Falvax

INSTRUCTIONS for medical use of the medicinal product FALVAX (FALVAX)

Composition:

Active substance: fulvestrant;

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

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: a clear, colorless to yellow, viscous liquid without visible particles.

Pharmacotherapeutic group. Hormone antagonists and related agents. Anti-estrogens. ATC code L02BA03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action and pharmacodynamic effect

Fulvestrant is an estrogen receptor (ER) antagonist with a binding affinity comparable to that of estradiol. Fulvestrant blocks the trophic effects of estrogens without exhibiting any partial agonist (estrogen-like) activity. Its mechanism of action involves 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 has also been observed, consistent with the absence of intrinsic estrogen agonist activity. Furthermore, it has been demonstrated that 500 mg of fulvestrant suppresses ER and the proliferation marker Ki67 to a greater extent than 250 mg of fulvestrant in the neoadjuvant treatment of breast tumors in postmenopausal women.

Clinical safety and efficacy of the medicinal product in advanced stages of breast cancer

Monotherapy

A phase III clinical trial was conducted in 736 postmenopausal women with advanced breast cancer who had disease recurrence during or after adjuvant endocrine therapy or disease progression on endocrine therapy for advanced disease. The study included 423 patients whose disease recurred or progressed during anti-estrogen therapy (AE subgroup) and 313 patients whose disease recurred or progressed while receiving aromatase inhibitors (AI subgroup). This study compared the efficacy and safety of fulvestrant administered at a dose of 500 mg (n = 362) versus 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). The efficacy results from the CONFIRM study are summarized below in Table 1.

Summary of results from the analysis of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the CONFIRM study

Table 1

and 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 Hazard ratio (HR) value presented for the final survival analysis at 75% maturity.

c Nominal p-value without any adjustments made for multiplicity of comparisons between the primary overall survival analysis at 50% maturity and the updated survival analysis at 75% maturity.

d CBR 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 achieving best objective response of complete response, partial response, or stable disease lasting ≥24 weeks.

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

A randomized, double-blind, double-dummy, multicenter Phase III study was conducted to evaluate the efficacy of fulvestrant 500 mg compared to anastrozole 1 mg in postmenopausal women with estrogen receptor 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), prior chemotherapy for advanced disease, and clinical presentation of disease.

The primary efficacy endpoint was progression-free survival (PFS) assessed by the investigator 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 to 90 years). The majority of patients (87.0%) had metastatic disease at study initiation. 55% of patients had visceral metastases at baseline. Overall, 17.1% of patients had received prior chemotherapy for advanced disease; 84.2% of patients had measurable disease.

Significant results were observed in the majority of prespecified 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, 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.

Summary of results from the analysis of the primary efficacy endpoint (PFS) and key
secondary efficacy endpoints in the FALCON study (investigator assessment,
"all randomized patients" intent-to-treat population)

Table 2

* - (31% mature) – the AE analysis is not final.

** - For patients with measurable disease.

Figure 1

Kaplan–Meier curve of PFS (investigator assessment, "all randomized patients according to assigned treatment" population), FALCON study

Two phase III clinical studies were conducted overall in 851 postmenopausal women with advanced breast cancer who had disease recurrence during or after adjuvant hormonal therapy or disease progression following hormonal therapy for advanced disease. 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, fulvestrant administered at a monthly dose of 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 found the hazard ratio for fulvestrant 250 mg versus anastrozole for progression-free survival was 0.95 (95% CI 0.82–1.10). The objective response rate for fulvestrant 250 mg was 19.2% compared with 16.5% for anastrozole. Median time to death was 27.4 months for patients receiving fulvestrant and 27.6 months for those receiving anastrozole. The hazard ratio for fulvestrant 250 mg versus anastrozole for time to death was 1.01 (95% CI 0.86–1.19).

Combination therapy with palbociclib

A global, randomized, double-blind, multicenter, parallel-group phase III study was conducted to evaluate fulvestrant 500 mg plus palbociclib 125 mg versus fulvestrant 500 mg plus placebo in women with HR-positive, 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 endocrine therapy in the (neo)adjuvant or metastatic setting.

A total of 521 pre-/peri- 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. Patients were stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre-/peri- or postmenopausal), and presence of visceral metastases. Women who were pre-/perimenopausal received the GnRH agonist goserelin. Patients with extensive/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 exceeding 50%) were not eligible for the study.

Patients continued their assigned treatment until objective disease progression, symptomatic deterioration, 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 plus palbociclib and fulvestrant plus placebo groups. The median age of enrolled patients 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 received prior systemic therapy, and most patients in each treatment group had received prior chemotherapy for their initial diagnosis. More than half of the patients (62%) had an ECOG PS of 0, 60% had visceral metastases, and 60% had received more than one prior hormonal therapy for their initial diagnosis.

The primary endpoint of the study was progression-free survival (PFS), defined according to RECIST 1.1 criteria, as assessed by the investigator. Additional PFS analyses were determined based on independent central radiological review. Secondary endpoints included objective response (OR), clinical benefit rate (CBR), overall survival (OS), safety, and time to deterioration of symptoms (TTD) using pain intensity as the endpoint.

The study met its primary endpoint—prolonged PFS as assessed by the investigator, at an interim analysis of 82% of planned PFS events; results crossed the pre-specified Haybittle–Peto efficacy boundary (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 plus palbociclib group versus 4.6 months in the fulvestrant plus 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 death events (60% of randomized patients). A difference in median OS of 6.9 months was observed in favor of the palbociclib plus fulvestrant group compared to placebo plus fulvestrant; however, this result did not reach statistical significance at the prespecified 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.

PFS and final OS results, as assessed by the investigator, from the PALOMA-3 study are presented in Table 3.

Efficacy results from the PALOMA-3 study (investigator assessment, population: all randomized patients according to assigned treatment)

Table 3

PFS – progression-free survival; CRR – clinical benefit rate; CI – confidence interval; N – number of patients; OR – objective response.

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

* Statistically not significant.

† One-sided p-values, stratified using the 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 plus palbociclib treatment group was observed across all prespecified patient subgroups 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 prior lines of therapy in the presence of metastases, with 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 prior lines (HR 0.59 [95% CI: 0.28; 1.22]). Additional efficacy outcomes (OR and CBR), evaluated in subgroups of patients with or without visceral disease, are shown in Table 4.

PALOMA-3 study results on efficacy in visceral and non-visceral disease
(population: all randomized patients according to assigned treatment)

Table 4

* – Results based on confirmed and unconfirmed responses.

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

Patient-reported symptoms were collected and overall quality of life was assessed 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 completed the questionnaire at baseline and at least during the first visit after treatment initiation.

Time to worsening was predefined as the time between baseline pain level and the first occurrence of an increase ≥10 points compared to baseline on the pain symptom scale. Adding palbociclib to fulvestrant treatment resulted in a significantly delayed time to worsening of pain symptoms 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).

Effect on the endometrium in the postmenopausal period

Preclinical data indicate the absence of a stimulatory effect of fulvestrant on the endometrium in the postmenopausal period. A two-week study in healthy postmenopausal volunteers receiving ethinylestradiol 20 µg daily showed that pretreatment with fulvestrant 250 mg significantly reduced the stimulatory effect on the postmenopausal endometrium compared to placebo pretreatment, 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 the absence of an agonistic effect. Currently, there is no evidence of adverse effects on the endometrium in the treatment of patients with breast cancer. There are no available data regarding 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 findings.

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 lead to clinically significant changes in serum markers of bone remodeling.

Pediatric population

The medicinal product is not indicated for the treatment of children. The European Medicines Agency has waived the obligation to submit results of studies with fulvestrant in all pediatric subgroups of patients with breast cancer (information on use of the medicinal product in children is provided in section "Posology and method of administration").

In an open-label Phase II 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). 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 medicinal product 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 comparable to those 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 of the prolonged-release formulation of Falvax, fulvestrant is slowly absorbed, reaching peak plasma concentration (Cmax) approximately on day 5. Administration of the 500 mg dose achieves or approaches exposure levels and steady-state concentrations during the first month of dosing (mean value [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 rapidly and extensively 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). The role of sex hormone-binding globulin has not been established.

Biotransformation

The metabolism of fulvestrant is not fully characterized but involves a combination of several possible biotransformation pathways, similar to those of endogenous steroids. Identified metabolites (including 17-keto, sulfone, 3-sulfate, 3- and 17-glucuronide metabolites) are less active or have the same activity as fulvestrant in antiestrogenic models. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome (CYP3A4) is the only P450 isoenzyme involved in the oxidation of fulvestrant; however, it is believed that in vivo, non-P450 pathways predominate. 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 coefficient. The terminal half-life (t1/2) after intramuscular administration is determined by the absorption rate and is approximately 50 days.

Special patient populations

No differences in the pharmacokinetic profile of fulvestrant were observed according to age (range 33 to 89 years), body weight (40 to 127 kg), or race.

Patients with renal impairment

Mild and moderate renal impairment did not have any clinically significant effect on the pharmacokinetics of fulvestrant.

Patients with hepatic impairment

The pharmacokinetics of fulvestrant were evaluated in patients with mild and moderate hepatic impairment (Child-Pugh classes A and B). High doses were administered intramuscularly for a short duration. In subjects with hepatic impairment, the mean area under the curve increased by almost 2.5-fold compared to healthy volunteers. An increase in exposure of this magnitude in patients receiving fulvestrant is likely to be well tolerated.

Children

The pharmacokinetics of fulvestrant were clinically evaluated in 30 girls with progressive precocious puberty due to McCune-Albright-Sternberg syndrome. Pediatric patients (aged 1 to 8 years) received a dose of fulvestrant 4 mg/kg administered intramuscularly monthly. The geometric mean (standard deviation) of the steady-state minimum concentration (Cmin,ss) and AUCss was 4.2 (0.9) ng/mL and 3680 (1020) ng·h/mL, respectively. Although data are limited, steady-state minimum concentrations of fulvestrant in children appear to be comparable to those in adults.

Clinical characteristics.

Indications.

Fulvax is indicated:

• as monotherapy for the treatment of postmenopausal women with locally advanced or metastatic estrogen receptor-positive breast cancer:
  • who have not previously received hormonal therapy, or
  • who have experienced disease recurrence during or after adjuvant antiestrogen therapy or disease progression while on antiestrogen therapy;
• in combination with palbociclib for the treatment of hormone receptor-positive (HR-positive), human epidermal growth factor receptor type 2-negative (HER2-negative) locally advanced or metastatic breast cancer in women who have received prior endocrine therapy.

In premenopausal or perimenopausal women, combination treatment with palbociclib should be administered in combination with a gonadotropin-releasing hormone (GnRH) agonist.

Contraindications.

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

Pregnancy or breastfeeding (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.

It has been reported that fulvestrant does not inhibit CYP3A4 when coadministered with midazolam (a CYP3A4 substrate). No clinically significant changes in fulvestrant clearance were observed when administered with rifampicin (a CYP3A4 inducer) or ketoconazole (a CYP3A4 inhibitor). Therefore, dose adjustment is not necessary for patients receiving fulvestrant concomitantly with CYP3A4 inhibitors or inducers.

Special precautions for use.

Fulvax should be used with caution in patients with mild to moderate hepatic impairment.

Fulvax 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, Fulvax should be used with caution in patients with hemorrhagic diathesis, thrombocytopenia, or those taking anticoagulant medicinal products.

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 taken into account when prescribing fulvestrant to patients at risk.

Injection site reactions, including lumbosacral radiculitis, sciatica, neuralgia, neuropathic pain, and peripheral neuropathy, have been reported following administration of Fulvax. Due to the close proximity of the sciatic nerve, caution should be exercised when administering Fulvax into the upper outer quadrant of the gluteal region (see sections "Dosage and administration" and "Adverse reactions").

There is no long-term information available on the effect of fulvestrant on bone tissue. Given the mechanism of action of fulvestrant, there is a potential risk of developing osteoporosis.

The safety and efficacy of Fulvax (as monotherapy or in combination with palbociclib) have not been studied in patients with severe internal organ disease.

For combination of Fulvax with palbociclib, see also the summary of product characteristics for palbociclib.

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

The medicinal product contains 10% w/v ethanol (alcohol) as excipient, equivalent to 10 mL of beer or 4 mL of wine per 500 mg injection. This may be harmful for individuals suffering from alcoholism and should be considered in high-risk groups such as patients with liver disease and epilepsy.

Benzyl alcohol

The medicinal product contains benzyl alcohol as excipient, which may cause allergic reactions.

Children

Fulvax is not recommended for use in children and adolescents, as the safety and efficacy of the medicinal product in this age group have not been established.

Use during pregnancy or breastfeeding

Women of reproductive potential

Women of reproductive potential should be advised to use effective contraception during treatment with the medicinal product and for 2 years after the last dose.

Pregnancy

Fulvax is contraindicated during pregnancy. Reproductive toxicity, including increased incidence of fetal abnormalities and fetal death, has been observed in animal studies. Fulvestrant has been shown to cross the placental barrier after single intramuscular administration in rats and rabbits. If pregnancy occurs during treatment with fulvestrant, the patient should be informed of the potential risk to the fetus and the potential risk of pregnancy loss.

Breastfeeding

Breastfeeding must be discontinued during treatment with Fulvax. It is currently unknown whether fulvestrant is excreted in human breast milk. Animal studies have shown that fulvestrant is excreted in the milk of lactating rats. Due to the potential for serious adverse reactions in breastfed infants, fulvestrant is contraindicated during breastfeeding.

Effect on fertility

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

Ability to influence the ability to drive and use machines

Fulvax has negligible or no influence on the ability to drive or use machines. However, since asthenia has been very commonly reported 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 administered every month, with an additional 500 mg dose given two weeks after the first dose.

Women in the pre-/perimenopausal period should receive GnRH agonists (gonadotropin-releasing hormone agonists) prior to and during combination therapy with the medicinal product Falvax and palbociclib, in accordance with local clinical practice guidelines.

Special Patient Populations

Patients with Renal Impairment

Patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min) do not require dose adjustment. The safety and efficacy of the medicinal product in patients with severe renal impairment (creatinine clearance < 30 mL/min) have not been established; therefore, the product should be used with caution in such patients.

Patients with Hepatic Impairment

Patients with mild to moderate hepatic impairment do not require dose adjustment. However, caution should be exercised in these patients due to the potential for increased fulvestrant exposure. There are no data on the use of the medicinal product in patients with severe hepatic impairment.

Administration Method

The medicinal product Falvax 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 close proximity of the sciatic nerve, caution should be exercised when administering Falvax into the upper outer quadrant of the gluteal region.

Instructions for Administration

Caution! Do not sterilize safety needles in an autoclave prior to use. Hands must always remain behind the needle during application and disposal.

For each of the two syringes:

Disposal

Pre-filled syringes are intended for single use only.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Children.

Safety and efficacy of Folvax in children from birth to 18 years of age have not been established. The currently available data described in the sections "Pharmacokinetics" and "Pharmacodynamics" are insufficient to establish dosing recommendations for pediatric use.

Overdose.

Cases of overdose have been reported in humans. In the event of overdose, symptomatic and supportive treatment is recommended. Animal studies indicate that effects of higher doses of fulvestrant are directly or indirectly related to its antiestrogenic activity.

Adverse reactions.

Summary of safety profile

Monotherapy

This section provides information based on all adverse reactions reported from clinical trials, post-marketing studies, or spontaneous reports. In the pooled monotherapy safety dataset with fulvestrant, the most frequently reported adverse reactions were injection site reactions, asthenia, nausea, and increased levels of liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase).

The frequency categories of adverse reactions listed in Table 5 were derived from the fulvestrant 500 mg treatment group in the pooled safety analysis of studies comparing fulvestrant 500 mg versus 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 the FALCON study, the higher frequency was selected. The frequencies listed in Table 5 are 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 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 system organ class (SOC) and frequency. Frequencies are categorized according to the following conventional criteria: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions reported in patients during monotherapy with the medicinal product

Table 5

a Includes adverse drug reactions for which the influence of fulvestrant on their occurrence could not be precisely assessed due to the underlying disease.

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 as 3/560 (where 560 is the number of patients in the main 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 between the respective categories based on the combined safety data 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 of a group of 228 patients who received at least one (1) dose of fulvestrant and a group of 232 patients who received at least one (1) 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 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 66.2% (43/65) during the first 3 months of treatment. None of the patients reported events of grade ≥3 according to CTCAE 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 median duration of palbociclib treatment in the fulvestrant + palbociclib group was 10.8 months.

Adverse reactions from the PALOMA3 study (N=517)

Table 6

ALT = alanine aminotransferase; AST = aspartate aminotransferase; N/n = number of patients

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

b 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 Anaemia includes the following PTs: anaemia, decreased haemoglobin, decreased haematocrit.

f Thrombocytopenia includes the following PTs: thrombocytopenia, decreased platelet count.

g Stomatitis includes the following PTs: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.

h Rash includes the following PTs: rash, maculopapular rash, rash with pruritus, erythematous rash, papular rash, dermatitis, acneiform dermatitis, toxic skin eruption.

Description of selected adverse reactions.

Neutropenia.

In patients receiving fulvestrant in combination with palbociclib in the PALOMA-3 study, neutropenia of any grade was reported in 290 (84.1%) patients, grade III neutropenia in 200 (58.0%) patients, and grade IV 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 III or IV 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), and the median duration of neutropenia of grade ≥III was 16 days. Febrile neutropenia was reported in 3 (0.9%) patients receiving fulvestrant in combination with palbociclib.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization. This allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals and pharmaceutical personnel, 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: https://aisf.dec.gov.ua/, as well as via the Applicant’s email address.

Shelf life.

2 years.

Storage conditions.

Store in a refrigerator at 2 °C to 8 °C.

Store in the original packaging in a place protected from light. Keep out of the reach of children.

Packaging.

5 ml in a pre-filled syringe; 2 pre-filled syringes together with two safety needles in a blister pack or contour cell packaging; 1 blister pack or 1 contour cell pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Dr. Reddy’s Laboratories Limited, Manufacturing Unit - 9.

Manufacturer’s address and place of business.

Units Q1–Q5, Phase III, Duvada, Visakhapatnam, Andhra Pradesh 530 046, India.