Amifostine: Difference between revisions

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{{DrugProjectFormSinglePage
{{DrugProjectFormSinglePage
|authorTag=
|authorTag={{AV}}
 
|genericName=Amifostine
 
|aOrAn=an
<!--Overview-->
|drugClass= radiation-protective agent
 
|indicationType=treatment
|genericName=
|hasBlackBoxWarning=Yes
 
|adverseReactions=<!--Black Box Warning-->
 
|blackBoxWarningTitle=Title
 
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
|aOrAn=
 
a
 
|drugClass=
 
 
 
|indication=
 
 
 
|hasBlackBoxWarning=
 
Yes
 
|adverseReactions=
 
 
 
<!--Black Box Warning-->
 
|blackBoxWarningTitle=
Title
 
|blackBoxWarningBody=
<i><span style="color:#FF0000;">ConditionName: </span></i>


* Content
* Content
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<!--FDA-Labeled Indications and Dosage (Adult)-->
<!--FDA-Labeled Indications and Dosage (Adult)-->
|fdaLIADAdult======Condition1=====
Amifostine for Injection is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.


|fdaLIADAdult=
Amifostine for Injection is indicated to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands (see CLINICAL STUDIES).
 
=====Condition1=====


For the approved indications, the clinical data do not suggest that the effectiveness of cisplatin based chemotherapy regimens or radiation therapy is altered by Amifostine for Injection. There are at present only limited data on the effects of amifostine on the efficacy of chemotherapy or radiotherapy in other settings. Amifostine should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study
* Dosing Information
* Dosing Information


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<!--Guideline-Supported Use (Adult)-->
<!--Guideline-Supported Use (Adult)-->
 
|offLabelAdultGuideSupport======Condition1=====
|offLabelAdultGuideSupport=
 
=====Condition1=====


* Developed by:  
* Developed by:  
Line 92: Line 63:


<!--Non–Guideline-Supported Use (Adult)-->
<!--Non–Guideline-Supported Use (Adult)-->
 
|offLabelAdultNoGuideSupport======Condition1=====
|offLabelAdultNoGuideSupport=
 
=====Condition1=====


* Dosing Information
* Dosing Information
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<!--FDA-Labeled Indications and Dosage (Pediatric)-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
 
|fdaLIADPed======Condition1=====
|fdaLIADPed=
 
=====Condition1=====


* Dosing Information
* Dosing Information
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<!--Guideline-Supported Use (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
 
|offLabelPedGuideSupport======Condition1=====
|offLabelPedGuideSupport=
 
=====Condition1=====


* Developed by:  
* Developed by:  
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<!--Non–Guideline-Supported Use (Pediatric)-->
<!--Non–Guideline-Supported Use (Pediatric)-->
 
|offLabelPedNoGuideSupport======Condition1=====
|offLabelPedNoGuideSupport=
 
=====Condition1=====


* Dosing Information
* Dosing Information
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<!--Contraindications-->
<!--Contraindications-->
|contraindications=* Amifostine for Injection is contraindicated in patients with known hypersensitivity to aminothiol compounds.
<!--Warnings-->
|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


|contraindications=
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.


* Condition1
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.


<!--Warnings-->
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
 
Serious cutaneous reactions have been associated with Amifostine for Injection administration. Serious cutaneous reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These reactions have been reported more frequently when amifostine is used as a radioprotectant (see ADVERSE REACTIONS). Some of these reactions have been fatal or have required hospitalization and/or discontinuance of therapy. Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration (see PRECAUTIONS).
 
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 ADMINISTRATLON). When amifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.


|warnings=
7.    Hypocalcemia


* Description
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.


====Precautions====
====Precautions====
General
Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored (see DOSAGE AND ADMINISTRATION).
The safety of Amifostine for Injection administration has not been established in elderly patients, or in patients with preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias, congestive heart failure, or history of stroke or transient ischemic attacks. Amifostine should be used with particular care in these and other patients in whom the common amifostine adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.
Prior to chemotherapy, Amifostine for Injection should be administered as a 15-minute infusion (see DOSAGE AND ADMINISTRATION). Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
Prior to radiation therapy, Amifostine for Injection should be administered as a 3-minute infusion (see DOSAGE AND ADMINISTRATION). Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
Cutaneous Reactions
Cutaneous reactions may require permanent discontinuation of Amifostine for Injection or urgent dermatologic consultation and biopsy (see below).
Cutaneous evaluation of the patient prior to each Amifostine for Injection administration should be performed with particular attention paid to the development of the following:
    -      Any rash involving the lips or involving mucosa not known to be due to another etiology (e.g., radiation mucositis, herpes simplex, etc.)
    -      Erythematous, edematous, or bullous lesions on the palms of the hands or soles of the feet and/or other cutaneous reactions on the trunk (front, back, abdomen)
    -      Cutaneous reactions with associated fever or other constitutional symptoms
Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from cutaneous reactions related to an alternate etiology. Amifostine for Injection should be permanently discontinued for serious or severe cutaneous reactions (see WARNINGS and ADVERSE REACTIONS) or for cutaneous reactions associated with fever or other constitutional symptoms not known to be due to another etiology. Amifostine should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown etiology appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms of the hand or soles of the feet. Reinitiation of amifostine should be at the physician’s discretion based on medical judgment and appropriate dermatologic evaluation. 
Allergic Reactions
In case of severe acute allergic reactions Amifostine for Injection should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.


* Description
* Description
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<!--Clinical Trials Experience-->
<!--Clinical Trials Experience-->
 
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
|clinicalTrials=
 
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.


=====Body as a Whole=====
=====Body as a Whole=====
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<!--Postmarketing Experience-->
<!--Postmarketing Experience-->
 
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
|postmarketing=
 
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.


=====Body as a Whole=====
=====Body as a Whole=====
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<!--Drug Interactions-->
<!--Drug Interactions-->
 
|drugInteractions=* Special consideration should be given to the administration of Amifostine for Injection in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension.
|drugInteractions=
 
* Drug
:* Description


<!--Use in Specific Populations-->
<!--Use in Specific Populations-->
 
|useInPregnancyFDA=* Pregnancy Category C. Amifostine has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. Amifostine for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
|useInPregnancyFDA=
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
* '''Pregnancy Category'''
 
|useInPregnancyAUS=
* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''


There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
 
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInLaborDelivery=
|useInNursing=No information is available on the excretion of amifostine or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with Amifostine for Injection.
There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
 
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInNursing=
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
 
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInPed=
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
 
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
 
|useInGender=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
 
|useInRace=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
 
|useInRenalImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
 
|useInHepaticImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
 
|useInReproPotential=
There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
 
|useInImmunocomp=
There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.


<!--Administration and Monitoring-->
<!--Administration and Monitoring-->
 
|administration=* Oral
|administration=
 
* Oral


* Intravenous
* Intravenous
 
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
|monitoring=
 
There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.


* Description
* Description


<!--IV Compatibility-->
<!--IV Compatibility-->
 
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
|IVCompat=
 
There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.


<!--Overdosage-->
<!--Overdosage-->
 
|overdose====Acute Overdose===
|overdose=
 
===Acute Overdose===


====Signs and Symptoms====
====Signs and Symptoms====
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<!--Drug box 2-->
<!--Drug box 2-->
|drugBox=<!--Mechanism of Action-->
|mechAction=*Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. The ability of  amifostine to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation.


|drugBox=
<!--Structure-->
 
|structure=* Amifostine for Injection is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) and has the following structural formula:
 
 
<!--Mechanism of Action-->


|mechAction=
H2N(CH2)3NH(CH2)2S-PO3H2


*
Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C5H15N2O3PS and it has a molecular weight of 214.22.


<!--Structure-->
Amifostine for Injection is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis.


|structure=
*
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]


<!--Pharmacodynamics-->
<!--Pharmacodynamics-->
 
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
|PD=
 
There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.


<!--Pharmacokinetics-->
<!--Pharmacokinetics-->
 
|PK=*Clinical pharmacokinetic studies show that amifostine is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of amifostine remains in the plasma 6 minutes after drug administration. Amifostine is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m2 of amifostine, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on amifostine pharmacokinetics.
|PK=
 
There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
 
<!--Nonclinical Toxicology-->
<!--Nonclinical Toxicology-->
 
|nonClinToxic=Carcinogenesis, Mutagenesis, Impairment of Fertility
|nonClinToxic=
No long term animal studies have been performed to evaluate the carcinogenic potential of amifostine. Amifostine was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes.
 
There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.


<!--Clinical Studies-->
<!--Clinical Studies-->
|clinicalStudies======Chemotherapy for Ovarian Cancer=====
*A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without Amifostine for Injection pretreatment at 910 mg/m2, in two successive cohorts of 121 patients with advanced ovarian cancer. *In both cohorts, after multiple cycles of chemotherapy, pretreatment with amifostine significantly reduced the cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had ≥40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine (>1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of amifostine was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of amifostine in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.
[[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]


|clinicalStudies=
*In the randomized ovarian cancer study, Amifostine for Injection had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the amifostine and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.
 
[[File:{{PAGENAME}}02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
=====Radiotherapy for Head and Neck Cancer=====
*A randomized controlled trial of standard fractionated radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without Amifostine for Injection, administered at 200 mg/m2 as a 3 minute i.v. infusion 15-30 minutes prior to each fraction of radiation, was conducted in 315 patients with head and neck cancer.  Patients were required to have at least 75% of both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less from start of radiation) and late xerostomia (9-12 months following radiation) as assessed by RTOG Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving amifostine (TABLE 4).
[[File:{{PAGENAME}}03.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
*At one year following radiation, whole saliva collection following radiation showed that more patients given Amifostine for Injection produced >0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production at one year was higher in those patients who received amifostine (0.26 gm vs. 0.1 gm). Stimulated saliva collections did not show a difference between treatment arms.  These improvements in saliva production were supported by the patients' subjective responses to a questionnaire regarding oral dryness.
*In the randomized head and neck cancer study, locoregional control, disease-free survival and overall survival were all comparable in the two treatment groups after one year of follow-up (see TABLE 5).
[[File:{{PAGENAME}}04.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]


<!--How Supplied-->
<!--How Supplied-->
 
|howSupplied=*  
|howSupplied=
 
*  


<!--Patient Counseling Information-->
<!--Patient Counseling Information-->
 
|fdaPatientInfo=There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
|fdaPatientInfo=
 
There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.


<!--Precautions with Alcohol-->
<!--Precautions with Alcohol-->
 
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=
 
* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.


<!--Brand Names-->
<!--Brand Names-->
 
|brandNames=* ®<ref>{{Cite web | title =  | url =  }}</ref>
|brandNames=
 
* ®<ref>{{Cite web | title =  | url =  }}</ref>


<!--Look-Alike Drug Names-->
<!--Look-Alike Drug Names-->
 
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>
|lookAlike=
 
* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>


<!--Drug Shortage Status-->
<!--Drug Shortage Status-->
|drugShortage=
|drugShortage=
}}
}}
{{PillImage
|fileName=No image.jpg
}}
{{LabelImage
|fileName={{PAGENAME}}11.png
}}
{{LabelImage
|fileName={{PAGENAME}}11.png
}}
<!--Pill Image-->


<!--Pill Image-->


{{PillImage
|fileName=No image.jpg|This image is provided by the National Library of Medicine.
|drugName=
|NDC=
|drugAuthor=
|ingredients=
|pillImprint=
|dosageValue=
|dosageUnit=
|pillColor=
|pillShape=
|pillSize=
|pillScore=
}}


<!--Label Display Image-->
<!--Label Display Image-->


{{LabelImage
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
}}


{{LabelImage
 
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
 
}}


<!--Category-->
<!--Category-->


[[Category:Drug]]
[[Category:Drug]]

Revision as of 15:05, 29 January 2015

Amifostine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]

Disclaimer

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Black Box Warning

Title
See full prescribing information for complete Boxed Warning.
ConditionName:
  • Content

Overview

Amifostine is an radiation-protective agent that is FDA approved for the treatment of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition1

Amifostine for Injection is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.

Amifostine for Injection is indicated to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands (see CLINICAL STUDIES).

For the approved indications, the clinical data do not suggest that the effectiveness of cisplatin based chemotherapy regimens or radiation therapy is altered by Amifostine for Injection. There are at present only limited data on the effects of amifostine on the efficacy of chemotherapy or radiotherapy in other settings. Amifostine should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study

  • Dosing Information
  • Dosage
Condition2
  • Dosing Information
  • Dosage
Condition3
  • Dosing Information
  • Dosage
Condition4
  • Dosing Information
  • Dosage

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Amifostine in adult patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Amifostine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding FDA-Labeled Use of Amifostine in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Amifostine in pediatric patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Amifostine in pediatric patients.

Contraindications

  • Amifostine for Injection is contraindicated in patients with known hypersensitivity to aminothiol compounds.

Warnings

Title
See full prescribing information for complete Boxed Warning.
ConditionName:
  • Content
  • 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

Serious cutaneous reactions have been associated with Amifostine for Injection administration. Serious cutaneous reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These reactions have been reported more frequently when amifostine is used as a radioprotectant (see ADVERSE REACTIONS). Some of these reactions have been fatal or have required hospitalization and/or discontinuance of therapy. Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration (see PRECAUTIONS).

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 ADMINISTRATLON). 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.

Precautions

General Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored (see DOSAGE AND ADMINISTRATION).

The safety of Amifostine for Injection administration has not been established in elderly patients, or in patients with preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias, congestive heart failure, or history of stroke or transient ischemic attacks. Amifostine should be used with particular care in these and other patients in whom the common amifostine adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.

Prior to chemotherapy, Amifostine for Injection should be administered as a 15-minute infusion (see DOSAGE AND ADMINISTRATION). Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.

Prior to radiation therapy, Amifostine for Injection should be administered as a 3-minute infusion (see DOSAGE AND ADMINISTRATION). Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.

Cutaneous Reactions Cutaneous reactions may require permanent discontinuation of Amifostine for Injection or urgent dermatologic consultation and biopsy (see below).

Cutaneous evaluation of the patient prior to each Amifostine for Injection administration should be performed with particular attention paid to the development of the following: 

   -       Any rash involving the lips or involving mucosa not known to be due to another etiology (e.g., radiation mucositis, herpes simplex, etc.) 
   -       Erythematous, edematous, or bullous lesions on the palms of the hands or soles of the feet and/or other cutaneous reactions on the trunk (front, back, abdomen)
   -       Cutaneous reactions with associated fever or other constitutional symptoms

Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from cutaneous reactions related to an alternate etiology. Amifostine for Injection should be permanently discontinued for serious or severe cutaneous reactions (see WARNINGS and ADVERSE REACTIONS) or for cutaneous reactions associated with fever or other constitutional symptoms not known to be due to another etiology. Amifostine should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown etiology appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms of the hand or soles of the feet. Reinitiation of amifostine should be at the physician’s discretion based on medical judgment and appropriate dermatologic evaluation.

Allergic Reactions In case of severe acute allergic reactions Amifostine for Injection should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.

  • Description

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Amifostine in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Amifostine in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Drug Interactions

  • Special consideration should be given to the administration of Amifostine for Injection in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category C. Amifostine has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. Amifostine for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amifostine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Amifostine during labor and delivery.

Nursing Mothers

No information is available on the excretion of amifostine or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with Amifostine for Injection.

Pediatric Use

There is no FDA guidance on the use of Amifostine with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Amifostine with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Amifostine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Amifostine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Amifostine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Amifostine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Amifostine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Amifostine in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Amifostine in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Amifostine in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Amifostine in the drug label.

Pharmacology

There is limited information regarding Amifostine Pharmacology in the drug label.

Mechanism of Action

  • Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. The ability of amifostine to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation.

Structure

  • Amifostine for Injection is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) and has the following structural formula:

H2N(CH2)3NH(CH2)2S-PO3H2

Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C5H15N2O3PS and it has a molecular weight of 214.22.

Amifostine for Injection is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Amifostine in the drug label.

Pharmacokinetics

  • Clinical pharmacokinetic studies show that amifostine is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of amifostine remains in the plasma 6 minutes after drug administration. Amifostine is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m2 of amifostine, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on amifostine pharmacokinetics.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal studies have been performed to evaluate the carcinogenic potential of amifostine. Amifostine was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes.

Clinical Studies

Chemotherapy for Ovarian Cancer
  • A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without Amifostine for Injection pretreatment at 910 mg/m2, in two successive cohorts of 121 patients with advanced ovarian cancer. *In both cohorts, after multiple cycles of chemotherapy, pretreatment with amifostine significantly reduced the cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had ≥40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine (>1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of amifostine was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of amifostine in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.
This image is provided by the National Library of Medicine.
  • In the randomized ovarian cancer study, Amifostine for Injection had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the amifostine and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.
This image is provided by the National Library of Medicine.
Radiotherapy for Head and Neck Cancer
  • A randomized controlled trial of standard fractionated radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without Amifostine for Injection, administered at 200 mg/m2 as a 3 minute i.v. infusion 15-30 minutes prior to each fraction of radiation, was conducted in 315 patients with head and neck cancer. Patients were required to have at least 75% of both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less from start of radiation) and late xerostomia (9-12 months following radiation) as assessed by RTOG Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving amifostine (TABLE 4).
This image is provided by the National Library of Medicine.
  • At one year following radiation, whole saliva collection following radiation showed that more patients given Amifostine for Injection produced >0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production at one year was higher in those patients who received amifostine (0.26 gm vs. 0.1 gm). Stimulated saliva collections did not show a difference between treatment arms. These improvements in saliva production were supported by the patients' subjective responses to a questionnaire regarding oral dryness.
  • In the randomized head and neck cancer study, locoregional control, disease-free survival and overall survival were all comparable in the two treatment groups after one year of follow-up (see TABLE 5).
This image is provided by the National Library of Medicine.

How Supplied

Storage

There is limited information regarding Amifostine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Amifostine in the drug label.

Precautions with Alcohol

  • Alcohol-Amifostine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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