Class: Protective Agents
ATC Class: V03AF05
VA Class: AN700
Chemical Name: 2-[(3-Aminopropyl)amino]-ethanethiol dihydrogen phosphate (ester)
Molecular Formula: C5H15N2O3PS
CAS Number: 20537-88-6
Cytoprotective agent; a chemoprotectant and radioprotectant.1 2 3 9 11 14 16 20 21 22 23 24
Uses for Amifostine
Prophylaxis of Cisplatin-induced Nephrotoxicity
Reduction of cumulative nephrotoxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancera 2 14 (designated an orphan drug by FDA for this use).25
Not recommended for patients in other settings where chemotherapy can produce a significant survival benefit or cure, except in the context of a clinical study.a (See Effectiveness of Cytotoxic Regimen under Warnings)
Prophylaxis of Radiation Therapy-induced Xerostomia
Reduction in the incidence of moderate to severe xerostomia in patients undergoing postoperative standard fractionated radiation therapy for the treatment of head and neck cancer, where the radiation port includes a substantial portion of the parotid glands (i.e., ≥75% of both parotid glands exposed to radiation).a
Not recommended in patients receiving definitive radiotherapy, except in the context of a clinical study.a (See Effectiveness of Radiotherapy under Warnings)
Not evaluated in patients undergoing accelerated or hyperfractionated radiation or combined chemotherapy and radiation.1
Amifostine Dosage and Administration
Adequately hydrate patient prior to administration.a
Monitor BP every 5 minutes during infusion and thereafter as clinically indicated; if infusion period is <5 minutes duration, monitor BP at least before and immediately after completion of the infusion.a
All patients should receive antiemetics (e.g., dexamethasone 20 mg IV and a type 3 serotonin [5-HT3] receptor antagonist) prior to and during infusion.1 Additional antiemetics may be required based on the chemotherapy regimen.a (See GI Effects under Cautions.)
For solution and drug compatibility information, see Compatibility under Stability.
Administer by IV infusion.1
Patient should remain in supine position during infusion.a
Interrupt infusion if a clinically important decline in SBP occurs as listed below:
Baseline SBP (mm Hg)
Decreases in SBP during infusion (mm Hg)
Resume infusion, if BP returns to normal within 5 minutes and patient is asymptomatic.a
Reconstitute vial containing 500 mg of amifostine powder with 9.7 mL of 0.9% sodium chloride for injection, to provide a solution containing 50 mg/mL.a
May be diluted with 0.9% sodium chloride for injection in a PVC container to a final concentration of 5–40 mg/mL.a
Rate of Administration
Prophylaxis of cisplatin-induced nephrotoxicity: Administer over 15 minutes.1 Infusions over >15 minutes are associated with increased side effectsa (see Hypotension under Cautions) and more rapid infusions have not been studied systematically.1
Prophylaxis of radiation therapy-induced xerostomia: Administer over 3 minutes.1
Available as the trihydrate form of amifostine; dosage expressed in terms of amifostine.a
Prophylaxis of Cisplatin-induced Nephrotoxicity
Initially, 910 mg/m2 once daily over 15 minutes, starting 30 minutes prior to cisplatin administration.a
If full initial dose is tolerated, repeat the full dose during subsequent courses of chemotherapy as tolerated.1
If the full dose cannot be administered, reduce dosage to 740 mg/m2 during subsequent chemotherapy cycles.a
Prophylaxis of Radiation Therapy-induced Xerostomia
200 mg/m2 once daily over 3 minutes; initiate infusion 15–30 minutes prior to standard fractionated radiation therapy (1.8–2 Gy).a
No specific dosage recommendations at this time.a
No specific dosage recommendations at this time.a
Careful dosage selection recommended due to possible age-related decreases in hepatic, renal, or cardiac function and concomitant diseases or drug therapies.a
Cautions for Amifostine
Known sensitivity to aminothiol compounds.a
Effectiveness of Cytotoxic Regimen
Possible interference in antitumor effect of chemotherapy; however, most tumor models suggest amifostine does not alter antitumor effect.a Limited data available regarding preservation of antitumor efficacy when amifostine administered prior to cisplatin in malignancies other than advanced ovarian cancer.a
Effectiveness of Radiotherapy
Insufficient data available to exclude the possibility that amifostine might interfere with the efficacy of high-dose (definitive) radiation therapy; use not recommended in patients receiving such therapy, except in clinical trials.a
Hypotension occurs frequently during or shortly after infusion, despite hydration and positioning.a May be associated with dyspnea, apnea, hypoxia, and rarely seizures, unconsciousness, respiratory arrest, and renal failure.1
Administer IV infusions over ≤15 minutes to minimize the risk of hypotensive reactions.a
If hypotension occurs, interrupt infusion, place patient in Trendelenburg's position and initiate IV infusion of 0.9% sodium chloride in a separate line.a (See Guideline for Interrupting Infusion due to Decreases in SBP under Dosage and Administration.)
Use not recommended in hypotensive or dehydrated patients or in patients concurrently receiving antihypertensive agents.a (See Specific Drugs under Interactions.)
Withdrawal of antihypertensive therapy and IV hydration may exacerbate hypertension in patients whose antihypertensive therapy has been interrupted for amifostine therapy; carefully monitor BP during and after IV infusion in such patients.1
Nausea and/or vomiting occurs frequently and may be severe.1 Administer effective antiemetic therapy (e.g., an IV corticosteroid such as dexamethasone and a type 3 serotonin [5-HT3] receptor antagonist) prior to and in conjunction with amifostine therapy.1
Carefully monitor patient’s fluid balance in those receiving highly emetogenic chemotherapy.1
Hypocalcemia occurs rarely.a Monitor serum calcium concentrations in patients at risk of hypocalcemia (e.g., those with nephrotic syndrome, those receiving multiple doses of amifostine); initiate calcium supplementation as necessary.1
Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis and severe cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma, exfoliative dermatitis) reported.a
Serious cutaneous reactions reported more frequently when used as a radioprotectant.a Withhold amifostine and consider dermatologic consultation and biopsy if cutaneous reactions or mucosal lesions of unknown etiology occur.a
Careful monitoring during and after administration is recommended.a If acute hypersensitivity reactions occur, immediately and permanently discontinue infusion and institute appropriate therapy as indicated (e.g., epinephrine and other appropriate measures).a
Safety not established in patients with preexisting cardiovascular or cerebrovascular disease (e.g., ischemic heart disease, arrhythmias, CHF, history of stroke or TIAs; use with caution in such patients.
Not known whether amifostine is distributed into milk.a Use not recommended.a
Response in patients ≥65 years of age does not appear to differ from that in younger adults; however, use with caution due to greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.a
Common Adverse Effects
Hypotension, nausea, vomiting.a
Interactions for Amifostine
Additive hypotensive effectsa
Temporarily discontinue antihypertensive therapy ≥24 hours prior to amifostine administration; concurrent administration is not recommendeda
Pharmacokinetic interaction unlikelya
Pharmacokinetic interaction unlikely.a
Following IV administration, rapidly distributed into tissues; <10% of amifostine remains in plasma 6 minutes after administration.a
Not known whether amifostine is distributed into milk.a
Measurable levels of metabolites have been found in bone marrow cells.a
Rapidly and extensively metabolized, principally via alkaline phosphatase, to the active free sulfhydryl (thiol) metabolite (WR-1065)1 2 9 11 15 22 and subsequently, to a less active disulfide metabolite.a
Minimal renal excretion, averaging 0.69, 2.64, and 2.22% for amifostine, thiol metabolite, and disulfide metabolite respectively.a
Biphasic; terminal half-life is approximately 8 minutes.a
Powder for Injection
Reconstituted solution is stable for 5 hours at room temperature (approximately 25°C) or 24 hours under refrigeration (2–8°C).a
For information on systemic interactions resulting from concomitant use, see Interactions.
Compatibility with solutions other than 0.9% sodium chloride for injection without additives has not been examined.a Use of other solutions is not recommended.a
Pharmacologically active free sulfhydryl binds to and detoxifies cytotoxic platinum-containing metabolites of cisplatin and scavenges free radicals induced by the drug.1 2 9 11 16
Cytoprotection against cisplatin-induced toxicity appears to result from prevention and/or, to a lesser extent, reversal of DNA platination by the drug (cisplatin-DNA adducts).2
Radioprotectant effect appears to be mediated at least in part by removal of oxygen from tissues2 15 20 and by scavenging hydroxyl radicals and repairing radiation-induced DNA radicals through donation of hydrogen.2 11 12 15 20
Preferentially protects healthy cells because of increased cellular uptake of amifostine and more rapid generation of the active free sulfhydryl metabolite in these cells compared with malignant cells.1 2 9 12 16
Advice to Patients
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., antihypertensive medications), as well as any concomitant illnesses.a
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.a
Importance of informing patients of other important precautionary information.a (See Cautions)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
For injection, for IV infusion
500 mg (of anhydrous amifostine)
AHFS DI Essentials. © Copyright 2018, Selected Revisions March 1, 2007. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
1. MedImmune Oncology, Inc. Ethyol (amifostine) for injection prescribing information. Gaithersburg, MD; 2001 Oct.
2. Spencer CM, Goa KL. Amifostine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as a radioprotector and cytotoxic chemoprotector. Drugs. 1995; 50:1001-31.
3. Anon. U.S. Bioscience Ethyol to be marketed in U.S. by Alza via $35 mil. deal. F-D-C Rep. 1995; Dec 18: T&G-2–3.
4. Rose P, Kemp G, Glick J. Ethyol (amifostine) protects against cumulative cisplatin toxicities. Paper presented at the 1996 Annual Meeting of the American Society of Clinical Oncology (ASCO). Philadelphia, PA: 1996 May 18-21. Abstract.
5. Budd GT, Bukowski RM, Adelstein D et al. Mature results of a randomized trial of carboplatin (C) and amifostine (A) vs. C alone in patients (pts) with advanced malignancies. Paper presented at the 1996 Annual Meeting of the American Society of Clinical Oncology (ASCO). Philadelphia, PA: 1996 May 18-21. Abstract.
6. Planting AST, Vermorken JB, Catimel G et al. Randomized phase II study of weekly cisplatin with or without amifostine in patients with advanced head and neck cancer. Paper presented at the 1996 Annual Meeting of the American Society of Clinical Oncology (ASCO). Philadelphia, PA: 1996 May 18-21. Abstract.
7. Schiller JH, Larson ML, Larson MH et al. Amifostine (A), cisplatin (C), vinblastine (V): a highly active regimen for non small cell lung cancer (NSCLC). Eur J Cancer. 1995; 31A(Suppl 5):S230.
8. Schiller JH, Berry W, Storer B et al. Phase II trial of amifostine, cisplatin and vinblastine for metastatic nonsmall cell lung cancer. Proc Am Soc Clin Oncol. 1995; 14:356.
9. Treskes M, Holwerda U, Nijtmans LGJ et al. The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278. Cancer Chemother Pharmacol. 1992; 29:467-70.
10. Glick J, Kemp G, Rose P et al. A randomized trial of cyclophosphamide and cisplatin ± amifostine in the treatment of advanced epithelial ovarian cancer. Proc Am Soc Clin Oncol. 1994; 13:432.
11. Peters GJ, van der Vijgh WJF. Protection of normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (WR-2721): preclinical aspects. Eur J Cancer. 1995; 31A(Suppl 1):S1-7.
12. Turrisi AT, Glover DJ, Hurwitz S et al. Final report of the phase I trial of single-dose WR-2721 [S-2-(3-Aminopropyl-amino)ethylphosphorothioic acid]. Cancer Treat Rep. 1986; 70:1389-93.
13. Perry DJ, Krasnow SH, Reilly JG et al. Phase II study of cisplatin and etoposide with WR-2721 for advanced non-small cell lung cancer. Paper presented at the 1994 Annual Meeting of the American Society of Clinical Oncology (ASCO). Abstract.
14. Facchini T, Belpomme D, Kemp G et al. Amifostine (AMI) selectively protects against cumulative toxicities of cyclophosphamide (C) and cisplatin (P). Eur J Cancer. 1995; 31A(Suppl 5):Abstract No.
15. Liu T, Liu Y, He S et al. Use of radiation with or without WR-2721 in advanced rectal cancer. Cancer. 1992; 69:2820-25.
16. Anand AJ, Bashey B. Newer insights into cisplatin nephrotoxicity. Ann Pharmacother. 1993; 27:1519-25.
17. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med. 1992; 326:1196-203.
18. Glover D, Riley L, Carmichael K et al. Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent). N Engl J Med. 1983; 309:1137-41.
19. Glover DJ, Shaw L, Glick JH et al. Treatment of hypercalcemia in parathyroid cancer with WR-2721, S-2-(3-aminopropylamino) ethyl-phosphorothioic acid. Ann Intern Med. 1985; 103:55-7.
20. Smoluk GD, Fahey RC, Calabro-Jones PM et al. Radioprotection of cells in culture by WR-2721 and derivatives: form of the drug responsible for protection. Cancer Res. 1988; 48:3641-7.
21. Brown JM. Sensitizers and protectors in radiotherapy. Cancer. 1985; 55:2222-8.
22. Ryan SV, Carrithers SL, Parkinson SJ et al. Hypotensive mechanisms of amifostine. J Clin Pharmacol. 1996; 36:365-73.
23. Gandara DR, Perez EA, Wiebe V et al. Cisplatin chemoprotection and rescue: pharmacologic modulation of toxicity. Semin Oncol. 1991; 18(Suppl 3):49-55.
24. Yuhas JM. Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2-(3-aminopropylamino)-ethylphosphorothioic acid. Cancer Res. 1980; 40:1519-24.
25. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.
26. Pameijer FA, Mancuso AA, Mendenhall WM et al. Evaluation of pretreatment computed tomography as a predictor of local control in T1/T2 pyriform sinus carcinoma treated with definitive radiotherapy. Head Neck. 1998; 20:159-68.
27. Murakami M, Kuroda Y, Okamoto Y et al. Neoadjuvant concurrent chemoradiotherapy followed by definitive radiotherapy or surgery for operable thoracic esophageal carcinoma. Int J Radiat Oncol Biol Phys. 1998; 40:1049-59.
a. MedImmune Oncology, Inc. Ethyol (amifostine) for injection prescribing information. Gaithersburg, MD; 2005 Sept.
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