DrugindexOnline^{2nd edition}

Pronouncation: (am-ih-FOSS-teen)
Class: Cytoprotective agent

Trade Names:
Ethyol
- Powder for injection, lyophilized 500 mg (anhydrous basis)

Mechanism of Action

Pharmacology

Organic thiophosphate cytoprotective agent that can reduce the toxicity of cisplatin. It binds to and thereby detoxifies, reactive metabolites of cisplatin. It scavenges reactive oxygen species generated by exposure to cisplatin radiation.

Pharmacokinetics

Distribution

Distribution t _½ is less than 1 min.

Metabolism

Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to the active free thiol metabolite. A disulfide metabolite is then subsequently produced.

Elimination

Rapidly cleared from plasma; elimination t _½ is about 8 min. Renal excretion is 0.69% to 2.64% (parent compound and metabolites).

Indications and Usage

Prevent or reduce renal damage in patients receiving repeated cisplatin doses for advanced ovarian or non-small cell lung cancer; reduce incidence of moderate to severe xerostomia in patients undergoing radiation of the parotid gland for head and neck cancer.

Unlabeled Uses

Prevent or reduce cisplatin-induced neurotoxicity and cyclophosphamide-induced granulocytopenia; prevent or reduce toxicity of radiation therapy to other areas; reduce toxicity of paclitaxel.

Contraindications

Sensitivity to aminothiol compounds.

Dosage and Administration

Reduction of Cumulative Renal Toxicity with Chemotherapy
Adults

IV Amifostine 910 mg/m ² once daily as a 15 min IV infusion, 30 min before chemotherapy.

Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck
Adults

IV Amifostine 200 mg/m ² once daily as a 3 min IV infusion, 15 to 30 min prior to standard fraction radiation therapy (1.8 to 2 Gy).

General Advice

• Reconstitute powder with 9.7 mL of 0.9% NaCl for a final amifostine concentration of 50 mg/mL.
• Prior to infusion further dilute amifostine in 0.9% NaCl to a final concentration of 5 to 40 mg/mL.
• Do not mix with other IV medications or IV fluids.
• Do not administer if cloudiness or particulate matter is noted.

Storage/Stability

Store vials at controlled room temperature (68° to 77°F). Reconstituted and diluted solutions are stable for up to 5 h at controlled room temperature or for up to 24 h if refrigerated (36° to 46°F).

Drug Interactions

Antihypertensives

Coadministration of drugs with similar pharmacologic effects may potentiate hypotension or cause additive side effects, including toxicity.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension (all grades 61%); hypotension (associated with apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain, MI, respiratory and cardiac arrest); arrhythmias (including atrial fibrillation/flutter and supraventricular tachycardia); cardiac arrest; transient hypertension; exacerbation of preexisting hypertension; syncope.

CNS

Dizziness; somnolence; seizures.

Dermatologic

Erythema multiforme; exfoliative dermatitis; Stevens-Johnson syndrome; toxic epidermal necrolysis.

GI

Nausea and vomiting (all grades 96%).

Metabolic

Hypocalcemia.

Renal

Renal failure.

Respiratory

Sneezing; hiccoughs.

Miscellaneous

Flushing; feeling of warmth; chills, feeling of coldness, fever; allergic reactions (including hypotension, fever, chills, rigors, dyspnea, hypoxia, chest tightness, cutaneous eruption, urticaria, laryngeal edema); anaphylactoid reactions.

Precautions

Monitor BP Monitor BP every 5 min during the 15 min infusion and thereafter as clinically indicated. Follow manufacturer's guidelines for interrupting and restarting amifostine if a decrease in systolic BP is noted. Stop the infusion for significant decreases in systolic BP. If systolic BP returns to normal and the patient is asymptomatic within 5 min, restart the infusion and continue to monitor BP. If systolic BP remains low, do not administer remainder of dose but administer reduced dose for subsequent cycles.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Safety and efficacy not established.

Hypersensitivity

Allergic manifestations including anaphylaxis and severe cutaneous reactions have occurred rarely.

Special Risk Patients

Avoid use in patients with hypersensitivity to amifostine and/or aminothiol compounds. Use cautiously in patients with cerebrovascular or CV disease or hypocalcemia.

Effectiveness of the cytotoxic regimen

Do not use in patients receiving chemotherapy for malignancies in which chemotherapy can produce a significant survival benefit or cure.

Effectiveness of radiotherapy

Do not administer in patients receiving definitive radiotherapy.

Hypotension

Do not give to patients who are hypotensive or dehydrated. If symptomatic hypotension develops, discontinue the infusion, place the patient in the Trendelenburg position, and administer normal saline via a separate IV line.

Overdosage

Symptoms

Anxiety, reversible urinary retention, hypotension.

Patient Information

• Advise patient that medication will be prepared and administered by health care provider in a health care setting just before chemotherapy or radiation therapy.
• Advise patient to remain supine for 15 min after completion of infusion and to use caution when standing up.
• Instruct patient to inform health care provider if noting any of the following during the administration of drug: anxiety, sweating, rapid heart beat, shortness of breath or difficulty breathing, swelling of the throat, rash, itching.