CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` NDA 21344/S-029
`
`
`
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
` FASLODEX
`
`fulvestrant solution for injection, 250 mg/5 ml
`
`AstraZeneca Pharmaceuticals LP
`
`July 12, 2016
`
`To update the Dosage and Administration, Warnings and
`Precautions, and Adverse Reactions sections of the Full
`Prescribing Information regarding the risk of severe
`injection site related neurological events
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`NDA 21344/S-029
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`X
`
`X
`
`
`
`
`
`X
`
`
`
`
`
`
` X
`
`
`X
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`
`
`APPLICATION NUMBER:
`NDA 21344/S-029
`
`NDA 21344/S-029
`
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 021344/S-029
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`
`
`AstraZeneca Pharmaceuticals LP
`Attention: Jamie L. Austin, PhD, RAC
`Regulatory Affairs Director, Oncology
`One MedImmune Way
`Gaithersburg, MD 20878
`
`
`Dear Dr. Austin:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated April 28, 2016, received
`April 28, 2016, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for FASLODEX® (fulvestrant) Solution for Injection, 250 mg/5 ml.
`
`This Prior Approval supplemental new drug application proposes to update the Dosage and
`Administration, Warnings and Precautions, and Adverse Reactions sections of the Full
` Prescribing Information regarding the risk of severe injection site related neurological events.
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`
`patient package insert), with the addition of any labeling changes in pending “Changes Being
`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
`labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Reference ID: 3957054
`
`

`

`NDA 021344/S-029
`Page 2
`
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because none of these criteria apply to your application, you are exempt from this requirement.
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Charlene Wheeler, MSHS, Senior Regulatory Project Manager, at
`(301) 796-1141.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Geoffrey Kim, MD
`Director
`
`Division of Oncology Products 1
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`Content of Labeling
`
`
`
`Reference ID: 3957054
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GEOFFREY S KIM
`07/12/2016
`
`Reference ID: 3957054
`
`(
`
`
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 21344/S-029
`NDA 21344/S-029
`
`
`LABELING
`
`APPLICA TION NUMBER:
`
`LABELING
`
`

`

`----------------------------- 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)
`
`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: 07/2016
`
`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)
`
`03/2016
`
`
`
`
`Dosage and Administration (2 1, 2 2, 2 3)
`03/2016
`
`
`Dosage and Administration (2 3)
`05/2016
`
`
`
`
`Dosage and Administration (2 1, 2 2, 2 3)
`07/2016
`
`
`07/2016
`Warnings and Precautions (5 3)
`
`
`
`
`
` 03/2016
`Warnings and Precautions (5 4)
`
`
`
`
`
`05/2016
`
`
`
`Warnings and Precautions (5 5)
`
`
`
`-------------------------- INDICATIONS AND USAGE -------------------------
`
`
`
`FASLODEX is an estrogen receptor antagonist indicated for the:
`
`Treatment of hormone receptor (HR)-positive metastatic breast cancer in
`
`postmenopausal women with disease progression following antiestrogen
`therapy (1)
`
`
`Treatment of HR-positive, human epidermal growth factor receptor 2
`(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)
`
`
`
`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
`
`
`
`
`
`
`
` 
`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
`
`
`
`
`1
`
`Reference ID: 3957054
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`Monotherapy
`
`FASLODEX is indicated for the treatment of hormone receptor (HR)-positive metastatic breast cancer in
`
`
`
`
`
`postmenopausal women with disease progression following antiestrogen therapy.
`
`
`Combination Therapy with Palbociclib
`
`
`
`FASLODEX is indicated for the treatment of HR-positive, human epidermal growth factor receptor 2
`
`
`(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:
`
`
`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)].
`
`
`
`
`
`
`2
`
`Reference ID: 3957054
`
`

`

`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`3
`
`Reference ID: 3957054
`
`

`

`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`4
`
`Reference ID: 3957054
`
`

`

`
`
` 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)].
`
`
`
`FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see
`
`
`
`
`
`Use in Specific Populations (8.6)].
`
`
`
`
`5
`
`Reference ID: 3957054
`
`

`

`
`
` 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)]
`
`
`
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` 6.1 Clinical Trials Experience
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` Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed
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` cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical
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`practice.
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`Monotherapy
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`Comparison of FASLODEX 500 mg and FASLODEX 250 mg
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`The following adverse reactions (ARs) were calculated based on the safety analysis of Study 1 comparing
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`the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg
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`intramuscularly once a month. The most frequently reported adverse reactions in the fulvestrant 500 mg
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`group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of
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`patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea
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`(13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).
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`6
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`Reference ID: 3957054
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`

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`Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless ofassessed
`causality, from Study 1.
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`Table 1: Adverse Reactions in Study 1 (25% in Either Treatment Group)
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`Body System
`and Adverse Reaction
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`Number % of Patients
`Fulvestrant 500 mg
`Fulvestrant 250 mg
`N=361
`N=374
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`BodvIasa-W'hole
`I—E_ 42 11 .
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`—_nm— 22 5-9
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`——IM—_-—
`-_—___
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`Im'__mm_—m~n_
`' Including more severe injection site related sciatica, neuralgia neuropathic pair; and peripheral neuropathy.
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`In the pooled safety population (N=l 127) from clinical trials comparing FASDODEX 500 mg to
`FASIJODEX 250 mg, post-baseline increases of21 CTC grade in either AST, ALT, or alkaline
`phosphatase were obsaved in >15% ofpatients receiving FASIJODEX. Grade 3-4 increases were
`observed in 1-2% ofpatients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP)
`didnotdiflerbetwemthe 250 mgandthe 500 mgFASIDDEX arms.
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`Co
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`arison of FASLODEX 250 In and Anastrozole l
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`in Combined Trials Studies 2 and 3
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`The most commonly reported adverse reactions in the FASIDDEX and anastrozole treatment groups
`were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain),
`headache, back pain, vasodilatation (hot flashes), and pharyngitis.
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`Injection site reactions with mild transient pain and inflammation were seal with FASIDDEX and
`occurred in 7% ofpatients (1% of treatmmts) given the single 5 mL injection (predominantly European
`Trial Study 3) and in 27% ofpatients (4.6% oftreatments) given the 2 x 2.5 mL injections (North
`American Trial Study 2).
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`Reference ID: 3957054
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` 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
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` intramuscularly once a month with anastrozole 1 mg orally once a day.
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` Anastrozole 1 mg
`N=423
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`(%)
`67.6
`27.0
`20.3
`16.8
`13.2
`11.6
`6.6
`9.0
`5.0
`6.4
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`6.4
`
`5.7
`27.9
`17.3
`48.0
`25.3
`11.8
`10.6
`12.8
`10.9
`13.5
`5.0
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`17.7
`10.2
`27.9
`13.7
`6.1
`33.8
`6.6
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`8.5
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`7.6
`6.9
`3.8
`33.6
`11.6
`12.3
`10.4
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`23.4
`8.0
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` Table 2: Adverse Reactions in Studies 2 and 3 (≥5% from Combined Data)
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` FASLODEX 250 mg
` Body System and Adverse Reaction
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`N=423
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`(%)
`68.3
`22.7
`18.9
`15.4
`14.4
`11.8
`10.9
`9.9
`7.1
`7.1
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`6.4
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`4.5
`30.3
`17.7
`51.5
`26.0
`13.0
`12.5
`12.3
`9.0
`13.7
`4.5
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`18.2
`9.0
`25.5
`15.8
`2.8
`34.3
`6.9
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`6.9
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`6.4
`5.7
`5.0
`38.5
`16.1
`14.9
`10.4
`22.2
`7.3
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` Body as a Whole
`Asthenia
`Pain
`Headache
`Back Pain
`Abdominal Pain
`Injection Site Pain1
`Pelvic Pain
`Chest Pain
`Flu Syndrome
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`Fever
`Accidental Injury
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`Cardiovascular System
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`Vasodilatation
`Digestive System
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`Nausea
`Vomiting
`Constipation
`Diarrhea
`Anorexia
`Hemic and Lymphatic Systems
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`Anemia
`Metabolic and Nutritional Disorders
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`Peripheral Edema
`Musculoskeletal System
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`Bone Pain
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`Arthritis
`Nervous System
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`Dizziness
`Insomnia
`Paresthesia
`Depression
`Anxiety
`Respiratory System
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`Pharyngitis
`Dyspnea
`Cough Increased
`Skin and Appendages
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`Rash
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`8
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`Reference ID: 3957054
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` Body System and Adverse Reaction
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` Anastrozole 1 mg
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` FASLODEX 250 mg
`N=423
`N=423
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`(%)
`(%)
`5.2
`5.0
`Sweating
`14.9
`18.2
`Urogenital System
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`3.5
`6.1
`Urinary Tract Infection
`1.
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` Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. All
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` patients on FASLODEX received injections, but only those anastrozole patients who were in the North
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` American Study 2 received placebo injections.
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`Combination Therapy with Palbociclib
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`The safety of FASLODEX (500 mg) plus palbociclib (125 mg/day) versus FASLODEX plus placebo was
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`evaluated in Study 4. The data described below reflect exposure to FASLODEX plus palbociclib in
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`345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who
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`received at least 1 dose of treatment in Study 4.
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`No dose reduction was allowed for FASLODEX in Study 4. Dose reductions of palbociclib due to an
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`adverse reaction of any grade occurred in 36% of patients receiving FASLODEX plus palbociclib.
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`Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients
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`receiving FASLODEX plus palbociclib, and in 6 of 172 (3%) patients receiving FASLODEX plus
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`placebo. Adverse reactions leading to discontinuation for those patients receiving FASLODEX plus
`palbociclib included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).
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`The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX plus
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`palbociclib arm were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache,
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`diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia.
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`The most frequently reported serious adverse reactions in patients receiving FASLODEX plus palbociclib
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`were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).
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`Adverse reactions reported in patients who received FASLODEX plus palbociclib in Study 4 are listed in
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`Table 3, and laboratory abnormalities are listed in Table 4.
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`Reference ID: 3957054
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`9
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` Table 3: Adverse Reactions in Study 4
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`Adverse Reaction
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` FASLODEX plus placebo
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` FASLODEX plus palbociclib
`(N=172)
` (N=345)
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`All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
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`%
`%
`%
`%
`%
`%
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` 3
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`1
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`55
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`30
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`3
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`2
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`0
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`0
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`0
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`1
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`0
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` 1
`0
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`0
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`1
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`1
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`0
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`11
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`1
`0
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`1
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`0
`0
`0
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`
`0
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`0
`0
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`0
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`0
`0
`0
`0
`0
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` N/A
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` 0
`0
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`0
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`0
`0
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`31
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`1
`4
`5
`13
`0
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`2
`1
`2
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`8
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`20
`3
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`2
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`28
`13
`19
`16
`15
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`6d
`6
`1
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`29
`5
`5
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`Infections and infestations
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` Infectionsa
`47
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`Blood and lymphatic system disorders
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`Febrile neutropenia
`1
`Neutropenia
`83
`Leukopenia
`53
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`Anemia
`30
`Thrombocytopenia
`23
`Eye disorders
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`6
`Vision blurred
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`6
`Lacrimation increased
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`4
`Dry eye
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`Metabolism and nutrition disorders
`Decreased appetite
`16
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`Nervous system disorders
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`26
`Headache
`1
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`7
`Dysgeusia
`0
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`Respiratory, thoracic and mediastinal disorders
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`Epistaxis
`0
`7
`Gastrointestinal disorders
`34
`Nausea
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` Stomatitisb
`28
`24
`Diarrhea
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`20
`Constipation
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`19
`Vomiting
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`Skin and subcutaneous tissue disorders
`18c
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` N/A
`Alopecia
`Rashe
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` 1
`17
`0
`Dry skin
`6
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`General disorders and administration site conditions
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`2
`Fatigue
`41
`<1
`Pyrexia
`13
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`0
`Asthenia
`8
`Grading according to CTCAE 4.0.
`CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
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`a Most common infections (>1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection,
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`influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection.
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`b Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal
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`inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
`c Grade 1 events – 17%; Grade 2 events – 1%.
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`d Grade 1 events – 6%.
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`e Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis
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`acneiform, toxic skin eruption.
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`3
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`0
`1
`1
`2
`0
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`0
`0
`0
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`1
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`0
`0
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`0
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`1
`0
`1
`0
`1
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`0
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`1
`0
`1
`0
`0
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`0
`0
`0
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`0
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`0
`0
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`0
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`0
`0
`0
`0
`0
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` N/A
`0
`0
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`1
`0
`1
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` N/A
`0
`0
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`0
`0
`0
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`10
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`Reference ID: 3957054
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`

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` Table 4: Laboratory Abnormalities in Study 4
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`Laboratory Abnormality
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`All Grades
`%
`WBC decreased
`99
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`Neutrophils decreased
`96
`Anemia
`78
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`Platelets decreased
`62
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`N=number of patients; WBC=white blood cells.
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`FASLODEX plus palbociclib
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`(N=345)
`Grade 3
`%
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`45
`56
`3
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`2
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`Grade 4
`%
`1
`11
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`0
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`1
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`FASLODEX plus placebo
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`(N=172)
`Grade 3
`%
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`0
`0
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`2
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`0
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`All Grades
`%
`26
`14
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`40
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`10
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`Grade 4
`%
`1
`1
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`0
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`0
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` 6.2 Postmarketing Experience
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` For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%)
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` include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions
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` including angioedema and urticaria.
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` Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after
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` changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further
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` evaluation should be considered.
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` Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently
`(<1%).
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` 7 DRUG INTERACTIONS
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` There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro,
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` 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
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`Pharmacology (12.3)].
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` 8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
`Risk Summary
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`Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm
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`when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data
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`in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of
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`fulvestrant to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicity, including
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`skeletal malformations and fetal loss, at daily doses that were 6% and 30% of the maximum
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`recommended human dose based on mg/m2, respectively [see Data]. Advise pregnant women of the
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`potential risk to a fetus.
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`The estimated background risk of major birth defects and miscarriage for the indicated population is
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`unknown. In the U.S. general population, the estimated background risk of major birth defects and
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`miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
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` 11
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`Reference ID: 3957054
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`

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`Data
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`Animal Data
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`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
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`administered to pregnant rats during the period of organogenesis, intramu