AHFS Class:

• Chemotherapy antidotes/protectants 91:04.12

Generic Name(s):

• Amifostine

Amifostine is a cytoprotective agent that acts both as a chemoprotectant and radioprotectant.1,2,3,9,11,14,16,20,21,22,23,24

Amifostine is used prophylactically as a cytoprotective agent to reduce the cumulative renal toxicity of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer.1,2,14 Amifostine also is used to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation therapy for the treatment of head and neck cancer where the radiation port includes a substantial portion of the parotid glands.1 Efficacy of cisplatin chemotherapy and that of radiation therapy for the described uses do not appear to be altered by the administration of amifostine.1 However, because the effect of amifostine on antitumor efficacy in other settings has not been elucidated, the manufacturer states that the drug should not be used in settings except under clinical study conditions.1

Prophylaxis in Patients Receiving Cisplatin

Amifostine is used as a cytoprotective agent to prevent or reduce the cumulative renal toxicity of cisplatin in patients with ovarian or non-small cell lung cancer.1,2,14 The drug is designated an orphan drug by the US Food and Drug Administration (FDA) for such use in advanced ovarian carcinoma.25 Although amifostine preferentially protects healthy cells against the cytotoxic effects of cisplatin (See Description) and there currently is no evidence of interference with the antineoplastic activity of cisplatin-based chemotherapy in patients with either of these cancers,1,2,4,10,16 this cytoprotective preference for healthy versus malignant cells is not absolute, and the possibility that amifostine might interfere with the antineoplastic activity of chemotherapeutic regimens in other patients currently cannot be excluded.1 The possibility of interference with antineoplastic efficacy would be of particular concern in patients whose cancer carries a good prognosis.1 Therefore, pending accumulation of additional experience, the manufacturer currently recommends that amifostine not be used in patients receiving chemotherapy for other malignancies where a significant survival benefit or cure is likely (e.g., in certain malignancies of germ cell origin), except under protocol conditions.1

The ability of amifostine to reduce the incidence and severity of cisplatin-induced nephrotoxicity has been demonstrated in a randomized, controlled study of patients receiving 6 cycles of a cisplatin-containing chemotherapeutic regimen (e.g., cyclophosphamide 1000 mg/m² and cisplatin 100 mg/m²).1,4,10,14 Cumulative renal toxicity was defined as a decrease in creatinine clearance of 40% or greater from baseline, protracted elevations in serum creatinine (i.e., exceeding 1.5 mg/dL), or severe hypomagnesemia (i.e., serum magnesium concentration of 1.4 mEq/L or less).1 Patients with advanced ovarian cancer receiving prophylactic amifostine before combination chemotherapy that included cisplatin developed less cumulative renal toxicity than those not receiving such protection.1,4,6,14 Subgroup analyses demonstrated a protective effect against nephrotoxicity both in patients with additional risk factors for developing nephrotoxicity (i.e., those receiving nephrotoxic anti-infectives concomitantly, those with preexisting diabetes mellitus or hypertension) and in those with no preexisting risk.1 Decreases in creatinine clearance of 40% or greater from baseline occurred in 30% of patients receiving chemotherapy without cytoprotection but in 13% of patients receiving prophylactic amifostine cytoprotection.1,3 The incidence of hypomagnesemia (serum magnesium concentration of 1.4 mEq/mL or less) in patients receiving a cisplatin regimen with amifostine compared with patients receiving a cisplatin regimen alone was 15 versus 30%, respectively.1 In addition, there was no detectable evidence of interference with the antineoplastic efficacy of cisplatin-containing chemotherapy regimens in patients with ovarian cancer receiving prophylactic amifostine therapy.1,2,4,10,14 No differences in pathologically confirmed remission rates,10,14 time to tumor progression, or duration of survival were observed in patients receiving amifostine before combination chemotherapy compared with those receiving combination chemotherapy alone.1,2

Limited information indicates that amifostine also may reduce cisplatin-induced renal toxicity without interfering with the efficacy of the antineoplastic regimen in patients with non-small cell lung cancer.1,5,7,8 In a phase II uncontrolled study in 25 patients with stage IV non-small cell lung cancer, a regimen of cisplatin (120 mg/m²monthly) and vinblastine (5 mg/m² weekly) and prophylactic amifostine (740-910 mg/m²monthly) was administered until disease progression or severe toxicity developed or a total of 6 chemotherapy cycles were administered.1 Of 13 patients receiving 4 or more chemotherapy cycles, one patient developed nephrotoxicity (evidenced by a 40 % or greater reduction in creatinine clearance compared with baseline).1 During a median follow-up of 19 months, the median survival was 17 months, with 64% of patients exhibiting a partial response and 64% surviving at least 1 year, suggesting that the cytoprotective effect of amifostine in such patients may not adversely effect antineoplastic efficacy.1

Prophylaxis in Patients Undergoing Radiation Therapy

Amifostine is used to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation therapy for the treatment of head and neck cancer where the radiation port includes a substantial portion of the parotid glands.1

In a randomized, controlled clinical trial in patients with head and neck cancer undergoing radiation therapy (at least 75% of both parotid glands having been exposed to radiation), the addition of amifostine (200 mg/m² as a 3-minute infusion administered 15-30 minutes prior to each fraction of radiation) reduced the incidence of both acute xerostomia (occurring within 90 days of initiation of radiation) and late xerostomia (occurring at 9-12 months following radiation).1 The incidence of substantial acute xerostomia was 51 or 78% of patients (undergoing radiation therapy) receiving amifostine or placebo, respectively, while late xerostomia was reported in 35 or 57% of those receiving the drug or placebo, respectively.1 In addition at 1 year following radiation therapy, median saliva production was higher in patients receiving adjuvant amifostine than in patients receiving radiation therapy alone.1 At 1-year follow-up, amifostine therapy did not affect overall survival rate, disease-free survival rate, or locoregional control.1 However, amifostine should not be administered to patients receiving high-dose (definitive) radiation therapy except those participating in a clinical trial, since there are insufficient data to exclude the possibility that the drug might interfere with the efficacy of such radiation therapy.1,26,27 In addition, amifostine was only studied in patients undergoing standard fractionated radiation when at least 75% of both parotid glands were exposed to radiation, and the drug was not studied in patients undergoing accelerated and hyperfractionated radiation therapy.1 The effects of amifostine on the incidence of xerostomia and other adverse effects have not been studied in patients undergoing combined chemotherapy and radiation.1

Reconstitution and Administration

Amifostine is administered by IV infusion.1 The sterile powder for injection is reconstituted by adding 9.7 mL of 0.9% sodium chloride injection to a vial labeled as containing 500 mg of amifostine.1 When reconstituted as directed, the reconstituted solution contains 50 mg of amifostine (calculated on the anhydrous basis) per mL.1 The manufacturer states that the reconstituted solution may be diluted in a compatible IV infusion solution (e.g., 0.9% sodium chloride injection) in a PVC container to a final concentration ranging from 5-40 mg of amifostine per mL.1 The resultant solutions are stable for 5 hours when stored at a room temperature of approximately 25°C or for 24 hours when refrigerated at 2-8°C.1 Amifostine solutions should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.1

As a chemoprotectant, amifostine generally is infused IV over 15 minutes, initiating the infusion 30 minutes prior to cisplatin administration.1 More extended IV infusions are not tolerated as well,1 and more rapid infusions have not been studied systematically.1 As a radioprotectant, amifostine is infused IV over 3 minutes, initiating the infusion 15-30 minutes prior to standard fractionated radiation therapy.1

Risk of Hypotension

Patients should be well hydrated prior to IV infusion of amifostine and maintained in a supine position during the infusion.1 The manufacturer warns that dehydrated patients and those who are hypotensive should not receive the drug.1 Antihypertensive therapy should be interrupted at least 24 hours prior to administration of amifostine at doses recommended for cytoprotection in patients receiving cisplatin.1 In addition, amifostine should not be used as a chemoprotectant in patients whose antihypertensive therapy cannot be withheld temporarily for at least 24 hours prior to infusion of the cytoprotective agent.1 Caution should be exercised in any patient receiving other drugs that could potentiate amifostine's hypotensive effect.1 Hypotension may occur during or shortly after completion of amifostine infusion, despite adequate hydration and positioning of the patient.1 Hypotension has been reported to be associated with dyspnea, apnea, hypoxia, and rarely seizures, unconsciousness, respiratory arrest, and renal failure.1 Because hypertensive conditions may be exacerbated by discontinuance of antihypertensive therapy or other factors associated with amifostine therapy (e.g., IV hydration), blood pressure should be carefully monitored during and after IV infusion of the drug in patients whose antihypertensive therapy has been temporarily withheld.1 In addition, blood pressure should be monitored frequently (e.g., every 5 minutes) during amifostine infusion in all patients receiving the drug, and the infusion should be interrupted if a clinically important decline in blood pressure occurs (e.g., a 20-mm Hg decline for those with a pretreatment systolic pressure of less than 100 mm Hg, or a 25-, 30-, 40-, or 50-mm Hg decline for those with a pretreatment systolic pressure of 100-119, 120-139, 140-179, or 180 mm Hg or greater, respectively).1,2 During infusions of less than 5 minutes' duration, blood pressure should be monitored at least before and immediately after completion of the infusion, and thereafter if needed.1 If hypotension requiring interruption of the amifostine infusion occurs, the patient should be placed in the Trendelenburg position and an IV infusion of 0.9% sodium chloride initiated in a separate line.1 If the patient's blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the amifostine infusion may be resumed.1,2

Risk of Hypersensitivity Reactions

Patients also should be closely monitored during and after IV administration of amifostine for possible allergic manifestations, including anaphylactic reactions that have rarely been associated with cardiac arrest.1 If acute hypersensitivity reactions occur, the infusion should be immediately and permanently discontinued.1 The manufacturer states that epinephrine and other appropriate measures should be available for immediate treatment of such events.1

Risk of Nausea and/or Vomiting

Because nausea and/or vomiting occur frequently during amifostine therapy and may be severe, effective antiemetic therapy (e.g., an IV corticosteroid such as dexamethasone and a serotonin 5-HT₃ receptor antagonist) should be administered prior to and in conjunction with amifostine therapy.1 Additional antiemetics may be required depending on the emetogenic potential of concomitantly administered chemotherapy or radiation therapy.1 In addition, the patient's fluid balance should be monitored carefully in those receiving highly emetogenic chemotherapy.1

Risk of Hypocalcemia

Although hypocalcemia occurs only rarely during cytoprotective therapy with amifostine, serum calcium concentrations should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or those receiving multiple doses of amifostine, and calcium supplementation initiated as necessary.1

Dosage

Dosages and concentrations of amifostine, which is available for parenteral use as the trihydrate, are calculated on the anhydrous basis.1

The manufacturer cautions that there currently is only limited experience with amifostine therapy in children or geriatric patients older then 70 years of age, although no special recommendations for dosage modification in these age groups are made.1 However, special care should be exercised if the drug is administered to geriatric patients or patients with preexisting cardiovascular or cerebrovascular conditions (e.g., ischemic heart disease, arrhythmias, congestive heart failure, history of stroke or transient ischemic attacks) since safety in such patients has not been established.1 Amifostine also should be used with caution in patients in whom common adverse effects of the drug (e.g., nausea/vomiting, hypotension) may have potentially serious consequences.1

Prophylaxis in Patients Receiving Cisplatin

The recommended initial dose of amifostine is 910 mg/m².1,2 If a clinically important decline in systolic blood pressure occurs, the infusion should be interrupted.1 (See Risk of Hypotension under Dosage and Administration: Reconstitution and Administration.) If the infusion is resumed to complete administration of the full dose and the patient experiences additional clinically important hypotension during the infusion, the dose of amifostine infusions during subsequent courses of chemotherapy should be reduced to 740 mg/m².1,2 For patients who tolerate the full initial amifostine dose, the full dose can be repeated during subsequent courses of chemotherapy as tolerated.1

Prophylaxis in Patients Undergoing Radiation Therapy

The recommended dose of amifostine is 200 mg/m² administered once daily over 3 minutes, initiated 15-30 minutes prior to standard fractionated radiation therapy.1

Dosage in Renal and Hepatic Impairment

Safety and efficacy of amifostine have not been evaluated systematically in patients with renal or hepatic impairment.2

Description

Amifostine, a phosphorylated aminosulfhydryl (aminothiol) compound, is a cytoprotective agent that acts both as a chemoprotectant and radioprotectant.1,2,3,9,11,14,16,20,21,22,23,24 Potency of the drug, which is commercially available for parenteral use as the trihydrate, is expressed in terms of amifostine, calculated on the anhydrous basis.

Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase to an active free sulfhydryl (thiol) metabolite (WR-1065).1,2,9,11,15,22 The pharmacologically active free sulfhydryl is believed to bind to and detoxify cytotoxic platinum-containing metabolites of cisplatin and scavenge 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 Healthy cells appear to be protected preferentially because of the 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 Because healthy cells have better perfusion, higher capillary alkaline phosphatase activity, and higher pH than malignant cells,1,2,12,15,23,24 and actively concentrate amifostine while malignant cells absorb the drug passively,9,11,12 there is increased cellular uptake of amifostine and more rapid generation of the free active sulfhydryl; therefore, compared with malignant cells, healthy cells appear to be selectively protected by amifostine against cisplatin-induced cytotoxicity.2,11,12,15,16

Similar to the drug's chemoprotection, amifostine's radioprotective effect may occur preferentially in healthy rather than malignant cells secondary to the drug's increased cellular uptake and conversion to the active sulfhydryl.2,11,15,21,24 Amifostine's radioprotectant effect appears to be mediated at least in part by removal of oxygen from tissues.2,15,20 Sulfhydryl compounds such as amifostine also appear to protect cells from the cytotoxic effects of radiation by scavenging hydroxyl radicals and repairing radiation-induced DNA radicals through donation of hydrogen.2,11,12,15,20

Amifostine can lower serum calcium concentrations, including total, ionized, and ultrafilterable calcium,1,2,17,18,19 but clinically important hypocalcemia occurs rarely during cytoprotective therapy with the drug.2 The hypocalcemic effect of amifostine appears to result from inhibition of parathyroid hormone secretion and bone resorption and from facilitation of urinary calcium excretion.2,17,18,19

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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