PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

CARTON PRINCIPAL DISPLAY PANEL - 500 mg

NDC 76310-017-50

Ethyol® Rx only

(amifostine) for Injection

500 mg per vial

For Intravenous Use

Sterile

CLINIGEN 3 VIALS

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DESCRIPTION SECTION

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:

H2N(CH2)3NH(CH2)2S-PO3H****2

Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C5H15N2O3PS 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.

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INDICATIONS & USAGE SECTION

Highlight: 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 INDICATIONS AND USAGE

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 & ADMINISTRATION SECTION

Highlight: * For reduction of cumulative renal toxicity with chemotherapy, the recommended starting dose is 910 mg/m2 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/m2 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 DOSAGE AND ADMINISTRATION

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/m2 dose, antiemetic medications, including intravenous dexamethasone 20 mg and a serotonin 5HT3 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/m2 dose, it is recommended that antiemetic medication be administered prior to ETHYOL administration. Oral 5HT3 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/m2 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/m2 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/m2 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/m2 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

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/m2 dose, if the full dose of ETHYOL cannot be administered, the dose of ETHYOL for subsequent chemotherapy cycles should be 740 mg/m2.

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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: * For injection: sterile lyophilized powder in 10 mL single-dose vials.

• Each vial contains 500 mg of amifostine on the anhydrous basis.

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.

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CONTRAINDICATIONS SECTION

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

4 CONTRAINDICATIONS

ETHYOL is contraindicated in patients with known hypersensitivity to aminothiol compounds.

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DRUG INTERACTIONS SECTION

Highlight: * Closely monitor patients receiving anti-hypertensive medications or other drugs that could cause or potentiate hypotension. (7)

7 DRUG INTERACTIONS

Closely monitor patients receiving anti-hypertensive medications or other drugs that could cause or potentiate hypotension.

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions are hypotension, nausea and vomiting. (6)

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**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.

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)]

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

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.

CLINICAL STUDIES SECTION

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/m2, and cisplatin 100 mg/m2 with or without ETHYOL pretreatment at 910 mg/m2, 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* Table 4: Patients with Increasing Grades of Hypomagnesemia

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

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/m2 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)

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

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OVERDOSAGE SECTION

10 OVERDOSAGE

In clinical trials, the maximum single dose of ETHYOL was 1300 mg/m2. 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)].

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