Introduction
Fulvestrant is a selective estrogen receptor downregulator (SERD) used in the treatment of hormone receptor-positive advanced breast cancer in postmenopausal women. Marketed under the brand name Faslodex®, it represents an important endocrine therapy option for patients who have progressed on prior antiestrogen therapy. Unlike other endocrine agents, fulvestrant lacks agonist activity and functions as a pure estrogen receptor antagonist.
Mechanism of Action
Fulvestrant competitively binds to estrogen receptors (ER) with an affinity similar to estradiol. Unlike selective estrogen receptor modulators (SERMs), fulvestrant has no agonist effects. Its mechanism involves:
- Blocking estrogen binding to ERα and ERβ receptors
- Accelerating degradation of estrogen receptors
- Reducing cellular ER concentration by approximately 50%
- Inhibiting estrogen-dependent gene transcription
This results in complete abrogation of estrogen receptor signaling, making it particularly effective in tumors that may have developed resistance to other endocrine therapies.
Indications
FDA-approved indications include:
- Treatment of hormone receptor (HR)-positive, HER2-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy
- Treatment of HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy
- In combination with palbociclib or abemaciclib for women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy
Dosage and Administration
Standard dosing: 500 mg intramuscularly (IM) on days 1, 15, 29, and once monthly thereafter Administration:- Administer as two 5 mL injections (250 mg each) or one 10 mL injection (500 mg)
- Give slowly intramuscularly into the buttocks
- Alternate buttocks for subsequent injections
- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Mild to moderate impairment requires no adjustment; use caution in severe impairment
- Elderly patients: No dosage adjustment required
Pharmacokinetics
Absorption: Slow and limited following IM administration; peak concentrations reached in approximately 7 days Distribution: Extensive tissue distribution; volume of distribution approximately 3-5 L/kg; highly bound to plasma proteins (99%) Metabolism: Extensive hepatic metabolism via multiple pathways similar to endogenous steroids, including CYP3A4 Elimination: Primarily hepatobiliary excretion; terminal half-life approximately 40 days; steady-state concentrations achieved after 3-6 months of monthly dosingContraindications
- Hypersensitivity to fulvestrant or any component of the formulation
- Pregnancy or women who may become pregnant (Pregnancy Category X)
- Patients with bleeding diatheses or thrombocytopenia
- Patients receiving anticoagulant therapy (relative contraindication due to IM administration)
Warnings and Precautions
- Injection site reactions: May include pain, inflammation, and rarely, nerve injury
- Hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment
- Blood dyscrasias: Monitor blood counts periodically
- Thromboembolic events: Increased risk of venous thromboembolism
- Osteoporosis: May accelerate bone loss; monitor bone density
- Elevated liver enzymes: Transaminase elevations observed in clinical trials
Drug Interactions
Strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): May decrease fulvestrant concentrations; avoid concomitant use CYP3A4 inhibitors: No clinically significant interactions expected Anticoagulants: Increased risk of bleeding and hematoma formation at injection sitesAdverse Effects
Common (≥10%):- Injection site pain (27%)
- Nausea (26%)
- Fatigue (19%)
- Arthralgia (18%)
- Hot flashes (18%)
- Headache (15%)
- Back pain (14%)
- Constipation (13%)
- Vomiting (12%)
- Dyspnea (16%)
- Venous thromboembolism (1-2%)
- Elevated liver enzymes (5-7%)
- Hematoma at injection site
- Peripheral sensory neuropathy
- Anaphylactoid reactions (rare)
Monitoring Parameters
- Clinical response and disease progression assessment every 2-3 months
- Liver function tests at baseline and periodically during treatment
- Complete blood count periodically
- Bone density assessment in patients receiving long-term therapy
- Signs and symptoms of thromboembolic events
- Injection sites for reactions, hematomas, or infections
- Pain assessment and management
Patient Education
- Explain the purpose and expected benefits of treatment
- Inform about the intramuscular administration schedule and need for regular appointments
- Discuss common side effects and management strategies
- Advise to report any signs of injection site problems (pain, redness, swelling)
- Educate about symptoms requiring immediate medical attention (shortness of breath, leg swelling, severe abdominal pain)
- Discuss importance of adherence to the treatment schedule
- Inform about potential effects on bone health and discuss calcium/vitamin D supplementation
- Advise against pregnancy during treatment and use effective contraception
- Provide information on support resources for breast cancer patients
References
1. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997-3005. 2. Di Leo A, 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):4594-4600. 3. Faslodex® (fulvestrant) prescribing information. AstraZeneca Pharmaceuticals LP; 2021. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2022. 5. Howell A, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20(16):3396-3403. 6. Cardoso F, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol. 2018;29(8):1634-1657.