FULVESTRANT ACCORD fulvestrant 250 mg/5 mL solution for injection pre-filled syringe

Australia - English - Department of Health (Therapeutic Goods Administration)

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Active ingredient:
fulvestrant
Available from:
Accord Healthcare Pty Ltd
Authorization status:
Registered
Authorization number:
328533

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FULVESTRANT ACCORD

Fulvestrant injection 250 mg/5 mL pre-filled syringe

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Fulvestrant Accord. It

does not contain all the available

information.

It does not take the place of talking to

your doctor or pharmacist.

All medicines have risks and benefits.

Your doctor has weighed the risks of

you taking Fulvestrant Accord against

the benefits expected for you.

If you have any concerns about

taking this medicine, ask your doctor

or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Fulvestrant

Accord is used for

Fulvestrant Accord is used to treat

hormone receptor positive, locally

advanced or metastatic breast cancer in

women who have been through

menopause and have received prior

treatment with tamoxifen.

Fulvestrant Accord stops some of the

actions of oestrogen within the body.

Oestrogen is a female sex hormone that

may help cancer cells grow in women

with breast cancer.

Fulvestrant Accord should only be

given to women.

Fulvestrant Accord is not

recommended for use in men or

children.

Fulvestrant Accord does not kill cancer

cells, however it stops or slows their

growth.

Your doctor will have explained why

you are being treated with Fulvestrant

Accord and will determine what dose

to give you.

Follow all directions given to you by

your doctor.

They may differ from the information

contained in this leaflet.

Your doctor may prescribe this

medicine for another use. Ask your

doctor if you want more information.

Fulvestrant Accord is not addictive.

Before you are given

Fulvestrant Accord

When you must not be

given it

Do not use Fulvestrant Accord if you

have any allergies to the active

ingredient fulvestrant, or any of the

other ingredients used in Fulvestrant

Accord.

Do not use Fulvestrant Accord if you

have not reached menopause.

We do not have information on its use

in women before menopause.

Do not use Fulvestrant Accord if you

are pregnant or breastfeeding.

It is not known if it is safe for you to be

given it while you are pregnant. It may

affect your baby if you are given it at

any time during pregnancy. If you can

become pregnant, you should use

effective contraception while you are

being treated with Fulvestrant Accord

and for 2 years after the last dose.

Do not use Fulvestrant Accord if you

are breastfeeding.

Fulvestrant Accord should not be

given to children.

There is no information on its use in

children.

Fulvestrant Accord should not be

given to men.

There is no information on its use in

men.

Fulvestrant Accord injection should

only be used if the solution is clear,

the package is undamaged and the

use by (expiry) date marked on the

pack has not been passed.

Before you are given

Fulvestrant Accord

You must tell your doctor if:

1.

you have any allergies to:

any medicines

any other substances, such as

foods, preservatives or dyes

If you have an allergic reaction, you

may get a skin rash, swelling of the

extremities, hay fever, difficulty

breathing or feel faint.

2.

you have any of these medical

conditions

liver problems

kidney problems

bleeding disorders

a low blood platelet count

It may not be safe for you to be given

Fulvestrant Accord if you have any of

these conditions.

Taking other medicines

Tell your doctor if you are taking

any other medicines, including:

tamoxifen or any medicine which

contains oestrogen (female sex

hormone). These medicines may

reduce the effect of Fulvestrant

Version 1.0

Page 2 of 3

Accord

other medicines used to treat

cancer

medicines that you buy at the

chemist, supermarket or health

food shop.

These medicines may affect the way

Fulvestrant Accord works.

Your doctor or pharmacist can tell you

what to do if you are taking any of

these medicines.

If you have not told your doctor about

any of these things, tell them before

you are given Fulvestrant Accord.

How Fulvestrant

Accord is given

The usual dose is 500 mg fulvestrant

(two (2) x 250 mg/5 ml injections)

given once a month with an additional

500 mg dose given 2 weeks after the

initial dose.

Your doctor or nurse will give you

Fulvestrant Accord as a slow

intramuscular injection, one into each

of your buttocks.

Overdose

The doctor or nurse giving you

Fulvestrant Accord will be

experienced in its use, so it is unlikely

that you will be given too much. If

you are concerned that you have

been given too much Fulvestrant

Accord, tell your doctor or nurse

immediately. Otherwise telephone

the Poisons information Centre

(telephone 13 11 26) for advice.

While you are being

given Fulvestrant

Accord

Things you must do

Be sure to keep all your

appointments with your doctor so

your progress can be checked.

Tell any other doctors, dentists and

pharmacists who are treating you

that you have been given Fulvestrant

Accord.

If you are about to be started on any

new medicine, tell your doctor,

dentist or pharmacist that you have

been given Fulvestrant Accord.

If you go into hospital, please let the

medical staff know that you are being

treated with Fulvestrant Accord.

Things to be careful of

Be careful driving or operating

machinery until you know how

Fulvestrant Accord affects you.

Some patients may occasionally feel

weak, tired or sleepy.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking Fulvestrant

Accord.

Fulvestrant Accord helps most people

with breast cancer, but it may have

unwanted side-effects in some people.

All medicines can have side effects.

Sometimes they are serious, most of the

time they are not. You may need

medical attention if you get some of the

side effects.

Ask your doctor or pharmacist to

answer any questions you may have.

Tell your doctor or pharmacist if you

notice any of the following and they

worry you:

pain or inflammation at the

injection site

hot flushes

headache

weakness, tiredness, sleepiness

nausea or vomiting

diarrhoea

loss of appetite

skin rash

urinary tract infections

hypersensitivity, including

swelling of the face, lips, tongue

and/or throat and hives/welts

joint or muscle pain.

The above list includes the more

common side effects of Fulvestrant

Accord.

Fulvestrant Accord may be associated

with changes in your blood, urine or

liver. Your doctor may want to perform

tests from time to time to check on

your progress and detect any unwanted

side effects.

Tell your doctor if you notice

anything else that is making you feel

unwell.

Some people may get other side effects

while being treated with Fulvestrant

Accord.

Storage

Fulvestrant Accord should be stored

in a fridge (2°C to 8°C) until ready

for use. Your doctor or pharmacist

will usually store the medicine for

you.

Disposal

Your doctor or pharmacist will

dispose of any needles, syringes and

Fulvestrant Accord that may be left

over.

Product description

What Fulvestrant Accord

looks like

Fulvestrant Accord is a clear,

colourless to yellow viscous liquid for

injection. Packs contain one or two

5 mL pre-filled syringes.

Ingredients

Active ingredient:

Fulvestrant

Inactive ingredients:

Ethanol

Benzyl alcohol

Benzyl benzoate

Castor oil

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Name and Address of

the Sponsor

Accord Healthcare Pty Ltd

Level 24, 570 Bourke Street

Melbourne, VIC, 3000

Australia

Australian Registration Numbers

AUST R 328533

Date of Preparation

This leaflet was prepared on 22

December 2020.

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Page 1 of 10

AUSTRALIAN PRODUCT INFORMATION

FULVESTRANT ACCORD (FULVESTRANT) SOLUTION FOR INJECTION

1

NAME OF THE MEDICINE

Fulvestrant

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 250 mg fulvestrant in 5 mL solution for injection.

Excipients with known effects: benzoates and alcohol.

For the full list of excipients, see

Section 6.1 List of Excipients.

3

PHARMACEUTICAL FORM

Fulvestrant Accord 250 mg/5 mL solution for injection is a clear, colourless to yellow, viscous liquid.

4

CLINICAL PARTICULARS

4.1

T

HERAPEUTIC INDICATIONS

Fulvestrant Accord is indicated for the treatment of postmenopausal women with hormone-receptor

positive, locally advanced or metastatic breast cancer who have progressive disease following prior

tamoxifen therapy.

4.2

D

OSE AND METHOD OF ADMINISTRATION

In the absence of incompatibility studies, Fulvestrant Accord must not be mixed with other drugs.

Fulvestrant Accord is not recommended for use in men.

Adult females (including the elderly)

The recommended dose (500 mg) is to be administered intramuscularly as two 5 mL injections, one in

each buttock (gluteal area), at intervals of 1 month.

An additional 500 mg dose is to be given 2 weeks after the initial dose.

It is recommended that the injection be administered slowly (1-2 minutes/injection).

Caution should be taken if injecting Fulvestrant Accord at the dorsogluteal site due to the proximity of

the underlying sciatic nerve.

Special patient populations

Patients with hepatic insufficiency

No dose adjustments are recommended for patients with mild hepatic impairment. Safety and efficacy

have not been further evaluated in patients with moderate to severe hepatic impairment (see

Section 4.4

Special Warnings and Precautions for Use

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 further evaluated in patients with creatinine clearance less than

30 mL/min (see

Section 4.4 Special Warnings and Precautions for Use).

Use in the elderly

No dose adjustment is required for elderly patients.

Paediatric use

Not recommended for use in children or adolescents as safety and effectiveness have not been established

in this age group.

Product is for single use in one patient only. Discard any residue.

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4.3

C

ONTRAINDICATIONS

Fulvestrant Accord is contraindicated in patients with a known hypersensitivity to the drug substance or

to any of the excipients.

Fulvestrant Accord is contraindicated in pregnancy.

4.4

S

PECIAL WARNINGS AND PRECAUTIONS FOR USE

Use in hepatic impairment

Fulvestrant is metabolised primarily in the liver. In clinical trials in patients with advanced breast cancer,

in which Fulvestrant Accord has been administered to patients with mild hepatic impairment (alanine

aminotransferase concentration greater than the upper limit of the normal reference range [ULN] but less

than twice the ULN). There was no clear relationship between fulvestrant clearance and hepatic

impairment. The safety profile in patients with mild hepatic impairment was similar to that seen in

patients with no hepatic impairment. Caution should be used with Fulvestrant Accord in patients with

moderate to severe hepatic impairment, as clearance may be reduced.

Use in renal impairment

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

Section 5.2 Pharmacokinetic Properties.

Coagulation disorders

Caution should be used before treating patients with bleeding diatheses or thrombocytopenia or patients

on anticoagulants due to the route of administration.

Injection site related events

Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy

have been reported with fulvestrant injection. Caution should be taken while administering Fulvestrant

Accord at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve (see

Sections

4.2 Dosage and Method of Administration and 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly

Section 4.2 Dose and Method of Administration

Paediatric use

Section 4.2 Dose and Method of Administration.

Effects on laboratory tests

Interference with oestradiol assay

Due to the structural similarity of fulvestrant and oestradiol, fulvestrant may interfere with antibody

based oestradiol assays and may result in falsely increased levels of oestradiol.

4.5

I

NTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS

Fulvestrant does not significantly inhibit any of the major cytochrome P450 (CYP) isoenzymes

in vitro

and results from a clinical pharmacokinetic trial involving co-administration of fulvestrant with

midazolam 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 with rifampicin

showed no change in fulvestrant clearance as a result of the induction of CYP3A4. Dosage adjustment is

not necessary in patients co-prescribed CYP3A4 inhibitors or inducers.

There are no known drug-drug interactions requiring dose adjustment.

4.6

F

ERTILITY

,

P

REGNANCY

A

ND

L

ACTATION

Effects on fertility

Fulvestrant affected oestrus cycling in rats causing a reduction in female fertility at doses as low as

0.01 mg/kg/day, considerably lower than the clinical dose on a body surface area basis. Embryonic

survival was also reduced. These effects are consistent with the antioestrogenic activity of fulvestrant.

These effects were largely reversible in rats after a 1-month withdrawal period from the drug. Fulvestrant

Accord is not proposed for use in males, but loss of spermatozoa from the seminiferous tubules,

Page 3 of 10

seminiferous tubular atrophy and degenerative changes in the epidiymides were observed in a 6-month

study in rats given fulvestrant by the intramuscular route.

Use in pregnancy (Category D)

Fulvestrant Accord is proposed for use in postmenopausal women only. Fulvestrant Accord may cause

foetal harm when administered to a pregnant woman. If Fulvestrant Accord is used during pregnancy or

if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential

hazard to the foetus or potential risk for loss of the pregnancy. If Fulvestrant Accord is used in patients

of childbearing potential, patients should use effective contraception during treatment with Fulvestrant

Accord and for 2 years after the last dose. In rats, fulvestrant caused a reversible reduction in embryonic

survival at intramuscular doses as low as 0.01 mg/kg/day, considerably lower than the clinical dose

calculated on a body surface area basis. Fulvestrant also caused dystocia and an increased occurrence of

foetal

abnormalities

rats,

including

tarsal

flexure,

intramuscular

dose

mg/kg/day,

corresponding to approximately twice the clinical dose calculated on a body surface area basis. Rabbits

given intramuscular fulvestrant at ≥1 mg/kg/day (corresponding to approximately twice the clinical dose

calculated on a body surface area) failed to maintain pregnancy, while at doses of 0.25 mg/kg/day, there

were small increases in post-implantation loss, placental weight and incidences of two foetal variations

Use in lactation

Studies in rats have shown that fulvestrant levels in rat milk are significantly higher than those in rat

plasma. The potential risk for nursing infants is unknown. Therefore, breastfeeding should be avoided in

women receiving Fulvestrant Accord.

4.7

E

FFECTS ON ABILITY TO DRIVE AND USE MACHINES

During treatment with Fulvestrant Accord, asthenia has been reported and caution should be observed

by those patients who experience this symptom when driving or operating machinery.

4.8

A

DVERSE EFFECTS

(U

NDESIRABLE EFFECTS

)

The following frequency categories for adverse drug reactions (ADRs) were calculated based on the

fulvestrant 500 mg treatment group in pooled safety analyses of studies that compared fulvestrant 500

mg with fulvestrant 250 mg [CONFIRM (Study D6997C00002), FINDER 1 (Study D6997C00004),

FINDER 2 (Study D6997C00006), and NEWEST (Study D6997C00003) studies], or from FALCON

(Study D699BC00001) that compared fulvestrant 500 mg with anastrozole 1 mg. Where frequencies

differ between the pooled safety analysis and FALCON, the highest frequency is presented. The

frequencies in the following tables were based on all reported events, regardless of the investigator

assessment of causality.

Table 1: Summary of Adverse Drug Reactions (ADR) seen in clinical trials for fulvestrant 500 mg

Frequency descriptor

System Order Class

ADR

Very common

(≥ 10%)

General disorders and administration

site conditions

Injection site reactions

, asthenia

Hepatobiliary disorders

Elevated liver enzymes (ALT, AST,

ALP)

Gastrointestinal disorders

Nausea

Immune system disorders

Hypersensitivity reactions

Musculoskeletal and connective

tissue disorders

Joint and musculoskeletal pain

Skin and subcutaneous tissue

disorders

Rash

Vascular disorders

Hot flushes

Common (≥1 - <10%)

Nervous system disorders

Headache

Hepatobiliary disorders

Elevated bilirubin

Blood and lymphatic system

Reduced platelet count

Gastrointestinal disorders

Vomiting, diarrhoea

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Frequency descriptor

System Order Class

ADR

Metabolism and nutrition disorders

Anorexia

Infections and infestations

Urinary tract infections

Uncommon (≥0.1% and <1%)

Hepatobiliary disorders

Hepatic failure

, hepatitis

, elevated

gamma-GT

Based on any CTC grade change from baseline.

The event was not observed in major clinical studies (CONFIRM, FINDER1, FINDER2, NEWEST). The frequency has been

calculated using the upper limit of the 95% confidence interval for the point estimate. This is calculated as 3/560 (where 560 is the number

of patients in the major clinical studies), which equates to a frequency category of ‘uncommon’

Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.

Includes: arthralgia, and less frequently musculoskeletal pain, back pain, myalgia and pain in extremity.

Frequency category differs between pooled safety dataset and FALCON.

ADR was not observed in FALCON.

In the combined studies (CONFIRM, NEWEST, FIRST, FINDER1 and FINDER2) the adverse effect

profile of the 500 mg dose was comparable to that seen with the 250 mg dose but more cases of

osteoporosis (4 vs 0), vaginitis (3 vs 1) and pruritus (23 vs 8) were reported with the higher dose.

Table 2: Adverse experiences reported with an incidence of 5% or greater, regardless of assessed

causality, from the two controlled clinical trials comparing the administration of fulvestrant 250

mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Body system and adverse event

a

Fulvestrant 250 mg

N=423

(%)

Anastrozole 1 mg

N=423

(%)

Body as a whole

69.7

68.8

Asthenia

24.6

27.9

Pain

20.3

22.5

Headache

16.5

17.7

Back pain

16.1

15.4

Abdominal pain

12.8

13.2

Injection site pain*

11.3

Pelvic Pain

11.1

Chest pain

Flu syndrome

Fever

Accidental injury

Cardiovascular system

31.9

32.2

Vasodilatation

18.4

18.7

Hypertension

Digestive system

53.9

49.9

Nausea

28.1

27.0

Vomiting

15.1

12.3

Constipation

13.9

11.8

Diarrhoea

13.9

13.9

Anorexia

11.3

Haemic and lymphatic Systems

15.6

14.7

Anaemia

Metabolic and Nutritional disorders

21.5

21.0

Peripheral oedema

10.9

11.3

Musculoskeletal system

29.1

31.7

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Body system and adverse event

a

Fulvestrant 250 mg

N=423

(%)

Anastrozole 1 mg

N=423

(%)

Bone pain

18.0

15.4

Myalgia

Arthritis

Nervous system

38.1

37.1

Dizziness

Insomnia

Paresthaesia

Depression

Anxiety

Respiratory system

40.7

35.7

Pharyngitis

17.3

12.5

Dyspnoea

16.1

13.5

Cough increased

12.3

12.1

Sinusitis

Skin and appendages

24.1

25.8

Rash

Sweating

Urogenital system

20.1

18.9

Urinary tract infection

A patient may have more than one adverse event.

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

placebo injections.

Fulvestrant has been commonly associated with elevation of liver enzymes, the vast majority <2 x ULN

(frequency >1 - <10%).

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows

continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9

OVERDOSE

There are isolated reports of overdose with fulvestrant in humans. If overdose occurs, this should be

managed symptomatically. The acute toxicity of fulvestrant in laboratory animal species is low. Animal

studies suggested that no effects, other than those related directly or indirectly to antioestrogenic activity,

were

evident

with

higher

doses

fulvestrant.

studies

following

oral

intravenous

administration, effects on the cardiovascular system (slight elevations of the S-T segment of the ECG

[oral] and sinus arrest in one dog [intravenous]) were seen, but these

occurred in animals exposed to far

higher levels of fulvestrant than those recorded in patients (C

>15 times).

For information on the management of overdose, contact the Poison Information Centre on 13 11 26

(Australia).

5

PHARMACOLOGICAL PROPERTIES

5.1

P

HARMACODYNAMIC PROPERTIES

Mechanism of action

Fulvestrant is an antioestrogen that binds to oestrogen receptors in a competitive manner, with a high

affinity comparable to that of oestradiol, and downregulates the oestrogen receptor. Fulvestrant

completely inhibited the uterotrophic action of exogenous oestradiol, but showed no agonistic effects in

Page 6 of 10

uterotrophic assays in immature or ovariectomised mice, rats and monkeys. Thus, it appears to have

antioestrogen activity without having any partial agonist (oestrogen-like) activity.

Fulvestrant inhibited the growth of the oestrogen-sensitive human breast cancer cell line MCF-7

in vitro

and of xenografts of MCF-7 cells in nude mice. Fulvestrant inhibited the growth of tamoxifen-resistant

breast cancer cells

in vitro

and of tamoxifen-resistant breast tumours in nude mice.

Effects on breast cancer tissue in vivo

Clinical trials in postmenopausal women with primary breast cancer have shown that fulvestrant

significantly downregulates oestrogen receptor expression in oestrogen receptor positive tumours

compared with placebo and tamoxifen. There was also a significant decrease in progesterone receptor

expression consistent with the preclinical data demonstrating that fulvestrant lacks intrinsic oestrogen

agonist activity. These changes in oestrogen receptor and progesterone receptor expression were

accompanied by reductions in expression of Ki67, a marker of tumour cell proliferation, which were also

related to dose with fulvestrant 500 mg having a significantly greater effect than the 250 mg dose.

Effects on the postmenopausal endometrium

preclinical

data

fulvestrant

suggest

that

will

have

stimulatory

effect

postmenopausal endometrium. 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 micrograms per day ethinyl oestradiol. This

demonstrates a potent antioestrogenic effect on the postmenopausal endometrium.

Clinical trials

Effects on advanced breast cancer

A Phase III clinical trial (CONFIRM) was completed in 736 postmenopausal women with advanced

breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following

endocrine therapy for advanced disease. This trial compared the efficacy and safety of fulvestrant 500

mg (n = 362) with fulvestrant 250 mg (n = 374). Progression free survival (PFS) was the primary

endpoint; key secondary efficacy endpoints included objective response rate (ORR); clinical benefit rate

(CBR) and overall survival (OS). PFS for fulvestrant 500 mg was significantly longer than for fulvestrant

250 mg. Efficacy results are summarized in Table 3 and Figure 1 below. In the initial Overall Survival

(OS) analysis after a minimum follow-up duration of 18 months, there was no statistically significant

difference in OS between the two treatment groups. After a minimum follow-up duration of 50 months,

an updated OS analysis was performed. Final OS analysis at 75% maturity showed that fulvestrant 500

mg was associated with a 4.1-month increase in median OS and a 19% reduction in the risk of death

compared with fulvestrant 250 mg [HR=0.81; 95% CI 0.69-0.96; p = 0.016 (nominal p-value as no

adjustment was made for multiplicity)].

Table 3: Efficacy results for the CONFIRM study: Intention To Treat Population

Endpoint

Fulvestrant 500 mg

(N = 362)

Fulvestrant 250 mg

(N = 374)

PFS

a

Median (months)

Hazard Ratio

(95% CI

0.80 (0.68 – 0.94)

p-value

0.006

OS

d

Updated Analysis (% of patients

who died)

261 (72.1%)

293 (78.3%)

Median OS (months)

26.4

22.3

Hazard Ratio

(95% CI

0.81 (0.69 – 0.96)

ORR

g

(95% CI

13.8% (9.7%, 18.8%)

(33/240)

14.6% (10.5%, 19.4%)

(38/261)

PFS (Progression Free Survival) = the time between randomisation and the earliest of progression or death from any cause.

Minimum follow-up duration of 18 months.

Hazard ratio <1 favours fulvestrant 500 mg.

CI = Confidence Interval

OS = Overall Survival

Page 7 of 10

Minimum follow-up duration of 50 months.

Not statistically significant as no adjustments were made for multiplicity.

ORR (Objective Response Rate), defined as the number (%) of patients with complete or partial response, was analysed in the

evaluable patients with measurable disease at baseline (fulvestrant 500 mg N = 240; fulvestrant 250 mg N = 261). Minimum follow- up

duration of 18 months.

Figure 1: Kaplan-Meier plot of the updated Overall Survival data for the CONFIRM study

Irrespective

last

endocrine

therapy

(anti-oestrogen

aromatase

inhibitor),

treatment

effect(PFS) for fulvestrant 500 mg vs. fulvestrant 250 mg was consistent. There was no significant

difference in clinical benefit rate for patients receiving fulvestrant 500 mg vs 250 mg (45.6% vs 39.6%;

odds ratio 1.28 [95% CI 0.95, 1.71]; p=0.1) or in duration of clinical benefit (median 16.6 vs 13.9 months

for fulvestrant 500 mg and fulvestrant 250 mg, respectively).

Two Phase III clinical trials (Study 9238IL/0020 & 9238IL/0021) were completed in a total of 851

postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant

endocrine therapy or progression following endocrine therapy for advanced disease. These trials

compared the safety and efficacy of fulvestrant with a third-generation aromatase inhibitor, anastrozole.

Both trials used a dose of 250 mg every 28 days. The primary endpoint was progression free survival.

Overall, fulvestrant 250 mg was at least as effective as anastrozole in terms of progression free survival

(PFS), objective response, clinical benefit, time to treatment failure and quality of life.

In Study 21, median PFS was 165 days with fulvestrant and 103 days with anastrozole (HR 0.92; 95%

CI: 0.74 - 1.14). In Study 20, median PFS was 166 days with fulvestrant and 156 days with anastrozole

(HR 0.98; 95% CI: 0.80 - 1.21)

Fulvestrant 250 mg had an objective response rate of 20.7% in Study 20 (vs 15.7% with anastrozole) and

17.5% in Study 21 (vs 17.5% with anastrozole).

Fulvestrant 250 mg showed durable responses in both trials. In Study 20, the median duration of response

was 19.3 months for fulvestrant 250 mg and 10.5 months for anastrozole. In Study 21, the median

duration of response was 14.3 months and 14.0 months for Fulvestrant

250 mg and anastrozole 1 mg

respectively.

The majority of patients in these trials had ER+ and/or PgR+ tumours (about 80%). Patients who had

ER-/PgR- or unknown disease must have shown prior response to endocrine therapy.

There are no efficacy data to support use of fulvestrant in premenopausal patients with advanced breast

cancer.

Page 8 of 10

5.2

P

HARMACOKINETIC PROPERTIES

Absorption

After administration of fulvestrant long-acting intramuscular injection, fulvestrant is slowly absorbed

and maximum plasma concentrations are reached after about 7 days. Absorption continues for over one

month and monthly administration results in an approximate 2-fold accumulation. Steady-state levels are

reached after about 6 doses during monthly injections with the major part of the accumulation achieved

after 3-4 doses. The terminal half-life is governed by the absorption rate and was estimated to be 50 days.

At steady state, fulvestrant plasma concentrations are maintained within a relatively narrow range with

approximately 2- to 3-fold difference between maximum and trough concentrations.

Results from single-dose studies of fulvestrant are predictive of multiple dose pharmacokinetics.

Administration of fulvestrant 500 mg at day 0 and 14 achieves exposure levels at or close to steady state

within the first month of dosing (mean [CV]): AUC 475 (33.4%) ng.days/mL, C

25.1 (35.3%) ng/mL,

16.3 (25.9%) ng/mL, respectively).

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. Very low density lipoprotein

(VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major

binding components. Therefore, no drug interaction studies were conducted on competitive protein

binding. The role of sex hormone-binding globulin has not been determined.

Metabolism

The metabolism of fulvestrant has not been fully evaluated but involves combinations of a number of

possible biotransformation pathways analogous to those of endogenous steroids (includes 17-ketone,

sulphone, 3-sulphate, 3- and 17-glucuronide metabolites). Identified metabolites are either less active or

exhibit similar activity to fulvestrant in anti-oestrogen models. Studies using human liver preparations

and recombinant human enzymes indicate that CYP 3A4 is the only P450 isoenzyme involved in the

oxidation of fulvestrant, however non-P450 routes appear to be more predominant

in vivo

Excretion

Fulvestrant is eliminated mainly by metabolism. The major route of excretion is via the faeces with less

than 1% being excreted in the urine. Fulvestrant has a high clearance, 11±1.7 mL/min/kg, suggesting a

high hepatic extraction ratio.

Special patient groups

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 fulvestrant 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.

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

Sections 4.4 Special Warnings and Precautions for Use and 4.2 Dosage and Method

of Administration

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

Page 9 of 10

with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine

(see

Section 4.4 Special Warnings and Precautions for Use

Other populations

No difference in fulvestrant pharmacokinetic profile was detected with regard to age (range 33 to

89 years).

No difference in fulvestrant pharmacokinetic profile was detected with regard to ethnic groups.

5.3

P

RECLINICAL SAFETY DATA

Genotoxicity

Fulvestrant showed no genotoxic potential in bacterial reverse mutation assays,

in vitro

mouse lymphoma

assays, an

in vitro

chromosome aberration assay in human lymphocytes, and an

in vivo

micronucleus

assay in rats.

Carcinogenicity

A two-year rat oncogenicity study (intramuscular administration with the fulvestrant formulation)

showed increased incidence of benign ovarian granulosa cell tumours in females at the high dose, 10

mg/rat/15 days (approx. 5-times the human dose based on plasma AUC values). Induction of such

tumours is consistent with the pharmacology-related endocrine feedback alteration in gonadotropin levels

caused by anti-oestrogen in cycling animals. Therefore, this finding is not considered to be clinically

relevant to the use of fulvestrant in postmenopausal women with advanced breast cancer.

6

PHARMACEUTICAL PARTICULARS

6.1

L

IST OF EXCIPIENTS

Ethanol

Benzyl alcohol

Benzyl benzoate

Castor oil

6.2

I

NCOMPATIBILITIES

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3

S

HELF LIFE

In Australia, information on the shelf life can be found on the public summary of the Australian Register

of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4

S

PECIAL PRECAUTIONS FOR STORAGE

Store at 2°C to 8°C (Refrigerate. Do not freeze).

6.5

N

ATURE AND CONTENTS OF CONTAINER

Fulvestrant Accord is available as a 250 mg/5 mL solution in pre-filled Type 1 glass syringes (one or two

syringes per pack). Each pack also includes one or two safetyglide 21G needles for use with the pre-

filled syringes.

6.6

S

PECIAL PRECAUTIONS FOR DISPOSAL

In Australia, any unused medicine or waste material should be disposed of by taking to your local

pharmacy.

Page 10 of 10

6.7

P

HYSICOCHEMICAL PROPERTIES

Chemical structure

CAS number

129453-61-8

7

MEDICINE SCHEDULE (POISONS STANDARD)

S4 – Prescription Only Medicine

8

SPONSOR

Accord Healthcare Pty Limited

Level 24, 570 Bourke Street

Melbourne, VIC, 3000

Australia

9

DATE OF FIRST APPROVAL

22 December 2020

Version 1.0

Read the complete document

Public Summary

Summary for ARTG Entry:

328533

FULVESTRANT ACCORD fulvestrant 250 mg/5 mL solution for injection pre-filled syringe

ARTG entry for

Medicine Registered

Sponsor

Accord Healthcare Pty Ltd

Postal Address

Level 24 570 Bourke Street, Melbourne, VIC, 3000

Australia

ARTG Start Date

22/12/2020

Product Category

Medicine

Status

Active

Approval Area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods Under

Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered or

Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1 . FULVESTRANT ACCORD fulvestrant 250 mg/5 mL solution for injection pre-filled syringe

Product Type

Single Medicine Product

Effective Date

22/12/2020

Permitted Indications

No Permitted Indications included on Record

Indication Requirements

No Indication Requirements included on Record

Standard Indications

No Standard Indications included on Record

Specific Indications

FULVESTRANT ACCORD is indicated for the treatment of postmenopausal women with hormone-receptor positive, locally advanced or metastatic breast

cancer who have progressive disease following prior tamoxifen therapy.

Warnings

See Product Information and Consumer Medicine Information for this product

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Syringe

Glass Type I Clear

36 Months

Store at 2 to 8

degrees Celsius

Not recorded

Refrigerate

Do not Freeze

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1 . FULVESTRANT ACCORD fulvestrant 250 mg/5 mL solution for injection pre-filled syringe

Dosage Form

Injection, solution

Route of Administration

Intramuscular

Visual Identification

A clear, colourless to yellow viscous solution

Active Ingredients

fulvestrant

250 mg

Other Ingredients (Excipients)

Public Summary

Page 1 of

Produced at 12.01.2021 at 05:15:45 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

benzyl alcohol

benzyl benzoate

Castor Oil

ethanol

© Commonwealth of Australia. This work is copyright. You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth. Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 2 of

Produced at 12.01.2021 at 05:15:45 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

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