Ethyol

>10%

Nausea/vomiting (96%)

Hypotension (61%) - discontinue infusion if significant BP drop

1-10%

Hypocalcemia (1%)

Stevens-Johnson syndrome (1%)

Frequency Not Defined

Chills/feeling of coldness

Flushing/feeling of warmth

Dizziness

Fever

Somnolence

Rash

Malaise

Hiccups

Sneezing

Postmarketing Reports

Seizures and syncope (loss of consciousness)

Contraindications

Hypersensitivity to aminothiol, monitor closely during and after IV

Cautions

Cardiovascular disease, hypocalcemia, hypotension, cutaneous reactions, or nausea/vomiting may occur

Ensure adequate hydration

Do not give to 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

Use caution in hypotension and cerebrovascular disease

Interrupt antihypertensive therapy 24 hr before treatment; patients unable to safely interupt antihypertensive therapy should not recieve amifostine

Fatal and serious cutaneous reactions reported with therapy, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxicoderma, exfoliative dermatitis and drug reaction with biopsy-confirmed eosinophilia and systemic symptoms (DRESS); reactions have been reported more frequently when drug is used as a radioprotectant; monitor patients carefully prior to, during and after therapy administration; discontinue therapy for cutaneous reactions or mucosal lesions appearing outside of injection site or radiation port and for erythematous, edematous or bullous lesions on palms or soles

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Ethyol is part of the drug class:

• Detoxifying agents for antineoplastic treatment

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

Cytoprotective agent; a chemoprotectant and radioprotectant.1 2 3 9 11 14 16 20 21 22 23 24

• If you have an allergy to amifostine, aminothiol compounds, or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Fluid loss or low blood pressure.
• If you are breast-feeding. Do not breast-feed while you take Ethyol.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Ethyol with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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

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 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.

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.

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 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).

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).

Applies to amifostine: intravenous powder for solution

Along with its needed effects, amifostine (the active ingredient contained in Ethyol) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking amifostine:

• Blurred vision
• confusion
• dizziness, faintness, or lightheadedness when suddenly getting up from a lying or sitting position
• fainting or loss of consciousness
• fast or irregular breathing
• itching
• nausea, vomiting
• red, scaly, swollen, or peeling areas of the skin
• skin rash
• sweating
• swelling of the eyes or eyelids
• tightness in the chest
• trouble with breathing
• unusual tiredness or weakness

• Blistering, peeling, or loosening of the skin
• burning or tingling sensation
• chills
• cough
• cracks in the skin
• diarrhea
• fast, slow, or irregular heartbeat or pulse
• fever
• joint or muscle pain
• loss of bladder control
• loss of heat from the body
• muscle cramps in the hands, arms, feet, legs, or face
• muscle spasm or jerking of all extremities
• no blood pressure or pulse
• numbness and tingling around the mouth, fingertips, or feet
• palpitations
• red irritated eyes
• red skin lesions, often with a purple center
• seizures
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• stomach cramps
• stopping of the heart
• sudden loss of consciousness
• tremor

• Bloody urine
• decreased frequency or amount of urine
• difficulty in swallowing
• hives or welts
• hoarseness
• increased blood pressure
• increased thirst
• lower back or side pain
• loss of appetite
• pain or discomfort in the arms, jaw, back, or neck
• slow or irregular breathing
• swelling of the face, fingers, or lower legs
• weight gain

Some side effects of amifostine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Feeling unusually warm or cold
• flushing or redness of the face or neck
• headache
• hiccups
• nervousness
• pounding in the ears
• sleepiness (severe)
• sneezing