General Articles

Amifostine

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Ethyol® may be confused with ethanol

U.S. BRAND NAMES — Ethyol®

PHARMACOLOGIC CATEGORY
Adjuvant, Chemoprotective Agent (Cytoprotective)
Antidote

DOSING: ADULTS — Note: Antiemetic medication, including dexamethasone 20 mg I.V. and a serotonin 5-HT3 receptor antagonist, is recommended prior to and in conjunction with amifostine.

Cisplatin-induced renal toxicity, reduction: I.V.: 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 100-119
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 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.: 200 mg/m2 over 3 minutes once daily 15-30 minutes prior to radiation therapy or
SubQ (unlabeled route): 500 mg once daily prior to radiation therapy

Prevention of radiation proctitis in rectal cancer (unlabeled use): I.V.: 340 mg/m2 once daily prior to radiation therapy (Keefe, 2007; Peterson, 2008)

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution: 500 mg
Ethyol®: 500 mg

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution: 500 mg
Ethyol®: 500 mg

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — I.V.: Administer over 3 minutes (prior to radiation therapy) or 15 minutes (prior to cisplatin); administration as a longer infusion is associated with a higher incidence of side effects. Patients should be kept in supine position during infusion. Note: SubQ administration (unlabeled) has been used.

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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 HCl, dexamethasone sodium phosphate, diphenhydramine, dobutamine, docetaxel, dopamine, doxorubicin HCl, doxycycline, droperidol, enalaprilat, etoposide, famotidine, floxuridine, fluconazole, fludarabine, fluorouracil, furosemide, gallium nitrate, gemcitabine, gentamicin, granisetron, haloperidol lactate, heparin, hydrocortisone sodium succinate, hydromorphone, idarubicin, ifosfamide, imipenem/cilastatin, leucovorin calcium, lorazepam, magnesium sulfate, mannitol, mechlorethamine, meperidine, mesna, methotrexate, methylprednisolone sodium succinate, metoclopramide, metronidazole, mitomycin, mitoxantrone, morphine, nalbuphine, ondansetron, pemetrexed, piperacillin, potassium chloride, promethazine, ranitidine, sodium bicarbonate, streptozocin, teniposide, thiotepa, ticarcillin/clavulanate, tobramycin, vancomycin, vinblastine, vincristine, zidovudine. Incompatible: Acyclovir, amphotericin B, chlorpromazine, cisplatin, ganciclovir, hydroxyzine HCl, prochlorperazine edisylate.

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

USE – UNLABELED / INVESTIGATIONAL — Prevention of radiation proctitis in patients with rectal cancer

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Hypotension (15% to 61%; grades 3/4: 3% to 8%; dose dependent)
Gastrointestinal: Nausea/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): Apnea, anaphylactoid reactions, anaphylaxis, arrhythmia, atrial fibrillation, atrial flutter, back pain, bradycardia, cardiac arrest, chest pain, chest tightness, chills, cutaneous eruptions, dizziness, erythema multiforme, exfoliative dermatitis, extrasystoles, dyspnea, fever, flushing, hiccups, hypersensitivity reactions (fever, rash, hypoxia, dyspnea, laryngeal edema), hypertension (transient), hypoxia, malaise, MI, myocardial ischemia, pruritus, rash (mild), renal failure, respiratory arrest, rigors, seizure, sneezing, somnolence, Stevens-Johnson syndrome, supraventricular tachycardia, syncope, tachycardia, toxic epidermal necrolysis, toxoderma, urticaria CONTRAINDICATIONS — Hypersensitivity to aminothiol compounds or any component of the formulation 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 with amifostine. May be delayed, developing up to weeks after treatment initiation. Cutaneous reactions have been reported more frequently when used as a radioprotectant. Discontinue treatment for severe/serious cutaneous reaction, or with fever. 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 reactions: Rare hypersensitivity reactions, including anaphylaxis and allergic reaction, have been reported. Discontinue if 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 I.V. line; subsequent infusions may require a dose reduction. Infusions >15 minutes are associated with a higher incidence of adverse effects. Nausea/vomiting: The incidence of nausea and vomiting is higher in patients receiving amifostine, compared to chemotherapy alone. Antiemetic medications, including dexamethasone 20 mg I.V. 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.

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Disease-related concerns: Cardiovascular di

sease: 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: Antihypertensive therapy: Interrupt antihypertensive therapy for 24 hours before treatment; patients who cannot safely stop their antihypertensives 24 hours before should not receive amifostine.

Special populations: Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions: Appropriate use: 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.

DRUG INTERACTIONS
Antihypertensives: May enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

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PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Animal studies have demonstrated embryotoxicity. There are no adequate and well-controlled studies in pregnant women.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Due to the potential for adverse reactions in the nursing infant, breast-feeding should be discontinued.

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.

CANADIAN BRAND NAMES — Ethyol®

INTERNATIONAL BRAND NAMES — Amiphos (IN); Erifostine (AR); Ethyol (AR, AT, AU, BE, BG, BR, CH, CN, CO, CR, CZ, DE, DK, DO, EC, ES, FI, FR, GB, GT, HK, HN, IE, IL, IT, LU, MX, NI, NL, PA, PE, PH, PL, PT, SE, SV, TH, UY, VE)

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 (by cisplatin or radiation therapy) in tissues.

PHARMACODYNAMICS / KINETICS
Distribution: Vd: 3.5 L

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

Half-life elimination: ~8-9 minutes

Excretion: Urine
Clearance, plasma: 2.17 L/minute

PATIENT INFORMATION — This medication is given to help reduce side effects of your cancer therapy. Report immediately lightheadedness, dizziness, fainting, or any nausea; you will be given medication. Report chills, severe dizziness, tremors or shaking, or sudden onset of hiccups.

June 2010
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