AMIFOSTINE
DESCRIPTION:
ETHYOL (amifostine) is an organic thiophosphate cytoprotective agent known
chemically as ethanethiol, 2-((3-aminopropyl)amino)-, 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.
ACTIONS/CLINICAL PHARMACOLOGY:
ETHYOL is a prodrug that is dephosphorylated by alkaline phosphatase in tissues
to a pharmacologically active free thiol metabolite that can reduce the toxic
effects of cisplatin. The ability 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. The higher concentration of free thiol in normal tissues is
available to bind to, and thereby detoxify, reactive metabolites of cisplatin;
and also can act as a scavenger of free radicals that may be generated in
tissues exposed to cisplatin. Several preclinical studies in mice and rats have
demonstrated that pretreatment with ETHYOL results in protection from
nephrotoxicity following administration of single and multiple doses of
cisplatin.
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/M(squared) 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
amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on
ETHYOL pharmacokinetics.
CLINICAL STUDIES:
A randomized controlled trial compared six cycles of cyclophosphamide 1000
mg/M(squared), and cisplatin 100 mg/M(squared) with or without amifostine
pretreatment at 910 mg/M(squared), 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 pre-
existing 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*
____________________________________________________________________________________________________________
Amifostine +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
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* 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
(mEq/L) >1.4 =1.4->1.1 =1.1->0.8 =0.8->0.5 =0.5 p-value*
____________________________________________________________________________________________________________
ALL PATIENTS 0.001
Amifostine + CP 92 13 3 0 0
CP 73 18 7 5 1
FIRST COHORT 0.017
Amifostine + CP 49 10 3 0 0
CP 35 8 6 3 1
SECOND COHORT 0.012
Amifostine + 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 (amifostine) 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.
TABLE 3
---------------------------------- P N ---------------------------- P N -----------------------------------------------
ETHYOL +CP CP
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COMPLETE PATHOLOGIC TUMOR
15.8% J G 15.8% J G 15.8%
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TIME TO PROGRESSION (MONTHS)
Median (+/- 95% Cl) 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)
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SURVIVAL (MONTHS)
.3, 38.2) 31.8 (26.3, L J .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)
A Phase II trial of Ethyol, 740-910 mg/M(squared), and cisplatin, 120
mg/M(squared), administered on day 1 and vinblastine, 5mg/M(squared),
administered on days 1, 8, 15 and 22 of each monthly cycle was conducted in 25
patients with Stage IV non-small cell lung cancer. This regimen was repeated
until disease progression or unacceptable toxicity occurred, or a maximum of six
cycles had been administered. Among 13 patients who received 4 or more cycles of
this intensive cisplatin regimen, 1 had a >/=40% reduction in creatinine
clearance. These results are consistent with the randomized ovarian cancer
trial.
Sixteen of the 25 patients treated demonstrated a partial response to
chemotherapy. With a median follow-up of 19 months, the median survival was 17
months. At one year, 64% of the patients were alive. These results indicate that
ETHYOL may not adversely affect the efficacy of this chemotherapy for non-small
cell lung cancer.
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 OR NON-SMALL CELL LUNG CANCER. IN THESE SETTINGS, THE CLINICAL
DATA DO NOT SUGGEST THAT THE EFFECTIVENESS OF CISPLATIN BASED CHEMOTHERAPY
REGIMENS IS ALTERED BY ETHYOL. There are at present only limited data on the
effects of ETHYOL on the efficacy of chemotherapy in other settings; therefore
ETHYOL should not be administered to patients in other settings where
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.
CONTRAINDICATIONS:
ETHYOL is contraindicated in patients with known sensitivity to aminothiazole
compounds.
WARNINGS:
1. Effectiveness of the Cytotoxic Regimen
Limited data are currently available regarding the preservation of antitumor
efficacy when amifostine is administered prior to cisplatin therapy in settings
other than advanced ovarian cancer or non-small cell lung cancer. Although some
animal data suggest interference is possible, in most tumor models the antitumor
effects of chemotherapy are not altered by amifostine. The possibility of
interference with the efficacy of cancer treatment would be of particular
concern in those settings where chemotherapy can produce a significant survival
benefit or cure. ETHYOL should therefore 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. Hypotension
Patients who are hypotensive or in a state of dehydration should not receive
ETHYOL. Patients receiving antihypertensive therapy that cannot be stopped for
24 hours preceding ETHYOL treatment also should not receive ETHYOL. Patients
should be adequately hydrated prior to ETHYOL infusion and kept in a supine
position during the infusion. Blood pressure should be monitored every 5 minutes
during the infusion. It is important that the duration of the infusion be 15
minutes, as administration of ETHYOL as a longer infusion is associated with a
higher incidence of side effects. If hypotension requiring interruption of
therapy occurs, patients should be placed in the Trendelenburg position and be
given an infusion of normal saline using a separate i.v. line. Guidelines for
interrupting and restarting ETHYOL infusion if a decrease in systolic blood
pressure should occur are provided in the DOSAGE AND ADMINISTRATION section.
3. Nausea and Vomiting
Antiemetic medication should be administered prior to and in conjunction with
ETHYOL (see DOSAGE and ADMINISTRATION). When ETHYOL is administered with highly
emetogenic chemotherapy, the fluid balance of the patient should be carefully
monitored.
4. 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. If necessary, calcium supplements can be administered.
PRECAUTIONS:
GENERAL
Patients should be adequately hydrated prior to the infusion and blood pressure
should be monitored during the infusion. ETHYOL (amifostine) should be
administered as a 15- minute infusion (See DOSAGE and ADMINISTRATION).
The safety of ETHYOL administration has not been established in elderly
patients, or 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.
DRUG INTERACTIONS
There are no known drug interactions with ETHYOL. However, special consideration
should be given to the administration of ETHYOL in patients receiving
antihypertensive medications or other drugs that could potentiate hypotension.
CARCINOGENESIS, MUTAGENESIS AND 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, however, 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.
DRUG INTERACTIONS:
There are no known drug interactions with ETHYOL. However, special consideration
should be given to the administration of ETHYOL in patients receiving
antihypertensive medications or other drugs that could potentiate hypotension.
ADVERSE REACTIONS:
ETHYOL produced a transient reduction in blood pressure 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. Short term, reversible loss of consciousness has been
reported rarely. Blood pressure reductions during ETHYOL administration have not
been reported to cause long-term CNS, cardiovascular or renal sequelae, but
clinical studies performed to date have not evaluated the safety of ETHYOL in
elderly patients or patients with pre-existing cardiovascular or cerebrovascular
conditions.
Hypotension that requires interruption of the ETHYOL infusion should be treated
with fluid infusion and postural management of the patient (supine or
Trendelenburg position). 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 ETHYOL can be administered.
Nausea and/or vomiting occur frequently after amifostine infusion and may be
severe. In the ovarian cancer randomized study, the incidence of severe
nausea/vomiting on day 1 of cyclophosphamide-cisplatin chemotherapy was 10% in
patients who did not receive ETHYOL, and 19% in patients who did receive ETHYOL.
Other effects which have been described during or following ETHYOL infusion are
flushing/feeling of warmth, chills/feeling of coldness, dizziness, somnolence,
hiccups and sneezing. These effects have not generally precluded the completion
of chemotherapy.
Decrease in serum calcium concentrations is a known pharmacological effect of
ETHYOL. At the recommended doses, clinically significant hypocalcemia has
occurred rarely (<1%).
Allergic reactions, ranging from mild skin rashes to rigors, have occurred
rarely (<1%). There has been no reported occurrence of anaphylaxis with ETHYOL.
OVERDOSAGE:
In clinical trials, the maximum single dose of ETHYOL was 1300 mg/M(squared). No
information is available on single doses higher than this in adults. In the
setting of a clinical trial, children have received single ETHYOL doses of up to
2700 mg/M(squared) with no unexpected effects. Multiple infusions (up to three)
of 740-910 mg/M(squared) doses of ETHYOL have been administered within a 24-hour
period under study conditions without unexpected effects. Administration of
ETHYOL at 2 and 4 hours after the initial dose has not led to increased or
cumulative side effects, such as 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.
DOSAGE AND ADMINISTRATION:
In adults, the recommended starting dose of ETHYOL is 910 mg/M(squared)
administered once daily as a 15-minute i.v. infusion, starting 30 minutes prior
to chemotherapy.
The 15-minute infusion is better tolerated than more extended infusions. Further
reductions in infusion times have not been systematically investigated.
The infusion of ETHYOL should be interrupted if the systolic blood pressure
decreases significantly from the baseline value as listed in the guideline
below:
GUIDELINE FOR INTERRUPTING ETHYOL INFUSION DUE TO
DECREASE IN SYSTOLIC BLOOD PRESSURE
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BASELINE SYSTOLIC BLOOD PRESSURE (MM HG)
-------------------------------------------------------------------------------------------------------
<100 100-119 120-139 140-179 >/=180
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Decrease in
systolic blood
pressure during 20 25 30 40 50
infusion of
ETHYOL (mm Hg)
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 ETHYOL may
be administered. If the full dose of ETHYOL cannot be administered, the dose of
ETHYOL for subsequent cycles should be 740 mg/M(squared).
Only limited experience is available for the usage of ETHYOL in children or
elderly patients (more than 70 years of age).
It is recommended that antiemetic medication, including dexamethasone 20 mg i.v.
and a serotonin 5HT3 receptor antagonist, be administered prior to and in
conjunction with ETHYOL. Additional antiemetics may be required based on the
chemotherapy drugs administered.
RECONSTITUTION
ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized powder
requiring reconstitution for intravenous infusion. Each single-use vial contains
500 mg of amifostine on the anhydrous basis.
Prior to intravenous injection, ETHYOL is reconstituted with 9.7 mL of sterile
0.9% Sodium Chloride Injection, USP. The reconstituted solution (500 mg
amifostine/ 10 mL) is chemically stable for up to 5 hours at room temperature
(approximately 25 deg C) or up to 24 hours under refrigeration (2 deg C to 8 deg
C).
ETHYOL prepared in polyvinylchloride (PVC) bags at concentrations ranging from 5
mg/mL to 40 mg/mL is chemically stable for up to 5 hours when stored at room
temperature (approximately 25 deg C) or up to 24 hours when stored under
refrigeration (2 deg C to 8 deg C).
CAUTION: Parenteral products should be inspected visually for particulate
matter and discoloration prior to administration whenever solution and container
permit. Do not use if cloudiness or precipitate is observed.
INCOMPATIBILITIES
The compatibility of amifostine with solutions other than 0.9% Sodium Chloride
for Injection, or Sodium Chloride solutions with other additives, has not been
examined. The use of other solutions is not recommended.
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