Faslodex

Section 4.8 Undesirable effects

Updates to the frequency of adverse reactions based on the PALOMA-3 study

5.1 Pharmacodynamic properties

Final OS analysis data included from the PALOMA-3 study

New figure for the PALOMA-3 study (Figure 3).

Minor editorial changes to align with the QRD template 10.1.

5.3 Preclinical safety data

Minor editorial changes to align with the QRD template 10.1.

8 MARKETING AUTHORISATION NUMBER(S)

To ensure the right EU number is printed on the right package the below in green has been added:

EU/1/03/269/001 1 Syringe

EU/1/03/269/002 2 Syringe

10. DATE OF REVISION OF THE TEXT

Updated to 04/2020

4.6     Fertility, pregnancy and lactation

Women of childbearing potential

Patients of childbearing potential should be advised  to use effective contraception while onduring  treatment with Faslodex and for 2 years after the last dose.

 

In addition, the UK adverse event reporting details have been removed, HPRA adverse event reporting details have been updated and date of revision updated from September 2018 to 11/2019.

Section 2 – update to excipeints with known effect to include benzyl alcohol

Section 4.4 – inclusion of ethanol and benzyl alcohol  warnings for the patient populations at risk

Section 5.1 – Removal of DOR (Duration of Response) from table 5 (Efficacy results from PALOMA 3 study)

Section 10 – date of last revision amended to 6^th September 2018

Section 7 - change to marketing authorisation holder

Section 10 - updated date of revision

·         Section 4.1 – therapeutic indications: updated to include combination treatment with palbociclib.

·          Section 4.2 – text added to reference palbociclib SmPC when used in combination with Faslodex and considerations prior to combination treatment.

·         Section 4.4 – efficacy and safety of Faslodex as monotherapy and in combination with palbociclib with visceral disease. Addition of text to reference palbociclib SmPC when using combination treatment.

·         Section 4.8 – addition of information on data in table 1 (ADRs reported in patients treated with Faslodex monotherapy). Addition of information on safety profile of combination treatment. Addition of table 2 outlining ADRs based on Paloma-3 study.

·         Section 5.1 – editorial changes. Addition of information on trial - combination therapy with palbociclib 

·         Section 5.2 – editorial changes

·         Section 5.3 – addition of text on environmental risk assessment

·         Section 6.1 – amendment to excipient naming to read ‘castor oil refined’

·         Section 6.3 – editorial change

·         Section 6.5 – removal of reference to BD SafetyGlide as a trademark of Becton Dickinson and company. Removal of CE mark. Removal of ‘TM’ from ‘BD SafetyGlide’

·         Section 6.6 - Removal of ‘TM’ from ‘BD SafetyGlide’. Text added that this medicine may pose a risk to the aquatic environment. Reference to section 5.3 added.

·         Section 10 – updated date of revision

Section 4. 8 - addition of uncommon side effect anaphylactic reactions

Section 10 - updated date of revision

Section 4.8 Adverse event reporting details for UK amended to be aligned with Appendix V of the QRD template.

Section 4.1 - therapeutic indications - updated to Faslodex is indicated for the treatment of oestrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women:

​​not previously treated with endocrine therapy, or with disease relapse on or after adjuvant antioestrogen therapy, or disease progression on antioestrogen therapy.

Section 4.4 - editorial changes

Section 4.8 - Undesirable effects and frequencies updated as per FALCON ADRs. Description of selected adverse reactions added to provide additional information on Joint and musculoskeletal pain.

Section 4.9 - Updated to include human overdose case.

Section 5.1 - The Phase 3 FALCON study overview and outcome data was added to support the revised indication.

Section 5.2 - editorial changes

Section 6.1 - editorial changes

Section 6.2 -editorial changes

Section 10 - updated date of revision

section 6.6 - deletion of some images from this section

Section 7- Correction to Marketing Authorisation Holder details



 

Section 4.2 caution with regards to injecting site added and minor editorial update.

Section 4.4 Injection site related events and caution with regards to injecting site added. Information on interference with estradiol antibody assays added.

Section 4.8: Sciatica, neuralgia, neuropathy peripheral added as uncommon side effects. Footnote b updated. Minor editorial change to the ordering of the address details for adverse reaction reporting.

Section 6.6: update to instruction for administration, caution statement regarding injecting site added.

Section 10 Date of revision updated

Section 2 editorial changes to reflect QRD template

Section 4.2 editorial changes to reflect QRD template

Section 4.8 editorial changes to reflect QRD template

Section 4.8 ADR reporting statement

Section 5.1 editorial changes to reflect QRD template

Section 10 update to revision date

- Section 4.8 addition of reduced platelet count as an uncommon side effect, minor amendment of text in footnote at end of table in 4.8
- Section 5.2 amendement of Cmax % from 35.1% to 35.3% in absorption subsection

-section 10 updated date of revision

Section 10 - date of revision of text
Section 5.1 – Overall Survival data

Section 6.4

 

New storage information added.

 

Temperature excursions outside 2°C-8°C should be limited. This includes avoiding storage at temperatures exceeding 30°C, and not exceeding a 28 day period where the average storage temperature for the product is below 25°C (but above 2°C-8°C). After temperature excursions, the product should be returned immediately to the recommended storage conditions (store and transport in a refrigerator 2°C-8°C). Temperature excursions have a cumulative effect on the product quality and the 28 day time period must not be exceeded over the duration of the 4-year shelf life of Faslodex (see section 6.3). Exposure to temperatures below 2°C will not damage the product providing it is not stored below - 20°C.

 

Section 10

 

Date of revision updated to 14^th December 2012.

Section 2

 

Minor editorial changes

 

Section 4.3

 

Minor editorial changes

 

Section 4.8

Table 1

 

Hepatobiliary disorders

 

Addition of

Common	Elevated bilirubina
Uncommon	Hepatic failurec, hepatitisc, elevated gamma-GT

 



 

New footnote c

 

c        The event was not observed in major clinical studies (CONFIRM, FINDER 1, FINDER 2, NEWEST). The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate. This is calculated as 3/563 (where 563 is the number of patients in the major clinical studies), which equates to a frequency category of ‘uncommon’.

 

Section 5.3

 

Inclusion of mouse oncogenicity study information

 

Section 10

 

Change of Date of Revision to 17^th February 2012.

 

 

Text added to following sections relating to pediatric populations

 

Section 4.2

 

Text added

 

Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

 

Text deleted

 

No data are available.

 

Section 4.4

 

Text added

 

Paediatric population

 

Faslodex is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).

 

Section 5.1

 

Text added

 

Faslodex is not indicated for use in children.

 

An open-label phase II study investigated the safety, efficacy and pharmacokinetics of fulvestrant in 30 girls aged 1 to 8 years with Progressive Precocious Puberty associated with McCune Albright Syndrome (MAS). The paediatric patients received 4 mg/kg monthly intramuscular dose of fulvestrant. This 12-month study investigated a range of MAS endpoints and showed a reduction in the frequency of vaginal bleeding and a reduction in the rate of bone age advancement. The steady-state trough concentrations of fulvestrant in children in this study were consistent with that in adults (see section 5.2). There were no new safety concerns arising from this small study, but 5-year data are yet not available.

 

Section 5.2

 

Text added

 

Paediatric population

The pharmacokinetics of fulvestrant has been evaluated in a clinical trial conducted in 30 girls with Progressive Precocious Puberty associated with McCune Albright Syndrome (see section 5.1). The paediatric patients were aged 1 to 8 years and received 4 mg/kg monthly intramuscular dose of fulvestrant. The geometric mean (standard deviation) steady state trough concentration (Cmin,ss) and AUCss was 4.2 (0.9) ng/mL and 3680 (1020) ng*hr/mL, respectively. Although the data collected were limited, the steady-state trough concentrations of fulvestrant in children appear to be consistent with those in adults.

 

Section 10

 

Date of Revision changed to 29^th July 2011

Section 4.2

Changed text:

Paediatric population

The safety and efficacy of Faslodex in children from birth to 18 years of age have not been established. No data are available.

 

Section 4.6

Changed text including information regarding Fertility

 

Section 4.8

Additional adverse event frequency under ‘General disorders and administration site conditions’ – Uncommon: Injection site haemorrhage, injection site haemotoma

 

Additional footnote ‘b’ under table

Section 5.1

Endocrine therapy added to Pharmacotherapeutic group

 

Additional and change of text and table 2 throughout section.

 

Section 5.3

Additional text:

Arteritis involving a range of different tissues was seen in some dogs after chronic (12 months) dosing.

Section 10

Revision date of text: 25 October 2010

Section 4.8

Change of format of table

 

Section 6.5

Additional text

A safety needle (BD SafetyGlide™) for connection to the barrel is also provided.

Or

Two clear type 1 glass pre-filled syringes with polystyrene plunger rod, fitted with a tamper‑evident closure, each containing 5 ml Faslodex solution for injection. Safety needles (BD SafetyGlide™) for connection to each barrel are also provided.

Not all pack sizes may be marketed.

Section 8

Additional MA number

EU/1/03/269/002

 

Section 10

Date of revision of text: 9 April 2010

Section 1

Change of text from 250mg/5ml to:

Faslodex 250 mg solution for injection.

Section 3

Change of text from ‘viscous liquid’ to ‘viscous solution’

Clear, colourless to yellow, viscous solution

 

Section 4.2

Change of text to Posology first paragraph:

from

The recommended dose is 250 mg at intervals of 1 month

to

The recommended dose is 500 mg at intervals of one month, with an additional 500 mg dose given two weeks after the initial dose.

 

Change of text to last paragraph of section:

 

Faslodex should be administered as two consecutive 5 ml injections by slow intramuscular injection (1-2 minutes/injection), one in each buttock.

For detailed instructions for administration, see section 6.6.

Section 4.6

Additional text:

Faslodex is contraindicated in pregnancy (see section 4.3). Fulvestrant has been shown to cross the placenta after single intramuscular doses in rat and rabbit. Studies in animals have shown reproductive toxicity including an increased incidence of foetal abnormalities and deaths (see section 5.3). Patients of child-bearing potential should be advised to use effective contraception while on treatment. If pregnancy occurs while taking Faslodex, the patient must be informed of the potential hazard to the foetus and potential risk for loss of pregnancy.

Breast-feeding must be discontinued during treatment with Faslodex. Fulvestrant is excreted in milk in lactating rats. It is not known whether fulvestrant is excreted in human milk. Considering the potential for serious adverse reactions due to fulvestrant in breast-fed infants, use during lactation is contraindicated (see section 4.3).

 

Section 4.7

Faslodex has no or negligible influence on the ability to drive or use machines. However, since asthenia has been reported very commonly with Faslodex, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery.

Section 4.8

Change of text.

Change of format of table.

 

 

Section 4.9

Change of text:

There is no human experience of overdose. Animal studies suggest that no effects other than those related directly or indirectly to anti-oestrogenic activity were evident with higher doses of fulvestrant (see section 5.3). If overdose occurs, symptomatic supportive treatment is recommended.

 

Section 5.1

Additional text under heading ‘Clinical safety and efficacy in advanced breast cancer’

Addition of table

 

Section 5.2

 

Change of text in first paragraph under ‘Absorption’ heading

And

Change of text in second paragraph under ‘Absorption’ heading

After intramuscular administration, the exposure is approximately dose proportional in the dose range 50 to 500 mg.

Additional text under ‘Elimination’ heading

Fulvestrant is eliminated mainly in metabolised form. 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. The terminal half-life (t1/2) after intramuscular administration is governed by the absorption rate and was estimated to be 50 days.

 

Change of text to last section heading ‘Hepatic impairment’

 

The pharmacokinetics of fulvestrant has been evaluated in a single-dose clinical trial conducted in subjects with mild to moderate hepatic impairment (Child-Pugh class A and B). A high dose of a shorter duration intramuscular injection formulation was used.  There was up to about 2.5-fold increase in AUC in subjects with hepatic impairment compared to healthy subjects. In patients administered Faslodex, an increase in exposure of this magnitude is expected to be well tolerated. Subjects with severe hepatic impairment (Child-Pugh class C) were not evaluated.

 

Section 6.4

Additional text:

Store the pre-filled syringe in the original package in order to protect from light

 

Section 6.5

Change of text to whole section.

 

Section 6.6

Change to whole section including layout of diagrams

 

 

Section 10

Revision date of text: 16 March 2010

Section 4.2 -  under the heading "Patients with hepatic impairment." -Change of text to read:  "No dose adjustments are recommended for patients with mild to moderate hepatic impairment.  However, as fulvestrant exposure may be increased, Faslodex should be used with caution in these patients.  There are no data in patients with severe hepatic impairment (see 4.3, 4.4 and 5.2)."

 

Section 5.2 - under the heading "Hepatic impairment" - change of text and new text to read: "The phamacokinetics of fulvestrant has been evaluated in a single-dose clinical trial conducted in subjects with Child-Pugh category A and B hepatic impairment due to cirrhosis.  A high dose of a short duration intramuscular injection formulation was used.  There was up to about 2.5 fold increase in AUC in subject with hepatic impairment compared to healthy subjects.  In patients administered Faslodex, an increase in exposure of this magnitude is expected to be well tolerated.  Child-Pugh category C subjects were not evaluated.

 

Section 10: Date of Revision of Text - 9th November 2006"