Usage
- Fosfestrol is prescribed for the treatment of advanced prostate cancer in men. It is specifically used in castration-resistant prostate cancer (CRPC) when the disease progresses despite other interventions like orchiectomy, gonadotropin-releasing hormone modulators, and nonsteroidal antiandrogens. It has also been used to prevent the testosterone flare at the start of gonadotropin-releasing hormone agonist therapy.
- Pharmacological classification: Fosfestrol is a synthetic non-steroidal estrogen; antineoplastic agent; hormonal chemotherapy agent.
- Mechanism of Action: Fosfestrol acts as a prodrug of diethylstilbestrol (DES). It is metabolized into DES, which then exerts its effects by binding to estrogen receptors. This leads to a reduction in androgen levels and inhibition of androgen action on prostate cancer cells, slowing their growth.
Alternate Names
- Diethylstilbestrol diphosphate (DESDP)
- Brand name: Honvan
How It Works
- Pharmacodynamics: Fosfestrol, after conversion to DES, acts as an estrogen receptor agonist. It binds to estrogen receptors, reducing the production of androgens like testosterone, thereby hindering the growth of prostate cancer cells that rely on these androgens for growth.
- Pharmacokinetics: Fosfestrol is administered intravenously or orally. Following intravenous administration, it is rapidly distributed and converted to diethylstilbestrol. Oral administration requires a higher dosage due to the first pass effect. DES is metabolized in the liver and is eliminated mainly via hepatic excretion in the bile with some renal excretion. The half life of DES is 20-24 hours
- Mode of Action: Fosfestrol inhibits androgen action on the prostate gland and hormone-induced cancer cell growth. It competitively binds to androgen receptors, forming a drug-receptor complex that inhibits DNA synthesis and cell proliferation.
- Elimination Pathways: The active metabolite DES undergoes hepatic metabolism and is eliminated primarily through biliary excretion, with a smaller proportion excreted renally.
Dosage
Standard Dosage
Adults:
- Intravenous: Initial: 600–1200 mg/day by slow intravenous infusion (over 1 hour) for 5–10 days, followed by 300 mg/day for 10–20 days.
- Intravenous (Maintenance): 300-600 mg, gradually reduced over several months from four times per week to once weekly dosing.
- Oral: Initial: 360–480 mg three times per day.
- Oral (Maintenance): 120-240 mg three times per day; may gradually reduce to 240 mg daily.
Children:
- Fosfestrol is not recommended for use in children.
Special Cases:
- Elderly Patients: Use with caution due to higher risk of adverse effects. Close monitoring is recommended.
- Patients with Renal Impairment: Dose adjustments may be necessary due to slower elimination. Monitor renal function closely.
- Patients with Hepatic Dysfunction: Use with caution as metabolism may be impaired. Close monitoring is recommended.
- Patients with Comorbid Conditions: Particular caution in patients with a history of diabetes, cardiovascular disease, blood clots, or liver problems. Monitor closely for potential exacerbations.
Clinical Use Cases
The dosage guidelines provided above apply to the clinical use of fosfestrol in the management of castration-resistant prostate cancer and the prevention of testosterone flare associated with GnRH agonist therapy. The specific dosage regimen should be tailored to the individual patient’s clinical presentation, treatment response, and tolerance of side effects. Close monitoring and dose adjustments are essential, particularly in elderly patients and those with renal or hepatic impairment.
Dosage Adjustments
- Dose modifications may be necessary based on renal/hepatic dysfunction and other relevant patient-specific factors.
- Consider genetic polymorphisms affecting drug metabolism when making dosage adjustments.
Side Effects
Common Side Effects
- Nausea and vomiting (can be severe)
- Fluid retention, edema
- Gynecomastia (breast enlargement in males)
- Impotence
- Hot flashes
Rare but Serious Side Effects
- Thromboembolic complications (blood clots), including deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction
- Cardiovascular complications
- Hepatic dysfunction
- Hypercalcemia (high blood calcium) and bone pain
Long-Term Effects
- Osteoporosis (bone loss) and increased risk of fractures
- Increased risk of cardiovascular events
Adverse Drug Reactions (ADR)
- Thromboembolic events
- Cardiovascular events
- Severe nausea and vomiting
- Hepatotoxicity
- Hypercalcemia
Contraindications
- Hypersensitivity to fosfestrol or DES
- History of or current venous thromboembolism
- Pre-existing severe cardiovascular disease
- Severe hepatic impairment
- Pregnancy and Breastfeeding
Drug Interactions
- Calcium and magnesium containing IV solutions (incompatible, can cause precipitation)
- Inform healthcare providers of all medications the patient is taking.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Contraindicated in pregnancy. Can cause harm to the fetus (teratogenic).
- Breastfeeding: Contraindicated in breastfeeding. DES can be excreted in breast milk and may cause harm to the infant.
Drug Profile Summary
- Mechanism of Action: Estrogen receptor agonist; reduces androgen production and inhibits androgen action.
- Side Effects: Nausea, vomiting, fluid retention, gynecomastia, impotence, thromboembolic events, cardiovascular complications.
- Contraindications: Hypersensitivity, thromboembolism history, severe cardiovascular disease, hepatic impairment, pregnancy, breastfeeding.
- Drug Interactions: Calcium- or magnesium-containing IV solutions.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: See Dosage section above.
- Monitoring Parameters: PSA levels, liver function tests, renal function tests, blood calcium levels.
Popular Combinations
- Fosfestrol is typically used as a single agent in hormonal therapy for prostate cancer.
Precautions
- General Precautions: Assess for history of cardiovascular disease, liver disease, thromboembolism. Monitor for these conditions during treatment.
- Specific Populations: Contraindicated in pregnancy and breastfeeding. Use with caution in the elderly.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Fosfestrol?
A: See the detailed Dosage section above.
Q2: What is the mechanism of action of Fosfestrol?
A: Fosfestrol is a prodrug of diethylstilbestrol. It works by binding to estrogen receptors, reducing androgen production, and inhibiting androgen action in prostate cancer cells.
Q3: What are the common side effects of Fosfestrol?
A: Common side effects include nausea, vomiting, fluid retention, gynecomastia, and impotence.
Q4: What are the serious side effects of Fosfestrol?
A: Serious side effects include thromboembolic complications (blood clots), cardiovascular events, and hypercalcemia.
Q5: Can Fosfestrol be used in patients with liver disease?
A: Fosfestrol should be used with caution in patients with hepatic impairment as its metabolism might be affected. Close monitoring is required.
Q6: Can Fosfestrol be used in patients with kidney disease?
A: Use with caution in patients with renal impairment. Dose adjustments may be necessary.
Q7: Is Fosfestrol safe to use during pregnancy or breastfeeding?
A: No, Fosfestrol is contraindicated during pregnancy and breastfeeding due to the risk of serious harm to the fetus or infant.
Q8: What should I monitor in a patient taking Fosfestrol?
A: Closely monitor PSA levels, liver and kidney function, complete blood counts, and blood calcium levels regularly. Monitor for signs and symptoms of thromboembolism, cardiovascular complications, and hypercalcemia.
Q9: Can Fosfestrol interact with other medications?
A: It is incompatible with calcium and magnesium containing IV solutions and healthcare providers should be aware of all other medication the patient is taking.
