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Amifostine

Pronunciation

(am i FOS teen)

Index Terms

  • Ethiofos
  • Gammaphos
  • WR-2721
  • YM-08310

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intravenous:

Ethyol: 500 mg (1 ea)

Generic: 500 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 500 mg (1 ea [DSC])

Brand Names: U.S.

  • Ethyol

Pharmacologic Category

  • Antidote
  • Chemoprotective Agent

Pharmacology

Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically-active free thiol metabolite. The free thiol is available to bind to, and detoxify, reactive metabolites of cisplatin; and can also act as a scavenger of free radicals that may be generated (by cisplatin or radiation therapy) in tissues.

Metabolism

Hepatic dephosphorylation to two metabolites (active-free thiol and disulfide)

Excretion

Urine (minimal; as amifostine and metabolites)

Half-Life Elimination

Children: 9.3 minutes (Fouladi 2001); Adults: ~8 minutes

Use: Labeled Indications

Renal toxicity (cisplatin-induced): Reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.

Xerostomia due to radiation therapy for head and neck cancer: Reduce the incidence of moderate-to-severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands.

Limitations of use: The clinical data do not suggest the efficacy of cisplatin-based chemotherapy or radiation therapy for the approved indications is altered by amifostine. Data on the effects of amifostine on the efficacy of chemotherapy or radiotherapy in other settings is limited. Do not administer amifostine in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, unless within the context of a clinical study.

Use: Unlabeled

Prevention of radiation proctitis in patients with rectal cancer

Contraindications

Hypersensitivity to amifostine, aminothiol compounds, or any component of the formulation

Dosing: Adult

Note: Amifostine doses >300 mg/m2 are associated with a moderate emetic potential. Antiemetic medication, including dexamethasone (20 mg IV when used for cisplatin-induced renal toxicity) and a serotonin 5-HT3 receptor antagonist, is recommended prior to and in conjunction with amifostine.

Renal toxicity (cisplatin-induced): IV: 910 mg/m2 once daily over 15 minutes 30 minutes prior to cytotoxic therapy

For 910 mg/m2 doses, the manufacturer suggests the following blood pressure-based adjustment schedule:

The infusion of amifostine should be interrupted if the systolic blood pressure decreases significantly from baseline, as defined below:

Decrease of 20 mm Hg if baseline systolic blood pressure <100

Decrease of 25 mm Hg if baseline systolic blood pressure 100 to 119

Decrease of 30 mm Hg if baseline systolic blood pressure 120 to 139

Decrease of 40 mm Hg if baseline systolic blood pressure 140 to 179

Decrease of 50 mm Hg if baseline systolic blood pressure ≥180

If blood pressure returns to normal within 5 minutes (assisted by fluid administration and postural management) and the patient is asymptomatic, the infusion may be restarted so that the full dose of amifostine may be administered. If the full dose of amifostine cannot be administered, the dose of amifostine for subsequent cycles should be 740 mg/m2.

Xerostomia due to radiation therapy for head and neck cancer: IV: 200 mg/m2 over 3 minutes once daily 15 to 30 minutes prior to radiation therapy

Radiation proctitis in rectal cancer, prevention (off-label use): IV: 340 mg/m2 once daily prior to radiation therapy (Lalla 2014; Peterson 2015)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for Toxicity

Dermatologic toxicity:

Severe/serious cutaneous reaction associated with fever (or other constitutional symptoms): Discontinue treatment permanently.

Rash involving lips or mucosa (of unknown etiology outside of radiation port) and for bullous, edematous or erythematous lesions on hands, feet or trunk: Withhold treatment and obtain dermatologic consultation; reinitiate only after careful evaluation.

Severe acute allergic reaction: Discontinue permanently.

Reconstitution

For IV infusion, reconstitute intact vials with 9.7 mL NS injection and dilute in NS to a final concentration of 5 mg/mL to 40 mg/mL.

Administration

Amifostine doses >300 mg/m2 are associated with a moderate emetic potential; antiemetics are recommended to prevent nausea/vomiting (Dupuis 2011)

IV: Administer over 3 minutes (15 to 30 minutes prior to radiation therapy) or over 15 minutes (30 minutes prior to cisplatin); administration as a longer infusion is associated with a higher incidence of side effects. Patients should be adequately hydrated and kept in supine position during infusion.

Compatibility

See Trissel’s IV Compatibility Database

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F). Reconstituted solutions (500 mg/10 mL) and solutions diluted in NS (in polyvinyl chloride [PVC] bags) for infusion are chemically stable for up to 5 hours at room temperature (~25°C [~77°F]) or up to 24 hours under refrigeration (2°C to 8°C [36°F to 46°F]).

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypotension (15% to 61%; grades 3/4: 3% to 8%; dose dependent)

Gastrointestinal: Nausea and vomiting (53% to 96%; grades 3/4: 8% to 30%; dose dependent)

1% to 10%: Endocrine & metabolic: Hypocalcemia (clinically significant: 1%)

<1% (Limited to important or life-threatening): Anaphylactoid reaction, anaphylaxis, apnea, atrial fibrillation, atrial flutter, back pain, bradycardia, cardiac arrest, cardiac arrhythmia, chest pain, chest tightness, chills, dizziness, drowsiness, dyspnea, erythema multiforme, exfoliative dermatitis, extrasystoles, fever, flushing, hiccups, hypersensitivity reaction (fever, skin rash, hypoxia, laryngeal edema), hypoxia, ischemic heart disease, malaise, myocardial infarction, pruritus, renal failure, respiratory arrest, rigors, seizure, skin rash (including mild), sneezing, Stevens-Johnson syndrome, supraventricular tachycardia, syncope, tachycardia, toxic epidermal necrolysis, toxoderma, transient hypertension, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Cutaneous reactions: Serious cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma, and exfoliative dermatitis have been reported (case reports) with amifostine. May be delayed, developing up to weeks after treatment initiation. Cutaneous reactions have been reported more frequently when used as a radioprotectant. Evaluate for dermatologic reactions prior to each dose. Discontinue treatment permanently for severe/serious cutaneous reaction associated with fever (or other constitutional symptoms). Withhold treatment and obtain dermatologic consultation for rash involving lips or mucosa (of unknown etiology outside of radiation port) and for bullous, edematous or erythematous lesions on hands, feet or trunk; reinitiate only after careful evaluation.

• Hypersensitivity: Rare hypersensitivity reactions, including anaphylaxis and allergic reaction, have been reported. Discontinue if severe acute allergic reaction occurs; do not rechallenge. Medications for the treatment of hypersensitivity reactions should be available.

• Hypocalcemia: Reports of clinically-relevant hypocalcemia are rare, but serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome, or patients receiving multiple amifostine doses. May require calcium supplementation.

• Hypotension: Hypotension may occur during or shortly after infusion. Patients who are hypotensive or dehydrated should not receive amifostine. Adequately hydrate prior to treatment and keep in a supine position during the infusion. Monitor blood pressure every 5 minutes during the infusion. If hypotension requiring interruption of therapy occurs, patients should be placed in the Trendelenburg position and given an infusion of normal saline using a separate IV line; subsequent infusions may require a dose reduction. Infusions >15 minutes are associated with a higher incidence of adverse effects. Interrupt antihypertensive therapy for 24 hours before treatment; patients who cannot safely stop their antihypertensives 24 hours before should not receive amifostine.

• Nausea/vomiting: Amifostine doses >300 mg/m2 are associated with a moderate emetic potential (Dupuis 2011). The incidence of nausea and vomiting is higher in patients receiving amifostine compared to chemotherapy alone. Antiemetic medications, including dexamethasone 20 mg IV and a serotonin 5-HT3 receptor antagonist, should be administered prior to and in conjunction with amifostine. Use with caution in patients whom the adverse effects of nausea/vomiting may have serious adverse events.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease or whom the adverse effects of hypotension may have serious adverse events.

• Cerebrovascular disease: Use with caution in patients with cerebrovascular disease.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Amifostine should not be used (in patients receiving chemotherapy for malignancies other than ovarian cancer) where chemotherapy is expected to provide significant survival benefit or in patients receiving definitive radiotherapy, unless within the context of a clinical trial. The American Society of Clinical Oncology (ASCO) guidelines for the use of protectants for chemotherapy and radiation do not recommend the use of amifostine to reduce the incidence of neutropenia or thrombocytopenia associated with chemotherapy or radiation therapy, neurotoxicity or ototoxicity associated with platinum-based chemotherapy, neurotoxicity associated with paclitaxel, radiation therapy-induced mucositis associated with head and neck cancer, or esophagitis due to chemotherapy in patients with non-small cell lung cancer; additionally, the guidelines do not support the use of amifostine in patients with head and neck cancer receiving concurrent platinum-based chemotherapy (Hensley 2009).

Monitoring Parameters

Blood pressure should be monitored every 5 minutes during the infusion and after administration if clinically indicated; serum calcium levels (in patients at risk for hypocalcemia). Evaluate for cutaneous reactions prior to each dose.

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber shortness of breath, angina, bradycardia, tachycardia, abnormal heartbeat, severe dizziness, passing out, severe nausea, severe vomiting, redness or irritation of palms or soles of feet, severe injection site irritation, signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures),or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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