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:

Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C ₅ H ₁₅ N ₂ O ₃ PS 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/m ² 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 and Non-Small Cell Lung Cancer.    A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m ² , and cisplatin 100 mg/m ² with or without ETHYOL ^® pretreatment at 910 mg/m ² , 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.

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.

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/m ² 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).

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).

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.

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 sensitivity to aminothiol compounds.

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 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. 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/m ² 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. Hypersensitivity
   Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated rarely with ETHYOL ^® administration. Serious cutaneous hypersensitivity reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis, which 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 ^® administration (see PRECAUTIONS ).
5. 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.
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.

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.

Allergic Reactions

In case of severe acute allergic reaction ETHYOL ^® should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis. ETHYOL ^® 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 ^® 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.

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 of 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/m ² 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 study of patients with head and neck cancer given ETHYOL ^® at a dose of 200 mg/m ² prior to radiotherapy, hypotension was observed in 15% of patients treated (see TABLE 6).

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.

Short term, reversible loss of consciousness has been reported rarely.

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

Decrease in serum calcium concentrations is a known pharmacological effect of ETHYOL ^® . At the recommended doses, clinically significant hypocalcemia has occurred rarely (<1%) (see WARNINGS ).

Other effects which have been described during or following ETHYOL ^® infusion are flushing/feeling of warmth, chills/feeling of coldness, fever, 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 ^® administration: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest tightness, cutaneous eruptions, urticaria and laryngeal edema. Serious, sometimes fatal skin reactions including erythema multiforme, and in rare cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred. The reported incidence of serious skin reactions associated with ETHYOL ^® is higher in patients receiving ETHYOL ^® as a radioprotectant than in patients receiving ETHYOL ^® 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 arrythmias 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 ^® administration.

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

OVERDOSAGE

In clinical trials, the maximum single dose of ETHYOL ^® was 1300 mg/m ² . 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 ^® doses of up to 2700 mg/m ² . At the higher doses, anxiety and reversible urinary retention occurred.

Administration of ETHYOL ^® 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.

DOSAGE AND ADMINISTRATION

For Reduction of Cumulative Renal Toxicity with Chemotherapy:    The recommended starting dose of ETHYOL ^® is 910 mg/m ² 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 ^® 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 ^® should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:

It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin 5HT ₃ receptor antagonist, be administered prior to and in conjunction with ETHYOL ^® . 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 ^® is 200 mg/m ² 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 ^® 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 ^® . Oral 5HT ₃ 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 ^® is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. This 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 ^® 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 ^® 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].

U.S. Patents 5,424,471; 5,591,731; 5,994,409

Manufactured by:

MedImmune Pharma B.V.

6545 CG Nijmegan

The Netherlands

Or:

Ben Venue, Inc.

Bedford, Ohio 44146

Marketed by:

MedImmune Oncology, Inc.

a subsidiary of MedImmune, Inc.

Gaithersburg, MD 20878

MedImmune

Oncology, Inc.

For product information, please call 1-877-633-4411

©2003 MedImmune Oncology, Inc.

Revision Date 3/2003                               N-LB2022 PI