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fulvestrant

( FULL-ves-trant )
Funding:
ODB - General Benefit
  • fulvestrant
Other Name(s): Faslodex®
Appearance: Clear, colourless to yellow liquid in pre-filled syringes for injection
A - Drug Name

fulvestrant

COMMON TRADE NAME(S):   Faslodex®

 
B - Mechanism of Action and Pharmacokinetics

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.



Absorption

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


Distribution

Fulvestrant is subject to extensive and rapid distribution, which is largely extravascular.

Cross blood brain barrier?

No information

PPB

99% (lipoproteins)

Metabolism

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

Elimination

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)

 
C - Indications and Status
Health Canada Approvals:

  • For the hormonal treatment of locally advanced or metastatic breast cancer in postmenopausal women, regardless of age, who have disease progression following prior anti-estrogen therapy.
  • For the treatment of estrogen receptor-positive, human epidermal growth receptor 2 (HER2) negative locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy


 
D - Adverse Effects

Emetogenic Potential:  

Not applicable

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.

 
E - Dosing

Refer to protocol by which patient is being treated.



Adults:

Intramuscular: 500 mg on day 1, 15, 29 (loading dose) and then every 28 days

Dosage with Toxicity:

Toxicity
Action
Hypersensitivity

Consider discontinuing if severe.

Mild hepatotoxicity

Hold until recovery and then restart.

Moderate to severe hepatotoxicity

Discontinue.


Dosage with Hepatic Impairment:

Fulvestrant is metabolized primarily in the liver. There are no efficacy and safety data in patients with breast cancer and hepatic impairment. Decreased clearance (by 2.2 fold) and changes in exposure (↑ 70%) were observed in women with moderate hepatic impairment compared to patients with normal hepatic function.
 
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.


Dosage with Renal Impairment:

Creatinine Clearance (mL/min) Fulvestrant Dose
≥ 30 No dosage adjustment required.
< 30 Use with caution; no data.


Dosage in the elderly:

No dosage adjustment required.



Children:

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



 
F - Administration Guidelines

  • 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.


 
G - Special Precautions
Contraindications:

  • Patients with known hypersensitivity to the drug or to any of the formulation or container
  • Pregnant and breastfeeding women

Other Warnings/Precautions:

  • 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.

Pregnancy and Lactation:
  • 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.

 
H - Interactions

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. 

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

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

 



Suggested Clinical Monitoring

Monitor Type Monitor Frequency
Renal function tests Baseline and repeat as clinically indicated
 
J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

  • fulvestrant

 
K - References

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.


November 2020 Updated monitoring section

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.