Amifostine

Get emergency medical help if you have any of these signs of an allergic reaction: hives, itching; chest tightness, difficult breathing; fever or chills; swelling of your face, lips, tongue, or throat.

Some of the side effects of amifostine may occur up to several weeks after you receive this medication.

Tell your caregiver right away if you have a serious side effect such as:

• feeling like you might pass out;
• chest pain, fast or slow heart rate;
• weak or shallow breathing;
• seizure (convulsions);
• urinating less than usual or not at all;
• severe skin rash on your stomach, back, or trunk;
• redness, rash, or blisters on the palms of your hands or the soles of your feet; or
• severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Less serious side effects may include:

• nausea, vomiting;
• dizziness, drowsiness;
• flushing (warmth, redness, or tingly feeling);
• cold feeling;
• hiccups;
• sneezing; or
• mild fever, general ill feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Avoid taking blood pressure medication within 24 hours before you receive amifostine. Talk with your doctor if you are concerned about stopping the blood pressure medication for a short time.

Avoid getting up too fast from a sitting or lying position after your amifostine infusion, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Tell your doctor about all other medicines you use, especially medicines to treat high blood pressure.

There may be other drugs that can interact with amifostine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

ETHYOL (amifostine) for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 58178-017-01). 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 58178-017-03)

Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].

Ethyol® (amifostine) is a registered trademark of MedImmune Oncology, Inc. Manufactured by: MedImmune Pharma B.V. 6545 CG Nijmegen, The Netherlands Or: Ben Venue, Inc. Bedford, Ohio 44146. For product information, please call 1 877 633 4411. Revision Date 5/2007. FDA Rev date: 03/28/06

Amifostine is a prescription medication used to treat the following:

• protect the kidneys against the harmful effects of the chemotherapy drug cisplatin for the treatment of ovarian cancer.
• reduce dry mouth caused by radiation treatment after surgery for head and neck cancer.

This medication may be prescribed for other uses.  Ask your doctor or pharmacist for more information.

Amifostine is used to help lessen the side effects of certain cancer chemotherapy medications or radiation treatment.

Amifostine is used to protect the kidneys from harmful effects caused by cisplatin when given to patients with ovarian cancer.

Amifostine is also used to prevent severe dry mouth caused by radiation treatment of the head and neck, which can affect the salivary gland.

Amifostine will not prevent all side effects of chemotherapy medications. However, this medicine may help protect your body from some of the serious side effects that chemotherapy can cause.

Amifostine may also be used for purposes not listed in this medication guide.

You should not be treated with amifostine if you are allergic to it, or if:

• you are dehydrated; or

• you have taken blood pressure medication in the past 24 hours.

You will need to stop taking any blood pressure medication for at least 24 hours before you are treated with amifostine. Talk with your doctor if you are concerned about stopping your blood pressure medication for a short time.

To make sure amifostine is safe for you, tell your doctor if you have ever had:

• kidney disease;

• low blood pressure;

• high blood pressure;

• low levels of calcium in your blood (hypocalcemia);

• heart disease or prior heart attack; or

• a stroke (including "mini-stroke").

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether amifostine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Cytoprotective agent; a chemoprotectant and radioprotectant.1 2 3 9 11 14 16 20 21 22 23 24

Contraindications

Known sensitivity to aminothiol compounds.a

Warnings/Precautions

Warnings

Possible interference in antitumor effect of chemotherapy; however, most tumor models suggest amifostine does not alter antitumor effect.a Limited data available regarding preservation of antitumor efficacy when amifostine administered prior to cisplatin in malignancies other than advanced ovarian cancer.a

Insufficient data available to exclude the possibility that amifostine might interfere with the efficacy of high-dose (definitive) radiation therapy; use not recommended in patients receiving such therapy, except in clinical trials.a

Hypotension occurs frequently during or shortly after infusion, despite hydration and positioning.a May be associated with dyspnea, apnea, hypoxia, and rarely seizures, unconsciousness, respiratory arrest, and renal failure.1

Administer IV infusions over ≤15 minutes to minimize the risk of hypotensive reactions.a

If hypotension occurs, interrupt infusion, place patient in Trendelenburg's position and initiate IV infusion of 0.9% sodium chloride in a separate line.a (See Guideline for Interrupting Infusion due to Decreases in SBP under Dosage and Administration.)

Use not recommended in hypotensive or dehydrated patients or in patients concurrently receiving antihypertensive agents.a (See Specific Drugs under Interactions.)

Withdrawal of antihypertensive therapy and IV hydration may exacerbate hypertension in patients whose antihypertensive therapy has been interrupted for amifostine therapy; carefully monitor BP during and after IV infusion in such patients.1

Nausea and/or vomiting occurs frequently and may be severe.1 Administer effective antiemetic therapy (e.g., an IV corticosteroid such as dexamethasone and a type 3 serotonin [5-HT3] receptor antagonist) prior to and in conjunction with amifostine therapy.1

Carefully monitor patient’s fluid balance in those receiving highly emetogenic chemotherapy.1

Hypocalcemia occurs rarely.a Monitor serum calcium concentrations in patients at risk of hypocalcemia (e.g., those with nephrotic syndrome, those receiving multiple doses of amifostine); initiate calcium supplementation as necessary.1

Sensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis and severe cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma, exfoliative dermatitis) reported.a

Serious cutaneous reactions reported more frequently when used as a radioprotectant.a Withhold amifostine and consider dermatologic consultation and biopsy if cutaneous reactions or mucosal lesions of unknown etiology occur.a

Careful monitoring during and after administration is recommended.a If acute hypersensitivity reactions occur, immediately and permanently discontinue infusion and institute appropriate therapy as indicated (e.g., epinephrine and other appropriate measures).a

General Precautions

Safety not established in patients with preexisting cardiovascular or cerebrovascular disease (e.g., ischemic heart disease, arrhythmias, CHF, history of stroke or TIAs; use with caution in such patients.

Specific Populations

Category C.a

Not known whether amifostine is distributed into milk.a Use not recommended.a

Response in patients ≥65 years of age does not appear to differ from that in younger adults; however, use with caution due to greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.a

Common Adverse Effects

Hypotension, nausea, vomiting.a

Amifostine for Injection is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) and has the following structural formula:

H2N(CH2)3NH(CH2)2S-PO3H2

Amifostine 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.

Amifostine for Injection is the trihydrate form of Amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of Amifostine on the anhydrous basis.

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 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).

In clinical trials, the maximum single dose of Amifostine for Injection 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 Amifostine doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible urinary retention occurred.

Administration of Amifostine for Injection 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.

For IV infusion, reconstitute intact vials with 9.7 mL NS injection and dilute in NS to a final concentration of 5 mg/mL to 40 mg/mL.

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Adverse events have been observed in animal reproduction studies.

Commonly reported side effects of amifostine include: nausea. See below for a comprehensive list of adverse effects.

Data not available.

Patients who are hypotensive or in a state of dehydration should not receive 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. 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, 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 duration 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 IV line.

Hypotension may occur during or shortly after amifostine infusion, despite adequate hydration and positioning of the patient Hypotension has been associated with dyspnea, apnea, hypoxia, and in rare cases seizures, unconsciousness, respiratory arrest and renal failure.

The safety of amifostine administration has not been established 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. Amifostine should be used with particular care in these and other patients in whom the common amifostine adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.

Safety and effectiveness have not been established in pediatric patients (less than 18 years of age).