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` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
` Approval Package for:
`
`
`APPLICATION NUMBER:
`
`
`
` 021344Orig1s020
`
`
`
`
`
`
`Trade Name:
`
`
`
`
` Generic or Proper
`
`Name:
`
`
` Sponsor:
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`
`
`Approval Date:
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`
` Change:
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` FASLODEX
`
` fulvestrant Injection, 250 mg/5 mL
`
` AstraZeneca Pharmaceuticals LP
`
` November 9, 2012
`
` For updated results of overall survival data from a
`
`
` Randomized, Double-Blind, Parallel-group, Multicentre,
`
` Phase III Study Comparing the Efficacy and Tolerability
`
`
` of Fulvestrant (Faslodex®) 500 mg with Fulvestrant
`
`
`(Faslodex®) 250 mg in Postmenopausal Women with
`
`Oestrogen Receptor Positive Advanced Breast Cancer
`
`Progressing or Relapsing after Previous Endocrine
`
`
`
`Therapy (D6997C00002), also known as the 'CONFIRM'
`
` study.
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
` 021344Orig1s020
`
`
`
` CONTENTS
`
`
` Reviews / Information Included in this NDA Review.
`
`
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
`
` X
`
`
` X
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`
`
` X
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`
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` X
`
`
`
` X
`
` X
`
`
` X
`
` X
`
`
` X
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`
`

`

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`
` CENTER FOR DRUG EVALUATION AND
`
` RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`
`
` 021344Orig1s020
`
`
`
`APPROVAL LETTER
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 021344/S-019/S-020
`
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
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`
`AstraZeneca Pharmaceuticals LP
`Attention: Nicholas J. Troise
`1800 Concord Pike
`P.O. Box 8355
`Wilmington DE 19803-8355
`
`Dear Mr. Troise:
`
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated May 10, and
`
`June 28, 2012 received May 10 and June 28, 2012, respectively, submitted under section 505(b)
`
`of the Federal Food, Drug, and Cosmetic Act (FDCA) for Faslodex® (fulvestrant) Injection,
`
`250 mg/5 mL.
`
`
`We acknowledge receipt of your amendments dated May 15, July 24, October 12, and
`
`October 19, 2012 (S-019).
`
`
`We also acknowledge receipt of your amendments dated July 13 and July 25, 2012 (S-020).
`
`
`S-019: “Changed Being Effective” supplemental new drug application S-019 provides an update
`
`for nonclinical toxicology for post-marketing safety data and information from a mouse
`
`carcinogenicity study (VKS0539 (0118CM).
`
`
`S-020: “Prior Approval” efficacy supplemental new drug application S-020 provides for updated
`
`results of overall survival data from a Randomized, Double-Blind, Parallel-group, Multicentre,
`
`Phase III Study Comparing the Efficacy and Tolerability of Fulvestrant (Faslodex®) 500 mg
`
`
`with Fulvestrant (Faslodex®) 250 mg in Postmenopausal Women with Oestrogen Receptor
`
`Positive Advanced Breast Cancer Progressing or Relapsing after Previous Endocrine Therapy
`
`(D6997C00002), also known as the 'CONFIRM' study.
`
`
`
`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 Medication
`Guide), 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.
`
`
`
`
`Reference ID: 3215285
`
`

`

`NDA 021344/S-019/S-020
`Page 2
`
`
`
`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.
`
`Also within 14 days, amend all pending supplemental applications 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).
`
`
`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:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`
`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/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Division of Drug Marketing, Advertising, and Communications
`(DDMAC), 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).
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3215285
`
`

`

`
`
`If you have any questions, call Techiya Toaff, Regulatory Project Manager, at (301) 796-4256.
`
`
`NDA 021344/S-019/S-020
`Page 3
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Amna Ibrahim, M.D.
`Deputy Director
`Division of Drug Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE:
`Content of Labeling
`
`
`
`
`Reference ID: 3215285
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMNA IBRAHIM
`11/09/2012
`
`Reference ID: 3215285
`
`

`

`
`
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`
`021344Orig1s020
`
`
`
`LABELING
`
`
`
`

`

`
`reactions
`The most common, clinically significant adverse
`
`
`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.
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or
`
`www fda.gov/medwatch for voluntary reporting of adverse
`
`reactions
`
`-------------------------DRUG INTERACTIONS------------------------------
`
`There are no known drug-drug interactions. (7)
`
`
`
`
`-------------------USE IN SPECIFIC POPULATIONS----------------------
`
`
` Nursing Mothers: discontinue drug or nursing taking into account
`
`the importance of drug to the mother. (8.3)
`
` Pediatric Patients: efficacy has not been demonstrated in girls with
`McCune-Albright Syndrome and progressive precocious puberty.
`(8.4)
` SEE 17 FOR PATIENT COUNSELING INFORMATION AND
`FDA-APPROVED PATIENT 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
`
`INITIAL US APPROVAL: 2002
`
`-----------------------INDICATIONS AND USAGE-------------------------
`
`FASLODEX is an estrogen receptor antagonist indicated for the:
`
`Treatment of hormone receptor positive metastatic breast cancer in
`
`
`
`postmenopausal women with disease progression
`following
`
`antiestrogen therapy.
`
`
`
`
`
`
`-------------------DOSAGE AND ADMINISTRATION---------------------
`
`
`
`
`
`FASLODEX 500 mg should be administered intramuscularly into
`
`
`the buttocks slowly (1 - 2 minutes per injection) as two 5 mL
`injections, one in each buttock, on days 1, 15, 29 and once monthly
`
`thereafter. (2.1, 14)
`
`
` A dose of 250 mg is recommended in patients with moderate
`
`hepatic impairment to be administered intramuscularly into the
`
`buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15,
`
`
`29 and once monthly thereafter. (2.2, 5.2, 8.6)
`
`-----------------DOSAGE FORMS AND STRENGTHS--------------------
`
`FASLODEX, an injection for intramuscular administration, is supplied
`
`as 50 mg/mL fulvestrant. (3)
`
`------------------------CONTRAINDICATIONS------------------------------
`
` Hypersensitivity (4)
`
`
`
`
`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 Blood Disorders
`
`
`
`
`
`5.2 Hepatic Impairment
`
`5.3 Use in Pregnancy
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Post-Marketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`
`8.1 Pregnancy
`
`
`
`
`
`
`
`Reference ID: 3215285
`
`
`
`
`
`------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
` Blood Disorders: Should be used with caution in patients with
`
`
`
`bleeding diatheses, thrombocytopenia, or anticoagulant use. (5.1)
`
`
` Hepatic Impairment: A 250 mg dose is recommended in patients
`
`
`
`with moderate hepatic impairment (2.2, 5.2, 8.6)
`Pregnancy: Fetal harm can occur when administered to a pregnant
`woman. Women should be advised of the potential hazard to the
`
`fetus and to avoid becoming pregnant while receiving FASLODEX.
`
`(5.3)
`
`--------------------------ADVERSE REACTIONS-----------------------------
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 11/2012
`
`
`8.3 Nursing Mothers
`
`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
`
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information are
`
`not listed.
`
`

`

`
`
`
`
`1
`
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`FASLODEX is indicated for the treatment of hormone
`receptor positive metastatic breast cancer in postmenopausal
`women with disease progression following antiestrogen
`therapy.
`
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dose
`The recommended dose is 500 mg to be administered
`intramuscularly into the buttocks slowly (1 - 2 minutes per
`
`injection) as two 5 mL injections, one in each buttock, on
`
`days1, 15, 29 and once monthly thereafter [see Clinical
`Studies (14)].
`
`
`
`
`
`
`2.2 Dose Modification
`Hepatic Impairment:
`A dose of 250 mg is recommended for patients with moderate
`
`hepatic impairment (Child-Pugh class B) to be administered
`intramuscularly into the buttock slowly (1 - 2 minutes) as one
`5 mL injection on days 1, 15, 29 and once monthly thereafter.
`
`FASLODEX has not been evaluated in patients with severe
`hepatic impairment (Child-Pugh class C) [see Warnings and
`Precautions (5.2) and Use in Specific Populations (8.6)].
`
` 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.
`the safety needle (SafetyGlide™) outer
` Peel open
`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).
`
` Administer intramuscularly slowly in the buttock.
` Immediately activate needle protection device upon
`withdrawal from patient by pushing lever arm completely
`forward until needle tip is fully covered (see Figure 2).
`
`2.3
`
`8.
`9.
`
`
`
`Reference ID: 3215285
`
`

`

`
`
` 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
`
`the 500 mg
`syringes must be
`injected
`to receive
`
`recommended dose.
`
`SAFETYGLIDE™ INSTRUCTIONS FROM BECTON
`DICKINSON
`
`
`SafetyGlide™ is a trademark of Becton Dickinson and
`Company
`
`
`
`Reorder number 305917
`
`CAUTION CONCERNING SAFETYGLIDE™
`
`Federal (USA) law restricts this device to sale by or on the
`order of a physician. 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.
`
`WARNING CONCERNING SAFETYGLIDE™
`
`Do not autoclave SafetyGlide™ Needle before use. Hands
`
`must remain behind the needle at all times during use and
`
`disposal.
`
`DIRECTIONS FOR USE OF SAFETYGLIDE™
`For each syringe:
`
`Remove glass syringe barrel from tray and check that it is
`not damaged.
`
`Peel apart packaging of the SafetyGlide™, break the seal
`of the white plastic cover on the syringe Luer connector
`
`and attach the SafetyGlide™ needle to the Luer Lock of
`
`the syringe by twisting.
`
`
`Transport filled syringe to point of administration.
`
`Pull shield straight off needle to avoid damaging needle
`point.
`
`Administer injection following package instruction.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3215285
`
`

`

`For user convenience, the needle 'bevel up' position is
`orientated to the lever aim, as shown in Figme 3.
`
`Immediately activate needle protection device upon
`withdrawal from patient by pushing lever aim completely
`fo1wai·d until needle tip is fully covered (Figure 2).
`
`Visually confnm that the lever aim has fully advanced and
`the needle tip is covered. If unable to activate, discard
`immediately into an approved sha1ps 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 shaips collector in
`accordance with applicable regulations and institutional
`policy.
`
`the contents of their
`Becton Dickinson guai·antees
`unopened or undamaged packages to be sterile, non-toxic
`and non-pyrogenic.
`
`Figure 1
`
`Figure 2
`
`Reference ID: 3215285
`
`

`

`
`
`
`
`
`
`
`
`
`Figure 3
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`FASLODEX, an injection for intramuscular administration, is
`supplied as 5-mL prefilled syringes containing 50 mg/mL
`fulvestrant.
`
`
` CONTRAINDICATIONS
`FASLODEX is contraindicated in patients with a known
`
`hypersensitivity to the drug or to any of its components.
`
`and
`Hypersensitivity
`reactions,
`including
`urticaria
`in association with
`angioedema, have been
`reported
`FASLODEX.
`
`
`
`WARNINGS AND PRECAUTIONS
` Blood Disorders
`Because FASLODEX is administered intramuscularly, it
`should be used with caution in patients with bleeding
`diatheses, thrombocytopenia, or anticoagulant use.
`
` 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)].
`
`
`
`3
`
`4
`
`5
`5.1
`
`5.2
`
`
`
`
`
`Reference ID: 3215285
`
`

`

`
`
`FASLODEX has not been studied in patients with severe
`
`
` hepatic impairment (Child-Pugh class C) [see Use in Specific
`Populations (8.6)].
`
`5.3 Use in Pregnancy
`Based on its mechanism of action and findings in animals,
`FASLODEX can cause fetal harm when administered to a
`pregnant woman. Fulvestrant
`caused
`fetal
`loss or
`abnormalities in animals when administered during the period
`
`of organogenesis at doses significantly smaller than the
`maximum recommended human dose based on the body
`surface area. There are no adequate and well-controlled
`studies in pregnant women using FASLODEX. Women of
`childbearing potential should be advised not to become
`pregnant while receiving FASLODEX. If FASLODEX is
`used during pregnancy, or if the patient becomes pregnant
`while receiving this drug, the patient should be apprised of the
`potential hazard to the fetus [see Use in Specific Populations
`(8.1)].
`
`
`6
` ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
` Because clinical trials are conducted under widely varying
`
` conditions, the adverse reaction rates observed cannot be directly
`compared to rates in other trials and may not reflect the rates
`observed in clinical practice.
`
` Comparison of FASLODEX 500 mg and FASLODEX
`
`250 mg
`The following frequency categories for adverse reactions
`(ARs) were calculated based on the safety analysis of Study 1
`that compared FASLODEX 500 mg with FASLODEX 250
`mg. 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 the
`controlled clinical trial Study 1 comparing the administration
`of FASLODEX 500 mg intramuscularly once a month with
`FASLODEX 250 mg intramuscularly once a month.
`
`
`
`
`
`
`Reference ID: 3215285
`
`

`

`Table 1: Summary of Most Commonly Reported Adverse
`Reactions in Study 1 (≥ 5% in either treatment group):
`Safety Population
`
`Body System
`
`and Adverse Reaction
`
`
`
`Number (%) of Patients
`
`Fulvestrant 500 mg
`
`
`N=361
`
`Fulvestrant 250 mg
`
`
`N=374
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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)
`
`
`
`
`
`
`
`Reference ID: 3215285
`
`

`

`The most commonly reported adverse reactions in the
`FASLODEX and anastrozole treatment groups, regardless of
`the
`investigator’s
`assessment
`of
`causality, were
`gastrointestinal symptoms
`(including nausea, vomiting,
`
`constipation, diarrhea and abdominal pain), headache, back
`pain, vasodilatation (hot flashes), and pharyngitis.
`
`Injection site reactions with mild
`transient pain and
`
`inflammation were seen with FASLODEX and occurred in
`
`7% of patients (1% of treatments) given the single 5 mL
`injection (predominantly European Trial Study 3) and in 27%
`of patients (4.6% of treatments) given the 2 x 2.5 mL
`injections (North American Trial Study 2).
`
`Table 2 lists adverse reactions reported with an incidence of
`
`5% or greater, regardless of assessed causality, from the two
`controlled clinical trials comparing the administration of
`
`FASLODEX 250 mg intramuscularly once a month with
`anastrozole 1 mg orally once a day.
`
`Table 2: Combined Data from Studies 2 and 3, Adverse
`Reactions  5%
`
`Body System
`and Adverse Reactiona
`
`
`
`FASLODEX 250 mg Anastrozole 1 mg
`
`
` N=423
`N=423
`
`
`(%)
` (%)
`
`
`
`
`
`
`
`Body as a Whole
`
` Asthenia
` Pain
`
` Headache
`
` Back Pain
`
` Abdominal Pain
` Injection Site Painb
`
` 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
`
`Reference ID: 3215285
`
`
`
`
`
`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
`
`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
`
`

`

`
`
`6.2
`
`
`7
`
`8
`8.1
`
` 2.8
`
` Arthritis
` Nervous System
`
`34.3
`6.9
` Dizziness
`
`6.9
` Insomnia
`6.4
` Paresthesia
`5.7
` Depression
`
`5.0
`Anxiety
`
`Respiratory System
`38.5
`
`16.1
` Pharyngitis
`14.9
` Dyspnea
`10.4
` Cough Increased
`
`Skin and Appendages
`22.2
`7.3
` Rash
`5.0
` Sweating
`Urogenital System
`18.2
`
`6.1
`Urinary Tract Infection
` aA patient may have more than one adverse reaction.
`
`bAll patients on FASLODEX received
`injections, but only
`those
`
`anastrozole patients who were in the North American Study 2 received
`placebo injections.
`
` 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
`
`
` Post-Marketing Experience
`For FASLODEX 250 mg, other adverse reactions reported as
`include
`drug-related
`and
`seen
`infrequently
`(<1%)
`
`thromboembolic phenomena, myalgia, vertigo, leukopenia,
`and hypersensitivity reactions including angioedema and
`
`urticaria.
`
`Vaginal bleeding has been reported infrequently (<1%),
`mainly in patients during the first 6 weeks after changing from
`
` existing hormonal therapy to treatment with FASLODEX. If
`bleeding persists, further evaluation should be considered.
`
`Elevation of bilirubin, elevation of gamma GT, hepatitis, and
`liver failure have been reported infrequently (<1%).
`
` DRUG INTERACTIONS
`There are no known drug-drug interactions. Although,
`fulvestrant is metabolized by CYP 3A4 in vitro, drug
`interactions studies with ketoconazole or rifampin did not alter
`
`fulvestrant pharmacokinetics. Dose adjustment is not needed
`
`in patients co-prescribed CYP3A4 inhibitors or inducers [see
`Clinical Pharmacology (12.3)].
`
`
`USE IN SPECIFIC POPULATIONS
` Pregnancy
`
`Pregnancy Category D [see Warnings and Precautions (5.3)]
`FASLODEX can cause fetal harm when administered to a
`pregnant woman.
` Fulvestrant caused
`fetal
`loss or
`
`abnormalities in animals when administered during the period
`of organogenesis at doses significantly smaller than the
`maximum recommended human dose based on the body
`
`
`
`
`
`Reference ID: 3215285
`
`

`

`
`
`surface area (BSA). Women of childbearing potential should
`
`be advised not
`to become pregnant while
` receiving
`FASLODEX. If FASLODEX is used during pregnancy, or if
`the patient becomes pregnant while receiving this drug, the
`patient should be apprised of the potential hazard to the fetus.
`
`In studies in female rats at intramuscular doses  0.01
`mg/kg/day (0.6% of the human recommended dose based on
`BSA), fulvestrant caused a reversible reduction in female
`fertility, as well as effects on embryo-fetal development
`consistent with its antiestrogenic activity. Fulvestrant caused
`
`an increased incidence of fetal abnormalities in rats (tarsal
`flexure of the hind paw at 2 mg/kg/day; equivalent to the
`human dose based on BSA) and non-ossification of the
`odontoid and ventral tubercle of the first cervical vertebra at
`doses  0.1 mg/kg/day (6% the human dose based on BSA)
`
`
`when administered during the period of organogenesis.
`
`Rabbits
`failed
`to maintain pregnancy when dosed
`intramuscularly with 1 mg/kg/day fulvestrant (equivalent to
`the human dose based on BSA) during the period of
`organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day
`(30% the human dose based on BSA), increases in placental
`weight and post-implantation loss were observed. Fulvestrant
`was associated with an increased incidence of fetal variations
`
`in rabbits (backwards displacement of the pelvic girdle, and
`27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human
`dose based on BSA) when administered during the period of
`organogenesis. Because pregnancy could not be maintained in
`
`the rabbit following doses of fulvestrant of 1 mg/kg/day and
`above, this study was inadequate to fully define the possible
`adverse effects on fetal development at clinically relevant
`exposures.
`
`8.3 Nursing Mothers
`It is not known if fulvestrant is excreted in human milk.
`
`Fulvestrant is found in rat milk at levels significantly higher
`(approximately 12-fold) than plasma after administration of 2
`mg/kg. Drug exposure in rodent pups from fulvestrant-treated
`lactating dams was estimated as 10% of the administered
`dose. Because many drugs are excreted in human milk and
`
`because of the potential for serious adverse reactions in
`nursing infants from FASLODEX, a decision should be made
`whether to discontinue nursing or to discontinue the drug,
`taking into account the importance of the drug to the mother.
`
`8.4 Pediatric Use
`A multi-center, single-arm, open-label, study of fulvestrant was
`conducted in 30 girls with McCune-Albright Syndrome (MAS)
`associated with progressive precocious puberty (PPP). The
`
`median age at informed consent was 6 years old (range: 1 to 8).
`
`
`
`Reference ID: 3215285
`
`
`

`

`
`The first 10 patients initially received fulvestrant 2 mg/kg.
`Based on PK data from the first 6 patients, all 10 patients
`receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all
`other patients received 4 mg/kg from study entry.
`
`Baseline measurements for vaginal bleeding days, bone age,
`growth velocity, and Tanner staging for at least 6 months prior
`to study entry were provided retrospectively by the parent,
`guardian or local consultant. All measurements during the
`study period were collected prospectively. Patients’ baseline
`characteristics
`included
`the
`following: a mean ± SD
`chronological age of 5.9 ± 1.8 years; a mean rate of bone age
`
`advancement (change in bone age in years divided by change
`in chronological age in years) of 2.0 ± 1.03; and a mean growth
`velocity z-score of 2.4 ± 3.26.
`
`Twenty-nine of 30 patients completed the 12-month study
`period. The following results were observed: 35% (95% CI:
`16%, 57%) of the 23 patients with baseline vaginal bleeding
`experienced a complete cessation of vaginal bleeding on-
`treatment (month 0 to 12); a reduction in the rate of bone age
`advancement during the 12-month study period compared to
`baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a
`reduction in mean growth velocity Z-score on-treatment
`compared to baseline (mean change = -1.1 [95% CI = -2.7,
`0.4]). There were no clinically meaningful changes in median
`Tanner stage (breast or pubic), mean uterine volume, or mean
`ovarian volume, or predicted adult height (PAH) on-treatment
`compared to baseline. The effect of Faslodex on bone mineral
`density in children has not been studied and is not known.
`
`Eight patients (27%) experienced adverse reactions that were
`considered possibly related to Faslodex. These included
`injection site reactions (inflammation, pain, hematoma, pruritis,
`
`rash), abdominal pain, contusion, tachycardia, hot flush,
`extremity pain, and vomiting. Nine (30.0%) patients reported
`an SAE, none of which were considered related to Faslodex.
`
`No patients discontinued study treatment due to an AE and no
`patients died.
`
`
`
`
`
`
`Reference ID: 3215285
`
`

`

`
`
`8.5
`
`8.6
`
`Pharmacokinetics
`The pharmacokinetics of fulvestrant was characterized using a
`population pharmacokinetic analysis with sparse samples per
`patient obtained from 30 female pediatric patients aged 1 to 8
`years with PPP associated with MAS. Pharmacokinetic data
`from 294 postmenopausal women with breast cancer who
`received 125 or 250 mg monthly dosing regimen were also
`included in the analysis.
`
`In these pediatric patients receiving 4 mg/kg monthly
`intramuscular dose of fulvestrant, the geometric mean (SD)
`CL/F was 444 (165) mL/min which was 32% lower than
`adults. The geometric mean (SD) steady state trough
`concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL
`
`and 3680 (1020) ng*hr/mL, respectively.
`
` Geriatric Use
`tumor response was
`For FASLODEX 250 mg, when
`considered by age, objective responses were seen in 22% and
`24% of patients under 65 years of age and in 11% and 16% of
`patients 65 years of age and older, who were treated with
`FASLODEX in Study 2 and Study 3, respectively.
`
` Hepatic Impairment
`FASLODEX is metabolized primarily in the liver.
`
`
`
`The pharmacokinetics of fulvestrant were evaluated after a
`single dose of 100 mg in subjects with mild and moderate
`
`hepatic impairment and normal hepatic function (n = 7
`subjects/group), using a shorter-acting intramuscular injection
`formulation. Subjects with mild hepatic impairment (Child-
`Pugh class A) had comparable mean AUC and clearance
`values to those with normal hepatic function. In subjects with
`moderate hepatic impairment (Child-Pugh class B) the
`
`average AUC of fulvestrant increased by 70% compared to
`patients with normal hepatic function. AUC was positively
`correlated with total bilirubin concentration (p = 0.012).
`FASLODEX has not been studied in patients with severe
`hepatic impairment (Child-Pugh class C).
`
`A dose of FASLODEX 250 mg is recommended in patients
`with moderate hepatic impairment (Child-Pugh class B) [see
`
`(2.2) and Warning and
`Dosage and Administration
`
`Precautions (5.2)].
`
`
`
`Reference ID: 3215285
`
`

`

`
`8.7
`
`10
`
`11
`
`
`
` Renal Impairment
`Negligible amounts of fulvestrant are eliminated in urine;
`therefore, a study in patients with renal impairment was not
`conducted. In the advanced breast cancer trials, fulvestrant
`concentrations in women with estimated creatinine clearance
`as low as 30 mL/min were similar to women with normal
`creatinine.
`
`
` OVERDOSAGE
`Animal studies have shown no effects other than