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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
   ≥ 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%)
   ≥ 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)