Amifostine

(BAN, USAN, rINN)
Amifostine Chemical formula
Synonyms: Amifostiini; Amifostin; Amifostina; Amifostinum; Ethiofos; Gammaphos; NSC-296961; WR-2721. S-[2-(3-Aminopropylamino)ethyl] dihydrogen phosphorothioate.
Cyrillic synonym: Амифостин.

💊 Chemical information

Chemical formula: C5H15N2O3PS = 214.2.
CAS — 20537-88-6 (amifostine); 63717-27-1 (amifostine monohydrate).
ATC — V03AF05.
ATC Vet — QV03AF05.

Pharmacopoeias.

US includes the trihydrate.

USP 31

(Amifostine). The trihydrate is a white crystalline powder. Freely soluble in water. pH of a 5% solution in water is between 6.5 and 7.5. Store in airtight containers at a temperature of 2° to 8°. Protect from light.

Incompatibility.

Amifostine has been reported 1 to be physically incompatible with aciclovir sodium, amphotericin B, cefoperazone sodium, chlorpromazine hydrochloride, cisplatin, ganciclovir sodium, hydroxyzine hydrochloride, miconazole, minocycline hydrochloride, and prochlorperazine edisilate during simulated Y-site administration. 1. Trissel LA, Martinez JF. Compatibility of amifostine with selected drugs during simulated Y-site administration. Am J HealthSyst Pharm 1995; 52: 2208–12.

💊 Adverse Effects, Treatment, and Precautions

Amifostine may cause a transient reduction, usually in systolic, or, less frequently, in diastolic blood pressure. However, more pronounced reductions in blood pressure may occur and transient loss of consciousness has been reported very rarely. To minimise hypotension, patients should be adequately hydrated before treatment begins and should be in a supine position. Amifostine is contra-indicated in patients who are hypotensive or dehydrated. Patients taking antihypertensive drugs should discontinue treatment 24 hours before starting amifostine. Arterial blood pressure must be monitored during the amifostine infusion and if systolic blood pressure decreases significantly, the infusion must stop. It may be continued if blood pressure returns to normal within 5 minutes. Nausea and vomiting are frequently reported and concurrent antiemetic therapy is recommended. Amifostine reduces serum-calcium concentrations, although clinical hypocalcaemia has occurred only very rarely in patients who received multiple doses of amifostine within 24 hours. Serum-calcium concentrations should be monitored in patients at risk of hypocalcaemia. Other adverse effects include flushing, chills, somnolence, hiccups, and sneezing. Hypersensitivity reactions and anaphylactoid reactions have been reported. Skin rashes may occur and there have been reports of more severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, in some cases resulting in fatality. Administration of amifostine over a longer period than the recommended 15 minutes is associated with a higher incidence of adverse effects.

Effects on the skin.

Amifostine has been associated with severe skin reactions, including Stevens-Johnson syndrome1,2 and toxic epidermal necrolysis,1,2 and fatalities have occurred.2 The reactions appear to be more common in patients receiving radiotherapy.2
1. Lale Atahan I, et al. Two cases of Stevens-Johnson syndrome: toxic epidermal necrolysis possibly induced by amifostine during radiotherapy. Br J Dermatol 2000; 143: 1072–3
2. Boccia R, et al. Assessment and management of cutaneous reactions with amifostine administration: findings of the ethyol (amifostine) cutaneous treatment advisory panel (ECTAP). Int J Radiat Oncol Biol Phys 2004; 60: 302–9.

💊 Pharmacokinetics

Amifostine is rapidly cleared from the plasma after intravenous administration and is dephosphorylated by alkaline phosphatase to the active metabolite WR1065, a free thiol compound. The elimination half-life of amifostine after a 15-minute infusion is less than 10 minutes. About 6% or less of a dose is excreted in the urine.

💊 Uses and Administration

Amifostine, an aminothiol compound, is a cytoprotective agent. It is converted in the body to its active metabolite WR-1065, which protects noncancerous cells against the toxic effects of antineoplastics and ionising radiation. It is used in patients with advanced ovarian cancer to reduce neutropenia-related infection associated with cyclophosphamide and cisplatin therapy and, in patients with advanced solid tumours of non-germ cell origin, to reduce the cumulative renal toxicity associated with repeated cisplatin use. It is also used to reduce the incidence of xerostomia (dry mouth) in patients undergoing radiation therapy for head and neck cancer. Amifostine is under investigation in ameliorating the adverse effects of other antineoplastics and in the treatment of myelodysplasia. In chemotherapy, amifostine is given by intravenous infusion over 15 minutes starting no more than 30 minutes before the antineoplastic therapy. The dose in adults is 910 mg/m 2 once daily. Subsequent doses should be reduced to 740 mg/m 2 in patients unable to tolerate the full dose. A dose of 740 mg/m 2 is also recommended for the reduction of renal toxicity of cisplatin if doses of cisplatin of less than 100 mg/m 2 are used. In the prevention of xerostomia, amifostine is given in a dose of 200 mg/m 2 daily as a 3-minute intravenous infusion started 15 to 30 minutes before radiotherapy.

Cytoprotection.

WR-1065, the active metabolite of amifostine, readily enters non-malignant cells where it deactivates cytotoxics such as alkylating and platinum-containing antineoplastics and protects against the effects of ionising radiation.1-3 The cytoprotective effects of amifostine are reported to be selective for normal cells and not to interfere with the cytotoxic effects of antineoplastics and radiation on malignant cells. Several factors contribute to this selectivity, including the lower alkaline phosphatase content of malignant cells compared with normal cells, and the lower pH of malignant tissues, both of which decrease the formation and uptake of WR-1065 by malignant cells.2,3 Benefit has been reported with amifostine in various malignancies and the American Society of Clinical Oncology currently recommends4 that its use may be considered in patients receiving cisplatin- or alkylating agent-based chemotherapy, and in patients receiving radiation therapy in the head and neck region. Although it is usually given intravenously, there is some evidence5,6 that the subcutaneous route may be effective and may be associated with fewer adverse effects.
1. Foster-Nora JA, Siden R. Amifostine for protection from antineoplastic drug toxicity. Am J Health-Syst Pharm 1997; 54: 787–800
2. Mabro M, et al. A risk-benefit assessment of amifostine in cytoprotection. Drug Safety 1999; 21: 367–87
3. Culy CR, Spencer CM. Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Drugs 2001; 61: 641–84
4. Schuchter LM, et al. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002; 20: 2895–903. Also available at: http:// www.jco.org/cgi/reprint/20/12/2895.pdf (accessed 4/10/05
5. Koukourakis MI, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study. J Clin Oncol 2000; 18: 2226–33
6. Bonner HS, Shaw LM. New dosing regimens for amifostine: a pilot study to compare the relative bioavailability of oral and subcutaneous administration with intravenous infusion. J Clin Pharmacol 2002; 42: 166–74.

💊 Preparations

USP 31: Amifostine for Injection.

Proprietary Preparations

Arg.: Erifostine; Ethyol†; Austral.: Ethyol; Belg.: Ethyol; Braz.: Ethyol; Chile: Ethyol; Cz.: Ethyol; Denm.: Ethyol; Fin.: Ethyol; Fr.: Ethyol; Ger.: Ethyol; Gr.: Ethyol; Hong Kong: Ethyol†; Hung.: Ethyol†; India: Amiphos; Israel: Ethyol; Ital.: Ethyol; Malaysia: Ethyol†; Mex.: Ethyol; Neth.: Ethyol; NZ: Ethyol; Philipp.: Ethyol; Pol.: Ethyol; Port.: Ethyol; S.Afr.: Ethyol; Singapore: Ethyol†; Spain: Ethyol; Swed.: Ethyol; Switz.: Ethyol; Thai.: Cytofos; Ethyol; Turk.: Ethyol; UK: Ethyol†; USA: Ethyol; Venez.: Ethyol.
Published October 11, 2018.