Amifostine

Name: Amifostine

Overdose

In clinical trials, the maximum single dose of ETHYOL (amifostine) was 1300 mg/m2. No information is available on single doses higher than this in adults. In the setting of a clinical trial, pediatric patients have received single ETHYOL (amifostine) doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible urinary retention occurred.

Administration of ETHYOL (amifostine) at 2 and 4 hours after the initial dose has not led to increased nausea and vomiting or hypotension. The most likely symptom of overdosage is hypotension, which should be managed by infusion of normal saline and other supportive measures, as clinically indicated.

Amifostine Overview

Amifostine is a prescription medication used to protect the kidneys during chemotherapy and reduces dry mouth during radiation.  Amifostine belongs to a group of drugs called cytoprotectants.  These work by protecting against the harmful effects of chemotherapy medications and radiation treatment.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects of amifostine include nausea, vomiting, and low blood pressure.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Amifostine side effects

Get emergency medical help if you have signs of an allergic reaction: hives, itching; chest tightness, difficult breathing; fever or chills; swelling of your face, lips, tongue, or throat.

Tell your caregivers right away if you have:

  • severe or ongoing vomiting;

  • a light-headed feeling, like you might pass out;

  • weak or shallow breathing;

  • chest pain, fast or slow heart rate;

  • a seizure;

  • redness, rash, or blisters on the palms of your hands or the soles of your feet; or

  • severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

In rare cases, amifostine may cause a severe drug reaction that can affect many parts of the body. This type of reaction can start several weeks after you begin using this medicine. Seek medical treatment if you have new or worsening symptoms of:

  • fever, flu symptoms, swollen glands, weight loss, feeling weak or tired;

  • severe tingling or numbness;

  • facial swelling, red or blistering skin rash;

  • pain or burning when you urinate, lower back pain, swelling in your legs or feet;

  • upper stomach pain, loss of appetite, jaundice (yellowing of the skin or eyes); or

  • cough, chest pain, or trouble breathing.

Common side effects may include:

  • nausea, vomiting;

  • flushing (warmth, redness, or tingly feeling);

  • fever, chills, general ill feeling;

  • rash;

  • dizziness, drowsiness;

  • hiccups, sneezing;

  • blurred vision, double vision; or

  • pain, itching, redness, bruising, or swelling around the IV needle.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Amifostine dosing information

Usual Adult Dose for Non-Small Cell Lung Cancer:

To reduce the cumulative renal toxicity associated with repeated administration of cisplatin: 910 mg/m2 administered once daily as a 15 minute IV infusion, starting 30 minutes prior to chemotherapy.

The 15 minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.

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, and thereafter as clinically indicated.

The infusion of amifostine should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
1) baseline systolic blood pressure is =180 mm Hg and decreases by 50 mm Hg during treatment

If the blood pressure returns to normal within 5 minutes 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 chemotherapy cycles should be 740 mg/m2.

It is recommended that antiemetic medication, including dexamethasone 20 mg intravenously and a serotonin 5-HT3 receptor antagonist, be administered prior to and in conjunction with amifostine. Additional antiemetics may be required based on the chemotherapy drugs administered.

Usual Adult Dose for Ovarian Cancer:

To reduce the cumulative renal toxicity associated with repeated administration of cisplatin: 910 mg/m2 administered once daily as a 15 minute IV infusion, starting 30 minutes prior to chemotherapy.

The 15 minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.

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, and thereafter as clinically indicated.

The infusion of amifostine should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
1) baseline systolic blood pressure is =180 mm Hg and decreases by 50 mm Hg during treatment

If the blood pressure returns to normal within 5 minutes 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 chemotherapy cycles should be 740 mg/m2.

It is recommended that antiemetic medication, including dexamethasone 20 mg intravenously and a serotonin 5-HT3 receptor antagonist, be administered prior to and in conjunction with amifostine. Additional antiemetics may be required based on the chemotherapy drugs administered.

Usual Adult Dose for Malignant Disease:

For reduction 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:
The recommended dose of amifostine is 200 mg/m2 administered once daily as a 3 minute intravenous infusion, starting 15 to 30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy).

Patients should be adequately hydrated prior to amifostine infusion. Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.

It is recommended that antiemetic medication be administered prior to and in conjunction with amifostine. Oral 5-HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.

Amifostine Dosage and Administration

General

  • Adequately hydrate patient prior to administration.a

  • Monitor BP every 5 minutes during infusion and thereafter as clinically indicated; if infusion period is <5 minutes duration, monitor BP at least before and immediately after completion of the infusion.a

  • All patients should receive antiemetics (e.g., dexamethasone 20 mg IV and a type 3 serotonin [5-HT3] receptor antagonist) prior to and during infusion.1 Additional antiemetics may be required based on the chemotherapy regimen.a (See GI Effects under Cautions.)

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Patient should remain in supine position during infusion.a

Interrupt infusion if a clinically important decline in SBP occurs as listed below:

Guideline for Interrupting Infusion due to Decreases in SBP12

Baseline SBP (mm Hg)

Decreases in SBP during infusion (mm Hg)

<100

20

100–119

25

120–139

30

140–179

40

≥180

50

Resume infusion, if BP returns to normal within 5 minutes and patient is asymptomatic.a

Reconstitution

Reconstitute vial containing 500 mg of amifostine powder with 9.7 mL of 0.9% sodium chloride for injection, to provide a solution containing 50 mg/mL.a

Dilution

May be diluted with 0.9% sodium chloride for injection in a PVC container to a final concentration of 5–40 mg/mL.a

Rate of Administration

Prophylaxis of cisplatin-induced nephrotoxicity: Administer over 15 minutes.1 Infusions over >15 minutes are associated with increased side effectsa (see Hypotension under Cautions) and more rapid infusions have not been studied systematically.1

Prophylaxis of radiation therapy-induced xerostomia: Administer over 3 minutes.1

Dosage

Available as the trihydrate form of amifostine; dosage expressed in terms of amifostine.a

Adults

Prophylaxis of Cisplatin-induced Nephrotoxicity IV

Initially, 910 mg/m2 once daily over 15 minutes, starting 30 minutes prior to cisplatin administration.a

If full initial dose is tolerated, repeat the full dose during subsequent courses of chemotherapy as tolerated.1

If the full dose cannot be administered, reduce dosage to 740 mg/m2 during subsequent chemotherapy cycles.a

Prophylaxis of Radiation Therapy-induced Xerostomia IV

200 mg/m2 once daily over 3 minutes; initiate infusion 15–30 minutes prior to standard fractionated radiation therapy (1.8–2 Gy).a

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.a

Renal Impairment

No specific dosage recommendations at this time.a

Geriatric Patients

Careful dosage selection recommended due to possible age-related decreases in hepatic, renal, or cardiac function and concomitant diseases or drug therapies.a

Interactions for Amifostine

Specific Drugs

Drug

Interaction

Comments

Antihypertensive agents

Additive hypotensive effectsa

Temporarily discontinue antihypertensive therapy ≥24 hours prior to amifostine administration; concurrent administration is not recommendeda

Dexamethasone

Pharmacokinetic interaction unlikelya

Metoclopramide

Pharmacokinetic interaction unlikely.a

Stability

Storage

Parenteral

Powder for Injection

20–25°C.a

Reconstituted solution is stable for 5 hours at room temperature (approximately 25°C) or 24 hours under refrigeration (2–8°C).a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Compatibility with solutions other than 0.9% sodium chloride for injection without additives has not been examined.a Use of other solutions is not recommended.a

What are some things I need to know or do while I take Amifostine?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • If you are taking drugs for high blood pressure, talk with your doctor. Your doctor may ask you to skip that drug the day before and on the morning of care.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Have your blood pressure checked often. Talk with your doctor.
  • You will need to be sure that you are not dehydrated before getting amifostine. Check with your doctor to see if you need to drink extra fluids before getting this medicine.
  • Other drugs will be given with amifostine to help avoid side effects.
  • A very bad and sometimes deadly reaction has happened with this medicine. Most of the time, this reaction has signs like fever, rash, or swollen glands with problems in body organs like the liver, kidney, blood, heart, muscles and joints, or lungs. Talk with the doctor.
  • If you are 65 or older, use amifostine with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of low calcium levels like muscle cramps or spasms, numbness and tingling, or seizures.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Very bad dizziness or passing out.
  • Shortness of breath.
  • Seizures.
  • Chest pain or pressure.
  • Fast or slow heartbeat.
  • A heartbeat that does not feel normal.
  • Very upset stomach or throwing up.
  • Swollen gland.
  • Redness or irritation of the palms of hands or soles of feet.
  • Very bad irritation where the shot was given.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

Warnings

1.    Effectiveness of the Cytotoxic Regimen

Limited data are currently available regarding the preservation of antitumor efficacy when Amifostine for Injection is administered prior to cisplatin therapy in settings other than advanced ovarian cancer. Although some animal data suggest interference is possible, in most tumor models the antitumor effects of chemotherapy are not altered by Amifostine. Amifostine should not be used in patients receiving chemotherapy for other malignancies in which chemotherapy can produce a significant survival benefit or cure (e.g., certain malignancies of germ cell origin), except in the context of a clinical study.

2.    Effectiveness of Radiotherapy

Amifostine for Injection should not be administered in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are at present insufficient data to exclude a tumor-protective effect in this setting. Amifostine was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of Amifostine on the incidence of xerostomia and on toxicity in the setting of combined chemotherapy and radiotherapy and in the setting of accelerated and hyperfractionated therapy have not been systematically studied.

3.    Hypotension

Patients who are hypotensive or in a state of dehydration should not receive Amifostine for Injection. Patients receiving Amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of Amifostine. Patients receiving Amifostine at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding Amifostine treatment, should not receive Amifostine.

Prior to Amifostine for Injection infusion patients should be adequately hydrated. During Amifostine infusion patients should be kept in a supine position. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. It is important that the duration of the 910 mg/m2 infusion not exceed 15 minutes, as administration of Amifostine as a longer infusion is associated with a higher incidence of side effects. For infusion durations less than 5 minutes, blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated. If hypotension occurs, patients should be placed in the Trendelenburg position and be given an infusion of normal saline using a separate i.v. line. During and after Amifostine infusion, care should be taken to monitor the blood pressure of patients whose antihypertensive medication has been interrupted since hypertension may be exacerbated by discontinuation of antihypertensive medication and other causes such as i.v. hydration.

Guidelines for interrupting and restarting Amifostine for Injection infusion if a decrease in systolic blood pressure should occur are provided in the DOSAGE AND ADMINISTRATION section. Hypotension may occur during or shortly after Amifostine infusion, despite adequate hydration and positioning of the patient (see ADVERSE REACTIONS and PRECAUTIONS). Hypotension has been reported to be associated with dyspnea, apnea, hypoxia, and in rare cases seizures, unconsciousness, respiratory arrest and renal failure.

4.    Cutaneous Reactions

Fatal and serious cutaneous reactions have been reported with Amifostine for Injection treatment, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxicoderma, exfoliative dermatitis and drug reaction with biopsy-confirmed eosinophilia and systemic symptoms (DRESS). These reactions have been reported more frequently when Amifostine for Injection is used as a radioprotectant (see ADVERSE REACTIONS). Serious cutaneous reactions may develop weeks after initiation of Amifostine for Injection administration. Monitor patients carefully prior to, during and after Amifostine for Injection administration. Discontinue Amifostine for Injection for cutaneous reactions or mucosal lesions appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms or soles.

5.    Hypersensitivity

Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with Amifostine for Injection administration.

6.    Nausea and Vomiting

Antiemetic medication should be administered prior to and in conjunction with Amifostine for Injection (see DOSAGE AND ADMINISTRATION). When Amifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.

7.    Hypocalcemia

Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Amifostine for Injection (see ADVERSE REACTIONS). If necessary, calcium supplements can be administered.

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]:

Generic: 500 mg (1 ea [DSC])

Pharmacology

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)

Excretion

Urine (minimal; as amifostine and metabolites)

Half-Life Elimination

Children: 9.3 minutes (Fouladi 2001); Adults: ~8 minutes

Dosing Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

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. 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 treatment for severe/serious cutaneous reactions or mucosal lesions that appear outside of the radiation port and for bullous, edematous, or erythematous lesions on the palms or soles.

• Hypersensitivity: Rare hypersensitivity reactions, including anaphylaxis and allergic reaction, have been reported. Discontinue if severe acute 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. Short term (reversible) syncope (loss of consciousness) has been rarely reported. 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 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 treatment; 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). The incidence of nausea and vomiting is higher in patients receiving amifostine compared to chemotherapy alone. Antiemetic medications, including dexamethasone 20 mg IV and a serotonin 5-HT3 receptor antagonist, should be administered prior to and in conjunction with amifostine. Use with caution in patients for whom the adverse effects of nausea/vomiting may have serious adverse events.

Disease-related concerns:

• Cardiovascular disease: 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:

• 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: According to the manufacturer, amifostine 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. 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 is 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.

Dosing & Uses

Dosage Forms & Strengths

powder for injection

  • 500mg/vial

Nephrotoxicity

Indicated to reduce cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer

910 mg/m² IV (15-minute infusion), 30 minutes before chemotherapy 

Blood pressure should be followed following its administration and interrupted if systolic blood pressure decreases signficantly from baseline as described below

Interrupt Therapy If Systolic Blood Pressure Baseline Decreased

  • Decreased by 20 mm Hg if baseline <100
  • Decreased by 25 mm Hg if baseline <100-119
  • Decreased by 30 mm Hg if baseline <120-139
  • Decreased by 40 mm Hg if baseline <140-179
  • Decreases by 50 mm Hg if baseline ≥180

Xerostomia

Indicated to reduce 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

200 mg/m² IV (3-minute infusion), 15-30 minutes before radiation therapy 

500 mg SC qDay prior to radiation therapy

Chemoprotective Agent (Orphan)

Orphan indications

  • Chemoprotection for cisplatin in the treatment of metastatic melanoma
  • Reduction of incidence and severity of toxicities associated with cisplatin administration
  • Chemoprotection for cyclophosphamide in the treatment of advanced ovarian carcinoma
  • Treatment of myelodysplastic syndromes

Orphan indications sponsor

  • Medimmune Oncology, Inc; One MedImmune Way; Gaithersburg, MD 20878

Administration

Ensure adequate hydration and premedicate with antiemetic treatment

Safety and efficacy not established

Pharmacology

Mechanism of Action

Thiol metabolite binds to reactive metabolites of cisplatin and scavenges free radicals

Pharmacokinetics

Half-Life: 8 min

Metabolite: Free thiol

Metabolism: Liver

Vd: 3.5 L

Half-life: 8-9 min

Excretion: Urine

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Dialysis

Data not available.

Other Comments

Amifostine should not be administered in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are at present insufficient data to exclude a tumor protective effect in this setting.

Antiemetic medication should be administered prior to and in conjunction with amifostine. When amifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.

Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of amifostine. If necessary, calcium supplements can be administered.

Amifostine Breastfeeding Warnings

There are no data on the excretion of amifostine into human milk. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants, discontinuation of breast-feeding is recommended if the mother is to be treated with amifostine.

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