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ETHYOL®
(amifostine) for Injection
Description Clinical Pharmacology Indications and Usage
Contraindications Warnings Precautions
Adverse Reactions Overdosage Dosage and Administration
How Supplied
Rx only
DESCRIPTION
ETHYOL (amifostine) 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.
ETHYOL 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.
CLINICAL PHARMACOLOGY
ETHYOL 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 ETHYOL 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.
Pharmacokinetics: Clinical pharmacokinetic studies show that ETHYOL 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 ETHYOL remains in the plasma 6 minutes after drug administration.
ETHYOL 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
ETHYOL, 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 ETHYOL. Pretreatment with
dexamethasone or metoclopramide has no effect on ETHYOL pharmacokinetics.
Clinical Studies
Chemotherapy for Ovarian Cancer . A randomized controlled trial compared six cycles of
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cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without ETHYOL 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 ETHYOL 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
ETHYOL 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 ETHYOL in reducing the
cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES
1 and 2, below.
TABLE 1
Proportion of Patients with ≥40% Reduction in Calculated Creatinine Clearance*
ETHYOL+CP CP p-value
(2-sided)
All Patients 16/122 (13%) 36/120 (30%) 0.001
First Cohort 10/63 20/58 0.018
Second Cohort 6/59 16/62 0.026
*Creatinine clearance values were calculated using the Cockcroft-Gault formula, Nephron 1976;
16:31-41.
TABLE 2
NCI Toxicity Grades of Serum Magnesium Levels
for Each Patient's Last Cycle of Therapy
NCI-CTC Grade: 0 1 2 3 4 p-value* (mEq/L) >1.4 ≤1.4->1.1 ≤1.1->0.8 ≤0.8->0.5 ≤0.5
All Patients 0.001
92 13 3 0 0 ETHYOL+CP
73 18 7 5 1 CP
First Cohort 0.017
49 10 3 0 0 ETHYOL+CP
35 8 6 3 1 CP
0.012 Second Cohort
ETHYOL+CP 43 3 0 0 0
CP 38 10 1 2 0
* Based on 2-sided Mantel-Haenszel Chi-Square statistic.
In the randomized ovarian cancer study, ETHYOL 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
ETHYOL and control study groups. The table below summarizes the principal efficacy findings of the
randomized ovarian cancer study.
TABLE 3
Comparison of Principal Efficacy Findings
ETHYOL +CP CP
Complete pathologic tumor 21.3% 15.8% response rate
Time to progression (months)
Median (± 95% CI) 15.8 (13.2, 25.1) 18.1 (12.5, 20.4)
Mean (± Std error) 19.8 (±1.04) 19.1 (±1.58)
Hazard ratio .98 (.64, 1.4)
(95% Confidence Interval)
Survival (months)
Median (± 95% CI) 31.3 (28.3, 38.2) 31.8 (26.3, 39.8)
Mean (± Std error) 33.7 (±2.03) 34.3 (±2.04)
Hazard ratio .97 (.69, 1.32)
(95% Confidence Interval)
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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 ETHYOL, 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
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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 ETHYOL
(TABLE 4).
TABLE 4
Incidence of Grade 2 or Higher Xerostomia
(RTOG criteria)
Acute
(≤90 days from
start of radiation)
Latea
(9-12 months
post radiation)
ETHYOL +RT
51% (75/148)
35% (36/103)
RT
78% (120/153)
57% (63/111)
p-value
p<0.0001
p=0.0016
aBased on the number of patients for whom actual data were available.
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At one year following radiation, whole saliva collection following radiation showed that more patients
given ETHYOL 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 ETHYOL (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).
TABLE 5
Comparison of Principal Efficacy Findings at 1 Year
Locoregional Control Ratea
Hazard Ratiob
95% Confidence Interval
Disease-Free Survival Ratea
Hazard Ratiob
95% Confidence Interval
Overall Survival Ratea
Hazard Ratiob
95% Confidence Interval
ETHYOL +RT RT
76.1% 75.0%
1.013
(0.671, 1.530)
74.6% 70.4%
1.035
(0.702, 1.528)
89.4% 82.4%
1.585
(0.961, 2.613)
a1 year rates estimated using Kaplan-Meier method
bHazard ratio >1.0 is in favor of the ETHYOL + RT arm
INDICATIONS AND USAGE
ETHYOL (amifostine) is indicated to reduce the cumulative renal toxicity associated with
repeated administration of cisplatin in patients with advanced ovarian cancer.
ETHYOL 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 ETHYOL. There are at present only limited
data on the effects of ETHYOL on the efficacy of chemotherapy or radiotherapy in other settings.
ETHYOL 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 (see WARNINGS).
CONTRAINDICATIONS
ETHYOL is contraindicated in patients with known hypersensitivity to aminothiol compounds.
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WARNINGS
1. Effectiveness of the Cytotoxic Regimen
Limited data are currently available regarding the preservation of antitumor efficacy when ETHYOL 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. ETHYOL 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
ETHYOL 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. ETHYOL was studied only with standard fractionated radiotherapy and only
when ≥75% of both parotid glands were exposed to radiation. The effects of ETHYOL 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 ETHYOL. Patients
receiving ETHYOL at doses recommended for chemotherapy should have antihypertensive therapy
interrupted 24 hours preceding administration of ETHYOL. Patients receiving ETHYOL at doses
recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24
hours preceding ETHYOL treatment, should not receive ETHYOL.
Prior to ETHYOL infusion patients should be adequately hydrated. During ETHYOL 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 ETHYOL 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 ETHYOL 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 ETHYOL 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 ETHYOL 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 ETHYOL 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 ETHYOL
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
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monitored prior to, during and after ETHYOL administration. Serious cutaneous reactions may
develop weeks after initiation of ETHYOL administration (see PRECAUTIONS).
5. Hypersensitivity
Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated
with ETHYOL administration.
Nausea and Vomiting
Antiemetic medication should be administered prior to and in conjunction with ETHYOL (see
DOSAGE AND ADMINISTRATlON). When ETHYOL is administered with highly emetogenic
chemotherapy, the fluid balance of the patient should be carefully monitored.
6. 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 ETHYOL (see ADVERSE REACTIONS).
If necessary, calcium supplements can be administered.
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PRECAUTIONS
General
Patients should be adequately hydrated prior to the ETHYOL infusion and blood pressure should be
monitored (see DOSAGE AND ADMINISTRATION).
The safety of ETHYOL 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. ETHYOL should be used
with particular care in these and other patients in whom the common ETHYOL adverse effects of
nausea/vomiting and hypotension may be more likely to have serious consequences.
Prior to chemotherapy, ETHYOL 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, ETHYOL 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 ETHYOL or urgent dermatologic
consultation and biopsy (see below).
Cutaneous evaluation of the patient prior to each ETHYOL 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. ETHYOL 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. ETHYOL
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 ETHYOL should be at the physician’s discretion based
on medical judgment and appropriate dermatologic evaluation.
Allergic Reactions
In case of severe acute allergic reactions ETHYOL should be immediately and permanently
discontinued. Epinephrine and other appropriate measures should be available for treatment of serious
allergic events such as anaphylaxis.
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Drug Interactions
Special consideration should be given to the administration of ETHYOL in patients receiving
antihypertensive medications or other drugs that could cause or potentiate hypotension.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term animal studies have been performed to evaluate the carcinogenic potential of ETHYOL.
ETHYOL 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.
Pregnancy
Pregnancy Category C. ETHYOL 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. ETHYOL should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
No information is available on the excretion of ETHYOL 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 ETHYOL.
Pediatric Use
The safety and effectiveness in pediatric patients have not been established.
Geriatric Use
The clinical studies did not include sufficient number of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between elderly and younger patients. In general, dose selection for
an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or other drug therapy in elderly patients.
ADVERSE REACTIONS
Controlled Trials
In the randomized study of patients with ovarian cancer given ETHYOL at a dose of 910 mg/m2 prior
to chemotherapy, transient hypotension was observed in 62% of patients treated. The mean time of
onset was 14 minutes into the 15-minute period of ETHYOL infusion, and the mean duration was 6
minutes. In some cases, the infusion had to be prematurely terminated due to a more pronounced drop
in systolic blood pressure. In general, the blood pressure returned to normal within 5-15 minutes.
Fewer than 3% of patients discontinued ETHYOL due to blood pressure reductions. In the randomized