Uncommon Vaginal moniliasis f, leukorrhea f 
General disorders and administration site 
conditions 

Very common Astheniaa, injection site reactionsb 
Common Neuropathy peripherale, sciaticae 
Uncommon Injection site haemorrhage f, 

injection site haematoma f, 
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, 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, and thrombocytopenia. 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. 



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Median duration of exposure to fulvestrant was 11.2 months in the fulvestrant + palbociclib arm and 
4.9 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 

Fulvestrant + Palbociclib 
(N=345) 

Fulvestrant + placebo 
(N=172) 

All Grades 
n (%) 

Grade ≥ 3 
n (%) 

All Grades 
n (%) 

Grade ≥ 3 
n (%) 

Infections and infestations 
Very common     
   Infectionsb 163 (47.2) 11 (3.2) 54 (31.4) 5 (2.9) 
Blood and lymphatic system disorders 
Very common     
   Neutropeniac 287 (83.2) 228 (66.1) 7 (4.1) 1 (0.6) 
   Leukopeniad 183 (53.0) 105 (30.4) 9 (5.2) 2 (1.2) 
   Anaemiae 102 (29.6) 12 (3.5) 22 (12.8) 3 (1.7) 
   Thrombocytopeniaf 78 (22.6) 8 (2.3) 0 (0.0) 0 
Uncommon     
   Febrile neutropenia 3 (0.9) 3 (0.9) 1 (0.6) 1 (0.6) 
Metabolism and nutrition disorders 
Very common     
   Decreased appetite 55 (15.9) 3 (0.9) 14 (8.1) 1 (0.6) 
Nervous system disorders 
Common     
   Dysgeusia 23 (6.7) 0 5 (2.9) 0 
Eye disorders 
Common     
   Lacrimation increased 22 (6.4) 0 2 (1.2) 0 
   Vision blurred 20 (5.8) 0 3 (1.7) 0 
   Dry eye 13 (3.8) 0 3 (1.7) 0 
Respiratory, thoracic and mediastinal disorders 
Common     
   Epistaxis 23 (6.7) 0 3 (1.7) 0 
Gastrointestinal disorders 
Very common     
   Nausea 117 (33.9) 0 48 (27.9) 1 (0.6) 
   Stomatitisg 97 (28.1) 2 (0.6) 22 (12.8) 0 
   Diarrhoea 81 (23.5) 0 33 (19.2) 2 (1.2) 
   Vomiting 65 (18.8) 2 (0.6) 26 (15.1) 1 (0.6) 
Skin and subcutaneous tissue disorders 
Very common     
   Alopecia 62 (18.0) 0 11 (6.4) 0 
   Rashh 58 (16.8) 2 (0.6) 11 (6.4) 0 
Common     
   Dry skin 21 (6.1) 0 2 (1.2) 0 



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General disorders and administration site conditions 
Very common     
   Fatigue 142 (41.2) 8 (2.3) 50 (29.1) 2 (1.2) 
   Pyrexia 44 (12.8) 1 (0.3) 9 (5.2) 0 
Common     
   Asthenia 26 (7.5) 0 9 (5.2) 1 (0.6) 
Investigations 
Common     
   AST increased 26 (7.5) 10 (2.9) 9 (5.2) 3 (1.7) 
   ALT increased 20 (5.8) 6 (1.7) 6 (3.5) 0 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; N/n=number of patients 
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 287 (83.2%) patients, with Grade 3 neutropenia being reported in 191 
(55.4%) patients, and Grade 4 neutropenia being reported in 37 (10.7%) patients. In the fulvestrant + 
placebo arm (n=172), neutropenia of any grade was reported in 7 (4.1%) patients, with Grade 3 
neutropenia reported in 1 (0.6%) patient. There were no reports of Grade 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: 13-317) and the median duration of Grade ≥3 neutropenia 
was 7 days. Febrile neutropenia has been reported in 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. 
 
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).  
 

 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Endocrine therapy, anti-estrogens, ATC code: L02BA03 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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 fulvestrant 
significantly down-regulates 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 anti-estrogen 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 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 study 
are summarized in Table 3. 
 



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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 

Fulvestrant   
500 mg  
(N=362) 

Fulvestrant  
250 mg  
(N=374) 

Comparison between groups 

(Fulvestrant 500 mg/ Fulvestrant 250 mg) 

Hazard ratio 95% CI p-value 

PFS K-M median 
in 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 median  

in 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 
estimate 

Fulvestrant 
500 mg 

Fulvestrant 
250 mg 

Comparison between groups  
(Fulvestrant 500 mg/Fulvestrant 250 mg) 

 treatment 
comparison 

(N=362) (N=374) Absolute  
difference in % 

95% CI 

ORRd % of patients 
with OR 
absolute 
difference 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 patients 
with CB; 
absolute 
difference 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, 15.2 

a 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 at 

baseline: 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 versus 
anastrozole 1 mg was conducted in postmenopausal women with ER-positive and/or PgR-positive 
locally advanced or metastatic breast cancer who had not previously been treated with any hormonal 
therapy. A total of 462 patients were randomised 1:1 sequentially to receive either fulvestrant 500 mg 
or anastrozole 1 mg. 
 
Randomisation was stratified by disease setting (locally advanced or metastatic), prior chemotherapy 
for advanced disease, and measurable disease. 
 



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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 secondary 
efficacy 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 visceral 
metastasis at baseline. A total of 17.1% of patients received a prior chemotherapy regimen for 
advanced disease; 84.2% of patients had measurable disease. 
 
Consistent results were observed across the majority of pre-specified patient subgroups. For the 
subgroup 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 patients 
with visceral metastasis (n=254), the HR was 0.993 (95% CI: 0.740, 1.331) for the fulvestrant arm 
compared to the anastrozole arm. The efficacy results of the FALCON study are presented in Table 4 
and Figure 1. 
 
Table 4 Summary of results of the primary efficacy endpoint (PFS) and key secondary 

efficacy endpoints (Investigator Assessment, Intent-To-Treat Population) ─ 
FALCON study 

 Fulvestrant 
500 mg 
(N=230) 

Anastrozole 
1 mg 

(N=232) 
Progression-Free Survival 
Number of PFS Events (%) 143 (62.2%) 166 (71.6%) 
PFS Hazard Ratio (95% CI) and p-
value 

HR 0.797 (0.637 - 0.999) 
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 
p-value 

HR 0.875 (0.629 – 1.217) 
p = 0.4277 

ORR** 89 (46.1%) 88 (44.9%) 
ORR Odds Ratio (95% CI) and 
p-value 

OR 1.074 (0.716 – 1.614) 
p = 0.7290 

Median DoR (months) 20.0 13.2 
CBR 180 (78.3%) 172 (74.1%) 
CBR Odds Ratio (95% CI) and 
p-value 

OR 1.253 (0.815 – 1.932) 
p = 0.3045 

*(31% maturity)-not final OS analysis 
**for patients with measurable disease 
 



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Figure 1  Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, 
Intent-To-Treat Population) ─ FALCON Study 

 

 

 

 
Two phase-3 clinical studies were completed in a total of 851 postmenopausal women with advanced 
breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression 
following endocrine therapy for advanced disease. Seventy seven percent (77%) of the study 
population had estrogen receptor positive breast cancer. These studies compared the safety and 
efficacy of monthly administration of fulvestrant 250 mg versus the daily administration of 1 mg 
anastrozole (aromatase inhibitor). Overall, fulvestrant at the 250 mg monthly dose was at least as 
effective 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 treatment 
groups. Progression-free survival was the primary endpoint. Combined analysis of both studies 
showed that 83% of patients who received fulvestrant progressed, compared with 85% of patients who 
received anastrozole. Combined analysis of both studies showed the hazard ratio of fulvestrant 250 mg 
to anastrozole for progression-free survival was  
0.95 (95% CI 0.82 to 1.10). The objective response rate for Fulvestrant 250 mg was 19.2% compared 
with 16.5% for anastrozole. The median time to death was 27.4 months for patients treated with 
fulvestrant and 27.6 months for patients treated with anastrozole. The hazard ratio of fulvestrant 
250 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 fulvestrant 
500 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 radiation 
therapy with curative intent or metastatic breast cancer, regardless of their menopausal status, whose 
disease progressed after prior endocrine therapy in the (neo) adjuvant or metastatic setting. 
 

Time from randomisation (months) 

Pr
ob

ab
ili

ty
 o

f P
FS

 

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 
 

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



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A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 months from 
completion of adjuvant endocrine therapy on or within 1 month from prior endocrine therapy for 
advanced disease, were randomised 2:1 to fulvestrant plus palbociclib or fulvestrant 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. Pre/perimenopausal women 
received the LHRH agonist goserelin. Patients with advanced/metastatic, symptomatic, visceral 
spread, that were at risk of life-threatening complications in the short term (including patients with 
massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 
50% liver involvement), were not eligible for enrolment into the study. 
 
Patients continued to receive assigned treatment until objective disease progression, symptomatic 
deterioration, 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 the 
fulvestrant plus palbociclib arm and the fulvestrant plus placebo arm. The median age of patients 
enrolled 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 systemic 
therapy and most patients in each treatment arm had received a previous chemotherapy regimen for 
their 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. Secondary 
endpoints included OR, CBR, OS, safety, and time-to-deterioration (TTD) in pain endpoint. 
 
The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysis 
conducted on 82% of the planned PFS events; the results crossed the pre-specified Haybittle-Peto 
efficacy boundary (α=0.00135), demonstrating a statistically significant prolongation in PFS and a 
clinically meaningful treatment effect. A more mature update of efficacy data is reported in Table 5. 
 
Table 5  Efficacy results – PALOMA3 study (Investigator assessment, intent-to-treat 

population) 
 
 Updated Analysis 

(23 October 2015 cut-off) 
 Fulvestrant plus palbociclib 

(N=347) 
Fulvestrant plus placebo 

(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)  
and p-value 

0.497 (0.398, 0.620), p <0.000001 

Secondary end points* 
OR [% (95% CI)] 26.2 (21.7, 31.2) 13.8 (9.0, 19.8) 
OR (measurable disease) [% 
(95% CI)] 

33.7 (28.1, 39.7) 17.4 (11.5, 24.8) 

CBR [% (95% CI)] 68.0 (62.8, 72.9) 39.7 (32.3, 47.3) 
*Response endpoints based on confirmed and unconfirmed responses.  
N=number of patients; CI=confidence interval; OR=objective response; CBR=clinical benefit response 



14 

Figure 2  Kaplan-Meier plot of progression-free survival (investigator assessment, intent-
to-treat population) – PALOMA3 study 

 

0 2 4 6 8 10 12 14 16 18 20 22

Time (Month)

0

10

20

30

40

50

60

70

80

90

100

P
ro

g
re

s
s
io

n
-F

re
e
 S

u
rv

iv
a
l 
P

ro
b

a
b

il
it

y
 (

%
)

palbociclib+fulvestrant

placebo+fulvestrant

347 276 245 215 189 168 137 69 38 12 2 1PAL+FUL
174 112 83 62 51 43 29 15 11 4 1PCB+FUL

Number of patients at risk

 
FUL=fulvestrant; PAL=palbociclib; PCB=placebo. 
 
A reduction in the risk of disease progression or death in the fulvestrant plus palbociclib arm was 
observed in all individual patient subgroups defined by stratification factors and baseline 
characteristics. 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 of 
metastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of 
0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless of lines of prior therapy in the 
metastatic 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]). Additional 
efficacy measures (OR and TTR) assessed in the sub-groups of patients with or without visceral 
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 

palbociclib 
(N=206) 

Fulvestrant plus 
placebo 
(N=105) 

Fulvestrant plus 
palbociclib 

(N=141) 

Fulvestrant plus 
placebo 
(N=69) 

OR [% (95% CI)] 35.0 
(28.5, 41.9) 

13.3 
(7.5, 21.4) 

13.5 
(8.3, 20.2) 

14.5 
(7.2, 25.0) 

TTR*, Median 
[months (range)] 

3.8 
(3.5, 16.7) 

5.4 
(3.5, 16.7) 

3.7 
(1.9, 13.7) 

3.6 
(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 patients 
in the fulvestrant plus placebo arm completed the questionnaire at baseline and at least 1 post-baseline 
visit. 
 



15 

Time-to-Deterioration was pre-specified as time between baseline and first occurrence of ≥10 points 
increase from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in a 
symptom benefit by significantly delaying Time-to-Deterioration in pain symptom compared with 
fulvestrant 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 
ethinylestradiol showed that pre-treatment with fulvestrant 250 mg resulted in significantly reduced 
stimulation of the postmenopausal endometrium, compared to pre-treatment with placebo, as judged 
by ultrasound measurement of endometrium thickness. 
 
Neoadjuvant treatment for up to 16 weeks in breast cancer patients treated with either fulvestrant 
500 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 breast 
cancer patients studied. No data are available regarding endometrial morphology.  
 
In two short-term studies (1 and 12 weeks) in premenopausal patients with benign gynaecologic 
disease, no significant differences in endometrial thickness were observed by ultrasound measurement 
between 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 16 
weeks in breast cancer patients with either fulvestrant 500 mg or fulvestrant 250 mg did not result in 
clinically significant changes in serum bone-turnover markers. 
 
Paediatric population 
Fulvestrant is not indicated for use in children. The European Medicines Agency has waived the 
obligation to submit the results of studies with fulvestrant in all subsets of the paediatric population in 
breast cancer (see section 4.2 for information on paediatric use). 
 
An open-label phase 2 study investigated the safety, efficacy and pharmacokinetics of fulvestrant in  
30 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 of 
fulvestrant. This 12-month study investigated a range of MAS endpoints and showed a reduction in the 
frequency of vaginal bleeding and a reduction in the rate of bone age advancement. The steady-state 
trough concentrations of fulvestrant in children in this study were consistent with that in adults (see 
section 5.2). There were no new safety concerns arising from this small study, but 5-year data are yet 
not available. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
After administration of fulvestrant long-acting intramuscular injection, fulvestrant is slowly absorbed 
and maximum plasma concentrations (Cmax) are reached after about 5 days. Administration of 
fulvestrant 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. 
 



16 

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 anti-estrogen 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 
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 intramuscular 
administration is governed by the absorption rate and was estimated to be 50 days.  
 
Special populations 
In a population pharmacokinetic analysis of data from phase 3 studies, no difference in fulvestrant’s 
pharmacokinetic profile was detected with regard to age (range 33 to 89 years), weight (40-127 kg) or 
race.  
 
Renal impairment 

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

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

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). The 
paediatric patients were aged 1 to 8 years and received 4 mg/kg monthly intramuscular dose of 
fulvestrant. 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 collected 
were limited, the steady-state trough concentrations of fulvestrant in children appear to be consistent 
with those in adults. 
 
5.3 Preclinical safety data 
 
The acute toxicity of fulvestrant is low.  
 



17 

Fulvestrant solution for injection and other formulations of fulvestrant were well tolerated in animal 
species used in multiple dose studies. Local reactions, including myositis and granulomata at the 
injection site were attributed to the vehicle but the severity of myositis in rabbits increased with 
fulvestrant, compared to the saline control. In toxicity studies with multiple intramuscular doses of 
fulvestrant in rats and dogs, the antiestrogenic activity of fulvestrant was responsible for most of the 
effects seen, particularly in the female reproductive system, but also in other organs sensitive to 
hormones in both sexes. Arteritis involving a range of different tissues was seen in some dogs after 
chronic (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 to 
be 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 its 
anti-estrogenic activity, at doses similar to the clinical dose. In rats, a reversible reduction in female 
fertility and embryonic survival, dystocia and an increased incidence of foetal abnormalities 
including 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 an 
increased incidence of foetal variations in rabbits (backwards displacement of the pelvic girdle and 
27 pre-sacral vertebrae). 
 
A two-year oncogenicity study in rats (intramuscular administration of fulvestrant) showed increased 
incidence of ovarian benign granulosa cell tumours in female rats at the high dose, 10 mg/rat/15 days 
and an increased incidence of testicular Leydig cell tumours in males. In a two-year mouse 
oncogenicity study (daily oral administration) there was an increased incidence of ovarian sex cord 
stromal tumours (both benign and malignant) at doses of 150 and 500 mg/kg/day. At the no-effect 
level for these findings, systemic exposure levels (AUC) were, in rats, approximately 1.5–fold the 
expected 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 is 
consistent with pharmacology-related endocrine feedback alterations in gonadotropin levels caused 
by anti-estrogens in cycling animals. Therefore these findings are not considered to be relevant to the 
use of fulvestrant in postmenopausal women with advanced breast cancer. 
 
Environmental risk assessment (ERA) 
Environmental risk assessment studies have shown that fulvestrant may have potential to cause 
adverse effects to the aquatic environment (see section 6.6). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 

Benzyl benzoate 
Benzyl alcohol  
Ethanol, anhydrous  
Castor oil, refined 
 

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



18 

6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Store and transport refrigerated (2°C - 8°C).  
 
Temperature excursions outside 2°C - 8°C should be limited and not exceeding a 28 day period 
where the average storage temperature for the product is below 25°C (but above 2°C - 8°C). After 
temperature excursions, the product should be returned immediately to the recommended storage 
conditions (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 period 
must 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 stored 
below -20°C.  
 
Store the pre-filled syringe in the original package in order to protect from light. 
 
6.5 Nature and contents of container  
 
The pre-filled syringe presentation consists of:  
 
One clear type 1 glass pre-filled syringe with polypropylene plunger rod, fitted with a tamper-evident 
closure, 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 connection 
to each barrel are also provided.  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for administration 
 
Administer the injection according to the local guidelines for performing large volume intramuscular 
injections. 
 
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. 
 



19 

Figure 1 

Figure 2 
 
 

Figure 4 

Figure 5 

Figure 3 
 

For each of the two syringes: 
 
• Remove glass syringe barrel from tray and check that it is   

not damaged. 
• Peel open the safety needle (SafetyGlide) outer packaging.  
• Parenteral solutions must be inspected visually for  

particulate matter and discolouration prior to 
administration. 

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

 
 

• Remove the cap (A) in a straight upward direction. To 
maintain sterility do not touch the syringe tip (B) (see 
Figure 2). 
 
 
 
 
 
 
 

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

• Check that the needle is locked to the Luer connector 
before moving out of the vertical plane. 

• Pull shield straight off needle to avoid damaging needle  
point. 

• Transport filled syringe to point of administration. 
• Remove needle sheath. 
• Expel excess gas from the syringe. 
 

 
 

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

 
• After injection, immediately apply a single-finger stroke to 

the activation assisted lever arm to activate the shielding  
mechanism (see Figure 5).  
NOTE: Activate away from self and others. Listen for click  
and visually confirm needle tip is fully covered. 

 
 
 
 
Disposal 
Pre-filled syringes are for single use only.  



20 

This medicine may pose a risk to the aquatic environment. Any unused medicinal product or waste 
material should be disposed of in accordance with local requirements (see section 5.3). 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
MYLAN S.A.S. 
117 Allée des Parcs 
69800 SAINT-PRIEST 
FRANCE  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1253/001 
EU/1/17/1253/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 08 january 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

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


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



22 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer(s) responsible for batch release 
 

Mylan Teoranta 
Coill Rua 
Inverin 
Co. Galway 
IRELAND 

 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

Medicinal product subject to medical prescription. 
 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 
• Periodic Safety Update Reports (PSURs) 

 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 

 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



25 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Fulvestrant Mylan 250 mg solution for injection in prefilled syringe.  
fulvestrant 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One pre-filled syringe contains 250 mg fulvestrant in 5 ml solution  
 
 
3. LIST OF EXCIPIENTS 
 
Benzyl benzoate 
Benzyl alcohol  
Ethanol, anhydrous 
Castor oil, refined 
 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection.   
 
1 pre-filled syringe (5 ml) 
1 safety needle  
2 pre-filled syringes (5 ml each) 
2 safety needles  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intramuscular use. 
For single use only. 
For full instructions on the administration of Fulvestrant Mylan and the use of the safety needle see 
enclosed, Instructions for administration. 
Two syringes must be administered to receive the 500 mg recommended monthly dose.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
 OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 



26 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store and transport refrigerated.  
Store the pre-filled syringe in the original package in order to protect from light. See package leaflet 
for information on temperature excursions. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
 OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
 APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
MYLAN S.A.S.  
117 Allée des Parcs 
69800 Saint-Priest 
FRANCE  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1253/001 
EU/1/17/1253/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 



27 

 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



28 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Fulvestrant Mylan 250 mg solution for injection in prefilled syringe 
fulvestrant 
IM use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 
 
 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



30 

Package leaflet: Information for the user 
 

Fulvestrant Mylan 250 mg solution for injection in prefilled syringe 
fulvestrant 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Fulvestrant Mylan is and what it is used for  
2. What you need to know before you use Fulvestrant Mylan  
3. How to use Fulvestrant Mylan  
4. Possible side effects  
5. How to store Fulvestrant Mylan  
6. Contents of the pack and other information 
 
 
1.  What Fulvestrant Mylan is and what it is used for 
 
Fulvestrant Mylan contains the active substance fulvestrant, which belongs to the group of estrogen 
blockers. Estrogens, a type of female sex hormones, can in some cases be involved in the growth of 
breast cancer.  
 
Fulvestrant Mylan is used either:  
• alone, to treat postmenopausal women with a type of breast cancer called estrogen receptor 

positive breast cancer that is locally advanced or has spread to other parts of the body 
(metastatic), or 

• in combination with palbociclib to treat women with a type of breast cancer called hormone 
receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, that is 
locally advanced or has spread to other parts of the body (metastatic). Women who have not 
reached menopause will also be treated with a medicine called a luteinizing hormone releasing 
hormone (LHRH) agonist. 

 
When fulvestrant is given in combination with palbociclib, it is important that you also read the 
package leaflet for palbociclib. If you have any questions about palbociclib, please ask your doctor. 
 
 
2. What you need to know before you use Fulvestrant Mylan  
 
Do not use Fulvestrant Mylan 
- if you are allergic to fulvestrant or to any of the other ingredients of this medicine (listed in 

section 6) 
- if you are pregnant or breast-feeding 
- if you have severe liver problems 
 
Warnings and precautions  
Talk to your doctor or pharmacist or nurse before using Fulvestrant Mylan if any of these apply to 
you: 
- kidney or liver problems 
- low numbers of platelets (which help blood clotting) or bleeding disorders  
- previous problems with blood clots 



31 

- osteoporosis (loss of bone density) 
- alcoholism 

 
Children and adolescents 
Fulvestrant Mylan is not indicated in children and adolescents under 18 years. 
 
Other medicines and Fulvestrant Mylan 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
In particular, you should tell your doctor if you are using anticoagulants (medicines to prevent blood 
clots). 
 
Pregnancy and breast-feeding 
You must not use Fulvestrant Mylan if you are pregnant. If you can become pregnant, you should use 
effective contraception while you are being treated with Fulvestrant Mylan and for 2 years after your 
last dose. 
 
You must not breast-feed while on treatment with Fulvestrant Mylan.  
 
Driving and using machines 
Fulvestrant Mylan is not expected to affect your ability to drive or use machines. However, if you feel 
tired after treatment do not drive or use machines. 
 
Fulvestrant Mylan contains 10% w/v ethanol (alcohol) i.e.  500 mg in each 5 ml, equivalent to 25 
ml beer or 10 ml wine  per one treatment dose (i.e. two syringes). The small amount of alcohol in this 
medicine will not have any noticeable effects. 
 
 
Fulvestrant Mylan contains benzyl alcohol 
This medicine 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.  
 
Fulvestrant Mylan contains benzyl benzoate 
This medicine contains 750 mg benzyl benzoate in each 5 ml, which is equivalent to 150 mg/ml 
(15%w/v). 
 
 
3. How to use Fulvestrant Mylan 
 
Always use this medicine exactly as your doctor or pharmacist has told you.  Check with your doctor 
or pharmacist if you are not sure.   
 
The recommended dose is 500 mg fulvestrant (two 250 mg/5 ml injections) given once a month, with 
an additional 500 mg dose given 2 weeks after the initial dose. 
 
Your doctor or nurse will give you Fulvestrant Mylan as a slow intramuscular injection, one into each 
of your buttocks. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 



32 

You may need immediate medical treatment if you experience any of the following side effects:  
 
• Allergic (hypersensitivity) reactions, including swelling of the face, lips, tongue and/or throat 

that may be signs of anaphylactic reactions 
• Thromboembolism (increased risk of blood clots)* 
• Inflammation of the liver (hepatitis)   
• Liver failure 

 
Tell your doctor, pharmacist, or nurse if you notice any of the following side effects: 
 
Very common side effects (may affect more than 1 in 10 people) 
• Injection site reactions, such as pain and/or inflammation  
• Abnormal levels of liver enzymes (in blood tests)* 
• Nausea (feeling sick)  
• Weakness, tiredness* 
• Joint and musculoskeletal pain 
• Hot flushes 
• Skin rash 
• Allergic (hypersensitivity) reactions, including swelling of the face, lips, tongue and/or throat 

 
All other side effects: 
 
Common side effects (may affect up to 1 in 10 people) 
• Headache 
• Vomiting, diarrhoea, or loss of appetite* 
• Urinary tract infections 
• Back pain* 
• Increase of bilirubin (bile pigment produced by the liver)  
• Thromboembolism (increased risk of blood clots)* 
• Decreased levels of platelets (thrombocytopenia) 
• Vaginal bleeding 
• Lower back pain irradiating to leg on one side (sciatica) 
• Sudden weakness, numbness, tingling, or loss of movement in your leg, especially on only one 

side of your body, sudden problems with walking or balance (peripheral neuropathy) 
 

Uncommon side effects (may affect up to 1 in 100 people) 
• Thick, whitish vaginal discharge and candidiasis (infection) 
• Bruising and bleeding at the site of injection 
• Increase of gamma-GT, a liver enzyme seen in a blood test 
• Inflammation of the liver (hepatitis) 
• Liver failure 
• Numbness, tingling and pain 
• Anaphylactic reactions 

 
* Includes side effects for which the exact role of Fulvestrant Mylan cannot be assessed due to the 
underlying disease. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


33 

5. How to store Fulvestrant Mylan 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton or syringe labels after 
EXP. The expiry date refers to the last day of that month. 
 
Store and transport refrigerated (2°C - 8°C).  
 
Temperature excursions outside 2°C - 8°C should be limited and not exceeding a 28 day period 
where the average storage temperature for the product is below 25°C (but above 2°C - 8°C). After 
temperature excursions, the product should be returned immediately to the recommended storage 
conditions (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 period must not be exceeded over the 
duration of the shelf life of Fulvestrant Mylan. Exposure to temperatures below 2°C will not damage 
the product providing it is not stored below – 20°C.  
 
Keep the pre-filled syringe in the original package in order to protect from light. 
 
Your healthcare professional will be responsible for the correct storage, use and disposal of 
Fulvestrant Mylan. 
 
This medicine may pose a risk to the aquatic environment. Do not throw away any medicines via 
wastewater or household waste.  Ask your pharmacist how to throw away medicines you no longer 
use.  These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Fulvestrant Mylan contains  
- The active substance is fulvestrant. Each pre-filled syringe (5 ml) contains 250 mg fulvestrant. 
- The other ingredients (excipients) are benzyl benzoate (see section 2 ‘Fulvestrant Mylan 

contains benzyl benzoate’), benzyl alcohol (see section 2 ‘Fulvestrant Mylan contains benzyl 
alcohol’), ethanol anhydrous (see section 2 ‘Fulvestrant Mylan contains 10% w/v ethanol 
(alcohol)’), castor oil, refined. 

 
What Fulvestrant Mylan looks like and contents of the pack 
Fulvestrant Mylan is a clear, colourless to yellow, viscous solution in a pre-filled syringe fitted with a 
tamper-evident closure, containing 5 ml solution for injection.  
Fulvestrant Mylan has 2 pack presentations, either a pack containing 1 glass pre-filled syringe or a 
pack containing 2 glass pre-filled syringes. Safety needles (BD SafetyGlide) for connection to each 
barrel are also provided.  
 
Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder  
MYLAN S.A.S.  
117 Allée des Parcs 
69800 SAINT-PRIEST 
FRANCE  
 
Manufacturer 
MYLAN TEORANTA 
Inverin 
Co. Galway 
IRELAND 
 



34 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Mylan bvba/sprl 
Tél/Tel: + 32 (0)2 658 61 00 
 

Lietuva 
 BGP Products UAB  
Tel: +370 5 205 1288 

България 
Майлан ЕООД 
Тел: +359 2 44 55 400 
 

Luxembourg/Luxemburg 
Mylan bvba/sprl 
Tel: + 32 (0)2 658 61 00 
(Belgique/Belgien) 
 

Česká republika 
Mylan Healthcare CZ s.r.o. 
Tel: +420 222 004 400 
 

Magyarország 
Mylan EPD Kft 
Tel: + 36 1 465 2100  

Danmark 
Mylan Denmark ApS 
Tel: +45 28 11 69 32  
 

Malta 
V.J.Salomone Pharma Ltd 
Tel: + 356 21 22 01 74 

Deutschland 
Mylan Healthcare GmbH  
Tel: + 49 800 0700 800 
 

Nederland 
Mylan BV 
Tel: +31 (0)20 426 3300 

Eesti 
BGP Products Switzerland GmbH Eesti 
filiaal  
Tel: + 372 6363 052 

Norge 
Mylan Healthcare Norge AS 
Tel: + 47 66 75 33 00 
 
 

Ελλάδα  
Generics Pharma Hellas ΕΠΕ  
Τηλ:  +30 210 993 6410  
 

Österreich 
Arcana Arzneimittel GmbH 
Tel: +43 1 416 2418 
 

España 
Mylan Pharmaceuticals, S.L 
Tel: + 34 900 102 712 
 

Polska 
Mylan Healthcare Sp. z.o.o. 
Tel: + 48 22 546 64 00 
 

France 
Mylan S.A.S 
Tel: +33 4 37 25 75 00 
 

Portugal 
Mylan, Lda. 
Tel: + 351 21 412 72 56 
 

Hrvatska 
Mylan Hrvatska d.o.o.  
Tel: +385 1 23 50 599  

România 
BPG Products SRL 
Tel: + 40 372 579 000 
 

Ireland 
Mylan Ireland Limited 
Tel: +353 (0) 87 1694982 

Slovenija 
Mylan Healthcare d.o.o. 
Tel: + 386 1 23 63 180 
 



35 

Ísland 
Icepharma hf 
Tel: + 354 540 8000 
 

Slovenská republika 
Mylan s.r.o. 
Tel: +421 2 32 199 100 

Italia 
Mylan Italia S.r.l. 
Tel: + 39 02 612 46921 
 

Suomi/Finland 
Mylan Finland OY 
Puh/Tel: + 358 20 720 9555 
 

Κύπρος 
Varnavas Hadjipanayis Ltd 
Τηλ: + 357 2220 7700 
 

Sverige 
Mylan AB  
Tel: + 46 855 522 750 
 

Latvija 
Mylan Healthcare SIA  
Tel: +371 676 055 80 
 

United Kingdom 
Generics [UK] Ltd 
Tel: +44 1707 853000 

 
This leaflet was last revised in {MM/YYYY}. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
Fulvestrant Mylan 500 mg (2 x 250 mg/5 ml solution for injection) should be administered using two 
pre-filled syringes, see section 3. 
 
Instructions for administration 
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   

not damaged. 
• Peel open the safety needle (SafetyGlide) outer packaging. 
• Parenteral solutions must be inspected visually for  

particulate matter and discolouration prior to 
administration. 



36 

Figure 1 

Figure 2 

Figure 4 

Figure 5 

Figure 3 
 

 
• Hold the syringe upright on the ribbed part (C). With the 

other hand, take hold of the cap (A) and carefully tilt back 
and forth until the cap disconnects and can be pulled off, 
do not twist (see Figure 1). 

 
 
 
 
 
 
• Remove the cap (A) in a straight upward direction. To 

maintain sterility do not touch the syringe tip (B) (see 
Figure 2). 
 
 
 
 
 

 
 

 
• Attach the safety needle to the Luer-Lok and twist until 

firmly seated (see Figure 3). 
• Check that the needle is locked to the Luer connector 

before moving out of the vertical plane.  
• Pull shield straight off needle to avoid damaging needle 

point. 
• Transport filled syringe to point of administration. 
• Remove needle sheath. 
• Expel excess gas from the syringe. 

 
 

 
• Administer intramuscularly slowly (1-2 minutes/injection)  

into the buttock (gluteal area). For user convenience, the needle 
bevel- up position is oriented to the lever arm (see Figure 4).  
 
 
 
 
 
 
 
 

• After injection, immediately apply a single-finger stroke to 
the activation assisted lever arm to activate the shielding  
mechanism (see Figure 5).  
NOTE: Activate away from self and others. Listen for click  
and visually confirm needle tip is fully covered. 

 
 
 
 
 
 



37 

Disposal 
Pre-filled syringes are for single use only.  
This medicine may pose a risk to the aquatic environment. Any unused medicinal product or waste 
material should be disposed of in accordance with local requirements. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET