CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`021344Orig1s026
`
`Faslodex Injection
`
`
`Trade Name:
`
`fulvestrant
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`AstraZeneca Pharmaceuticals LP
`
`03/02/2016
`
`
`
`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.
`• 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.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`021344Orig1s026
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`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 Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`
`
`
`X
`
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`021344Orig1s026
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 021344/S-026
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`
`
` AstraZeneca Pharmaceuticals LP
` Attention: Elinore Mercer, PhD
`
` Director Global Regulatory Affairs
`
`
`
` One MedImmune Way
` Gaithersburg, MD 20878
`
`
`
`
`
`Dear Dr. Mercer:
`
`
`
`
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated November 17, 2015,
`
`
`
`
`received November 17, 201, and your amendments, submitted under section 505(b) of the
` Federal Food, Drug, and Cosmetic Act (FDCA) for Faslodex® Injection (fulvestrant) Solution for
`
`
`
`
` Injection 250 mg/5 mL.
`
`
`
` This Prior Approval supplemental new drug application provides for Faslodex® (fulvestrant)
`
`
`
` Solution for Injection as 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.
`
`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 and 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.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3895794
`
`

`

`
`
`
`
`
`
` NDA 021344/S-026
`
` Page 2
`
`
` The SPL will be accessible from publicly available labeling repositories.
`
`
`
`
`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.
`
`
`We are waiving the pediatric study requirement for this application because necessary studies are
`impossible or highly impracticable because the disease does not exist in children.
`
`
`
`PROMOTIONAL MATERIALS
`
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`
`
`
`
`
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`
`
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`
`OPDP Regulatory Project Manager
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion (OPDP)
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`
`
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf).
`
`
`Reference ID: 3895794
`
`

`

`
`
`
`
` NDA 021344/S-026
`
` Page 3
`
`
`
`
` You must submit final promotional materials and package insert(s), accompanied by a Form
` FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`
`
`
`
` FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`
`more information about submission of promotional materials to the Office of Prescription Drug
`
`
`
`
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`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 Amy Tilley, Regulatory Project Manager, at 301-796-3994 or
`
`
`
`amy.tilley@fda.hhs.gov.
`
`
`
`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:
`
`Content of Labeling
`
`
`
`
`
`Reference ID: 3895794
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`03/02/2016
`
`Reference ID: 3895794
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`021344Orig1s026
`
`LABELING
`
`
`
`
`
`

`

`
`
`•
`
`
` 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
`
`
`
`
`
`Warnings and Precautions (5.3)
`03/2016
`
`
`
`
`
`
`
`
`--------------------------- 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)
`
`
`•
`
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`
`
`
`
`Hypersensitivity. (4)
`•
`
`
`
`
`•
`
`
`•
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
`
`
`
`
`Risk of Bleeding: Use with caution in patients with bleeding diatheses,
`•
`
`
`
`
`
`thrombocytopenia, or anticoagulant use. (5.1)
`
`
`Increased Exposure in Patients with Hepatic Impairment: Use a 250 mg
`
`
`
`
`dose for patients with moderate hepatic impairment. (2 2, 5.2, 8.6)
`
`
`
`
`Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`
`
`
`reproductive potential of the potential risk to a fetus and to use effective
`
`
`
`
`contraception. (5.3, 8.1, 8.3)
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`The most common adverse reactions occurring in ≥5% of patients
`•
`
`
`
`
`
`
`receiving FASLODEX 500 mg were: injection site pain, nausea, bone
`
`
`pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot
`
`
`
`flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough,
`dyspnea, and constipation. (6.1)
`
`
`Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of
`
`FASLODEX patients and were not dose-dependent. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
`------------------------------ DRUG INTERACTIONS ----------------------------­
`
`
`
`
`There are no known drug-drug interactions. (7)
`•
`
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ---------------------­
`
`
`
`
`Lactation: Advise not to breast-feed. (8.2)
`•
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`approved patient labeling.
`
`
`•
`
`
`Revised: 03/2016
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`FASLODEX 500 mg should be administered intramuscularly into the
`•
`
`
`
`
`
`
`buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one
`
`
`
`
`in each buttock, on days 1, 15, 29 and once monthly thereafter. (2.1, 14)
`
`
`
`
`
`
`
`A dose of 250 mg is recommended in patients with moderate hepatic
`
`
`
`
`impairment to be administered intramuscularly into the buttock slowly
`
`
`
`(1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once
`
`
`
`
`
`monthly thereafter. (2.2, 5.2, 8.6)
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`
`
`FASLODEX, an injection for intramuscular administration, is supplied as
`
`
`50 mg/mL fulvestrant. (3)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose
`
`
`2.2 Dose Modification
`
`2.3 Administration Technique
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Risk of Bleeding
`
`
`5.2 Increased Exposure in Patients with Hepatic Impairment
`
`5.3 Embryo-Fetal Toxicity
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 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.
`
`
`
`
`
`Reference ID: 3895794
`
`
`
` 1
`
`

`

`
`
` 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 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 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 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)].
`
`
`
`
`Reference ID: 3895794
`
`
`
` 2
`
`

`

`
`
` 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
`
`
` The proper method of administration of FASLODEX for intramuscular use is described in the instructions
`
` that follow:
`
`
`
`
`
` 1. Remove glass syringe barrel from tray and check that it is not damaged.
`
` 2. Remove perforated patient record label from syringe.
`
`
`
`
`3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions
`
`
`
`
`
` refer below to the "Directions for Use of SafetyGlide™".
`
`
`
` 4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the
`
` attached rubber tip cap (see Figure 1).
`
`
` 5. Twist to lock the needle to the luer connector.
`
`
`
` 6. Remove needle sheath.
`
`
` 7. Remove excess gas from the syringe (a small gas bubble may remain).
`
` 8. Administer intramuscularly into the buttock slowly.
`
`
`
`
`
` 9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm
`
` completely forward until needle tip is fully covered (see Figure 2).
`
` 10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to
`
`
` activate, discard immediately into an approved sharps collector.
`
`
` 11. Repeat steps 1 through 10 for second syringe.
`
`
` How To Use FASLODEX
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg
`
` recommended dose.
`
`
`
`SAFETYGLIDE™ INSTRUCTIONS FROM BECTON DICKINSON
`
`
`
`
`SafetyGlide™ is a trademark of Becton Dickinson and Company.
`
`
`
`
`Important Administration Information
`
`
`To help avoid HIV (AIDS), HBV (Hepatitis), and other infectious diseases due to accidental needlesticks,
`
`
`
`contaminated needles should not be recapped or removed, unless there is no alternative or that such action
`
`
`
`
`is required by a specific medical procedure. Hands must remain behind the needle at all times during use
`
`
`and disposal.
`
`
`Do not autoclave SafetyGlide™ Needle before use.
`
`
`
`Parenteral drug products should be visually inspected for any particulate matter and discoloration prior to
`administration, whenever solution and container permit.
`
`
`
`DIRECTIONS FOR USE OF SAFETYGLIDE™
`
`
`
`
`
`Reference ID: 3895794
`
`
`
` 3
`
`

`

`
`For each syringe:
`
`
`
`Remove glass syringe barrel from tray and check that it is not damaged.
`
`
`Peel apart packaging of the SafetyGlide™, break the seal of the white plastic cover on the syringe Luer
`
`
`
`
`
`connector and attach the SafetyGlide™ needle to the Luer Lock of the syringe by twisting.
`
`
`
`
`
`
`
`Transport filled syringe to point of administration.
`
`
`
`
`Pull shield straight off needle to avoid damaging needle point.
`
`
`
`
`Administer injection following package instruction.
`
`
`
`For user convenience, the needle ‘bevel up’ position is orientated to the lever arm, as shown in Figure 3.
`
`
`
`
`
`
`Immediately activate needle protection device upon withdrawal from patient by pushing lever arm
`
`
`
`
`completely forward until needle tip is fully covered (Figure 2).
`
`
`
`
`Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate,
`
`
`
`
`discard immediately into an approved sharps collector.
`
`
`
`Activation of the protective mechanism may cause minimal splatter of fluid that may remain on the
`
`
`
`
`
`needle after injection.
`
`
`
`For greatest safety, use a one-handed technique and activate away from self and others.
`
`
`
`After single use, discard in an approved sharps collector in accordance with applicable regulations and
`
`
`institutional policy.
`
`
`Becton Dickinson guarantees the contents of their unopened or undamaged packages to be sterile, non­
`
`
`toxic and non-pyrogenic.
`
`
`
`Figure 1
`
`
`
`
`
`
`Reference ID: 3895794
`
`
`
` 4
`
`

`

`
`
` Figure 2
`
`Figure 3
`
`
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` FASLODEX, an injection for intramuscular administration, is supplied as 5-mL prefilled syringes
`
` containing 50 mg/mL fulvestrant.
`
`
`
` 4 CONTRAINDICATIONS
`
` FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its
`
`
`
` components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in
`
` association with FASLODEX [see Adverse Reactions (6.2)].
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Risk of Bleeding
`
` Because FASLODEX is administered intramuscularly, it should be used with caution in patients with
`
`
`
` bleeding diatheses, thrombocytopenia, or anticoagulant use.
`
`
`
`
`
`Reference ID: 3895794
`
`
`
` 5
`
`

`

` 5.2 Increased Exposure in Patients with Hepatic Impairment
`
` The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with
`
`
`
`
` moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.
`
` Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is
`
` recommended [see Dosage and Administration (2.2)].
`
`
`FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see
`
`
`Use in Specific Populations (8.6)].
`
`
`
` 5.3 Embryo-Fetal Toxicity
` Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm
`
`
`
`
`
` when administered to a pregnant woman. In animal reproduction studies, administration of fulvestrant to
` pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at daily doses that are
`
`
`
`
`
` significantly less than the maximum recommended human dose. Advise pregnant women of the potential
`
` risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment
`
`
`
` with FASLODEX and for one year after the last dose [see Use in Specific Populations (8.1), (8.3) and
`
`
`
`
`Clinical Pharmacology (12.1)].
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
` The following adverse reactions are discussed in more detail in other sections of the labeling:
`
`
`
`
`
`
`
` • Risk of Bleeding [see Warnings and Precautions (5.1)]
`
`
`Increased Exposure in Patients with Hepatic Impairment [see Warnings and Precautions (5.2)]
`
`
`
`
`
`•
`• Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)]
`
`
`
`
` 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 Study 1 comparing
`
`
`
`the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg
`
`intramuscularly once a month. The most frequently reported adverse reactions in the fulvestrant 500 mg
`
`
`
`group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of
`
`
`
`patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea
`
`
`
`(13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).
`
`
`
`
`Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed
`
`
`
`causality, from Study 1.
`
`
`
`
`Reference ID: 3895794
`
`
`
` 6
`
`

`

`
`
` Table 1: Adverse Reactions in Study 1 (≥5% in Either Treatment Group)
`
`
`
`
`
` Body System
`
` and Adverse Reaction
`
`
`
`
`
`
`
`
` Body as a Whole
`
` Injection Site Pain
`
` Headache
`
` Back Pain
`
` Fatigue
`
` Pain in Extremity
`
` Asthenia
`
` Vascular System
`
` Hot Flash
` Digestive System
`
` Nausea
`
` Vomiting
`
` Anorexia
` Constipation
`
` Musculoskeletal System
`
` Bone Pain
`
` Arthralgia
`
` Musculoskeletal Pain
`
` Respiratory System
`
` Cough
` Dyspnea
`
`
`
`
`
` Number (%) of Patients
`
`
` Fulvestrant 500 mg
`
` Fulvestrant 250 mg
`
` N=361
`
` N=374
`
`
`
`
`
`
` 42 (11.6)
` 28 (7.8)
`
`
` 27 (7.5)
`
` 27 (7.5)
`
` 25 (6.9)
`
` 21 (5.8)
`
`
`
` 24 (6.6)
`
`
` 35 (9.7)
`
` 22 (6.1)
`
` 22 (6.1)
`
` 18 (5.0)
`
`
` 34 (9.4)
`
` 29 (8.0)
`
` 20 (5.5)
`
`
` 19 (5.3)
`
` 16 (4.4)
`
`
` 34 (9.1)
`
` 25 (6.7)
` 40 (10.7)
`
` 24 (6.4)
`
`
` 26 (7.0)
`
` 23 (6.1)
`
`
`
` 22 (5.9)
`
`
` 51 (13.6)
` 21 (5.6)
`
`
` 14 (3.7)
`
` 13 (3.5)
`
`
` 28 (7.5)
`
` 29 (7.8)
`
` 12 (3.2)
`
`
` 20 (5.3)
`
` 19 (5.1)
`
`In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to
`
`FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline
`
`phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were
`
`observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP)
`
`did not differ between the 250 mg and the 500 mg FASLODEX arms.
`
`
`
`Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3)
`
`
`
`
`
`
`
`
`The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups
`were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain),
`
`
`
`headache, back pain, vasodilatation (hot flashes), and pharyngitis.
`
`
`
`
`Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and
`occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European
`
`
`
`
`
`Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North
`
`American Trial Study 2).
`
`
`
`
`Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed
`
`
`
`
`causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg
`
`intramuscularly once a month with anastrozole 1 mg orally once a day.
`
`
`
`Reference ID: 3895794
`
`
`
` 7
`
`

`

`
`
`
`
`
`
`
`
`
`
` 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
`
` Dyspnea
` Cough Increased
`
` Skin and Appendages
`
` Rash
` Sweating
`
` Urogenital System
`
` Urinary Tract Infection
`
`
`
`
` Table 2: Adverse Reactions in Studies 2 and 3 (≥5% from Combined Data)
`
` Body System and Adverse Reaction
`
`
` FASLODEX 250 mg
`
`
`N=423
`
`
` (%)
`
` 68.3
`
` 22.7
`
` 18.9
`
` 15.4
`
` 14.4
`
` 11.8
`
` 10.9
`
` 9.9
`
` 7.1
`
` 7.1
`
` 6.4
`
` 4.5
`
` 30.3
`
` 17.7
`
` 51.5
`
` 26.0
`
` 13.0
`
` 12.5
`
` 12.3
`
` 9.0
`
` 13.7
`
` 4.5
`
` 18.2
`
` 9.0
`
` 25.5
`
` 15.8
`
` 2.8
`
` 34.3
`
` 6.9
`
` 6.9
`
` 6.4
`
` 5.7
`
` 5.0
`
` 38.5
`
` 16.1
`
` 14.9
`
` 10.4
`
` 22.2
`
` 7.3
`
` 5.0
`
` 18.2
`
` 6.1
`
`
`
`
`
`
`
`Reference ID: 3895794
`
`
`
` 8
`
`
`
`
`
`
`
` Anastrozole 1 mg
` N=423
`
`
` (%)
`
` 67.6
`
` 27.0
`
` 20.3
`
` 16.8
`
` 13.2
`
` 11.6
`
` 6.6
`
` 9.0
`
` 5.0
`
` 6.4
`
` 6.4
`
` 5.7
`
` 27.9
`
` 17.3
`
` 48.0
`
` 25.3
`
` 11.8
`
` 10.6
`
` 12.8
`
` 10.9
`
` 13.5
`
` 5.0
`
` 17.7
`
` 10.2
`
` 27.9
`
` 13.7
`
` 6.1
`
` 33.8
`
` 6.6
`
` 8.5
`
` 7.6
`
` 6.9
`
` 3.8
`
` 33.6
`
` 11.6
`
` 12.3
`
` 10.4
`
` 23.4
`
` 8.0
`
` 5.2
`
` 14.9
`
` 3.5
`
`

`

`1 All patients on FASLODEX received injections, but only those anastrozole patients who were in the North
`
`
`
`
`American Study 2 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 Study 4. 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 Study 4.
`
`
`
`
`No dose reduction was allowed for FASLODEX in Study 4. 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 Study 4 are listed in
`
`
`
`
`
`Table 3, and laboratory abnormalities are listed in Table 4.
`
`
`
`
`
`Reference ID: 3895794
`
`
`
` 9
`
`

`

`
`
` Table 3: Adverse Reactions in Study 4
`
`
`
` Adverse Reaction
`
`
`
`
`
` FASLODEX plus placebo
` FASLODEX plus palbociclib
`
`
` (N=345)
` (N=172)
`
`
`
` 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
`
`
`
` 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
`
` Infections and infestations
`
` Infectionsa
` 47
`
`
` Blood and lymphatic system disorders
` Febrile neutropenia
`
`
` 1
`
` 83
`
` Neutropenia
`
` 53
`
` Leukopenia
`
` 30
`
` Anemia
` Thrombocytopenia
`
` 23
`
` 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
`
`
` Dysgeusia
` 7
`
` Respiratory, thoracic and mediastinal disorders
`
`
`
` Epistaxis
` 7
` 0
` Gastrointestinal disorders
`
` 34
`
` Nausea
`
` Stomatitisb
`
` 28
`
` 24
`
` Diarrhea
`
` 20
`
` Constipation
`
` 19
`
` Vomiting
` Skin and subcutaneous tissue disorders
`
` 18c
`
` N/A
`
` Alopecia
`
` Rashe
`
` 1
`
` 17
`
` 0
`
`
` Dry skin
` 6
`
` General disorders and administration site conditions
`
`
`
` Fatigue
` 41
` 2
`
`
` Pyrexia
`
` 13
` <1
`
` Asthenia
`
`
` 8
` 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.
`
`
`
`
`
`Reference ID: 3895794
`
`
`10
`
`

`

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