Ethyol (Amifostine)

ETHYOL®

Lilly

Amifostine

Cytoprotective Agent

Action And Clinical Pharmacology: Amifostine is a prodrug that is dephosphorylated to a pharmacologically active metabolite, the free thiol (WR-1065), at the tissue site by membrane-bound alkaline phosphatase. The ability of amifostine to selectively protect normal tissues is based upon the differential metabolism and uptake of the free thiol into normal versus malignant tissues. This differential effect is attributed to the higher capillary alkaline phosphatase activity, as well as higher pH and better vascularity of normal tissues relative to tumor tissue. This results in a more rapid generation of the active free thiol metabolite as well as a higher rate constant for uptake into normal tissues. In addition, cell culture studies have shown that amifostine uptake by normal tissues occurs through facilitated uptake against a concentration gradient, whereas tumor tissue relies on passive, non-facilitated uptake. The higher concentration of free thiol in normal tissues is available to bind to, and thereby detoxify the reactive species of alkylating and platinum agents, as well as act as a scavenger of oxygen free radicals.

Indications And Clinical Uses: As a cytoprotective agent against the cumulative renal toxicities associated with cisplatin and the hematologic toxicities associated with cyclophosphamide as well as platinum anticancer agents in patients with advanced solid tumors of non-germ cell origin.

This indication is based on the results of a randomized controlled trial of 6 cycles of cyclophosphamide 1 000 mg/mand cisplatin 100 mg/mwith or without amifostine pretreatment at 910 mg/mwhich was conducted in 2 successive cohorts of 121 patients with advanced ovarian cancer. The results of this trial demonstrate that pretreatment with amifostine can protect against both acute and cumulative hematologic and renal toxicity associated with cyclophosphamide and cisplatin (CP), which should allow better adherence to chemotherapy regimens. The protection of bone marrow and kidney was achieved with no reduction in the antitumor efficacy of the CP regimen.

Contra-Indications: Patients with known sensitivity to aminothiol compounds.

Manufacturers’ Warnings In Clinical States: Patients who are hypotensive or in a state of dehydration should not receive amifostine. Patients receiving antihypertensive therapy which cannot be stopped for 24 hours preceding amifostine treatment should not receive amifostine.

Patients should be adequately hydrated prior to amifostine infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 minutes during the infusion. It is important that the infusion of the recommended dose range (740 to 910 mg/m be given over 15 minutes. The administration of amifostine as a longer infusion is associated with a higher incidence of side effects. If hypotension occurs, patients should be placed in the Trendelenburg position and be given an additional infusion of normal saline using a separate i.v. line. Guidelines for interrupting and re-starting amifostine infusion if a decrease in systolic blood pressure should occur are provided in the Dosage section.

Antiemetic medication should be administered prior to and in conjunction with amifostine. When amifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.

Reports of clinically relevant hypocalcemia are rare; however, serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome. If necessary, calcium supplements can be administered as needed.

Precautions: General: Patients should be adequately hydrated prior to amifostine infusion, and blood pressure should be monitored during the infusion. The recommended dose range of amifostine, 740 to 910 mg/m should be administered as a 15-minute infusion (see Dosage).

Drug Interactions: There are no known drug interactions with amifostine. The rapid clearance of amifostine from the plasma minimizes the risk of interaction between amifostine and other drugs. However, special consideration should be given to the concurrent administration of amifostine with antihypertensive medication or other drugs that could potentiate hypotension.

Carcinogenesis, Mutagenesis and Impairment of Fertility: No long-term animal studies have been performed to evaluate the carcinogenic potential of amifostine. The Ames Salmonella typhimurium test revealed no mutagenic activity. Data from both in vitro and in vivo studies demonstrate that amifostine protects against the mutagenicity and genotoxicity of chemotherapeutic agents such as cisplatin, bleomycin and nitrogen mustard and against the carcinogenicity associated with radiation therapy.

Pregnancy: Pregnancy Category C: While amifostine has been shown to have dose-related embryotoxicity in rats at doses greater than 200 mg/kg, it is not teratogenic. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Lactation : No information is available on the excretion of amifostine 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 amifostine.

Adverse Reactions: The safety profile of amifostine was examined in detail in the randomized trial of cyclophosphamide and cisplatin±amifostine in patients with ovarian cancer. The principal side effects of amifostine were hypotension, characterized as a transient decrease in blood pressure with no long-term CNS or cardiovascular sequelae, and nausea and vomiting. Of the 122 patients treated with amifostine, 75 patients (61%) had reductions in systolic blood pressure which met the protocol definition of hypotension. Seventeen patients required discontinuation of an amifostine infusion prior to receiving the full protocol dose (this includes 5 patients who had terminated their infusion prior to the protocol amendment allowing the infusion to be restarted); 27 patients had an infusion temporarily interrupted but went on to receive the full protocol dose, and 31 patients received the full protocol dose with no interruption at each infusion. Over the course of the study, 145/581 (25%) of the amifostine infusions were associated with reductions in blood pressure which met the protocol definition of hypotension. Reductions were generally noted towards the end of the infusion. The mean time to onset was 14 minutes, and the mean duration was 6 minutes. Hypotension was readily managed by placing the patient into a supine, or if already in a supine position, into the Trendelenburg position and infusing normal saline. Overall, hypotension did not result in lasting medical sequelae in any of the 122 patients treated with amifostine in this study.

The overall frequency of nausea and vomiting was 96% in the amifostine+CP arm versus 88% in the CP arm though the difference was not statistically significant, p=0.08 (2-sided). This increased incidence was restricted to the day of chemotherapy; the incidence of delayed nausea/vomiting, which is commonly associated with cisplatin, was comparable in both arms: 66% in the amifostine+CP arm and 69% in the CP arm. Nausea and vomiting are amenable to treatment with standard antiemetics.

The only other side effects or laboratory abnormalities which occurred more frequently in the amifostine arm were flushing/feeling of warmth, chills/feeling of coldness, dizziness, somnolence, hiccups and sneezing. These effects were transient and did not interfere with the administration of therapy.

Decreased serum calcium concentrations is a known pharmacological effect of amifostine. At the recommended doses, clinical hypocalcemia has occurred rarely.

Allergic reactions, ranging from mild skin rashes to rigors, have occurred in some patients. There has been no reported occurrence of anaphylaxis with amifostine.

The side effect profile of amifostine observed in Phase I/II clinical trials of 256 patients (139 receiving amifostine prior to chemotherapy and 117 receiving amifostine prior to radiation) was comparable to that observed in the ovarian cancer trials.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In Phase I trials, the maximum single dose of amifostine administered was 1 330 mg/m No information is available on single doses higher than this in adults. In the setting of a clinical trial, children have received single doses of amifostine up to 2.7 g/mwith no untoward effects. Multiple doses (up to 3 times the recommended single dose of 740 to 910 mg/m have been safely administered within a 24-hour period under study conditions. Following the repeated administration of amifostine at 2 and 4 hours after the initial dose, there has not been any evidence of increased or cumulative side effects, especially nausea and vomiting or hypotension. The most likely symptom of overdosage would be hypotension which should be managed by infusion of normal saline or other appropriate symptomatic treatment.

Dosage And Administration: Amifostine for injection is supplied as a sterile lyophilized powder requiring reconstitution for i.v. infusion. Each vial contains 500 mg of amifostine (anhydrous basis). It is reconstituted with 9.7 mL of sterile Sodium Chloride Injection, USP.

In adults, the recommended starting dose is 910 mg/madministered once daily as a 15-minute i.v. infusion starting within 30 minutes prior to chemotherapy.

The 15-minute infusion is reportedly better tolerated than infusions of more extended duration. Further reduced infusion times have not been systematically investigated.

The infusion of amifostine should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in Table V.

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 amifostine may be administered. If the full dose of amifostine cannot be administered, the dose of amifostine for subsequent cycles should be 740 mg/m

Children and Geriatrics: Only limited experience is available for the usage of amifostine in children as well as elderly patients (more than 70 years of age).

It is recommended that antiemetic medication be administered prior to and in conjunction with amifostine especially when used with strongly emetogenic chemotherapy such as cisplatin.

Reconstituted Solutions: Each 10 mL vial of amifostine for injection should be reconstituted with 9.7 mL of sterile Sodium Chloride Injection, USP. The solution is chemically stable for up to 6 hours at room temperature (15 to 25°C) or up to 24 hours under refrigeration (2 to 8°C). Amifostine is administered as an i.v. infusion.

I.V. Infusion (Diluent: Sterile Sodium Chloride Injection, USP): When reconstituted with 9.7 mL of sterile Sodium Chloride Injection, USP, each mL contains 50 mg of amifostine at a pH of 6.0 to 8.0. Reconstituted solutions may be further diluted with sterile Sodium Chloride Injection, USP for dosage adjustment.

Amifostine prepared in polyvinylchloride (PVC) bags at concentration ranges from 5 to 40 mg/mL is chemically stable for up to 6 hours when stored at room temperature (15 to 25°C) or up to 24 hours when stored under refrigerated conditions (2 to 8°C). All unused solutions should be discarded.

Special Instructions: 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. There are no known incompatibilities.

Availability And Storage: Each vial of sterile lyophilized powder contains: amifostine (anhydrous basis) 500 mg. Nonmedicinal ingredients: ethyl alcohol (remvoed during lyophilization), nitrogen (manufacturing auxiliary) and water for injection (removed during lyophilization). Single-use vials of 10 mL, cartons of 3 . Store lyophilized powder at room temperature (15 to 25°C).

ETHYOL® Lilly Amifostine Cytoprotective Agent

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