NDA 21-344
`Page 4
`
`Rev 04/25/02
`
`(fulvestrant) Injection
`
`DESCRIPTION
`FASLODEX® (fulvestrant) Injection for intramuscular administration is an estrogen receptor
`antagonist without known agonist effects. 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 C32H47F5O3S and its structural formula is:
`
`OH
`
`OH
`
`(CH2)9SO(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.
`
`Each injection contains as inactive ingredients: Alcohol, USP, Benzyl Alcohol, NF, and
`Benzyl Benzoate, USP, as co-solvents, and Castor Oil, USP as a co-solvent and release rate
`modifier.
`
`FASLODEX is supplied in sterile single patient pre-filled syringes containing 50-mg/mL
`fulvestrant either as a single 5 mL or two concurrent 2.5 mL injections to deliver the required
`monthly dose. FASLODEX is administered as an intramuscular injection of 250 mg once
`monthly.
`
`CLINICAL PHARMACOLOGY
`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.
`Fulvestrant downregulates the ER protein in human breast cancer cells.
`
`In a clinical study in postmenopausal women with primary breast cancer treated with single
`
`

`

`NDA 21-344
`Page 5
`
`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.
`
`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.
`Fulvestrant resistant breast tumor xenografts may also be cross-resistant to tamoxifen.
`
`Fulvestrant showed no agonist-type effects in in vivo uterotropic assays in immature or
`ovariectomized mice and rats. In in vivo studies in immature rats and ovariectomized
`monkeys, fulvestrant blocked the uterotrophic action of estradiol. In postmenopausal
`women, the absence of changes in plasma concentrations of FSH and LH in response to
`fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects.
`
`Pharmacokinetics
`Following intravenous administration, fulvestrant is rapidly cleared at a rate approximating
`hepatic blood flow (about 10.5 ml plasma/min/Kg). After an intramuscular injection plasma
`concentrations are maximal at about 7 days and are maintained over a period of at least one
`month, with trough concentration about one-third of Cmax. The apparent half-life was about
`40 days. After administration of 250 mg of fulvestrant intramuscularly every month, plasma
`levels approach steady-state after 3 to 6 doses, with an average 2.5 fold increase in plasma
`AUC compared to single dose AUC and trough levels about equal to the single dose Cmax
`(see Table 1).
`
`Table 1: Summary of fulvestrant pharmacokinetic parameters in postmenopausal advanced breast cancer
`patients after intramuscular administration of a 250 mg dose (Mean ± SD)
`
`Cmax
`ng/ml
`
`8.5 ± 5.4
`15.8 ± 2.4
`
`Cmin
`ng/ml
`
` 2.6 ± 1.1
`7.4 ± 1.7
`
`AUC
`ng.d/ml
`
`131± 62
`328 ± 48
`
`t½
`days
`
`CL
`ml/min
`
` 40 + 11
`
`690 ± 226
`
`Single dose
`Multiple dose
` steady state
`
`Fulvestrant was subject to extensive and rapid distribution. The apparent volume of
`distribution at steady state was approximately 3 to 5 L/kg. This suggests that distribution is
`largely extravascular. Fulvestrant was 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 and Excretion:
`Biotransformation and disposition of fulvestrant in humans have been determined following
`
`

`

`NDA 21-344
`Page 6
`
`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.
`
`Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the
`feces (approximately 90%). Renal elimination was negligible (less than 1%).
`
`Special Populations:
`Geriatric-- In patients with breast cancer, there was no difference in 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 apparent 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.
`
`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.
`
`Hepatic Impairment-- Fulvestrant is metabolized primarily in the liver. In clinical trials in
`patients with locally advanced or metastatic breast cancer, pharmacokinetic data were
`obtained following administration of a 250 mg dose of FASLODEX to 261 patients classified
`as having normal liver function and to 24 patient with mild impairment. Mild impairment
`was defined as an alanine aminotransferase concentration (at any visit) greater than the upper
`limit of the normal (ULN) reference range, but less than 2 times the ULN; or if any 2 of the
`following 3 parameters were between 1- and 2-times the ULN: aspartate aminotransferase,
`alkaline phosphatase, or total bilirubin.
`
`

`

`NDA 21-344
`Page 7
`
`There was no clear relationship between fulvestrant clearance and hepatic impairment and
`the safety profile in patients with mild hepatic impairment was similar to that seen in patients
`with no hepatic impairment. Safety and efficacy have not been evaluated in patients with
`moderate to severe hepatic impairment (see PRECAUTIONS-Hepatic Impairment and
`DOSAGE AND ADMINISTRATION-Hepatic Impairment sections).
`
`Pediatric--The pharmacokinetics of fulvestrant have not been evaluated in pediatric 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, 2C19, 2D6, and 3A4 in vitro, and
`studies of co-administration of fulvestrant with midazolam indicate that therapeutic doses of
`fulvestrant have no inhibitory effects on CYP 3A4 or alter blood levels of drug metabolized
`by that enzyme. Also, 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. Clinical studies of the effect of strong CYP 3A4 inhibitors on the
`pharmacokinetics of fulvestrant have not been performed.
`
`Clinical Studies
`Efficacy of FASLODEX was established by comparison to the selective aromatase inhibitor
`anastrozole in two randomized, controlled clinical trials (one conducted in North America,
`the other in Europe) in postmenopausal women with locally advanced or metastatic breast
`cancer. All patients had progressed after previous therapy with an antiestrogen or progestin
`for breast cancer in the adjuvant or advanced disease setting. The majority of patients in
`these trials had ER+ and/or PgR+ tumors. Patients who had ER-/PgR- or unknown disease
`must have shown prior response to endocrine therapy.
`
`In both trials, eligible patients with measurable and/or evaluable disease were randomized
`to receive either FASLODEX 250 mg intramuscularly once a month (28 days + 3 days) or
`anastrozole 1 mg orally once a day. All patients were assessed monthly for the first three
`months and every three months thereafter. The North American trial was a double-blind,
`randomized trial in 400 postmenopausal women. The European trial was an open,
`randomized trial conducted in 451 patients. Patients on the FASLODEX arm of the North
`American trial received two separate injections (2 X 2.5 ml), whereas FASLODEX patients
`received a single injection (1 X 5 ml) in the European trial. In both trials, patients were
`initially randomized to a 125 mg per month dose as well, but interim analysis showed a very
`low response rate and low dose groups were dropped.
`
`The effectiveness endpoints were response rates (RR), based on the Union Internationale
`Contre le Cancer (UICC) criteria, and time to progression (TTP). Survival time was also
`determined. Confidence intervals (95.4%) were calculated for the difference in RR between
`the FASLODEX and anastrozole groups. The hazard ratio for an unfavorable event, (such
`as disease progression or death) between FASLODEX and anastrozole groups was also
`determined.
`
`Table 2 provides the demographics and baseline characteristics of the postmenopausal
`
`

`

`NDA 21-344
`Page 8
`
`women randomized to FASLODEX 250 mg or anastrozole 1 mg.
`
`

`

`TABLE 2: STUDY POPULATION DEMOGRAPHICS
`North American Trial
`European Trial
`
`FASLODEX
`250 mg
`
`Anastrozole
`1 mg
`
`FASLODEX
`250 mg
`
`Anastrozole
`1 mg
`
`206
`
`64
`
`33 - 89
`
`194
`
`61
`
`36 - 94
`
`222
`
`64
`
`35 - 86
`
`229
`
`65
`
`33 – 89
`
`NDA 21-344
`Page 9
`
`Parameter
`
`No. of Participants
`
`Median Age (yrs)
`
`Age Range (yrs)
`
`Receptor Status # (%)
`
`ER Positive
`
`ER/PgR Positive
`
`ER/PgR Unknown
`
`Previous Therapy
`
`Tamoxifen
`
`Adjuvant antiestrogen only
`
`Antiestrogen for advanced disease
`+/- adjuvant use
`
`Cytotoxic Chemotherapy
`
`Site of Metastases
`
`Visceral only *
`
`Viscera
`Liver involvement
`
`Lung involvement
`
`Bone only
`
`Soft Tissue only
`
`170 (83%)
`
`179 (87%)
`
`13 (6%)
`
`196 (95%)
`
`94 (46%)
`
`110 (53%)
`
`156 (80%)
`
`169 (87%)
`
`15 (8%)
`
`187 (96%)
`
`94 (48%)
`
`97 (50%)
`
`156 (70%)
`
`163 (73%)
`
`51 (23%)
`
`215 (97%)
`
`95 (43%)
`
`126 (57%)
`
`173 (76%)
`
`183 (80%)
`
`37 (16%)
`
`225 (98%)
`
`100 (44%)
`
`129 (56%)
`
`129 (63%)
`
`122 (63%)
`
`94 (42%)
`
`98 (43%)
`
`39 (19%)
`
`45 (23%)
`
`30 (14%)
`
`41 (18%)
`
`47 (23%)
`
`63 (31%)
`
`47 (23%)
`
`12 (6%)
`
`45 (23%)
`
`60 (31%)
`
`43 (22%)
`
`13 (7%)
`
`48 (22%)
`
`56 (25%)
`
`38 (17%)
`
`11 (5%)
`
`40 (18%)
`
`56 (24%)
`
`60 (26%)
`
`40 (17%)
`
`8 (3%)
`
`35 (15%)
`
`Skin and soft tissue
`43 (21%)
`41 (21%)
`*Defined as liver or lung metastatic, or recurrent, disease
`ER/PgR Positive defined as ER positive or PgR positive
`ER/PgR Unknown defined as ER unknown and PgR unknown
`
`

`

`NDA 21-344
`Page 10
`
`Results of the trials, after a minimum follow-up duration of 14.6 months, are summarized in
`Table 3. The effectiveness of FASLODEX 250 mg was determined by comparing RR and
`TTP results to anastrozole 1 mg, the active control. With respect to response rate, the two
`studies ruled out (by one-sided 97.7% confidence limit) inferiority of FASLODEX to
`anastrozole of 6.3% and 1.4%.
`
`Table 3: Efficacy Results
`
` European Trial
` North American Trial
`FASLODEX
`Anastrozole
`FASLODEX
`Anastrozole
`250 mg
`1 mg
`250 mg
`1 mg
`End point (n=206) (n=194) (n=222) (n=229)
`
`Objective tumor response
` Number (%) of subjects
` with CR + PR
`
`35 (17.0)
`
`33 (17.0)
`
`45 (20.3)
`
`34 (14.9)
`
`% Difference in Tumor
` Response Rate (FAS-ANA)
` 2-sided 95.4% CI
`
`0.0
`(-6.3, 8.9)
`
`Stable Disease for > 24
` weeks (%)
`
`Time to progression (TTP)
` Median TTP (days)
` Hazard ratio (FAS/ANA)
` 2-sided 95.4% CI
`
`26.7
`
`165
`
`19.1
`
`103
`
`
`
`0.9
`(0.7 to 1.1)
`
`5.4
`(-1.44, 14.8)
`
`24.3
`
`166
`
`30.1
`
`156
`
`1.0
`(0.8 to 1.26)
`
`109 (52.9%)
`837
`
`Survival Time
` Died n (%)
` Median Survival (days)
`1.0
`1.1
` Hazard Ratio
` (0.8, 1.3)
`(0.8, 1.5)
` 2-sided 95% CI
`____________________________________________________________________
`CR = Complete Response; PR = Partial Response; CI = Confidence Interval;
`FAS = FASLODEX; ANA = anastrozole
`
`92 (47.4%)
`901
`
`125 (56.3%)
`803
`
`130 (56.8%)
`742
`
`There are no efficacy data for the use of FASLODEX in premenopausal women with
`advanced breast cancer (women with functioning ovaries as evidenced by menstruation
`and/or premenopausal LH, FSH and estradiol levels).
`
`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.
`
`CONTRAINDICATIONS
`FASLODEX is contraindicated in pregnant women, and in patients with a known
`hypersensitivity to the drug or to any of its components.
`
`

`

`NDA 21-344
`Page 11
`
`WARNINGS
`Women of childbearing potential should be advised not to become pregnant while receiving
`FASLODEX. FASLODEX can cause fetal harm when administered to a pregnant woman and
`has been shown to cross the placenta following single intramuscular doses in rats and in
`rabbits. In studies in the pregnant rat, intramuscular doses of fulvestrant 100 times lower than
`the maximum recommended human dose (based on body surface area [BSA]), caused an
`increased incidence of fetal abnormalities and death. Similarly, rabbits failed to maintain
`pregnancy and the fetuses showed an increased incidence of skeletal variations when
`fulvestrant was administered at one-half the recommended human dose (based on BSA).
`
`There are no studies in pregnant women using 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, or potential risk for loss of the pregnancy. See
`Pregnancy section of PRECAUTIONS.
`
`Because FASLODEX is administered intramuscularly, it should not be used in patients
`with bleeding diatheses, thrombocytopenia or patients on anticoagulants.
`
`PRECAUTIONS
`General
`Before starting treatment with FASLODEX, pregnancy must be excluded (see
`WARNINGS).
`
`Hepatic Impairment
`Safety and efficacy have not been evaluated in patients with moderate to severe hepatic
`impairment (see CLINICAL PHARMACOLOGY-Hepatic Impairment and DOSAGE
`AND ADMINISTRATION-Hepatic Impairment sections).
`
`Drug Interactions
`Fulvestrant is metabolized by CYP 3A4 in vitro. Clinical studies of the effect of strong CYP
`3A4 inhibitors on the pharmacokinetics of fulvestrant have not been performed (see
`CLINICAL PHARMACOLOGY-Drug-Drug Interactions).
`
`Carcinogenesis, Mutagenesis and Impairment of Fertility
`A two-year carcinogenesis study was conducted in female and male rats, at intramuscular
`doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days. These doses
`correspond to approximately 1-, 3-, and 5-fold (in females) and 1.3-, 1.3-, and 1.6-fold (in
`males) the systemic exposure [AUC0-30 days]] achieved in women receiving the recommended
`dose of 250 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. Induction of such tumors is consistent with the
`pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an
`antiestrogen.
`
`

`

`NDA 21-344
`Page 12
`
`Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests with and without the
`addition of a mammalian liver metabolic activation factor (bacterial mutation assay in strains
`of Salmonella typhimurium and Escherichia coli, in vitro cytogenetics study in human
`lymphocytes, mammalian cell mutation assay in mouse lymphoma cells and in vivo
`micronucleus test in rat.
`
`In female rats, fulvestrant administered at doses > 0.01 mg/kg/day (approximately one-
`hundredth of the human recommended dose based on body surface area [BSA], for 2 weeks
`prior to and for 1 week following mating, caused a reduction in fertility and embryonic
`survival. No adverse effects on female fertility and embryonic survival were evident in
`female animals dosed at 0.001 mg/kg/day (approximately one-thousandth of the human dose
`based on BSA). Restoration of female fertility to values similar to controls was evident
`following a 29-day withdrawal period after dosing at 2 mg/kg/day (twice the human dose
`based on BSA). The effects of fulvestrant on the fertility of female rats appear to be
`consistent with its anti-estrogenic activity. The potential effects of fulvestrant on the fertility
`of male animals were not studied but in a 6-month toxicology study, male rats treated with
`intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant
`showed a loss of spermatozoa from the seminiferous tubules, seminiferous tubular atrophy,
`and degenerative changes in the epididymides. Changes in the testes and epididymides had
`not recovered 20 weeks after cessation of dosing. These fulvestrant doses correspond to
`approximately 2-, 3-, and 3-fold the systemic exposure [AUC0-30 days] achieved in women.
`
`Pregnancy
`Pregnancy Category D: (See WARNINGS).
`In studies in female rats at doses > 0.01 mg/kg/day (IM; approximately one-hundredth of the
`human recommended dose based on body surface area [BSA]), fulvestrant caused a
`reversible reduction in female fertility, as well as effects on embryo/fetal development
`consistent with its anti-estrogenic activity. Fulvestrant caused an increased incidence of fetal
`abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day IM; twice the human dose
`on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical
`vertebra at doses > 0.1 mg/kg/day IM (approximately one-tenth of the human dose on BSA)
`when administered during the period of organogenesis. Rabbits failed to maintain pregnancy
`when dosed with 1 mg/kg/day fulvestrant IM (twice the human dose on BSA) during the
`period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (about one-half the
`human dose on BSA), increases in placental weight and post-implantation loss were observed
`but, there were no observed effects on fetal development. 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 IM; one-half the human dose 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.
`
`
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`

`NDA 21-344
`Page 13
`
`Nursing Mothers
`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. It is not known if
`fulvestrant is excreted in human milk. Because many drugs are excreted in human milk, and
`because of the potential for serious adverse reactions from FASLODEX in nursing infants,
`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.
`
`Pediatric Use
`The safety and efficacy of FASLODEX in pediatric patients have not been established.
`
`Geriatric Use
`When tumor response was considered by age, objective responses were seen in 24% and 22%
`of patients under 65 years of age and in 16% and 11% of patients 65 years of age and older,
`who were treated with FASLODEX in the European and North American trials, respectively.
`
`ADVERSE REACTIONS
`The most commonly reported adverse experiences 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 flushes), and pharyngitis.
`
`Injection site reactions with mild transient pain and inflammation were seen with
`FASLODEX and occurred in 8 7% of patients (1% of treatments) given the single 5 mL
`injection (European Trial) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL
`injections (North American Trial).
`
`Table 4 lists adverse experiences 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.
`
`

`

`NDA 21-344
`Page 14
`
`Body system
`and adverse eventa
`
`Body as a whole
`Asthenia
`Pain
`Headache
`Back pain
`Abdominal pain
`Injection site pain*
`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
`
`Table 4: Combined Trials Adverse Events > 5%
`
`FASLODEX 250 mg
`N=423
`(%)
`
`Anastrozole 1 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
`
`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
`
`

`

`NDA 21-344
`Page 15
`
`Body system
`and adverse eventa
`
`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
`
`Fulvestrant 250 mg
`N=423
`n (%)
`
`Anastrozole 1 mg
`N=423
`n (%)
`
`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
`
`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
`
`aA patient may have more than one adverse event.
`*All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American study received placebo
`injections.
`
`Other adverse events reported as drug-related and seen infrequently (<1%) include thromboembolic
`phenomena, myalgia, vertigo, and leukopenia.
`
`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.
`
`OVERDOSAGE
`Animal studies have shown no effects other than those related directly or indirectly to anti-estrogen
`activity with intramuscular doses of fulvestrant higher than the recommended human dose. There
`is no clinical experience with overdosage in humans. No adverse effects 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.
`
`DOSAGE AND ADMINISTRATION
`Adults (including the elderly): The recommended dose is 250 mg to be administered
`intramuscularly into the buttock at intervals of one month as either a single 5 mL injection or two
`concurrent 2.5 mL injections (see HOW SUPPLIED). The injection should be administered slowly.
`
`

`

`NDA 21-344
`Page 16
`
`Patients with Hepatic Impairment
`FASLODEX has not been studied in patients with moderate or severe hepatic compromise. No
`dosage adjustment is recommended in patients with mild hepatic impairment (see CLINICAL
`PHARMACOLOGY-Hepatic Impairment and PRECAUTIONS-Hepatic Impairment sections).
`
`4.
`
`5.
`6.
`7.
`8.
`9.
`
`Instructions for Intramuscular use, handling and disposal
`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."
`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).
`Twist to lock the needle to the luer connector.
`Remove needle sheath.
`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).
`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.
`Repeat steps 1 through 10 for second syringe.
`
`10.
`
`11.
`
`For the 2 x 2.5 mL syringe package only, both syringes must be administered to receive the
`250 mg recommended monthly 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
`
`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.
`
`

`

`NDA 21-344
`Page 17
`
`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.
`
`

`

`NDA 21-344
`Page 18
`
`Faslodex
`Figure 1
`
`Faslodex
`Figure 2
`
`
`
`
`
`

`

`NDA 21-344
`Page 19
`
`Faslodex
`Figure 3
`
`HOW SUPPLIED
`One 5 mL clear neutral glass (Type 1) barrel containing 5 mL (50 mg/mL) FASLODEX Injection for
`intramuscular injection and fitted with a tamper evident closure.
`NDC 0310-0720-50 5 mL Prefilled Syringes
`Two 5 mL clear neutral glass (Type 1) barrels, each containing 2.5 mL (50 mg/mL) of FASLODEX
`Injection for intramuscular injection and fitted with a tamper-evident closure.
`NDC 0310-0720-25 Two 5 mL Prefilled Syringes containing 2.5 mL
`The syringes are presented in a tray with polystyrene plunger rod and a safety needle (Safety Glide™) for
`connection to the barrel.
`Storage
`Store in a refrigerator, 2°-8°C (36°F -46°F). Store in original container.
`Distributed by:
`AstraZeneca Pharmaceuticals LP
`Wilmington, DE 19850
`Manufactured for:
`IPR Pharmaceuticals Inc.
`Carolina, PR
`by:
`Vetter Pharma-Fertigung GMBH & Co. KG
`Ravensburg, Germany
`Made in Germany
`
`Rev 04/25/02
`
`

`

`DRAFT
`Faslodex 2.5mL Carton
`
`™
`
`Two pre-filled
`syringes
`containing
`2.5mL
`
`0 000000 000000
`
`For Single-Patient Use Only
`
`NDC 0310-0720-25
`
`™
`
`250 mg (50 mg/mL)
`Two Pre-filled Syringes each containing 2.5mL or 125 mg
`fulvestrant (50 mg/mL)
`For Intramuscular Use Only
`
`Rx only
`
`XXXXX-XX
`XXXXX-XX
`XXXXX-XX
`
`LOT
`EXP
`
`unvarnished area
`
`™
`
`Two pre-filled syringes
`containing 2.5mL
`
`USUAL DOSAGE: See Prescribing Information for details of administration. See below for assembly instructions.
`STORAGE: Refrigerate, 2-8°C (36-46°F). Store in the original package.
`WARNING: As with all medications, keep out of the reach of children.
`
`Carton contains: Two 5mL prefilled syringes containing 2.5mL or 125 mg of FASLODEX™ (50 mg/mL), sterile alcohol
`prep pad and 2 SafetyGlide™ shielding IM injection needles.
`PLEASE NOTE: The syringes are supplied half full. Both syringes must be administered to receive the 250 mg
`recommended monthly dose.
`
`FASLODEX™ also contains: Alcohol (96%), Benzyl alcohol, Benzyl Benzoate, and Castor Oil.
`
`INSTRUCTIONS FOR USE:
`1. Remove glass syringe barrel from tray and check
`that it is not damaged.
`2. Peel open the SafetyGlide™ outer packaging.
`3. 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).
`4. Twist to lock the needle to the luer
`connector.
`5. Remove needle sheath.
`6. Remove excess gas from the syringe
`(a small gas bubble may remain).
`
`Figure 1
`
`Figure 2
`
`7. Administer intramuscularly in the buttock.
`8.
`Immediately activate needle protection device upon
`withdrawal from patient by pushing lever arm
`completely forward until needle tip is fully covered
`(see Figure 2).
`9. 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.
`For complete SafetyGlide™ instruction refer to
`prescribing information.
`
`XXXXX-XX
`XXXXX-XX
`XXXXX-XX
`
`2.5mL
`
`containing
`syringes
`
`Two pre-filled
`
`™
`
`™
`
`Two pre-filled
`
`syringes
`containing
`
`2.5mL
`
`Activated After Use
`
`Distributed by:
`AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850
`Manufactured for:
`IPR Pharmaceuticals, Inc., Carolina, PR 00984
`By: Vetter Pharma-Fertigung GMBH & Co. KG
`Ravensburg, Germany Made in Germany
`
`SafetyGlide™ is a trademark of Becton Dickinson and Company.
`All other trademarks are the property of the AstraZeneca group
`© AstraZeneca 2001
`
`Rev. 2/28/01
`
`

`

`Rev. 2/28/01
`
`DRAFT
`Faslodex 2.5mL Syringe Label
`
`Web Direction
`
`Variable Data
`XXXXX-XX
`
`™
`
`NDC 0310-0720-25
`
`125 mg (50 mg/mL) / 2.5mL
`For Intramuscular Use Only
`Both syringes must be administered to receive
`the 250 mg recommended monthly dose.
`
`

`

`DRAFT
`Faslodex 5mL Carton
`
`™
`
`One 5mL
`pre-filled
`syringe
`
`0 000000 000000
`
`For Single-Patient Use Only
`
`NDC 0310-0720-50
`
`™
`
`250 mg (50 mg/mL)
`For Intramuscular Use Only
`Rx only
`
`USUAL DOSAGE: See Prescribing Information for details of
`administration. See bottom of carton for assembly instructions.
`STORAGE: Refrigerate, 2-8°C (36-46°F). Store in the original package.
`WARNING: As with all medications, keep out of the reach of children.
`
`LOT
`EXP
`
`unvarnished area
`
`INSTRUCTIONS FOR USE:
`1. Remove glass syringe barrel from tray
`and check that it is not damaged.
`2. Peel open the SafetyGlide™ outer
`packaging.
`3. 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).
`4. Twist to lock the needle to the luer
`connector.
`5. Remove needle sheath.
`6. Remove excess gas from the syringe
`(a sma