Amifostine (Ethyol)
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Amifostine (Ethyol)

ETHYOL®
(amifostine) for Injection

DRUG 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.

What are the precautions when taking amifostine (Ethyol)?

Before receiving amifostine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: low/high blood pressure, heart disease (e.g., irregular heartbeat, congestive heart failure), kidney disease, previous stroke.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

During pregnancy, this medication should be used only when clearly needed. Discuss the...

Read All Potential Precautions of Ethyol »

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

ETHYOL (amifostine) is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.

ETHYOL (amifostine) 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 (amifostine) . There are at present only limited data on the effects of ETHYOL (amifostine) on the efficacy of chemotherapy or radiotherapy in other settings. ETHYOL (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 (see WARNINGS).

DOSAGE AND ADMINISTRATION

For Reduction of Cumulative Renal Toxicity with Chemotherapy:

The recommended starting dose of ETHYOL (amifostine) is 910 mg/m2 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 for chemotherapy regimens have not been systematically investigated.

Patients should be adequately hydrated prior to ETHYOL (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 ETHYOL (amifostine) should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:

Guideline for Interrupting ETHYOL (amifostine) Infusion Due to Decrease in Systolic Blood Pressure

  Baseline Systolic Blood Pressure (mm Hg)
<100 100-119 120-139 140-179 ≥ 180
Decrease in systolic blood pressure during infusion of ETHYOL (mm Hg) 20 25 30 40 50

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 (amifostine) may be administered. If the full dose of ETHYOL (amifostine) cannot be administered, the dose of ETHYOL (amifostine) for subsequent chemotherapy cycles should be 740 mg/m2.

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 (amifostine) . Additional antiemetics may be required based on the chemotherapy drugs administered.

For Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck:

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

Patients should be adequately hydrated prior to ETHYOL (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 ETHYOL (amifostine) . Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.

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 (amifostine) 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°C) or up to 24 hours under refrigeration (2°C to 8°C).

ETHYOL (amifostine) 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°C) or up to 24 hours when stored under refrigeration (2°C to 8°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 ETHYOL (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.

HOW SUPPLIED

ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 58178-017-01). Each single-use vial contains 500 mg of amifostine on the anhydrous basis. The vials are available packaged as follows:

3 pack - 3 vials per carton (NDC 58178-017-03)

Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].

Ethyol® (amifostine) is a registered trademark of MedImmune Oncology, Inc. Manufactured by: MedImmune Pharma B.V. 6545 CG Nijmegen, The Netherlands Or: Ben Venue, Inc. Bedford, Ohio 44146. For product information, please call 1 877 633 4411. Revision Date 5/2007. FDA Rev date: 03/28/06

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Controlled Trials

In the randomized study of patients with ovarian cancer given ETHYOL (amifostine) 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 (amifostine) 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 (amifostine) due to blood pressure reductions. In the randomized study of patients with head and neck cancer given ETHYOL (amifostine) at a dose of 200 mg/m2 prior to radiotherapy, hypotension was observed in 15% of patients treated. (see TABLE 6)

TABLE 6: Incidence of Common Adverse Events in Patients Receiving ETHYOL (amifostine)

  Phase III Ovarian Cancer Trial(WR-1) 910mg/m2 Phase III Head and Neck Cancer Trial (WR-38) 200mg/m2
Per Patient Per Infusion Per Patient Per Infusion
Nausea/Vomiting
   ≥ Grade 3 36/122 (30%) 53/592 (9%) 12/150 (8%) 13/4314 (<1%)
  All Grades 117/122 (96%) 520/592 (88%) 80/150 (53%) 233/4314 (5%)
Hypotension
   ≥ Grade 3a 10/122 (8%)   4/150 (3%)  
  All Grades 75/122 (61%) 159/592 (27%) 22/150 (15%) 46/4314 (1%)
aAccording to protocol-definedcriteria. WR-1:requiring interruption of infusion; WR-38: drop of >20mm Hg.

In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued ETHYOL (amifostine) due to adverse events. All but one of these patients continued to receive radiation treatment until completion.

Hypotension that requires interruption of the ETHYOL (amifostine) 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 (amifostine) can be administered. Short term, reversible loss of consciousness has been reported rarely.

Nausea and/or vomiting occur frequently after ETHYOL (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 (amifostine) , and 19% in patients who did receive ETHYOL (amifostine) . In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received ETHYOL (amifostine) and 1% in patients who did not receive ETHYOL (amifostine) .

Decrease in serum calcium concentrations is a known pharmacological effect of ETHYOL (amifostine) . At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the randomized head and neck cancer study (see WARNINGS), and not reported in the ovarian cancer study.

Other effects, which have been described during, or following ETHYOL (amifostine) infusion are flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups and sneezing. These effects have not generally precluded the completion of therapy.

Clinical Trials and Pharmacovigilance Reports

Allergic reactions characterized by one or more of the following manifestations have been observed during or after ETHYOL (amifostine) administration: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest tightness, cutaneous eruptions, pruritus, urticaria and laryngeal edema. Cutaneous eruptions have been commonly reported during clinical trials and were generally non-serious. Serious, sometimes fatal skin reactions including erythema multiforme, and in rare cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have also occurred. The reported incidence of serious skin reactions associated with ETHYOL (amifostine) is higher in patients receiving ETHYOL (amifostine) as a radioprotectant than in patients receiving ETHYOL (amifostine) as a chemoprotectant. Rare anaphylactoid reactions and cardiac arrest have also been reported.

Hypotension, usually brief systolic and diastolic, has been associated with one or more of the following adverse events: apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain, myocardial ischemia and convulsion. Rare cases of renal failure, myocardial infarction, respiratory and cardiac arrest have been observed during or after hypotension. (See WARNINGS and PRECAUTIONS)

Rare cases of arrhythmias such as atrial fibrillation/flutter and supraventricular tachycardia have been reported. These are sometimes associated with hypotension or allergic reactions.

Transient hypertension and exacerbations of preexisting hypertension have been observed rarely after ETHYOL (amifostine) administration.

Seizures and syncope have been reported rarely. (See WARNINGS and PRECAUTIONS)

Read the Ethyol (amifostine) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Special consideration should be given to the administration of ETHYOL (amifostine) in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

1. Effectiveness of the Cytotoxic Regimen

Limited data are currently available regarding the preservation of antitumor efficacy when ETHYOL (amifostine) 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 (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

ETHYOL (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. ETHYOL (amifostine) was studied only with standard fractionated radiotherapy and only when ≥ 75% of both parotid glands were exposed to radiation. The effects of ETHYOL (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 ETHYOL (amifostine) . Patients receiving ETHYOL (amifostine) at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of ETHYOL (amifostine) . Patients receiving ETHYOL (amifostine) at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding ETHYOL (amifostine) treatment, should not receive ETHYOL (amifostine) .

Prior to ETHYOL (amifostine) infusion patients should be adequately hydrated. During ETHYOL (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 ETHYOL (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 ETHYOL (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 ETHYOL (amifostine) 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 (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 rarely with ETHYOL (amifostine) 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. monitored prior to, during and after ETHYOL (amifostine) administration. Serious cutaneous reactions may develop weeks after initiation of ETHYOL (amifostine) administration (see PRECAUTIONS).

5. Hypersensitivity

Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated rarely with ETHYOL (amifostine) administration.

6. Nausea and Vomiting

Antiemetic medication should be administered prior to and in conjunction with ETHYOL (see DOSAGE AND ADMINISTRATlON). When ETHYOL (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 ETHYOL (see ADVERSE REACTIONS). If necessary, calcium supplements can be administered.

PRECAUTIONS

General

Patients should be adequately hydrated prior to the ETHYOL (amifostine) infusion and blood pressure should be monitored (see DOSAGE AND ADMINISTRATION).

The safety of ETHYOL (amifostine) 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 (amifostine) should be used with particular care in these and other patients in whom the common ETHYOL (amifostine) adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.

Prior to chemotherapy, ETHYOL (amifostine) 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 (amifostine) 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

Based on cutaneous evaluation, cutaneous reactions may require permanent discontinuation of ETHYOL (amifostine) or urgent dermatologic consultation and biopsy (see below).

Cutaneous evaluation of the patient prior to each ETHYOL (amifostine) 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 (amifostine) should also 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 (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 ETHYOL (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 ETHYOL (amifostine) should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long term animal studies have been performed to evaluate the carcinogenic potential of ETHYOL (amifostine) . ETHYOL (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 typhimuriumstrain 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 (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. ETHYOL (amifostine) 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 (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 ETHYOL (amifostine) .

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.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

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.

CONTRAINDICATIONS

ETHYOL (amifostine) is contraindicated in patients with known hypersensitivity to aminothiol compounds.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

ETHYOL (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 ETHYOL (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.

Pharmacokinetics: Clinical pharmacokinetic studies show that ETHYOL (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 ETHYOL (amifostine) remains in the plasma 6 minutes after drug administration. ETHYOL (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 ETHYOL (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 ETHYOL (amifostine) . Pretreatment with dexamethasone or metoclopramide has no effect on ETHYOL (amifostine) pharmacokinetics.

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 ETHYOL (amifostine) 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 (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 ETHYOL (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 ETHYOL (amifostine) 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-Gaultformula, Nephron1976; 16:31-41.

TABLE 2: NCI Toxicity Grades of Serum Magnesium Levels for Each Patient's Last Cycle of Therapy

NCI-CTC Grade: (mEq/L) 0 1 2 3 4 p-value*
>1.4 ≤ 1.4->1.1 ≤ 1.1->0.8 ≤ = 0.8->0.5 ≤ 0.5
All Patients   0.001
  ETHYOL+CP 92 13 3 0 0
  CP 73 18 7 5 1
First Cohort   0.017
  ETHYOL+CP 49 10 3 0 0
  CP 35 8 6 3 1
Second Cohort   0.012
  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 (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 ETHYOL (amifostine) 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 response rate
21.3% 15.8%
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 (95% Confidence Interval) .98 (.64,1.4)
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 (95% Confidence Interval) .97 (.69,1.32)

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 (amifostine) , 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 ETHYOL (amifostine) (TABLE 4).

TABLE 4: Incidence of Grade 2 or Higher Xerostomia (RTOG criteria)

  ETHYOL +RT RT p-value
Acute
( ≤ 90 days from start of radiation)
51% (75/148) 78% (120/153) p<0.0001
Latea
(9-12 months post radiation)
35% (36/103) 57% (63/111) p=0.0016
a Based on the number of patients for whom actual data were available.

At one year following radiation, whole saliva collection following radiation showed that more patients given ETHYOL (amifostine) 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 (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).

TABLE 5: Comparison of Principal Efficacy Findings at 1 Year

  ETHYOL +RT RT
Locoregional Control Ratea 76.1% 75.0%
  Hazard Ratiob 1.013
  95% Confidence Interval (0.671, 1.530)
Disease-Free Survival Ratea 74.6% 70.4%
  Hazard Ratiob 1.035
  95% Confidence Interval (0.702, 1.528)
Overall Survival Ratea 89.4% 82.4%
  Hazard Ratiob 1.585
  95% Confidence Interval (0.961, 2.613)
a1 year rates estimated using Kaplan-Meier method
bHazard ratio >1.0 is in favor of the ETHYOL (amifostine) + RT arm

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Ethyol Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

AMIFOSTINE - INJECTION

(A-mi-FOS-teen)

COMMON BRAND NAME(S): Ethyol

USES: Amifostine is used to decrease the risk of kidney problems caused by treatment with a certain anti-cancer drug (cisplatin). It is also used to help prevent a certain side effect (dry mouth) caused by radiation treatment for head and neck cancer. Amifostine is thought to work by preventing certain chemicals from damaging healthy cells. It may also help repair cells damaged by cisplatin or radiation treatment.

HOW TO USE: This medication is given by injection into a vein by a health care professional, usually 15 to 30 minutes before cancer treatment or as directed by your doctor. Dosage is based on your medical condition, body size, and response to treatment.

To decrease the risk of a certain side effect (low blood pressure), your doctor may direct you to lie down while receiving this medication. Also, if you are taking blood pressure medication, your doctor may direct you to stop taking it for 1 day before receiving this drug. Be sure to ask your doctor when to restart blood pressure medication.

To decrease the risk of side effects (e.g., low blood pressure), drink plenty of fluids while using this medication unless otherwise directed by your doctor.

Disclaimer

Ethyol Consumer (continued)

SIDE EFFECTS: Flushing, chills, unusual feelings of warmth/coldness, dizziness, or drowsiness may occur. Nausea and vomiting occur frequently and can be severe. Your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fainting, fast/slow/irregular heartbeat, seizure.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: fever, rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Ethyol (amifostine) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before receiving amifostine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: low/high blood pressure, heart disease (e.g., irregular heartbeat, congestive heart failure), kidney disease, previous stroke.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this medication passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Ethyol Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: blood pressure medications.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, trazodone). Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (e.g., blood pressure, serum calcium levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule.

STORAGE: Not applicable. This medication is given in a hospital or clinic and will not be stored at home.

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

ETHYOL®
(amifostine) for Injection

DRUG 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.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

ETHYOL®
(amifostine) for Injection

DRUG 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.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

ETHYOL®
(amifostine) for Injection

DRUG 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.

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

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