Fulvadject
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FULVEDJECT
Composition:
Active substance: fulvestrant;
1 pre-filled syringe (5 ml) contains fulvestrant 250 mg;
Excipients: ethanol 96%, benzyl alcohol, benzyl benzoate, ricinus oil.
Pharmaceutical form. Solution for injection.
Main physicochemical characteristics: clear, viscous, oily solution ranging from colorless to yellow.
Pharmacotherapeutic group. Hormone antagonists and related agents. Anti-estrogenic agents. ATC code L02B A03.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of Action and Pharmacodynamic Effects
Fulvestrant is a competitive antagonist of estrogen receptors (ER), with affinity comparable to that of estradiol. Fulvestrant blocks the trophic effects of estrogens without demonstrating partial agonist (estrogen-like) activity. Its mechanism of action is associated with the downregulation of estrogen receptor protein levels. Clinical studies in postmenopausal women with primary breast cancer have shown that fulvestrant significantly reduces ER protein levels in ER-positive tumors compared to placebo. A significant reduction in progesterone receptor expression was also observed, consistent with the absence of typical estrogen agonist effects. Furthermore, it has been demonstrated that fulvestrant at a dose of 500 mg suppresses ER and the proliferation marker Ki67 in breast tumors to a greater extent than fulvestrant at a dose of 250 mg during neoadjuvant treatment of postmenopausal women.
Clinical Safety and Efficacy in Advanced Breast Cancer
Monotherapy. The phase III CONFIRM clinical trial was conducted in 736 postmenopausal women with advanced breast cancer who experienced disease recurrence during or after adjuvant endocrine therapy, or disease progression during endocrine therapy for advanced disease.
The study included 423 patients whose disease progressed or recurred during antiestrogen therapy (AE subgroup) and 313 patients whose disease progressed or recurred during aromatase inhibitor therapy (AI subgroup). This trial compared the efficacy and safety of fulvestrant 500 mg (n = 362) versus fulvestrant 250 mg (n = 374). The primary endpoint was progression-free survival (PFS); key secondary efficacy endpoints included objective response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Efficacy results from the CONFIRM trial are summarized below in Table 1.
Table 1
Summary of results from the analysis of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the CONFIRM trial
|
|
Type of estimate; treatment comparison |
Fulvestrant |
Fulvestrant 250 mg |
Comparison between groups |
||
| Hazard ratio |
95% CI |
p-value |
||||
| PFS |
K-M median in months; |
|||||
| All patients |
6.5 |
5.5 |
0.80 |
0.68, 0.94 |
0.006 |
|
|
8.6 |
5.8 |
0.76 |
0.62, 0.94 |
0.013 |
|
|
5.4 |
4.1 |
0.85 |
0.67, 1.08 |
0.195 |
|
| OSb |
K-M median in months; |
|||||
| All patients |
26.4 |
22.3 |
0.81 |
0.69, 0.96 |
0.016c |
|
|
30.6 |
23.9 |
0.79 |
0.63, 0.99 |
0.038c |
|
|
24.1 |
20.8 |
0.86 |
0.67, 1.11 |
0.241c |
|
| Variable |
Type of estimate; treatment comparison |
Fulvestrant |
Fulvestrant 250 mg |
Comparison between groups |
||
| Absolute difference in % |
95% CI |
|||||
| ORR d |
% of patients with OR; |
|||||
| All patients |
13.8 |
14.6 |
|
|
||
|
18.1 |
19.1 |
|
8.2,
|
||
|
7.3 |
8.3 |
|
|
||
| CBR e |
% of patients with CB; |
|||||
| All patients |
45.6 |
39.6 |
6.0 |
|
||
|
52.4 |
45.1 |
7.3 |
|
||
|
36.2 |
32.3 |
3.9 |
|
||
Fulvestrant is indicated for patients whose disease has recurred or progressed on prior antiestrogen therapy. Results in the AI subgroup are not mature.
b Hazard ratio (HR) value presented for final survival analysis at 75% data maturity.
c Nominal p-value without adjustments for multiplicity between the primary PFS analysis at 50% data maturity and the updated survival analysis at 75% data maturity.
d ORR was analyzed in patients whose response was evaluable at baseline (i.e., they had measurable disease at baseline: 240 patients in the 500 mg fulvestrant group and 261 patients in the 250 mg fulvestrant group).
e Patients with best objective response of complete response, partial response, or stable disease lasting ≥24 weeks.
PFS – progression-free survival.
ORR – objective response rate.
OR – objective response.
CBR – clinical benefit rate.
CE – clinical efficacy.
OS – overall survival.
K-M median – Kaplan-Meier median.
CI – confidence interval.
AI – aromatase inhibitor.
AE – antiestrogen.
A randomized, double-blind, multicenter, phase 3 study was conducted to evaluate the efficacy of fulvestrant 500 mg compared with anastrozole 1 mg in postmenopausal women with locally advanced or metastatic estrogen receptor and/or progesterone receptor-positive breast cancer who had not previously received hormonal therapy. A total of 462 patients were sequentially randomized 1:1 to receive either fulvestrant 500 mg or anastrozole 1 mg.
Randomization was stratified by disease setting (locally advanced or metastatic), prior chemotherapy for advanced disease, and measurable disease at baseline.
The primary efficacy endpoint was PFS, as assessed by the investigator according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). Key secondary efficacy endpoints included OS and ORR.
The median age of patients enrolled in this study was 63 years (range: 39 to 90 years). The majority of patients (87.0%) had metastatic disease at study entry. 55% of patients had visceral metastases at baseline. Overall, 17.1% of patients had received prior chemotherapy for advanced disease, and 84.2% of patients had measurable disease.
Significant results were observed in the majority of predefined patient subgroups. In the subgroup of patients with non-visceral metastases (n = 208) receiving fulvestrant, the HR was 0.592 (95% CI: 0.419–0.837) compared to those receiving anastrozole. In the subgroup of patients with visceral metastases (n = 254) receiving fulvestrant 500 mg, the HR was 0.993 (95% CI: 0.740–1.331) compared to those receiving anastrozole. Efficacy results from the FALCON study are presented in Table 2 and Figure 1.
Table 2
Summary of results for the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the FALCON study (investigator assessment, full analysis set according to assigned treatment)
| 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 |
|
| Median PFS in months [median (95 % CI)] |
16.6 (13.8, 21.0) |
13.8 (12.0, 16.6) |
| Number of OS events* |
67 (29.1 %) |
75 (32.3 %) |
| Overall survival: hazard ratio (95 % CI) and p-value |
HR = 0.875 (0.629–1.217) p = 0.4277 |
|
| CBR** |
89 (46.1 %) |
88 (44.9 %) |
| CBR: odds ratio (OR) (95 % CI) and p-value |
OR = 1.074 (0.716–1.614) p = 0.7290 |
|
| Median duration of response (months) |
20.0 |
13.2 |
| CER (clinical benefit rate) |
180 (78.3 %) |
172 (74.1 %) |
| CER: odds ratio (95 % CI) and p-value |
OR = 1.253 (0.815–1.932) p = 0.3045 |
|
* 31% processed – not final analysis of PFS.
** For patients with measurable disease.
Figure 1
Kaplan-Meier curve for PFS (investigator assessment, "all randomized patients as per assigned treatment" population) – FALCON study
| Probability of BCFI |
Time from randomization (months) |
| Treatment: fulvestrant 500 mg (n = 230) … anastrozole 1 mg (n = 232) |
|
| Number of patients at risk Ful 500 230 187 171 150 124 110 96 81 63 44 24 11 2 0 Anas 1 232 194 162 139 120 102 81 60 45 31 22 10 0 0 |
Two phase 3 clinical studies were conducted overall involving 851 postmenopausal women with advanced breast cancer who had disease recurrence during or after adjuvant hormonal therapy or progression during hormonal 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 with daily administration of 1 mg anastrozole (an aromatase inhibitor). Overall, monthly fulvestrant 250 mg was at least as effective as anastrozole in terms of progression-free survival, objective response rate, and time to death. There were no statistically significant differences between the two treatment groups for any of these endpoints. The primary endpoint was progression-free survival. A combined analysis of both studies showed disease progression in 83% of patients receiving fulvestrant compared with 85% of patients receiving anastrozole. A combined analysis of both studies revealed a hazard ratio for progression-free survival with fulvestrant 250 mg versus anastrozole of 0.95 (95% CI 0.82–1.10). The objective response rate with fulvestrant 250 mg was 19.2% compared with 16.5% with anastrozole. Median time to death was 27.4 months in patients receiving fulvestrant and 27.6 months in patients receiving anastrozole. The hazard ratio for time to death with fulvestrant 250 mg versus anastrozole was 1.01 (95% CI 0.86–1.19).
Combination therapy with palbociclib. An international, randomized, double-blind, multicenter, phase 3, parallel-group study was conducted to evaluate the use of fulvestrant 500 mg in combination with palbociclib 125 mg compared with fulvestrant 500 mg plus placebo in women with HR-positive (hormone receptor-positive), HER2-negative (human epidermal growth factor receptor 2-negative) locally advanced breast cancer that was not amenable to surgical or radiation therapy with curative intent, regardless of menopausal status, whose disease had progressed after prior endocrine therapy in the (neo)adjuvant setting or for metastatic disease.
Overall, 521 pre/perimenopausal and postmenopausal women with disease progression within 12 months or after completion of adjuvant endocrine therapy, or within 1 month or after completion of prior endocrine therapy for advanced disease, were randomized in a 2:1 ratio to receive fulvestrant plus palbociclib or fulvestrant plus placebo and were stratified according to documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/perimenopausal or postmenopausal), and presence of visceral metastases. Women in the pre/perimenopausal period received a luteinizing hormone-releasing hormone (LHRH) agonist, goserelin. Patients with advanced/metastatic, symptomatic, visceral disease with a short-term risk of life-threatening complications (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitic carcinomatosis, and liver involvement of more than 50%) were not eligible for the study.
Patients continued their assigned treatment until objective disease progression, worsening of symptoms, unacceptable toxicity, death, or withdrawal of consent. Cross-over between treatment groups was not permitted.
Patients were well balanced across baseline demographic and prognostic characteristics between the fulvestrant + palbociclib and fulvestrant + placebo groups. The median age of patients enrolled in the study was 57 years (range 29–88). In each treatment group, the majority of study participants were of Caucasian race, had documented sensitivity to prior hormonal therapy, and were postmenopausal. Approximately 20% of patients were pre/perimenopausal. All patients had previously received systemic therapy, and the majority in each treatment group had previously received chemotherapy for their primary diagnosis. More than half of the patients (62%) had an ECOG (Eastern Cooperative Oncology Group) performance status of 0, 60% had visceral metastases, and 60% had received more than one prior hormonal therapy for their primary diagnosis.
The primary endpoint of the study was progression-free survival, defined according to RECIST 1.1 criteria, as assessed by the investigator. Additional PFS analyses were based on independent central radiological review. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), safety, and time to deterioration (TTD) in the pain severity endpoint.
The study met its primary endpoint—prolonged PFS as assessed by the investigator at an interim analysis with 82% of planned PFS events; results exceeded the pre-specified Haybittle–Peto boundary for efficacy (α = 0.00135), demonstrating a statistically significant prolongation of PFS and a clinically meaningful treatment effect. Median progression-free survival was 11.2 months in the fulvestrant + palbociclib group versus 4.6 months in the fulvestrant + placebo group. Further details on efficacy are provided in Table 3.
After a median follow-up period of 45 months, a final OS analysis was performed based on 310 events (60% of randomized patients). A difference in median OS of 6.9 months was observed in the palbociclib plus fulvestrant group compared with placebo plus fulvestrant; however, this result was not statistically significant at the prespecified significance level of 0.0235 (one-sided). In the placebo plus fulvestrant group, 15.5% of randomized patients received palbociclib or other CDK4/6 inhibitors as subsequent lines of therapy after disease progression.
Results of PFS and final OS analyses, as assessed by the investigator, in the PALOMA-3 study are presented in Table 3.
Table 3
Efficacy results from the PALOMA-3 study (investigator assessment, patient population: "all randomized patients according to assigned treatment")
| Updated analysis (data cutoff date – October 23, 2015) |
||
| Fulvestrant + palbociclib (N = 347) |
Fulvestrant + 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 efficacy endpoints* |
||
| ORR [% (95% CI)] |
26.2 (21.7; 31.2) |
13.8 (9.0; 19.8) |
| ORR (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) |
| Final overall survival (OS) |
||
| 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-value† |
0.814 (0.644 – 1.029) p = 0.0429†* |
|
PFS – progression-free survival.
ORR – objective response rate.
CBR – clinical benefit rate.
CI – confidence interval.
N – number of patients.
OR – objective response.
Results for secondary endpoints are based on confirmed and unconfirmed responses according to RECIST 1.1 criteria.
* Statistically not significant.
† One-sided p-values, stratified by log-rank test according to presence of visceral metastases and sensitivity to prior endocrine therapy at randomization.
A reduction in the risk of disease progression or death in favor of the fulvestrant + palbociclib group was observed across all individual subgroups of patients defined by stratification factors and baseline characteristics. The effect was evident in pre-/perimenopausal women (HR 0.46 [95% CI: 0.28–0.75]) and postmenopausal women (HR 0.52 [95% CI: 0.40–0.66]), as well as in patients with visceral metastases (HR 0.50 [95% CI: 0.38–0.65]) and those without visceral metastases (HR 0.48 [95% CI: 0.33–0.71]). Benefit was also observed regardless of the number of prior metastatic therapy lines: 0 (HR 0.59 [95% CI: 0.37; 0.93]), 1 (HR 0.46 [95% CI: 0.32; 0.64]), 2 (HR 0.48 [95% CI: 0.30; 0.76]), or ≥3 lines (HR 0.59 [95% CI: 0.28–1.22]). Additional efficacy measures (OR and TTR [time to first tumor response]), evaluated in subgroups of patients with or without visceral disease, are shown in Table 4.
Table 4
PALOMA-3 study efficacy results by visceral and non-visceral disease (all randomized patients treated population)
| Visceral disease |
Non-visceral disease |
|||
| Fulvestrant + palbociclib (N = 206) |
Fulvestrant + placebo (N = 105) |
Fulvestrant + palbociclib (N = 141) |
Fulvestrant + placebo (N = 69) |
|
| ORR [% (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) |
| PFS*, 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) |
* Results based on confirmed and unconfirmed responses.
N − number of patients.
CI − confidence interval.
OR − objective response.
TTTF − time to first tumor response.
Information on patient-reported symptoms and overall quality of life was collected using the questionnaire developed by the European Organisation for Research and Treatment of Cancer (EORTC) (QLQ)-C30 and the breast cancer module (EORTC QLQ-BR23). Overall, 335 patients in the fulvestrant plus palbociclib group and 166 patients in the fulvestrant plus placebo group responded to the questionnaire at baseline and at least during the first visit after treatment initiation.
Time to deterioration was predefined as the time between baseline pain level and the first occurrence of an increase of ≥10 points compared to baseline on the pain symptom scale. Adding palbociclib to fulvestrant treatment resulted in a significantly delayed time to pain symptom deterioration compared to fulvestrant with placebo (median 8.0 months vs. 2.8 months, HR 0.64 [95% CI: 0.49–0.85]; p < 0.001).
Endometrial effects in postmenopausal women
Preclinical data indicate no stimulatory effect of fulvestrant on the endometrium in postmenopausal women. A two-week study in healthy postmenopausal women receiving ethinylestradiol 20 mcg daily showed that pretreatment with fulvestrant 250 mg significantly reduced the stimulatory effect on the endometrium compared to pretreatment with placebo, as assessed by ultrasound measurement of endometrial thickness.
Neoadjuvant treatment for up to 16 weeks in breast cancer patients receiving either fulvestrant 500 mg or fulvestrant 250 mg did not result in clinically significant changes in endometrial thickness, indicating absence of agonistic activity. To date, there is no evidence of adverse effects on the endometrium in breast cancer patients treated with fulvestrant. There are no available data on the morphological structure of the endometrium.
In two short-term studies (1 and 12 weeks) involving premenopausal women with benign gynecological conditions, no statistically significant differences in endometrial thickness were observed between the fulvestrant and placebo treatment groups, as confirmed by ultrasound imaging.
Effects on bone
Data on the long-term effects of fulvestrant on bone are lacking. Neoadjuvant treatment for up to 16 weeks in breast cancer patients receiving either fulvestrant 500 mg or fulvestrant 250 mg did not result in clinically significant changes in serum markers of bone remodeling.
Pediatric population
Fulvestrant is not indicated for the treatment of children. The European Medicines Agency has waived the requirement to submit results of studies on the use of fulvestrant in all pediatric subgroups of patients with breast cancer (for use of the medicinal product in children, see section "Paediatric population").
In an open-label, phase 2 study, the safety, efficacy, and pharmacokinetics of fulvestrant were evaluated in 30 girls aged 1 to 8 years with progressive precocious puberty associated with Albright’s syndrome (MAS). Children received monthly intramuscular injections of 4 mg/kg fulvestrant. This 12-month study evaluated a range of efficacy endpoints for the use of the drug in MAS. Study results showed a reduction in the frequency of vaginal bleeding and a slowing of bone age maturation. Steady-state minimum concentrations of fulvestrant in children in this study were consistent with concentrations observed in adults (see section "Pharmacokinetics"). No new safety concerns emerged during this small study, although five-year data are not yet available.
Pharmacokinetics
Absorption
After administration as a prolonged-release intramuscular injection, fulvestrant is slowly absorbed, with peak plasma concentration (Cmax) reached approximately on day 5. With a dosing regimen of fulvestrant 500 mg, steady-state or near-steady-state exposure levels are achieved within the first month of treatment (mean [coefficient of variation (CV)]: AUC 475 [33.4%] ng·day/mL, Cmax 25.1 [35.3%] ng/mL, Cmin 16.3 [25.9%] ng/mL, respectively). At steady state, plasma concentrations of fulvestrant remain within a relatively narrow range, with approximately a threefold difference between maximum and minimum concentrations. After intramuscular administration in the dose range of 50 to 500 mg, exposure is approximately dose-proportional.
Distribution
Fulvestrant is extensively and rapidly distributed. The large apparent volume of distribution at steady state (Vdss), approximately 3 to 5 L/kg, indicates predominantly extravascular distribution. Fulvestrant is highly bound (99%) to plasma proteins. The main binding components are very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) fractions. Studies on protein-binding drug interactions have not been conducted. The role of sex hormone-binding globulin (SHBG) has not been established.
Biotransformation
The metabolism of fulvestrant is not fully characterized but involves a combination of multiple possible biotransformation pathways, similar to those of endogenous steroids. Identified metabolites (including 17-keto, sulfone, 3-sulfate, 3- and 17-glucuronide) are either less active or show similar activity to fulvestrant in antiestrogenic 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 pathways are believed to predominate in vivo. In vitro data suggest that fulvestrant does not inhibit CYP450 isoenzymes.
Elimination
Fulvestrant is primarily eliminated in metabolized form. The main route of elimination is fecal, with less than 1% excreted in urine. Fulvestrant has a high clearance of 11 ± 1.7 mL/min/kg, indicating a high hepatic extraction ratio. The terminal half-life (t1/2) after intramuscular administration is determined by the absorption rate and is estimated at 50 days.
Special patient populations
Population pharmacokinetic analysis of phase 3 study data revealed no differences in the pharmacokinetic profile of fulvestrant with regard to age (range 33 to 89 years), body weight (40 to 127 kg), or race.
Renal impairment. The effect of mild or moderate renal impairment on the pharmacokinetics of fulvestrant is not considered clinically significant.
Hepatic impairment. The pharmacokinetics of fulvestrant were evaluated in a clinical study using a single dose in women with mild and moderate hepatic impairment (Child-Pugh class A and B). A high dose for intramuscular injection was administered for a short duration. Compared to healthy volunteers, women with hepatic impairment showed an almost 2.5-fold increase in AUC. This level of AUC increase in patients receiving fulvestrant is expected to be well tolerated. Women with severe hepatic impairment (Child-Pugh class C) were not studied.
Pediatric population. Fulvestrant is not indicated for the treatment of children.
The European Medicines Agency has waived the requirement to submit results of studies on the use of fulvestrant in all pediatric subgroups of patients with breast cancer (for use of the medicinal product in children, see section "Paediatric population").
The pharmacokinetics of fulvestrant were evaluated in a clinical study involving 30 girls with progressive precocious puberty associated with Albright’s syndrome (see section "Pharmacodynamics"). Pediatric patients aged 1 to 8 years received intramuscular fulvestrant at a dose of 4 mg/kg monthly. The geometric mean (standard deviation) of steady-state minimum concentration (Cmin,ss) and AUCss were 4.2 (0.9) ng/mL and 3680 (1020) ng·h/mL, respectively. Although the available data are limited, steady-state minimum concentrations of fulvestrant in children are likely consistent with those in adults.
Preclinical safety data
Fulvestrant has low acute toxicity.
In animal studies, repeated doses of fulvestrant were well tolerated. Local reactions, including myositis and granulomas at the injection site, were more likely related to the vehicle or excipients of the formulation; however, the severity of myositis in rabbits was increased with fulvestrant compared to saline in the control group. In repeat-dose toxicity studies with intramuscular administration of fulvestrant in rats and dogs, the antiestrogenic activity of fulvestrant caused most of the observed effects, particularly in the female reproductive system and other hormone-sensitive organs in both sexes. In some dogs, prolonged (12-month) treatment was associated with arteritis affecting various tissues.
In dog studies, cardiovascular effects were observed after oral and intravenous administration (minor elevation of the S–T segment on ECG after oral administration and sinus arrest in one dog after intravenous administration). These effects occurred at concentrations exceeding those in patients (Cmax >15-fold), so these findings are likely of limited relevance to human safety at clinical doses.
Fulvestrant did not demonstrate genotoxic potential.
The effects of fulvestrant on reproductive function and embryonic/fetal development were consistent with its antiestrogenic activity when administered at doses similar to clinical doses. In rats, reversible reductions in fertility and embryonic survival, dystocia, and increased frequency of fetal developmental abnormalities, including bending of the metatarsal bones, were observed. Pregnant rabbits treated with fulvestrant failed to maintain pregnancy. Placental weight increased and post-implantation fetal loss occurred. Increased fetal variations were observed in rabbits (posterior displacement of the pelvic girdle and the 27th presacral vertebra).
A two-year carcinogenicity study in rats (with intramuscular administration of fulvestrant) showed an increased incidence of benign granulosa cell tumors of the ovaries in female rats at the high dose of 10 mg/rat every 15 days and an increased incidence of Leydig cell tumors of the testes in males. A two-year carcinogenicity study in mice (with daily oral administration) showed an increased incidence of sex cord-stromal ovarian tumors (both benign and malignant) at doses of 150 and 500 mg/kg/day. At the no-effect level, systemic exposure (AUC) in rats exceeded the expected human exposure by approximately 1.5-fold in females and 0.8-fold in males, while in mice it was approximately 0.8-fold higher in both males and females.
The development of these tumors is related to pharmacological changes in the endocrine system, particularly gonadotropin levels, induced by antiestrogens in experimental animals.
Therefore, these findings are not considered relevant to the use of fulvestrant in postmenopausal women with advanced breast cancer.
Environmental risk assessment
Environmental risk studies have shown that fulvestrant may have a negative impact on the aquatic environment.
Clinical characteristics.
Indications.
The medicinal product Fulvestrant is indicated:
- as monotherapy for the treatment of estrogen receptor-positive locally advanced or metastatic breast cancer in postmenopausal women:
- who have not previously received endocrine therapy;
- in case of disease recurrence during or after adjuvant antiestrogen therapy or disease progression during antiestrogen therapy;
- in combination with palbociclib for the treatment of hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) locally advanced or metastatic breast cancer in women who have received prior endocrine therapy (see section "Pharmacodynamics").
In premenopausal or perimenopausal women, combination treatment with palbociclib should be administered in combination with a luteinizing hormone-releasing hormone (LHRH) agonist.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Pregnancy and lactation (see section "Use during pregnancy or breastfeeding").
Severe hepatic impairment (see sections "Pharmacokinetics" and "Special precautions").
Interaction with other medicinal products and other types of interactions.
A clinical interaction study with midazolam (a CYP3A4 substrate) demonstrated that fulvestrant does not inhibit CYP3A4. Clinical interaction studies with rifampicin (a CYP3A4 inducer) and ketoconazole (a CYP3A4 inhibitor) showed no clinically significant changes in fulvestrant clearance. Therefore, dose adjustment is not required for patients receiving fulvestrant concomitantly with CYP3A4 inhibitors or inducers.
Special precautions for use.
Fulvestrant should be used with caution in patients with mild to moderate hepatic impairment (see sections "Pharmacokinetics", "Contraindications", and "Dosage and administration").
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 cautiously in patients with haemorrhagic diathesis, thrombocytopenia, or those receiving anticoagulant therapy.
Thromboembolic events are commonly observed in women with advanced breast cancer and have been reported in clinical trials with fulvestrant (see section "Adverse reactions"). This should be considered when prescribing fulvestrant to patients at risk.
Injection site reactions, including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy, have been reported with the administration of Fulvject. Due to the proximity of the sciatic nerve, caution should be exercised when administering Fulvject into the upper outer quadrant of the gluteal region (see sections "Dosage and administration" and "Adverse reactions").
There are no long-term data on the effects of fulvestrant on bone. Due to the mechanism of action of fulvestrant, there is a potential risk of developing osteoporosis.
The safety and efficacy of Fulvject (either as monotherapy or in combination with palbociclib) in patients with severe internal organ disease have not been studied.
The medicinal product contains castor oil, which may cause severe allergic reactions.
When fulvestrant is used in combination with palbociclib, also refer to the palbociclib summary of product characteristics.
Effect on estradiol assays using antibodies
Due to structural similarity between fulvestrant and estradiol, fulvestrant may interfere with immunoassay-based estradiol measurements, leading to falsely elevated estradiol levels.
Ethanol
Fulvject contains 12.4% w/v ethanol (alcohol) as an excipient, i.e., up to 1000 mg per dose, equivalent to 25 mL of beer or 10 mL of wine. This may be harmful to individuals suffering from alcoholism. The ethanol content should also be considered when prescribing the medicinal product to patients in high-risk groups, particularly those with hepatic impairment or epilepsy.
Benzyl alcohol
Fulvject contains benzyl alcohol as an excipient, which may cause allergic reactions.
Pediatric population
Fulvestrant is not recommended for use in children and adolescents, as its safety and efficacy in this age group have not been established (see section "Pharmacological properties").
Use during pregnancy or breastfeeding.
Women of reproductive potential
Women of reproductive potential must use effective contraception during treatment with fulvestrant and for 2 years after the last dose.
Pregnancy
Fulvestrant is contraindicated during pregnancy (see section "Contraindications"). Fulvestrant has been shown to cross the placental barrier after a single intramuscular dose in rats and rabbits. Animal studies have revealed reproductive toxicity, including increased incidence of fetal abnormalities and fetal death. If a patient becomes pregnant during treatment with fulvestrant, she should be informed of the potential hazard to the fetus and the potential risk of pregnancy loss.
Breastfeeding
Breastfeeding should be discontinued during treatment with fulvestrant. Fulvestrant is excreted into milk in lactating rats. It is not known whether fulvestrant is excreted in human breast milk. Given the potential for serious adverse reactions in breastfed infants due to fulvestrant, breastfeeding is contraindicated during treatment with this medicinal product (see section "Contraindications").
Fertility
The effect of fulvestrant on fertility in humans has not been studied.
Ability to affect reaction speed when driving or operating machinery.
Fulvestrant has no or negligible influence on the ability to drive or operate machinery. However, since asthenia has been reported very commonly during treatment with fulvestrant, patients who experience this adverse reaction while driving or operating machinery should exercise caution.
Method of Administration and Dosage
Dosage
Adult Women (including elderly patients)
The recommended dose is 500 mg administered once monthly; an additional 500 mg dose should be given 2 weeks after the first injection.
When fulvestrant is used in combination with palbociclib, also refer to the palbociclib summary of product characteristics.
Pre- and perimenopausal women receiving combination therapy with fulvestrant and palbociclib should receive GnRH agonists (gonadotropin-releasing hormone agonists) in accordance with local clinical practice guidelines.
Special Patient Populations
Renal Impairment
No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min). The efficacy and safety of the medicinal product have not been evaluated in patients with severe renal impairment (creatinine clearance < 30 mL/min); therefore, the product should be used with caution in these patients (see section "Special Warnings and Precautions for Use").
Hepatic Impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment. However, fulvestrant should be administered with caution in these patients due to the potential for increased fulvestrant AUC. Data in patients with severe hepatic impairment are lacking (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics").
Method of Administration
Fulveject should be administered as two consecutive slow (1–2 minutes per injection) intramuscular injections of 5 mL each, one into each buttock (gluteal area).
Due to the proximity of the sciatic nerve, caution should be exercised when administering Fulveject into the upper outer quadrant of the gluteal region.
Instructions for Administration
The medicinal product should be administered in accordance with local guidelines for administering large-volume intramuscular injections.
NOTE. Due to the proximity of the sciatic nerve, caution should be exercised when administering Fulveject into the upper outer quadrant of the gluteal region (see section "Special Warnings and Precautions for Use").
Warning: Do not autoclave the safety 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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Fig. 1 |
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Fig. 2 |
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Fig. 3 |
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Disposal
Pre-filled syringes are intended for single use only.
This medicinal product may pose a hazard to the aquatic environment.
Any unused medicinal products or waste materials must be disposed of in accordance with local requirements.
Children
The safety and efficacy of fulvestrant in children (from birth to 18 years of age) have not been established. The information currently available is presented in the sections "Pharmacodynamics" and "Pharmacokinetics"; however, dosage recommendations cannot be provided.
Overdose
There are isolated reports of fulvestrant overdose in humans. In case of overdose, symptomatic and supportive treatment is recommended. In animal studies, high doses of fulvestrant did not reveal any effects other than those directly or indirectly related to its antiestrogenic activity.
Adverse reactions
Summary of safety profile
Monotherapy
This section provides information on all adverse reactions reported from clinical trials, post-marketing studies, or spontaneous reports.
The most commonly reported adverse reactions were injection site reactions, asthenia, nausea, and increased levels of liver enzymes [ALT (alanine aminotransferase), AST (aspartate aminotransferase), ALP (alkaline phosphatase)].
The adverse reaction frequency categories listed below were derived from data in the fulvestrant 500 mg treatment group of the pooled safety analysis from studies comparing fulvestrant 500 mg and fulvestrant 250 mg [CONFIRM (study D6997C00002), FINDER 1 (study D6997C00004), FINDER 2 (study D6997C00006), and NEWEST (study D6997C00003)], or from the individual FALCON study (study D699BC00001), which compared fulvestrant 500 mg with anastrozole 1 mg. When the frequency of adverse reactions differed between the pooled safety analysis and FALCON, the higher frequency was used. The frequencies in Table 5 were determined based on data for all reported adverse reactions, regardless of the investigator's assessment of causal relationship. The median duration of treatment with fulvestrant 500 mg in the pooled data set (including the above-mentioned studies and the FALCON study) was 6.5 months.
List of adverse reactions
The adverse reactions listed below are classified by frequency and by system organ class. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.
Table 5
Adverse reactions reported in patients during fulvestrant monotherapy.
| Adverse reactions classified by frequency and organ system class |
||
| Infections and infestations |
Common |
Urinary tract infections |
| Blood and lymphatic system disorders |
Common |
Decreased platelet count |
| Immune system disorders |
Very common |
Hypersensitivity reactions |
| Uncommon |
Anaphylactic reactions |
|
| Metabolism and nutrition disorders |
Common |
Anorexiaa |
| Nervous system disorders |
Common |
Headache |
| Vascular disorders |
Very common |
Hot flushes |
| Common |
Vein thrombosis and thromboembolisma |
|
| Gastrointestinal disorders |
Very common |
Nausea |
| Common |
Vomiting, diarrhea |
|
| Hepatobiliary disorders |
Very common |
Increased levels of liver enzymes (ALT, AST, ALP)a |
| Common |
Increased bilirubin levelsa |
|
| Uncommon |
Liver failurec,f, hepatitisf, increased gamma-glutamyl transferase (GGT) levelsf |
|
| Skin and subcutaneous tissue disorders |
Very common |
Rash |
| Musculoskeletal and connective tissue disorders |
Very common |
Joint and muscle paind |
| Common |
Back paina |
|
| Reproductive system and breast disorders |
Common |
Vaginal bleeding |
| Uncommon |
Vaginal candidiasisf, leucorrhoeaf |
|
| General disorders and administration site conditions |
Very common |
Astheniaa, injection site reactionsb |
| Common |
Peripheral neuropathye, sciaticae |
|
| Uncommon |
Injection site haemorrhagef, injection site bruisingf, neuralgiac,f |
|
a Adverse reactions to the drug, the relationship of which with fulvestrant cannot be established due to the underlying disease, are included.
b The term "injection site reactions" does not include the terms "haemorrhage at injection site", "haematoma at injection site", "sciatica", "neuralgia", "peripheral neuropathy".
c The reaction was not observed in large clinical trials (CONFIRM, FINDER 1, FINDER 2, NEWEST).
The frequency was calculated using the upper limit of the 95% CI for point estimation. It was calculated as 3/560 (where 560 is the number of patients in large clinical trials), corresponding to the frequency category "uncommon".
d Includes arthralgia and less frequently musculoskeletal pain, myalgia, and limb pain.
e There are some differences in the frequency of adverse reactions in the corresponding organ and system categories between the safety study and the FALCON study.
f Adverse reactions were not observed in the FALCON study.
Description of selected adverse reactions
The following description is based on safety analysis from a group of 228 female patients who received at least one dose of fulvestrant and a group of 232 female patients who received at least one dose of anastrozole in the phase 3 FALCON study.
Joint pain and musculoskeletal pain. According to data from the FALCON study, the number of female patients who reported joint pain and musculoskeletal pain was 65 (31.2%) and 48 (24.1%) in the fulvestrant and anastrozole groups, respectively. Of the 65 patients receiving fulvestrant, 40% (26/65) reported joint and musculoskeletal pain during the first month of treatment, and 66% (43/65) during the first 3 months of treatment. None of the patients reported events of grade ≥3 according to CTCAE (Common Terminology Criteria for Adverse Events) or events requiring dose reduction, temporary interruption, or discontinuation of the drug 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 locally advanced or metastatic breast cancer in the randomized PALOMA3 study (see section "Pharmacodynamics"). The most common (≥20%) adverse reactions of any grade reported in patients receiving fulvestrant in combination with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, and vomiting. The most common (≥2%) adverse reactions of grade ≥3 were neutropenia, leukopenia, infections, anemia, increased AST levels, thrombocytopenia, and fatigue.
Table 6 presents data on adverse reactions observed in the PALOMA3 study.
The median duration of fulvestrant treatment was 11.2 months in the fulvestrant + palbociclib group and 4.8 months in the fulvestrant + placebo group. The mean duration of palbociclib treatment in the fulvestrant + palbociclib group was 10.8 months.
Table 6
Adverse reactions from the PALOMA3 study (N = 517)
| System organ class |
Fulvestrant + palbociclib |
Fulvestrant + placebo (N = 172) |
||
| All grades |
Grade ≥ 3 |
All grades n (%) |
Grade ≥ 3 |
|
| Infections and infestations |
||||
| Very common |
||||
| Infectionsb |
188 (54.5) |
19 (5.5) |
60 (34.9) |
6 (3.5) |
| Blood and lymphatic system disorders |
||||
| Very common |
||||
| Neutropeniac |
290 (84.1) |
240 (69.6) |
6 (3.5) |
0 |
| Leukopeniad |
207 (60.0) |
132 (38.3) |
9 (5.2) |
1 (0.6) |
| Anemiae |
109 (31.6) |
15 (4.3) |
24 (14.0) |
4 (2.3) |
| Thrombocytopeniaf |
88 (25.5) |
10 (2.9) |
0 |
0 |
| Uncommon |
||||
| Febrile neutropenia |
3 (0.9) |
3 (0.9) |
0 |
0 |
| Metabolism and nutrition disorders |
||||
| Very common |
||||
| Decreased appetite |
60 (17.4) |
4 (1.2) |
18 (10.5) |
1 (0.6) |
| Nervous system disorders |
||||
| Common |
||||
| Dysgeusia |
27 (7.8) |
0 |
6 (3.5) |
0 |
| Eye disorders |
||||
| Common |
||||
| Lacrimation increased |
25 (7.2) |
0 |
2 (1.2) |
0 |
| Blurred vision |
24 (7.0) |
0 |
3 (1.7) |
0 |
| Dry eye |
15 (4.3) |
0 |
3 (1.7) |
0 |
| Respiratory, thoracic and mediastinal disorders |
||||
| Common |
||||
| Nasal hemorrhage |
25 (7.2) |
0 |
4 (2.3) |
0 |
| Gastrointestinal disorders |
||||
| Very common |
||||
| Nausea |
124 (35.9) |
2 (0.6) |
53 (30.8) |
1 (0.6) |
| Stomatitisg |
104 (30.1) |
3 (0.9) |
24 (14.0) |
0 |
| Diarrhea |
94 (27.2) |
0 |
35 (20.3) |
2 (1.2) |
| Vomiting |
75 (21.7) |
2 (0.6) |
28 (16.3) |
1 (0.6) |
| Skin and subcutaneous tissue disorders |
||||
| Very common |
||||
| Alopecia |
67 (19.4) |
Not applicable |
11 (6.4) |
Not applicable |
| Rashh |
63 (18.3) |
3 (0.9) |
10 (5.8) |
0 |
| Common |
||||
| Dry skin |
28 (8.1) |
0 |
3 (1.7) |
0 |
| General disorders and administration site conditions |
||||
| Very common |
||||
| Fatigue |
152 (44.1) |
9 (2.6) |
54 (31.4) |
2 (1.2) |
| Pyrexia |
47 (13.6) |
1 (0.3) |
10 (5.8) |
0 |
| Common |
||||
| Asthenia |
27 (7.8) |
1 (0.3) |
13 (7.6) |
2 (1.2) |
| Investigations |
||||
| Very common |
||||
| Increased AST levels |
40 (11.6) |
11 (3.2) |
13 (7.6) |
4 (2.3) |
| Common |
||||
| Increased ALT levels |
30 (8.7) |
7 (2.0) |
10 (5.8) |
1 (0.6) |
ALT – alanine aminotransferase.
AST – aspartate aminotransferase.
N/n – number of patients.
a Preferred terms (PT) for reactions according to MedDRA 17.1 (Medical Dictionary for Regulatory Activities) are listed.
b All PTs belonging to the class "Infections and infestations".
c Neutropenia includes the following PTs: neutropenia, decreased neutrophil count.
d Leukopenia includes the following PTs: leukopenia, decreased white blood cell count.
e Anemia includes the following PTs: anemia, decreased hemoglobin, decreased hematocrit.
f Thrombocytopenia includes the following PTs: thrombocytopenia, decreased platelet count.
g Stomatitis includes the following PTs: aphthous stomatitis, cheilitis, glossitis, glossodynia, oral ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
h Rash includes the following PTs: rash, maculopapular rash, rash with pruritus, erythematous rash, papular rash, dermatitis, acneiform dermatitis, toxic skin eruption.
Description of selected adverse reactions
Neutropenia. In the PALOMA3 study, in which fulvestrant was administered in combination with palbociclib, neutropenia of any grade was reported in 290 (84.1%) patients, grade 3 neutropenia in 200 (58.0%) patients, and grade 4 neutropenia in 40 (11.6%) patients. In the fulvestrant + placebo group (n = 172), neutropenia of any grade was reported in 6 (3.5%) patients. No cases of grade 3 or 4 neutropenia were reported in the fulvestrant + placebo group.
In patients receiving fulvestrant in combination with palbociclib, the median time to first episode of neutropenia was 15 days (range: 13–512 days), and the median duration of grade ≥3 neutropenia was 16 days. Febrile neutropenia was reported in 3 (0.9%) patients receiving fulvestrant in combination with palbociclib.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 4 years.
Storage conditions.
Store in the original packaging to protect from light at a temperature of 2 to 8 °C.
Keep out of the reach of children.
Incompatibilities.
Since compatibility studies are lacking, this medicinal product should not be mixed with other medicinal products.
Packaging.
5 ml in a pre-filled syringe and blister, 2 blisters with syringe and 2 needles in a cardboard carton.
Prescription status.
Prescription only.
Manufacturer.
C.T. ROMPHARM COMPANY S.R.L. /
S.C. ROMPHARM COMPANY S.R.L.
Manufacturer's address and location of its operations.
Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Rompharm 1 and Rompharm 2 buildings.