`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 --------------------------
`
`
`Indications and Usage (1)
`08/2017
`
`
`
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`
`
`FASLODEX is an estrogen receptor antagonist indicated for the:
`
`Treatment of hormone receptor (HR)-positive, human epidermal growth
`
`receptor 2 (HER2)-negative advanced breast cancer in postmenopausal
`women not previously treated with endocrine therapy. (1)
`
`
`Treatment of HR-positive advanced breast cancer in postmenopausal
`women with disease progression following endocrine therapy. (1)
`
`
`Treatment of HR-positive, HER2-negative advanced or metastatic breast
`cancer in combination with palbociclib in women with disease
`progression after endocrine therapy. (1)
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`
`
`
`
`
`FASLODEX 500 mg should be administered intramuscularly into the
`
`buttocks (gluteal area) 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 (gluteal
`area) 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
`
`250 mg/5 mL fulvestrant. (3)
`
`
`
` ------------------------------ CONTRAINDICATIONS -----------------------------
`
`
`
`Hypersensitivity. (4)
`
`
`
`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 Injection Site Reaction
` 
`5.4 Embryo-Fetal Toxicity
` 
`5.5 Immunoassay Measurement of Serum Estradiol
`
`
` 
`6 ADVERSE REACTIONS
` 
`6.1 Clinical Trials Experience
` 
`6.2 Postmarketing Experience
` 
`7 DRUG INTERACTIONS
` 
`8 USE IN SPECIFIC POPULATIONS
` 
`8.1 Pregnancy
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`----------------------- 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)
`Injection Site Reaction: Use caution while administering FASLODEX at
`the dorsogluteal injection site due to the proximity of the underlying
`sciatic nerve. (5.3)
`
`
`Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`reproductive potential of the potential risk to a fetus and to use effective
`contraception. (5.4, 8.1, 8.3)
`Immunoassay Measurement of Serum Estradiol: FASLODEX can
`
`interfere with estradiol measurement by immunoassay, resulting in
`falsely elevated estradiol levels. (5.5)
`
`
`------------------------------ 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: 08/2017
`
`
`
`
`
` 
`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
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`
`Reference ID: 4144559
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`Monotherapy
`
`FASLODEX is indicated for the treatment of:
`
`
` hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative
`
`
`advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, or
`
`
` HR-positive advanced breast cancer in postmenopausal women with disease progression following
`
`endocrine therapy.
`
`Combination Therapy with Palbociclib
`
`FASLODEX is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast
`cancer in combination with palbociclib in women with disease progression after endocrine therapy.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose
`Monotherapy
`
`The recommended dose is 500 mg to be administered intramuscularly into the buttocks (gluteal area)
`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)].
`
`
`Combination Therapy with Palbociclib
`
`When FASLODEX is used in combination with palbociclib, the recommended dose is 500 mg to be
`administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5
`mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter. The recommended
`dose of palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7
`days off treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food. Please
`refer to the full prescribing information of palbociclib.
`
`Pre/perimenopausal women treated with the combination FASLODEX plus palbociclib should be treated
`with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice
`standards [see Clinical Studies (14)].
`
`
`
`
`
` 2.2 Dose Modification
`Monotherapy
`
`Hepatic Impairment:
`
`
`
`
`Reference ID: 4144559
`
`2
`
`
`

`

`A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to
`be administered intramuscularly into the buttock (gluteal area) 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)].
`
`
`Combination Therapy with Palbociclib
`
`When FASLODEX is used in combination with palbociclib, refer to monotherapy dose modification
`instructions for FASLODEX. Refer to the full prescribing information of palbociclib for its dose
`modification, management of toxicities, and for use with concomitant medication.
`
`2.3 Administration Technique
`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
`FASLODEX at the dorsogluteal injection site [see Warnings and Precautions (5.3) and Adverse
`Reactions (6.1)].
`
`The proper method of administration of FASLODEX for intramuscular use is described in the following
`instructions.
`
`For each syringe:
`
`
`1. Remove glass syringe barrel from tray and check that it is not damaged.
`
`2. Remove perforated patient record label from syringe.
`
`3. Inspect drug product in glass syringe for any visible particulate matter or discoloration prior to use.
`Discard if particulate matter or discoloration is present.
`4. Peel open the safety needle (SafetyGlide™) outer packaging.
`
`
`
`5. Hold the syringe upright on the ribbed part (C). With the other hand, take hold of the cap (A) and
`carefully tilt cap back and forth (DO NOT TWIST CAP) until the cap disconnects for removal (see
`Figure 1).
`
`Figure 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4144559
`
`3
`
`
`

`

`
`6. Pull the cap (A) off in a straight upward direction. DO NOT TOUCH THE STERILE SYRINGE TIP
`(Luer-Lok) (B) (see Figure 2).
`Figure 2
`
`
`
`
`
`
`
`
`
`
`
`7. Attach the safety needle to the syringe tip (Luer-Lok). Twist needle until firmly seated (see Figure 3).
`Confirm that the needle is locked to the Luer connector before moving or tilting the syringe out of the
`vertical plane to avoid spillage of syringe contents.
`
`
`Figure 3
`
`
`
`
`
`
`
`
`
`For Administration:
`
`
`8. Pull shield straight off needle to avoid damaging needle point.
`
`9. Remove needle sheath.
`
`10. Expel excess gas from the syringe (a small gas bubble may remain).
`
`11. Administer intramuscularly slowly (1-2 minutes/injection) into the buttock (gluteal area). For user
`
`convenience, the needle ‘bevel up’ position is orientated to the lever arm, as shown in Figure 4.
`Figure 4
`
`
`
`
`
`
`
`12. After injection, immediately activate the lever arm to deploy the needle shielding by applying a
`single-finger stroke to the activation assisted lever arm to push the lever arm completely forward.
`
`
`Listen for a click. Confirm that the needle shielding has completely covered the needle (see Figure 5).
`
`NOTE: Activate away from self and others.
`Figure 5
`
`
`
`
`
`
`Reference ID: 4144559
`
`4
`
`
`

`

`
`13. Discard the empty single use syringe into an approved sharps collector in accordance with applicable
`
` regulations and institutional policy.
`
`14. Repeat steps 1 through 13 for second syringe.
` 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.
`
`
`Becton Dickinson guarantees the contents of their unopened or undamaged packages to be sterile, non­
`
`toxic and non-pyrogenic.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`FASLODEX, an injection for intramuscular administration, is supplied as 5-mL prefilled syringes
`containing 250 mg/5 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)].
`
`
`
`
`Reference ID: 4144559
`
`5
`
`
`

`

`FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see
`Use in Specific Populations (8.6)].
`
`
`
`
`5.3 Injection Site Reaction
` Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy
`have been reported with FASLODEX injection. Caution should be taken while administering
`
`FASLODEX at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve [see
`
`
`Dosage and Administration (2.3) and Adverse Reactions (6.1)].
`
`
`5.4 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)].
`
`
`5.5 Immunoassay Measurement of Serum Estradiol
`Due to structural similarity of fulvestrant and estradiol, FASLODEX can interfere with estradiol
`measurement by immunoassay, resulting in falsely elevated estradiol levels.
`
`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)]
`
`
`
`
`
`Injection Site Reaction [see Warnings and Precautions (5.3)]
`
`
`
`
`
` Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)]
`
`
`
`
`
`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.
`
`
`Monotherapy
`
`Comparison of FASLODEX 500 mg and FASLODEX 250 mg
`
`
`The following adverse reactions (ARs) were calculated based on the safety analysis of CONFIRM
`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%
`
`
`
`Reference ID: 4144559
`
`6
`
`
`

`

`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 CONFIRM.
`
`
`Table 1: Adverse Reactions in CONFIRM (≥5% in Either Treatment Group)
`
`
`Body System
`
`and Adverse Reaction
`
`
`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)
`
`
`
` 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)
`
`
`Body as a Whole
`
`Injection Site Pain1
`
`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
`
`20 (5.3)
`19 (5.3)
`Cough
`
`
`
`19 (5.1)
`16 (4.4)
`Dyspnea
`
`
`
` 1.Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.
`
`
`
`
`
`
`
`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
`
`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 500 mg and Anastrozole 1 mg (FALCON)
`
`
`The safety of FASLODEX 500 mg versus anastrozole 1 mg was evaluated in FALCON. The data
`
`described below reflect exposure to FASLODEX in 228 out of 460 patients with HR-positive advanced
`breast cancer in postmenopausal women not previously treated with endocrine therapy who received at
`least one (1) dose of treatment in FALCON.
`
`
`
`
`
`Reference ID: 4144559
`
`7
`
`
`

`

`Permanent discontinuation associated with an adverse reaction occurred in 4 of 228 (1.8%) patients
`receiving FASLODEX, and in 3 of 232 (1.3%) patients receiving anastrozole. Adverse reactions leading
`to discontinuation for those patients receiving FASLODEX included drug hypersensitivity (0.9%),
`
`injection site hypersensitivity (0.4%), elevated liver enzymes (0.4%).
`
`The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX arm
`
`
`were arthralgia, hot flash, fatigue and nausea.
`
`
`Adverse reactions reported in patients who received FASLODEX in FALCON at an incidence of ≥5% in
`either treatment arm are listed in Table 2, and laboratory abnormalities are listed in Table 3.
`
`
`
`
`Table 2: Adverse Reactions in FALCON
`
`26 (11.4%)
`
`0
`
`0
`0
`
`Adverse Reactions
`
`FASLODEX 500 mg
`N=228
`All Grades
`Grade 3 or 4
`
`Vascular disorders
`
`Hot flash
`Gastrointestinal disorders
`Nausea
`24 (10.5%)
`Diarrhea
`14 (6.1%)
`
`Musculoskeletal and connective tissue disorders
`
`0
`Arthralgia
`38 (16.7%)
`0
`Myalgia
`16 (7.0%)
`
`
`0
`Pain in extremity
`13 (5.7%)
`
`1 (0.4%)
`21 (9.2%)
`Back pain
`
`
`General disorders and administration site conditions
`
`1 (0.4%)
`Fatigue
`26 (11.4%)
`
`
`
`Anastrozole 1mg
`N=232
`Grade 3 or 4
`
`All Grades
`
`24 (10.3%)
`
`24 (10.3%)
`13 (5.6%)
`
`
`24 (10.3%)
`8 (3.4%)
`
`10 (4.3%)
`
`14 (6%)
`
`
`0
`
`1 (0.4%)
`
`1 (0.4%)
`
`
`0
`0
`0
`0
`
`16 (6.9%)
`
`
`1 (0.4%)
`
`
`Table 3: Laboratory Abnormalities in FALCON*
`
`
`Laboratory Parameters
`
`
`FASLODEX 500 mg
`
`N=228
`All Grades
`Grade 3 or 4
`16 (7%)
`3 (1.3%)
`
`
`
`Anastrozole 1mg
`N=232
`All Grades
`Grade 3 or 4
`
`7 (3%)
`0
`
`
`Alanine aminotransferase
`increased (ALT)
`Aspartate aminotransferase
`
`1 (0.4%)
`8 (3.4%)
`3 (1.3%)
`12 (5.3%)
`
`
`
`increased (AST)
` *In the FALCON, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were
`
`
` observed in >10% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1%-3% of patients.
`
`
`
`Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 0020 and
`0021)
`
`
`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.
`
`
`
`Reference ID: 4144559
`
`8
`
`
`

`

`Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and
`occurred in 7% of patients given the single 5 mL injection (Study 0020) and in 27% of patients given the
`
`
`2 x 2.5 mL injections (Study 0021) in the two clinical trials that compared FASLODEX 250 mg and
`anastrozole 1 mg.
`
`
`Table 4 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 4: Adverse Reactions in Studies 0020 and 0021 (≥5% from Combined Data)
`
`Anastrozole 1 mg
`Body System and Adverse Reaction
`FASLODEX 250 mg
`
`
`
`N=423
`N=423
`
`
`(%)
`(%)
`
`
`67.6
`68.3
`
`27.0
`22.7
`
`
`20.3
`18.9
`
`
`16.8
`15.4
`
`
`13.2
`14.4
`
`
`11.6
`11.8
`
`
` 6.6
`
`
` 10.9
`9.0
`9.9
`
`
`5.0
`7.1
`
`
`6.4
`7.1
`
`
`6.4
`6.4
`
`
`5.7
`4.5
`
`27.9
`30.3
`
`
`17.3
`17.7
`
`48.0
`51.5
`
`
`25.3
`26.0
`
`
`11.8
`13.0
`
`
`10.6
`12.5
`
`
`12.8
`12.3
`
`
`10.9
`9.0
`
`13.5
`13.7
`
`
`5.0
`4.5
`
`17.7
`18.2
`10.2
`9.0
`
`
`
`27.9
`25.5
`13.7
`15.8
`
`
`2.8
`6.1
`
`34.3
`33.8
`6.9
`6.6
`
`
`
`
`6.9
`8.5
`6.4
`7.6
`
`
`5.7
`6.9
`
`
`5.0
`3.8
`
`38.5
`33.6
`11.6
`16.1
`
`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
`Musculoskeletal System
`Bone Pain
`Arthritis
`Nervous System
`
`Dizziness
`Insomnia
`Paresthesia
`Depression
`Anxiety
`Respiratory System
`
`Pharyngitis
`
`
`
`
`
`Reference ID: 4144559
`
`9
`
`

`

`
`
` Body System and Adverse Reaction
`
`
`
`
` Anastrozole 1 mg
` FASLODEX 250 mg
`
` N=423
`N=423
`
`
` (%)
`
` (%)
`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.
`
`
` Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. All
`patients on FASLODEX received injections, but only those anastrozole patients who were in Study 0021
`received placebo injections.
`
`
`
`Combination Therapy with Palbociclib
`
`The safety of FASLODEX 500 mg plus palbociclib 125 mg/day versus FASLODEX plus placebo was
`evaluated in PALOMA-3. The data described below reflect exposure to FASLODEX plus palbociclib in
`345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who
`
`received at least 1 dose of treatment in PALOMA-3.
`
`
`No dose reduction was allowed for FASLODEX in PALOMA-3. Dose reductions of palbociclib due to an
`
`adverse reaction of any grade occurred in 36% of patients receiving FASLODEX plus palbociclib.
`
`Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients
`receiving FASLODEX plus palbociclib, and in 6 of 172 (3%) patients receiving FASLODEX plus
`placebo. Adverse reactions leading to discontinuation for those patients receiving FASLODEX plus
`palbociclib included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).
`
`
`The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX plus
`
`palbociclib arm were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache,
`diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia.
`
`The most frequently reported serious adverse reactions in patients receiving FASLODEX plus palbociclib
`were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).
`
`Adverse reactions reported in patients who received FASLODEX plus palbociclib in PALOMA-3 are
`
`listed in Table 5, and laboratory abnormalities are listed in Table 6.
`
`
`
`
`
`Reference ID: 4144559
`
`
`
` 10
`
`
`

`

`
`
` Table 5: Adverse Reactions in PALOMA-3
`
`Adverse Reaction
`
`FASLODEX plus placebo
`FASLODEX plus palbociclib
`(N=172)
`(N=345)
`All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
`%
`%
`%
`%
`%
`%
`
`3
`
`1
`55
`
`30
`
`3
`2
`
`0
`0
`0
`
`1
`
`0
`1
`0
`0
`1
`
`1
`
`0
`11
`
`1
`0
`1
`
`0
`0
`0
`
`0
`
`0
`0
`
`0
`
`0
`0
`0
`0
`0
`
`
`
` N/A
`0
`0
`
`0
`0
`0
`
`31
`
`1
`4
`5
`13
`0
`
`2
`1
`2
`
`8
`
`20
`3
`
`2
`
`28
`13
`19
`16
`15
`
`6d
`6
`1
`
`29
`5
`5
`
`Infections and infestations
`Infectionsa
` 47
`
`
`Blood and lymphatic system disorders
`
`Febrile neutropenia
`1
`Neutropenia
`83
`
`53
`Leukopenia
`
`30
`Anemia
`
`
`23
`Thrombocytopenia
`Eye disorders
`
`6
`Vision blurred
`6
`Lacrimation increased
`4
`Dry eye
`
`
`Metabolism and nutrition disorders
`Decreased appetite
`16
`Nervous system disorders
`
`1
`26
`Headache
`
`0
`7
`Dysgeusia
`Respiratory, thoracic and mediastinal disorders
`Epistaxis
`7
`0
`Gastrointestinal disorders
`Nausea
`34
`
` Stomatitisb
`
`
` 28
`
`Diarrhea
`24
`
`
`Constipation
`20
`
`Vomiting
`19
`Skin and subcutaneous tissue disorders
`18c
`
` N/A
`Alopecia
`Rashe
`1
`
`
` 17
`
`
`0
`Dry skin
`6
`General disorders and administration site conditions
`41
`Fatigue
`2
`
`
`13
`Pyrexia
`<1
`8
`Asthenia
`0
` Grading according to CTCAE 4.0.
`
`CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
`a Most common infections (>1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection,
`
`
`
`
`influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection.
`b Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal
`
`
`
`inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
`c Grade 1 events – 17%; Grade 2 events – 1%.
`
`
`
`
`
`d Grade 1 events – 6%.
`
`
`
`e Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis
`
`
`acneiform, toxic skin eruption.
`
`3
`
`0
`1
`1
`2
`0
`
`0
`0
`0
`
`1
`
`0
`0
`
`0
`
`1
`0
`1
`0
`1
`
`0
`
`1
`0
`1
`0
`0
`
`0
`0
`0
`
`0
`
`0
`0
`
`0
`
`0
`0
`0
`0
`0
`
`
` N/A
`0
`0
`
`1
`0
`1
`
`
` N/A
`0
`0
`
`0
`0
`0
`
`
`
`Reference ID: 4144559
`
`11
`
`
`
`

`

`
`Table 6: Laboratory Abnormalities in PALOMA-3
`
`
`Laboratory Abnormality
`
`FASLODEX plus placebo
`FASLODEX plus palbociclib
`(N=172)
`(N=345)
`
`
`All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
`%
`%
`%
`%
`%
`%
`
`
`
`99
`45
`26
`1
`0
`1
`WBC decreased
`
`96
`56
`14
`11
`0
`1
`Neutrophils decreased
`
`
`
`78
`3
`40
`0
`2
`0
`Anemia
`
`62
`2
`10
`1
`0
`0
`Platelets decreased
`
`N=number of patients; WBC=white blood cells.
`
`6.2 Postmarketing 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
`
`
`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.
`
`
`
`Reference ID: 4144559
`
`
`
` 12
`
`
`

`

`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
`
`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.
`
`
`
`
`Reference ID: 4144559
`
`
`
` 13
`
`
`

`

`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