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WARNINGS 1. Effectiveness of the Cytotoxic Regimen Limited data are currently available regarding the preservation of antitumor efficacy when Amifostine for Injection 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. 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 Amifostine for Injection 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. Amifostine was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of 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 Amifostine for Injection. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. Patients receiving amifostine at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment, should not receive amifostine. Prior to Amifostine for Injection infusion patients should be adequately hydrated. During 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/m 2 infusion not exceed 15 minutes, as administration of 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 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 Amifostine for Injection 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 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 Fatal and serious cutaneous reactions have been reported with Amifostine for Injection treatment, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxicoderma, exfoliative dermatitis and drug reaction with biopsy-confirmed eosinophilia and systemic symptoms (DRESS). These reactions have been reported more frequently when Amifostine for Injection is used as a radioprotectant (see ADVERSE REACTIONS ). Serious cutaneous reactions may develop weeks after initiation of Amifostine for Injection administration. Monitor patients carefully prior to, during and after Amifostine for Injection administration. Discontinue Amifostine for Injection for cutaneous reactions or mucosal lesions appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms or soles. 5. Hypersensitivity Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with Amifostine for Injection administration. 6. Nausea and Vomiting Antiemetic medication should be administered prior to and in conjunction with Amifostine for Injection (see DOSAGE AND ADMINISTRATION ). When 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 Amifostine for Injection (see ADVERSE REACTIONS ). If necessary, calcium supplements can be administered.
ADVERSE REACTIONS Controlled Trials In the randomized study of patients with ovarian cancer given Amifostine for Injection 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 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 amifostine due to blood pressure reductions. In the randomized study of patients with head and neck cancer given amifostine 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 Amifostine for Injection 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 Amifostine for Injection due to adverse events. All but one of these patients continued to receive radiation treatment until completion. Hypotension that requires interruption of the Amifostine for Injection 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 amifostine can be administered. Short term, reversible syncope (loss of consciousness) has been reported rarely. Nausea and/or vomiting occur frequently after Amifostine for Injection 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 amifostine, and 19% in patients who did receive amifostine. In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received amifostine and 1% in patients who did not receive amifostine. Decrease in serum calcium concentrations is a known pharmacological effect of Amifostine for Injection. 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 amifostine infusion are flushing/feeling of warmth, chills/feeling of coldness, malaise, pyrexia, rash, dizziness, somnolence, hiccups, diarrhea, sneezing, diplopia and blurred vision. These effects have not generally precluded the completion of therapy. Injection site reactions (including rash/erythema, pruritus, urticaria, pain, inflammation, bruising and local swelling) were also observed. Clinical Trials and Pharmacovigilance Reports Hypersensitivity and anaphylactic reactions characterized by one or more of the following manifestations have been observed during or after Amifostine for Injection administration: hypotension, pyrexia, chills/rigors, dyspnea, hypoxia, chest discomfort, 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 amifostine is higher in patients receiving amifostine as a radioprotectant than in patients receiving 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 seizure. 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 Amifostine for Injection administration. Seizures and syncope (loss of consciousness) have been reported rarely. (See WARNINGS and PRECAUTIONS )