英文药名: Ethyol (Amifostine Crystalline Vial)

中文药名: 氨磷汀（阿米福汀注射剂）

药品简介

氨磷汀(amifostine)是1996年FDA批准在美国上市的第二个细胞保护剂(抗辐射药)。商品名为Ethyol,Ethiofos. 通常用多剂量顺铂对晚期卵巢癌或非小细胞肺癌化疗和用环磷酰胺对晚期卵巢癌化疗时，易出现累积肾毒性。本品可预防和减少这种累积肾毒性。

药理作用
药效学
本品是硫代磷酸盐的前体药物。它的细胞保护作用是由于正常组织中pH较高、碱基磷酸酯酶活性较强，可将氨磷汀迅速完全地去磷酸化而成游离硫羟基(thiol-)的、有药理活性的代谢物(代号WR-1065)，因而保护非肿瘤组织免于化疗和放射疗法的毒性作用，降低环磷酰胺和顺铂对晚期卵巢癌化疗时引起的、与中性白血球减少症有关的感染发生率。正常组织的血液供应较好，提取的氨磷汀多于癌变组织，因而正常组织细胞内活性代谢物WR-1065的浓度较高，可起到区分保护的作用。
药动学
本品的胃肠吸收很差，故不宜口服。在10s内静脉推注本品150mg.m-2后癌症患者的血清药物峰浓度为100～900μmol.L-1，注射后1～4min活性代谢物WR-1 065的峰浓度为7～22μmol.L-1。若给癌症患者以740mg.m-2剂量15min静脉输注本品，则5min内可达到血浆浓度100μmol.L-1，输注结束时可达到100～200μmol.L-1。输注后30min时血浆浓度可下降至10μmol.L-1，45min时为2μmol.L-1左右。
本品自血浆中清除迅速，静脉推注或输注后6min内血浆药物水平可下降90%。分布半衰期不到1min，消除半衰期约9min，仅少量原型药物及代谢物自尿中排出。稳态时的平均分布容积为6L。
有限的资料表明，以910mg.m-2静脉输注本品后2.5h时，病人骨髓中WR-1065的水平较低，提示为了对抗半衰期较长的细胞毒性药物(如环磷酰胺)，需多剂量给予氨磷汀才能起到细胞保护作用。
动物实验结果表明，本品在骨髓、胃肠粘膜、皮肤、肝脏及唾液中的浓度较高，而在肌肉中水平较低，脑组织中几乎没有。

适应症
本品可预防顺铂引起的肾毒性和外周神经病，预防环磷酰胺引起的粒细胞白血病和放射疗法引起的骨髓抑制。与顺铂合用可增加顺铂的抗肿瘤效果。用于晚期卵巢癌及转移黑素瘤的放射疗法。亦可用于头颈部癌症、食道癌、肺癌及头部以上的放射疗法。颈动脉病或高钙血症的患者静脉给予本品易发生低血压，建议用较低剂量。

用法用量
建议本品的初始剂量为910mg.m-2，化疗前30min开始静脉输注，输注时间为15min。若收缩压显著低于正常低限则应停止输注。若停药5min内血压恢复正常且患者无任何症状，可继续输注，以使患者获得全部剂量。若患者不能耐受足量氨磷汀，则下一疗程的剂量应减为740mg.m2。本品的最大耐受剂量是每周4d按340mg.m2给予，连续5周。
本品为单剂量包装，每支500mg，应冷藏。

不良反应
本品最重要的不良反应是一过性低血压，在临床研究中约占62%。有低血压的或正处在脱水状态的患者，不得使用本品。正在服用抗高血压药物且24h内不能中断治疗的患者也不能使用本品。给予氨磷汀输注前，应给患者适当水化，静脉补充一些液体。输液氨磷汀的过程中患者应卧床，每隔5min测一次血压。若收缩压明显下降，应立即停药。
恶心或呕吐常发生于氨磷汀输液后，接受顺铂-环磷酰胺化疗第1天并给予本品的患者中有19%出现严重的反应，而未接受本品的患者反应发生率为10%。建议在给予本品之前给予抗呕吐治疗，如地塞米松20mg静注、或5-羟色胺受体阻断剂昂丹司琼和格拉司琼。抗呕吐剂也可与本品合用。
本品可降低血清钙水平，但引致临床上明显的低钙血症发生率低于1%。对有低钙血症危险性的患者(如肾病综合征)应监测血钙水平，必要时补充钙剂。
其它不良反应还有面色潮红、寒战、眩晕、嗜睡、呃逆和打喷嚏。皮疹变态反应发生率低于1%。

禁忌
属孕期用药C级(美国FDA颁布的妊娠期间使用药物危险性等级的分类之一，即动物实验证明对胎儿有不良反应——致畸或致死，尚未在孕妇中进行对照研究)，因可能危及胎儿而在怀孕期间禁用。哺乳期妇女若使用氨磷汀应停止授乳。本品对儿童和老年人的疗效和安全性尚未知。对氨磷汀、氨硫羟化合物、甘露醇等高敏的不良反应禁用。
不良反应有如下情况时慎用：脑血管病或心血管病、低钙血症的不良反应；有脱水或低血压的不良反应；孕妇和哺乳期妇女；正在服用抗高血压药物且24 h内不能停药者。

【原产地英文商品名】ETHYOL 500mg/vial 3vials/box
【原产地英文药品名】AMIFOSTINE CRYSTALLINE
【中文参考商品译名】氨磷汀 500毫克/瓶 3瓶/盒
【中文参考药品译名】阿米福汀晶体
【生产厂家中文参考译名】MEDIMMUNE
【生产厂家英文名】MEDIMMUNE

ETHYOL (amifostine) injection, powder, lyophilized, for solution
[MedImmune, LLC]

ETHYOL®
(amifostine) for Injection

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 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* 

* Creatinine clearance values were calculated using the Cockcroft-Gault formula, Nephron 1976; 16:31-41.
	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 2 NCI Toxicity Grades of Serum Magnesium Levels for Each Patient's Last Cycle of Therapy

* Based on 2-sided Mantel-Haenszel Chi-Square statistic.
NCI-CTC Grade: (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*
All Patients       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

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 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)

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 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)

* Based on the number of patients for whom actual data were available.
	ETHYOL +RT	RT	p-value
Acute (≤90 days from start of radiation)	51% (75/148)	78% (120/153)	p<0.0001
Late* (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 5).

TABLE 5 Comparison of Principal Efficacy Findings at 1 Year

1 year rates estimated using Kaplan-Meier method Hazard ratio >1.0 is in favor of the ETHYOL + RT arm
	ETHYOL +RT	RT
Locoregional Control Rate*	76.1%	75.0%
Hazard Ratio†	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)

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.

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 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.

6.    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.

7.    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.

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.

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 study of patients with head and neck cancer given ETHYOL at a dose of 200 mg/m2 prior to radiotherapy, hypotension was observed in 15% of patients treated. (see TABLE 6)

TABLE 6 Incidence of Common Adverse Events in Patients Receiving ETHYOL 

* According to protocol-defined criteria. WR-1: requiring interruption of infusion; WR-38: drop of >20mm Hg.
	Phase III Ovarian Cancer Trial (WR-1) 910 mg/m2		Phase III Head and Neck Cancer Trial (WR-38) 200 mg/m2
	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 (61%)	159/592 (27%)	22/150 (15%)	46/4314 (1%)

In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued ETHYOL due to adverse events. All but one of these patients continued to receive radiation treatment until completion.

Hypotension that requires interruption of the ETHYOL infusion should be treated with fluid infusion and postural management of the patient (supine or Trendelenburg position). 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. Short term, reversible loss of consciousness has been reported rarely.

Nausea and/or vomiting occur frequently after ETHYOL infusion and may be severe.
In the ovarian cancer randomized study, the incidence of severe nausea/vomiting on
day 1 of cyclophosphamide-cisplatin chemotherapy was 10% in patients who did not receive ETHYOL, and 19% in patients who did receive ETHYOL. In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received ETHYOL and 1% in patients who did not receive ETHYOL. 

Decrease in serum calcium concentrations is a known pharmacological effect of ETHYOL. At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the randomized head and neck cancer study (see WARNINGS).

Other effects, which have been described during, or following ETHYOL infusion are flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups and sneezing. These effects have not generally precluded the completion of therapy.

Clinical Trials and Pharmacovigilance Reports

Allergic reactions characterized by one or more of the following manifestations have been observed during or after ETHYOL administration: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest tightness, cutaneous eruptions, pruritus, urticaria and laryngeal edema. Cutaneous eruptions have been commonly reported during clinical trials and were generally non-serious. Serious, sometimes fatal skin reactions including erythema multiforme, and in rare cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have also occurred. The reported incidence of serious skin reactions associated with ETHYOL is higher in patients receiving ETHYOL as a radioprotectant than in patients receiving ETHYOL as a chemoprotectant. Rare anaphylactoid reactions and cardiac arrest have also been reported.

Hypotension, usually brief systolic and diastolic, has been associated with one or more of the following adverse events: apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain, myocardial ischemia and convulsion. Rare cases of renal failure, myocardial infarction, respiratory and cardiac arrest have been observed during or after hypotension. (See WARNINGS and PRECAUTIONS)

Rare cases of arrhythmias such as atrial fibrillation/flutter and supraventricular tachycardia have been reported. These are sometimes associated with hypotension or allergic reactions.

Transient hypertension and exacerbations of preexisting hypertension have been observed rarely after ETHYOL administration.

Seizures and syncope have been reported rarely. (See WARNINGS and PRECAUTIONS)

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. In the setting of a clinical trial, pediatric patients have received single ETHYOL doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible urinary retention occurred.

Administration of ETHYOL at 2 and 4 hours after the initial dose has not led to increased nausea and vomiting or hypotension. The most likely symptom of overdosage is hypotension, which should be managed by infusion of normal saline and other supportive measures, as clinically indicated.

DOSAGE AND ADMINISTRATION

For Reduction of Cumulative Renal Toxicity with Chemotherapy:

The recommended starting dose of ETHYOL is 910 mg/m2 administered once daily as a 15-minute i.v. infusion, starting 30 minutes prior to chemotherapy.

The 15-minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.

Patients should be adequately hydrated prior to ETHYOL infusion and kept in a supine position during the infusion.  Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.

The infusion of ETHYOL should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:

Guideline for Interrupting ETHYOL Infusion Due to Decrease 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. If the full dose of ETHYOL cannot be administered, the dose of ETHYOL for subsequent chemotherapy cycles should be 740 mg/m2.

It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin 5HT3 receptor antagonist, be administered prior to and in conjunction with ETHYOL. Additional antiemetics may be required based on the chemotherapy drugs administered.

For Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck:

The recommended dose of ETHYOL is 200 mg/m2 administered once daily as a 3-minute i.v. infusion, starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy).

Patients should be adequately hydrated prior to ETHYOL infusion. Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.

It is recommended that antiemetic medication be administered prior to and in conjunction with ETHYOL. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting. 

Reconstitution

ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use vial contains 500 mg of amifostine on the anhydrous basis.

Prior to intravenous injection, ETHYOL is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. The reconstituted solution (500 mg amifostine/10 mL) 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).

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).

CAUTION: Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if cloudiness or precipitate is observed.

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.

HOW SUPPLIED

ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 58178-017-01). Each single-use vial contains 500 mg of amifostine on the anhydrous basis. The vials are available packaged as follows:

3 pack - 3 vials per carton (NDC 58178-017-03)

Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].