HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`AND PRECAUTIONS-----------------------
`
`These highlights do not include all the information needed to use
`FASLODEX® safely and eflectively. See full prescribing information
`for FASL ODEX.
`FASLODEX® (fulvestrant) injection
`
`INITIAL US APPROVAL: 2002
`
`-----------------------INDICATIONS AND
`
`FASLODEX is an estrogen receptor antagonist indicated for the:
`0
`Treatment of hormone receptor positive metastatic breast cancer in
`postmenopausal women with disease progression following
`antiestrogen therapy.
`
`-------------------DOSAGE AND ADMINISTRATION---------------------
`
`o
`
`o
`
`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)
`
`------------------------C ONTRAINDICATIONS------------------------------
`
`o
`
`Hypersensitivity (4)
`
`0
`
`o
`
`0
`
`o
`
`0
`
`Should be used with caution in patients with
`Blood Disorders:
`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)
`
`REACTIONS-----------------------------
`
`reactions
`adverse
`significant
`clinically
`common,
`The most
`occurring in 2 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 0r
`
`WWW.fda.g0V/medwatch for voluntary reporting of adverse
`reactions
`
`INTERACTIONS------------------------------
`
`0
`
`There are no known drug-drug interactions. (7)
`
`-------------------USE IN SPECIFIC POPULATIONS----------------------
`
`0
`
`0
`
`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
`
`Revised: 11/2012
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dose
`2.2
`Dose Modification
`
`8.3
`8.4
`8.5
`
`Nursing Mothers
`Pediatric Use
`Geriatric Use
`
`*Sections or subsections omitted from the full prescribing information are
`not listed.
`
`8.1
`Pregnancy
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0001
`
`3
`
`2.3 Administration Technique
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Blood Disorders
`5.2
`
`Hepatic Impairment
`Use in Pregnancy
`5.3
`ADVERSE REACTIONS
`
`6
`
`Clinical Trials Experience
`6.1
`Post-Marketing Experience
`6.2
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`
`10
`11
`12
`
`13
`
`14
`16
`17
`
`Hepatic Impairment
`8.6
`Renal Impairment
`8.7
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1
`Mechanism ofAction
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`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.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Recommended Dose
`
`The recommended dose is 500 mg to be administered
`intramuscularly into the buttocks slowly (I - 2 minutes per
`injection) as two 5 mL injections, one in each buttock, on
`daysl, 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 (I - 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)].
`
`2.3 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
`(SafetyGlideTM) outer
`packaging. For complete SafetyGlideTM instructions refer
`below to the "Directions for Use of SafetyGlideTM".
`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 l).
`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 slowly in the buttock.
`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).
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0002
`
`

`

`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.
`
`SAFETYGLIDETIVI INSTRUCTIONS FROM BECTON
`
`DICKINSON
`
`SafetyGlideTM is a trademark of Becton Dickinson and
`Company
`
`Reorder number 305917
`
`CAUTION CONCERNING SAFETYGLIDETIVI
`
`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 SAFETYGLIDETIVI
`
`Do not autoclave SafetyGlideTM Needle before use. Hands
`must remain behind the needle at all times during use and
`disposal.
`
`DIRECTIONS FOR USE OF SAFETYGLIDETIVI
`
`For each syringe:
`
`Remove glass syringe barrel from tray and check that it is
`not damaged.
`
`Peel apart packaging of the SafetyGlideTM, break the seal
`of the white plastic cover on the syringe Luer connector
`and attach the SafetyGlideTM 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
`
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`

`

`the needle ‘bevel up’ position is
`For user convenience,
`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.
`
`the protective mechanism may cause
`Activation of
`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.
`
`their
`contents of
`the
`Becton Dickinson guarantees
`unopened or undamaged packages to be sterile, non-toxic
`and non-pyrogenic.
`
`Figure 1
`
`
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0004
`
`

`

`mated After Use
`
`Figure 3
`
`
` Havel Up- : Lever Arm Up
`
`
`
`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.
`Hypersensitivity
`reactions,
`including
`urticaria
`and
`angioedema,
`have
`been
`reported
`in
`association with
`FASLODEX.
`
`WARNINGS AND PRECAUTIONS
`
`Blood Disorders
`
`it
`Because FASLODEX is administered intramuscularly,
`should be used with caution in patients with bleeding
`diatheses, thrombocytopenia, or anticoagulant use.
`
`5.2
`
`Hepatic Impairment
`The
`safety and pharmacokinetics of FASLODEX were
`evaluated in a study in seven subjects with moderate hepatic
`impairment (Child-Pugh class B) and seven subjects with
`normal hepatic function. Exposure was increased in patients
`with moderate hepatic impairment, therefore a dose of 250 mg
`is recommended [see Dosage and Administration (2.2)].
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0005
`
`

`

`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
`
`or
`loss
`fetal
`caused
`Fulvestrant
`pregnant woman.
`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
`
`6.1
`
`ADVERSE REACTIONS
`
`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
`
`InnoPharma Exhibit 10210006
`
`

`

`Table 1: Summary of Most Commonly Reported Adverse
`Reactions in Study 1 (2 5% in either treatment group):
`
`Safety Population
`
`
`Number (%) of Patients
`Body System
`and Adverse Reaaion
`Fulvestrant 500 mg
`Fulvestrant 250 mg
`
`N=361
`N=374
`
`
`Body as a Whole
`
`
`Injection Site Pain
`42 (11.6)
`34 (9.1)
`
`
`Headache
`28 (7.8)
`25 (6.7)
`
`
`Back Pain
`27 (7.5)
`40 (10.7)
`
`
`Fatigue
`27 (7.5)
`24 (6.4)
`
`
`Pain in Extremity
`25 (6.9)
`26 (7.0)
`
`
`Asthenia
`21 (5.8)
`23 (6.1)
`
`
`Vascular System
`
`Hot Flash
`24 (6.6)
`22 (5.9)
`
`
`Digestive System
`
`
`Nausea
`35 (9.7)
`51 (13.6)
`
`
`Vomiting
`22 (6.1)
`21 (5.6)
`
`
`Anorexia
`22 (6.1)
`14 (3.7)
`
`
`Constipation
`18 (5.0)
`13 (3.5)
`
`
`Musculoskeletal System
`
`
`Bone Pain
`34 (9.4)
`28 (7.5)
`
`
`
`
`
`
`
`
`
`
`Arthralgia
`29 (8.0)
`29 (7.8)
`
`
`Musculoskeletal Pain
`20 (5.5)
`12 (3.2)
`
`
`Respiratory System
`
`
`Cough
`19 (5.3)
`20 (5.3)
`
`
`Dyspnea
`16 (4.4)
`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 21 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
`
`InnoPharma Exhibit 1021.0007
`
`

`

`in the
`The most commonly reported adverse reactions
`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.
`
`reactions with mild transient pain and
`site
`Injection
`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 2 5%
`
`FASLODEX 250 mg Anastrozole 1 mg
`Body System
`and Adverse Reaction3
`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
`
`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
`
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`InnoPharma Exhibit 1021.0008
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`

`

`Arthritis
`
`Nervous System
`Dizziness
`Insomnia
`Paresthesia
`
`Depression
`Anxiety
`Respiratory System
`Pharyngitis
`Dyspnea
`Cough Increased
`Skin and Appendages
`Rash
`
`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
`
`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
`5.0
`Sweating
`14.9
`18.2
`Urogenital System
`
`Urinary Tract Infection
`6.1
`3.5
`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.
`
`6.2
`
`Post-Marketing Experience
`For FASLODEX 250 mg, other adverse reactions reported as
`drug-related
`and
`seen
`infrequently
`(<l%)
`include
`thromboembolic phenomena, myalgia, vertigo,
`leukopenia,
`and hypersensitivity reactions
`including angioedema and
`urticaria.
`
`Vaginal bleeding has been reported infrequently (<l%),
`mainly in patients during the first 6 weeks after changing from
`existing hormonal therapy to treatment with FASLODEX.
`If
`bleeding persists, further evaluation should be considered.
`
`Elevation of bilirubin, elevation of gamma GT, hepatitis, and
`liver failure have been reported infrequently (<1%).
`
`7
`
`DRUG INTERACTIONS
`
`Although,
`There are no known drug-drug interactions.
`fulvestrant
`is metabolized by CYP 3A4 in vilro, drug
`interactions studies with ketoconazole or rifampin did not alter
`fulvestrant pharrnacokinetics. Dose adjustment is not needed
`in patients co-prescribed CYP3A4 inhibitors or inducers [see
`Clinical Pharmacology (12.3)].
`
`8
`
`8.1
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`Pregnancy Category D [see Warnings and Precautions (5.3)]
`FASLODEX can cause fetal harm when administered to a
`
`or
`loss
`fetal
`caused
`Fulvestrant
`pregnant woman.
`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
`
`InnoPharma Exhibit 1021.0009
`
`

`

`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 2 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 2 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
`
`InnoPharma Exhibit 1021.0010
`
`

`

`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 = -l.4, -0.4]); and a
`reduction in mean growth velocity Z-score on-treatment
`compared to baseline (mean change = -l.l [95% CI = -2.7,
`O.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 AB and no
`patients died.
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0011
`
`

`

`Pharmacokinetics
`
`The pharmacokinetics of fulvestrant was characterized using a
`population pharrnacokinetic analysis with sparse samples per
`patient obtained from 30 female pediatric patients aged 1 to 8
`years with PPP associated with MAS. Pharrnacokinetic 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.
`
`8.5
`
`Geriatric Use
`
`response was
`For FASLODEX 250 mg, when tumor
`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.
`
`8.6
`
`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 (11 = 7
`subj ects/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
`Dosage
`and Administration
`(2.2)
`and Warning and
`Precautions (5.2)].
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0012
`
`

`

`8.7
`
`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.
`
`10
`
`OVERDOSAGE
`
`Animal studies have shown no effects other than those related
`
`to
`
`activity with
`antiestrogen
`indirectly
`or
`directly
`fulvestrant
`higher
`than
`the
`of
`doses
`intramuscular
`recommended human dose. There is no clinical experience
`with overdosage in humans. No adverse reactions were seen
`in healthy male
`and female volunteers who received
`intravenous
`fulvestrant, which resulted in peak plasma
`concentrations
`at
`the
`end of
`the
`infusion,
`that were
`approximately 10 to 15 times those seen after intramuscular
`injection.
`
`11
`
`DESCRIPTION
`
`intramuscular
`for
`Injection
`FASLODEX® (fulvestrant)
`administration is an estrogen receptor antagonist.
`The
`chemical
`name
`is
`7-alpha-[9-(4,4,5,5,5-penta
`fluoropentylsulphinyl)
`nonyl]estra-1,3,5-(10)-
`triene-3,17-
`beta-diol.
`The molecular formula is C32H47F503S and its
`structural formula is:
`
`OH
`
`HO
`
`(CH2)QSO(CH2)3CF2CF3
`
`Fulvestrant is a white powder with a molecular weight of
`606.77. The solution for injection is a clear, colorless to
`yellow, viscous liquid.
`
`10% w/v
`Each injection contains as inactive ingredients:
`Alcohol, USP, 10% w/v Benzyl Alcohol, NF, and 15% w/v
`Benzyl Benzoate, USP, as co-solvents, and made up to 100%
`w/v with Castor Oil, USP as a co-solvent and release rate
`modif1er.
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 10210013
`
`

`

`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Many breast cancers have estrogen receptors (ER) and the
`growth of these tumors can be stimulated by estrogen.
`Fulvestrant is an estrogen receptor antagonist that binds to the
`estrogen receptor
`in a competitive manner with affinity
`comparable to that of estradiol and downregulates the ER
`protein in human breast cancer cells.
`
`In vitro studies demonstrated that fulvestrant is a reversible
`
`inhibitor of the growth of tamoxifen-resistant, as well as
`estrogen-sensitive human breast cancer (MCF-7) cell lines.
`In
`in vivo tumor studies, fulvestrant delayed the establishment of
`tumors from xenografts of human breast cancer MCF-7 cells
`in nude mice. Fulvestrant inhibited the growth of established
`MCF-7 xenografts and of tamoxifen-resistant breast tumor
`xenografts.
`
`in in vivo
`effects
`showed no agonist-type
`Fulvestrant
`uterotropic assays in immature or ovariectomized mice and
`rats.
`In in vivo studies in immature rats and ovariectomized
`
`fulvestrant blocked the uterotrophic action of
`monkeys,
`In postmenopausal women, the absence of changes
`estradiol.
`in plasma concentrations of FSH and LH in response to
`fulvestrant treatment (250 mg monthly) suggests no peripheral
`steroidal effects.
`
`12.2 Pharmacodynamics
`In a clinical study in postmenopausal women with primary
`breast cancer treated with single doses of FASLODEX 15-22
`days prior to surgery, there was evidence of increasing down-
`regulation of ER with increasing dose. This was associated
`with a dose-related decrease in the expression of the
`progesterone receptor, an estrogen-regulated protein. These
`effects on the ER pathway were also associated with a
`decrease in Ki67 labeling index, a marker of cell proliferation.
`
`12.3 Pharmacokinetics
`
`Absorption:
`The single dose and multiple dose PK parameters for the 500
`mg dosing regimen with an additional dose (AD) at Day 15
`are reported in Table 3. The additional dose of FASLODEX
`given two weeks after the initial dose allows for steady state
`concentrations to be reached within the first month of dosing.
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0014
`
`

`

`
`
`Table 3: Summary of fulvestrant pharmacokinetic
`
`parameters [gMean (CV%)] in postmenopausal advanced
`breast cancer patients after intramuscular administration
`500 mg + AD dosing regimen
`
`Cmax
`
`Cmin
`
`
`
`(ng/mL) (ng.hr/mL) (ng/mL)
`
`
`
`500 mg + AD*
`
`Single dose
`Multiple
`dosegteady
`28.0 (27.9)
`12.2 (21.7)
`13100 (23.4)
`
`state
`
`25.1 (35.3)
`
`16.3 (25.9)
`
`11400 (33.4)
`
`* additional 500 mg dose given on day 15
`** month 3
`
`Distribution:
`
`steady state is
`The apparent volume of distribution at
`approximately 3 to 5 L/kg. This suggests that distribution is
`largely extravascular. Fulvestrant is highly (99%) bound to
`plasma proteins; VLDL, LDL and HDL lipoprotein fractions
`appear to be the major binding components. The role of sex
`hormone-binding globulin, if any, could not be determined.
`
`Metabolism:
`
`Biotransformation and disposition of fulvestrant in humans
`have
`been
`determined
`following
`intramuscular
`and
`intravenous
`administration
`of
`14C-labeled
`fulvestrant.
`
`Metabolism of fulvestrant appears to involve combinations of
`a number of possible biotransformation pathways analogous to
`those of endogenous steroids, including oxidation, aromatic
`hydroxylation,
`conjugation with glucuronic
`acid and/or
`sulphate at the 2, 3 and 17 positions of the steroid nucleus, and
`oxidation of the side chain sulphoxide. Identified metabolites
`are either less active or exhibit similar activity to fulvestrant in
`antiestrogen models.
`
`Studies using human liver preparations and recombinant
`human enzymes indicate that cytochrome P-450 3A4 (CYP
`3A4) is the only P-450 isoenzyme involved in the oxidation of
`fulvestrant; however, the relative contribution of P-450 and
`non-P-450 routes in vivo is unknown.
`
`Excretion:
`
`Fulvestrant was rapidly cleared by the hepatobiliary route with
`excretion primarily Via the feces (approximately 90%). Renal
`elimination was negligible (less
`than 1%).
`After
`an
`
`intramuscular injection of 250 mg, the clearance (Mean i SD)
`
`was 690 i 226 mL/min with an apparent half-life about 40
`days.
`
`Special Populations:
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 1021.0015
`
`

`

`Geriatric:
`
`there was no difference in
`In patients with breast cancer,
`fulvestrant pharmacokinetic profile related to age (range 33 to
`89 years).
`
`Gender:
`
`Following administration of a single intravenous dose, there
`were no pharmacokinetic differences between men and
`women or between premenopausal
`and postmenopausal
`women. Similarly, there were no differences between men
`and
`postmenopausal
`women
`after
`intramuscular
`administration.
`
`Race:
`
`In the advanced breast cancer treatment trials, the potential for
`pharmacokinetic differences due to race have been evaluated
`in 294 women including 87.4% Caucasian, 7.8% Black, and
`4.4% Hispanic. No
`differences
`in
`fulvestrant plasma
`pharmacokinetics were observed among these groups.
`In a
`separate trial, pharmacokinetic data from postmenopausal
`ethnic Japanese women were similar to those obtained in non-
`Japanese patients.
`
`Drug-Drug Interactions:
`There are no known drug-drug interactions. Fulvestrant does
`not significantly inhibit any of the major CYP isoenzymes,
`including CYP 1A2, 2C9, 2Cl9, 2D6, and 3A4 in vitro, and
`studies of co-administration of fulvestrant with midazolam
`
`fulvestrant have no
`therapeutic doses of
`indicate that
`inhibitory effects on CYP 3A4 or alter blood levels of drug
`metabolized by that enzyme. Although fulvestrant is partly
`metabolized by CYP 3A4, a clinical study with rifampin, an
`inducer
`of CYP 3A4,
`showed
`no
`effect
`on
`the
`pharmacokinetics of fulvestrant. Also results from a healthy
`volunteer
`study with ketoconazole, a potent
`inhibitor of
`CYP3A4,
`indicated that ketoconazole had no effect on the
`pharmacokinetics of fulvestrant and dosage adjustment is not
`necessary in patients co-prescribed CYP3A4 inhibitors or
`inducers [see Drug Interactions (7)].
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Two-year carcinogenesis studies were conducted in rats and
`mice. Positive findings were observed in both species. Rats
`were treated at intramuscular doses of 15 mg/kg/3O days, 10
`mg/rat/3O days and 10 mg/rat/lS days.
`
`These doses correspond to 0.9-, 1.5-, and 3-fold (in females)
`and 0.8-, 0.8-, and 2-fold (in males) the systemic exposure
`
`Reference ID: 3215285
`
`InnoPharma Exhibit 10210016
`
`

`

`[AUC0_30 days] achieved in women receiving the recommended
`dose of 500 mg/month. An increased incidence of benign
`ovarian granulosa cell
`tumors and testicular Leydig cell
`tumors was evident, in females dosed at 10 mg/rat/ 15 days and
`males dosed at 15 mg/rat/30 days, respectively. Mice were
`treated at oral doses of 0, 20, 150 and 500 mg/kg/day. These
`doses correspond to 0.8-, 8.4- and 18-fold (in females) and
`0.8-, 7.1- and 11.9- fold (in males), the systemic exposure
`[AUC0_30 days] achieved in women receiving the recommended
`dose of 500 mg/month. There was an increased incidence of
`sex cord stromal tumors (both benign and malignant) in the
`ovary of mice at doses of 150 and 500 mg/kg/day. Induction
`of such tumors is consistent with the pharmacology-related
`endocrine feedback alterations in gonadotropin levels caused
`by an antiestrogen.
`
`Fulvestrant was not mutagenic or clastogenic in multiple
`in vitro tests wit