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Stability: Prior to intravenous injection, Amifostine for Injection 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).
Amifostine for Injection 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).
INDICATIONS AND USAGE
Amifostine for Injection is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.
Amifostine for Injection 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 PACKAGE INSERT - 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 Amifostine for Injection. There are at present only limited data on the effects of amifostine on the efficacy of chemotherapy or radiotherapy in other settings. Amifostine 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).
CLINICAL PHARMACOLOGY
Amifostine 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 amifostine 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 amifostine 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 amifostine remains in the plasma 6 minutes after drug administration. Amifostine 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 amifostine, 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 amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on amifostine pharmacokinetics.
CONTRAINDICATIONS
Amifostine for Injection 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 Amifostine for Injection 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. Amifostine 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
Amifostine for Injection 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. Amifostine was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of amifostine 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 Amifostine for Injection. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. Patients receiving amifostine at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment, should not receive amifostine.
Prior to Amifostine for Injection infusion patients should be adequately hydrated. During amifostine 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 amifostine 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 amifostine 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 Amifostine for Injection 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 amifostine infusion, despite adequate hydration and positioning of the patient (see PACKAGE INSERT - 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 Amifostine for Injection 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 amifostine is used as a radioprotectant (see PACKAGE INSERT - 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 amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration (see PACKAGE INSERT - PRECAUTIONS).
5. Hypersensitivity
Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with Amifostine for Injection administration.
6. Nausea and Vomiting
Antiemetic medication should be administered prior to and in conjunction with Amifostine for Injection (see DOSAGE AND ADMINISTRATlON). When amifostine 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 Amifostine for Injection (see PACKAGE INSERT - ADVERSE REACTIONS). If necessary, calcium supplements can be administered |
DOSAGE AND ADMINISTRATION
For Reduction of Cumulative Renal Toxicity with Chemotherapy:
The recommended starting dose of Amifostine for Injection 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 Amifostine for Injection 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 Amifostine for Injection should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
Guideline for Interrupting Amifostine for Injection 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 Amifostine for Injection (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 Amifostine for Injection may be administered. If the full dose of amifostine cannot be administered, the dose of amifostine 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 Amifostine for Injection. 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 Amifostine for Injection 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 Amifostine for Injection 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 Amifostine for Injection. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.
Reconstitution
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, Amifostine for Injection 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).
Amifostine for Injection 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 Amifostine for Injection 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
Amifostine for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 55390-308-03). 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 55390-308-03)
Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].
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