Ethyol Drug Information

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.

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.

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 .

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 . 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.

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.

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 . When ETHYOL is administered with highly emetogenic chemotherapy, closely monitor the fluid balance of the patient.

Hypocalcemia

Monitor serum calcium levels in patients at risk of hypocalcemia, such as those with nephrotic syndrome, or patients receiving multiple doses of ETHYOL. At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the head and neck cancer study (WR-38). If necessary, calcium supplements can be administered.

Embryo-Fetal Toxicity

Based on findings in animals, ETHYOL can cause fetal harm when administered to a pregnant woman. 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. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

When ETHYOL is used in combination with cisplatin, refer to the cisplatin full prescribing information for pregnancy and contraception information.