Fulvestrant ever pharma

INSTRUCTIONS for medical use of the medicinal product Fulvestrant EVER Pharma (Fulvestrant EVER Pharma)

Composition:

Active substance: fulvestrant;

1 pre-filled syringe (5 ml) contains 250 mg of fulvestrant;

1 ml of solution contains 50 mg of fulvestrant;

Excipients: ethanol 96 %; benzyl alcohol; benzyl benzoate; castor oil, unrefined.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution ranging from slightly yellow to yellow in color.

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 binding affinity comparable to that of estradiol. Fulvestrant blocks the trophic effects of estrogens without exhibiting partial agonist (estrogen-like) activity. Its mechanism of action is associated with negative regulation of estrogen receptor protein levels. Clinical studies in postmenopausal women with primary breast cancer have demonstrated that fulvestrant significantly reduces levels of ER proteins in ER-positive tumors compared to placebo. A significant reduction in progesterone receptor expression was also observed, consistent with the absence of estrogen agonist-like effects. It has also been shown that fulvestrant at a dose of 500 mg suppresses ER and the proliferation marker Ki67 in breast tumors to a greater extent than the 250 mg dose during neoadjuvant treatment of postmenopausal women.

Clinical Efficacy and Safety of the Medicinal Product in Advanced Breast Cancer

Monotherapy

A phase 3 study was conducted in 736 postmenopausal women with advanced breast cancer who had experienced disease recurrence during or after adjuvant endocrine therapy or disease progression on endocrine therapy for advanced disease. The study included 423 patients with recurrence or progression during antiestrogen therapy (AE subgroup) and 313 patients with recurrence or progression during aromatase inhibitor therapy (AI subgroup). This study 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 study are summarized 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 study

a Fulvestrant is indicated for patients whose disease has recurred or progressed on prior anti-estrogen therapy. Results in the AI subgroup are not conclusive.

b The HR value is presented for the final survival analysis at 75% maturity.

c Nominal p-value without any adjustments made for multiplicity across primary overall survival analyses at 50% maturity and updated survival analyses at 75% maturity.

d ORR was analyzed in patients who were 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 for ≥24 weeks.

PFS: progression-free survival; ORR: objective response rate; OR: objective response; CBR: clinical benefit rate; CE: clinical efficacy; OS: overall survival; KM: Kaplan–Meier; CI: confidence interval; AI: aromatase inhibitor; AE: anti-estrogen.

A randomized, double-blind, double-dummy, multicenter, phase 3 study was conducted to evaluate the efficacy of fulvestrant 500 mg compared to anastrozole 1 mg in postmenopausal women with estrogen and/or progesterone receptor-positive locally advanced or metastatic 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 characteristics (locally advanced or metastatic cancer), prior chemotherapy for advanced disease, and presence of measurable disease.

The primary efficacy endpoint was investigator-assessed PFS according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). Key secondary efficacy endpoints included overall survival (OS) and objective response rate (ORR).

The median age of patients enrolled in this study was 63 years (range: 36–90 years). The majority of patients (87.0%) had metastatic disease at baseline; 55% of patients had visceral metastases at baseline. Overall, 17.1% of patients had previously received chemotherapy for advanced disease; 84.2% of patients had measurable disease.

Consistent results were observed across most predefined subgroups. In the subgroup of patients receiving fulvestrant with non-visceral metastases (n = 208), the HR was 0.592 (95% CI: 0.419–0.837) compared to those receiving anastrozole. In the subgroup of patients with visceral metastases receiving fulvestrant 500 mg (n = 254), 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 from the analysis of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the FALCON study (investigator assessment, full analysis set according to assigned treatment)

*(31% processed) – interim analysis of OS.

**For patients with measurable disease.

Figure 1.

Kaplan-Meier curve for progression-free survival (investigator assessment, "all randomized patients as treated" population) – FALCON study

Two phase 3 clinical studies were conducted in a total of 851 postmenopausal women with advanced breast cancer who experienced disease recurrence during or after adjuvant endocrine therapy or progression during endocrine therapy for advanced disease. 77% of the study population had estrogen receptor-positive breast cancer. In these studies, the safety and efficacy of monthly intramuscular fulvestrant 250 mg was compared with daily oral anastrozole 1 mg (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 in 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 to 85% of patients receiving anastrozole. The pooled analysis of both studies demonstrated a hazard ratio for progression-free survival of 0.95 (95% CI: 0.82–1.10) for fulvestrant 250 mg versus anastrozole. The objective response rate was 19.2% for fulvestrant 250 mg compared to 16.5% for anastrozole. Median time to death was 27.4 months in the fulvestrant group and 27.6 months in the anastrozole group. The hazard ratio for time to death for fulvestrant 250 mg versus anastrozole was 1.01 (95% CI: 0.86–1.19).

Combination therapy with palbociclib

A phase 3, international, randomized, double-blind, parallel-group, multicenter study evaluated fulvestrant 500 mg with palbociclib 125 mg versus fulvestrant 500 mg with placebo in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer that was not amenable to curative surgery or radiotherapy, regardless of menopausal status, and whose disease had progressed on or after prior (neo)adjuvant endocrine therapy or in the metastatic setting.

A total of 521 pre-/peri- and postmenopausal women whose disease progressed during or within 12 months after adjuvant endocrine therapy, or during or within 1 month after prior endocrine therapy for advanced disease, were randomized in a 2:1 ratio to receive fulvestrant plus palbociclib or fulvestrant plus placebo. Randomization was stratified by documented sensitivity to prior endocrine therapy, menopausal status at study entry (pre-/peri- or postmenopausal), and presence of visceral metastases. Premenopausal and perimenopausal women received the gonadotropin-releasing hormone (GnRH) agonist goserelin. Patients with symptomatic advanced/metastatic disease, visceral metastases at high risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitic carcinomatosis, or >50% liver involvement) were excluded from the study.

Patients continued their assigned treatment until objective disease progression, worsening of symptoms, unacceptable toxicity, death, or withdrawal of informed consent, whichever occurred first. Crossover between treatment groups was not permitted.

Patients were well balanced across baseline demographic and prognostic characteristics between the fulvestrant plus palbociclib and fulvestrant plus placebo groups. The median age of patients enrolled in this study was 57 years (range: 29 to 88 years). In each treatment group, the majority of patients were Caucasian, had documented sensitivity to prior endocrine therapy, and were postmenopausal. Approximately 20% of patients were pre-/perimenopausal. All patients had received prior systemic therapy, and most patients in each group had received prior chemotherapy for their initial diagnosis. More than half (62%) of patients had an ECOG performance status of 0, 60% had visceral metastases, and 60% had received more than one line of endocrine therapy for their initial diagnosis.

The primary endpoint of the study was progression-free survival (PFS) as assessed by the investigator according to RECIST 1.1 criteria. Additional PFS analyses were performed based on Independent Central Radiologic Review. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), safety, and time to deterioration (TTD) in the pain endpoint.

The study met its primary endpoint—prolongation of PFS as assessed by the investigator at the interim analysis of 82% of planned PFS events; results crossed the pre-specified Haybittle-Peto efficacy boundary (α = 0.00135), demonstrating a statistically significant improvement in PFS and a clinically meaningful treatment effect. More comprehensive updated efficacy data are presented in Table 3.

After a median follow-up of 45 months, a final OS analysis was performed based on data from 310 events (60% of randomized patients). A 6.9-month difference in median OS was observed in the palbociclib plus fulvestrant group compared to the placebo plus fulvestrant group; however, this result was not statistically significant according to the pre-specified 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 therapy after disease progression.

Results from the PALOMA-3 study for PFS (investigator assessment) and final OS data are presented in Table 3. Corresponding Kaplan-Meier curves are shown in Figures 2 and 3, respectively.

Table 3

Efficacy results – PALOMA-3 study (investigator assessment, "all randomized patients as treated" population)

KE = clinical efficacy; CI = confidence interval; N = number of patients; OR = objective response.

Secondary efficacy endpoints based on confirmed and unconfirmed responses according to RECIST 1.1 criteria.

* Not statistically significant.

† One-sided p-value derived from the log-rank test, stratified by presence of visceral metastases and sensitivity to prior endocrine therapy at randomization.

Figure 2

Kaplan–Meier curve for progression-free survival (investigator assessment, "all randomized patients according to assigned treatment" population) – PALOMA3 study (data cutoff date: October 25, 2018)

FUL = fulvestrant; PAL = palbociclib; PBO = placebo

Figure 3

Kaplan–Meier curve for overall survival (the "all randomized patients according to assigned treatment" population) – PALOMA3 study (data cutoff date: April 13, 2018)

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

A reduction in the risk of disease progression or death with fulvestrant plus palbociclib was observed across all prespecified patient subgroups defined by stratification factors and baseline characteristics. This effect was evident in women who were pre-/perimenopausal (HR 0.46 [95% CI: 0.28–0.75]) and postmenopausal (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 non-visceral metastases (HR 0.48 [95% CI: 0.33–0.71]). Benefit was also observed regardless of the number of prior lines of therapy for metastatic disease: 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 time to first tumor response [TTFR]), evaluated in subgroups of patients with and without visceral disease, are presented in Table 4.

Table 4

Efficacy results from the PALOMA3 study by visceral and non-visceral disease status ("all randomized patients according to assigned treatment" population)

* Results based on confirmed and unconfirmed responses.

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

Symptoms reported by patients were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ)-C30 questionnaire and its breast cancer module (EORTC QLQ-BR23). Overall, 335 patients in the fulvestrant plus palbociclib group and 166 patients in the fulvestrant plus placebo group completed questionnaires at baseline and at least one visit after the start of the study.

Time to deterioration was predefined as the time between baseline and the first occurrence of an increase of ≥10 points from baseline in pain symptom score. Compared with fulvestrant plus placebo, adding palbociclib to fulvestrant resulted in symptom improvement by significantly delaying pain deterioration (median: 8.0 months vs. 2.8 months; HR 0.64 [95% CI: 0.49–0.85]; p<0.001).

Effect on the endometrium in the postmenopausal period

Preclinical data do not indicate a stimulatory effect of fulvestrant on the endometrium in the postmenopausal period. A two-week study in healthy postmenopausal female volunteers receiving ethinylestradiol 20 mcg daily demonstrated that, compared with prior placebo administration, prior administration of fulvestrant 250 mg significantly reduced the stimulatory effect on the postmenopausal endometrium, as measured by ultrasound assessment of endometrial thickness.

Neoadjuvant treatment for up to 16 weeks in patients with breast cancer receiving either fulvestrant 500 mg or fulvestrant 250 mg did not result in clinically significant changes in endometrial thickness, indicating absence of agonistic effects. There is no evidence of adverse effects on the endometrium in the studied breast cancer patients. Data on endometrial morphology are lacking.

In two short-term studies (1 and 12 weeks) in premenopausal women with benign gynecological conditions, no statistically significant differences in endometrial thickness measured by ultrasound were observed between the fulvestrant and placebo treatment groups.

Effect on bones

Long-term data on the effect of fulvestrant on bones are lacking. Neoadjuvant treatment for up to 16 weeks in patients with breast cancer receiving either fulvestrant 500 mg or fulvestrant 250 mg did not result in clinically significant changes in serum markers of bone remodeling.

Children

Fulvestrant EVER Pharma is not indicated for use in children. The European Medicines Agency has waived the obligation to submit the results of fulvestrant studies in all pediatric subpopulations for the treatment of breast cancer (see section "Posology and method of administration" for information on use in children).

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 McCune-Albright syndrome (MAS). Patients received monthly intramuscular fulvestrant at a dose of 4 mg/kg. In this 12-month study, a range of efficacy endpoints for MAS were evaluated, and a reduction in the frequency of vaginal bleeding and a slowing of bone age maturation rate were observed. The minimum steady-state concentration of fulvestrant in children in this study was consistent with concentrations observed in adults (see section "Pharmacokinetics"). No new safety concerns arose during this small study, although five-year data are not yet available.

Pharmacokinetics.

Absorption

After intramuscular administration as a prolonged-release formulation, fulvestrant is slowly absorbed, and maximum plasma concentration (Cmax) is reached approximately on day 5. With a dosing regimen of fulvestrant 500 mg, steady-state or near-steady-state exposure is achieved within the first month of treatment (mean value (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, fulvestrant plasma concentrations are maintained within a relatively narrow range, with approximately a 3-fold difference between maximum and minimum concentrations. After intramuscular administration over 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 competitive protein-binding interactions have not been conducted. The role of sex hormone-binding globulin (SHBG) has not been established.

Metabolism

The metabolism of fulvestrant is not fully characterized but involves a combination of several potential 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 exhibit activity similar 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 indicate 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 to be 50 days.

Special patient populations

Population pharmacokinetic analysis showed no differences in the pharmacokinetic profile of fulvestrant according to age (range 33 to 89 years), body weight (40 to 127 kg), or race.

Renal impairment

Mild to moderate renal impairment did not affect the pharmacokinetics of fulvestrant in a clinically meaningful way.

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 of the shorter-acting intramuscular formulation was used. Compared with healthy subjects, women with hepatic impairment showed an almost 2.5-fold increase in AUC. An increase in exposure of this magnitude in patients receiving fulvestrant is expected to be well tolerated. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Children

The pharmacokinetics of fulvestrant were evaluated in a clinical study in 30 girls with progressive precocious puberty associated with McCune-Albright syndrome (see section "Pharmacodynamics"). Patients were aged 1 to 8 years and received monthly intramuscular fulvestrant at a dose of 4 mg/kg. 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. Despite limited available data, steady-state minimum concentrations of fulvestrant in children are likely to correspond to those in adults.

Clinical characteristics.

Indications.

The medicinal product Fulvestrant EVER Pharma 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, or
  • 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 HR-positive, HER2-negative locally advanced or metastatic breast cancer in women who have previously received endocrine therapy (see section "Pharmacodynamics").

For pre- or perimenopausal women, combination treatment with palbociclib should be combined with GnRH analogues.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").

Severe hepatic impairment (see sections "Pharmacokinetics" and "Special precautions for use").

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 EVER Pharma should be used with caution in patients with mild to moderate hepatic impairment (see sections "Pharmacokinetics", "Contraindications", and "Dosage and administration").

Fulvestrant EVER Pharma 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 EVER Pharma should be used with caution when treating patients with hemorrhagic diathesis, thrombocytopenia, or patients receiving anticoagulant therapy.

Thromboembolic events are frequently observed in women with advanced breast cancer and have been reported in clinical trials of fulvestrant (see section "Adverse reactions"). This should be taken into account when prescribing Fulvestrant EVER Pharma to patients who are at risk.

Injection site reactions, including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy, have been reported with fulvestrant administration. Due to the proximity of the underlying sciatic nerve, caution should be exercised when administering Fulvestrant EVER Pharma into the upper outer quadrant of the gluteal region (see sections "Dosage and administration" and "Adverse reactions").

Fulvestrant EVER Pharma contains 500 mg of alcohol (ethanol) per pre-filled syringe (10 vol.%), equivalent to less than 10 mL of beer or 4 mL of wine. The small amount of alcohol in this medicinal product is unlikely to have a noticeable effect. However, it may be harmful to patients suffering from alcoholism. Caution should be exercised when using this medicinal product in patients with liver disease or epilepsy.

Fulvestrant EVER Pharma contains 500 mg of benzyl alcohol per pre-filled syringe, equivalent to 100 mg/mL. Benzyl alcohol may cause allergic reactions. Large volumes should be used with caution and only when necessary, particularly in women with impaired hepatic or renal function, due to the risk of accumulation and development of toxicity (metabolic acidosis).

This medicinal product contains 750 mg of benzyl benzoate per pre-filled syringe, equivalent to 150 mg/mL.

This medicinal product contains castor oil, which may cause severe allergic reactions.

Long-term data on the effects of fulvestrant on bone are lacking. Due to the mechanism of action of fulvestrant, there is a potential risk of developing osteoporosis.

The efficacy and safety of fulvestrant (as monotherapy or in combination with palbociclib) have not been studied in patients with critical visceral disease.

When using combination therapy with Fulvestrant EVER Pharma and palbociclib, refer also to the Summary of Product Characteristics for palbociclib.

Effect on estradiol assay measurements using antibodies

Due to structural similarity between fulvestrant and estradiol, fulvestrant may interfere with immunoassay-based estradiol measurements, leading to falsely elevated estradiol levels.

Children

Fulvestrant EVER Pharma is not recommended for use in children, as its safety and efficacy have not been established in this patient population (see section "Pharmacodynamics"). Fulvestrant EVER Pharma contains benzyl alcohol. The risk of toxicity is increased in young children due to accumulation.

Use during pregnancy or breastfeeding.

Women of reproductive potential

Women of reproductive potential should use effective contraception during treatment with Fulvestrant EVER Pharma and for 2 years after the last dose.

Pregnancy

Fulvestrant EVER Pharma is contraindicated during pregnancy (see section "Contraindications"). Fulvestrant has been shown to cross the placenta after a single intramuscular dose in rats and rabbits. Reproductive toxicity, including increased incidence of developmental abnormalities and fetal death, has been observed in animal studies. If a patient becomes pregnant while receiving Fulvestrant EVER Pharma, she should be informed of the potential risk to the fetus and the potential risk of pregnancy loss.

Breastfeeding

Breastfeeding should be discontinued during treatment with Fulvestrant EVER Pharma. Fulvestrant is excreted into the milk of lactating rats. There is no information available on the excretion of fulvestrant into human breast milk. Given the potential for serious adverse reactions in breastfed infants due to fulvestrant, the use of this medicinal product during breastfeeding is contraindicated (see section "Contraindications").

Fertility

The effect of fulvestrant on human fertility has not been studied.

Ability to affect the speed of reactions when driving or operating machinery.

Fulvestrant EVER Pharma has no effect or has a negligible effect on the ability to drive or operate machinery. However, since asthenia has been reported very commonly during treatment with fulvestrant, patients experiencing this adverse reaction should exercise caution when driving or operating machinery.

Administration and Dosage

Dosage

Adult Women (including elderly patients)

The recommended dose is 500 mg, followed by an additional 500 mg dose administered 2 weeks after the first injection, with subsequent doses given at monthly intervals.

When Fulvestrant EVER Pharma is used in combination with palbociclib, the Summary of Product Characteristics for palbociclib should also be consulted.

Premenopausal and perimenopausal women should receive GnRH agonists in accordance with local clinical practice guidelines prior to and throughout the duration of combination treatment with Fulvestrant EVER Pharma and palbociclib.

Special Patient Populations

Renal Impairment

No dose adjustment is recommended for 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 recommended for patients with mild to moderate hepatic impairment. However, Fulvestrant EVER Pharma should be administered with caution in these patients due to the potential for increased fulvestrant exposure. Data in patients with severe hepatic impairment are lacking (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").

Method of Administration

Fulvestrant EVER Pharma 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 underlying sciatic nerve, caution should be exercised when administering Fulvestrant EVER Pharma 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 underlying sciatic nerve, caution should be exercised when administering Fulvestrant EVER Pharma into the upper outer quadrant of the gluteal region (see section "Special Warnings and Precautions for Use").

Warning: Do not autoclave the safety needle (BD SafetyGlideTM needle with protective cap) before use. Hands must remain behind the needle during the entire period of use and disposal.

For one or each of the two syringes:

Disposal

Pre-filled syringes are intended for single use only.

This medicinal product may be hazardous to the aquatic environment. Any unused medicinal product or waste material 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. Current available data are described in the sections “Pharmacodynamics” and “Pharmacokinetics”, but no dosage recommendation can be made.

Overdose.

There have been isolated reports of fulvestrant overdose in humans. In the event of overdose, symptomatic and supportive treatment is recommended.

Animal studies indicate that administration of high doses of fulvestrant was not associated with any effects other than those directly or indirectly related to antiestrogenic activity.

Adverse reactions.

Summary of safety profile

Monotherapy

The information in this section is based on data on all adverse reactions obtained from clinical trials, post-marketing studies, or spontaneous reports. In the pooled safety dataset of fulvestrant monotherapy, the most commonly reported adverse reactions were injection site reactions, asthenia, nausea, and increased liver enzymes (ALT, AST, ALP).

The adverse reaction frequency categories listed in Table 5 were derived from the fulvestrant 500 mg treatment group in the pooled safety analysis of studies comparing fulvestrant 500 mg with fulvestrant 250 mg (CONFIRM (study D6997C00002), FINDER 1 (study D6997C00004), FINDER 2 (study D6997C00006), and NEWEST (study D6997C00003)), or from the separate 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 the FALCON study, the higher frequency is presented. The frequencies in Table 5 were determined based on data for all reported adverse reactions, regardless of the investigator's assessment of causality. The median duration of treatment with fulvestrant 500 mg in the pooled dataset (including the studies listed above and the FALCON study) was 6.5 months.

List of adverse reactions in tabular form

The adverse reactions listed below are classified by frequency and by system organ class (SOC). Frequency categories are defined according to the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 5

Adverse drug reactions in patients receiving fulvestrant as monotherapy

a Includes adverse drug reactions for which the relationship to fulvestrant administration cannot be precisely assessed due to the underlying disease.

b The term "injection site reactions" does not include the terms "hemorrhage at injection site", "hematoma at injection site", "sciatica", "neuralgia", "peripheral neuropathy".

c The event was not observed in large clinical trials. The frequency was calculated using the upper limit of the 95% CI for the point estimate. 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 The frequency category differs between the combined safety data set and the FALCON study.

f Adverse drug reactions were not observed in the FALCON study.

Description of selected adverse reactions

The description below is based on safety analysis in a group of 228 patients who received at least one dose of fulvestrant and a group of 232 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 patients reporting adverse reactions of joint pain and musculoskeletal pain was 65 (31.2%) and 48 (24.1%) in the fulvestrant and anastrozole groups, respectively. Of the 65 patients in the fulvestrant group, 40% (26/65) reported joint pain and musculoskeletal pain within the first month of treatment, and 66% (43/65) within the first 3 months of treatment. None of the patients reported events of grade ≥3 according to CTCAE scale or cases requiring dose reduction, temporary interruption, or discontinuation of 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 who participated in the randomized PALOMA3 study (see section "Pharmacodynamics"). The most common adverse reactions of any grade (≥20%) 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 lists the adverse reactions recorded during the PALOMA3 study.

The median duration of fulvestrant treatment was 11.2 months in the fulvestrant plus palbociclib group and 4.8 months in the fulvestrant plus placebo group. The median duration of palbociclib treatment in the fulvestrant plus palbociclib group was 10.8 months.

Table 6

Adverse reactions from the PALOMA3 study (N = 517)

ALT = alanine aminotransferase; AST = aspartate aminotransferase; N/n = number of patients; NA = not applicable

a Preferred Terms (PT) are listed according to MedDRA 17.1.

b Infections include all PTs belonging to the System Organ 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 pruritic, erythematous rash, papular rash, dermatitis, acneiform dermatitis, toxic skin eruption.

Description of selected adverse reactions

Neutropenia

Among patients who received fulvestrant in combination with palbociclib in the PALOMA-3 study, neutropenia of any grade was reported in 290 (84.1%) patients, including grade 3 neutropenia in 200 (58.0%) patients and grade 4 neutropenia in 40 (11.6%) patients. In the fulvestrant plus 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 plus placebo group.

In patients receiving fulvestrant in combination with palbociclib, the median time to first occurrence of neutropenia of any grade was 15 days (range 13 to 512 days), and the median duration of neutropenia ≥ grade 3 was 16 days. Febrile neutropenia was observed in 3 (0.9%) patients receiving fulvestrant in combination with palbociclib.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Keep out of the reach of children. No special storage conditions required.

Incompatibilities.

Since compatibility studies are lacking, this medicinal product must not be mixed with other medicinal products.

Packaging.

5 ml in a pre-filled syringe; 1 or 2 pre-filled syringes with 1 or 2 safety needles in a cardboard box

or pack pack:

5 ml in a pre-filled syringe; 2 pre-filled syringes with 2 safety needles in a cardboard box; 3 cardboard boxes packed in transparent film.

Prescription status. Prescription only.

Manufacturer.

EVER Pharma Jena GmbH.

Manufacturer's address.

Otto-Schott-Strasse 15, South, Jena, Thuringia, 07745, Germany.

Marketing Authorization Holder.

EVER Wellinject GmbH.

Address of the Marketing Authorization Holder.

Oberburgau 3, 4866 Unterach am Attersee, Austria.