ETHYOL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ETHYOL (ETHYOL).
Ethyl (amifostine) is a prodrug that is dephosphorylated by alkaline phosphatase to an active thiol metabolite, which scavenges free radicals and detoxifies reactive metabolites of cisplatin and radiation, thereby protecting normal tissues.
| Metabolism | Amifostine is rapidly metabolized by alkaline phosphatase to the active free thiol (WR-1065) and other metabolites. Further metabolism involves oxidation and conjugation. |
| Excretion | Renal: ~50-60% of the administered dose (including active metabolite WR-1065) excreted in urine within 24 hours, with minimal biliary/fecal elimination (<5%). |
| Half-life | A single i.v. dose of amifostine (ETHYOL) exhibits a terminal elimination half-life of approximately 0.6-1.1 hours, representing rapid clearance of the free thiol form (WR-1065) from plasma. Clinical context: The active metabolite WR-1065 has a slightly longer half-life (about 1-2 hours). The short half-life suggests protective effects are limited to the time immediately after infusion. |
| Protein binding | Amifostine itself exhibits negligible protein binding (<10% bound to plasma proteins). The active metabolite WR-1065 is also minimally protein bound (approximately 10%). |
| Volume of Distribution | Volume of distribution (Vd) for amifostine is approximately 0.6-0.8 L/kg, indicating distribution primarily into extracellular fluid and some tissues. The active metabolite WR-1065 is more widely distributed, with Vd of about 1.2 L/kg, reflecting uptake into cells. |
| Bioavailability | ETHYOL is administered only intravenously; oral bioavailability is negligible due to extensive first-pass metabolism. Bioavailability via i.v. route: 100%. |
| Onset of Action | Intravenous: Radioprotective and chemoprotective effects begin immediately after infusion, as WR-1065 is rapidly formed and taken up by tissues. Onset is within minutes of completing the 15-minute infusion. |
| Duration of Action | Intravenous: The active thiol WR-1065 persists in normal tissues for about 2-3 hours post-infusion, providing a window for radioprotection/chemoprotection. Duration is short, requiring careful timing relative to chemotherapy or radiation. |
| Action Class | Cytoprotective agents- Kidney & Salivary gland |
| Brand Substitutes | Natfost 500mg Injection, Cytofos 500mg Injection, Amfos 500mg Injection, Naprofos 500mg Injection, Amiget 500mg Injection |
For reduction of cisplatin-induced nephrotoxicity: 910 mg/m2 IV infused over 15 minutes, starting 30 minutes prior to cisplatin. For reduction of xerostomia from head and neck radiation: 200 mg/m2 IV bolus daily 15-30 minutes before radiation.
| Dosage form | INJECTABLE |
| Renal impairment | Contraindicated if CrCl < 40 mL/min. No data for modification between 40-60 mL/min; use with caution. No dose adjustment required for CrCl ≥60 mL/min. |
| Liver impairment | No specific dose adjustments provided for Child-Pugh classes. Use with caution in severe hepatic impairment (Child-Pugh C) due to lack of data. |
| Pediatric use | Safety and efficacy not established in pediatric patients. Limited data from clinical trials: 740 mg/m2 IV as a 15-minute infusion prior to cisplatin; no standard weight-based dosing recommendation. |
| Geriatric use | No specific dose adjustments recommended. Assess renal function as creatinine clearance may be reduced; ensure CrCl ≥40 mL/min before administration. Consider lower initial doses due to increased risk of hypotension and hypersensitivity reactions. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ETHYOL (ETHYOL).
| Breastfeeding | No data exist on excretion of amifostine into human breast milk or its effects on the nursing infant. The molecular weight (214.2 Da) suggests potential for excretion. Until further data, breastfeeding is not recommended during therapy and for a period after last dose. M/P ratio unknown. |
| Teratogenic Risk | Amifostine (ETHYOL) is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Animal studies have shown embryotoxicity and teratogenicity at doses lower than the human dose. First trimester exposure may increase risk of structural abnormalities; second and third trimester use may affect fetal growth and development. Risk cannot be ruled out. |
■ FDA Black Box Warning
Amifostine should not be administered to patients with hypotension or dehydration. Patients should be adequately hydrated prior to infusion and blood pressure monitored during infusion.
| Serious Effects |
["Hypersensitivity to amifostine or any of its components","Patients with hypotension or dehydration","Concurrent use with antihypertensive drugs (relative contraindication)"]
| Precautions | ["Hypotension: Can cause clinically significant hypotension, especially during rapid infusion. Monitor blood pressure every 5 minutes during infusion.","Nausea and vomiting: Antiemetic therapy recommended.","Hypocalcemia: Decrease in serum calcium levels; monitor calcium levels.","Cutaneous reactions: Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.","Infusion-related reactions: Flushing, chills, dizziness, somnolence, hiccups, sneezing."] |
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| Fetal Monitoring | Monitor complete blood counts (CBC) for myelosuppression, serum electrolytes (potassium, calcium, magnesium) for hypocalcemia, and blood pressure for hypotension. In pregnancy, additional monitoring of fetal growth and amniotic fluid index via ultrasound is recommended due to potential for placental insufficiency. |
| Fertility Effects | Amifostine may impair fertility. Animal studies demonstrate reduced spermatogenesis and testicular atrophy in males, and impaired ovulation and luteal function in females at clinically relevant doses. Effects may be reversible or permanent. No human fertility studies available. |