amifostine 500 MG Injection [Ethyol]

INDICATIONS AND USAGE ETHYOL is a cytoprotective agent indicated for: – reduction of cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer. ( 1.1 ) – reduction of 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. ( 1.2 ) Limitation of Use Avoid the use of ETHYOL in settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy. ( 1 , 5.1 , 5.2 ) 1.1 Reduction of Cumulative Renal Toxicity with Chemotherapy ETHYOL (amifostine) is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer [see Clinical Studies (14.1) ] . 1.2 Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck 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 (14.2) ] . Limitation of Use Do not use ETHYOL in other settings where chemotherapy can produce a significant survival benefit or cure [see Warnings and Precautions (5.1) ] , or in patients receiving definitive radiotherapy [see Warnings and Precautions (5.2) ] , except in the context of a clinical study.

DOSAGE AND ADMINISTRATION – For reduction of cumulative renal toxicity with chemotherapy, the recommended starting dose is 910 mg/m 2 administered once daily as a 15-minute intravenous infusion, starting 30 minutes prior to chemotherapy. ( 2.1 ) – For reduction of moderate to severe xerostomia from radiation of the head and neck, the recommended dose is 200 mg/m 2 administered once daily as a 3-minute intravenous infusion, starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy). ( 2.2 ) 2.1 Important Administration Instructions Hydration and Premedication Prior to ETHYOL infusion, verify that patients are adequately hydrated and correct existing dehydration if clinically indicated. When administering ETHYOL at the 910 mg/m 2 dose, antiemetic medications, including intravenous dexamethasone 20 mg and a serotonin 5HT 3 receptor antagonist, are recommended prior to ETHYOL administration. Additional antiemetics may be required based on the chemotherapy drugs administered. When administering ETHYOL at the 200 mg/m 2 dose, it is recommended that antiemetic medication be administered prior to ETHYOL administration. Oral 5HT 3 receptor antagonists, alone or in combination with other antiemetics are recommended in the radiotherapy setting. Supine Position and Blood Pressure Monitoring Patients should be kept in a supine position during the ETHYOL infusion. When administering ETHYOL at the 910 mg/m 2 dose, monitor blood pressure before, at least every 5 minutes during the infusion, at the end of the infusion, and thereafter as clinically indicated. When administering ETHYOL at the 200 mg/m 2 dose, monitor blood pressure before and at the end of the infusion, and thereafter as clinically indicated. 2.2 Recommended Dose for Reduction of Cumulative Renal Toxicity with Chemotherapy The recommended starting dose of ETHYOL is 910 mg/m 2 administered as a 15-minute intravenous infusion, starting 30 minutes prior to chemotherapy. Do not exceed a 15-minute infusion time due to the increased risk of infusion-related reactions. The use of less than 15-minute infusion times for ETHYOL use with chemotherapy have not been established. 2.3 Recommended Dose 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 as a 3-minute intravenous infusion, starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy). 2.4 Dose Modifications for Infusion-Related Reactions The infusion of ETHYOL should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in Table 1. If severe infusion-related reactions occur, immediately and permanently discontinue ETHYOL. Table 1: Interrupting ETHYOL Infusion Due to Decreases in Systolic Blood Pressure Baseline Systolic Blood Pressure(mm Hg) <100 100-119 120-139 140-179 ≥180 Decrease in systolic blood pressure during infusion of ETHYOL (mm Hg) 20 25 30 40 50 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 may be administered. When administering ETHYOL at the 910 mg/m 2 dose, if the full dose of ETHYOL cannot be administered, the dose of ETHYOL for subsequent chemotherapy cycles should be 740 mg/m 2 . 2.5 Preparation Reconstitution During reconstitution of ETHYOL, the use of gloves is recommended, and avoid contact with the skin or mucous membranes. Follow special handling and disposal procedures [see References (15) ]. A vial of ETHYOL may contain more drug than is required for the recommended dose or multiple vials may be needed to obtain the recommended dose. Reconstitute ETHYOL with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. The reconstituted solution contains a concentration of 50 mg/mL amifostine, and should be colorless. The reconstituted solution 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). Dilution Further dilute to ETHYOL with 0.9% Sodium Chloride Injection, USP to a final concentration of 5 mg/mL to 40 mg/mL before administration. 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). Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use ETHYOL if cloudiness or precipitate is observed. 2.6 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.

WARNINGS AND PRECAUTIONS – Hypotension and Cardiovascular Events: Patients who are hypotensive or dehydrated should not receive ETHYOL. If interruption of antihypertensive therapy is possible, interrupt antihypertensive therapy 24 hours prior to ETHYOL administration. Monitor blood pressure during infusion; interrupt and restart infusion if decrease in systolic blood pressure is observed. Do not administer ETHYOL to hypotensive patients who are taking antihypertensive therapy that cannot be stopped for 24 hours prior to ETHYOL administration. ( 5.3 ) – Severe Cutaneous Reactions: Monitor patients prior to, during, and weeks after administration for severe cutaneous reactions. Discontinue for cutaneous reactions or lesions appearing outside of the injection site/radiation port or on the palms or soles. ( 5.4 ) – Hypersensitivity: Discontinue for severe acute allergic reactions. Administer treatment for serious allergic events. ( 5.5 ) – Nausea and Vomiting: Administer antiemetic medication prior to and in conjunction with ETHYOL. Monitor fluid balance when administered with highly emetogenic chemotherapy. ( 5.6 ) – Hypocalcemia: Monitor serum calcium levels in patients at risk of hypocalcemia. If necessary, administer calcium supplements. ( 5.7 ) – Embryo-Fetal Toxicity: ETHYOL can cause fetal harm. Advise patients of the potential risk to a fetus ( 5.8 , 8.1 , 8.3 ). Also, refer to the cisplatin full prescribing information for pregnancy and contraception information. 5.1 Effectiveness of the Chemotherapy Regimen ETHYOL may interfere with the antitumor activity of chemotherapy regimens. Do not use ETHYOL 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. Limited data are currently available regarding interference with antitumor efficacy when ETHYOL is administered prior to cisplatin therapy in settings other than advanced ovarian cancer. 5.2 Effectiveness of Radiotherapy ETHYOL may interfere with the antitumor activity of the radiotherapy regimens. Do not use ETHYOL in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are insufficient data to exclude a tumor-protective effect in this setting. ETHYOL was studied with standard fractionated radiotherapy and when ≥75% of both parotid glands were exposed to radiation. The safety and efficacy of ETHYOL on the incidence of xerostomia in the setting of combined chemotherapy and radiotherapy, and in the setting of accelerated or hyperfractionated therapy, have not been established. 5.3 Hypotension and Cardiovascular Events Severe hypotension with serious sequelae have been reported in clinical studies and post-marketing experience in patients treated with ETHYOL. Severe hypotension events included apnea, dyspnea, hypoxia, chest pain, tachycardia, bradycardia, extrasystoles, supraventricular tachycardia, atrial fibrillation/flutter, myocardial ischemia, myocardial infarction, unconsciousness, syncope, seizure, renal failure, and respiratory and cardiac arrest. In the WR-1 study of patients with ovarian cancer dosing ETHYOL at 910 mg/m 2 , transient hypotension was observed in 62% of the patients treated, with 8% of the patients experiencing ≥ Grade 3 hypotension. The mean time of onset was 14 minutes after initiation of the ETHYOL infusion, the mean duration of hypotension was 6 minutes, and blood pressure returned to normal within 15 minutes after the onset of hypotension in most cases. Approximately 3% of patients permanently discontinued ETHYOL due to severe hypotension. In the WR-38 study of patients with head and neck cancer administering ETHYOL at a dose of 200 mg/m 2 prior to radiotherapy, hypotension was observed in 15% of patients treated, with 3% of the patients experiencing ≥ Grade 3 hypotension. Before administration of ETHYOL, verify that patients are not hypotensive or dehydrated. Adequately hydrate patients prior to initiating ETHYOL infusion. 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 avoid treatment with ETHYOL. During and after ETHYOL infusion, closely monitor the blood pressure of patients whose antihypertensive medication has been interrupted since hypertension may be exacerbated by discontinuation of antihypertensive medication or other causes such as intravenous hydration. During ETHYOL infusion, keep patients in a supine position and monitor blood pressure every 5 minutes during the infusion, and thereafter as clinically indicated. 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. It is important that the duration of the 910 mg/m 2 infusion does not exceed 15 minutes, as administration of ETHYOL as a longer infusion is associated with a higher incidence of adverse reactions. If hypotension occurs, place patients in the Trendelenburg position and give an infusion of normal saline using a separate intravenous line. 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. Guidelines for interrupting and restarting ETHYOL infusion if a decrease in systolic blood pressure should occur are provided [see Dosage and Administration (2.1) ] . 5.4 Severe Cutaneous Reactions Fatal and severe cutaneous reactions have been reported in clinical studies and post-marketing experience in patients treated with ETHYOL. Severe cutaneous reactions include 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 ETHYOL is used as a radioprotectant [see Adverse Reactions (6) ] . Severe cutaneous reactions may develop weeks after initiation of ETHYOL administration. Monitor patients carefully prior to, during, and after ETHYOL administration. Discontinue ETHYOL 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. 5.5 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have been reported in clinical studies and post-marketing experience with ETHYOL administration. Hypersensitivity and anaphylactic reactions observed during or after ETHYOL administration have included pyrexia, chills, dyspnea, hypoxia, chest discomfort, cutaneous eruptions, pruritus, urticaria, and laryngeal edema. Epinephrine and other appropriate measures should be available for treatment of serious infusion-related reactions when administering ETHYOL. When severe allergic reactions occur, immediately and permanently discontinue ETHYOL. 5.6 Nausea and Vomiting Nausea and/or vomiting occur frequently after ETHYOL infusion and may be severe. In the WR-1 study of patients with ovarian cancer dosing ETHYOL at 910 mg/m 2 , vomiting was observed in 96% of the patients treated, with severe nausea/vomiting on day 1 of cyclophosphamide-cisplatin chemotherapy in 19% of patients. In the WR-38 study of patients with head and neck cancer administering ETHYOL at a dose of 200 mg/m 2 prior to radiotherapy, vomiting was observed in 53% of patients treated, with severe nausea/vomiting in 8% of patients. Administer antiemetic medication(s) prior to and in conjunction with ETHYOL [see Dosage and Administration (2.1) ] . When ETHYOL is administered with highly emetogenic chemotherapy, closely monitor t

CONTRAINDICATIONS ETHYOL is contraindicated in patients with known hypersensitivity to aminothiol compounds. ETHYOL is contraindicated in patients with known hypersensitivity to aminothiol compounds. ( 4 )

Mechanism of Action 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.