ETHYOL® (amifostine) for Injection

NDA 20-221/S-024 Page 3 ETHYOL® (amifostine) for Injection Description Clinical Pharmacology Indications and Usage Contraindications Warnings Precautions Adverse Reactions Overdosage Dosage and Administration How Supplied Rx only 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-PO3H2 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-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis. CLINICAL PHARMACOLOGY 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. 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/m2 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. Clinical Studies Chemotherapy for Ovarian Cancer . A randomized controlled trial compared six cycles of NDA 20-221/S-024 Page 4 cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without ETHYOL pretreatment at 910 mg/m2, in two successive cohorts of 121 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. Subgroup analyses suggested that the effect of ETHYOL was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of ETHYOL in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below. TABLE 1 Proportion of Patients with ≥40% Reduction in Calculated Creatinine Clearance* 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 *Creatinine clearance values were calculated using the Cockcroft-Gault formula, Nephron 1976; 16:31-41. TABLE 2 NCI Toxicity Grades of Serum Magnesium Levels for Each Patient's Last Cycle of Therapy NCI-CTC Grade: 0 1 2 3 4 p-value* (mEq/L) >1.4 ≤1.4->1.1 ≤1.1->0.8 ≤0.8->0.5 ≤0.5 All Patients 0.001 92 13 3 0 0 ETHYOL+CP 73 18 7 5 1 CP First Cohort 0.017 49 10 3 0 0 ETHYOL+CP 35 8 6 3 1 CP 0.012 Second Cohort ETHYOL+CP 43 3 0 0 0 CP 38 10 1 2 0 * Based on 2-sided Mantel-Haenszel Chi-Square statistic. 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. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study. TABLE 3 Comparison of Principal Efficacy Findings ETHYOL +CP CP Complete pathologic tumor 21.3% 15.8% response rate 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 .98 (.64, 1.4) (95% Confidence Interval) 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 .97 (.69, 1.32) (95% Confidence Interval) NDA 20-221/S-024 Page 5 Radiotherapy for Head and Neck Cancer. A randomized controlled trial 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 i.v. 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 NDA 20-221/S-024 Page 6 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 4). TABLE 4 Incidence of Grade 2 or Higher Xerostomia (RTOG criteria) Acute (≤90 days from start of radiation) Latea (9-12 months post radiation) ETHYOL +RT 51% (75/148) 35% (36/103) RT 78% (120/153) 57% (63/111) p-value p<0.0001 p=0.0016 aBased on the number of patients for whom actual data were available. NDA 20-221/S-024 Page 7 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 5). TABLE 5 Comparison of Principal Efficacy Findings at 1 Year Locoregional Control Ratea Hazard Ratiob 95% Confidence Interval Disease-Free Survival Ratea Hazard Ratiob 95% Confidence Interval Overall Survival Ratea Hazard Ratiob 95% Confidence Interval ETHYOL +RT RT 76.1% 75.0% 1.013 (0.671, 1.530) 74.6% 70.4% 1.035 (0.702, 1.528) 89.4% 82.4% 1.585 (0.961, 2.613) a1 year rates estimated using Kaplan-Meier method bHazard ratio >1.0 is in favor of the ETHYOL + RT arm INDICATIONS AND USAGE ETHYOL (amifostine) is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer. 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). For the approved indications, the clinical data do not suggest that the effectiveness of cisplatin based chemotherapy regimens or radiation therapy is altered by ETHYOL. There are at present only limited data on the effects of ETHYOL on the efficacy of chemotherapy or radiotherapy in other settings. ETHYOL should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study (see WARNINGS). CONTRAINDICATIONS ETHYOL is contraindicated in patients with known hypersensitivity to aminothiol compounds. NDA 20-221/S-024 Page 8 WARNINGS 1. Effectiveness of the Cytotoxic Regimen Limited data are currently available regarding the preservation of antitumor efficacy when ETHYOL is administered prior to cisplatin therapy in settings other than advanced ovarian cancer. Although some animal data suggest interference is possible, in most tumor models the antitumor effects of chemotherapy are not altered by amifostine. ETHYOL should not be used 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. 2. Effectiveness of Radiotherapy ETHYOL should not be administered in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are at present insufficient data to exclude a tumor-protective effect in this setting. ETHYOL was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of ETHYOL on the incidence of xerostomia and on toxicity in the setting of combined chemotherapy and radiotherapy and in the setting of accelerated and hyperfractionated therapy have not been systematically studied. 3. Hypotension Patients who are hypotensive or in a state of dehydration should not receive ETHYOL. 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 not receive ETHYOL. Prior to ETHYOL infusion patients should be adequately hydrated. During ETHYOL infusion patients should be kept in a supine position. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. It is important that the duration of the 910 mg/m2 infusion not exceed 15 minutes, as administration of ETHYOL as a longer infusion is associated with a higher incidence of side effects. 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. If hypotension occurs, patients should be placed in the Trendelenburg position and be given an infusion of normal saline using a separate i.v. line. During and after ETHYOL infusion, care should be taken to monitor the blood pressure of patients whose antihypertensive medication has been interrupted since hypertension may be exacerbated by discontinuation of antihypertensive medication and other causes such as i.v. hydration. Guidelines for interrupting and restarting ETHYOL infusion if a decrease in systolic blood pressure should occur are provided in the DOSAGE AND ADMINISTRATION section. Hypotension may occur during or shortly after ETHYOL infusion, despite adequate hydration and positioning of the patient (see ADVERSE REACTIONS and PRECAUTIONS). Hypotension has been reported to be associated with dyspnea, apnea, hypoxia, and in rare cases seizures, unconsciousness, respiratory arrest and renal failure. 4. Cutaneous Reactions Serious cutaneous reactions have been associated with ETHYOL administration. Serious cutaneous reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These reactions have been reported more frequently when ETHYOL is used as a radioprotectant (see ADVERSE REACTIONS). Some of these reactions have been fatal or have required hospitalization and/or discontinuance of therapy. Patients should be carefully NDA 20-221/S-024 Page 9 monitored prior to, during and after ETHYOL administration. Serious cutaneous reactions may develop weeks after initiation of ETHYOL administration (see PRECAUTIONS). 5. Hypersensitivity Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with ETHYOL administration. Nausea and Vomiting Antiemetic medication should be administered prior to and in conjunction with ETHYOL (see DOSAGE AND ADMINISTRATlON). When ETHYOL is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored. 6. Hypocalcemia Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of ETHYOL (see ADVERSE REACTIONS). If necessary, calcium supplements can be administered. NDA 20-221/S-024 Page 10 PRECAUTIONS General Patients should be adequately hydrated prior to the ETHYOL infusion and blood pressure should be monitored (see DOSAGE AND ADMINISTRATION). The safety of ETHYOL administration has not been established in elderly patients, or in patients with preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias, congestive heart failure, or history of stroke or transient ischemic attacks. ETHYOL should be used with particular care in these and other patients in whom the common ETHYOL adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences. Prior to chemotherapy, ETHYOL should be administered as a 15-minute infusion (see DOSAGE AND ADMINISTRATION). Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. Prior to radiation therapy, ETHYOL should be administered as a 3-minute infusion (see DOSAGE AND ADMINISTRATION). Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated. Cutaneous Reactions Cutaneous reactions may require permanent discontinuation of ETHYOL or urgent dermatologic consultation and biopsy (see below). Cutaneous evaluation of the patient prior to each ETHYOL administration should be performed with particular attention paid to the development of the following: - Any rash involving the lips or involving mucosa not known to be due to another etiology (e.g., radiation mucositis, herpes simplex, etc.) - Erythematous, edematous, or bullous lesions on the palms of the hands or soles of the feet and/or other cutaneous reactions on the trunk (front, back, abdomen) - Cutaneous reactions with associated fever or other constitutional symptoms Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from cutaneous reactions related to an alternate etiology. ETHYOL should be permanently discontinued for serious or severe cutaneous reactions (see WARNINGS and ADVERSE REACTIONS) or for cutaneous reactions associated with fever or other constitutional symptoms not known to be due to another etiology. ETHYOL should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown etiology appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms of the hand or soles of the feet. Reinitiation of ETHYOL should be at the physician’s discretion based on medical judgment and appropriate dermatologic evaluation. Allergic Reactions In case of severe acute allergic reactions ETHYOL should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis. _____________________________ _____________________________ NDA 20-221/S-024 Page 11 Drug Interactions Special consideration should be given to the administration of ETHYOL in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension. Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal studies have been performed to evaluate the carcinogenic potential of 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. Pregnancy Pregnancy Category C. ETHYOL has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. ETHYOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers No information is available on the excretion of ETHYOL or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with ETHYOL. Pediatric Use The safety and effectiveness in pediatric patients have not been established. 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. ADVERSE REACTIONS Controlled Trials In the randomized study of patients with ovarian cancer given ETHYOL at a dose of 910 mg/m2 prior to chemotherapy, transient hypotension was observed in 62% of patients treated. The mean time of onset was 14 minutes into the 15-minute period of ETHYOL infusion, and the mean duration was 6 minutes. In some cases, the infusion had to be prematurely terminated due to a more pronounced drop in systolic blood pressure. In general, the blood pressure returned to normal within 5-15 minutes. Fewer than 3% of patients discontinued ETHYOL due to blood pressure reductions. In the randomized