Ethyol

1 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.

2 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 u…

5 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 no…

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

7 DRUG INTERACTIONS Closely monitor patients receiving anti-hypertensive medications or other drugs that could cause or potentiate hypotension. – Closely monitor patients receiving anti-hypertensive medications or other drugs that could cause or potentiate hypotension. ( 7 )

8.1 Pregnancy Risk Summary When ETHYOL is used in combination with cisplatin, refer to the cisplatin full prescribing information for pregnancy information. Based on findings in animals, ETHYOL can cause fetal harm when administered to a pregnant woman. There are no available data on ETHYOL use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of ETHYOL to pregnant rabbits during organogenesis was embryotoxic at doses approximately sixty percent of the recommended dose in humans based on body surface area (see Data) . Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population. Data Animal Data ETHYOL has been shown to be embryotoxic in rabbits at intravenous doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: – Hypotension and Cardiovascular Events [see Warnings and Precautions (5.3) ] – Severe Cutaneous Reactions [see Warnings and Precautions (5.4) ] – Hypersensitivity [see Warnings and Precautions (5.5) ] – Nausea and Vomiting [see Warnings and Precautions (5.6) ] – Hypocalcemia [see Warnings and Precautions (5.7) ] Most common adverse reactions are hypotension, nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Legacy Pharma Inc. at 1-800-727-7151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ETHYOL was administered to patients receiving chemotherapeutic agents for advanced ovarian cancer (WR-1 study) or who were receiving standard fractionated radiotherapy for head and neck cancer (WR-38 study) [see Clinical Studies (14) ] . In the WR-38 study of patients with head and neck cancer, 17% (26/150) discontinued ETHYOL due to adverse reactions. All but one of these patients continued to receive radiation treatment until completion. Table 2 summarizes adverse reactions reported in patients from the WR-1 and WR-38 clinical trials. Table 2: Incidence of Common Adverse Reactions in Patients Receiving ETHYOL Ovarian Cancer (WR-1 Trial) 910 mg/m 2 Head and Neck Cancer (WR-38 Trial) 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 10/122 (8%) 4/150 (3%) All Grades 75/122 (62%) 159/592 (27%) 22/150 (15%) 46/4314 (1%) Other clinically relevant adverse reactions reported in patients in the WR-1 and WR-38 trials include the following: Infusion-related Reactions: 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. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ETHYOL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following reported post-marketing adverse reactions are described elsewhere in the labeling: – Hypotension and Cardiovascular Events [see Warnings and Precautions (5.3) ] – Severe Cutaneous Reactions [see Warnings and Precautions (5.4) ] – Hypersensitivity [see Warnings and Precautions (5.5) ] Adverse reactions associated with the use of ETHYOL that have been identified in other clinical trials and/or post-marketing reports are described below: Immune system disorders: Hypersensitivity reactions including pruritus, urticaria, laryngeal edema, anaphylactic reactions, anaphylactoid reactions. Nervous system disorders: Seizure. Cardiac disorders: Myocardial ischemia, myocardial infarction, cardiac arrest, arrhythmias including tachycardia, bradycardia, atrial fibrillation/ flutter, supraventricular tachycardia, extrasystoles. Vascular disorders: Transient hypertension and exacerbations of preexisting hypertension. Respiratory, thoracic and mediastinal disorders: Apnea, dyspnea, hypoxia, respiratory arrest. Skin and subcutaneous tissue disorders: Erythema multiforme, dermatitis exfoliative, Stevens-Johnson syndrome, toxic epidermal necrolysis. Renal and urinary disorders: Renal failure. General…