Fulvestrant Dr. Reddy's 250 mg Solution For Injection in Pre-Filled Syringe

1. Name of the medicinal product

Fulvestrant Dr. Reddy's 250 mg Solution For Injection in Pre-Filled Syringe

 

2. Qualitative and quantitative composition

One pre-filled syringe contains 250 mg fulvestrant in 5 ml solution.

Each ml contains 50 mg fulvestrant.

Excipients with known effect:

One pre-filled syringe contains 500 mg ethanol 96 % (alcohol), 500 mg benzyl alcohol, 750 mg benzyl benzoate, up to 5 ml castor oil refined.

 

3. Pharmaceutical form

Solution for injection in pre-filled syringe.

Clear, colourless to yellow, viscous liquid solution.

 

4. Clinical particulars

4.1 Therapeutic indications

Fulvestrant is indicated

• as monotherapy for the treatment of estrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women:

- not previously treated with endocrine therapy, or

- with disease relapse on or after adjuvant antiestrogen therapy, or disease progression on antiestrogen therapy.

• in combination with palbociclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in women who have received prior endocrine therapy (see section 5.1).

In pre- or perimenopausal women, the combination treatment with palbociclib should be combined with a luteinizing hormone releasing hormone (LHRH) agonist.

 

4.2 Posology and method of administration

Posology

Adult females (including Elderly)

The recommended dose is 500 mg at intervals of one month, with an additional 500 mg dose given two weeks after the initial dose.

When Fulvestrant is used in combination with palbociclib, please also refer to the Summary of Product Characteristics of palbociclib.

Prior to the start of treatment with the combination of Fulvestrant plus palbociclib, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.

Special populations

Renal impairment

No dose adjustments are recommended for patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min). Safety and efficacy have not been evaluated in patients with severe renal impairment (creatinine clearance < 30 ml/min), and, therefore, caution is recommended in these patients (see section 4.4).

Hepatic impairment

No dose adjustments are recommended for patients with mild to moderate hepatic impairment. However, as fulvestrant exposure may be increased, fulvestrant should be used with caution in these patients. There are no data in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).

Paediatric population

The safety and efficacy of fulvestrant in children from birth to 18 years of age have not been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

Fulvestrant should be administered as two consecutive 5 ml injections by slow intramuscular injection (1-2 minutes/injection), one in each buttock (gluteal area).

Caution should be taken if injecting fulvestrant at the dorsogluteal site due to the proximity of the underlying sciatic nerve.

For detailed instructions for administration, see section 6.6.

 

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy and lactation (see section 4.6).

Severe hepatic impairment (see sections 4.4 and 5.2).

 

4.4 Special warnings and precautions for use

Fulvestrant should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).

Fulvestrant should be used with caution in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Due to the intramuscular route of administration, Fulvestrant should be used with caution if treating patients with bleeding diatheses, thrombocytopenia or those taking anticoagulant treatment.

Thromboembolic events are commonly observed in women with advanced breast cancer and have been observed in clinical studies with fulvestrant (see section 4.8). This should be taken into consideration when prescribing fulvestrant to patients at risk.

Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with fulvestrant injection. Caution should be taken while administering fulvestrant at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve (see sections 4.2 and 4.8).

There are no long-term data on the effect of fulvestrant on bone. Due to the mechanism of action of fulvestrant, there is a potential risk of osteoporosis.

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

When Fulvestrant is combined with palbociclib, please also refer to the Summary of Product Characteristics of palbociclib.

Interference with estradiol antibody assays

Due to the structural similarity of fulvestrant and estradiol, fulvestrant may interfere with antibody based-estradiol assays and may result in falsely increased levels of estradiol.

Paediatric population

Fulvestrant is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).

Excipients

This medicinal product contains 10 w/v % ethanol (alcohol), i.e. up to 1000 mg per dose, equivalent to 20 ml beer, 8 ml wine per dose. Harmful for those suffering from alcoholism. To be taken into account in children and high-risk groups such as patients with liver disease, or epilepsy.

This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in neonates (“gasping syndrome”). The minimum amount of benzyl alcohol at which toxicity may occur is not known. Increased risk due to accumulation in young children (less than 3 years).

This medicinal product contains benzyl benzoate. Benzyl benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old). Increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus (non-conjugated bilirubin deposits in the brain tissue).

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

 

4.5 Interaction with other medicinal products and other forms of interaction

A clinical interaction study with midazolam (substrate of CYP3A4) demonstrated that fulvestrant does not inhibit CYP3A4. Clinical interaction studies with rifampicin (inducer of CYP3A4) and ketoconazole (inhibitor of CYP3A4) showed no clinically relevant change in fulvestrant clearance. Dose adjustment is therefore not necessary in patients who are receiving fulvestrant and CYP3A4 inhibitors or inducers concomitantly.

 

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Patients of childbearing potential should be advised to use effective contraception while on treatment.

Pregnancy

Fulvestrant is contraindicated in pregnancy (see section 4.3). Fulvestrant has been shown to cross the placenta after single intramuscular doses in rat and rabbit. Studies in animals have shown reproductive toxicity including an increased incidence of foetal abnormalities and deaths (see section 5.3). If pregnancy occurs while taking fulvestrant, the patient must be informed of the potential hazard to the foetus and potential risk for loss of pregnancy.

Breast-feeding

Breast-feeding must be discontinued during treatment with fulvestrant. Fulvestrant is excreted in milk in lactating rats. It is not known whether fulvestrant is excreted in human milk. Considering the potential for serious adverse reactions due to fulvestrant in breast-fed infants, use during lactation is contraindicated (see section 4.3).

Fertility

The effects of fulvestrant on fertility in humans has not been studied.

 

4.7 Effects on ability to drive and use machines

Fulvestrant has no or negligible influence on the ability to drive or use machines. However, since asthenia has been reported very commonly with fulvestrant, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery.

 

4.8 Undesirable effects

Summary of the safety profile

Monotherapy

This section provides information based on all adverse reactions from clinical studies, post-marketing studies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequently reported adverse reactions were injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).

In Table 1, the following frequency categories for adverse drug reactions (ADRs) were calculated based on the Fulvestrant 500 mg treatment group in pooled safety analyses of studies that compared Fulvestrant 500 mg with Fulvestrant 250 mg [CONFIRM (Study D6997C00002), FINDER 1 (Study D6997C00004), FINDER 2 (Study D6997C00006), and NEWEST (Study D6997C00003) studies], or from FALCON (Study D699BC00001) alone that compared Fulvestrant 500 mg with anastrozole 1 mg.

Where frequencies differ between the pooled safety analysis and FALCON, the highest frequency is presented. The frequencies in Table 1 were based on all reported adverse drug reactions, regardless of the investigator assessment of causality. The median duration of fulvestrant 500 mg treatment across the pooled dataset (including the studies mentioned above plus FALCON) was 6.5 months.

Tabulated list of adverse reactions

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC).

Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100). Within each frequency grouping adverse reactions are reported in order of decreasing seriousness.

Table 1 Adverse Drug Reactions reported in patients treated with Fulvestrant monotherapy

^a Includes adverse drug reactions for which the exact contribution of fulvestrant cannot be assessed due to the underlying disease.

^b The term injection site reactions does not include the terms injection site haemorrhage and injection site haematoma, sciatica, neuralgia and neuropathy peripheral

^c The event was not observed in major clinical studies (CONFIRM, FINDER 1, FINDER 2, NEWEST).

The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate. This is calculated as 3/560 (where 560 is the number of patients in the major clinical studies), which equates to a frequency category of 'uncommon'.

^d Includes: arthralgia, and less frequently musculoskeletal pain, myalgia and pain in extremity.

^e Frequency category differs between pooled safety dataset and FALCON.

^f ADR was not observed in FALCON.

Description of selected adverse reactions

The descriptions included below are based on the safety analysis set of 228 patients who received at least one (1) dose of fulvestrant and 232 patients who received at least one (1) dose of anastrozole, respectively in the phase 3 FALCON study.

Joint and musculoskeletal pain

In the FALCON study, the number of patients who reported an adverse reaction of joint and musculoskeletal pain was 65 (31.2%) and 48 (24.1%) for fulvestrant and anastrozole arms, respectively. Of the 65 patients in the Fulvestrant arm, 40% (26/65) of patients reported joint and musculoskeletal pain within the first month of treatment, and 66.2% (43/65) of patients within the first 3 months of treatment. No patients reported events that were CTCAE Grade ≥3 or that required a dose reduction, dose interruption, or discontinued treatment due to these adverse reactions.

Combination therapy with palbociclib

The overall safety profile of fulvestrant when used in combination with palbociclib is based on data from 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer in the randomised PALOMA3 study (see section 5.1). The most common (≥20%) adverse reactions of any grade reported in patients receiving fulvestrant in combination with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anaemia, stomatitis, diarrhoea, and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse reactions were neutropenia, leukopenia, anaemia, infections, AST increased, thrombocytopenia, and fatigue.

Table 2 reports the adverse reactions from PALOMA3.

Median duration of exposure to fulvestrant was 11.2 months in the fulvestrant + palbociclib arm and 4.9 months in the fulvestrant + placebo arm. Median duration of exposure to palbociclib in the fulvestrant + palbociclib arm was 10.8 months.

Table 2 Adverse reactions based on PALOMA3 Study (N=517)

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

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

^b Infections includes all PTs that are part of the System Organ Class Infections and infestations.

^c Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.

^d Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.

^e Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.

^f Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.

^g Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.

^h Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular,Dermatitis, Dermatitis acneiform, Toxic skin eruption.

Description of selected adverse reactions

Neutropenia

In patients receiving fulvestrant in combination with palbociclib in the PALOMA3 study, neutropenia of any grade was reported in 287 (83.2%) patients, with Grade 3 neutropenia being reported in 191 (55.4%) patients, and Grade 4 neutropenia being reported in 37 (10.7%) patients. In the fulvestrant + placebo arm (n=172), neutropenia of any grade was reported in 7 (4.1%) patients, with Grade 3 neutropenia reported in 1 (0.6%) patient. There were no reports of Grade 4 neutropenia in the fulvestrant + placebo arm.

In patients receiving fulvestrant in combination with palbociclib, the median time to first episode of any grade neutropenia was 15 days (range: 13-317) and the median duration of Grade ≥3 neutropenia was 7 days. Febrile neutropenia has been reported in 0.9% patients receiving fulvestrant in combination with palbociclib.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

 

4.9 Overdose

There are isolated reports of overdose with Fulvestrant in humans. If overdose occurs, symptomatic supportive treatment is recommended. Animal studies suggest that no effects other than those related directly or indirectly to antiestrogenic activity were evident with higher doses of fulvestrant (see section 5.3).

 

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy, Antiestrogens, ATC code: L02BA03

Mechanism of action and pharmacodynamic effects

Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol. Fulvestrant blocks the trophic actions of estrogens without any partial agonist (estrogen-like) activity.

The mechanism of action is associated with downregulation of estrogen receptor protein levels. Clinical studies in postmenopausal women with primary breast cancer have shown that fulvestrant significantly downregulates ER protein in ER positive tumours compared with placebo. There was also a significant decrease in progesterone receptor expression consistent with a lack of intrinsic estrogen agonist effects. It has also been shown that fulvestrant 500 mg downregulates ER and the proliferation marker Ki67, to a greater degree than fulvestrant 250 mg in breast tumours in postmenopausal neoadjuvant setting.

Clinical efficacy and safety in advanced breast cancer

Monotherapy

A phase 3 clinical study was completed in 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease. The study included 423 patients whose disease had recurred or progressed during antiestrogen therapy (AE subgroup) and 313 patients whose disease had recurred or progressed during aromatase inhibitor therapy (AI subgroup). This study compared the efficacy and safety of fulvestrant 500 mg (n=362) with fulvestrant 250 mg (n=374). Progression-free survival (PFS) was the primary endpoint; key secondary efficacy endpoints included objective response rate (ORR), clinical benefit rate (CBR) and overall survival (OS). Efficacy results for the CONFIRM study are summarized in Table 2.

Table 3 Summary of results of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the CONFIRM study

^a Fulvestrant is indicated in patients whose disease had recurred or progressed on an anti-estrogen therapy.

The results in the AI subgroup are inconclusive.

^b OS is presented for the final survival analyses at 75% maturity.

^c Nominal p-value with no adjustments made for multiplicity between the initial overall survival analyses at 50%maturity and the updated survival analyses at 75% maturity.

^d ORR was assessed in patients who were evaluable for response at baseline (i.e., those with measurable disease at baseline: 240 patients in the fulvestrant 500 mg group and 261 patients in the fulvestrant 250 mg group).

^e Patients with a best objective response of complete response, partial response or stable disease ≥24 weeks.

PFS:Progression-free survival; ORR:Objective response rate; OR:Objective response; CBR:Clinical benefit rate; CB:Clinical benefit; OS:Overall survival; K-M:Kaplan-Meier; CI:Confidence interval; AI:Aromatase inhibitor; AE:Anti-estrogen.

A phase 3, randomised, double-blind, double-dummy, multicentre study of Fulvestrant 500 mg versus anastrozole 1 mg was conducted in postmenopausal women with ER-positive and/or PgR-positive locally advanced or metastatic breast cancer who had not previously been treated with any hormonal therapy. A total of 462 patients were randomised 1:1 sequentially to receive either fulvestrant 500 mg or anastrozole 1 mg.

Randomisation was stratified by disease setting (locally advanced or metastatic), prior chemotherapy for advanced disease, and measurable disease.

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

Patients enrolled in this study had a median age of 63 years (range 36-90). The majority of patients (87.0%) had metastatic disease at baseline. Fifty-five percent (55.0%) of patients had visceral metastasis at baseline. A total of 17.1% of patients received a prior chemotherapy regimen for advanced disease; 84.2% of patients had measurable disease.

Consistent results were observed across the majority of pre-specified patient subgroups. For the subgroup of patients with disease limited to non-visceral metastasis (n=208), the HR was 0.592 (95% CI: 0.419, 0.837) for the Fulvestrant arm compared to the anastrozole arm. For the subgroup of patients with visceral metastasis (n=254), the HR was 0.993 (95% CI: 0.740, 1.331) for the Fulvestrant arm compared to the anastrozole arm. The efficacy results of the FALCON study are presented in Table 4 and Figure 1.

Table 4 Summary of results of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints (Investigator Assessment, Intent-To-Treat Population) ─ FALCON study

*(31% maturity)-not final OS analysis

**for patients with measurable disease

• Peel open the safety needle (Terumo® SurGuard) outer packaging. Attach the safety needle to the Luer-Lok (see Figure 2).

• Twist until firmly seated.

• Transport filled syringe to point of administration.

• Move the safety sheath away from the needle and toward the syringe barrel to the angle shown, prior to removing the needle cap.

• Parenteral solutions must be inspected visually for particulate matter and discolouration prior to administration.

• Expel excess gas from the syringe.

• Administer intramuscularly slowly (1-2 minutes/injection) into the buttock. For user convenience, the needle bevel- up position is oriented to the lever arm (see Figure 3).

• Use the finger grip if necessary.

• After injection, use a one-handed technique to activate the safety mechanism using any of the three methods illustrated above (Activation is verified by an audible and/or tactile “click” and can be visually confirmed.) (see Figure 4).

NOTE: Activate away from self and others. Listen for click and visually confirm needle tip is fully covered.