Refer to individual protocols. Amifostine doses >300 mg/m2 are associated with a moderate emetic potential; depending on the amifostine dose, antiemetics may be recommended to prevent nausea/vomiting (POGO [Dupuis 2011]).
Cytoprotective agent against cisplatin or high-dose alkylating agents: Limited data available: Efficacy results variable:
Gastrointestinal and hematologic toxicity reduction: Infants, Children, and Adolescents: IV: 740 mg/m2/dose once daily prior to cytotoxic chemotherapy. In a study of patients (n=11, age range: 2.5 months to 17 years) receiving the same combination chemotherapy at the same doses (including cisplatin or high-dose alkylating agent) with or without amifostine, patients who received amifostine had significantly reduced incidences of mucositis and gastrointestinal toxicities and a significantly reduced requirement for erythrocyte transfusions. However, there was no difference in the number of platelet transfusions required (Cetingül 2009). In another study in osteosarcoma patients treated with cisplatin or carboplatin as part of combination chemotherapy, there was a reduction in neutrophil and leukocyte toxicity in patients who received amifostine (n=17) compared to those who did not (n=19); however, amifostine did not protect against platelet effects (Petrilli 2002). Other studies have not shown protection against myelosuppression (Adamson 1995; Bernstein 2006).
Nephrotoxicity reduction: Children and Adolescents: IV: 740 mg/m2/dose given immediately prior to cisplatin. In a small study of intracavitary cisplatin therapy for solid tumors, three patients (ages: 2 to 6 years) received amifostine. Of these patients, only one experienced persistent renal dysfunction (Katzenstein 2010).
Reduction of platinum-induced hearing loss: Children and Adolescents 3 to 20 years: IV: 600 mg/m2/dose given immediately prior to and 3 hours into cisplatin administration has been shown to reduce cisplatin-induced hearing loss in patients with average-risk medulloblastoma. Amifostine did not protect against hearing loss in patients with high-risk medulloblastoma (Fouladi 2008; Gurney 2014). Other studies using a single dose of 740 mg/m2 or 825 mg/m2 immediately prior to cisplatin did not prevent ototoxicity (Katzenstein 2009; Marina 2005; Petrilli 2002).
Xerostomia, moderate to severe from radiation of the head and neck, reduction: Limited data available: Children ≥7 years and Adolescents: SubQ: 200 mg once daily given 30 minutes prior to standard fraction radiation therapy. Dosing based on a small pilot study in pediatric patients who received subcutaneous amifostine (n=5, age range: 7 to 15 years) for a total of 129 injections. No grade 3 or 4 mucosal or skin reactions occurred (Anacak 2007).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.
Adult:
Dermatologic toxicity:
Cutaneous reactions or mucosal lesions appearing outside of the injection site or radiation port: Discontinue.
Bullous, edematous, or erythematous lesions on the palms or soles: Discontinue.
Severe acute allergic reaction: Discontinue permanently.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Amifostine: Drug information")
Note: Medications for the treatment of hypersensitivity reactions should be available during amifostine administration. Amifostine doses >300 mg/m2 are associated with a moderate emetic potential. Depending on the amifostine dose, antiemetics may be recommended to prevent nausea and vomiting. Antiemetics (including dexamethasone [20 mg IV] and a 5-HT3 receptor antagonist) are recommended with amifostine doses used for cisplatin-induced renal toxicity. Verify that patients are not hypotensive or dehydrated prior to amifostine administration. For patients receiving higher amifostine doses, interrupt antihypertensive therapy for 24 hours before amifostine treatment; patients who cannot safely stop their antihypertensives for 24 hours should not receive amifostine.
Radiation proctitis in rectal cancer, prevention (off-label use): IV: 340 mg/m2 once daily prior to radiation therapy (MASCC/ISOO (Lalla 2014); ESMO [Peterson 2015]).
Renal toxicity (cisplatin-induced): IV: 910 mg/m2 once daily over 15 minutes 30 minutes prior to chemotherapy.
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 standard fraction radiation therapy.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Intravenous:
Ethyol: 500 mg (1 ea [DSC])
Solution Reconstituted, Intravenous [preservative free]:
Ethyol: 500 mg (1 ea)
No
Amifostine doses >300 mg/m2 are associated with a moderate emetic potential; depending on the amifostine dose, antiemetics may be recommended to prevent nausea/vomiting (POGO [Dupuis 2011]).
Parenteral:
IV: Administer amifostine doses ≥600 mg/m2 as an IV intermittent infusion over 15 minutes since the 15-minute infusion is better tolerated than a more prolonged infusion. Administer 200 mg/m2 dose as a 3-minute infusion. Patients should be kept in supine position during infusion and amifostine should be interrupted if the blood pressure decreases significantly from baseline or if the patient develops symptoms related to decreased cerebral or cardiovascular perfusion. Patients experiencing decreased blood pressure should receive a rapid infusion of NS and be kept supine or placed in the Trendelenburg position. Amifostine can be restarted if the blood pressure returns to the baseline level.
SubQ: Administer dose 30 minutes prior to irradiation in abdominal wall; alternate sides; massage site locally following injection to reduce discomfort (Anacak 2007)
IV:
200 mg/m2 dose: Administer over 3 minutes starting 15 to 30 minutes prior to radiation therapy.
910 mg/m2 dose: Administer over 15 minutes starting 30 minutes prior to cisplatin. Do not exceed 15 minutes; longer infusions are associated with a higher incidence of side effects.
Patients who are hypotensive or dehydrated should not receive amifostine. Patients should be adequately hydrated and kept in supine position during infusion. Assess BP every 5 minutes during amifostine infusion and as clinically indicated following administration (for infusion duration <5 minutes, monitor BP before infusion, immediately after, and as clinically indicated thereafter). If hypotension occurs, place patient in the Trendelenburg position and administer NS via a separate IV line.
Amifostine doses >300 mg/m2 are associated with a moderate emetic potential. Depending on the amifostine dose, antiemetics may be recommended to prevent nausea and vomiting. Antiemetics (including dexamethasone [20 mg IV] and a 5-HT3 receptor antagonist) are recommended with amifostine doses used for cisplatin-induced renal toxicity.
Store intact vials at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°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 refrigerated (2°C to 8°C [36°F to 46°F]).
Reduction of cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer (FDA approved in adults); reduction of moderate to severe xerostomia from radiation treatment of the head and neck where the radiation port includes a substantial portion of the parotid glands (FDA approved in adults); has also been used as a cytoprotective agent to selectively protect normal tissues against toxicity due to cytotoxic chemotherapy. Note: 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.
Amifostine may be confused with amifampridine
Ethyol may be confused with ethanol
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Hypotension (ovarian cancer: 61% to 62%; head and neck cancer: 15%; generally transient)
Gastrointestinal: Nausea and vomiting (ovarian cancer: 96%; head and neck cancer: 53%), severe nausea and vomiting (ovarian cancer: 19%; head and neck cancer: 8%)
1% to 10%: Endocrine & metabolic: Hypocalcemia (head and neck cancer: 1%; clinically significant)
Frequency not defined:
Cardiovascular: Bradycardia, chest pain, extrasystoles, flushing, ischemic heart disease, tachycardia
Central nervous system: Chills, dizziness, drowsiness, malaise, sensation of cold
Dermatologic: Erythema multiforme, skin rash
Gastrointestinal: Diarrhea, hiccups
Hypersensitivity: Anaphylaxis
Local: Injection site reaction (includes bruising at injection site, erythema at injection site, inflammation at injection site, injection site pruritus, pain at injection site, rash at injection site, swelling at injection site, urticaria at injection site)
Ophthalmic: Blurred vision, diplopia
Respiratory: Apnea, dyspnea, hypoxia, sneezing
Miscellaneous: Fever
<1%, postmarketing, and/or case reports: Anaphylactoid reaction, atrial fibrillation, atrial flutter, cardiac arrhythmia, DRESS syndrome, hypersensitivity reaction (includes chest discomfort, laryngeal edema, pruritus, rigors, urticaria), myocardial infarction, renal failure, seizure, Stevens-Johnson syndrome, supraventricular tachycardia, syncope, toxic epidermal necrolysis, transient hypertension
Known hypersensitivity to amifostine, aminothiol compounds, or any component of the formulation.
Concerns related to adverse effects:
• Cutaneous reactions: Serious cutaneous reactions (some fatal), including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxicoderma, exfoliative dermatitis, and drug reaction with biopsy-proven eosinophilia and system symptoms (DRESS) have been reported with amifostine. Cutaneous reactions may be delayed, developing up to weeks after treatment initiation. Cutaneous reactions have been reported more frequently when used as a radioprotectant.
• Hypersensitivity: Hypersensitivity reactions (including anaphylaxis) have been reported, including chest discomfort, cutaneous eruptions, chills, dyspnea, hypoxia, laryngeal edema, pruritus, pyrexia, and urticaria.
• Hypocalcemia: Cases of clinically relevant hypocalcemia have been reported.
• Hypotension: Severe hypotension with complications have been reported, including (but not limited to) apnea, atrial fibrillation/flutter, bradycardia, dyspnea, myocardial ischemia/infarction, seizures, syncope, renal failure, tachycardia, and respiratory/cardiac arrest. The mean time of onset of hypotension was 14 minutes after amifostine infusion initiation and the mean hypotension duration was 6 minutes; in most cases BP returned to normal within 15 minutes. Patients who are hypotensive or dehydrated should not receive amifostine. Infusions >15 minutes are associated with a higher incidence of adverse effects. Interrupt antihypertensive therapy for 24 hours before amifostine treatment (monitor BP closely); patients who cannot safely stop their antihypertensives 24 hours before should not receive amifostine.
Other warnings/precautions:
• Chemotherapy/radiation therapy interference: Amifostine may interfere with the antitumor activity of chemotherapy or radiation therapy regimens. Unless within the context of a clinical trial, do not use amifostine in patients receiving definitive radiation therapy or in patients receiving chemotherapy for malignancies other than ovarian cancer in which chemotherapy can produce a significant survival benefit or cure. Data regarding interference with antitumor efficacy when amifostine is administered prior to cisplatin therapy in settings other than advanced ovarian cancer are limited. Data are also insufficient to exclude a tumor-protective effect in the definitive radiation therapy setting; amifostine was studied with standard fractionated radiotherapy and when ≥75% of both parotid glands were exposed to radiation. The safety and efficacy of amifostine on the incidence of xerostomia in the setting of combined chemotherapy and radiotherapy, and in the setting of accelerated or hyperfractionated therapy, have not been established.
None known.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Evaluate pregnancy status prior to use in patients who could become pregnant.
Based on data from animal reproduction studies, in utero exposure to amifostine may cause fetal harm.
Baseline blood pressure followed by a blood pressure reading every 5 minutes during the infusion and after administration if clinically indicated; monitor electrolytes, urinalysis, serum calcium, serum magnesium; monitor I & O; evaluate for cutaneous reactions prior to each dose
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)
Half-life elimination: Children: 9.3 minutes (Fouladi 2001); Adults: ~8 minutes
Excretion: Urine (minimal; as amifostine and metabolites)
Solution (reconstituted) (Ethyol Intravenous)
500 mg (per each): $1,285.69
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