Amifostine (Monograph)

Brand name: Ethyol
Drug 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

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:

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

Drug Interactions

Specific Drugs

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

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

Actions

• 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Medical Disclaimer