`•
`
`
`•
`
`
`•
`
`
`•
`
` 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
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE -------------------------­
`
`
`
`FASLODEX is an estrogen receptor antagonist 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. (1)
`HR-positive advanced breast cancer in postmenopausal women with
`
`
`
`
`
`disease progression following endocrine therapy. (1)
`
`
`
`HR-positive, HER2-negative advanced or metastatic breast cancer in
`
`
`
`postmenopausal women in combination with ribociclib, as initial
`
`
`endocrine based therapy or following disease progression on endocrine
`
`therapy. (1)
`
`HR-positive, HER2-negative advanced or metastatic breast cancer in
`
`
`combination with palbociclib or abemaciclib 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 breastfeed. (8.2)
`
`
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`approved patient labeling.
`
`
`Revised: 07/2020
`
`
`
`
`
`
`
`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: 4647251
`
`
`
` 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
`
`
`FASLODEX is indicated for the treatment of:
`
`
`
`
`• HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in
`
`
`
`combination with ribociclib as initial endocrine based therapy or following disease progression on
`
`
`
`endocrine therapy.
`
`
`• HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or
`
`
`
`
`abemaciclib in women with disease progression after endocrine therapy.
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
` 2.1 Recommended Dose
`
` Monotherapy
`
`The recommended dose of FASLODEX 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
`
`
`
`When FASLODEX is used in combination with palbociclib, abemaciclib, or ribociclib, the recommended
`
`
`
`
`
`
`dose of FASLODEX 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.
`
`
`When FASLODEX is used in combination with palbociclib, 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. Refer to the Full
`
`
`
`
`Prescribing Information for palbociclib.
`
`
`
`
`
`
`Reference ID: 4647251
`
`
`
` 2
`
`

`

`
`
`
`
` When FASLODEX is used in combination with abemaciclib, the recommended dose of abemaciclib is
` 150 mg orally, twice daily. Abemaciclib may be taken with or without food. Refer to the Full Prescribing
`
`
` Information for abemaciclib.
`
`
`
`
`
`
`
`
`
`
` When FASLODEX is used in combination with ribociclib, the recommended dose of ribociclib is 600 mg
` taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete
`
`
`
` cycle of 28 days. Ribociclib can be taken with or without food. Refer to the Full Prescribing Information
`
`
`
` for ribociclib.
`
`
`
`
`
`
`
`
` Pre/perimenopausal women treated with the combination of FASLODEX plus palbociclib, abemaciclib,
`
` or ribociclib, 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:
`
`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
`
`
`When FASLODEX is used in combination with palbociclib, abemaciclib, or ribociclib, refer to
`
`
`
`
`
`
`monotherapy dose modification instructions for FASLODEX.
`
`
`Refer to the Full Prescribing Information of co-administered palbociclib, abemaciclib, or ribociclib for
`
`
`
`
`
`
`
`
`dose modification guidelines in the event of toxicities, for use with concomitant medications, and other
`
`
`
`relevant safety information.
`
`
` 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.
`
`
`
`
`
`
`
`
`Reference ID: 4647251
`
`
`
` 3
`
`

`

`
`
` For each single-dose prefilled 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4647251
`
`
`
` 4
`
`

`

`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`13. Discard the empty 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.
`
`
`
`
`
`Reference ID: 4647251
`
`
`
` 5
`
`

`

`
`
` 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 single-dose 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)].
`
`
`
`
`
`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)].
`
`
`
`
`
`
`Reference ID: 4647251
`
`
`
` 6
`
`

`

` 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 (CONFIRM)
`
`
`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 FASLODEX
`
`
`
`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 FASLODEX 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)
`
`
`
`Adverse Reactions
`
`
`Body as a Whole
`
` Injection Site Pain1
`
`
` Headache
`
` Back Pain
`
` Fatigue
`
` Pain in Extremity
` Asthenia
`
`Vascular System
`
`
` Hot Flash
`Digestive System
`
`
`
`
`
`
`Reference ID: 4647251
`
`
` FASLODEX 500 mg
`
` N=361
`
`
` %
`
`
` FASLODEX 250 mg
`
` N=374
`
`
` %
`
`
` 12
`
` 8
`
` 8
`
` 8
`
` 7
`
` 6
`
`
`
` 7
`
`
`
` 7
`
`
` 9
`
` 7
`
` 11
`
` 6
`
` 7
`
` 6
`
`
`
` 6
`
`

`

`
`
` Adverse Reactions
`
`
` FASLODEX 500 mg
`
` N=361
`
`
` %
`
` 10
`
` 6
`
` 6
`
` 5
`
`
` FASLODEX 250 mg
`
` N=374
`
`
` %
`
` 14
`
` 6
`
` 4
`
` 4
`
` Nausea
`
`
` Vomiting
`
` Anorexia
` Constipation
`
`Musculoskeletal System
`
`
` Bone Pain
`
` Arthralgia
`
` Musculoskeletal Pain
`Respiratory System
`
`
` Cough
`
` 5
`
` 5
` Dyspnea
`
` 5
`
` 4
`
` 1. Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.
`
`
`
`
` 9
`
` 8
`
` 6
`
`
`
`
` 8
`
` 8
`
` 3
`
`
`
` 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.
`
`
`
`
`
`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%), and 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
`
`
`Adverse Reactions
`
`
`
`
` Vascular Disorders
`
` Hot flash
` Gastrointestinal Disorders
`
` Nausea
`
`
`
`
`
`
`
`Reference ID: 4647251
`
`
`
` FASLODEX 500 mg
`
` N=228
`
` Grade 3 or 4
`
` All Grades
`
`
` %
` %
`
`
`
` Anastrozole 1 mg
`
` N=232
` Grade 3 or 4
`
`
` %
`
`
` All Grades
`
` %
`
`
`
` 11
`
`
`
` 11
`
`
`
` 0
`
`
`
` 0
`
`
`
` 8
`
`
`
` 10
`
`
`
` 10
`
`
`
` 0
`
`
`
` <1
`
`

`

`
`
`
`
` 0
`
` 6
` Diarrhea
`
`
` Musculoskeletal and Connective Tissue Disorders
`
` 0
`
`
` Arthralgia
` 17
`
` 0
`
`
` Myalgia
` 7
`
` 0
` Pain in extremity
`
` 6
`
` <1
`
` Back pain
`
` 9
`
` General Disorders and Administration Site Conditions
`
`
`
`
`
` Fatigue
` 11
` <1
`
`
`
`
`
`
`
`
`
`
`
`
`Table 3: Laboratory Abnormalities in FALCON1
`
`
`
`
` 6
`
`
` 10
`
` 3
`
` 4
`
` 6
`
`
`
` 7
`
`
`
` <1
`
`
` 0
`
` 0
`
` 0
`
` 0
`
`
`
` <1
`
`
`
` Laboratory Parameters
`
`
` FASLODEX 500 mg
`
` N=228
` Grade 3 or 4
`
` All Grades
`
` %
`
` %
`
`
` 7
` 1
`
`
`
`
`
`
` Anastrozole 1 mg
`
` N=232
`
` Grade 3 or 4
`
` All Grades
`
` %
`
` %
`
`0
`
` 3
`
`Alanine aminotransferase
`
` increased (ALT)
`Aspartate aminotransferase
`
` 3
` 5
`<1
`
`
`
` 1
`
` increased (AST)
` 1. In 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.
`
`
`
`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)
`
`
`
` FASLODEX 250 mg
`
` Anastrozole 1 mg
`
`
`N=423
`N=423
`
`
`%
`%
`
`
`
` 68
`
` 68
`
` 23
`
` 27
`
` 19
`
` 20
`
` 15
`
` 17
`
` 14
`
` 13
`
`Body as a Whole
`
`
` Asthenia
`
` Pain
`
` Headache
`
` Back Pain
`
`Adverse Reactions
`
`
`
`
`Reference ID: 4647251
`
`
`
` 9
`
`

`

`Adverse Reactions
`
`
`
`
`
`
` Anastrozole 1 mg
` FASLODEX 250 mg
`N=423
`N=423
`
`
`%
`%
`
`
` Abdominal Pain
`
`
` 12
`
` 12
` Injection Site Pain1
`
`
` 7
`
` 11
`
` Pelvic Pain
`
` 9
`
` 10
`
` Chest Pain
`
` 5
`
` 7
`
` Flu Syndrome
`
` 6
`
` 7
`
` Fever
`
` 6
`
` 6
` Accidental Injury
`
`
` 6
`
` 5
`Cardiovascular System
`
`
` 28
`
` 30
`
` Vasodilatation
`
` 17
`
` 18
`Digestive System
`
`
` 48
`
` 52
`
` Nausea
`
` 25
`
` 26
` Vomiting
`
`
` 12
`
` 13
`
` Constipation
`
` 11
`
` 13
`
` Diarrhea
`
` 13
`
` 12
`
` Anorexia
`
` 11
`
` 9
`Hemic and Lymphatic Systems
`
`
` 14
`
` 14
`
` Anemia
`
`
` 5
` 5
`Metabolic and Nutritional Disorders
`
`
` 18
`
` 18
`
` Peripheral Edema
`
` 10
`
` 9
` Musculoskeletal System
`
`
` 28
`
` 26
`
` Bone Pain
`
` 14
`
` 16
`
` Arthritis
`
`
` 3
` 6
`Nervous System
`
`
` 34
`
` 34
`
` Dizziness
`
` 7
`
` 7
`
` Insomnia
`
` 9
`
` 7
`
` Paresthesia
`
` 8
`
` 6
`
` Depression
`
` 7
`
` 6
`
` Anxiety
`
` 4
`
` 5
`Respiratory System
`
`
` 34
`
` 39
`
` Pharyngitis
`
` 12
`
` 16
`
` Dyspnea
`
` 12
`
` 15
` Cough Increased
`
`
` 10
`
` 10
`Skin and Appendages
`
`
` 23
`
` 22
`
` Rash
`
` 8
`
` 7
` Sweating
`
`
` 5
`
` 5
`Urogenital System
`
`
` 15
`
` 18
` Urinary Tract Infection
`
`
`
` 6
` 4
`
`
`
`
` 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.
`
`
`
`
`
`
`
`Reference ID: 4647251
`
`
`10
`
`

`

`
`Combination Therapy
`Combination Therapy with Palbociclib (PALOMA-3)
`
`
`
`
`
`
`
`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. The median duration of treatment for FASLODEX
`
`
`plus palbociclib was 10.8 months while the median duration of treatment for FASLODEX plus placebo
`
`arm was 4.8 months.
`
`
`
`
`
`
`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 by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea,
`
`
`anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.
`
`
`
`
`
`
`The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving FASLODEX plus
`
`
`
`palbociclib in descending frequency were neutropenia and leukopenia.
`
`
`
`Adverse reactions (≥10%) reported in patients who received FASLODEX plus palbociclib or
`
`
`
`
`
`FASLODEX plus placebo in PALOMA-3 are listed in Table 5, and laboratory abnormalities are listed in
`
`
`Table 6.
`
`
`
`Reference ID: 4647251
`
`
`
` 11
`
`

`

`
`
` Table 5: Adverse Reactions (≥10%) in PALOMA-3
`
`
`
`
`
` FASLODEX plus Palbociclib
`
` N=345
`
` Grade 3
`
` %
`
` Grade 4
`
`
` %
`
`
`
` Adverse Reactions
`
`
` All Grades
`
` %
`
` Infections and Infestations
`
` 472
`
` Infections1
` 3
`
` Blood and Lymphatic System Disorders
`
`
`
`
` Neutropenia
` 83
` 55
`
` Leukopenia
`
` 53
`
` 30
`
` 30
`
`
` 4
` Anemia
` Thrombocytopenia
`
` 23
`
` 2
`
` Metabolism and Nutrition Disorders
`
`
` Decreased appetite
` 1
`
`
`
` 16
` Gastrointestinal Disorders
`
`
`
` 0
`
` 34
`
` Nausea
`
` Stomatitis3
`
` 1
`
` 28
`
` 0
`
` 24
`
` Diarrhea
`
` 1
` Vomiting
`
` 19
`
` Skin and Subcutaneous Tissue Disorders
`
`
` 184
` N/A
` N/A
`
`
` Alopecia
`
` Rash6
`
`
` 17
`
` 1
` 0
`
` General Disorders and Administration Site Conditions
`
`
`
`
` Fatigue
` 41
` 0
` 2
`
` Pyrexia
`
` 13
` <1
`
` 0
`
`
` Grading according to CTCAE v.4.0.
`
`
`
`
`
` CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
`
`
` Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and
`
`
` 1.
`
` infestations.
` 2. Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection,
`
`
`
`
` influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection,
` gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, paronychia.
`
`
`3. Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal
`
`
`inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
`
`4. Grade 1 events – 17%; Grade 2 events – 1%.
`
`
`
`
`
`
`
`5. Grade 1 events – 6%.
`
`
`
`
` 6. Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis
`
`
` acneiform, toxic skin eruption.
`
`
` FASLODEX plus Placebo
`
` N=172
`
` Grade 3
`
` %
`
`
`
` Grade 4
`
`
` %
`
` All Grades
`
`
` %
`
`
`
`
`
`
`
` 1
`
`
` 11
`
` 1
`
` 0
`
` 1
`
`
`
` 0
`
`
` 0
`
` 0
`
` 0
`
` 0
`
`
`
`
`
`
`
`
`
`
`
`
`
` 31
`
`
` 4
`
` 5
`
` 13
`
` 0
`
`
`
` 8
`
`
` 28
`
` 13
`
` 19
`
` 15
`
`
` 65
`
` 6
`
`
` 29
`
` 5
`
`
`
` 3
`
`
` 1
`
` 1
`
` 2
`
` 0
`
`
`
` 1
`
`
` 1
`
` 0
`
` 1
`
` 1
`
`
`
` 0
`
`
` 0
`
` 1
`
` 0
`
` 0
`
`
`
` 0
`
`
` 0
`
` 0
`
` 0
`
` 0
`
` N/A
`
`
` 0
`
`
` 1
`
` 0
`
`
`
` N/A
`
` 0
`
`
` 0
`
` 0
`
`
`
`
`
`
` Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving
`
`
`
`
`
`
` FASLODEX plus palbociclib in PALOMA-3 included asthenia (7.5%), aspartate aminotransferase
` increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%),
`
`
`
` alanine aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia
` (0.9%).
`
`
`
`
`
`
`
`
`Reference ID: 4647251
`
`
`
` 12
`
`

`

`
` FASLODEX plus Palbociclib
` N=345
`
`Grade
`
` 3
`%
`
`
` 45
`
` 56
`
`3
`
` 2
`
` 4
`
`
`
`Grade
`
` 4
`%
`
`
` 1
`
` 11
`
` 0
`
` 1
`
` 0
`
`All
`
` Grades
`%
`
`
` 99
`
` 96
`
` 78
`
` 62
`
` 43
`
`
`
` FASLODEX plus Placebo
`
` N=172
`Grade
`
` 3
`%
`
`
` 0
`
` 0
`
` 2
`
` 0
`
` 4
`
` All
`
`
` Grades
`%
`
`
` 26
`
` 14
`
` 40
`
` 10
`
` 48
`
`Grade
`
` 4
`%
`
`
` 1
`
` 1
`
` 0
`
` 0
`
` 0
`
`
`
` Table 6: Laboratory Abnormalities in PALOMA-3
`
`
`Laboratory Parameters
`
`
` WBC decreased
`
` Neutrophils decreased
`
`
` Anemia
` Platelets decreased
`
`Aspartate aminotransferase
`
` increased
`Alanine aminotransferase
`
` 36
`
` increased
`
`N=number of patients; WBC=white blood cells.
`
`
`
`
`Combination Therapy with Abemaciclib (MONARCH 2)
`
`
`
` 2
`
`
`
` 0
`
`
`
` 34
`
`
`
` 0
`
`
`
` 0
`
`
`
`
`The safety of FASLODEX (500 mg) plus abemaciclib (150 mg twice daily) versus FASLODEX plus
`
`placebo was evaluated in MONARCH 2. The data described below reflect exposure to FASLODEX in
`
`
`664 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of
`
`
`FASLODEX plus abemaciclib or placebo in MONARCH 2.
`
`
`
`
`
`
`
`
`Median duration of treatment was 12 months for patients receiving FASLODEX plus abemaciclib and 8
`
`
`
`
`months for patients receiving FASLODEX plus placebo.
`
`
`Dose reductions due to an adverse reaction occurred in 43% of patients receiving FASLODEX plus
`
`
`
`abemaciclib. Adverse reactions leading to dose reductions ≥5% of patients were diarrhea and neutropenia.
`
`
`
`
`Abemaciclib dose reduction due to diarrhea of any grade occurred in 19% of patients receiving
`FASLODEX plus abemaciclib compared to 0.4% of patients receiving FASLODEX plus placebo.
`
`
`
`
`
`Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving
`
`
`FASLODEX plus abemaciclib compared to no patients receiving FASLODEX plus placebo.
`
`
`
`Permanent study treatment discontinuation due to an adverse event was reported in 9% of patients
`
`
`
`
`
`
`
`receiving FASLODEX plus abemaciclib and in 3% of patients receiving FASLODEX plus placebo.
`
`
`
`
`
`Adverse reactions leading to permanent discontinuation for patients receiving FASLODEX plus
`
`
`abemaciclib were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%),
`
`abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).
`
`
`Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases
`
`
`
`
`
`
`(4%) of FASLODEX plus abemaciclib treated patients versus 10 cases (5%) of FASLODEX plus placebo
`
`
`
`
`
`
`treated patients. Causes of death for patients receiving FASLODEX plus abemaciclib included: 7 (2%)
`
`
`
`patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%)
`
`
`
`due to hepatotoxicity, and one (0.2%) due to cerebral infarction.
`
`
`
`
`
`
`The most common adverse reactions reported (≥20%) in the FASLODEX plus abemaciclib arm were
`diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite,
`
`
`
`Reference ID: 4647251
`
`
`
` 13
`
`

`

` vomiting, and headache (Table 7). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions
`
`
`
`
` were neutropenia, diarrhea, leukopenia, anemia, and infections.
`
` Table 7: Adverse Reactions ≥10% of Patients Receiving FASLODEX Plus Abemaciclib and ≥2%
`
`
`
`
`
`
` Higher Than FASLODEX Plus Placebo in MONARCH 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Adverse Reactions
`
`
`
`FASLODEX plus Abemaciclib
`
`
` N=441
`Grade
`