Amifostine

Mechanism of Action

Amifostine is dephosphorylated at the tissue site by alkaline phosphatase to form free thiol. Once inside the cell, the free thiol binds with and neutralizes the reactive species of cis-platin. It also acts as a potent scavenger of oxygen free radicals. This action is important because free radicals can damage cell membranes, DNA, and other important cell components, which will lead to cell death.

Indications
Used to reduce the cumulative renal toxicity associated with cisplatin-based therapies in advanced ovarian cancer or non-small cell lung cancer. It is also indicated to alleviate moderate xerostomia associated with radiation therapy.
Metabolism/Excretion
Rapidly cleared from the plasma. Elimination half-life: about 88 minutes. Excreted by the renal system.

Dosage Range
¨ With cisplatin therapy: 910 mg/m2 given as a 15-minute infusion once a day 30 minutes before the cisplatin-based treatment.
¨ For moderate xerostomia: 200 mg/m2 given as a 3-minute IV infusion starting 15 to 30 minutes before standard fraction radiation therapy.
¨ Use in children, elderly patients, and patients with pre-existing cardiovascular or cerebrovascular conditions has not been evaluated.

Drug Preparation/Stability
Supplied as a sterile lyophilized powder in 10-mL single-use vials. Each vial contains 500 mg of the drug and 500 mg of mannitol. When stored in the refrigerator at 2° to 8°C, theunused vial is chemically and physically stable for 15 months. Reconstitute the drug with 9.5 mL of sterile 0.9% sodium chloride solution, resulting in a formulation containing 50 mg of amifostine and 50 mg of mannitol/mL. The reconstituted solution can be further diluted with sterile sodium chloride solution for dosage adjustment and should be adjusted to equal a 50-mL solution. Reconstituted ami-fostine is stable for 5 hours at room temperature (15° to 25°C) or for up to 24 hours under refrigeration (2° to 8°C).

Drug Administration
¨ Before cisplatin treatment: give as a 15-minute IV infusion 30 minutes before chemotherapy. The patient should be adequately hydrated and maintained in a supine position. Monitor blood pressure every 5 minutes during the infusion.
¨ Before radiation: give as a 3-minute IV infusion. Patients should be well hydrated before the infusion. Give antiemetics before and in conjunction with the drug. Monitor blood pressure before and after the infusion.

Drug Interaction
None known. Use caution in patients taking antihyperten-sive drugs or other drugs that could potentiate hypotension. Contraindicated in patients sensitive to mannitol or am-inothiol compounds.

Side Effects and Toxicities
¨ Cardiac: Transient reduction in systolic blood pressure
¨ GI: Nausea and vomiting, which can be severe. Can be relieved with an antiemetic regimen containing dexametha-sone (20 mg) and a serotonin 5-HT3 receptor antagonist.
¨ Other: Hypocalcemia, fever, chills, dyspnea, skin rashes, urticaria, sneezing, sleepiness, flushing, hiccups, and chills

Special Considerations
¨ Ensure that the patient is sufficiently hydrated before treatment. Do not administer to patients who are dehydrated or are taking antihypertensive therapy that cannot be interrupted for 24 hours.
¨ Maintain the patient in a supine position during the infusion.
¨ Obtain a baseline blood pressure, and monitor blood pressure every 5 minutes during and 5 minutes after the infusion is completed. If the blood pressure drops below the threshold level, it may be necessary to interrupt the infusion. Restart the infusion if the blood pressure returns to threshold within 5 minutes and the patient is asymptomatic. Refer to the following manufacturer's guidelines for interruption of infusion in relation to blood pressure thresholds.

¨ Infuse the drug within 15 minutes; a longer infusion period increases the incidence of side effects.
¨ Administer antiemetics before and in conjunction with amifostine. Monitor fluid balance, especially when severe emesis occurs.