Usage
Amifostine is a cytoprotective agent used to reduce the cumulative renal toxicity associated with repeated cisplatin administration in patients with advanced ovarian cancer. It also reduces the incidence of moderate to severe xerostomia (dry mouth) in patients undergoing postoperative radiation treatment for head and neck cancer when the radiation port includes a substantial portion of the parotid glands. Its pharmacological classification is a cytoprotective agent and a free radical scavenger. The drug’s mechanism of action involves the dephosphorylation to an active thiol metabolite, which scavenges free radicals generated by radiation and some chemotherapeutic agents. It also promotes the repair of normal tissue damaged by these treatments.
Alternate Names
The international nonproprietary name is amifostine. A common brand name is Ethyol®.
How It Works
Pharmacodynamics: Amifostine is a prodrug converted to its active metabolite, WR-1065, by alkaline phosphatase in tissues. WR-1065 is preferentially taken up by normal tissues, offering selective cytoprotection against the toxic effects of chemotherapy and radiation. WR-1065 scavenges reactive oxygen species and other free radicals, protecting cellular components like DNA and cell membranes from damage. It also promotes cellular repair processes.
Pharmacokinetics: Amifostine is administered intravenously and is rapidly dephosphorylated to WR-1065. Plasma half-life of amifostine is short (less than one minute), while WR-1065 has a half-life of several minutes. It is primarily eliminated via renal excretion, with some hepatic metabolism.
Dosage
Standard Dosage
Adults:
- For reducing cumulative renal toxicity: 910 mg/m² IV infusion over 15 minutes, started 30 minutes before cisplatin chemotherapy. If the full dose isn’t tolerated, subsequent doses may be reduced to 740 mg/m².
- For reducing xerostomia: 200 mg/m² IV infusion over 3 minutes, started 15-30 minutes before radiation therapy.
Children:
The safety and efficacy of amifostine in pediatric patients have not been established, and its use is not recommended.
Special Cases:
- Elderly Patients: Dose selection should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function in elderly patients.
- Patients with Renal Impairment: Exercise caution in patients with renal impairment due to primary renal elimination of the drug.
- Patients with Hepatic Dysfunction: No specific dosage adjustments are indicated for hepatic dysfunction.
- Patients with Comorbid Conditions: Use with caution in patients with cardiovascular or cerebrovascular disease.
Clinical Use Cases
Dosing recommendations align with the standard adult dosages for cisplatin-induced nephrotoxicity and radiation-induced xerostomia. Specific use cases (intubation, surgical procedures, mechanical ventilation, ICU use, emergency situations) do not have unique amifostine dosing recommendations.
Dosage Adjustments
Dose adjustments are primarily based on tolerability related to hypotension. If a patient experiences significant hypotension during the initial 910 mg/m² dose for renal protection, subsequent doses can be reduced to 740 mg/m². Monitor blood pressure closely during infusion. If blood pressure decreases, interrupt the infusion and restart at a slower rate once the blood pressure has returned to normal. If the full dose cannot be administered due to persistent hypotension, use the reduced dose for subsequent cycles. Specific recommendations for hepatic or renal impairment and metabolic disorders or genetic polymorphisms aren’t available.
Side Effects
Common Side Effects
- Nausea and vomiting (can be severe)
- Flushing
- Chills
- Dizziness
- Somnolence
- Hiccups
- Sneezing
Rare but Serious Side Effects
- Severe hypotension
- Allergic reactions (rash, hives, itching, difficulty breathing or swallowing, swelling of the face, lips, or tongue)
- Hypocalcemia
- Seizures
- Serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
Long-Term Effects
Chronic complications from prolonged amifostine use are not well-characterized.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include severe hypotension, allergic reactions, and severe cutaneous reactions, all requiring immediate medical attention.
Contraindications
- Hypersensitivity to amifostine or aminothiol compounds
- Hypotension
- Dehydration
Drug Interactions
Amifostine can interact with antihypertensive medications and other drugs that can lower blood pressure. It can potentiate the hypotensive effects of these agents, increasing the risk of severe hypotension. Concurrent use requires careful monitoring of blood pressure. Concurrent use with agents that prolong the QT interval should also be avoided, if possible.
Pregnancy and Breastfeeding
Amifostine is classified as Pregnancy Category C. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Breastfeeding is not recommended while receiving amifostine. It is unknown if amifostine or its metabolites are excreted in human milk, but the potential for adverse reactions in nursing infants exists.
Drug Profile Summary
- Mechanism of Action: Prodrug converted to WR-1065; scavenges free radicals, protects normal tissues from chemo/radiotherapy damage.
- Side Effects: Nausea, vomiting, flushing, hypotension, allergic reactions, hypocalcemia, seizures, cutaneous reactions.
- Contraindications: Hypersensitivity, hypotension, dehydration.
- Drug Interactions: Antihypertensives and other blood pressure-lowering agents.
- Pregnancy & Breastfeeding: Category C; not recommended during breastfeeding.
- Dosage: Nephroprotection: 910 mg/m² IV (15 min infusion); Xerostomia: 200 mg/m² IV (3 min infusion).
- Monitoring Parameters: Blood pressure, serum calcium levels.
Popular Combinations
Amifostine is typically used prior to cisplatin chemotherapy or radiation therapy.
Precautions
- Monitor blood pressure closely during infusion.
- Ensure adequate hydration.
- Pre-screen for allergies to amifostine or aminothiols.
- Evaluate renal and hepatic function.
- Consider risks and benefits carefully in elderly patients and those with comorbid conditions.
- Advise patients of potential adverse reactions.
- Advise women of reproductive potential to avoid pregnancy.
- Advise against breastfeeding during treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Amifostine?
A: For nephroprotection, 910 mg/m² IV over 15 minutes prior to cisplatin. For xerostomia prevention, 200 mg/m² IV over 3 minutes prior to radiation.
Q2: How does Amifostine work?
A: Amifostine is metabolized to WR-1065, which scavenges free radicals and protects normal cells from chemotherapy and radiation damage.
Q3: What are the common side effects?
A: Nausea, vomiting, flushing, chills, dizziness, hypotension are common.
Q4: What are the serious side effects?
A: Severe hypotension, allergic reactions, hypocalcemia, seizures, and serious skin reactions are potential serious side effects.
Q5: Can Amifostine be given to children?
A: Safety and efficacy in children have not been established; use is not recommended.
Q6: Can pregnant or breastfeeding women receive Amifostine?
A: Pregnancy Category C; use only if benefit outweighs risk. Breastfeeding is not recommended during treatment.
Q7: What are the contraindications to Amifostine?
A: Hypersensitivity to amifostine or other aminothiols, hypotension, and dehydration.
Q8: What drug interactions should I be aware of?
A: Amifostine may interact with antihypertensives and other drugs that lower blood pressure, potentially causing severe hypotension.
Q9: What should patients be monitored for during Amifostine administration?
A: Closely monitor blood pressure, particularly during infusion. Monitor serum calcium levels in patients at risk of hypocalcemia. Evaluate for cutaneous reactions prior to each dose.
Q10: What is the primary route of elimination for Amifostine?
A: Amifostine is primarily eliminated via renal excretion.
