Amifostine

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
Brands: Ethyol

Introduction

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 cancer^{a 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

General

• 
  

  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.)

  
  

Administration

IV Administration

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:

Guideline for Interrupting Infusion due to Decreases in SBP12

Baseline SBP (mm Hg)	Decreases in SBP during infusion (mm Hg)
<100	20
100–119	25
120–139	30
140–179	40
≥180	50

Resume infusion, if BP returns to normal within 5 minutes and patient is asymptomatic.^a

Reconstitution

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

Dilution

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 effects^a (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

Dosage

Available as the trihydrate form of amifostine; dosage expressed in terms of amifostine.^a

Adults

Prophylaxis of Cisplatin-induced Nephrotoxicity

IV

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

IV

200 mg/m² once daily over 3 minutes; initiate infusion 15–30 minutes prior to standard fractionated radiation therapy (1.8–2 Gy).^a

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^a

Renal Impairment

No specific dosage recommendations at this time.^a

Geriatric Patients

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

Contraindications

Known sensitivity to aminothiol compounds.^a

Warnings/Precautions

Warnings

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

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.)

Hypertension

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

GI Effects

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

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

Sensitivity Reactions

Hypersensitivity

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

General Precautions

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.

Specific Populations

Pregnancy

Category C.^a

Lactation

Not known whether amifostine is distributed into milk.^a Use not recommended.^a

Geriatric Use

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

Specific Drugs

Drug	Interaction	Comments
Antihypertensive agents	Additive hypotensive effectsa	Temporarily discontinue antihypertensive therapy ≥24 hours prior to amifostine administration; concurrent administration is not recommendeda
Dexamethasone	Pharmacokinetic interaction unlikelya
Metoclopramide	Pharmacokinetic interaction unlikely.a

Amifostine Pharmacokinetics

Distribution

Extent

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

Elimination

Metabolism

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

Elimination Route

Minimal renal excretion, averaging 0.69, 2.64, and 2.22% for amifostine, thiol metabolite, and disulfide metabolite respectively.^a

Half-life

Biphasic; terminal half-life is approximately 8 minutes.^a

Stability

Storage

Parenteral

Powder for Injection

20–25°C.^a

Reconstituted solution is stable for 5 hours at room temperature (approximately 25°C) or 24 hours under refrigeration (2–8°C).^a

Compatibility

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

ActionsActions

• 
  

  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 tissues^{2 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)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Amifostine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	500 mg (of anhydrous amifostine)	Ethyol	MedImmune

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions March 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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. [PubMed 8612469]

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. [PubMed 1314713]

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. [IDIS 231530] [PubMed 2431774]

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. [IDIS 296600] [PubMed 1315211]

16. Anand AJ, Bashey B. Newer insights into cisplatin nephrotoxicity. Ann Pharmacother. 1993; 27:1519-25. [IDIS 323111] [PubMed 8305788]

17. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med. 1992; 326:1196-203. [IDIS 295128] [PubMed 1532633]

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. [IDIS 177688] [PubMed 6312315]

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. [IDIS 202120] [PubMed 2988391]

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. [PubMed 2837320]

21. Brown JM. Sensitizers and protectors in radiotherapy. Cancer. 1985; 55:2222-8. [IDIS 199245] [PubMed 2983876]

22. Ryan SV, Carrithers SL, Parkinson SJ et al. Hypotensive mechanisms of amifostine. J Clin Pharmacol. 1996; 36:365-73. [PubMed 8728352]

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. [PubMed 6245795]

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. [PubMed 9484948]

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. [PubMed 9539559]

a. MedImmune Oncology, Inc. Ethyol (amifostine) for injection prescribing information. Gaithersburg, MD; 2005 Sept.

More Amifostine resources

• Amifostine Side Effects (in more detail)
• Amifostine Use in Pregnancy & Breastfeeding
• Amifostine Drug Interactions
• Amifostine Support Group
• 0 Reviews for Amifostine - Add your own review/rating

• Amifostine Prescribing Information (FDA)


• Amifostine MedFacts Consumer Leaflet (Wolters Kluwer)


• Amifostine Professional Patient Advice (Wolters Kluwer)


• amifostine Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information


• Ethyol Prescribing Information (FDA)

Compare Amifostine with other medications

• Cancer
• Non-Small Cell Lung Cancer
• Ovarian Cancer