post-title portfolio-title Fulvestrant solution for injection IP 250mg Taj Pharma 2020-02-25 08:38:23 no no

Fulvestrant solution for injection IP 250mg Taj Pharma

Fulvestrant solution for injection IP 250mg Taj Pharma

Overview

INTRODUCTION

Fulvestrant 250mg Injection is an estrogen blocker. It is used in the treatment of breast cancer in women who have gone through menopause. It works by adjusting the level of estrogen and slow down the growth of cancer cells.

Fulvestrant 250mg Injection is given as an injection into the muscles under the supervision of a doctor. It should be taken as doctor your doctor’s advice. The dose and how often you take it depends on what you are taking it for. Your doctor will decide how much you need to improve your symptoms. You should take this medicine for as long as it is prescribed for you.

The most common side effects of this medicine include injection site reaction, headache, vomiting, allergic reaction, and nausea. If these bother you, or appear serious, let your doctor know. There may be ways of reducing or preventing them.

Before taking this medicine, tell your doctor if you ever had kidney or liver disease or had bleeding disorder or had any blood clotting medicine. Your doctor should also know about all other medicines you are taking as many of these may make this medicine less effective or change the way it works. Tell your doctor if you are pregnant, planning pregnancy or breastfeeding.

USES OF FULVESTRANT INJECTION

  • Breast cancer

SIDE EFFECTS OF FULVESTRANT INJECTION

Common

  • Headache
  • Vomiting
  • Weakness
  • Allergic reaction
  • Nausea
  • Injection site reaction
  • Urinary tract infection
  • Diarrhea

HOW TO USE FULVESTRANT INJECTION

Your doctor or nurse will give you this medicine. Kindly do not self administer.

HOW FULVESTRANT INJECTION WORKS

Fulvestrant 250mg Injection blocks the action of estrogen on breast cancer cells. This can lower or stop the growth of some breast cancer cells that need estrogen to grow.

SAFETY ADVICE

warningsAlcohol

CAUTION

Caution is advised when consuming alcohol with Fulvestrant 250mg Injection. Please consult your doctor.

warningsPregnancy

CONSULT YOUR DOCTOR

Fulvestrant 250mg Injection is unsafe to use during pregnancy as there is definite evidence of risk to the developing baby. However, the doctor may rarely prescribe it in some life-threatening situations if the benefits are more than the potential risks. Please consult your doctor.

warningsBreastfeeding

UNSAFE

Fulvestrant 250mg Injection is unsafe to use during breastfeeding. Data suggests that the drug may cause toxicity to the baby.

warningsDriving

SAFE

Fulvestrant 250mg Injection does not usually affect your ability to drive.

warningsKidney

CAUTION

Fulvestrant 250mg Injection should be used with caution in patients with severe kidney disease. Dose adjustment of Fulvestrant 250mg Injection may be needed. Please consult your doctor.
Limited information is available on the use of Fulvestrant 250mg Injection in these patients. No dose adjustment is recommended in patients with mild to moderate kidney disease.

warningsLiver

CAUTION

Fulvestrant 250mg Injection should be used with caution in patients with liver disease. Dose adjustment of Fulvestrant 250mg Injection may be needed. Please consult your doctor.

WHAT IF YOU FORGET TO TAKE FULVESTRANT INJECTION?

If you miss a dose of Fulvestrant 250mg Injection, please consult your doctor.

Fulvestrant solution for injection IP 250mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

Fulvestrant solution for injection IP 250mg Taj Pharma

2.QUALITATIVE AND QUANTITATIVE COMPOSITION??????????????????????????????

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

Excipients with known effect (per 5 ml)

Ethanol (96%, 500 mg)
Benzyl alcohol (500 mg)
Benzyl benzoate (750 mg)

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM????

Solution for injection.

Clear, colourless to yellow, viscous solution.

4.CLINICAL PARTICULARS

4.1 Therapeutic indications

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 antioestrogen therapy, or disease progression on antioestrogen 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 luteinising 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.

Ethanol

Fulvestrant contains 10% w/v ethanol (alcohol) as an excipient, i.e. up to 500 mg per injection, equivalent to 10 ml beer or 4 ml wine. This may be harmful for those suffering from alcoholism and should be taken into account in high risk groups such as patients with liver disease and epilepsy.

Benzyl alcohol

Fulvestrant contains benzyl alcohol as an excipient which may cause allergic reactions.

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).

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

Adverse reactions by system organ class and frequency
Infections and infestationsCommonUrinary tract infections
Blood and lymphatic system disordersCommonReduced platelet counte
Immune system disordersVery commonHypersensitivity reactionse
UncommonAnaphylactic reactions
Metabolism and nutrition disordersCommonAnorexiaa
Nervous system disordersCommonHeadache
Vascular disordersVery commonHot flushese
CommonVenous thromboembolisma
Gastrointestinal disordersVery commonNausea
CommonVomiting, diarrhoea
Hepatobiliary disordersVery commonElevated hepatic enzymes (ALT, AST, ALP)a
CommonElevated bilirubina
UncommonHepatic failurec, f, hepatitisf, elevated gamma-GTf
Skin and subcutaneous tissue disordersVery commonRashe
Musculoskeletal and connective tissue disordersVery commonJoint and musculoskeletal paind
CommonBack paina
Reproductive system and breast disordersCommonVaginal haemorrhagee
UncommonVaginal moniliasisf, leukorrheaf
General disorders and administration site conditionsVery commonAstheniaa, injection site reactionsb
CommonNeuropathy peripherale, sciaticae
UncommonInjection site haemorrhagef, injection site haematomaf, neuralgiac,f

 

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, 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)

System Organ Class

Frequency

Preferred Terma

Fulvestrant + Palbociclib

(N=345)

Fulvestrant + placebo

(N=172)

All Grades

n (%)

Grade ? 3

n (%)

All Grades

n (%)

Grade ? 3

n (%)

Infections and infestations
Very common
Infectionsb163 (47.2)11 (3.2)54 (31.4)5 (2.9)
Blood and lymphatic system disorders
Very common
Neutropeniac287 (83.2)228 (66.1)7 (4.1)1 (0.6)
Leukopeniad183 (53.0)105 (30.4)9 (5.2)2 (1.2)
Anaemiae102 (29.6)12 (3.5)22 (12.8)3 (1.7)
Thrombocytopeniaf78 (22.6)8 (2.3)0 (0.0)0
Uncommon
Febrile neutropenia3 (0.9)3 (0.9)1 (0.6)1 (0.6)
Metabolism and nutrition disorders
Very common
Decreased appetite55 (15.9)3 (0.9)14 (8.1)1 (0.6)
Nervous system disorders
Common
Dysgeusia23 (6.7)05 (2.9)0
Eye disorders
Common
Lacrimation increased22 (6.4)02 (1.2)0
Vision blurred20 (5.8)03 (1.7)0
Dry eye13 (3.8)03 (1.7)0
Respiratory, thoracic and mediastinal disorders
Common
Epistaxis23 (6.7)03 (1.7)0
Gastrointestinal disorders
Very common
Nausea117 (33.9)048 (27.9)1 (0.6)
Stomatitisg97 (28.1)2 (0.6)22 (12.8)0
Diarrhoea81 (23.5)033 (19.2)2 (1.2)
Vomiting65 (18.8)2 (0.6)26 (15.1)1 (0.6)
Skin and subcutaneous tissue disorders
Very common
Alopecia62 (18.0)011 (6.4)0
Rashh58 (16.8)2 (0.6)11 (6.4)0
Common
Dry skin21 (6.1)02 (1.2)0
General disorders and administration site conditions
Very common
Fatigue142 (41.2)8 (2.3)50 (29.1)2 (1.2)
Pyrexia44 (12.8)1 (0.3)9 (5.2)0
Common
Asthenia26 (7.5)09 (5.2)1 (0.6)
Investigations
Common
AST increased26 (7.5)10 (2.9)9 (5.2)3 (1.7)
ALT increased20 (5.8)6 (1.7)6 (3.5)0

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.

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 antioestrogenic activity were evident with higher doses of fulvestrant (see section 5.3).

5.PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy, Antioestrogens,

Mechanism of action and pharmacodynamic effects

Fulvestrant is a competitive oestrogen receptor (ER) antagonist with an affinity comparable to oestradiol. Fulvestrant blocks the trophic actions of oestrogens without any partial agonist (oestrogen-like) activity. The mechanism of action is associated with downregulation of oestrogen 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 oestrogen agonist effects. It has also been shown that fulvestrant 500 mg downregulates ER and the proliferation marker Ki67, to a greater degree than fulvestrant 250 mg in breast tumours in postmenopausal neoadjuvant setting.

Clinical 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 antioestrogen 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 3.

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

VariableType of estimate; treatment comparisonFulvestrant 500 mg

(N=362)

Fulvestrant 250 mg
(N=374)
Comparison between groups

(Fulvestrant 500 mg/Fulvestrant 250 mg)

Hazard ratio95% CIp-value
PFSK-M median in months; hazard ratio
All Patients6.55.50.800.68, 0.940.006
-AE subgroup (n=423)8.65.80.760.62, 0.940.013
-AI subgroup (n=313)a5.44.10.850.67, 1.080.195
OSbK-M median in months; hazard ratio
All Patients26.422.30.810.69, 0.960.016c
-AE subgroup (n=423)30.623.90.790.63, 0.990.038c
-AI subgroup (n=313)a24.120.80.860.67, 1.110.241c
VariableType of estimate; treatment comparisonFulvestrant 500 mg

(N=362)

Fulvestrant 250 mg
(N=374)
Comparison between groups

(Fulvestrant 500 mg/Fulvestrant 250 mg)

Absolute difference in %95% CI
ORRd% of patients with OR; absolute difference in %
All Patients13.814.6-0.8-5.8, 6.3
-AE subgroup (n=296)18.119.1-1.0-8.2, 9.3
-AI subgroup (n=205)a7.38.3-1.0-5.5, 9.8
CBRe% of patients with CB; absolute difference in %
All Patients45.639.66.0-1.1, 13.3
-AE subgroup (n=423)52.445.17.3-2.2, 16.6
-AI subgroup (n=313)a36.232.33.9-6.1, 15.2

a?Fulvestrant is indicated in patients whose disease had recurred or progressed on an antioestrogen 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:Antioestrogen.

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

 

 

Fulvestrant

500 mg

(N=230)

Anastrozole

1 mg

(N=232)

Progression-Free Survival
Number of PFS Events (%)143 (62.2%)166 (71.6%)
PFS Hazard Ratio (95% CI) and p-valueHR 0.797 (0.637 – 0.999)

p = 0.0486

PFS Median [months (95% CI)]16.6 (13.8, 21.0)13.8 (12.0, 16.6)
Number of OS Events*67 (29.1%)75 (32.3%)
OS Hazard Ratio (95% CI) and p-valueHR 0.875 (0.629 ? 1.217)

p = 0.4277

ORR**89 (46.1%)88 (44.9%)
ORR Odds Ratio (95% CI) and p-valueOR 1.074 (0.716 ? 1.614)

p = 0.7290

Median DoR (months)20.013.2
CBR180 (78.3%)172 (74.1%)
CBR Odds Ratio (95% CI) and p-valueOR 1.253 (0.815 ? 1.932)

p = 0.3045

*(31% maturity)-not final OS analysis

**for patients with measurable disease

Figure 1 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, Intent-To-Treat Population) ? FALCON Study

Two Phase 3 clinical studies were completed in a total of 851 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease. Seventy seven percent (77%) of the study population had oestrogen receptor positive breast cancer. These studies compared the safety and efficacy of monthly administration of Fulvestrant 250 mg versus the daily administration of 1 mg anastrozole (aromatase inhibitor). Overall, Fulvestrant at the 250 mg monthly dose was at least as effective as anastrozole in terms of progression-free survival, objective response, and time to death. There were no statistically significant differences in any of these endpoints between the two treatment groups. Progression-free survival was the primary endpoint. Combined analysis of both studies showed that 83% of patients who received Fulvestrant progressed, compared with 85% of patients who received anastrozole. Combined analysis of both studies showed the hazard ratio of Fulvestrant 250 mg to anastrozole for progression-free survival was 0.95 (95% CI 0.82 to 1.10). The objective response rate for Fulvestrant 250 mg was 19.2% compared with 16.5% for anastrozole. The median time to death was 27.4 months for patients treated with Fulvestrant and 27.6 months for patients treated with anastrozole. The hazard ratio of Fulvestrant 250 mg to anastrozole for time to death was 1.01 (95% CI 0.86 to 1.19).

Combination therapy with palbociclib

A Phase 3, international, randomised, double-blind, parallel-group, multicentre study of Fulvestrant 500 mg plus palbociclib 125 mg versus Fulvestrant 500 mg plus placebo was conducted in women with HR-positive, HER2-negative locally advanced breast cancer not amenable to resection or radiation therapy with curative intent or metastatic breast cancer, regardless of their menopausal status, whose disease progressed after prior endocrine therapy in the (neo) adjuvant or metastatic setting.

A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 months from completion of adjuvant endocrine therapy on or within 1 month from prior endocrine therapy for advanced disease, were randomised 2:1 to Fulvestrant plus palbociclib or Fulvestrant plus placebo and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri- versus postmenopausal), and presence of visceral metastases. Pre/perimenopausal women received the LHRH agonist goserelin. Patients with advanced/metastatic, symptomatic, visceral spread, that were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement), were not eligible for enrolment into the study.

Patients continued to receive assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. Crossover between treatment arms was not allowed.

Patients were well matched for baseline demographics and prognostic characteristics between the Fulvestrant plus palbociclib arm and the Fulvestrant plus placebo arm. The median age of patients enrolled in this study was 57 years (range 29, 88). In each treatment arm the majority of patients were

White, 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 arm had received a previous chemotherapy regimen for their primary diagnosis. More than half (62%) had an ECOG PS of 0, 60% had visceral metastases, and 60% had received more than 1 prior hormonal regimen for their primary diagnosis.

The primary endpoint of the study was investigator-assessed PFS evaluated according to RECIST 1.1. Supportive PFS analyses were based on an Independent Central Radiology Review. Secondary endpoints included OR, CBR, OS, safety, and time-to-deterioration (TTD) in pain endpoint.

The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysis conducted on 82% of the planned PFS events; the results crossed the pre-specified Haybittle-Peto efficacy boundary (?=0.00135), demonstrating a statistically significant prolongation in PFS and a clinically meaningful treatment effect. A more mature update of efficacy data is reported in Table 5.

Table 5 Efficacy results ? PALOMA3 study (Investigator assessment, intent-to-treat population)

?
Updated Analysis
(23 October 2015 cut-off)
Fulvestrant plus palbociclib

(N=347)

Fulvestrant plus placebo

(N=174)

Progression-Free Survival
Median [months (95% CI)]11.2 (9.5, 12.9)4.6 (3.5, 5.6)
Hazard ratio (95% CI) and p-value0.497 (0.398, 0.620), p <0.000001
Secondary end points*
OR [% (95% CI)]26.2 (21.7, 31.2)13.8 (9.0, 19.8)
OR (measurable disease) [% (95% CI)]33.7 (28.1, 39.7)17.4 (11.5, 24.8)
CBR [% (95% CI)]68.0 (62.8, 72.9)39.7 (32.3, 47.3)

*Response endpoints based on confirmed and unconfirmed responses.

N=number of patients; CI=confidence interval; OR=objective response; CBR=clinical benefit response

Figure 2. Kaplan-Meier plot of progression-free survival (investigator assessment, intent-to-treat population) ? PALOMA3 study

A reduction in the risk of disease progression or death in the Fulvestrant plus palbociclib arm was observed in all individual patient subgroups defined by stratification factors and baseline characteristics. This was evident for pre/perimenopausal women (HR of 0.46 [95% CI: 0.28, 0.75]) and postmenopausal women (HR of 0.52 [95% CI: 0.40, 0.66]) and patients with visceral site of metastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of 0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless of lines of prior therapy in the metastatic setting, whether 0 (HR of 0.59 [95% CI: 0.37, 0.93]), 1 (HR of 0.46 [95% CI: 0.32, 0.64]), 2 (HR of 0.48 [95% CI: 0.30, 0.76]), or ?3 lines (HR of 0.59 [95% CI: 0.28, 1.22]). Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or without visceral disease are displayed in Table 6.

Table 6 Efficacy results in visceral and non-visceral disease from PALOMA3 study (intent-to-treat population)

 

 

Visceral DiseaseNon-visceral Disease
Fulvestrant plus palbociclib

(N=206)

Fulvestrant plus placebo

(N=105)

Fulvestrant plus palbociclib

(N=141)

Fulvestrant plus placebo

(N=69)

OR [% (95% CI)]35.0

(28.5, 41.9)

13.3

(7.5, 21.4)

13.5

(8.3, 20.2)

14.5

(7.2, 25.0)

TTR*, Median

[months (range)]

3.8

(3.5, 16.7)

5.4

(3.5, 16.7)

3.7

(1.9, 13.7)

3.6

(3.4, 3.7)

*Response results based on confirmed and unconfirmed responses.

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

Patient-reported symptoms were assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and its Breast Cancer Module (EORTC QLQ-BR23). A total of 335 patients in the Fulvestrant plus palbociclib arm and 166 patients in the Fulvestrant plus placebo arm completed the questionnaire at baseline and at least 1 post-baseline visit.

Time-to-Deterioration was pre-specified as time between baseline and first occurrence of ?10 points increase from baseline in pain symptom scores. Addition of palbociclib to Fulvestrant resulted in a symptom benefit by significantly delaying Time-to-Deterioration in pain symptom compared with Fulvestrant plus placebo (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85]; p<0.001).

Effects on the postmenopausal endometrium

Preclinical data do not suggest a stimulatory effect of fulvestrant on the postmenopausal endometrium (see section 5.3). A 2-week study in healthy postmenopausal volunteers treated with 20 ?g per day ethinylestradiol showed that pretreatment with Fulvestrant 250 mg resulted in significantly reduced stimulation of the postmenopausal endometrium, compared to pre-treatment with placebo, as judged by ultrasound measurement of endometrium thickness.

Neoadjuvant treatment for up to 16 weeks in breast cancer patients treated with either Fulvestrant 500 mg or Fulvestrant 250 mg did not result in clinically significant changes in endometrial thickness, indicating a lack of agonist effect. There is no evidence of adverse endometrial effects in the breast cancer patients studied. No data are available regarding endometrial morphology.

In two short-term studies (1 and 12 weeks) in premenopausal patients with benign gynaecologic disease, no significant differences in endometrial thickness were observed by ultrasound measurement between fulvestrant and placebo groups.

Effects on bone

There are no long-term data on the effect of fulvestrant on bone. Neoadjuvant treatment for up to 16 weeks in breast cancer patients with either Fulvestrant 500 mg or Fulvestrant 250 mg did not result in clinically significant changes in serum bone-turnover markers.

Paediatric population

Fulvestrant is not indicated for use in children. The European Medicines Agency has waived the obligation to submit the results of studies with Fulvestrant in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).

An open-label Phase 2 study investigated the safety, efficacy and pharmacokinetics of fulvestrant in 30 girls aged 1 to 8 years with Progressive Precocious Puberty associated with McCune Albright Syndrome (MAS). The paediatric patients received 4 mg/kg monthly intramuscular dose of fulvestrant. This 12-month study investigated a range of MAS endpoints and showed a reduction in the frequency of vaginal bleeding and a reduction in the rate of bone age advancement. The steady-state trough concentrations of fulvestrant in children in this study were consistent with that in adults (see section 5.2). There were no new safety concerns arising from this small study, but 5-year data are yet not available.

5.2 Pharmacokinetic properties

Absorption

After administration of Fulvestrant long-acting intramuscular injection, fulvestrant is slowly absorbed and maximum plasma concentrations (Cmax) are reached after about 5 days. Administration of Fulvestrant 500 mg regimen achieves exposure levels at, or close to, steady state within the first month of dosing (mean [CV]: AUC 475 [33.4%] ng.days/ml, Cmax?25.1 [35.3%] ng/ml, Cmin?16.3 [25.9%] ng/ml, respectively). At steady state, fulvestrant plasma concentrations are maintained within a relatively narrow range with up to an approximately 3-fold difference between maximum and trough concentrations. After intramuscular administration, the exposure is approximately dose proportional in the dose range 50 to 500 mg.

Distribution

Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution at steady state (Vdss) of approximately 3 to 5 l/kg suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins. Very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major binding components. No interaction studies were conducted on competitive protein binding. The role of sex hormone-binding globulin (SHBG) has not been determined.

Biotransformation

The metabolism of fulvestrant has not been fully evaluated, but involves combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids. Identified metabolites (includes 17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronide metabolites) are either less active or exhibit similar activity to fulvestrant in antioestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant; however, non-P450 routes appear to be more predominant?in vivo.?In vitro?data suggest that fulvestrant does not inhibit CYP450 isoenzymes.

Elimination

Fulvestrant is eliminated mainly in metabolised form. The major route of excretion is via the faeces, with less than 1% being excreted in the urine. Fulvestrant has a high clearance, 11?1.7 ml/min/kg, suggesting a high hepatic extraction ratio. The terminal half-life (t1/2) after intramuscular administration is governed by the absorption rate and was estimated to be 50 days.

Special populations

In a population pharmacokinetic analysis of data from Phase 3 studies, no difference in fulvestrant’s pharmacokinetic profile was detected with regard to age (range 33 to 89 years), weight (40-127 kg) or race.

Renal impairment

Mild to moderate impairment of renal function did not influence the pharmacokinetics of fulvestrant to any clinically relevant extent.

Hepatic impairment

The pharmacokinetics of fulvestrant has been evaluated in a single-dose clinical study conducted in women with mild to moderate hepatic impairment (Child-Pugh class A and B). A high dose of a shorter duration intramuscular injection formulation was used. There was up to about 2.5-fold increase in AUC in women with hepatic impairment compared to healthy subjects. In patients administered Fulvestrant, an increase in exposure of this magnitude is expected to be well tolerated. Women with severe hepatic impairment (Child-Pugh class C) were not evaluated.

Paediatric population

The pharmacokinetics of fulvestrant has been evaluated in a clinical study conducted in 30 girls with Progressive Precocious Puberty associated with McCune Albright Syndrome (see section 5.1). The paediatric patients were aged 1 to 8 years and received 4 mg/kg monthly intramuscular dose of fulvestrant. The geometric mean (standard deviation) steady state trough concentration (Cmin,ss) and AUCss was 4.2 (0.9) ng/mL and 3680 (1020) ng*hr/mL, respectively. Although the data collected were limited, the steady-state trough concentrations of fulvestrant in children appear to be consistent with those in adults.

5.3 Preclinical safety data

The acute toxicity of fulvestrant is low.

Fulvestrant and other formulations of fulvestrant were well tolerated in animal species used in multiple dose studies. Local reactions, including myositis and granulomata at the injection site were attributed to the vehicle but the severity of myositis in rabbits increased with fulvestrant, compared to the saline control. In toxicity studies with multiple intramuscular doses of fulvestrant in rats and dogs, the antioestrogenic activity of fulvestrant was responsible for most of the effects seen, particularly in the female reproductive system, but also in other organs sensitive to hormones in both sexes. Arteritis involving a range of different tissues was seen in some dogs after chronic (12 months) dosing.

In dog studies following oral and intravenous administration, effects on the cardiovascular system (slight elevations of the S-T segment of the ECG [oral], and sinus arrest in one dog [intravenous]) were seen. These occurred at exposure levels higher than in patients (Cmax?>15 times) and are likely to be of limited significance for human safety at the clinical dose.

Fulvestrant showed no genotoxic potential.

Fulvestrant showed effects upon reproduction and embryo/foetal development consistent with its antioestrogenic activity, at doses similar to the clinical dose. In rats, a reversible reduction in female fertility and embryonic survival, dystocia and an increased incidence of foetal abnormalities including tarsal flexure were observed. Rabbits given fulvestrant failed to maintain pregnancy. Increases in placental weight and post-implantation loss of foetuses were seen. There was an increased incidence of foetal variations in rabbits (backwards displacement of the pelvic girdle and 27 pre-sacral vertebrae).

A two-year oncogenicity study in rats (intramuscular administration of Fulvestrant) showed increased incidence of ovarian benign granulosa cell tumours in female rats at the high dose, 10 mg/rat/15 days and an increased incidence of testicular Leydig cell tumours in males. In a two-year mouse oncogenicity study (daily oral administration) there was an increased incidence of ovarian sex cord stromal tumours (both benign and malignant) at doses of 150 and 500 mg/kg/day. At the no-effect level for these findings, systemic exposure levels (AUC) were, in rats, approximately 1.5-fold the expected human exposure levels in females and 0.8-fold in males, and in mice, approximately 0.8-fold the expected human exposure levels in both males and females. Induction of such tumours is consistent with pharmacology-related endocrine feedback alterations in gonadotropin levels caused by antioestrogens in cycling animals. Therefore these findings are not considered to be relevant to the use of fulvestrant in postmenopausal women with advanced breast cancer.

Environmental Risk Assessment (ERA)

Environmental risk assessment studies have shown that fulvestrant may have potential to cause adverse effects to the aquatic environment (see section 6.6).

6.PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethanol (96 per cent)
Benzyl alcohol
Benzyl benzoate
Castor oil refined

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Store and transport in a refrigerator (2?C-8?C).

Temperature excursions outside 2?C-8?C should be limited. This includes avoiding storage at temperatures exceeding 30?C, and not exceeding a 28 day period where the average storage temperature for the product is below 25?C (but above 2?C-8?C). After temperature excursions, the product should be returned immediately to the recommended storage conditions (store and transport in a refrigerator 2?C-8?C). Temperature excursions have a cumulative effect on the product quality and the 28 day time period must not be exceeded over the duration of the 4-year shelf life of Fulvestrant (see section 6.3). Exposure to temperatures below 2?C will not damage the product providing it is not stored below – 20?C.

Store the pre-filled syringe in the original package in order to protect from light.

6.5 Nature and contents of container

The pre-filled syringe presentation consists of:

One clear type 1 glass pre-filled syringe with polystyrene plunger rod, fitted with a tamper-evident closure, containing 5 ml Fulvestrant solution for injection.

A safety needle (BD SafetyGlide) for connection to the barrel is also provided.

Or

Two clear type 1 glass pre-filled syringes with polystyrene plunger rod, fitted with a tamper-evident closure, each containing 5 ml Fulvestrant solution for injection. Safety needles (BD SafetyGlide) for connection to each barrel are also provided.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Instructions for administration

Administer the injection according to the local guidelines for performing large volume intramuscular injections.

NOTE: Due to the proximity of the underlying sciatic nerve, caution should be taken if administering Fulvestrant at the dorsogluteal injection site (see section 4.4).

Warning – Do not autoclave safety needle (BD SafetyGlide Shielding Hypodermic Needle) before use. Hands must remain behind the needle at all times during use and disposal.

For each of the two syringes:

? Remove glass syringe barrel from tray and check that it is not damaged.

? Peel open the safety needle (SafetyGlide) outer packaging.

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

? Hold the syringe upright on the ribbed part (C). With the other hand, take hold of the cap (A) and carefully tilt back and forth until the cap disconnects and can be pulled off, do not twist (see Figure 1).

Figure 1
? Remove the cap (A) in a straight upward direction. To maintain sterility do not touch the syringe tip (B) (see Figure 2).Figure 2
? Attach the safety needle to the Luer-Lok and twist until firmly seated (see Figure 3).

? Check that the needle is locked to the Luer connector before moving out of the vertical plane.

? Pull shield straight off needle to avoid damaging needle point.

? Transport filled syringe to point of administration.

? Remove needle sheath.

? Expel excess gas from the syringe.

Figure 3
? Administer intramuscularly slowly (1-2 minutes/injection) into the buttock (gluteal area). For user convenience, the needle bevel-up position is oriented to the lever arm (see Figure 4).Figure 4
? After injection, immediately apply a single-finger stroke to the activation assisted lever arm to activate the shielding mechanism (see Figure 5).

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

Figure 5

Disposal

Pre-filled syringes are for single use?only.

This medicine may pose a risk to the aquatic environment. Any unused medicinal product or waste material should be disposed of in accordance with local requirements (see section 5.3).

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)

Fulvestrant solution for injection IP 250mg Taj Pharma
Package leaflet: Information for the patient

Fulvestrant

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Fulvestrant is and what it is used for
  2. What you need to know before you take Fulvestrant
  3. How to take Fulvestrant
  4. Possible side effects
  5. How to store Fulvestrant
  6. Contents of the pack and other information
1 WHAT FULVESTRANT IS AND WHAT IT IS USED FOR

Fulvestrant contains the active substance fulvestrant, which belongs to the group of estrogen blockers. Estrogens, a type of female sex hormones, can in some cases be involved in the growth of breast cancer.

Fulvestrant is used either:

  • alone, to treat postmenopausal women with a type of breast cancer called estrogen receptor positive breast cancer that is locally advanced or has spread to other parts of the body (metastatic), or
  • in combination with palbociclib to treat women with a type of breast cancer called hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, that is locally advanced or has spread to other parts of the body (metastatic). Women who have not reached menopause will also be treated with a medicine called a luteinizing hormone releasing hormone (LHRH) agonist.

When Fulvestrant is given in combination with palbociclib, it is important that you also read the package leaflet for palbociclib. If you have any questions about palbociclib, please ask your doctor.

2 WHAT YOU NEED TO KNOW BEFORE YOU TAKE FULVESTRANT

Do not use Fulvestrant:

  • if you are allergic to fulvestrant or to any of the other ingredients of this medicine (listed in section 6)
  • if you are pregnant or breast-feeding
  • if you have severe liver problems

Warnings and precautions
Talk to your doctor or pharmacist or nurse before using Fulvestrant if any of these apply to you:

  • kidney or liver problems
  • low numbers of platelets (which help blood clotting) or bleeding disorders
  • previous problems with blood clots
  • osteoporosis (loss of bone density)
  • alcoholism

Children and adolescents
Fulvestrant is not indicated in children and adolescents under 18 years.

Other medicines and Fulvestrant
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

In particular, you should tell your doctor if you are using anticoagulants (medicines to prevent blood clots).

Pregnancy and breast-feeding
You must not use Fulvestrant if you are pregnant. If you can become pregnant, you should use effective contraception while being treated with Fulvestrant.

You must not breast-feed while on treatment with Fulvestrant.

Driving and using machines
Fulvestrant is not expected to affect your ability to drive or use machines. However, if you feel tired after treatment do not drive or use machines.

Fulvestrant contains 10% w/v ethanol (alcohol), i.e. up to 500 mg per injection, equivalent to 10 ml beer or 4 ml wine.

Harmful for those suffering from alcoholism.

To be taken into account in high-risk groups such as patients with liver disease, or epilepsy.

Fulvestrant contains 500 mg benzyl alcohol per injection, equivalent to 100 mg/ml.

Benzyl alcohol may cause allergic reactions.

Fulvestrant contains 750 mg benzyl benzoate per injection, equivalent to 150 mg/ml.

3 HOW TO TAKE FULVESTRANT

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is 500 mg fulvestrant (two 250 mg/5 ml injections) given once a month, with an additional 500 mg dose given 2 weeks after the initial dose.

Your doctor or nurse will give you Fulvestrant as a slow intramuscular injection, one into each of your buttocks.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4 POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You may need immediate medical treatment if you experience any of the following side effects:

  • Allergic (hypersensitivity) reactions, including swelling of the face, lips, tongue and/or throat that may be signs of anaphylactic reactions
  • Thromboembolism (increased risk of blood clots)*
  • Inflammation of the liver (hepatitis)
  • Liver failure

Tell your doctor, pharmacist, or nurse if you notice any of the following side effects:

Very common side effects?(may affect more than 1 in 10 people)

  • Injection site reactions, such as pain and/or inflammation
  • Abnormal levels of liver enzymes (in blood tests)*
  • Nausea (feeling sick)
  • Weakness, tiredness*
  • Joint and musculoskeletal pain
  • Hot flushes
  • Skin rash
  • Allergic (hypersensitivity) reactions, including swelling of the face, lips, tongue and/or throat

All other side effects:

Common side effects?(may affect up to 1 in 10 people)

  • Headache
  • Vomiting, diarrhoea, or loss of appetite*
  • Urinary tract infections
  • Back pain*
  • Increase of bilirubin (bile pigment produced by the liver)
  • Thromboembolism (increased risk of blood clots)*
  • Decreased levels of platelets (thrombocytopenia)
  • Vaginal bleeding
  • Lower back pain irradiating to leg on one side (sciatica)
  • Sudden weakness, numbness, tingling, or loss of movement in your leg, especially on only one side of your body, sudden problems with walking or balance (peripheral neuropathy)

Uncommon side effects?(may affect up to 1 in 100 people)

  • Thick, whitish vaginal discharge and candidiasis (infection)
  • Bruising and bleeding at the site of injection
  • Increase of gamma-GT, a liver enzyme seen in a blood test
  • Inflammation of the liver (hepatitis)
  • Liver failure
  • Numbness, tingling and pain
  • Anaphylactic reactions

* Includes side effects for which the exact role of Fulvestrant cannot be assessed due to the underlying disease.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5 HOW TO STORE FULVESTRANT

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton or syringe labels after EXP. The expiry date refers to the last day of that month.

Store and transport in a refrigerator (2?C ? 8?C).

Temperature excursions outside 2?C – 8?C should be limited. This includes avoiding storage at temperatures exceeding 30?C, and not exceeding a 28-day period where the average storage temperature for the product is below 25?C (but above 2?C – 8?C). After temperature excursions, the product should be returned immediately to the recommended storage conditions (store and transport in a refrigerator 2?C – 8?C). Temperature excursions have a cumulative effect on the product quality and the 28-day time period must not be exceeded over the duration of the 4-year shelf life of Fulvestrant. Exposure to temperatures below 2?C will not damage the product providing it is not stored below -20?C.

Keep the pre-filled syringe in the original package, in order to protect from light.

Your healthcare professional will be responsible for the correct storage, use and disposal of Fulvestrant.

This medicine may pose a risk to the aquatic environment. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6 CONTENTS OF THE PACK AND OTHER INFORMATION

What Fulvestrant contains

The active substance is fulvestrant.

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

Excipients with known effect (per 5 ml)

Ethanol (96%, 500 mg)
Benzyl alcohol (500 mg)
Benzyl benzoate (750 mg)

The other ingredients (excipients) are ethanol (96 per cent), benzyl alcohol, benzyl benzoate and castor oil refined.

Contents of the pack

Fulvestrant is a clear, colourless to yellow, viscous solution in a pre-filled syringe fitted with a tamper-evident closure, containing 5 ml solution for injection. Two syringes must be administered to receive the 500 mg recommended monthly dose.

Fulvestrant has 2 pack presentations, either a pack containing 1 glass pre-filled syringe or a pack containing 2 glass pre-filled syringes. Safety needles (BD SafetyGlide) for connection to each barrel are also provided.

Not all pack sizes may be marketed.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
Mumbai, India
at SURVEY NO. 188/1, 190/1TO 4, ATHIYAWAD , DABHEL,
DAMAN- 396210 (INDIA)

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