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WARNINGS 1. Effectiveness of the Cytotoxic Regimen Limited data are currently available regarding the preservation of antitumor efficacy when ETHYOL is administered prior to cisplatin therapy in settings other than advanced ovarian cancer. Although some animal data suggest interference is possible, in most tumor models the antitumor effects of chemotherapy are not altered by amifostine. ETHYOL should not be used in patients receiving chemotherapy for other malignancies in which chemotherapy can produce a significant survival benefit or cure (e.g., certain malignancies of germ cell origin), except in the context of a clinical study. 2. Effectiveness of Radiotherapy ETHYOL should not be administered in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are at present insufficient data to exclude a tumor-protective effect in this setting. ETHYOL was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of ETHYOL on the incidence of xerostomia and on toxicity in the setting of combined chemotherapy and radiotherapy and in the setting of accelerated and hyperfractionated therapy have not been systematically studied. 3. Hypotension Patients who are hypotensive or in a state of dehydration should not receive ETHYOL. Patients receiving ETHYOL at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of ETHYOL. Patients receiving ETHYOL at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding ETHYOL treatment, should not receive ETHYOL. Prior to ETHYOL infusion patients should be adequately hydrated. During ETHYOL infusion patients should be kept in a supine position. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. It is important that the duration of the 910 mg/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. Cutaneous Reactions Serious cutaneous reactions have been associated with ETHYOL administration. Serious cutaneous reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These reactions have been reported more frequently when ETHYOL is used as a radioprotectant (see ADVERSE REACTIONS ). Some of these reactions have been fatal or have required hospitalization and/or discontinuance of therapy . Patients should be carefully monitored prior to, during and after ETHYOL administration. Serious cutaneous reactions may develop weeks after initiation of ETHYOL administration (see PRECAUTIONS ). 5. Hypersensitivity Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with ETHYOL administration. 6. Nausea and Vomiting Antiemetic medication should be administered prior to and in conjunction with ETHYOL (see DOSAGE AND ADMINISTRATlON ). When ETHYOL is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored. 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.
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) TABLE 6 Incidence of Common Adverse Events in Patients Receiving ETHYOL Phase III Ovarian Cancer Trial (WR-1) 910 mg/m 2 Phase III Head and Neck Cancer Trial (WR-38) 200 mg/m 2 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 3 According to protocol-defined criteria. WR-1: requiring interruption of infusion; WR-38: drop of >20mm Hg. 10/122 (8%) 4/150 (3%) All Grades 75/122 (61%) 159/592 (27%) 22/150 (15%) 46/4314 (1%) In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued ETHYOL due to adverse events. All but one of these patients continued to receive radiation treatment until completion. 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 was reported in 1% of patients in the randomized head and neck cancer study (see WARNINGS ). Other effects, which have been described during, or following ETHYOL 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 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 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 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 administration. Seizures and syncope have been reported rarely. (See WARNINGS and PRECAUTIONS )