Fulvestrant
Fulvestrant
Generic Name
Fulvestrant
Mechanism
- Estrogen receptor (ER) antagonism: Binds to the ligand‑binding domain of the ERα with high affinity, blocking estrogen from exerting proliferative signals.
- Receptor degradation: Induces conformational change and recruitment of the ubiquitin‑proteasome machinery, leading to accelerated ER degradation and decreased receptor density.
- Down‑regulation of ER‑target genes: Suppresses transcription of estrogen‑responsive genes, reducing tumor cell proliferation and survival.
- Synergy with PI3K/AKT/mTOR pathway inhibitors: By reducing ER signaling, fulvestrant enhances sensitivity to agents targeting downstream pathways.
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Pharmacokinetics
| Parameter | Detail | |
| Absorption | Delayed‑release intramuscular (IM) formulation; peak plasma concentration (Cmax) at ~24 h post‑injection. | |
| Distribution | Highly protein‑bound (~99 % to albumin). Extensive tissue distribution, particularly in bone and adipose tissue. | |
| Metabolism | Hepatic via CYP3A4/5 → glucuronidated metabolites. Minimal active metabolites. | |
| Elimination | Excreted primarily in feces (≈70 %) and urine (≈10 %). Half‑life ≈18 days, permitting monthly dosing. | |
| Drug interactions | Strong CYP3A4 inducers (e.g., rifampin) may lower exposure; no clinically relevant CYP3A4 inhibitors. |
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Indications
- Stage IV or metastatic, ER‑positive/HER2‑negative breast cancer in post‑menopausal women who have progressed on prior aromatase inhibitor (AI) therapy.
- Can be used as first‑line endocrine therapy in selected patients not suitable for tamoxifen.
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Contraindications
| Contraindication | Warning |
| Known hypersensitivity to fulvestrant or any excipient. | Liver disease: Fulvestrant is hepatically metabolized; monitor liver function tests (LFTs). |
| Pregnant or lactating women. | Injection site reactions: Persistent pain, swelling, or abscess formation. |
| Drug‑induced agranulocytosis (rare). | |
| Potential interactions with agents requiring CYP3A4 monitoring. |
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Dosing
- Initial series: 500 mg IM in the gluteal muscle on days 1, 15, 29, and 57 of the first cycle.
- Maintenance: 500 mg IM every 28 days thereafter.
- Route: Delayed‑release formulation; ensure proper mixing before injection.
- Adjuncts: Concomitant use of a SERM or AI is not recommended for patients with fulvestrant monotherapy.
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Adverse Effects
| Adverse Effect | Frequency | Notes |
| Injection site pain, erythema, swelling | ≥ 30 % | Use topical analgesics; switch site if worsening. |
| Fatigue, arthralgia | 15–20 % | Symptomatic treatment; avoid overexertion. |
| Nausea, diarrhea | < 10 % | Antiemetic/antidiarrheal as needed. |
| Transient hepatotoxicity (↑AST/ALT) | 5–7 % | Baseline and periodic LFTs. |
| Rare: hypersensitivity, anaphylaxis | < 1 % | Immediate discontinuation and emergency care. |
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Monitoring
- Baseline: CBC, CMP, LFTs, serum estradiol.
- During therapy:
- LFTs at weeks 4, 8, 12, then every 3 months.
- CBC monthly for early detection of agranulocytosis.
- Assess tumor response via imaging every 3–6 months.
- Monitor bone‑density if concomitant bisphosphonate therapy is present.
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Clinical Pearls
- Rapid ER depletion caused by fulvestrant makes it uniquely effective post‑AI failure; consider it earlier in the endocrine sequence for patients with limited options.
- IM injection technique matters: use an orifice (5 mm) to avoid pain; rotating injection sites reduces local inflammation.
- Fulvestrant + CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) is standard of care; the combination improves progression‑free survival by > 9 months.
- Avoid “drug holidays”: due to its long half‑life, cessation leads to rebound estrogen activity; continue monthly dosing without interruption.
- Elderly patients: renally compromised? No dose adjustment needed, but monitor for constipation.
- Non‑responders: Lack of tumor regression within 12 weeks is a trigger to switch therapy; consider alternative endocrine or chemotherapy.
- Pharmacogenomics: CYP3A4*22 allele may elevate exposure; consider dose reduction in susceptible individuals, though data are still evolving.
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• *References: European Medicines Agency, FDA labeling (2010‑2023), and UpToDate® (2025).*