Usage
Fulvestrant is prescribed for the treatment of Hormone Receptor (HR)-positive, Human Epidermal Growth Factor Receptor 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal women. It is used in several contexts:
- As initial endocrine-based therapy for women who have not received prior endocrine therapy for advanced or metastatic breast cancer.
- Following disease progression on or after endocrine therapy.
- In combination with other targeted therapies, such as palbociclib, abemaciclib, or ribociclib, for women whose disease has progressed after endocrine therapy.
It is classified as a selective estrogen receptor degrader (SERD) or estrogen receptor antagonist. Fulvestrant works by binding to estrogen receptors in breast cancer cells, preventing estrogen from binding and activating these receptors. It also promotes the degradation (breakdown) of these receptors, further inhibiting the growth of estrogen-dependent breast cancer cells.
Alternate Names
The International Nonproprietary Name (INN) is fulvestrant. A popular brand name is Faslodex®.
How It Works
Pharmacodynamics: Fulvestrant competitively binds to estrogen receptors (ER) with an affinity comparable to estradiol. It downregulates ER protein levels by increasing the rate of ER turnover and degradation. This ultimately reduces the number of ER available in cancer cells to stimulate growth, leading to tumor regression.
Pharmacokinetics:
- Absorption: Following intramuscular injection, fulvestrant is absorbed slowly, reaching maximum plasma concentration (Cmax) in about 7 days.
- Distribution: Fulvestrant is highly lipophilic and distributes extensively throughout the body, with high concentrations found in tissues such as the liver, lungs, and kidneys. It has a high volume of distribution, indicating significant extravascular penetration.
- Metabolism: Fulvestrant undergoes extensive metabolism, primarily through oxidation and conjugation. Although CYP3A4 is involved in its metabolism, co-administration with CYP3A4 inhibitors or inducers does not necessitate dose adjustments.
- Elimination: Fulvestrant is eliminated primarily via the hepatobiliary route, with a small portion excreted in the urine. The elimination half-life is approximately 50 days, reflecting slow release from fatty tissues.
Mode of Action: At the molecular level, fulvestrant binds to the ER, inducing a conformational change that prevents the receptor from dimerizing and binding to DNA. This inhibits estrogen-mediated gene transcription and ultimately suppresses tumor growth. Fulvestrant also targets the ER for degradation by the ubiquitin-proteasome pathway.
Dosage
Standard Dosage
Adults:
The standard dosage is 500 mg (two 250 mg/5 mL injections) administered intramuscularly (IM), one injection into each buttock. The initial dose is given on days 1, 15, and 29, followed by monthly injections thereafter.
Children:
Fulvestrant is not recommended for use in children. Safety and efficacy in pediatric patients have not been established.
Special Cases:
- Elderly Patients: No dosage adjustment is necessary based on age alone.
- Patients with Renal Impairment: No dosage adjustment is needed for patients with creatinine clearance ≥30 mL/min. Caution is advised in patients with creatinine clearance <30 mL/min, as there is limited data.
- Patients with Hepatic Dysfunction: For patients with moderate hepatic impairment (Child-Pugh B), the recommended dosage is 250 mg IM monthly. Fulvestrant is not recommended in patients with severe hepatic impairment (Child-Pugh C).
- Patients with Comorbid Conditions: Use with caution in patients with bleeding diatheses or thrombocytopenia due to the IM route of administration.
Clinical Use Cases
Fulvestrant is not indicated for use in acute clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary role is in the long-term management of advanced or metastatic breast cancer.
Dosage Adjustments
Dose adjustments may be necessary based on hepatic function as described above. No dose adjustments are required for concomitant use with CYP3A4 inhibitors or inducers.
Side Effects
Common Side Effects:
- Injection site pain
- Nausea
- Vomiting
- Fatigue
- Hot flashes
- Musculoskeletal pain (joint and muscle pain, back pain)
- Headache
- Diarrhea
- Constipation
- Elevated liver enzymes
Rare but Serious Side Effects:
- Hypersensitivity reactions (e.g., urticaria, angioedema)
- Liver dysfunction (including fatal hepatic failure)
- Sciatica, neuralgia, or peripheral neuropathy related to injection site
- Increased risk of thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism)
- Osteoporosis
Long-Term Effects:
Potential long-term effects include osteoporosis and ongoing risk of injection site reactions.
Adverse Drug Reactions (ADR):
Clinically significant ADRs primarily involve hypersensitivity reactions and liver dysfunction, requiring prompt medical attention.
Contraindications
- Hypersensitivity to fulvestrant or any component of the formulation
- Pregnancy and breastfeeding
Drug Interactions
While fulvestrant is not significantly metabolized by CYP3A4, it’s important to be aware of potential interactions. Clinically significant interactions are limited. Fulvestrant may interfere with antibody-based estradiol assays, leading to falsely elevated results. Etrasimod and siponimod increase the risk of infection when co-administered with fulvestrant. Mitapivat decreases fulvestrant levels.
Pregnancy and Breastfeeding
Fulvestrant is contraindicated in pregnancy and breastfeeding. It can cause fetal harm and is excreted in breast milk. Effective contraception should be used during treatment and for 2 years after the last dose. Breastfeeding is not recommended during treatment and for 1 year after the last dose.
Drug Profile Summary
- Mechanism of Action: SERD that binds to and degrades estrogen receptors, inhibiting estrogen-dependent breast cancer cell growth.
- Side Effects: Common: Injection site pain, nausea, fatigue, hot flashes, musculoskeletal pain. Serious: Hypersensitivity, liver dysfunction, thromboembolic events.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding.
- Drug Interactions: Limited clinical interactions. Interference with estradiol assays, increased infection risk with etrasimod/siponimod.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 500 mg IM on days 1, 15, and 29, then monthly. Adjust for moderate hepatic impairment.
- Monitoring Parameters: Liver function tests, signs of hypersensitivity, thromboembolic events.
Popular Combinations
Fulvestrant is commonly combined with CDK4/6 inhibitors such as:
- Palbociclib: For HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy.
- Abemaciclib: Similar indication to palbociclib.
- Ribociclib: For HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women as initial endocrine-based therapy or following disease progression on endocrine therapy.
These combinations provide synergistic antitumor activity.
Precautions
- General Precautions: Assess for hypersensitivity, hepatic dysfunction, bleeding disorders.
- Specific Populations: Contraindicated in pregnancy and breastfeeding. Caution in patients with renal impairment.
- Lifestyle Considerations: Alcohol may exacerbate hot flashes.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Fulvestrant?
A: 500 mg IM on days 1, 15, and 29, and then monthly thereafter. 250 mg IM monthly for patients with moderate hepatic impairment.
Q2: What is the mechanism of action of Fulvestrant?
A: Fulvestrant is a SERD that binds to estrogen receptors, leading to their degradation and preventing estrogen from stimulating cancer cell growth.
Q3: What are the most common side effects of Fulvestrant?
A: Injection site reactions, nausea, hot flashes, fatigue, musculoskeletal pain, and headache.
Q4: Is Fulvestrant safe during pregnancy or breastfeeding?
A: No, Fulvestrant is contraindicated during pregnancy and breastfeeding due to potential fetal harm and excretion in breast milk.
Q5: How is Fulvestrant administered?
A: Intramuscular injection into the buttock (gluteal area), one injection in each buttock.
Q6: What monitoring is required during Fulvestrant treatment?
A: Regular monitoring of liver function tests and vigilance for signs of hypersensitivity reactions or thromboembolic events.
Q7: Are there any drug interactions with Fulvestrant?
A: Some drugs may interact with fulvestrant: etrasimod, siponimod, mitapivat. It can also interfere with estradiol assays.
Q8: What are the contraindications for Fulvestrant use?
A: Known hypersensitivity to fulvestrant, pregnancy, and breastfeeding.
Q9: Can Fulvestrant be used in premenopausal women?
A: Fulvestrant is primarily used in postmenopausal women. In premenopausal women, it may be used in combination therapy with LHRH agonists.
Q10: How should Fulvestrant be stored?
A: Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original package. Protect from light. Do not freeze.
