Amifostine

Pronunciation

(am i FOS teen)

U.S. Brand Names

Ethyol®

Synonyms

Ethiofos; Gammaphos; WR2721; YM-08310

Generic Available

Canadian Brand Names

Ethyol®

Use

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. Reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or nonsmall cell lung cancer.

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

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

Warnings/Precautions

Patients who are hypotensive or in a state of dehydration should not receive amifostine. Interrupt antihypertensive therapy for 24 hours before amifostine. Patients receiving antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment also should not receive amifostine. Patients should be adequately hydrated prior to amifostine infusion and kept in a supine position during the infusion. Blood pressure should be monitored 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 I.V. line.

It is recommended that antiemetic medication, including dexamethasone 20 mg I.V. and a serotonin 5-HT3 receptor antagonist be administered prior to and in conjunction with amifostine. Rare hypersensitivity reactions, including anaphylaxis and severe cutaneous reaction, have been reported with a higher frequency in patients receiving amifostine as a radioprotectant. Discontinue if allergic reaction occurs; do not rechallenge.

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.

Adverse Reactions

>10%:

Cardiovascular: Flushing; hypotension (62%)

Central nervous system: Chills, dizziness, somnolence

Gastrointestinal: Nausea/vomiting (may be severe)

Respiratory: Sneezing

Miscellaneous: Feeling of warmth/coldness, hiccups

<1%, postmarketing, and/or case reports: Apnea, anaphylactoid reactions, anaphylaxis, arrhythmia, atrial fibrillation, cardiac arrest, erythema multiforme, exfoliative dermatitis; hypersensitivity reactions (fever, rash, hypoxia, dyspnea, laryngeal edema); hypocalcemia, mild rash, myocardial ischemia, rigors, seizure, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma

Overdosage/Toxicology

Symptoms of overdose include hypotension, nausea, and vomiting. Treatment includes supportive measures as clinically indicated.

Drug Interactions

Increased toxicity: Special consideration should be given to patients receiving antihypertensive medications or other drugs that could potentiate hypotension

Stability

Store intact vials of lyophilized powder at room temperature (20°C to 25°C/68°F to 77°F). Reconstitute with 9.7 mL of sterile 0.9% sodium chloride. The reconstituted solution (500 mg/10 mL) is chemically stable for up to 5 hours at room temperature (25°C) or up to 24 hours under refrigeration (2°C to 8°C). Amifostine should be further diluted in 0.9% sodium chloride to a concentration of 5-40 mg/mL; diluted solutions (5-40 mg/mL) are stable for up to 5 hours at room temperature (25°C) or up to 24 hours under refrigeration (2°C to 8°C). For SubQ administration, reconstitute with 2.4 mL NS or SWFI.

Compatibility

Stable in NS

Y-site administration: Compatible: Amikacin, aminophylline, ampicillin, ampicillin/sulbactam, aztreonam, bleomycin, bumetanide, buprenorphine, butorphanol, calcium gluconate, carboplatin, carmustine, cefazolin, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cimetidine, ciprofloxacin, clindamycin, co-trimoxazole, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, dexamethasone sodium phosphate, diphenhydramine, dobutamine, docetaxel, dopamine, doxorubicin, doxycycline, droperidol, enalaprilat, etoposide, famotidine, floxuridine, fluconazole, fludarabine, fluorouracil, furosemide, gemcitabine, gentamicin, granisetron, haloperidol, heparin, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydromorphone, idarubicin, ifosfamide, imipenem/cilastatin, leucovorin, lorazepam, magnesium sulfate, mannitol, mechlorethamine, meperidine, mesna, methotrexate, methylprednisolone sodium succinate, metoclopramide, metronidazole, mitomycin, mitoxantrone, morphine, nalbuphine, netilmicin, ondansetron, piperacillin, plicamycin, potassium chloride, promethazine, ranitidine, sodium bicarbonate, streptozocin, teniposide, thiotepa, ticarcillin, ticarcillin/clavulanate, tobramycin, trimetrexate, vancomycin, vinblastine, vincristine, zidovudine. Incompatible: Acyclovir, amphotericin B, cefoperazone, chlorpromazine, cisplatin, ganciclovir, hydroxyzine, minocycline, prochlorperazine edisylate

Mechanism of Action

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 in tissues.

Pharmacodynamics/Kinetics

Distribution: Vd: 3.5 L

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

Half-life elimination: 9 minutes

Excretion: Urine

Clearance, plasma: 2.17 L/minute

Dosage

Adults:

Cisplatin-induced renal toxicity, reduction: I.V.: 740-910 mg/m² once daily 30 minutes prior to cytotoxic therapy

Note: Doses >740 mg/m² are associated with a higher incidence of hypotension and may require interruption of therapy or dose modification for subsequent cycles. 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 100-119

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

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

Decrease of 50 mm Hg if baseline systolic blood pressure 180

If the 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 from head and neck cancer, reduction:

I.V.: 200mg/m² /day during radiation therapy or

SubQ: 500 mg/day during radiation therapy

Administration

I.V.: Administer over 3-15 minutes; administration as a longer infusion is associated with a higher incidence of side effects

Monitoring Parameters

Blood pressure should be monitored every 5 minutes during the infusion

Patient Education

This I.V. medication is given to help reduce side effects of your chemotherapy. Report immediately any nausea; you will be given medication. Report chills, severe dizziness, tremors or shaking, or sudden onset of hiccups. Breast-feeding precaution: Do not breast-feed.

Additional Information

Mean onset of hypotension is 14 minutes into the 15-minute infusion and the mean duration was 6 minutes.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Drowsiness is common

Mental Health: Effects on Psychiatric Treatment

Hypotension is common and may be additive with psychotropics

Oncology: Emetic Potential

High (60% to 90%)

Oncology: Vesicant

Dosage Forms

Injection, powder for reconstitution: 500 mg

References

Anne PR and 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.

Bonner HS and Shaw LM, "New Dosing Regimens for Amifostine: A Pilot Study to Compare the Relative Bioavailability of Oral and Subcutaneous Administration With Intravenous Infusion," J Clin Pharmacol , 2002, 42(2):166-74.

Capizzi RL and Oster W, "Chemoprotective and Radioprotective Effects of Amifostine: An Update of Clinical Trials," Int J Hematol , 2000, 72(4):425-35.

Culy CR and 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.

Koukourakis MI, "Amifostine in Clinical Oncology: Current Use and Future Applications," Anticancer Drugs , 2002, 13(3):181-209.

Koukourakis MI, Kyrias G, and Kakolyris S, "Subcutaneous Administration of Amifostine During Fractionated Radiotherapy: A Randomized Phase II Study," J Clin Oncol , 2000, 18(11):2226-33.

Spencer CM and Goa KL, "Amifostine. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential as a Radioprotector and Cytotoxic Chemoprotector," Drugs , 1995, 50(6):1001-31.

Wasserman TH and Brizel DM, "The Role of Amifostine as a Radioprotector," Oncology (Huntingt) , 2001, 15(10):1349-54.

International Brand Names

Amiphos® (IN); Ethyol® (AR, AU, BE, CA, CH, CL, CR, CZ, DE, DK, DO, ES, FI, FR, GB, GT, HN, HR, HU, ID, IL, IT, LU, MX, NL, NZ, PA, PL, RO, RU, SE, SG, SV, TH, TR)

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