DRUGS & SUPPLEMENTS
Erifostine (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
Erifostine 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.
Erifostine is the trihydrate form of Erifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of Erifostine on the anhydrous basis.
Erifostine 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 Erifostine 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.
Clinical pharmacokinetic studies show that Erifostine 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 Erifostine remains in the plasma 6 minutes after drug administration. Erifostine 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 Erifostine, 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 Erifostine pharmacokinetics.
Chemotherapy for Ovarian Cancer. A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without Erifostine 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 Erifostine 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 Erifostine 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 Erifostine in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.
In the randomized ovarian cancer study, Erifostine 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 Erifostine and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.
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 Erifostine, 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 Erifostine (TABLE 4).
At one year following radiation, whole saliva collection following radiation showed that more patients given Erifostine 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 Erifostine (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.
INDICATIONS AND USAGE
Erifostine (amifostine) is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patient s with advanced ovarian cancer.
Erifostine 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 Erifostine. There are at present only limited data on the effects of Erifostine on the efficacy of chemotherapy or radiotherapy in other settings. Erifostine 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.
Erifostine is contraindicated in patients with known hypersensitivity to aminothiol compounds.
1. Effectiveness of the Cytotoxic Regimen
Limited data are currently available regarding the preservation of antitumor efficacy when Erifostine 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 Erifostine. Erifostine 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
Erifostine 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. Erifostine was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of Erifostine 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.
Patients who are hypotensive or in a state of dehydration should not receive Erifostine. Patients receiving Erifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of Erifostine. Patients receiving Erifostine at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding Erifostine treatment, should not receive Erifostine.
Prior to Erifostine infusion patients should be adequately hydrated. During Erifostine 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 Erifostine 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 Erifostine 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 Erifostine 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 Erifostine infusion, despite adequate hydration and positioning of the patient. 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
Fatal and serious cutaneous reactions have been reported with Erifostine treatment, including 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 Erifostine is used as a radioprotectant. Serious cutaneous reactions may develop weeks after initiation of Erifostine administration. Monitor patients carefully prior to, during and after Erifostine administration. Discontinue Erifostine 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.
Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with Erifostine administration.
6. Nausea and Vomiting
Antiemetic medication should be administered prior to and in conjunction with Erifostine. When Erifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.
Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Erifostine. If necessary, calcium supplements can be administered.
The safety of Erifostine 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. Erifostine should be used with particular care in these and other patients in whom the common Erifostine adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.
Prior to chemotherapy, Erifostine should be administered as a 15-minute infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
Prior to radiation therapy, Erifostine should be administered as a 3-minute infusion. Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
In case of severe acute allergic reactions Erifostine should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term animal studies have been performed to evaluate the carcinogenic potential of Erifostine. Erifostine 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.
Erifostine 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. Erifostine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
No information is available on the excretion of Erifostine 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 Erifostine.
The safety and effectiveness in pediatric patients have not been established therefore Erifostine is not recommended for use in the pediatric population.
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.
In the randomized study of patients with ovarian cancer given Erifostine 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 Erifostine 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 Erifostine due to blood pressure reductions. In the randomized study of patients with head and neck cancer given Erifostine at a dose of 200 mg/m2 prior to radiotherapy, hypotension was observed in 15% of patients treated.
In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued Erifostine due to adverse events. All but one of these patients continued to receive radiation treatment until completion.
Hypotension that requires interruption of the Erifostine 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 Erifostine can be administered. Short term, reversible syncope (loss of consciousness) has been reported rarely.
Nausea and/or vomiting occur frequently after Erifostine 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 Erifostine, and 19% in patients who did receive Erifostine. In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received Erifostine and 1% in patients who did not receive Erifostine.
Decrease in serum calcium concentrations is a known pharmacological effect of Erifostine. At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the randomized head and neck cancer study.
Other effects, which have been described during or following Erifostine infusion are 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.
Clinical Trials and Pharmacovigilance Reports
Hypersensitivity and anaphylactic reactions characterized by one or more of the following manifestations have been observed during or after Erifostine administration: hypotension, pyrexia, chills/rigors, dyspnea, hypoxia, chest discomfort, 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 Erifostine is higher in patients receiving Erifostine as a radioprotectant than in patients receiving Erifostine 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 seizure. Rare cases of renal failure, myocardial infarction, respiratory and cardiac arrest have been observed during or after hypotension.
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 Erifostine administration.
Seizures and syncope (loss of consciousness) have been reported rarely.
In clinical trials, the maximum single dose of Erifostine 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 Erifostine doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible urinary retention occurred.
Administration of Erifostine 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 Erifostine 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 Erifostine 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 Erifostine should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
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 Erifostine may be administered. If the full dose of Erifostine cannot be administered, the dose of Erifostine 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 Erifostine. 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 Erifostine 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 Erifostine 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 Erifostine. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.
Erifostine (amifostine) for Injection is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use vial contains 500 mg of Erifostine on the anhydrous basis.
Prior to intravenous injection, Erifostine 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).
Erifostine 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.
The compatibility of Erifostine 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.
Erifostine (amifostine) for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 66220-017-03). Each single-use vial contains 500 mg of Erifostine on the anhydrous basis. The vials are available packaged as follows:
3 pack - 3 vials per carton (NDC 66220-017-03)
Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F).
U.S. Patent 5,994,409
Cumberland Pharmaceuticals Inc.
Nashville, TN 37203
Erifostine is a registered trademark owned by the Clinigen Group.
For product information, please call Cumberland Pharmaceuticals Inc. Medical Information at 1 877 484 2700.
Revision Date 05/2017
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The information was verified by Dr. Arunabha Ray, MD Pharmacology