Amifostine

214.22

214.22

1308068-626-2

ILA426L95O

758236|296961

DTXSID8022585

C66724

White crystalline powder

V - Various

2922499990

130.69000

-1.68

powder

1.4±0.1 g/cm3

160-161 °C

441.7±51.0 °C at 760 mmHg

220.9±30.4 °C

1.555

1000 mg/mL

2-8°C

1.96X10-8 mm Hg at 25 °C (est)

Peritoneal-rat LD50: 418 mg/kg; oral-mouse LD50: 842mg/kg

Flammable; burning produces toxic nitrogen oxides, phosphorus oxides and sulfur oxide fumes

Henry's Law constant = 7.26X10-20 atm-cu m/mol at 25 °C (est)

146.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

White solid from methanol/ether. Mp 160-161 °C (dec). /Monohydrate/|Solubility in water: >9 g/100 ml, pKa1 <2.0; pKa2: 4.2; pKa3: 9.0; pKa4: 11.7 /Trihydrate/|Hydroxyl radical reaction rate constant = 1.41X10-14 cu cm/molec-sec at 25 °C (est)

3

22-36/37/38

26-36

TE6491000

Xn,Xi

Warehouse ventilated, low temperature and dry

Bulk: A small sample stored in a small container at 60 °C showed about 14% decomposition in 24 hours. A small sample stored in a large container at 60 °C for 30 days appeared to be stable. The stability of the compound is dependent on the temperature and the relative amount of moisture present (HPLC and TLC). The compound should be stored under refrigeration in tightly closed containers. Solution: A 5% aqueous solution showed about 1% decomposition after 24 hours at room temperature (TLC).

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl amifostine approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 39 companies from 1 notifications to the ECHA C&L Inventory.

highly toxic

Rat LD50: 826 mg/kg

Repeated peroral administration of melatonin and ascorbic acid in a dose of 200 mg/kg 30 min before treatment with gammafos reduced its cumulative toxic effect. Succinic acid in a dose of 100 mg/kg was ineffective under these conditions. The cumulative death time for 50% animals receiving gammafos alone or in combination with melatonin, ascorbic acid, and succinic acid was 3.08, 4.29, 4.06, and 2.97 days, respectively.|Amifostine may temporarily produce hypotension; antihypertensive or other potentially hypotension-producing medications should be discontinued 24 hours prior to amifostine administration; patients receiving antihypertensive therapy that cannot be discontinued should not receive amifostine.

LD50 Mouse ip 700 mg/kg /Amifostine monohydrate/

While data specific to amifostine were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

It is not known whether amifostine or its metabolites are distributed into breast milk.

For reduction in the cumulative renal toxicity in patients with ovarian cancer (using cisplatin) and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer.|FDA Label|Drug: Amifostine

Radiation-protective agents|Amifostine is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer. /Included in US product label/|Amifostine is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced solid tumor of non-germ cell origin. /NOT included in US product label/|Amifostine is indicated to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where radiation port includes a substantial portion of the parotid gland. /Included in US product label/|For more Therapeutic Uses (Complete) data for AMIFOSTINE (8 total), please visit the HSDB record page.

Although hypocalcemia occurs only rarely during cytoprotective therapy with amifostine, serum calcium concentrations should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or those receiving multiple doses of amifostine, and calcium supplementation initiated as necessary.|Because nausea and/or vomiting occur frequently during amifostine therapy and may be severe, effective antiemetic therapy (e.g., an IV corticosteroid such as dexamethasone and a serotonin 5-HT3 receptor antagonist) should be administered prior to and in conjunction with amifostine therapy. Additional antiemetics may be required depending on the emetogenic potential of concomitantly administered chemotherapy or radiation therapy. In addition, the patient's fluid balance should be monitored carefully in those receiving highly emetogenic chemotherapy.|Patients also should be closely monitored during and after IV administration of amifostine for possible allergic manifestations, including anaphylactic reactions that have rarely been associated with cardiac arrest. If acute hypersensitivity reactions occur, the infusion should be immediately and permanently discontinued. The manufacturer states that epinephrine and other appropriate measures should be available for immediate treatment of such events.|During infusions of less than 5 minutes' duration, blood pressure should be monitored at least before and immediately after completion of the infusion, and thereafter if needed. If hypotension requiring interruption of the amifostine infusion occurs, the patient should be placed in the Trendelenburg position and an iv infusion of 0.9% sodium chloride initiated in a separate line.|For more Drug Warnings (Complete) data for AMIFOSTINE (9 total), please visit the HSDB record page.

Amifostine is an organic thiophosphate cytoprotective agent indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite, 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. Healthy cells are preferentially protected because amifostine and metabolites are present in healthy cells at 100-fold greater concentrations than in tumour cells.

Drugs used to protect against ionizing radiation. They are usually of interest for use in radiation therapy but have been considered for other purposes, e.g. military. (See all compounds classified as Radiation-Protective Agents.)

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 concentrations of the active free thiol metabolite have been found in bone marrow cells 5 to 8 minutes after intravenous administration.|It is not known whether amifostine or its metabolites are distributed into breast milk.|Elimination /is/ primarily via rapid metabolism and uptake into tissues.|... Studies in rats using a single dose of amifostine showed that /with/ SC administration, there is no evidence of drug accumulation in either normal or tumor tissue, with tumor WR-1065 levels peaking just above the limits of quantitation during treatment. ...|The pharmacokinetics of the cytoprotective agent amifostine (EthyolR; WR 2721) and its main metabolites (WR 1065 and the disulphides) were studied in patients participating in two phase I trials concerning carboplatin or cisplatin in combination with amifostine. Patients were treated with a single dose or three doses of amifostine (740 or 910 mg/sq m). The single or first dose was given as a 15 min iv infusion just before administration of the chemotherapeutic agent. The additional two infusions were administered 2 and 4 hr thereafter. Amifostine was rapidly cleared from the plasma, due to, at least in part, the fast conversion into WR 1065. A biphasic decrease with a final half-life of 0.8 hr was observed. The active metabolite WR 1065 was cleared from the plasma with a final half-life of 7.3 +/- 3.6 hr. The short initial half-life of WR 1065 can be explained by its fast uptake in tissues and the formation of disulphides. The disulphides were cleared with a final half-life of 8.4-13.4 hr and were detectable for at least 24 hr after treatment. They may serve as an exchangeable pool of WR 1065. The amifostine peak values at the end of each 15 min infusion did not accumulate in the multiple dosing schedule. For WR 1065 a trend towards an increase in the peak levels was observed [C1,max: 47.5 +/- 11.9 uM, C2,max: 79.0 +/- 13.2 uM, C3,max: 84.8 +/- 15.1 uM, (n = 6)], whereas a trend towards a small decrease was observed for the peak levels of the disulphides [C1,max: 184.2 +/- 12.6 uM, C2,max: 175.0 +/- 23.7 uM, C3,max: 166.0 +/- 17.2 uM, (n = 6)]. This latter finding might suggest a saturation of the disulphide formation or a change in the uptake or elimination of WR 1065, which would result in higher WR 1065 levels in plasma and tissues, after multiple doses of amifostine.

Amifostine is rapidly dephosphorylated by alkaline phosphatase in tissues primarily to the active free thiol metabolite and, subsequently, to a less active disulfide metabolite.|Amifostine is dephosphorylated by alkaline phosphatase in tissues primarily to the active free thiol metabolite and, subsequently, to a less active disulfide metabolite.|Within 1 hour after infusion of 740 to 910 mg per square meter of body surface area over 15 minutes or rapid intravenous injection of 150 mg per square meter body surface area over 10 seconds, urinary recovery of unchanged amifostine, of the disulfide metabolite, and the thiol metabolite accounts for only 0.69%, 2.22%, and 2.64%, respectively, of the dose.|This study investigated the metabolism of the radio- and chemoprotector compound, WR-2721 [amifostine; s-2-(3- aminopropylamino)ethylphosphorothioate], in the Balb/c mouse. ... It is known that /radiation/ protection requires conversion of the parent drug to its free thiol metabolite, WR-1065, in cultured cells. Because it is possible that metabolites of WR-1065 could be involved in protection and because thiols are metabolically very reactive molecules, we investigated the metabolism of WR-2721 using electrochemical detection-HPLC methods. The following are the major findings in this study: 1) WR-2721 drug was rapidly cleared from the bloodstream. Blood concentration of the parent drug decreased 10-fold 30 min after administration from the maximal observed value at 5 min 2) WR-1065 rapidly appeared in the perchloric acid (PCA)-soluble fraction of normal solid tissues. The highest WR-1065 concentrations in liver and kidney were 965 and 2195 mumol/kg, respectively, 10 min after parent drug administration, whereas for heart and small intestine the highest values were 739 and 410 mumol/kg at 30 min. 3) WR-1065 accumulated in the PCA-soluble fraction of two experimental tumors at a lower rate than for the other tissues.

8 minutes|Approximately 8 minutes; less than 10% of amifostine remains in the plasma 6 minutes after drug administration.|The pharmacokinetics of the cytoprotective agent amifostine (EthyolR; WR 2721) and its main metabolites (WR 1065 and the disulphides) were studied in patients participating in two phase I trials concerning carboplatin or cisplatin in combination with amifostine. Patients were treated with a single dose or three doses of amifostine (740 or 910 mg/sq m). The single or first dose was given as a 15 min iv infusion just before administration of the chemotherapeutic agent. The additional two infusions were administered 2 and 4 hr thereafter. Amifostine was rapidly cleared from the plasma, due to, at least in part, the fast conversion into WR 1065. A biphasic decrease with a final half-life of 0.8 hr was observed. The active metabolite WR 1065 was cleared from the plasma with a final half-life of 7.3 +/- 3.6 hr. The short initial half-life of WR 1065 can be explained by its fast uptake in tissues and the formation of disulphides. The disulphides were cleared with a final half-life of 8.4-13.4 hr and were detectable for at least 24 hr after treatment. They may serve as an exchangeable pool of WR 1065. ...

The thiol metabolite is responsible for most of the cytoprotective and radioprotective properties of amifostine. It is readily taken up by cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. Other possible effects include inhibition of apoptosis, alteration of gene expression and modification of enzyme activity.|Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase to an active free sulfhydryl (thiol) metabolite (WR-1065). The pharmacologically active free sulfhydryl is believed to bind to and detoxify cytotoxic platinum-containing metabolites of cisplatin and scavenge free radicals induced by the drug. Cytoprotection against cisplatin-induced toxicity appears to result from prevention and/or, to a lesser extent, reversal of DNA platination by the drug (cisplatin-DNA adducts). Healthy cells appear to be protected preferentially because of the increased cellular uptake of amifostine and more rapid generation of the active free sulfhydryl metabolite in these cells compared with malignant cells. Because healthy cells have better perfusion, higher capillary alkaline phosphatase activity, and higher pH than malignant cells, and actively concentrate amifostine while malignant cells absorb the drug passively, there is increased cellular uptake of amifostine and more rapid generation of the free active sulfhydryl; therefore, compared with malignant cells, healthy cells appear to be selectively protected by amifostine against cisplatin-induced cytotoxicity.|Similar to the drug's chemoprotection, amifostine's radioprotective effect may occur preferentially in healthy rather than malignant cells secondary to the drug's increased cellular uptake and conversion to the active sulfhydryl. Amifostine's radioprotectant effect appears to be mediated at least in part by removal of oxygen from tissues. Sulfhydryl compounds such as amifostine also appear to protect cells from the cytotoxic effects of radiation by scavenging hydroxyl radicals and repairing radiation-induced DNA radicals through donation of hydrogen.|Amifostine can lower serum calcium concentrations, including total, ionized, and ultrafilterable calcium, but clinically important hypocalcemia occurs rarely during cytoprotective therapy with the drug. The hypocalcemic effect of amifostine appears to result from inhibition of parathyroid hormone secretion and bone resorption and from facilitation of urinary calcium excretion.|Amifostine (WR-2721) is an inorganic thiophosphate-cytoprotective agent developed to selectively protect normal tissues against the toxicity of chemotherapy and radiation. We have previously shown that amifostine protects both chicken embryo chorioallantoic membrane (CAM) vessels and cells from the effects of X-rays. In the present work, we studied the effect of amifostine on angiogenesis in vivo, using the CAM model. Amifostine decreased the number of CAM vessels in a dose-dependent manner, without being toxic for the tissue. It also decreased the mRNA levels of both vascular endothelial growth factor (VEGF) isoforms VEGF(165) and VEGF(190), 6 and up to 48 hr after its application onto the CAM. Similarly, it decreased the mRNA levels of inducible nitric-oxide synthase, 24 and 48 hr after drug application. Furthermore, amifostine decreased the deposited amounts of laminin and collagen I 24 hr after its application, without affecting the expression of the corresponding genes. The protein amounts and activity of matrix metalloproteinase-2 were not affected, whereas the expression of the corresponding gene was decreased up to 48 hr after drug application. Finally, the activity of plasmin was increased 6 hr after amifostine application and remained increased at later time points. These findings suggest that amifostine alters the expression of several molecules implicated in the angiogenesis process and affects the composition of the extracellular matrix in a way that leads to inhibition of angiogenesis. Such an antiangiogenic action of amifostine, together with its radioprotective effects, further supports its use in combination with radiotherapy for increased therapeutic efficacy.|For more Mechanism of Action (Complete) data for AMIFOSTINE (7 total), please visit the HSDB record page.

Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ The maximum single dose of amifostine was 1300 mg/sq m . No information is available on single doses higher than this in adults. In the setting of a clinical trial, pediatric patients have received single amifostine doses of up to 2700 mg/sq m. At the higher doses, anxiety and reversible urinary retention occurred. ... Administration of amifostine 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...|/CASE REPORTS/ ... A 56-year-old Caucasian man who received concomitant chemotherapy and radiation for head and neck cancer developed fever concurrent with the administration of amifostine. ...This is the first case report that demonstrates the occurrence of fever with low-dose amifostine therapy without the manifestation of accompanying rash or hypotension. Patients receiving amifostine who develop only fever should be evaluated for an adverse drug reaction, as well as for sepsis and fevers of neutropenia, and it may be necessary to discontinue the drug. ...|/CASE REPORTS/ The most common side effects associated with amifostine are nausea, vomiting, hypotension, hypocalcemia and allergic reactions. /The authors/ describe the case of a man with dermatomyositis and stage IV nasopharyngeal cancer treated with chemoradiotherapy and sc amifostine. The patient suffered a life-threatening anaphylactoid reaction to amifostine.|/CASE REPORTS/ Amifostine is a phosphorylated aminothiol prodrug that can selectively protect normal tissues against the toxic effects of chemotherapy and radiotherapy. In clinical use amifostine is well tolerated and may rarely cause allergic reactions. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two closely related entities that present with severe acute mucocutaneous reactions most often triggered by drugs. There are only two case reports related to the use of amifostine during radiotherapy, one case with SJS and the other with SJS-TEN overlap. In this paper, a case with amifostine-induced TEN during radiotherapy is presented.|/OTHER TOXICITY INFORMATION/ Although hypocalcemia occurs only rarely during cytoprotective therapy with amifostine, serum calcium concentrations should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or those receiving multiple doses of amifostine, and calcium supplementation initiated as necessary.

Amifostine

Ethyol

Analyte: amifostine; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: amifostine; matrix: chemical identification; procedure: retention time of the major peak of the liquid chromatogram with comparison to standards|Analyte: amifostine; matrix: chemical purity; procedure: liquid chromatography with detection at 220 nm and comparison to standards|Analyte: amifostine; matrix: pharmaceutical preparation (solid for injection); procedure: liquid chromatography with detection at 220 nm and comparison to standards (chemical purity)

Analyte: amifostine; matrix: blood (plasma); procedure: high-performance liquid chromatography with fluorescence detection at 370 nm (excitation) and 418-700 nm (emission); limit of quantitation: 500 ng/mL

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients