`Page 3
`
`Rev 08-04
`
`
`
`
`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 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.
`
`
`
`
`NDA 21-344/S-004
`Page 4
`
`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
`
`Cmin
`ng/mL
`
`AUC
`ng.d/mL
`
`131 ± 62
`
`328 ± 48
`
`t½
`days
`
`CL
`mL/min
`
`
`40 ± 11
`
`
`
`
`690 ± 226
`
`
`
`
`
`8.5 ± 5.4
`
`15.8 ± 2.4
`
`
`
`2.6 ± 1.1
`
`7.4 ± 1.7
`
`
`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.
`
`
`
`
`NDA 21-344/S-004
`Page 5
`
`Metabolism and Excretion:
`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.
`
`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 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 patients 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/S-004
`Page 6
`
`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
`PRECAUTIONS-Hepatic
`Impairment
`DOSAGE
`AND
`impairment
`(see
`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. 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 CYP
`3A4 inhibitors or inducers.
`
`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
`predominately 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 women
`randomized to FASLODEX 250 mg or anastrozole 1 mg.
`
`
`
`
`NDA 21-344/S-004
`Page 7
`
`TABLE 2: STUDY POPULATION DEMOGRAPHICS
`
`
`North American Trial
`FASLODEX
`Anastrozole
`250 mg
`1 mg
`
`Parameter
`
`
`European Trial
`FASLODEX
`Anastrozole
`250 mg
`1 mg
`
`206
`64
`33 - 89
`
`194
`61
`36 - 94
`
`222
`64
`35 - 86
`
`229
`65
`33 - 89
`
`170 (83%)
`179 (87%)
`13 (6%)
`
`156 (80%)
`169 (87%)
`15 (8%)
`
`156 (70%)
`163 (73%)
`51 (23%)
`
`173 (76%)
`183 (80%)
`37 (16%)
`
`196 (95%)
`94 (46%)
`110 (53%)
`
`187 (96%)
`94 (48%)
`97 (50%
`
`215 (97%)
`95 (43%)
`126 (57%)
`
`225 (98%)
`100 (44%)
`129 (56%)
`
`129 (63%)
`
`122 (63%)
`
`94 (42%)
`
`98 (43%)
`
`30 (14%)
`
`
`48 (22%)
`56 (25%)
`38 (17%)
`11 (5%)
`40 (18%)
`
`41 (18%)
`
`
`56 (24%)
`60 (26%)
`40 (17%)
`8 (3%)
`35 (15%)
`
`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
`
`45 (23%)
`39 (19%)
`Visceral only*
`
`
`Viscera
`
`
`
`45 (23%)
`47 (23%)
` Liver involvement
` Lung involvement
`60 (31%)
`63 (31%)
`43 (22%
`47 (23%)
`Bone only
`13 (7%)
`12 (6%)
`Soft Tissue only
`41 (21%)
`43 (21%)
`Skin and soft tissue
`* 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
`
`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%. There was
`no statistically significant difference in the survival time between the two treatment groups.
`
`Table 3: Efficacy Results
`
`
`North American Trial
`
`European Trial
`
`
`
`
`Endpoint
`
`Objective tumor response
` Number (%) of subjects
` with CR + PR
`
`
`FASLODEX
`250 mg
`(n=206)
`
`Anastrozole
`1 mg
`(n=194)
`
`FASLODEX
`250 mg
`(n=222)
`
`Anastrozole
`1 mg
`(n=229)
`
`
`
`
`
`
`
`35 (17.0)
`
`
`
`
`
`
`
`33 (17.0)
`
`
`
`
`
`
`
`45 (20.3)
`
`
`
`
`
`
`
`34 (14.9)
`
`
`
`
`0.0
`(-6.3, 8.9)
`
`
`0.9
`(0.7, 1.1)
`
`
`
`165
`
`
`26.7
`
`
`
`
`103
`
`
`19.1
`
`
`
`
`
`
`
`
`5.4
`(-1.4, 14.8)
`
`
`
`166
`
`
`24.3
`
`
`156
`
`
`30.1
`
`1.0
`(0.8, 1.2)
`
`
`
`
`
`
`
`
`
`
`NDA 21-344/S-004
`Page 8
`
` %
`
`
`
`152 (73.8%)
`844
`
`
`
`149 (76.8%)
`913
`
`
`
`167 (75.2%)
`803
`
`0.97
`(0.78, 1.21)
`
`
`
`173 (75.5%)
`736
`
` Difference in Tumor
` Response Rate (FAS-ANA)
` 2-sided 95.4% CI
`
`Time to progression (TTP
` Median TTP (days)
` Hazard ratio (FAS/ANA)
` 2-sided 95.4% CI
`
`Stable Disease for ≥ 24
` weeks (%)
`
`
`Survival Time
` Died n (%)
` Median Survival (days)
`0.98
` Hazard Ratio
`(0.78, 1.24)
` 2-sided 95% CI
`
`
`
`CR = Complete Response; PR = Partial Response; CI =Confidence Interval;
`FAS = FASLODEX ; ANA - anastrozole
`
`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.
`
`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 in patients on anticoagulants.
`
`
`
`NDA 21-344/S-004
`Page 9
`
`
`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:
`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-Drug-Drug Interactions).
`
`
`Carcinogenesis, Mutagenesis, 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.
`
`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 antiestrogenic 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.
`
`
`
`
`NDA 21-344/S-004
`Page 10
`
`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 antiestrogenic
`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.
`
`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 7% of patients (1% of treatments) given the single 5 mL injection (predominately
`European Trial) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North
`American Trial).
`
`
`
`
`NDA 21-344/S-004
`Page 11
`
`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.
`
`Table 4: Combined Trials Adverse Event ≥ 5%
`Body system
`FASLODEX 250 mg
`Anastrozole 1 mg
` and adverse event
`N=423
`N=423
`(%)
`(%)
`
`
`
`
`
`
`Body as a whole
`68.3
`22.7
` Asthenia
`18.9
` Pain
`15.4
` Headache
`14.4
` Back pain
`11.8
` Abdominal pain
`10.9
` Injection site pain*
`9.9
` Pelvic Pain
`7.1
` Chest pain
`7.1
` Flu syndrome
`6.4
` Fever
`4.5
` Accidental injury
`Cardiovascular system
`30.3
`17.7
` Vasodilatation
`Digestive system
`51.5
`26.0
` Nausea
`13.0
` Vomiting
`12.5
` Constipation
`12.3
` Diarrhea
`9.0
` Anorexia
`Hemic and lymphatic
`
` Systems
`13.7
`4.5
` Anemia
`Metabolic and
`
` Nutritional disorders
`18.2
`9.0
` Peripheral edema
`Musculoskeletal system
`25.5
`15.8
` Bone pain
`2.8
` Arthritis
`Nervous system
`34.3
`6.9
` Dizziness
`6.9
` Insomnia
`6.4
` Paresthesia
`5.7
` Depression
` Anxiety
`5.0
`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 event.
`*All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American
`study received placebo injections.
`
`67.6
`27.0
`20.3
`16.8
`13.2
`11.6
`6.6
`9.0
`5.0
`6.4
`6.4
`5.7
`27.9
`17.3
`48.0
`25.3
`11.8
`10.6
`12.8
`10.9
`
`13.5
`5.0
`
`17.7
`10.2
`27.9
`13.7
`6.1
`33.8
`6.6
`8.5
`7.6
`6.9
`3.8
`33.6
`11.6
`12.3
`10.4
`23.4
`8.0
`5.2
`14.9
`3.5
`
`
`
`NDA 21-344/S-004
`Page 12
`
`
`Other adverse events reported as drug-related and seen infrequently (<1%) include thromboembolic
`phenomena, myalgia, vertigo, leukopenia and hypersensitivity reactions including angioedema and
`urticaria.
`
`Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks
`after changing from 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 antiestrogen
`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.
`
`Patients with Hepatic Impairment
`FASLODEX has not been studied in patients with moderate or severe hepatic compromise. No dosage
`impairment (see CLINICAL
`adjustment
`is recommended
`in patients with mild hepatic
`PHARMACOLOGY-Hepatic Impairment and PRECAUTIONS-Hepatic Impairment sections).
`
`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™".
`4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with
`the attached rubber tip cap (see Figure 1).
`5. Twist to lock the needle to the luer connector.
`6. Remove needle sheath.
`7. Remove excess gas from the syringe (a small gas bubble may remain).
`8. Administer intramuscularly 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).
`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.
`
`For the 2 x 2.5 mL syringe package only, both syringes must be administered to receive the 250
`mg recommended monthly dose.
`
`
`
`NDA 21-344/S-004
`Page 13
`
`
`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.
`
`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/S-004
`Page 14
`
`Figure 1
`
`Figure 2
`
`
`
`Figure 3
`
`
`
`
`
`
`
`
`
`
`
`
`
`HOW SUPPLIED
`FASLODEX is supplied in two different packaging configurations:
`
`1.
`
`FASLODEX is supplied as one clear neutral glass (Type 1) barrel containing 250 mg/5mL (50
`mg/mL) FASLODEX injection for intramuscular injection and fitted with a tamper evident
`closure.
`NDC 0310-0720-50
`
`
`
` 2.
`
`
`
`FASLODEX is also supplied as two clear neutral glass (Type 1) barrels each containing 125
`mg/2.5 mL (50 mg/mL) FASLODEX Injection for intramuscular injection and fitted with a
`tamper-evident closure. PLEASE NOTE: THE SYRINGES ARE SUPPLIED HALF
`FULL. BOTH SYRINGES MUST BE ADMINISTERED TO RECEIVE THE 250 MG
`RECOMMENDED MONTHLY DOSE.
`NDC 0310-0720-25
`
`
`The syringes are presented in a tray with polystyrene plunger rod and a safety needles (SafetyGlide™)
`for connection to the barrel.
`
`
`
`
`NDA 21-344/S-004
`Page 15
`
`Storage:
`REFRIGERATE, 2°-8°C (36°-46°F). TO PROTECT FROM LIGHT, STORE IN THE ORIGINAL
`CARTON UNTIL TIME OF USE.
`
`SafetyGlide™ is a trademark of Becton Dickinson and Company
`All other trademarks are the property of the AstraZeneca group of companies
`©AstraZeneca 2002, 2004
`
`
`Distributed by:
`AstraZeneca Pharmaceuticals LP
`Wilmington, DE 19850
`
`Manufactured for:
`AstraZeneca UK Limited
`Macclesfield, Cheshire, England
`By: Vetter Pharma-Fertigung GMBH & Co. KG
`Ravensburg, Germany
`
`Made in Germany
`
`Rev 08-04
`
`
`SIC 31003-00
`
`