PRODUCT MONOGRAPH 1 TABLE OF CONTENTS 2 PART I: HEALTH PROFESSIONAL INFORMATION 3 SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS. 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 14 DOSAGE FORMS, COMPOSITION AND PACKAGING 15 PART II: SCIENTIFIC INFORMATION 16 PHARMACEUTICAL INFORMATION 16 CLINICAL TRIALS 17 DETAILED PHARMACOLOGY 21 TOXICOLOGY 22 REFERENCES 24

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength Clinically Relevant Nonmedicinal

Ingredients

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Body as a Whole

FASLODEX (fulvestrant) is unlikely to impair the ability of patients to drive or operate machinery. However, during treatment with FASLODEX, asthenia has been reported, and caution should be observed by those patients who experience this symptom when driving or operating machinery.

Hematologic

Due to the route of administration (intramuscular injection), caution should be used before treating patients on anticoagulants or patients with bleeding diatheses or thrombocytopenia.

Hepatic

Fulvestrant is metabolised primarily in the liver. Caution should be used with FASLODEX in patients with hepatic impairment, as clearance may be reduced. Pharmacokinetic data show that the mean clearance is reduced 2.2 fold in subjects with moderate hepatic impairment in comparison to healthy subjects (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency). The safety profile in patients with mild hepatic impairment was similar to that seen in patients with no hepatic impairment in clinical trials of advanced breast cancer. Fulvestrant has not been investigated in subjects with severe hepatic impairment. The potential risk/benefit to such patients should be carefully considered before administration of FASLODEX.

Renal

Caution should be used before treating patients with creatinine clearance less than 30 mL/min.

Special Populations

Pregnant Women:

FASLODEX can cause fetal harm if administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If a patient becomes pregnant while receiving FASLODEX she should be apprised of the potential hazard to the fetus, or the potential risk for loss of pregnancy.

Nursing Women:

FASLODEX is found in rats' milk at levels significantly higher than those in rat plasma. It is not known if fulvestrant is excreted in human milk. However, since 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.

Pediatrics:

FASLODEX is not recommended for use in the pediatric population, as safety and efficacy have not been established in this age group.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The table below summarizes the adverse drug reactions seen in FASLODEX (fulvestrant) clinical trials and post-marketing experience.

Table 1 Summary of adverse drug reactions seen in clinical trials and post-marketing experience

Very common (>10%)	Cardiovascular	Hot flushes, which are predominately mild in nature.
Common (>1% - <= 10%)	Gastrointestinal	Gastrointestinal disturbance including nausea, vomiting, diarrhea, and anorexia, which were usually mild in nature.
	Hepatobiliary	Elevated liver enzymes, the vast majority <2x ULN (upper limit of normal).
	Nervous system	Headache, usually mild.
	Skin	Rash, usually mild in nature.
	Urogenital	Urinary tract infections, usually mild in nature.
	Whole body	Injection site reactions including mild transient pain and inflammation (frequency based on administration of one 5 mL injection, the recommended administration), and asthenia, usually mild or moderate in nature.
Uncommon (>0.1% - <= 1%)	Immune system	Hypersensitivity reactions including angioedema and urticaria. These reactions may occur shortly after injection, or in one reported case of angioedema, several days after injection. Local injection site reactions (e.g. pruritus, urticaria) may occur even after prior uneventful injections, and have been reported to develop with time into a systemic allergic response (e.g. widespread urticaria). FASLODEX therapy may need to be discontinued.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. In patients with locally advanced or metastatic breast cancer treated with FASLODEX, the most commonly reported adverse events (irrespective of causality) were vasodilation (hot flushes), nausea and injection site reactions. Injection site reactions, with mild transient pain and inflammation, occurred in 7% of patients (1% of injections) when given the 5 mL injection in the predominantly European Clinical trial (9238IL/0020). In the North American trial (9238IL/0021), where patients were given a 250 mg dose of fulvestrant as two 2.5 mL injections, injection site reaction occurred in 27% of patients (5% of all administered injections). Approximately 47% of patients experienced adverse events reported as treatment related; however, only 0.9% of patients stopped therapy because of such events in the clinical trial programme. Table 2 lists adverse events reported with an incidence of >= 5% in the two controlled trials 9238IL/0020 and 9238IL/0021, regardless of causality, during treatment or the specified safety follow-up period (defined as 8 weeks after the last injection or 30 days after ingestion of the last tablet).

Table 2 Adverse events occurring at an incidence of >= 5% (irrespective of causality): Combined results from Trials 9238IL/0020 and 9238IL/0021

Body System and Adverse Event a	FASLODEX 250mg (IM injection/month) N=423 (%)	Anastrozole 1 mg (oral tablet/day) N=423 (%)
Body As A Whole	68.3	67.6
Asthenia	22.7	27.0
Pain	18.9	20.3
Headache	15.4	16.8
Back Pain	14.4	13.2
Abdominal Pain	11.8	11.6
Injection Site Pain *	10.9	6.6
Pelvic Pain	9.9	9.0
Chest Pain	7.1	5.0
Body System and Adverse Event a	FASLODEX 250mg (IM injection/month) N=423 (%)	Anastrozole 1 mg (oral tablet/day) N=423 (%)
Flu Syndrome	7.1	6.4
Fever	6.4	6.4
Accidental Injury	4.5	5.7
Cardiovascular System	30.3	27.9
Vasodilation	17.7	17.3
Digestive System	51.5	48.0
Nausea	26.0	25.3
Vomiting	13.0	11.8
Constipation	12.5	10.6
Diarrhea	12.3	12.8
Anorexia	9.0	10.9
Hemic and Lymphatic Systems	13.7	13.5
Anemia	4.5	5.0
Metabolic and Nutritional Disorders	18.2	17.7
Peripheral Edema	9.0	10.2
Musculoskeletal System	25.5	27.9
Bone Pain	15.8	13.7
Arthritis	2.8	6.1
Nervous System	34.3	33.8
Dizziness	6.9	6.6
Insomnia	6.9	8.5
Paresthesia	6.4	7.6
Depression	5.7	6.9
Anxiety	5.0	3.8
Respiratory System	38.5	33.6
Pharyngitis	16.1	11.6
Body System and Adverse Event a	FASLODEX 250mg (IM injection/month) N=423 (%)	Anastrozole 1 mg (oral tablet/day) N=423 (%)
Dyspnea	14.9	12.3
Cough increased	10.4	10.4
Skin and Appendages	22.2	23.4
Rash	7.3	8.0
Sweating	5.0	5.2
Urogenital System	18.2	14.9
Urinary tract infection	6.1	3.5

A patient may have more then one adverse event

* All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American study received placebo injections

DRUG INTERACTIONS

FASLODEX (fulvestrant) does not significantly inhibit any of the major cytochrome P450 (CYP) isoenzymes in vitro, and results from a clinical pharmacokinetic trial in 8 healthy males involving co-administration of fulvestrant (36 mg intramuscularly) with midazolam (7.5 mg p.o.) also suggest that therapeutic doses of fulvestrant will have no inhibitory effects on CYP3A4. In addition, although fulvestrant can be metabolised by CYP3A4 in vitro, a clinical study in 8 healthy males with rifampicin (600 mg p.o. ), an inducer of CYP3A4, showed no change in the pharmacokinetics of a 10 mg IV dose of fulvestrant as a result of the induction of CYP3A4. Results from a clinical study in 18 healthy subjects (17 male, 1 female) with ketoconazole (400 mg daily), a potent inhibitor of CYP3A4, also indicated that there is no clinically relevant change in the pharmacokinetics of an 8 mg IV dose of fulvestrant. Dosage adjustment is not necessary in patients co-prescribed CYP3A4 inhibitors or inducers.

DOSAGE AND ADMINISTRATION

Adult Females:

The recommended dose of FASLODEX (fulvestrant) is 250 mg, administered intramuscularly into the buttock at intervals of 1 month as a single 5 mL injection. It is recommended that the injection be administered slowly.

Patients with hepatic insufficiency:

No dose adjustments are recommended for patients with Child-Pugh category A and B hepatic impairment. However, as the clearance of fulvestrant may be decreased in patients with hepatic impairment, these patients should be monitored for side effects when treated with fulvestrant (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency). The use of fulvestrant has not been evaluated in patients or pharmacokinetic study subjects with Child- Pugh C hepatic impairment.

Patients with renal insufficiency:

No dose adjustments are recommended for patients with a creatinine clearance greater than 30 mL/min. Safety and efficacy have not been evaluated in patients with creatinine clearance less than 30 mL/min.

Elderly:

Children:

Not recommended for use in children or adolescents, as safety and efficacy have not been established in this age group.

SafetyGlide(tm) is a trademark of Becton Dickinson and Company. Reorder number 305917.

Warning

: Do not autoclave SafetyGlide(tm) needle before use. Hands must remain behind the needle at all times during use and disposal.

Peel apart packaging of the SafetyGlide(tm), break the seal of the white plastic cover on the syringe luer connector and attach the SafetyGlide(tm) 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 oriented 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 (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. Activation of the protective mechanism may cause minimal splatter of fluid that may remain on the needle after injection.

For greatest safety, use a one-handed technique and activate away from self and others.

After single use, discard in an approved sharps collector in accordance with applicable regulations and institutional policy. Becton Dickinson guarantees the contents of their unopened or undamaged packages to be sterile, non-toxic and non-pyrogenic.

Figure 1

Figure 2

Figure 3

OVERDOSAGE

There is no clinical experience of overdosage with FASLODEX (fulvestrant) in humans. Animal studies have shown no adverse effects with intramuscular doses of greater than 400-fold of the clinical dose. Further animal studies, in which fulvestrant was dosed either monthly or twice monthly and achieved plasma levels several-fold higher than those seen in humans, showed no effects other than those related directly or indirectly to antiestrogen activity. If overdosage occurs, this should be managed symptomatically.

ACTION AND CLINICAL PHARMACOLOGY

FASLODEX (fulvestrant) is an estrogen receptor (ER) antagonist that has a mode of action leading to downregulation of ER protein. Fulvestrant is a nonagonist ER antagonist that blocks the trophic actions of estrogens without itself having any partial agonist (estrogen-like) activity. Fulvestrant binds to estrogen receptors in a competitive manner with an affinity comparable to that of estradiol. Fulvestrant is a reversible inhibitor of the growth of estrogen-sensitive human breast cancer cells in vitro. Fulvestrant inhibits the growth of estrogen-sensitive xenografts of human breast cancer in nude mice, prevents the establishment of tumours from xenografts of human breast cancer cells, and suppresses the growth of breast tumours. Furthermore, fulvestrant inhibits the growth of tamoxifen-resistant breast cancer cells in vitro and of tamoxifen-resistant breast tumours in vivo. Fulvestrant resistant breast tumours may also be cross-resistant to tamoxifen.

A clinical trial in postmenopausal women with primary breast cancer has shown that a single 250 mg dose of fulvestrant significantly downregulates ER expression in ER positive tumours, when compared to placebo. This same study also showed for fulvestrant a significant decrease in progesterone receptor (PgR) expression compared to placebo after 15 - 22 days of treatment. These data are consistent with fulvestrant having no agonist activity. A trial in healthy postmenopausal volunteers showed that, compared to placebo, pre-treatment with 250 mg fulvestrant resulted in significantly reduced stimulation of the postmenopausal endometrium in volunteers treated with 20 mcg per day ethinyl estradiol. Mean endometrial thickness after treatment with 250 mg fulvestrant was 4.2 mm, and with placebo it was 11.22 mm. 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. The reduction in levels of sex hormone-binding globulin indicates a lack of agonist properties.

Following intravenous or intramuscular administration, fulvestrant is rapidly cleared at a rate approximating the hepatic blood flow (nominally 10.5 mL plasma/min/kg). FASLODEX long-acting intramuscular injection maintains plasma fulvestrant concentrations within a range of 2- to 3-fold difference between peak and trough concentrations over a period of at least 28+-3 days after injection. Administration of 250 mg of fulvestrant intramuscularly every month results in limited accumulation, approaching steady-state levels after approximately 3 to 6 doses, with an approximate 2-fold increase in plasma AUC. Results from single-dose studies of fulvestrant are predictive of multiple-dose pharmacokinetics.

Table 3 Summary of fulvestrant pharmacokinetic parameters in postmenopausal advanced breast cancer patients after intramuscular administration of a 250 mg dose (Mean+-SD)

Absorption:

Distribution:

Fulvestrant is subject to extensive and rapid distribution; the apparent volume of distribution at steady state is large (approximately 3 to 5 L/kg), which suggests that the compound 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. No studies were conducted on drug-drug competitive protein binding interactions, as most reported interactions of this type involved binding to albumin and a-1-acid-glycoproteins.

Metabolism: Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of 14C-labelled 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, and 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. The metabolism of fulvestrant in humans yields a similar profile of metabolites to that found in other species. 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 CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant. However, the relative contribution of P450 and non-P450 routes in vivo is unknown.

Excretion:

Fulvestrant is rapidly cleared by the hepatobiliary route with the overall rate of elimination being determined by the mode of administration, i.e., with monthly administration of FASLODEX long acting intramuscular formulation, exposure, and hence elimination, is primarily determined by the rate of release from the injection site. Excretion is primarily via the feces (approximately 90%). Renal elimination of drug-related material is negligible (less than 1%).

Geriatrics:

No difference in the fulvestrant pharmacokinetic profile was detected with regard to age (range 33 to 89 years).

Gender:

Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and either premenopausal or 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 discernible differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic

data from postmenopausal Japanese women living in Japan were comparable to those obtained in non-Japanese patients.

Hepatic Insufficiency:

The pharmacokinetics of fulvestrant has been evaluated in a single- dose clinical trial conducted in 21 subjects (7 subjects with Child-Pugh category A and 7 with category B hepatic impairment due to cirrhosis, 7 healthy subjects), using a high dose (100 mg) of a shorter duration intramuscular injection formulation. There was a 1.3 and 2.2-fold reduction in mean clearance in subjects with Child-Pugh category A and B hepatic impairment respectively compared to healthy subjects. Child-Pugh category C subjects were not evaluated; it is expected that clearance would be further reduced in this group of subjects.

Modelled intramuscular mean steady state plasma concentrations of fulvestrant in subjects with Child-Pugh category A and B hepatic impairment fall within the upper 95% confidence limit of the mean steady state concentrations expected for patients with normal hepatic function given the intramuscular formulation. Given the known safety profile of fulvestrant, no dose adjustment is considered to be necessary in patients with Child-Pugh category A or B hepatic impairment, although they should be monitored for side effects.

STORAGE AND STABILITY

Store refrigerated at 2 to 8degC. Store in original package. Single dose syringe. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

FASLODEX (fulvestrant) solution for injection is a clear, colourless to yellow, viscous liquid. In addition to the active ingredient fulvestrant, each pre-filled syringe contains the following inactive ingredients: ethanol 96%, benzyl alcohol, benzyl benzoate, and castor oil. FASLODEX is available in a 250 mg/5 mL (50 mg/mL) pre-filled syringe. The syringe is presented in a tray with polystyrene plunger rod and a safety needle (SafetyGlide(tm)) for connection to the barrel. As with all parenteral drug products, syringes should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

	C max	C min	AUC	t 1/2	CL
	ng/mL	ng/mL	ng.d/mL	days	mL/min
Single dose	8.5 +- 5.4	2.6 +- 1.1	131 +- 62.0	39.8 +- 10.8	690 +- 226
Multiple dose steady state	15.8 +- 2.4	7.4 +- 1.7	328 +- 48	49.9	537 +- 57