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fulvestrant
Fulvestrant is a competitive estrogen receptor antagonist that blocks the trophic action of estrogen without any partial agonist activity. Fulvestrant inhibits the growth of tamoxifen-resistant breast cancer cells; however, fulvestrant-resistant breast tumors may be cross-resistant to tamoxifen.
After a long-acting intramuscular injection, plasma concentrations are maintained over a period of at least one month, with trough concentration about one-third of Cmax.
| Time to reach steady state |
Within 1st month of 500mg loading doses on days 1, 15, and 29 |
Fulvestrant is subject to extensive and rapid distribution, which is largely extravascular.
| Cross blood brain barrier? |
No information |
| PPB |
99% (lipoproteins) |
Metabolism of fulvestrant appears similar to those of endogenous steroids, including oxidation, aromatic hydroxylation, and conjugation. Cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant.
| Active metabolites |
Yes |
| Inactive metabolites |
Yes |
Fulvestrant is rapidly cleared by the hepatobiliary route. Excretion is primarily via the feces. Renal elimination is negligible.
| Feces |
~ 90% |
| Urine |
< 1% |
| Half-life |
40 days (apparent) |
- Breast cancer
Refer to the product monograph for a full list of approved indications.
Emetogenic Potential:
Extravasation Potential: None
The following side effects are from the fulvestrant 500mg arms of randomized controlled trials in patients with prior anti-estrogen therapy. It also includes severe, life-threatening or post-marketing adverse events from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial/venous thromboembolism (1%) | E | |||
| Hypertension (4%) | E | ||||
| Gastrointestinal | Anorexia (6%) | I E | |||
| Diarrhea (5%) | I E | ||||
| Nausea, vomiting (10%) | I E | ||||
| General | Fatigue (10%) | E | |||
| Hematological | Myelosuppression ± infection, bleeding (<10%) (mostly thrombocytopenia) | D | |||
| Hepatobiliary | ↑ LFTs (14%) (may be severe) | E | |||
| Hypersensitivity | Hypersensitivity (rare) | I E | |||
| Injection site | Injection site reaction (14%) (may be severe) | I E | |||
| Musculoskeletal | Musculoskeletal pain (7%) | E | |||
| Osteoporosis (<1%) | D | ||||
| Other (19%) (joint disorder) | D | ||||
| Nervous System | Headache (8%) | E | |||
| Reproductive and breast disorders | Estrogen deprivation symptoms (9%) | E | |||
| Respiratory | Cough (6%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for fulvestrant include joint disorders, ↑ LFTs, injection site reaction, fatigue, nausea and vomiting.
Injection site reactions with mild transient pain and inflammation were seen with fulvestrant. They may occur even after previous uneventful injections; systemic allergic response (e.g. widespread urticaria) has been reported to develop with time. More severe injection site reactions, including sciatica, neuralgia and peripheral neuropathy have also been reported when using dorsogluteal injections.
Hypersensitivity may occur shortly after injection; a case of angioedema has been reported several days after injection.
Increases in LFTs and bilirubin have been commonly reported with fulvestrant, and may rarely be fatal. Discontinuation of treatment resulted in improvements in some cases. In a retrospective analysis, 1% of cases met the criteria for Hy's Law.
Due to fulvestrant’s mechanism of action, there is a risk of osteoporosis; however, this data was not collected in the long-term follow-up of the CONFIRM trial.
Refer to protocol by which patient is being treated.
|
Toxicity
|
Action
|
|
Hypersensitivity
|
Consider discontinuing if severe. |
|
Mild hepatotoxicity
|
Hold until recovery and then restart. |
|
Moderate to severe hepatotoxicity |
Discontinue.
|
| Hepatic Impairment | Fulvestrant Dose |
|
Mild to Moderate (Child-Pugh Class A or B) |
Use with caution. No dose adjustment required. |
|
Severe (Child-Pugh Class C) |
Not studied. Use not recommended. |
| Creatinine Clearance (mL/min) | Fulvestrant Dose |
| ≥ 30 | No dosage adjustment required. |
| < 30 | Use with caution; no data. |
No dosage adjustment required.
Not recommended for use in children or adolescents as safety and effectiveness have not been established in this age group.
- Each dose consists of 2 pre-filled syringes (250 mg/5mL). Administer each pre-filled syringe as SLOW intramuscular injection (1-2 minutes per injection) into EACH buttock.
- Caution should be taken due to proximity of the sciatic nerve and large blood vessels.
- Administer according to local guidelines at the Cancer Centre or physician's office.
- Store refrigerated at 2 to 8°C in original package.
- Patients with known hypersensitivity to the drug or to any of the formulation or container
- Pregnant and breastfeeding women
- Due to the route of administration, use with caution in patients with bleeding disorders or on anticoagulants.
- Exercise caution when driving or operating machinery due to fatigue.
- There is a potential osteoporosis risk due to fulvestrant's mechanism of action.
-
Mutagenicity:
No
-
Teratogenicity:
Yes
-
Fetotoxicity:
Yes
Fulvestrant is contraindicated in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 2 years after the last dose.
-
Breastfeeding:
Contraindicated
-
Fertility effects:
Probable
In animals, fulvestrant caused reversible reduction in female fertility and in embryonic survival, dystocia, fetal abnormalities and loss of sperm.
Fulvestrant does not significantly inhibit any of the major cytochrome P450 (CYP) isoenzymes and has no inhibitory effects on CYP3A4. Although CYP3A4 is involved in the metabolism of fulvestrant, clinical trials have shown that dosage adjustment is not necessary in patients co-prescribed CYP3A4 inhibitors or inducers.
Fulvestrant may interfere with estradiol immunoassay measurements (falsely elevated estradiol levels) due to its structural similarity with estradiol.
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and as clinically indicated |
Clinical assessment of injection site reactions, hypersensitivity, estrogen deprivation symptoms, fatigue, thromboembolism and musculoskeletal effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| Renal function tests | Baseline and repeat as clinically indicated |
Di Leo A, Jerusalem G, Petruzelka L, et al. Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg. San Antonio Breast Cancer Symposium 2012, Oral presentation # S1-4.
Di Leo A, Jerusalem G, Petruzelka L et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol 2010;28(30):4594-600.
Product Monograph: Faslodex® (fulvestrant). AstraZeneca Canada, June 18, 2020.
January 2024 Modified Indications and Dosing sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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