Amifostine

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 [DSC])

Solution Reconstituted, Intravenous [preservative free]:

Ethyol: 500 mg (1 ea)

Generic: 500 mg (1 ea [DSC])

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

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: 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: Off Label

Radiation proctitis in patients with rectal cancer (prevention)yes

Based on the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the Management of Mucositis Secondary to Cancer Therapy and the European Society for Medical Oncology (ESMO) Clinical Recommendations for the management of oral and gastrointestinal mucositis, intravenous amifostine given for prevention of radiation proctitis in patients receiving radiation for rectal cancer is effective and recommended for the prevention of this condition.

Contraindications

Known hypersensitivity to amifostine, aminothiol compounds, or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: 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.

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Refer to individual protocols.

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).

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.

Dosing: Adjustment for Toxicity

Dermatologic toxicity:

Cutaneous reactions or mucosal lesions appearing outside of the injection site or radiation port: Discontinue amifostine.

Bullous, edematous or erythematous lesions on the palms or soles: Discontinue amifostine.

Hypotension: Interrupt amifostine infusion if 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 and the patient is asymptomatic, the infusion may be restarted so that the full amifostine dose may be administered. When the dose is 910 mg/m², if the full amifostine dose cannot be administered, reduce the amifostine dose for subsequent cycles to 740 mg/m².

Infusion reaction, severe: Discontinue amifostine immediately and permanently.

Severe allergic reaction: Discontinue amifostine immediately and permanently.

Reconstitution

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

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.

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.

Storage

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]).

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

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

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

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. 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 (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

Warnings/Precautions

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. Evaluate for dermatologic reactions prior to each dose, during therapy, and after treatment discontinuation. Discontinue amifostine for cutaneous reactions or mucosal lesions that appear outside of the injection site or radiation port and for bullous, edematous, or erythematous lesions on the palms or soles.
• Hypersensitivity: Hypersensitivity reactions (including anaphylaxis) have been reported, including chest discomfort, cutaneous eruptions, chills, dyspnea, hypoxia, laryngeal edema, pruritus, pyrexia, and urticaria. Discontinue immediately and permanently if severe allergic reaction occurs. Medications for the treatment of hypersensitivity reactions should be available during amifostine administration.
• Hypocalcemia: Cases of clinically relevant hypocalcemia have been reported. Monitor serum calcium levels in patients at risk of hypocalcemia, such as those with nephrotic syndrome, or patients receiving multiple amifostine doses. May require calcium supplementation.
• 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 blood pressure returned to normal within 15 minutes. Severe hypotension may require treatment interruption, dose reduction, and/or discontinuation. 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 amifostine infusion and after amifostine infusion as clinically indicated. If infusion duration is <5 minutes, monitor blood pressure at least before and immediately after infusion, and thereafter as clinically indicated. If hypotension occurs, place patient in the Trendelenburg position and administer IV NS 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 amifostine treatment (monitor blood pressure closely); 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). 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. Closely monitor fluid balance when administering amifostine in combination with highly emetic chemotherapy.

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: The American Society of Clinical Oncology (ASCO) has published guidelines for the use of protectants for chemotherapy and radiation (Hensley 2009). According to the ASCO guidelines, amifostine may be considered for prevention of nephrotoxicity in patients receiving cisplatin-based therapy. While amifostine may be considered to reduce the incidence of grade 3 or 4 neutropenia associated with chemotherapy, the guidelines suggest that alternative strategies (eg, growth factors) may be utilized in this situation. The guidelines recommend against the use of amifostine to reduce the incidence of thrombocytopenia associated with chemotherapy or radiation therapy. Data are insufficient to recommend amifostine for prevention of neurotoxicity or ototoxicity associated with platinum-based chemotherapy, for prevention of neurotoxicity associated with paclitaxel, for prevention of radiation therapy-induced mucositis associated with head and neck cancer, or for prevention of esophagitis due to chemotherapy in patients with non-small cell lung cancer. Additionally, amifostine may be considered to decrease the incidence of acute and late xerostomia in patients undergoing radiation therapy alone (for head and neck cancer); however, the guidelines do not support the use of amifostine in patients with head and neck cancer receiving concurrent platinum-based chemotherapy.
• 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.

Monitoring Parameters

Blood pressure (at baseline, every 5 minutes during the infusion, and thereafter if clinically indicated); serum calcium levels (in patients at risk for hypocalcemia). Evaluate pregnancy status prior to use in females of reproductive potential. Evaluate for cutaneous reactions prior to each dose, during therapy, and after treatment discontinuation. Monitor hydration status.

Pregnancy

Pregnancy Considerations

Based on data from animal reproduction studies, in utero exposure to amifostine may cause fetal harm.

Evaluate pregnancy status prior to use in females of reproductive potential.

Patient Education

What is this drug used for?

• It is used to lower the side effects of some chemo drugs or radiation.

Frequently reported side effects of this drug

• Nausea
• Vomiting

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Shortness of breath
• Chest pain
• Slow heartbeat
• Fast heartbeat
• Abnormal heartbeat
• Severe dizziness
• Passing out
• Chills
• Swollen glands
• Redness or irritation of palms or soles of feet
• Severe injection site irritation
• Seizures
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Low calcium like muscle cramps or spasms, numbness and tingling, or seizures
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

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