1. Name Of The Medicinal Product
Faslodex 250 mg solution for injection.
2. Qualitative And Quantitative Composition
One pre-filled syringe contains 250 mg fulvestrant in 5 ml solution.
For a 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
Faslodex is indicated for the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen.
4.2 Posology And Method Of Administration
Posology
Adult females (including the 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.
Special population
Renal impairment
No dose adjustments are recommended for patients with mild to moderate renal impairment (creatinine clearance
Hepatic impairment
No dose adjustments are recommended for patients with mild to moderate hepatic impairment. However, as fulvestrant exposure may be increased, Faslodex should be used with caution in these patients. There are no data in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).
Paediatric population
The safety and efficacy of Faslodex in children from birth to 18 years of age have not been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.
Method of administration
Faslodex should be administered as two consecutive 5 ml injections by slow intramuscular injection (1-2 minutes/injection), one in each buttock.
For detailed instructions for administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance, or to any of the other excipients.
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
Faslodex should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Faslodex should be used with caution in patients with severe renal impairment (creatinine clearance less than 30 ml/min).
Due to the intramuscular route of administration, Faslodex should be used with caution if treating patients with bleeding diatheses, thrombocytopenia or those taking anticoagulant treatment.
Thromboembolic events are commonly observed in women with advanced breast cancer and have been observed in clinical trials with Faslodex (see section 4.8). This should be taken into consideration when prescribing Faslodex to patients at risk.
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.
Paediatric population
Faslodex is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).
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 Pregnancy And Lactation
Women of childbearing potential
Patients of child-bearing potential should be advised to use effective contraception while on treatment.
Pregnancy
Faslodex is contraindicated in pregnancy (see section 4.3). Fulvestrant has been shown to cross the placenta after single intramuscular doses in rat and rabbit. Studies in animals have shown reproductive toxicity including an increased incidence of foetal abnormalities and deaths (see section 5.3). If pregnancy occurs while taking Faslodex, the patient must be informed of the potential hazard to the foetus and potential risk for loss of pregnancy.
Breast-feeding
Breast-feeding must be discontinued during treatment with Faslodex. Fulvestrant is excreted in milk in lactating rats. It is not known whether fulvestrant is excreted in human milk. Considering the potential for serious adverse reactions due to fulvestrant in breast-fed infants, use during lactation is contraindicated (see section 4.3).
Fertility
The effects of Faslodex on fertility in humans has not been studied.
4.7 Effects On Ability To Drive And Use Machines
Faslodex has no or negligible influence on the ability to drive or use machines. However, since asthenia has been reported very commonly with Faslodex, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery.
4.8 Undesirable Effects
This section provides information based on all adverse reactions from clinical trials, post-marketing studies or spontaneous reports. The most frequently reported adverse reactions are injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).
The following frequency categories for adverse drug reactions (ADRs) were calculated based on the Faslodex 500 mg treatment group in pooled safety analyses of the CONFIRM (Study D6997C00002), FINDER 1 (Study D6997C00004), FINDER 2 (Study D6997C00006), and NEWEST (Study D6997C00003) studies that compared Faslodex 500 mg with Faslodex 250 mg. The frequencies in the following table were based on all reported events, regardless of the investigator assessment of causality.
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 (
Table 1 Adverse Drug Reactions
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a Includes adverse drug reactions for which the exact contribution of Faslodex cannot be assessed due to the underlying disease.
b The term injection site reactions does not include the terms injection site haemorrhage and injection site haematoma.
4.9 Overdose
There is no human experience of overdose. Animal studies suggest that no effects other than those related directly or indirectly to anti-oestrogenic activity were evident with higher doses of fulvestrant (see section 5.3). If overdose occurs, symptomatic supportive treatment is recommended.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Endocrine therapy, Anti-oestrogens, ATC code: L02BA03
Mechanism of action and pharmacodynamic effects
Fulvestrant is a competitive oestrogen receptor (ER) antagonist with an affinity comparable to oestradiol. Fulvestrant blocks the trophic actions of oestrogens without any partial agonist (oestrogen-like) activity. The mechanism of action is associated with down-regulation of oestrogen receptor protein levels.
Clinical trials 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 oestrogen 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 safety and efficacy in advanced breast cancer
A phase III clinical trial 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
Table 2 Summary of results of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the CONFIRM study
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a Faslodex is indicated in patients whose disease had recurred or progressed on an anti-estrogen therapy. The results in the AI subgroup are inconclusive.
b ORR was assessed in patients who were evaluable for response at baseline (ie, those with measurable disease at baseline: 240 patients in the Faslodex 500 mg group and 261 patients in the Faslodex 250 mg group).
c Patients with a best objective response of complete response, partial response or stable disease
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.
Two Phase III clinical trials 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. 77% of the study population had oestrogen receptor positive breast cancer. These trials compared the safety and efficacy of monthly administration of Faslodex 250 mg versus the daily administration of 1 mg anastrozole (aromatase inhibitor). Overall, Faslodex 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 trials showed that 83% of patients who received Faslodex progressed, compared with 85% of patients who received anastrozole. Combined analysis of both trials showed the hazard ratio of Faslodex 250 mg to anastrozole for progression-free survival was 0.95 (95% CI 0.82 to 1.10). The objective response rate for Faslodex 250 mg was 19.2% compared with 16.5% for anastrozole. The median time to death was 27.4 months for patients treated with Faslodex and 27.6 months for patients treated with anastrozole. The hazard ratio of Faslodex 250 mg to anastrozole for time to death was 1.01 (95% CI 0.86 to 1.19).
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 micrograms per day ethinylestradiol showed that pre-treatment with Faslodex 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 Faslodex 500 mg or Faslodex 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 Faslodex 500 mg or Faslodex 250 mg did not result in clinically significant changes in serum bone-turnover markers.
Paediatric population
Faslodex is not indicated for use in children. The European Medicines Agency has waived the obligation to submit the results of studies with Faslodex in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).
An open-label phase II 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 Faslodex long-acting intramuscular injection, fulvestrant is slowly absorbed and maximum plasma concentrations (Cmax) are reached after about 5 days. Administration of Faslodex 500 mg regimen achieves exposure levels at, or close to, steady state within the first month of dosing (mean [CV]: AUC 475 [33.4%] ng.days/ml, Cmax 25.1 [35.1%] ng/ml, Cmin 16.3 [25.9%] ng/ml, respectively). At steady state, fulvestrant plasma concentrations are maintained within a relatively narrow range with up to an approximately 3-fold difference between maximum and trough concentrations. After intramuscular administration, the exposure is approximately dose proportional in the dose range 50 to 500 mg.
Distribution
Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution at steady state (Vdss) of approximately 3 to 5 l/kg suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins. Very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major binding components. No interaction studies were conducted on competitive protein binding. The role of sex hormone-binding globulin (SHBG) has not been determined.
Metabolism
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-oestrogen 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 III 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 trial conducted in subjects 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 subjects with hepatic impairment compared to healthy subjects. In patients administered Faslodex, an increase in exposure of this magnitude is expected to be well tolerated. Subjects with severe hepatic impairment (Child-Pugh class C) were not evaluated.
Paediatric population
The pharmacokinetics of fulvestrant has been evaluated in a clinical trial 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.
Faslodex 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 anti-oestrogenic 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-oestrogenic 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 Faslodex) 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. Induction of such tumours is consistent with pharmacology-related endocrine feedback alterations. These findings are not of clinical relevance for the use of fulvestrant in postmenopausal women with advanced breast cancer.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Ethanol (96%)
Benzyl alcohol
Benzyl benzoate
Castor oil
6.2 Incompatibilities
In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
4 years.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C-8°C).
Store the pre-filled syringe in the original package in order to protect from light.
6.5 Nature And Contents Of Container
BD SafetyGlide is a trademark of Becton Dickinson and Company and is CE-marked: CE 0050.
The pre-filled syringe presentation consists of:
One clear type 1 glass pre-filled syringe with polystyrene plunger rod, fitted with a tamper
A safety needle (BD SafetyGlide™) for connection to the barrel is also provided.
Or
Two clear type 1 glass pre-filled syringes with polystyrene plunger rod, fitted with a tamper
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
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:
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• After injection, immediately apply a single-finger stroke to the activation assisted lever arm to activate the shielding mechanism (see Figure 4). 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.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
AstraZeneca UK Limited
Alderley Park
Macclesfield
Cheshire
SK10 4TG
United Kingdom
8. Marketing Authorisation Number(S)
EU/1/03/269/001
EU/1/03/269/002
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 10th March 2004
Date of last renewal: 10th March 2009
10. Date Of Revision Of The Text
29th July 2011
Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu
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