Summary of the safety profile: Monotherapy:
This section provides information based on all adverse reactions from clinical studies, post-marketing studies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequently reported adverse reactions are injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).
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) alone 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 list were based on all reported adverse drug reactions, regardless of the investigator assessment of causality.
The median duration of fulvestrant 500 mg treatment across the pooled dataset (including the studies mentioned previously plus FALCON) was 6.5 months.
List of adverse reactions:
Adverse reactions listed as follows are classified according to frequency and System Organ Class (SOC).
Frequency groupings are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). Within each frequency grouping adverse reactions are reported in order of decreasing seriousness.
Infections and infestations:
Common: Urinary tract infections.
Blood and lymphatic system disorders:
Common: Reduced platelet counte
Immune system disorders:
Very common: Hypersensitivity reactionse
Uncommon: Anaphylactic reactions.
Metabolism and nutrition disorders:
Nervous system disorders:
Very common: Hot flushese
Common: Venous thromboembolisma
Very common: Nausea.
Common: Vomiting, diarrhoea.
Very common: Elevated hepatic enzymes (ALT, AST, ALP)a
Common: Elevated bilirubina
Uncommon: Hepatic failurec,f
, elevated gamma-GTf
Skin and subcutaneous tissue disorders:
Very common: Rashe
Musculoskeletal and connective tissue disorders:
Very common: Joint and musculoskeletal paind
Common: Back paina
Reproductive system and breast disorders:
Common: Vaginal haemorrhagee
Uncommon: Vaginal moniliasisf
General disorders and administration site conditions:
Very common: Astheniaa
, injection site reactionsb
Common: Neuropathy peripherale
Uncommon: Injection site haemorrhagef
, injection site haematomaf
Includes adverse drug reactions for which the exact contribution of fulvestrant cannot be assessed due to the underlying disease.
The term injection site reactions does not include the terms injection site haemorrhage, injection site haematoma, sciatica, neuralgia and neuropathy peripheral.
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 3/560 (where 560 is the number of patients in the major clinical studies), which equates to a frequency category of 'uncommon'.
Includes: arthralgia, and less frequently musculoskeletal pain, myalgia and pain in extremity.
Frequency category differs between pooled safety dataset and FALCON.
ADR was not observed in FALCON.
Description of selected adverse reactions:
The descriptions included as follows are based on the safety analysis set of 228 patients who received at least one (1) dose of fulvestrant and 232 patients who received at least one (1) dose of anastrozole, respectively in the Phase 3 FALCON study.
Joint and musculoskeletal pain:
In the FALCON study, the number of patients who reported an adverse reaction of joint and musculoskeletal pain was 65 (31.2%) and 48 (24.1%) for fulvestrant and anastrozole arms, respectively. Of the 65 patients in the fulvestrant arm, 40% (26/65) of patients reported joint and musculoskeletal pain within the first month of treatment, and 66.2% (43/65) of patients within the first 3 months of treatment. No patients reported events that were CTCAE Grade ≥3 or that required a dose reduction, dose interruption, or discontinued treatment due to these adverse reactions.
[Fulvestrant in indication "combination with palbociclib"]: Combination therapy with palbociclib:
The overall safety profile of fulvestrant when used in combination with palbociclib is based on data from 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer in the randomised PALOMA3 study (see Pharmacology: Pharmacodynamics under Actions). The most common (≥20%) adverse reactions of any grade reported in patients receiving fulvestrant in combination with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anaemia, stomatitis, diarrhoea, and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse reactions were neutropenia, leukopenia, anaemia, infections, AST increased, thrombocytopenia, and fatigue.
The table as follows reports the adverse reactions from PALOMA3.
Median duration of exposure to fulvestrant was 11.2 months in the fulvestrant + palbociclib arm and 4.9 months in the fulvestrant + placebo arm. Median duration of exposure to palbociclib in the fulvestrant + palbociclib arm was 10.8 months. (See table.)
Click on icon to see table/diagram/image
Description of selected adverse reactions: Neutropenia:
In patients receiving fulvestrant in combination with palbociclib in the PALOMA3 study, neutropenia of any grade was reported in 287 (83.2%) patients, with Grade 3 neutropenia being reported in 191 (55.4%) patients, and Grade 4 neutropenia being reported in 37 (10.7%) patients. In the fulvestrant + placebo arm (n=172), neutropenia of any grade was reported in 7 (4.1%) patients, with Grade 3 neutropenia reported in 1 (0.6%) patient. There were no reports of Grade 4 neutropenia in the fulvestrant + placebo arm.
In patients receiving fulvestrant in combination with palbociclib, the median time to first episode of any grade neutropenia was 15 days (range: 13-317) and the median duration of Grade ≥3 neutropenia was 7 days. Febrile neutropenia has been reported in 0.9% patients receiving fulvestrant in combination with palbociclib.