What Is Faslodex (Fulvestrant)? FDA Approval, Turkish Authorization, and Reimbursement

• FDA Approved: Yes (initial approval: April 25, 2002)
• Product Name: Faslodex
• Active Ingredient: Fulvestrant
• Administration: Intramuscular (IM) injection
• Class: Endocrine therapy, estrogen receptor antagonist
• Category: Targeted hormonal agent
• Manufacturer: AstraZeneca
• Distribution in Turkey: AstraZeneca İlaç San. ve Tic. A.Ş.
• Approved Cancer Indications:
  • Metastatic breast cancer:
    1. For postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced breast cancer who have not previously received endocrine therapy.
    2. As endocrine treatment for postmenopausal women with HR-positive metastatic breast cancer that progresses after endocrine therapy.
    3. With palbociclib or abemaciclib for women with HR-positive, HER2-negative advanced or metastatic breast cancer progressing after endocrine therapy.
    4. With ribociclib for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or after progression on endocrine therapy.

What Is Faslodex?

Faslodex contains fulvestrant, an estrogen receptor antagonist for metastatic or advanced HR-positive, HER2-negative breast cancer. It is particularly used in postmenopausal patients responding to or progressing after endocrine treatment, alone or with CDK 4/6 inhibitors.

What Are Estrogen Receptor Antagonists?

These medicines prevent estrogen from binding cancer cell receptors, stopping growth. Because some breast cancer cells depend on estrogen, the medicines help slow progression.

Authorization in Turkey

The authorized therapeutic indications in Turkey are stated as follows:

For HR-positive, HER2-negative disease:

• Postmenopausal locally advanced or metastatic breast cancer without previous endocrine therapy; 
• Postmenopausal breast cancer recurring during or after antiestrogen treatment for adjuvant or metastatic disease; 
• With a CDK 4/6 inhibitor for postmenopausal locally advanced or metastatic breast cancer without previous endocrine therapy; 
• With a CDK 4/6 inhibitor for postmenopausal locally advanced or metastatic breast cancer after previous endocrine therapy.

Is Faslodex Reimbursed?

SGK, Turkey's Social Security Institution, covers the following situations:

• Combination with ribociclib or palbociclib is reimbursed for clinical and/or radiological progression after more than 6 months of first-line aromatase inhibitor treatment for recurrent/metastatic breast cancer. Coverage does not apply after previous fulvestrant, relapse within the first 12 months of adjuvant aromatase inhibitor treatment, or more than one aromatase inhibitor line for metastatic disease.
• Combination with ribociclib or palbociclib is reimbursed for recurrence/metastasis during adjuvant aromatase inhibitor treatment after at least 12 months of therapy, or within 12 months after completion. Coverage does not apply after previous fulvestrant, relapse within the first 12 months of adjuvant aromatase inhibitor therapy, or more than one aromatase inhibitor line for metastatic disease.

Faslodex on the List of Off-Label Medicines Usable Without Additional TİTCK Approval

• For HR-positive locally advanced or metastatic breast cancer recurring during or after endocrine therapy with tamoxifen or an aromatase inhibitor (anastrozole, exemestane, or letrozole), coverage applies to pre-, peri-, or postmenopausal patients, whether menopause is natural or induced. Any specialist may prescribe based on a medical board report specifying the protocol and including at least one medical oncologist.
• For recurrent/metastatic breast cancer in pre-, peri-, or postmenopausal patients with estrogen receptor positivity of at least 10% and human epidermal growth factor receptor 2 (HER-2)-negative disease, SGK coverage follows the criteria below. A medical oncologist must prescribe based on a board report valid for at most 6 months and including at least one medical oncologist.
  • Combination with ribociclib or palbociclib is reimbursed for clinical and/or radiological progression after more than 6 months of first-line aromatase inhibitor treatment for recurrent/metastatic breast cancer. Coverage does not apply after previous fulvestrant, relapse within the first 12 months of adjuvant aromatase inhibitor treatment, or more than one aromatase inhibitor line for metastatic disease.
  • Combination with ribociclib or palbociclib is reimbursed for recurrence/metastasis during adjuvant aromatase inhibitor treatment after at least 12 months of therapy, or within 12 months after completion. Coverage does not apply after previous fulvestrant, relapse within the first 12 months of adjuvant aromatase inhibitor therapy, or more than one aromatase inhibitor line for metastatic disease.

Price: Faslodex 250 mg costs 8,299.42 TL. 

Mechanism of Action

• Fulvestrant binds estrogen receptors with high affinity, acting as an antagonist without agonist activity.
• It reduces ER expression and the number of intracellular receptors, blocking estrogen signaling.
• It inhibits estrogen-dependent tumor growth and proliferation.
• With CDK4/6 inhibitors, it promotes cell-cycle arrest and apoptosis, thereby preventing cancer cells from developing resistance.

FDA (US Food and Drug Administration) Approval History

• April 25, 2002:
  • AstraZeneca received approval for Faslodex in tamoxifen-resistant metastatic breast cancer.
• September 13, 2010:
  • A new dosage regimen was approved for HR-positive metastatic breast cancer in postmenopausal women.
• August 28, 2017:
  • Monotherapy was approved for HR-positive, HER2-negative advanced breast cancer.
• November 15, 2017:
  • Faslodex was approved with abemaciclib for advanced breast cancer.

Resistance Mechanisms

• Reduced Estrogen Receptor Expression:
  • Cancer cells may reduce estrogen receptor levels to resist treatment, leaving fewer receptors for fulvestrant to target.
• Reduced G Protein-Coupled Estrogen Receptor 1 (GPER) Expression:
  • GPER is an alternative receptor involved in estrogen signaling. Reduced expression may decrease the effectiveness of fulvestrant, an estrogen receptor antagonist.
• Increased Cell Division Protein Kinase 6 (CDK6) Expression:
  • Increased CDK6 may alter cell-cycle regulation, contributing to growth and treatment resistance.
• Increased Growth Factor Receptors:
  • Cancer cells may overexpress EGFR (epidermal growth factor receptor) or HER2/neu, activating alternative signaling to bypass fulvestrant.

These mechanisms may reduce effectiveness over time and require combinations with CDK 4/6 inhibitors or other targeted treatments in some patients.

Pharmacokinetics

• Absorption 
  • Fulvestrant is not absorbed orally. After IM injection, peak plasma levels occur within approximately 7 days and persist for at least 1 month.
• Distribution 
  • It distributes rapidly and extensively throughout the body, with approximately 99% bound to plasma proteins. The main binding proteins are described as very-high-density lipoprotein (VHDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
• Metabolism:
  • Liver microsomal CYP3A4 enzymes metabolize fulvestrant to active and inactive metabolites.
    • Steady-state levels are achieved 7 days after monthly injection and maintained for at least 1 month.
    • The main elimination route is hepatobiliary excretion in feces, approximately 90%.
    • Only 1% is eliminated through the kidneys.
    • The half-life is approximately 40 days.
• Dosage Range 
  • The recommended dose alone or in combination is:
    • Administer 500 mg as an intramuscular (IM) injection on days 1, 14, and 28, then continue every 28 days.
  • 2. Moderate hepatic impairment (Child-Pugh B):
    • Administer 250 mg intramuscularly (IM) on days 1, 14, and 28, then continue every 28 days.
  • No adjustment is needed for renal impairment.

Drug Interactions 

No clear, well-characterized interaction has been reported. Because fulvestrant is metabolized by CYP3A4, interactions with strong CYP3A4 inducers or inhibitors are theoretically possible; their clinical significance is not fully established.

Precautions

• No adjustment is required in renal impairment.
• No adjustment is needed for mild hepatic impairment. For moderate impairment (Child-Pugh B), 250 mg IM is recommended on days 1, 14, and 28, then monthly. Safety and efficacy have not been studied in severe impairment (Child-Pugh C).
• Use cautiously with bleeding diathesis, thrombocytopenia, or anticoagulants.
• Fulvestrant may interfere with serum estradiol immunoassays, producing falsely elevated results.
• Pregnancy category D: It may harm the fetus. Breastfeeding is not recommended because transfer into human milk is unknown.

Side Effects 

• Asthenia (Weakness):
  • Asthenia, including fatigue and weakness, may occur in up to 25% of patients receiving fulvestrant.
• Gastrointestinal Effects:
  • Mild nausea, vomiting, constipation, and/or diarrhea may occur.
• Vasomotor Symptoms:
  • Hot flashes have been reported in 20%.
• Headache:
  • Some patients may experience mild headache.
• Injection-Site Reactions:
  • IM administration may cause mild local pain and inflammation. These reactions are generally temporary.
• Musculoskeletal Effects:
  • Back pain and joint pain (arthralgia) may occur. Some patients develop a flu-like syndrome with fever, weakness, and muscle pain (myalgia), observed in approximately 10%.
• Skin Reactions:
  • Dry, flaky rash is uncommon.