Ethyol

6 ADVERSE REACTIONS Most common adverse reactions are hypotension, nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Clinigen, Inc. at 1-877-776-5385 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 )] 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 _____________________________________________ Per Patient Per Infusion Head and Neck Cancer (WR -38 Trial) 200 mg/m 2 _______________________________________________ Per Patient Per Infusion Nausea/Vomiting ≥Grade 3 All Grades 36/122 (30%) 117/122 (96%) 53/592 (9%) 520/592 (88%) 12/150 (8%) 80/150 (53%) 13/4314 (<1%) 233/4314 (5%) Hypotension ≥Grade 3 All Grades 10/122 (8%) 75/122 (62%) 159/592 (27%) 4/150 (3%) 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 disorders and administration site conditions: Chest discomfort and chest pain.

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 )

11 DESCRIPTION ETHYOL (amifostine) is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) and has the following structural formula: H 2 N(CH 2 ) 3 NH(CH 2 ) 2 S-PO 3 H 2 Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C 5 H 15 N 2 O 3 PS and it has a molecular weight of 214.22. ETHYOL is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-dose 10 mL vial contains 500 mg of amifostine on the anhydrous basis.

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 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.

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.

10 OVERDOSAGE In clinical trials, the maximum single dose of ETHYOL was 1300 mg/m 2 . No information is available on single doses higher than this in adults. At the higher doses, anxiety and reversible urinary retention occurred. The most likely symptom of overdosage is hypotension, which should be managed by infusion of normal saline and other supportive measures, as clinically indicated [see Warnings and Precautions ( 5.3 )].

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 )

12 CLINICAL PHARMACOLOGY 12.1 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. 12.3 Pharmacokinetics Clinical pharmacokinetic studies show that ETHYOL is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of ETHYOL remains in the plasma 6 minutes after drug administration. ETHYOL is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m 2 of ETHYOL, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of ETHYOL. Pretreatment with dexamethasone or metoclopramide has no effect on ETHYOL pharmacokinetics.

12.1 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.

12.3 Pharmacokinetics Clinical pharmacokinetic studies show that ETHYOL is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of ETHYOL remains in the plasma 6 minutes after drug administration. ETHYOL is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m 2 of ETHYOL, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of ETHYOL. Pretreatment with dexamethasone or metoclopramide has no effect on ETHYOL pharmacokinetics.

20231102

4

3 DOSAGE FORMS AND STRENGTHS For Injection: sterile lyophilized white powder in 10 mL single-dose vials. Each vial contains 500 mg of amifostine on the anhydrous basis. For injection: sterile lyophilized powder in 10 mL single-dose vials. Each vial contains 500 mg of amifostine on the anhydrous basis.

Ethyol amifostine AMIFOSTINE AMIFOSTINE ANHYDROUS

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with ETHYOL. ETHYOL was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes. Fertility studies in animals have not been conducted with amifostine. In a 3-month repeat-dose toxicity study in rats, intravenous administration of amifostine resulted in bilateral degeneration of the germinal epithelium of the testes and bilateral hypospermia in the epididymides at doses of 50 mg/kg/day (approximately 0.3 times the maximum clinical dose based on body surface area).

NDA020221

Ethyol

amifostine

76310-017

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

VIAL PRINCIPAL DISPLAY PANEL - 500 mg NDC 76310-017-01 Ethyol ® (amifostine) for Injection 500 mg per vial For Intravenous Use Sterile Rx only CLINIGEN Vial 500mg

17 PATIENT COUNSELING INFORMATION Hypotension and Cardiovascular Events Inform the patient that he or she may experience hypotension after ETHYOL infusion [see Adverse Reactions ( 6.1 )] . Advise the patient to inform the prescriber if he or she is receiving anti-hypertensive medications or other drugs that could cause or potentiate hypotension [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Severe Cutaneous Reactions Inform the patient that severe cutaneous reactions may develop during or weeks after initiation of ETHYOL administration. Advise the patient to inform the prescriber if they experience any cutaneous reactions or mucosal lesions outside of the injection site or radiation port, or on the palms or soles, as discontinuation of the drug may be necessary [see Warnings and Precautions ( 5.4 )] . Hypersensitivity Inform the patient that he or she may experience allergic reactions after ETHYOL infusion [see Adverse Reactions ( 6.1 )] . ETHYOL might need to be discontinued for severe acute allergic reactions and the patient receive other treatments [See Warnings and Precautions ( 5.5 )] . Nausea and Vomiting Inform the patient that he or she may experience severe nausea and/or vomiting after ETHYOL infusion [see Adverse Reactions ( 6.1 )] . Hypocalcemia Inform the patient that calcium supplements may be necessary if hypocalcemia is identified [see Warnings and Precautions ( 5.7 )] . Blood tests may be needed to identify this, and correct the condition. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 )] . Refer to the cisplatin full prescribing information for pregnancy and contraception information. Lactation Advise lactating women not to breastfed during treatment with ETHYOL [see Use in Specific Populations ( 8.2 )] . Refer to the cisplatin full prescribing information for lactation information. Infertility Advise males of reproductive potential that ETHYOL may impair fertility [see Use in Specific Populations ( 8.3 )] . Refer to the cisplatin full prescribing information for infertility information. U.S. Patent 5,994,409 Manufactured for: Clinigen, Inc. Yardley, PA 19067 ETHYOL is a registered trademark owned by the Clinigen Group. For additional information, contact Clinigen, Inc. 1-877-776-5385. Revision Date: 12/2019

14 CLINICAL STUDIES 14.1 Reduction of Cumulative Renal Toxicity with Chemotherapy A randomized controlled trial (WR-1) compared six cycles of cyclophosphamide 1000 mg/m 2 , and cisplatin 100 mg/m 2 with or without ETHYOL pretreatment at 910 mg/m 2 , in two successive cohorts with a total of 242 patients with advanced ovarian cancer. In both cohorts, after multiple cycles of chemotherapy, pretreatment with ETHYOL significantly reduced the cumulative renal toxicity associated with cisplatin, as assessed by the proportion of patients who had ≥40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine (>1.5 mg/dL), or severe hypomagnesemia. Table 3: Patients with ≥40% Reduction in Calculated Creatinine Clearance Creatinine clearance values were calculated using the Cockcroft-Gault formula. ETHYOL + CP CP p-value (2-sided) All Patients 16/122 (13%) 36/120 (30%) 0.001 First Cohort 10/63 20/58 0.018 Second Cohort 6/59 16/62 0.026 Table 4: Patients with Increasing Grades of Hypomagnesemia NCI-CTC Grade NCI toxicity grades of serum magnesium levels for each patient's last cycle of therapy. : (mEq/L) 0 >1.4 1 ≤1.4->1.1 2 ≤1.1->0.8 3 ≤0.8->0.5 4 ≤0.5 p-value Based on 2-sided Mantel-Haenszel Chi-Square statistic. All Patien ts ETHYOL+CP CP 92 73 13 18 3 7 0 5 0 1 0.001 First Cohort ETHYOL+CP CP 49 35 10 8 3 6 0 3 0 1 0.017 Second Cohort ETHYOL+CP CP 43 38 3 10 0 1 0 2 0 0 0.012 Exploratory subgroup analyses suggested that the effect of ETHYOL was consistent in patients with increased risks for nephrotoxicity (i.e., nephrotoxic antibiotics, preexisting diabetes, or hypertension) compared to patients who lacked these risks. The effects of ETHYOL in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are shown in Tables 3 and 4 . In the randomized ovarian cancer study, ETHYOL had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the ETHYOL and control study groups. Table 5 summarizes the efficacy findings of the WR-1 ovarian cancer study. Table 5: Efficacy Results from the WR-1 Study ETHYOL + CP CP Complete pathologic tumor response rate 21.3% 15.8% Time to progression (months) Median (± 95% CI) 15.8 (13.2, 25.1) 18.1 (12.5, 20.4) Mean (± Std error) 19.8 (±1.04) 19.1 (±1.58) Hazard ratio (95% Confidence Interval) .98 (.64, 1.4) Survival (months) Median (± 95% CI) 31.3 (28.3, 38.2) 31.8 (26.3, 39.8) Mean (± Std error) 33.7 (±2.03) 34.3 (±2.04) Hazard ratio (95% Confidence Interval) .97 (.69, 1.32) 14.2 Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck A randomized controlled trial (WR-38) of standard fractionated radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without ETHYOL, administered at 200 mg/m 2 as a 3 minute intravenous infusion 15‑30 minutes prior to each fraction of radiation, was conducted in 315 patients with head and neck cancer. Patients were required to have at least 75% of both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less from start of radiation) and late xerostomia (9‑12 months following radiation) as assessed by RTOG Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving ETHYOL ( Table 6 ). Table 6: Incidence of Grade 2 or Higher Xerostomia (RTOG criteria) ETHYOL + RT RT p-value Acute (≤90 days from start of radiation) 51% (75/148) 78% (120/153) p<0.0001 Late Based on the number of patients for whom actual data were available. (9-12 months post radiation) 35% (36/103) 57% (63/111) p=0.0016 At one year following radiation, whole saliva collection following radiation showed that more patients given ETHYOL produced >0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production at one year was higher in those patients who received ETHYOL (0.26 gm vs. 0.1 gm). Stimulated saliva collections did not show a difference between treatment arms. These improvements in saliva production were supported by the patients' subjective responses to a questionnaire regarding oral dryness. In the randomized head and neck cancer study, locoregional control, disease-free survival and overall survival were all comparable in the two treatment groups after one year of follow-up (see Table 7 ). Table 7: Efficacy Results at 1 Year from the WR-38 Study ETHYOL + RT RT Locoregional Control Rate 1 year rates estimated using Kaplan-Meier method 76.1% 75.0% Hazard Ratio Hazard ratio >1.0 is in favor of the ETHYOL + RT arm 1.013 95% Confidence Interval (0.671, 1.530) Disease-Free Survival Rate 74.6% 70.4% Hazard Ratio 1.035 95% Confidence Interval (0.702, 1.528) Overall Survival Rate 89.4% 82.4% Hazard Ratio 1.585 95% Confidence Interval (0.961, 2.613)

15 REFERENCES 1. "OSHA Hazardous Drugs." OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html

8 USE IN SPECIFIC POPULATIONS Advise not to breastfeed. ( 8.2 ) 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. 8.2 Lactation Risk Summary When ETHYOL is used in combination with cisplatin, refer to the cisplatin full prescribing information for lactation information. There are no data on the presence of amifostine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with ETHYOL. 8.3 Females and Males of Reproductive Potential When ETHYOL is used in combination with cisplatin, refer to the cisplatin full prescribing information for contraception and infertility information. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating ETHYOL. Infertility Males Based on findings from animal studies, ETHYOL may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use The clinical studies did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.

16 HOW SUPPLIED/STORAGE AND HANDLING ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized white powder in 10 mL single-dose vials (NDC 76310-017-50). Each vial contains 500 mg of amifostine on the anhydrous basis. The vials are available packaged as follows: Carton containing 3 vials (NDC 76310-017-50) Discard unused portion. Store the lyophilized dosage form at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Follow special handling and disposal procedures [see References ( 15 )].