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Cancer Drug Manual
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Amifostine

Revised 01 Mar 2006

SYNONYM(S): Ethiofos, WR2721, ethanethiol, gammaphos, NSC-296961

COMMON TRADE NAME(S): ETHYOL®

CLASSIFICATION: cytoprotectant, noncytotoxic

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Amifostine is a pro-drug which is activated to the free thiol metabolite at the tissue site. The thiol metabolite is responsible for most of the cytoprotective and radioprotective properties of amifostine. It is readily taken up by cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. Other possible effects include inhibition of apoptosis, alteration of gene expression and modification of enzyme activity.1 Healthy cells are preferentially protected because amifostine and metabolites are present in healthy cells at 100-fold greater concentrations than in tumour cells.1-3

PHARMACOKINETICS:

 
Interpatient Variability no information found
Oral Absorption not orally absorbed4
Distribution widely distributed throughout body5 (highest: kidney, salivary gland, intestinal mucosa, liver, lung; lowest: brain, skeletal muscle)6
cross blood brain barrier? No6
volume of distribution1 7.4-8.7 L
plasma protein binding4,7 4%
Metabolism dephosphorylated by alkaline phosphatase in tissues primarily to WR-10652
active metabolite thiol (WR-1065)2,3
inactive metabolite disulfide (WR-33278)2,3
Excretion non-linear elimination via rapid metabolism and tissue uptake1
urine amifostine (0.7%), thiol (2.6%), disulfide (2.2%)4
terminal half life1 amifostine 8 min, thiol 7.3 h
clearance2,3 126-258 L/h
Gender no information found
Elderly no information found
Children no information found
Ethnicity no information found

USES:

 
Primary uses: Other uses:
Chemoprotective agent1,8-20 Myelodysplastic syndrome1
Radioprotective agent21-32  

*Health Canada Therapeutic Products Programme approved indication

SPECIAL PRECAUTIONS:

Contraindicated in patients with hypersensitivity reaction to aminothiols. Due to its potential to cause nausea, vomiting and hypotension, amifostine should be used cautiously in patients with cardiovascular conditions, cerebrovascular disease, dehydration, preexisting hypotension or predisposition to hypocalcemia.2

Use with curative chemotherapy: Animal data suggest that amifostine may interfere with antitumorigenic effects of chemotherapy and amifostine is not recommended with curative chemotherapy outside of a clinical trial. Interference has not been seen in human studies of amifostine thus far.2,3

Carcinogenicity: no information found.

Mutagenicity: Amifostine was not mutagenic in Ames test or clastogenic in mammalian in vitro chromosome test. Thiol metabolite (WR-1065) was mutagenic in Ames test and in mammalian in vitro mutation test but not clastogenic in mammalian chromosome tests.2

Fertility: no information found.

Pregnancy: FDA Pregnancy Category C. Studies in animals have revealed adverse effects on the fetus and there are no controlled studies in women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.2

Breast feeding is not recommended due to the potential secretion into breast milk.2

SIDE EFFECTS:

 
ORGAN SITE

SIDE EFFECT

ONSET

Dose-limiting side effects are in bold, italics
I = immediate (onset in hours to days); E = early (days to weeks);
D = delayed (weeks to months); L = late (months to years)

allergy/immunology allergic reactions (3-5%)4 I      
sneezing (17-35%) I      
cardiovascular (general) hypotension (67%, symptomatic 3-15%)1,4,22,24,26 I      
constitutional symptoms fatigue (10%)4   E    
feeling of coldness (rare)7,19   E    
feeling unusually warm or flushed (rare)7,19 I      
sneezing (17%)7   E    
dermatology/skin extravasation hazard: none        
mild rash (rare)1 I      
gastrointestinal emetogenic potential: variable
alone: moderate (3-7%)1
with chemotherapy: moderate-high (70-90%)1
with radiotherapy: low-moderate (40%, severe 3-5%)1,4		 I      
hiccups (rare) I      
metabolic/laboratory hypocalcemia (rare)33 I      
neurology dizziness (5%)4 I      
somnolence (13%) I      

Adapted from reference 2 unless specified otherwise.

Hypotension is usually asymptomatic but rarely causes dizziness or fainting. It may be associated with dyspnea, apnea, hypoxia, and rarely, seizures, loss of consciousness, respiratory arrest or renal failure.2,3 It commonly occurs 14 minutes after the start of the infusion and lasts for 5-15 minutes. Hypotension is mediated by the active thiol metabolite, probably due to direct relaxation of vascular smooth muscle.19 Patients should be adequately hydrated prior to amifostine infusion. Consider holding antihypertensives for 24 hours prior to amifostine infusion.1

  • for patients treated with amifostine 200 mg/m2 dose for radiation-induced xerostomia, blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.34
  • for patients treated with amifostine 910 mg/m2 dose for cytotoxic chemoprotection , blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. Patients should be kept in a supine position during the infusion.34 Patients with symptomatic or significant reduction in systolic blood pressure (see table below) should have their infusion interrupted and managed symptomatically2,5,34:

 

 

Baseline Systolic Blood Pressure (mm Hg)

< 100

100-119

120-139

140-179

> 180

Decrease in systolic blood pressure during infusion

> 20

> 25

> 30

> 40

> 50

If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted so that the full dose of amifostine may be given. If the full dose cannot be given, the dose for subsequent cycles should be reduced to 740 mg/m2.

Hypocalcemia may occur transiently but is rarely clinically significant.1,33 Tetany secondary to hypocalcemia has been reported in one patient.33 Onset of hypocalcemia seems to be about four hours after the amifostine infusion.33,35 Hypocalcemia may be due to inhibition of parathyroid hormone (PTH) excretion and enhanced calciuria.19,33 Calcium levels may return to normal within a week without further treatment.35 Serum calcium should be monitored in patients at risk for hypocalcemia (eg, nephrotic syndrome, multiple doses of amifostine).1,33 If clinically significant hypocalcemia occurs, calcium supplements should be considered.1,2 In one patient with documented reduced PTH levels, calcium carbonate and calcitriol orally were given for 24 hours before amifostine therapy.33

Nausea and Vomiting: Prophylactic antiemetics were used in most clinical trials (usually serotonin antagonists)22,26 and the manufacturer recommends low dose serotonin receptor antagonist 1-2 hours prior to amifostine.36

INTERACTIONS:
AGENT EFFECT MECHANISM MANAGEMENT
anthracyclines (doxorubicin, epirubicin)1 small increase in anthracyclines AUC unknown no adjustments needed
docetaxel1 no alteration of pharmacokinetics   no adjustments needed
fluorouracil37 no alteration of pharmacokinetics   no adjustments needed
mitomycin1,7 no alteration of pharmacokinetics   no adjustments needed
paclitaxel1 small decrease in paclitaxel AUC unknown no adjustments needed
platinum agents (carboplatin,17,38-40 cisplatin41) moderate reduction in carboplatin and cisplatin elimination reduced renal clearance of carboplatin and cisplatin monitor for possible increase in carboplatin and cisplatin toxicity during concomitant use in patients with renal dysfunction17
topotecan no effect on topotecan pharmacokinetics42   no adjustments needed

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on solution preparation and compatibility, see Chemotherapy Chart in Appendix

Injection : 500mg single-dose vial containing sterile, lyophilized powder of amifostine (anhydrous). Store at room temperature.2

Reconstitute powder with 9.7 mL NS to give final concentration of 50 mg/mL.2

Reconstituted solution for injection: Reconstituted solution is stable for up to 5 hours at room temperature and for up to 24 hours in the refrigerator.2

Diluted solution for infusion: Solution should be further diluted with NS to a final concentration of 5-40 mg/mL. Diluted solution is stable for up to 5 hours at room temperature and up to 24 hours in refrigerator.2

Compatibility: The following chemotherapy agents are compatible via Y-site: bleomycin, carboplatin, carmustine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, docetaxel, doxorubicin, etoposide, fludarabine, fluorouracil, gemcitabine, ifosfamide, methotrexate, mitomycin, mitoxantrone, vinblastine, and vincristine.43

The following non-chemotherapy agents are compatible via Y-site: calcium gluconate, cimetidine, diphenhydramine, dopamine, dobutamine, furosemide, granisetron, heparin, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, leucovorin, lorazepam, magnesium sulfate, mannitol, mesna, methylprednisolone, metoclopramide, morphine sulfate, ondansetron, potassium chloride, promethazine, ranitidine, sodium bicarbonate.43

Incompatibility: The following are incompatible via Y-site: chlorpromazine, cisplatin, hydroxyzine, prochlorperazine.43

PARENTERAL ADMINISTRATION:

BCCA administration guideline noted in bold, italics

Subcutaneous investigational44
Intramuscular no information found
Direct intravenous no information found
Intermittent infusion for radioprotection, infuse over 3 min, 15-30 min prior to radiation
for chemoprotection, infuse over 15 min, initiated 30 min prior to chemotherapy; longer infusions not well tolerated.
Continuous infusion no information found
Intraperitoneal no information found
Intrapleural no information found
Intrathecal no information found
Intra-arterial no information found
Intrarectal (topical) investigational45
Intravesical no information found

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy.

Adults:

 

BCCA usual dose noted in bold, italics

Intravenous: For cytotoxic chemoprotection 500-910 mg/m2 IV once daily started 30 min before chemotherapy.2,3,11,14,46
    For patients receiving 910 mg/m2 who experience hypotension which does not resolve quickly, the amifostine dose2,3,34 for subsequent courses should be reduced to 740 mg/m2.
  For prevention of radiation-induced xerostomia 200 mg/m2 (range 200-340 mg/m2) IV once daily, beginning 15-30 min prior to radiation therapy.22,23,26 Blood pressure should be monitored immediately before and after the infusion.2,3,47
     
Duration of therapy:   no information found
     
Concurrent radiation:   protection of radiation-induced xerostomia
     
Dosage in myelosuppression: no adjustment required
     
Dosage in renal failure: no information found
     
Dosage in hepatic failure: no information found
     
Dosage in dialysis no information found  
     

Children:

Doses similar to those for adults have been used. However, the safety, efficacy and dosage have not been established.2

References:

1. 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(5):641-84.

2. Amifostine. USP DI. Volume 1. Drug information for the health care professional. 2Oth ed. Englewood, Colorado: Micromedex, Inc.; 2002.

3. McEvoy GK, editor. AHFS 2002 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2002.

4. MedImmune Oncology Inc. Ethyol (amifostine) product information. Gaithersburg, MD; 2002.

5. Schucter L. Guidelines for the administration of amifostine. Semin Oncol 1996;23(4 Suppl 8):40-3.

6. Capizzi RL. Clinical status and optimal use of amifostine. Oncology (Huntington) 1999;13(1):47-59; discussion 63, 7.

7. Spencer CM, Goa KL. Amifostine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as a radiopreotector and cytotoxic chemoprotector. Drugs 1995;50(6):1001-31.

8. Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996;14(7):2101-12.

9. Alberts DS. Protection by amifostine of cyclophosphamide-induced myelosuppression. Semin Oncol 1999;26(2 Suppl 7):37-40.

10. Capizzi RL. Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Semin Oncol 1999;26(2 Suppl 7):72-81.

11. Gelmon K, Eisenhauer E, Bryce C, et al. Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer. J Clin Oncol 1999;17(10):3038-47.

12. Genvresse I, Lange C, Schanz J, et al. Tolerability of the cytoprotective agent amifostine in elderly patients receiving chemotherapy: a comparative study. Anticancer Drugs 2001;12(4):345-9.

13. Ghielmini M, Van der Bosch S, Bosshard M, et al. Phase I-II study of escalating doses of amifostine combined with high-dose cyclophosphamide. Cancer Chemother Pharmacol 2001;47(6):532-6.

14. Hartmann JT, Fels LM, Knop S, et al. A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors. Invest New Drugs 2000;18(3):281-9.

15. Hartmann JT, von Vangerow A, Fels LM, et al. A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplantation. Br J Cancer 2001;84(3):313-20.

16. Johnson PW, Muers MF, Peake MD, et al. A randomized trial of amifostine as a cytoprotective agent in patients receiving chemotherapy for small cell lung cancer. Br J Cancer 2001;84(1):19-24.

17. Korst AE, van der Sterre ML, Eeltink CM, et al. Pharmacokinetics of carboplatin with and without amifostine in patients with solid tumors. Clin Cancer Res 1997;3(5):697-703.

18. Van den Brande J, Nannan Panday VR, Hoekman K, et al. Pharmacologic study of paclitaxel administered with or without the cytoprotective agent amifostine, and given as a single agent or in combination with epirubicin and cisplatin in patients with advanced solid tumors. Am J Clin Oncol 2001;24(4):401-3.

19. Foster-Nora J, Siden R. Amifostine for protection from antineoplastic drug toxicity. Am J Health-Syst Pharm 1997;54:787-800.

20. Schiller J, Storer B, Berlin J, et al. Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival. J Clin Oncol 1996;14(6):1913-21.

21. Anne PR, Curran WJ, Jr. A phase II trial of subcutaneous amifostine and radiation therapy in patients with head and neck cancer. Semin Radiat Oncol 2002;12(1 Suppl 1):18-9.

22. Antonadou D, Coliarakis N, Synodinou M, et al. Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 2001;51(4):915-22.

23. Antonadou D. Radiotherapy or chemotherapy followed by radiotherapy with or without amifostine in locally advanced lung cancer. Semin Radiat Oncol 2002;12(1 Suppl 1):50-8.

24. Antonadou D, Pepelassi M, Synodinou M, et al. Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;52(3):739-47.

25. Bourhis J, De Crevoisier R, Abdulkarim B, et al. A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2000;46(5):1105-8.

26. Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18(19):3339-45.

27. Buntzel J, Glatzel M, Kuttner K, et al. Amifostine in simultaneous radiochemotherapy of advanced head and neck cancer. Semin Radiat Oncol 2002;12(1 Suppl 1):4-13.

28. Komaki R, Lee JS, Kaplan B, et al. Randomized phase III study of chemoradiation with or without amifostine for patients with favorable performance status inoperable stage II-III non-small cell lung cancer: preliminary results. Semin Radiat Oncol 2002;12(1 Suppl 1):46-9.

29. Momm F, Bechtold C, Rudat V, et al. Alteration of radiation-induced hematotoxicity by amifostine. Int J Radiat Oncol Biol Phys 2001;51(4):947-51.

30. Movsas B. Exploring the role of the radioprotector amifostine in locally advanced non-small cell lung cancer: Radiation Therapy Oncology Group trial 98-01. Semin Radiat Oncol 2002;12(1 Suppl 1):40-5.

31. Peters K, Mucke R, Hamann D, et al. Supportive use of amifostine in patients with head and neck tumors undergoing radio-chemotherapy. Is it possible to limit the duration of the application of amifostine? Strahlenther Onkol 1999;175(Suppl 4):23-6.

32. Koukourakis MI, Kyrias G, Kakolyris S, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study. J Clin Oncol 2000;18(11):2226-33.

33. Wadler S, Haynes H, Beitler J, et al. Management of hypocalcemic effects of WR2721 administered on a daily times five schedule with cisplatin and radiation therapy. The New York Gynecologic Oncology Group. J Clin Oncol 1993;11(8):1517-22.

34. MedImmune Oncology Inc. Ethyol (amifostine) product information. Gaithersburg, MD; March 2003.

35. 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(19):1137-41.

36. MedImmune Oncology Inc. Antiemetic Regimen for Ethyol as a Radioprotectant. Gaithersburg, MD; 2002.

37. Martens-Lobenhoffer J, Fuhlroth J, Ridwelski K. Influence of the administration of amifostine on the pharmacokinetics of 5-fluorouracil in patients with metastatic colorectal carcinoma. Int J Clin Pharmacol Ther 2000;38(1):41-4.

38. van der Vijgh WJ, Korst AE. Amifostine (Ethyol): pharmacokinetic and pharmacodynamic effects in vivo. Eur J Cancer 1996;32A(Suppl 4):S26-30.

39. Korst AE, Boven E, van der Sterre ML, et al. Influence of single and multiple doses of amifostine on the efficacy and the pharmacokinetics of carboplatin in mice. Br J Cancer 1997;75(10):1439-46.

40. Korst AE, Eeltink CM, Vermorken JB, et al. Pharmacokinetics of amifostine and its metabolites in patients. Eur J Cancer 1997;33(9):1425-9.

41. Korst AE, van der Sterre ML, Gall HE, et al. Influence of amifostine on the pharmacokinetics of cisplatin in cancer patients. Clin Cancer Res 1998;4(2):331-6.

42. Zackrisson AL, Malmstrom H, Peterson C. No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients. Eur J Clin Pharmacol 2002;58(2):103-8.

43. Trissel LA. Handbook on injectable drugs. 10th ed. Bethesda (MD): American Society of Health-System Pharmacists; 2001.

44. Anne PR. Phase II trial of subcutaneous amifostine in patients undergoing radiation therapy for head and neck cancer.[erratum appears in Semin Oncol. 2003 Jun;30(3):417]. Semin Oncol 2002;29(6 Suppl 19):80-3.

45. Ben-Josef E, Han S, Tobi M, et al. A pilot study of topical intrarectal application of amifostine for prevention of late radiation rectal injury. Int J Radiat Oncol Biol Phys 2002;53(5):1160-4.

46. Hartmann JT, Knop S, Fels LM, et al. The use of reduced doses of amifostine to ameliorate nephrotoxicity of cisplatin/ifosfamide-based chemotherapy in patients with solid tumors. Anticancer Drugs 2000;11(1):1-6.

47. Schuchter LM, Hensley ML, Meropol NJ, 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(12):2895-903.
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