HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`FASLODEX safely and effectively. See full prescribing information for
`FASLODEX.
`
`
`FASLODEX® (fulvestrant) injection, for intramuscular use
`
`Initial U.S. Approval: 2002
`
`-------------------------- RECENT MAJOR CHANGES --------------------------
`
`
`Dosage and Administration (2.3)
`03/2016
`
`
`
`
`03/2016
`Warnings and Precautions (5.3)
`
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`
`
`FASLODEX is an estrogen receptor antagonist indicated for the:
`
`Treatment of hormone receptor positive metastatic breast cancer in
`
`postmenopausal women with disease progression following antiestrogen
`therapy. (1)
`
`
`
`
`
`
`
`
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`
`
`
`
`
`FASLODEX 500 mg should be administered intramuscularly into the
`
`buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one
`in each buttock, on days 1, 15, 29 and once monthly thereafter. (2.1, 14)
`A dose of 250 mg is recommended in patients with moderate hepatic
`
`impairment to be administered intramuscularly into the buttock slowly
`(1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once
`monthly thereafter. (2.2, 5.2, 8.6)
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`
`
`FASLODEX, an injection for intramuscular administration, is supplied as 50
`mg/mL fulvestrant. (3)
`
`
`
` ------------------------------ CONTRAINDICATIONS -----------------------------
`
`
`
`Hypersensitivity. (4)
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`
`
`
`Risk of Bleeding: Use with caution in patients with bleeding diatheses,
`
`
`thrombocytopenia, or anticoagulant use. (5.1)
`
`
`Increased Exposure in Patients with Hepatic Impairment: Use a 250 mg
`
`dose for patients with moderate hepatic impairment. (2.2, 5.2, 8.6)
`Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`reproductive potential of the potential risk to a fetus and to use effective
`contraception. (5.3, 8.1, 8.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------
`
`
`
`The most common adverse reactions occurring in ≥5% of patients
`
`receiving FASLODEX 500 mg were: injection site pain, nausea, bone
`
`pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot
`flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough,
`
`
`dyspnea, and constipation. (6.1)
`
`
`Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of
`FASLODEX patients and were not dose-dependent. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------ DRUG INTERACTIONS -----------------------------
`
`
`
`There are no known drug-drug interactions. (7)
`
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`
`
`
`Lactation: Advise not to breast-feed. (8.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 03/2016
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
` 
`1 INDICATIONS AND USAGE
` 
`2 DOSAGE AND ADMINISTRATION
` 
`2.1 Recommended Dose
` 
`2.2 Dose Modification
` 
`2.3 Administration Technique
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
`4 CONTRAINDICATIONS
` 
`5 WARNINGS AND PRECAUTIONS
` 
`5.1 Risk of Bleeding
` 
`5.2 Increased Exposure in Patients with Hepatic Impairment
` 
`5.3 Embryo-Fetal Toxicity
` 
`6 ADVERSE REACTIONS
` 
`6.1 Clinical Trials Experience
` 
`6.2 Post-Marketing Experience
` 
`7 DRUG INTERACTIONS
` 
`8 USE IN SPECIFIC POPULATIONS
` 
`8.1 Pregnancy
` 
`8.2 Lactation
`
` 
`8.3 Females and Males of Reproductive Potential
` 
`8.4 Pediatric Use
` 
`8.5 Geriatric Use
` 
`8.6 Hepatic Impairment
` 
`8.7 Renal Impairment
` 
`10 OVERDOSAGE
` 
`11 DESCRIPTION
` 
`12 CLINICAL PHARMACOLOGY
` 
`12.1 Mechanism of Action
` 
`12.2 Pharmacodynamics
` 
`12.3 Pharmacokinetics
` 
`13 NONCLINICAL TOXICOLOGY
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
`14 CLINICAL STUDIES
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
`17 PATIENT COUNSELING INFORMATION
` 
`FDA-APPROVED PATIENT LABELING
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`
`
`
`Reference ID: 3894565
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`
` 1 INDICATIONS AND USAGE
`
`FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in
`postmenopausal women with disease progression following antiestrogen therapy.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose
`The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2
`minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly
`
`thereafter [see Clinical Studies (14)].
`
`
`
` 2.2 Dose Modification
`
` Hepatic Impairment:
`
`A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to
`be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1,
`15, 29 and once monthly thereafter.
`
`
`FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see
`
`
`Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
`
`
`2.3 Administration Technique
`The proper method of administration of FASLODEX for intramuscular use is described in the instructions
`that follow:
`
`
`
`1. Remove glass syringe barrel from tray and check that it is not damaged.
`
`2. Remove perforated patient record label from syringe.
`3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions
`
`refer below to the "Directions for Use of SafetyGlide™".
`
`
`4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the
`
`attached rubber tip cap (see Figure 1).
`
`5. Twist to lock the needle to the luer connector.
`
`6. Remove needle sheath.
`
`
`7. Remove excess gas from the syringe (a small gas bubble may remain).
`
`
`8. Administer intramuscularly into the buttock slowly.
`
`
`
`
`9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm
`completely forward until needle tip is fully covered (see Figure 2).
`
`
`10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to
`activate, discard immediately into an approved sharps collector.
`
`11. Repeat steps 1 through 10 for second syringe.
`
`
`
`Reference ID: 3894565
`
`2
`
`
`

`

`
`
` How To Use FASLODEX
`
`
`
` For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg
`
` recommended dose.
`
`SAFETYGLIDE™ INSTRUCTIONS FROM BECTON DICKINSON
`
`
`SafetyGlide™ is a trademark of Becton Dickinson and Company.
`
`
`Important Administration Information
`
`
`To help avoid HIV (AIDS), HBV (Hepatitis), and other infectious diseases due to accidental needlesticks,
`contaminated needles should not be recapped or removed, unless there is no alternative or that such action
`is required by a specific medical procedure. Hands must remain behind the needle at all times during use
`and disposal.
`
`
`Do not autoclave SafetyGlide™ Needle before use.
`
`
`Parenteral drug products should be visually inspected for any particulate matter and discoloration prior to
`administration, whenever solution and container permit.
`
`DIRECTIONS FOR USE OF SAFETYGLIDE™
`
`
`For each syringe:
`
`
`Remove glass syringe barrel from tray and check that it is not damaged.
`
`
`Peel apart packaging of the SafetyGlide™, break the seal of the white plastic cover on the syringe Luer
`
`connector and attach the SafetyGlide™ needle to the Luer Lock of the syringe by twisting.
`
`
`
`
`Transport filled syringe to point of administration.
`
`
`
`Pull shield straight off needle to avoid damaging needle point.
`
`
`Administer injection following package instruction.
`
`
`
`
`For user convenience, the needle ‘bevel up’ position is orientated to the lever arm, as shown in Figure 3.
`
`
`
`
`
`Immediately activate needle protection device upon withdrawal from patient by pushing lever arm
`
`completely forward until needle tip is fully covered (Figure 2).
`
`
`
`Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate,
`
`discard immediately into an approved sharps collector.
`
`
`Activation of the protective mechanism may cause minimal splatter of fluid that may remain on the
`
`needle after injection.
`
`
`For greatest safety, use a one-handed technique and activate away from self and others.
`
`
`
`
`Reference ID: 3894565
`
`3
`
`
`

`

`After single use, discard in an approved sharps collector in accordance with applicable regulations and
`institutional policy.
`
`Becton Dickinson guarantees the contents of their unopened or undamaged packages to be sterile, non­
`toxic and non-pyrogenic.
`
`
`Figure 1
`
`
`
`Figure 2
`
`
`
`Figure 3
`
`
`
`
`
`Reference ID: 3894565
`
`4
`
`
`
`
`
`
`
`
`

`

`3 DOSAGE FORMS AND STRENGTHS
`
`
`FASLODEX, an injection for intramuscular administration, is supplied as 5-mL prefilled syringes
`containing 50 mg/mL fulvestrant.
`
`4 CONTRAINDICATIONS
`
`FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its
`components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in
`association with FASLODEX [see Adverse Reactions (6.2)] .
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Bleeding
`Because FASLODEX is administered intramuscularly, it should be used with caution in patients with
`bleeding diatheses, thrombocytopenia, or anticoagulant use.
`
`5.2 Increased Exposure in Patients with Hepatic Impairment
`The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with
`moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.
`Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is
`recommended [see Dosage and Administration (2.2)].
`
`
`FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see
`Use in Specific Populations (8.6)].
`
`
`5.3 Embryo-Fetal Toxicity
` Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm
`
`when administered to a pregnant woman. In animal reproduction studies, administration of fulvestrant to
`pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at daily doses that are
`significantly less than the maximum recommended human dose. Advise pregnant women of the potential
`risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment
`with FASLODEX and for one year after the last dose [see Use in Specific Populations (8.1), (8.3) and
`Clinical Pharmacology (12.1)].
`
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed in more detail in other sections of the labeling:
`
`
` Risk of Bleeding [see Warnings and Precautions (5.1)]
`
`
`
`
`
`Increased Exposure in Patients with Hepatic Impairment [see Warnings and Precautions (5.2)]
`
`
`
`
`
` Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`Reference ID: 3894565
`
`5
`
`
`

`

`6.1 Clinical Trials Experience
` Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed
`
`cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical
`
`practice.
`
`Comparison of FASLODEX 500 mg and FASLODEX 250 mg
`
`
`The following adverse reactions (ARs) were calculated based on the safety analysis of Study 1 comparing
`the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg
`
`intramuscularly once a month. The most frequently reported adverse reactions in the fulvestrant 500 mg
`
`group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of
`patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea
`(13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).
`
`Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed
`causality, from Study 1.
`
`Table 1: Adverse Reactions in Study 1 (≥5% in Either Treatment Group)
`
`
`Body System
`
`and Adverse Reaction
`
`
`Body as a Whole
`
`Injection Site Pain
`Headache
`Back Pain
`Fatigue
`Pain in Extremity
`Asthenia
`Vascular System
`
`Hot Flash
`Digestive System
`
`Nausea
`Vomiting
`Anorexia
`Constipation
`
`Musculoskeletal System
`
`Bone Pain
`Arthralgia
`Musculoskeletal Pain
`
`Respiratory System
`
`Cough
`
`Dyspnea
`
`
`
`Number (%) of Patients
`
`Fulvestrant 250 mg
`Fulvestrant 500 mg
`
`
`N=361
`N=374
`
`42 (11.6)
`
`28 (7.8)
`
`27 (7.5)
`
`27 (7.5)
`
`25 (6.9)
`
`21 (5.8)
`
`
`24 (6.6)
`
`
`35 (9.7)
`
`22 (6.1)
`
`22 (6.1)
`
`18 (5.0)
`
`
`34 (9.4)
`
`29 (8.0)
`
`20 (5.5)
`
`
`19 (5.3)
`
`16 (4.4)
`
`
`34 (9.1)
`
`25 (6.7)
`
`40 (10.7)
`
`24 (6.4)
`
`26 (7.0)
`
`23 (6.1)
`
`
`22 (5.9)
`
`
`51 (13.6)
`
`21 (5.6)
`
`14 (3.7)
`
`13 (3.5)
`
`
`28 (7.5)
`
`29 (7.8)
`
`12 (3.2)
`
`
`20 (5.3)
`
`19 (5.1)
`
`
`In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to
`
`FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline
`
`
`
`
`
`Reference ID: 3894565
`
`6
`
`

`

`phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were
`observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP)
`did not differ between the 250 mg and the 500 mg FASLODEX arms.
`
`Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3)
`
`
`The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups
`were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain),
`headache, back pain, vasodilatation (hot flashes), and pharyngitis.
`
`Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and
`occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European
`
`Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North
`
`
`American Trial Study 2).
`
`Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed
`causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg
`
`intramuscularly once a month with anastrozole 1 mg orally once a day.
`
`
`Table 2: Adverse Reactions in Studies 2 and 3(≥5% from Combined Data)
`
`
`Body System and Adverse Reaction
`
`
`Body as a Whole
`
`Asthenia
`Pain
`Headache
`Back Pain
`Abdominal Pain
`Injection Site Pain1
`Pelvic Pain
`Chest Pain
`Flu Syndrome
`Fever
`Accidental Injury
`
`Cardiovascular System
`
`Vasodilatation
`Digestive System
`
`Nausea
`Vomiting
`Constipation
`Diarrhea
`Anorexia
`Hemic and Lymphatic Systems
`
`Anemia
`Metabolic and Nutritional Disorders
`
`Peripheral Edema
`
`
`
`Reference ID: 3894565
`
`FASLODEX 250 mg
`
`N=423
`
`(%)
`
`68.3
`22.7
`
`18.9
`
`15.4
`
`14.4
`
`11.8
`
`
` 10.9
`9.9
`7.1
`
`7.1
`
`6.4
`
`4.5
`
`30.3
`17.7
`
`51.5
`26.0
`
`13.0
`
`12.5
`
`12.3
`
`9.0
`
`13.7
`4.5
`
`18.2
`9.0
`
`
`7
`
`Anastrozole 1 mg
`
`N=423
`
`(%)
`
`67.6
`
`27.0
`
`20.3
`
`16.8
`
`13.2
`
`11.6
`
` 6.6
`
`9.0
`5.0
`
`6.4
`
`6.4
`
`5.7
`
`27.9
`
`17.3
`
`48.0
`
`25.3
`
`11.8
`
`10.6
`
`12.8
`
`10.9
`
`13.5
`
`5.0
`
`17.7
`
`10.2
`
`
`

`

`
`
` Body System and Adverse Reaction
`
`
`
`
` Anastrozole 1 mg
` FASLODEX 250 mg
`
` N=423
`N=423
`
`
` (%)
`
` (%)
`Musculoskeletal System
`27.9
`25.5
`
`13.7
`15.8
`Bone Pain
`
`
`6.1
`2.8
`Arthritis
`Nervous System
`33.8
`34.3
`
`
`6.6
`6.9
`Dizziness
`
`
`8.5
`6.9
`Insomnia
`
`
`7.6
`6.4
`Paresthesia
`6.9
`5.7
`Depression
`
`
`3.8
`5.0
`Anxiety
`
`
`Respiratory System
`33.6
`38.5
`
`
`11.6
`16.1
`Pharyngitis
`12.3
`14.9
`Dyspnea
`
`
`10.4
`10.4
`Cough Increased
`
`
`Skin and Appendages
`23.4
`22.2
`
`
`8.0
`7.3
`Rash
`
`
`5.2
`5.0
`Sweating
`
`
`Urogenital System
`14.9
`18.2
`
`
`3.5
`6.1
`Urinary Tract Infection
`1. All patients on FASLODEX received injections, but only those anastrozole patients who were in the North
`
`American Study 2 received placebo injections.
`
`
`
`6.2 Post-Marketing Experience
`For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%)
`include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions
`including angioedema and urticaria.
`
`Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after
`changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further
`
`evaluation should be considered.
`
`Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently
`
`(<1%).
`
`
`7 DRUG INTERACTIONS
`
`There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro,
`drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose
`
`adjustment is not needed in patients co-prescribed CYP 3A4 inhibitors or inducers [see Clinical
`Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
` Risk Summary
`
`
`
`Reference ID: 3894565
`
`8
`
`
`

`

` Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm
`
`
` when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data
`in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of
`fulvestrant to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicity, including
`skeletal malformations and fetal loss, at daily doses that were 6% and 30% of the maximum
`
`recommended human dose based on mg/m2, respectively [see Data]. Advise pregnant women of the
`
`
`potential risk to a fetus.
`
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`unknown. In the U.S. general population, the estimated background risk of major birth defects and
`
`miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
`
`
`Data
`
`Animal Data
`
`Administration of fulvestrant to rats prior to and up to implantation caused embryonic loss at daily doses
`
`that were 0.6% of the daily maximum recommended human dose based on mg/m2. When fulvestrant was
`administered to pregnant rats during the period of organogenesis, intramuscular doses ≥0.1 mg/kg/day
`(6% of the human recommended dose based on mg/m2) caused effects on embryo-fetal development
`consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities
`in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on mg/m2) and
`
`non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1
`mg/kg/day. Fulvestrant administered at 2 mg/kg/day caused fetal loss.
`
`When administered to pregnant rabbits during the period of organogenesis, fulvestrant caused pregnancy
`
`loss at an intramuscular dose of 1 mg/kg/day (equivalent to the human dose based on mg/m2). Further, at
`0.25 mg/kg/day (30% the human dose based on mg/m2), fulvestrant caused increases in placental weight
`and post-implantation loss in rabbits. Fulvestrant was associated with an increased incidence of fetal
`variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25
`mg/kg/day; 30% the human dose based on mg/m2) when administered during the period of organogenesis.
`
`8.2 Lactation
`
`Risk Summary
`
`There is no information regarding the presence of fulvestrant in human milk, nor of its effects on milk
`production or breast-fed infant. Fulvestrant can be detected in rat milk [see Data]. Because of the
`potential for serious adverse reactions in breast-fed infants from FASLODEX, advise a lactating woman
`not to breast-feed during treatment with FASLODEX and for one year after the final dose.
`
`Data
`
`
`Levels of fulvestrant were approximately 12-fold higher in milk than in plasma after exposure of lactating
`rats to a dose of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was
`
`estimated as 10% of the administered dose. In a study in rats of fulvestrant at 10 mg/kg given twice or 15
`
`
`
`
`Reference ID: 3894565
`
`9
`
`
`

`

`mg/kg given once (less than the recommended human dose based on mg/m2) during lactation, offspring
`survival was slightly reduced.
`
`8.3 Females and Males of Reproductive Potential
`Pregnancy Testing
`
`Pregnancy testing is recommended for females of reproductive potential within seven days prior to
`initiating FASLODEX.
`
`
`Contraception
`
`Females
`
`
`FASLODEX can cause fetal harm when administered to a pregnant woman [see Use in Specific
`
`Populations (8.1)]. Advise females of reproductive potential to use effective contraception during
`treatment and for one year after the last dose.
`
`Infertility
`
`Based on animal studies, FASLODEX may impair fertility in females and males of reproductive potential.
`The effects of fulvestrant on fertility were reversible in female rats [see Nonclinical Toxicology (13.1)].
`
`
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established. A multi-center, single-arm, open-
`label, study of fulvestrant was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated
`with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1
`to 8).
`
`The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all
`10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg
`from study entry.
`
`
`Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at
`least 6 months prior to study entry were provided retrospectively by the parent, guardian or local
`
`consultant. All measurements during the study period were collected prospectively. Patients’ baseline
`
`characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of
`bone age advancement (change in bone age in years divided by change in chronological age in years) of
`2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.
`
`
`
`Twenty-nine of 30 patients completed the 12-month study period. The following results were observed:
`
`35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete
`cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age
`
`advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI: -1.4,
`-0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change
`= -1.1 [95% CI: -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast
`
`or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment
`
`
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`Reference ID: 3894565
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`compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied
`and is not known.
`
`Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX.
`These included injection site reactions (inflammation, pain, hematoma, pruritus, rash), abdominal pain,
`contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE,
`none of which were considered related to FASLODEX. No patients discontinued study treatment due to
`an AE and no patients died.
`
`
`Pharmacokinetics
`
`The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with
`
`sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP
`associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who
`
`received 125 or 250 mg monthly dosing regimen were also included in the analysis.
`
`
`In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric
`mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD)
`steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0.87) ng/mL and 3680 (1020) ng*hr/mL,
`respectively.
`
`
`8.5 Geriatric Use
`For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in
`22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older,
`
`
`who were treated with FASLODEX in Study 2 and Study 3, respectively.
`
`
`
`
`8.6 Hepatic Impairment
`FASLODEX is metabolized primarily in the liver.
`
`The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild
`and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-
`acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A)
`had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with
`moderate hepatic impairment (Child-Pugh class B), the average AUC of fulvestrant increased by 70%
`compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin
`concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment
`(Child-Pugh class C).
`
`A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-
`Pugh class B) [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].
`
`
` 8.7 Renal Impairment
`
`Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal
`
`impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women
`with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.
`
`
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`Reference ID: 3894565
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`10 OVERDOSAGE
`
` Animal studies have shown no effects other than those related directly or indirectly to antiestrogen
`
`activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no
`clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and
`female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at
`the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.
`
`11 DESCRIPTION
`
`FASLODEX® (fulvestrant) injection for intramuscular administration is an estrogen receptor antagonist.
`The chemical name is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)- triene­
`3,17-beta-diol. The molecular formula is C32H47F5O3S and its structural formula is:
`
`
`
`Fulvestrant is a white powder with a molecular weight of 606.77. The solution for injection is a clear,
`colorless to yellow, viscous liquid.
`
`Each injection contains as inactive ingredients: 10% w/v Alcohol, USP, 10% w/v Benzyl Alcohol, NF,
`and 15% w/v Benzyl Benzoate, USP, as co-solvents, and made up to 100% w/v with Castor Oil, USP as a
`co-solvent and release rate modifier.
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Many breast cancers have estrogen receptors (ER) and the growth of these tumors can be stimulated by
`
`
`estrogen. Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive
`manner with affinity comparable to that of estradiol and downregulates the ER protein in human breast
`cancer cells.
`
`
`In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant,
`as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant
`delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice.
`Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor
`xenografts.
`
`
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`Reference ID: 3894565
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`Fulvestrant showed no agonist-type effects in in vivo uterotropic assays in immature or ovariectomized
`mice and rats. In in vivo studies in immature rats and ovariectomized monkeys, fulvestrant blocked the
`uterotrophic action of estradiol. In postmenopausal women, the absence of changes in plasma
`concentrations of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests no
`
`peripheral steroidal effects.
`
`12.2 Pharmacodynamics
`In a clinical study in postmenopausal women with primary breast cancer treated with single doses of
`FASLODEX 15-22 days prior to surgery, there was evidence of increasing down-regulation of ER with
`increasing dose. This was associated with a dose-related decrease in the expression of the progesterone
`receptor, an estrogen-regulated protein. These effects on the ER pathway were also associated with a
`decrease in Ki67 labeling index, a marker of cell proliferation.
`
`12.3 Pharmacokinetics
`Absorption:
`
`The single dose and multiple dose PK parameters for the 500 mg dosing regimen with an additional dose
`
`
`(AD) at Day 15 are reported in Table 3. The additional dose of FASLODEX given two weeks after the
`initial dose allows for steady state concentrations to be reached within the first month of dosing.
`
`Table 3: Summary of Fulvestrant Pharmacokinetic Parameters [gMean (CV%)] in Postmenopausal
`
`Advanced Breast Cancer Patients after Intramuscular Administration 500 mg + AD Dosing
`Regimen
`
`
`
`
`
`
`500 mg + AD1
`
`
` Single dose
`
`Multiple dose steady state2
`
`
` 1. Additional 500 mg dose given on Day 15
`
`2. Month 3
`
`
`
`
`
` Distribution:
`
`Cmax
`
`(ng/mL)
`
`
` 25.1 (35.3)
`
` 28.0 (27.9)
`
`Cmin
`
`(ng/mL)
`
`
` 16.3 (25.9)
`
` 12.2 (21.7)
`
`AUC
`
`(ng.hr/mL)
`
`
` 11400 (33.4)
`
` 13100 (23.4)
`
` The apparent volume of distribution at steady state is approximately 3 to 5 L/kg. This suggests that
`
`distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins; VLDL, LDL
`and HDL lipoprotein fractions appear to be the major binding components. The role of sex hormone-
`binding globulin, if any, could not be determined.
`
`Metabolism:
`
`
`Biotransformation and disposition of fulvestrant in humans have been determined following
`intramuscular and intravenous administration of 14C-labeled fulvestrant. Metabolism of fulvestrant
`appears to involve combinations of a number of possible biotransformation pathways analogous to those
`of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid
`and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain
`
`
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`Reference ID: 3894565
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`

`sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in
`antiestrogen models.
`
`Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450
`3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the
`relative contribution of P-450 and non-P-450 routes in vivo is unknown.
`
`Excretion:
`
`
`Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces
`(approximately 90%). Renal elimination was negligible (less than 1%). After an intramuscular injection
`of 250 mg, the clearance (Mean ± SD) was 690 ± 226 mL/min with an apparent half-life about 40 days.
`
`
`Special Populations:
`
`
`Geriatric:
`
`
`In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to
`age (range 33 to 89 years).
`
`Gender:
`
`
`Following administration of a single intravenous dose, there were no pharmacokinetic differences
`between men and women or between premenopausal and postmenopausal women. Similarly, there were
`no differences between men and postmenopausal women after intramuscular administration.
`
`Race:
`
`
`In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race
`have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hi