Desferal, deferoxamine mesylate USP, is an iron-chelating agent, available in vials for intramuscular, subcutaneous, and intravenous administration. Desferal is supplied as vials containing 500 mg and 2 g of deferoxamine mesylate USP in sterile, lyophilized form. Deferoxamine mesylate is N-[5-[3-[(5-aminopentyl)hydroxycarbamoyl]propionamido]pentyl]-3-[[5-(N-hydroxyacetamido)pentyl]carbamoyl]propionohydroxamic acid monomethanesul-fonate (salt), and its structural formula is

Deferoxamine mesylate USP is a white to off-white powder. It is freely soluble in water and slightly soluble in methanol. Its molecular weight is 656.79.

Desferal is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.

Acute Iron Intoxication

Desferal is an adjunct to, and not a substitute for, standard measures used in treating acute iron intoxication, which may include the following: induction of emesis with syrup of ipecac; gastric lavage; suction and maintenance of a clear airway; control of shock with intravenous fluids, blood, oxygen, and vasopressors; and correction of acidosis.

Chronic Iron Overload

Desferal can promote iron excretion in patients with secondary iron overload frommultiple transfusions (as may occur in the treatment of some chronic anemias, including thalassemia). Long-termtherapy with Desferal slows accumulation of hepatic iron and retards or eliminates progression of hepatic fibrosis.

Iron mobilization with Desferal is relatively poor in patients under the age of 3 years with relatively little iron overload. The drug should ordinarily not be given to such patients unless significant iron mobilization (e.g., 1 mg or more of iron per day) can be demonstrated.

Desferal is not indicated for the treatment of primary hemochromatosis, since phlebotomy is the method of choice for removing excess iron in this disorder.

Acute Iron Intoxication

Intramuscular Administration

This route is preferred and should be used for ALL PATIENTS NOT IN SHOCK.

A dose of 1000 mg should be administered initially. This may be followed by 500 mg every 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours. For reconstitution instructions for intramuscular administration see Table 1 below.

Table 1: Preparation for Intramuscular Administration

The reconstituted Desferal solution is a yellow-colored solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion.

Intravenous Administration

THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION. THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO EXCEED 125 MG/HR.

The reconstituted solution is added to physiologic saline (e.g., 0.9% sodiumchloride, 0.45% sodiumchloride), glucose in water, or Ringer's lactate solution.

An initial dose of 1000 mg should be administered at a rate NOT TO EXCEED 15 mg/kg/hr. This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours.

As soon as the clinical condition of the patient permits, intravenous administration should be discontinued and the drug should be administered intramuscularly. For reconstitution instructions for intravenous administration see Table 2 below.

Table 2: Preparation for Intravenous Administrations

The reconstituted Desferal solution is an isotonic, clear and colorless to slightly yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion.

Chronic Iron Overload

The more effective of the following routes of administration must be chosen on an individual basis for each patient.

Intramuscular Administration

A daily dose of 500-1000 mg should be administered intramuscularly. In addition, 2000 mg should be administered intravenously with each unit of blood transfused; however, Desferal should be administered separately fromthe blood. The rate of intravenous infusion must not exceed 15 mg/kg/hr. The total daily dose should not exceed 1000 mg in the absence of a transfusion, or 6000 mg even if transfused three or more units of blood or packed red blood cells. For reconstitution instructions for intramuscular administration see Table 3 below.

Table 3: Preparation for Intramuscular Administration

The reconstituted Desferal solution is a yellow-colored solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion

Subcutaneous Administration

A daily dose of 1000-2000 mg (20-40 mg/kg/day) should be administered over 8-24 hours, utilizing a small portable pump capable of providing continuous mini-infusion. The duration of infusion must be individualized. In some patients, as much iron will be excreted after a short infusion of 8-12 hours as with the same dose given over 24 hours. For reconstitution instructions for subcutaneous administration see Table 4 below.

Table 4: Preparation for Subcutaneous Administration

The reconstituted Desferal solution is an isotonic, clear and colorless to slightly yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion.

Stability after Reconstitution

The product should be used immediately after reconstitution (commencement of treatment within 3 hours) for microbiological safety. When reconstitution is carried out under validated aseptic conditions (in a sterile laminar flow hood using aseptic technique), the product may be stored at roomtemperature for a maximumperiod of 24 hours before use. Do not refrigerate reconstituted solution. Reconstituting Desferal in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used.

Vials - each containing 500 mg of sterile, lyophilized deferoxamine mesylate

Cartons of 4 vials...................................................NDC 0083-3801-04

Vials - each containing 2 g of sterile, lyophilized deferoxamine mesylate

Cartons of 4 vials...................................................NDC 0078-0347-51

Do not store above 25°C (77°F).

Manufactured by: Novartis Pharma Stein AG, Schaffhauserstrasse CH-4332 Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, FDA revision date: 1/19/2007

The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency.

At the Injection Site: localized irritation, pain, burning, swelling, induration, infiltration, pruritus, erythema, wheal formation, eschar, crust, vesicles, local edema. Injection site reactions may be associated with systemic allergic reactions (see Body as a Whole, below).

Hypersensitivity Reactions and Systemic Allergic Reactions: generalized rash, urticaria, anaphylactic reaction with or without shock, angioedema.

Body as a Whole: Local injection site reactions may be accompanied by systemic reactions like arthralgia, fever, headache, myalgia, nausea, vomiting, abdominal pain, or asthma.

Rare infections with Yersinia and Mucormycosis have been reported in association with Desferal use (see PRECAUTIONS).

Cardiovascular: tachycardia, hypotension, shock.

Digestive:abdominal discomfort, diarrhea, nausea, vomiting.

Hematologic: blood dyscrasia (e.g., cases of thrombocytopenia and/or leukopenia have been reported. A causal relationship has not been clearly established).

Musculoskeletal: Leg cramps. Growth retardation and bone changes (e.g., metaphyseal dysplasia) are common in chelated patients given doses above 60 mg/kg, especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk may be reduced (see WARNINGS, PRECAUTIONS/Pediatric Use).

Nervous system: neurological disturbances including dizziness, peripheral sensory, motor, or mixed neuropathy, paresthesias; exacerbation or precipitation of aluminum-related dialysis encephalopathy (see PRECAUTIONS/INFORMATION FOR PATIENTS).

Special Senses: High-frequency sensorineural hearing loss and/or tinnitus are uncommon if dosage guidelines are not exceeded and if dose is reduced when ferritin levels decline. Visual disturbances are rare if dosage guidelines are not exceeded. These may include decreased acuity, blurred vision, loss of vision, dyschromatopsia, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts (see WARNINGS).

Respiratory: acute respiratory distress syndrome (with dyspnea, cyanosis, and/or interstitial infiltrates) (see WARNINGS).

Skin: very rare generalized rash.

Urogenital: dysuria, impaired renal function (see CONTRAINDICATIONS).

Vitamin C: Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with Desferal (see PRECAUTIONS). Vitamin C increases availability of iron for chelation. In general, 50 mg daily suffices for children under 10 years old and 100 mg daily for older children. Larger doses of vitamin C fail to produce any additional increase in excretion of iron complex.

Prochlorperazine: Concurrent treatment with Desferal and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness.

Gallium-67: Imaging results may be distorted because of the rapid urinary excretion of Desferal-bound gallium-67. Discontinuation of Desferal 48 hours prior to scintigraphy is advisable.

Ocular and auditory disturbances have been reported when Desferal was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances observed have been blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment (see PRECAUTIONS: INFORMATION FOR PATIENTS and ADVERSE REACTIONS/Special Senses).

Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early.

High doses of Desferal and concomitant low ferritin levels have also been associated with growth retardation. After reduction of Desferal dose, growth velocity may partially resume to pretreatment rates (see PRECAUTIONS/Pediatric Use).

Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of Desferal in patients with acute iron intoxication or thalassemia.

General

Flushing of the skin, urticaria, hypotension, and shock have occurred in a few patients when Desferal was administered by rapid intravenous injection. THEREFORE, DESFERAL SHOULD BE GIVEN INTRAMUSCULARLY OR BY SLOW SUBCUTANEOUS OR INTRAVENOUS INFUSION.

Iron overload increases susceptibility of patients to Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In some rare cases, treatment with Desferal has enhanced this susceptibility, resulting in generalized infections by providing this bacteria with a siderophore otherwise missing. In such cases, Desferal treatment should be discontinued until the infection is resolved.

In patients receiving Desferal, rare cases of mucormycosis, some with a fatal outcome, have been reported. If any of the suspected signs or symptoms occur, Desferal should be discontinued, mycological tests carried out and appropriate treatment instituted immediately.

In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with Desferal and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Desferal are to be used concomitantly:

• Vitamin C supplements should not be given to patients with cardiac failure.
• Start supplemental vitamin C only after an initial month of regular treatment with Desferal.
• Give vitamin C only if the patient is receiving Desferal regularly, ideally soon after setting up the infusion pump.
• Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses.
• Clinical monitoring of cardiac function is advisable during such combined therapy.

In patients with aluminum-related encephalopathy, high doses of Desferal may exacerbate neurological dysfunction (seizures), probably owing to an acute increase in circulating aluminum. Desferal may precipitate the onset of dialysis dementia. Treatment with Desferal in the presence of aluminumoverload may result in decreased serumcalciumand aggravation of hyperparathyroidism.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-termcarcinogenicity studies in animals have not been performed with Desferal.

Cytotoxicity may occur, since Desferal has been shown to inhibit DNA synthesis in vitro.

Pregnancy Category C

Delayed ossification in mice and skeletal anomalies in rabbits were observed after Desferal was administered in daily doses up to 4.5 times the maximumdaily human dose. No adverse effects were observed in similar studies in rats.

There are no adequate and well-controlled studies in pregnant women. Desferal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Desferal is administered to a nursing woman.

Pediatric Use

Pediatric patients receiving Desferal should be monitored for body weight and growth every 3 months.

Safety and effectiveness in pediatric patients under the age of 3 years have not been established (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS: DRUG INTERACTIONS/Vitamin C, and ADVERSE REACTIONS).

Geriatric Use

Clinical Studies of Desferal did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently fromthe younger subjects. Postmarketing reports suggest a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of color blindness, maculopathy, and scotoma. However, it is unclear if these eye disorders were dose related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking Desferal. Postmarketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population. (see ADVERSE REACTIONS). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Acute Toxicity

Intravenous LD₅₀s (mg/kg): mice, 287; rats, 329.

Signs and Symptoms

Inadvertent administration of an overdose or inadvertent intravenous bolus administration/rapid intravenous infusion may be associated with hypotension, tachycardia and gastrointestinal disturbances; acute but transient loss of vision, aphasia, agitation, headache, nausea, pallor, CNS depression including coma, bradycardia and acute renal failure have been reported.

Treatment

There is no specific antidote. Desferal should be discontinued and appropriate symptomatic measures undertaken.

Desferal is readily dialyzable.

Desferal is contraindicated in patients with severe renal disease or anuria, since the drug and the iron chelate are excreted primarily by the kidney. (See WARNINGS).

Desferal chelates iron by forming a stable complex that prevents the iron fromentering into further chemical reactions. It readily chelates iron fromferritin and hemosiderin but not readily fromtransferrin; it does not combine with the iron fromcytochromes and hemoglobin. Desferal does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of Desferal is capable of binding approximately 8.5 parts by weight of ferric iron.

Desferal is metabolized principally by plasma enzymes, but the pathways have not yet been defined. The chelate is readily soluble in water and passes easily through the kidney, giving the urine a characteristic reddish color. Some is also excreted in the feces via the bile.

Patients experiencing dizziness or other nervous system disturbances, or impairment of vision or hearing, should refrain from driving or operating potentially hazardous machines (see ADVERSE REACTIONS ).

Patients should be informed that occasionally their urine may show a reddish discoloration.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DEFEROXAMINE - INJECTION

(deff-er-OX-uh-meen)

COMMON BRAND NAME(S): Desferal

USES: This medication is used along with other treatments (e.g., causing vomiting with syrup of ipecac, stomach pumping) to treat sudden iron poisoning. It is most effective when given as soon as possible after the iron has been consumed. This medication can also be used to help get rid of iron in patients with high iron levels due to multiple blood transfusions. Deferoxamine belongs to a class of drugs known as heavy metal antagonists. It works by helping the kidneys and gallbladder to get rid of the extra iron.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat high levels of aluminum in dialysis patients and people with aluminum poisoning.

HOW TO USE: Depending upon your medical condition, this medication is injected directly into a muscle, under the skin, or into a vein as directed by your doctor. The manufacturer recommends giving this medication into a vein only in an extreme emergency (e.g., shock). Consult your doctor or pharmacist for more details.

Dosage is based on your medical condition and response to treatment. The manufacturer recommends giving no more than 6000 milligrams in 24 hours (or 1000 milligrams in patients with long-term iron overload if a blood transfusion is not given with it).

Follow all instructions for proper mixing and dilution with the correct fluids. If you have questions about using this medication properly, consult your pharmacist.

The product should be clear and colorless to slightly yellow. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist.

If you are using this medication to treat high iron levels, your doctor may direct you to take vitamin C (ascorbic acid) after you have been taking this medication for at least 1 month. Taking vitamin C will help replace the loss of vitamin C due to high iron levels and help the medication work to get rid of the iron. If you have heart disease (e.g., heart failure), tell your doctor before taking vitamin C while using this medication (see also Drug Interactions). The manufacturer recommends that people using this drug take no more than 200 milligrams of vitamin C a day.

Tell your doctor if your condition persists or worsens.

SIDE EFFECTS: Pain and swelling at the injection site or blurred vision may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

This medicine may cause your urine to turn reddish. This effect is harmless.

When this medication is given into a vein, flushing of the skin, severe itching, severe dizziness, and fainting can occur. Therefore, the manufacturer recommends that this medication be given either in the muscle or under the skin.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: vision changes, eye pain, hearing changes (trouble hearing, ringing ears).

This drug may infrequently cause serious (rarely fatal) bacterial or fungal infections. If you notice any of the following unlikely but very serious side effects, seek immediate medical attention: unexplained diarrhea/abdominal pain/fever, sudden/severe stuffy nose with facial pain, dark scabbing on the nose, protruding eyes.

This drug may infrequently cause a serious (rarely fatal) lung condition (acute respiratory distress syndrome or ARDS). If you notice any of the following unlikely but very serious side effects, seek immediate medical attention: sudden or severe shortness of breath, labored or rapid breathing, severe dizziness.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using deferoxamine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney problems including an inability to make urine (anuria).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: long-term kidney problems (e.g., pyelonephritis), rheumatoid arthritis, diabetes, cataracts.

If you are using this medication for aluminum poisoning, tell your doctor or pharmacist if you have: seizures, decreased calcium levels in the blood, hyperparathyroidism, a fungal infection.

Caution is advised when using this drug in children younger than 3 years because they may be more sensitive to the effects of the drug on bone growth.

Caution is advised when using this drug in the elderly because they may be more sensitive to the side effects of the drug, especially vision/hearing problems.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

If you have a certain heart problem (heart failure), this drug should not be used with vitamin C (ascorbic acid) because very serious interactions may occur. Consult your doctor or pharmacist for more details before starting deferoxamine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: prochlorperazine.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: dizziness, fainting, fast/pounding heartbeat, loss of vision, sudden paleness in face/lips/palms of hands.

NOTES: Do not share this medication with others.

In patients receiving this medication long-term, laboratory and/or medical tests (e.g., vision tests, slit-lamp eye examinations, hearing tests, growth and body weight in children, cardiac function tests in patients taking deferoxamine and vitamin C) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule.

STORAGE: Do not store deferoxamine vials above 77 degrees F (25 degrees C). Once the medication has been diluted, store it at room temperature at 68-77 degrees F (20-25 degrees C) and use within 24 hours. Do not refrigerate the diluted medication. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.