ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. 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 Whole, below).Hypersensitivity Reactions and Systemic Allergic Reactions: Generalized rash, urticaria, anaphylactic reaction with or without shock, angioedema.Body as Whole: Local injection site reactions may be accompanied by systemic reactions like arthralgia, fever, headache, myalgia, nausea, vomiting, abdominal pain, or asthma.Infections with Yersinia and Mucormycosis have been reported in association with deferoxamine mesylate use (see PRECAUTIONS).Cardiovascular: Tachycardia, hypotension, shock.Digestive: Abdominal discomfort, diarrhea, nausea, vomiting.Hematologic: Blood dyscrasia (thrombocytopenia, leukopenia).Hepatic: Increased transaminases, hepatic dysfunction.Musculoskeletal: Muscle spasms. 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, seizures; 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, acute renal failure, increased serum creatinine and renal tubular disorders (see CONTRAINDICATIONS and WARNINGS).Postmarketing ReportsThere are postmarketing reports of deferoxamine-associated renal dysfunction, including renal failure. Monitor patients for changes in renal function (e.g., increased serum creatinine).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies in animals have not been performed with deferoxamine mesylate.Cytotoxicity may occur, since deferoxamine mesylate has been shown to inhibit DNA synthesis in vitro.Delayed ossification in mice and skeletal anomalies in rabbits were observed after deferoxamine mesylate was administered in daily doses up to 4.5 times the maximum daily human dose. No adverse effects were observed in similar studies in rats.There are no adequate and well-controlled studies in pregnant women. Deferoxamine mesylate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Deferoxamine mesylate chelates iron by forming stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. Deferoxamine mesylate does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of deferoxamine mesylate is capable of binding approximately 8.5 parts by weight of ferric iron.Deferoxamine mesylate 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 characteristic reddish color. Some is also excreted in the feces via the bile.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Known hypersensitivity to the active substance.Deferoxamine mesylate 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).

DESCRIPTION SECTION.

DESCRIPTION. Deferoxamine Mesylate for Injection, USP, is an iron-chelating agent, available in vials for intramuscular, subcutaneous, and intravenous administration. Deferoxamine mesylate is supplied as vials containing 500 mg and 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 monomethanesulfonate (salt), and its structural formula isDeferoxamine mesylate USP is white to off-white powder. It is freely soluble in water and slightly soluble in methanol. Its molecular weight is 656.79 g/mol.. structural formula deferoxamine mesylate.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Acute Iron Intoxication Intramuscular Administration This route is preferred and should be used for ALL PATIENTS NOT IN SHOCK. dose of 1,000 mg should be administered initially. This may be followed by 500 mg every hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every to 12 hours. The total amount administered should not exceed 6,000 mg in 24 hours. For reconstitution instructions for intramuscular administration see Table 1.Intravenous Administration THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION. THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1,000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT SLOWER RATE, NOT TO EXCEED 125 MG/HR. For reconstitution instructions for intravenous administration see Table 2. The reconstituted solution is added to physiologic saline, (e.g., 0.9% sodium chloride, 0.45% sodium chloride), glucose in water, or Ringers lactate solution. An initial dose of 1,000 mg should be administered at rate NOT TO EXCEED 15 mg/kg/hr. This may be followed by 500 mg over hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over to 12 hours. The total amount administered should not exceed 6,000 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.Chronic Iron OverloadSubcutaneous AdministrationA daily dose of 1,000 to 2,000 mg (20 to 40 mg/kg/day) should be administered over to 24 hours, utilizing 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 short infusion of to 12 hours as with the same dose given over 24 hours. For reconstitution instructions for subcutaneous administration see Table 3.Intravenous AdministrationThe standard recommended method of Deferoxamine Mesylate for Injection, USP administration is via slow subcutaneous infusion over to 12 hours. In patients with intravenous access, the daily dose of Deferoxamine Mesylate for Injection, USP can be administered intravenously. The standard dose is 20 to 40 mg/kg/day for children and 40 to 50 mg/kg/day over to 12 hours in adults for to days per week. In children, average doses should not exceed 40 mg/kg/day until growth has ceased. In adults, average doses should not exceed 60 mg/kg/day. The intravenous infusion rate should not exceed 15 mg/kg/hour. For reconstitution instructions for intravenous administration see Table 2.In patients who are poorly compliant, Deferoxamine Mesylate for Injection, USP may be administered prior to or following same day blood transfusion (for example gram over hours on the day of transfusion); however, the contribution of this mode of administration to iron balance is limited. Deferoxamine Mesylate for Injection, USP should not be administered concurrently with the blood transfusion as this can lead to errors in interpreting side effects such as rash, anaphylaxis and hypotension.Intramuscular AdministrationA daily dose of 500 to 1,000 mg may be administered intramuscularly. The total daily dose should not exceed 1,000 mg. For reconstitution instructions for intramuscular administration see Table 1.Reconstitution and PreparationTable 1: Preparation for Intramuscular AdministrationRECONSTITUTE DEFEROXAMINE MESYLATE FOR INJECTION, USP WITHSTERILE WATER FOR INJECTIONVial SizeAmount of Sterile Water for Injection Required for ReconstitutionTotal Drug Content after ReconstitutionFinal Concentration per mL after Reconstitution500 mg2 mL500 mg/2.35 mL213 mg/mL2 grams8 mL2 grams/9.4 mL213 mg/mLTable 2: Preparation for Intravenous AdministrationRECONSTITUTE DEFEROXAMINE MESYLATE FOR INJECTION, USP WITH STERILE WATER FOR INJECTIONVial SizeAmount of Sterile Water for Injection Required for ReconstitutionTotal Drug Content after ReconstitutionFinal Concentration per mL after Reconstitution500 mg5 mL500 mg/5.3 mL95 mg/mL2 grams20 mL2 grams/21.1 mL95 mg/mLTable 3: Preparation for Subcutaneous AdministrationRECONSTITUTE DEFEROXAMINE MESYLATE FOR INJECTION, USP WITHSTERILE WATER FOR INJECTIONVial SizeAmount of Sterile Water for Injection Required for ReconstitutionTotal Drug Content after ReconstitutionFinal Concentration per mL after Reconstitution500 mg5 mL500 mg/5.3 mL95 mg/mL2 grams20 mL2 grams/21.1 mL95 mg/mLThe reconstituted deferoxamine mesylate solution is an isotonic, clear and colorless to slightly-yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Deferoxamine Mesylate for Injection, USP reconstituted with Sterile Water for Injection IS FOR SINGLE-DOSE ONLY. Discard unused portion. The product should be used immediately after reconstitution (commencement of treatment within hours) for microbiological safety. When reconstitution is carried out under validated aseptic conditions (in sterile laminar flow hood using aseptic technique), the product may be stored at room temperature for maximum period of 24 hours before use. Do not refrigerate reconstituted solution. Reconstituting Deferoxamine Mesylate for Injection, USP in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used.

DRUG INTERACTIONS SECTION.

Drug Interactions. Vitamin C: Patients with iron overload usually become vitamin deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with deferoxamine mesylate (see PRECAUTIONS). Vitamin 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 fail to produce any additional increase in excretion of iron complex.Prochlorperazine: Concurrent treatment with deferoxamine mesylate and prochlorperazine, phenothiazine derivative, may lead to temporary impairment of consciousness.Gallium-67: Imaging results may be distorted because of the rapid urinary excretion of deferoxamine mesylate-bound gallium-67. Discontinuation of deferoxamine mesylate 48 hours prior to scintigraphy is advisable.

GENERAL PRECAUTIONS SECTION.

General. Flushing of the skin, urticaria, hypotension, and shock has occurred in few patients when deferoxamine mesylate was administered by rapid intravenous injection. THEREFORE, DEFEROXAMINE MESYLATE 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 deferoxamine mesylate has enhanced this susceptibility, resulting in generalized infections by providing these bacteria with siderophore otherwise missing. In such cases, deferoxamine mesylate treatment should be discontinued until the infection is resolved.In patients receiving deferoxamine mesylate, rare cases of mucormycosis, some with fatal outcome, have been reported. If any of the suspected signs or symptoms occur, deferoxamine mesylate 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 deferoxamine mesylate and high doses of vitamin (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin was discontinued. The following precautions should be taken when vitamin and deferoxamine mesylate are to be used concomitantly:oVitamin supplements should not be given to patients with cardiac failure. oStart supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate.oGive vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.oDo not exceed daily vitamin dose of 200 mg in adults, given in divided doses.oClinical monitoring of cardiac function is advisable during such combined therapy.In patients with aluminum-related encephalopathy and receiving dialysis, deferoxamine mesylate may cause neurological dysfunction (seizures), possibly due to an acute increase in circulating aluminum (see ADVERSE REACTIONS). Deferoxamine mesylate may precipitate the onset of dialysis dementia. Treatment with deferoxamine mesylate in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism.. oVitamin supplements should not be given to patients with cardiac failure. oStart supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate.. oGive vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.. oDo not exceed daily vitamin dose of 200 mg in adults, given in divided doses.. oClinical monitoring of cardiac function is advisable during such combined therapy.

GERIATRIC USE SECTION.

Geriatric Use. Clinical Studies of deferoxamine mesylate did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest 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 deferoxamine mesylate. 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.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Unit of SaleConcentrationNDC 0409-2336-10500 mgCarton of Single-doseFliptop vialsNDC 0409-2337-252 gCarton of Single-doseFliptop vialsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]For single-dose only.Discard unused portion.Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1006-3.0Revised: 8/2020. Hospira Logo.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Deferoxamine Mesylate for Injection, USP is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.Acute Iron IntoxicationDeferoxamine mesylate is an adjunct to, and not 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 clear airway; control of shock with intravenous fluids, blood, oxygen, and vasopressors; and correction of acidosis.Chronic Iron OverloadDeferoxamine mesylate can promote iron excretion in patients with secondary iron overload from multiple transfusions (as may occur in the treatment of some chronic anemias, including thalassemia). Long-term therapy with deferoxamine mesylate slows accumulation of hepatic iron and retards or eliminates progression of hepatic fibrosis.Iron mobilization with deferoxamine mesylate is relatively poor in patients under the age of years with relatively little iron overload. The drug should ordinarily not be given to such patients unless significant iron mobilization (e.g., mg or more of iron per day) can be demonstrated.Deferoxamine mesylate is not indicated for the treatment of primary hemochromatosis, since phlebotomy is the method of choice for removing excess iron in this disorder.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. 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 reddish discoloration.

NURSING MOTHERS SECTION.

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 deferoxamine mesylate is administered to nursing woman.

OVERDOSAGE SECTION.

OVERDOSAGE. Acute ToxicityIntravenous LD50s (mg/kg): mice, 287; rats, 329.Signs and SymptomsInadvertent 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.Acute respiratory distress syndrome has been reported following treatment with excessively high intravenous doses of Deferoxamine Mesylate for Injection, USP in patients with acute iron intoxication and in patients with thalassemia.TreatmentThere is no specific antidote. Deferoxamine mesylate should be discontinued and appropriate symptomatic measures undertaken.Deferoxamine mesylate is readily dialyzable.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 500 mg Vial Label. Single-dose Vial Rx onlyDeferoxamineMesylate for Injection, USP500 mg/vialINTRAVENOUS,INTRAMUSCULAR, SUBCUTANEOUS USEDistributed byHospira, Inc., Lake Forest, IL 60045 USA. PRINCIPAL DISPLAY PANEL 500 mg Vial Label.

PEDIATRIC USE SECTION.

Pediatric Use. Pediatric patients receiving deferoxamine mesylate should be monitored for body weight and growth every months.Safety and effectiveness in pediatric patients under the age of years have not been established (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS/Drug Interactions/Vitamin C, and ADVERSE REACTIONS).

PRECAUTIONS SECTION.

PRECAUTIONS. General. Flushing of the skin, urticaria, hypotension, and shock has occurred in few patients when deferoxamine mesylate was administered by rapid intravenous injection. THEREFORE, DEFEROXAMINE MESYLATE 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 deferoxamine mesylate has enhanced this susceptibility, resulting in generalized infections by providing these bacteria with siderophore otherwise missing. In such cases, deferoxamine mesylate treatment should be discontinued until the infection is resolved.In patients receiving deferoxamine mesylate, rare cases of mucormycosis, some with fatal outcome, have been reported. If any of the suspected signs or symptoms occur, deferoxamine mesylate 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 deferoxamine mesylate and high doses of vitamin (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin was discontinued. The following precautions should be taken when vitamin and deferoxamine mesylate are to be used concomitantly:oVitamin supplements should not be given to patients with cardiac failure. oStart supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate.oGive vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.oDo not exceed daily vitamin dose of 200 mg in adults, given in divided doses.oClinical monitoring of cardiac function is advisable during such combined therapy.In patients with aluminum-related encephalopathy and receiving dialysis, deferoxamine mesylate may cause neurological dysfunction (seizures), possibly due to an acute increase in circulating aluminum (see ADVERSE REACTIONS). Deferoxamine mesylate may precipitate the onset of dialysis dementia. Treatment with deferoxamine mesylate in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism.. oVitamin supplements should not be given to patients with cardiac failure. oStart supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate.. oGive vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.. oDo not exceed daily vitamin dose of 200 mg in adults, given in divided doses.. oClinical monitoring of cardiac function is advisable during such combined therapy.. Drug Interactions. Vitamin C: Patients with iron overload usually become vitamin deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with deferoxamine mesylate (see PRECAUTIONS). Vitamin 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 fail to produce any additional increase in excretion of iron complex.Prochlorperazine: Concurrent treatment with deferoxamine mesylate and prochlorperazine, phenothiazine derivative, may lead to temporary impairment of consciousness.Gallium-67: Imaging results may be distorted because of the rapid urinary excretion of deferoxamine mesylate-bound gallium-67. Discontinuation of deferoxamine mesylate 48 hours prior to scintigraphy is advisable.. Information for Patients. 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 reddish discoloration.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies in animals have not been performed with deferoxamine mesylate.Cytotoxicity may occur, since deferoxamine mesylate has been shown to inhibit DNA synthesis in vitro.Delayed ossification in mice and skeletal anomalies in rabbits were observed after deferoxamine mesylate was administered in daily doses up to 4.5 times the maximum daily human dose. No adverse effects were observed in similar studies in rats.There are no adequate and well-controlled studies in pregnant women. Deferoxamine mesylate 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 deferoxamine mesylate is administered to nursing woman.. Pediatric Use. Pediatric patients receiving deferoxamine mesylate should be monitored for body weight and growth every months.Safety and effectiveness in pediatric patients under the age of years have not been established (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS/Drug Interactions/Vitamin C, and ADVERSE REACTIONS).. Geriatric Use. Clinical Studies of deferoxamine mesylate did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest 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 deferoxamine mesylate. 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.. Hepatic Impairment. No studies have been performed in patients with hepatic impairment.

SPL UNCLASSIFIED SECTION.

Fliptop VialsFor subcutaneous, intramuscular or intravenous administration.

WARNINGS SECTION.

WARNINGS. Ocular and auditory disturbances have been reported when deferoxamine mesylate 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.Increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders, associated with the administration of deferoxamine, have been reported in postmarketing experience (see ADVERSE REACTIONS). Monitor patients for changes in renal function.High doses of deferoxamine mesylate and concomitant low ferritin levels have also been associated with growth retardation. After reduction of deferoxamine mesylate dose, growth velocity may partially resume to pre-treatment rates (see PRECAUTIONS/Pediatric Use).Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of deferoxamine mesylate in patients with acute iron intoxication or thalassemia.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment For patients with hepatic impairment, dose selection should usually start at the low end of the dosing range.

LACTATION SECTION.

8.2 Lactation There are no data on the presence of deferoxamine or its metabolite in either human or animal milk, the effects on the breastfed child, or the effects on milk production. It is not known whether deferoxamine is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child, advise patients not to breastfeed during treatment with Deferoxamine mesylate, and for one week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Deferoxamine mesylate chelates iron by forming stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. Deferoxamine mesylate does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of deferoxamine mesylate is capable of binding approximately 8.5 parts by weight of ferric iron.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been performed with deferoxamine mesylate. Cytotoxicity may occur, since deferoxamine mesylate has been shown to inhibit DNA synthesis in vitro.Deferoxamine mesylate was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) and was not genotoxic in an in vivo micronucleus assay in rats.Animal studies to assess fertility effects have not been conducted.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Deferoxamine mesylate 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 characteristic reddish color. Some is also excreted in the feces via the bile.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS For injection: 500 mg of deferoxamine mesylate (corresponding to 426.82 mg of deferoxamine as free base) as white to off-white lyophilized powder in single-dose fliptop vial for reconstitution.For injection: g of deferoxamine mesylate (corresponding to 1707.28 mg of deferoxamine as free base) as white to off-white lyophilized powder in single-dose fliptop vial for reconstitution.. For injection: 500 mg of deferoxamine mesylate as lyophilized powder in single-dose fliptop vial for reconstitution. (3)For injection: g of deferoxamine mesylate as lyophilized powder in single-dose fliptop vial for reconstitution. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Based on animal data, Deferoxamine mesylate can cause malformations at doses less than the human dose [see Use in Specific Populations (8.1)].ContraceptionFemalesDeferoxamine mesylate can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with Deferoxamine mesylate and for one month after the last dose.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are no available data on Deferoxamine mesylate use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriages or adverse maternal or fetal outcomes.In animal reproduction studies subcutaneous administration of deferoxamine to pregnant animals (mice or rabbits) during organogenesis at doses approximately >=0.2- (mice) and >=0.7 (rabbits) times the maximum recommended human dose resulted in maternal toxicity and adverse developmental outcomes (see Data). Advise pregnant women of the potential risk to fetus. Consider the benefits and risks of Deferoxamine mesylate for the mother and possible risks to the fetus when prescribing Deferoxamine mesylate to pregnant woman.The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal Data In an embryo-fetal developmental study in mice, pregnant animals administered subcutaneous doses of deferoxamine at 180, and 540 mg/kg/day from gestation day to gestation day 12 resulted in dose dependent delay and irregularities of fetal skeletal maturation at doses >=0.2 times the MRHD. At the highest dose of 540 mg/kg, in 1/23 fetuses had unilateral lesion to the eye lens (approximately 0.5 times the MRHD). In the embryo-fetal developmental studies in rabbits, pregnant animals administered subcutaneous doses of deferoxamine either 200 mg/kg or 200, 300, and 540 mg/kg from gestation day to gestation day 14 resulted in maternal toxicity and embryo-fetal developmental effects at 0.7 times the MRHD. Maternal toxicity included reduced fetal body weights and embryo-fetal effects included malformations of spina bifida, and increased incidence of abnormally ossified ribs and vertebrae. No maternal toxicity or embryo-fetal effects were observed in rats at deferoxamine doses tested (up to 0.9 times the MRHD).

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment Deferoxamine mesylate is contraindicated in patients with severe renal disease [see Contraindications (4)].For patients with renal impairment, dose selection should usually start at the low end of the dosing range.Deferoxamine can cause increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders [see Warnings and Precautions (5.3)]. Monitor patients for changes in renal function.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise not to breastfeed. (8.2)oGeriatric Use: Increased risk of ocular disorders. (8.5). oLactation: Advise not to breastfeed. (8.2). oGeriatric Use: Increased risk of ocular disorders. (8.5). 8.1 Pregnancy Risk SummaryThere are no available data on Deferoxamine mesylate use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriages or adverse maternal or fetal outcomes.In animal reproduction studies subcutaneous administration of deferoxamine to pregnant animals (mice or rabbits) during organogenesis at doses approximately >=0.2- (mice) and >=0.7 (rabbits) times the maximum recommended human dose resulted in maternal toxicity and adverse developmental outcomes (see Data). Advise pregnant women of the potential risk to fetus. Consider the benefits and risks of Deferoxamine mesylate for the mother and possible risks to the fetus when prescribing Deferoxamine mesylate to pregnant woman.The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal Data In an embryo-fetal developmental study in mice, pregnant animals administered subcutaneous doses of deferoxamine at 180, and 540 mg/kg/day from gestation day to gestation day 12 resulted in dose dependent delay and irregularities of fetal skeletal maturation at doses >=0.2 times the MRHD. At the highest dose of 540 mg/kg, in 1/23 fetuses had unilateral lesion to the eye lens (approximately 0.5 times the MRHD). In the embryo-fetal developmental studies in rabbits, pregnant animals administered subcutaneous doses of deferoxamine either 200 mg/kg or 200, 300, and 540 mg/kg from gestation day to gestation day 14 resulted in maternal toxicity and embryo-fetal developmental effects at 0.7 times the MRHD. Maternal toxicity included reduced fetal body weights and embryo-fetal effects included malformations of spina bifida, and increased incidence of abnormally ossified ribs and vertebrae. No maternal toxicity or embryo-fetal effects were observed in rats at deferoxamine doses tested (up to 0.9 times the MRHD).. 8.2 Lactation There are no data on the presence of deferoxamine or its metabolite in either human or animal milk, the effects on the breastfed child, or the effects on milk production. It is not known whether deferoxamine is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child, advise patients not to breastfeed during treatment with Deferoxamine mesylate, and for one week after the last dose.. 8.3 Females and Males of Reproductive Potential Based on animal data, Deferoxamine mesylate can cause malformations at doses less than the human dose [see Use in Specific Populations (8.1)].ContraceptionFemalesDeferoxamine mesylate can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with Deferoxamine mesylate and for one month after the last dose.. 8.4 Pediatric Use Safety and effectiveness in pediatric patients years of age and older have been established for the treatment of acute iron intoxication and for the treatment of transfusional iron overload in patients with chronic anemia. Safety and effectiveness in pediatric patients under the age of years have not been established.Iron mobilization with Deferoxamine mesylate is relatively poor in patients under the age of years with relatively little iron overload. Deferoxamine mesylate is not recommended for use. The drug should ordinarily not be given to these patients unless significant iron mobilization (e.g., mg or more of iron per day) can be demonstrated.High doses of Deferoxamine mesylate and concomitant low ferritin levels have been associated with growth suppression in pediatric patients. Monitor weight and height in pediatric patients receiving Deferoxamine mesylate every months [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].. 8.5 Geriatric Use Clinical Studies of deferoxamine mesylate did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest 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 deferoxamine mesylate. Postmarketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population [see Adverse Reactions (6)]. 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.. 8.6 Renal Impairment Deferoxamine mesylate is contraindicated in patients with severe renal disease [see Contraindications (4)].For patients with renal impairment, dose selection should usually start at the low end of the dosing range.Deferoxamine can cause increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders [see Warnings and Precautions (5.3)]. Monitor patients for changes in renal function.. 8.7 Hepatic Impairment For patients with hepatic impairment, dose selection should usually start at the low end of the dosing range.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity Reactions: More common with rapid intravenous infusion. Administer intramuscularly or by slow subcutaneous or intravenous infusion. (5.1) oAuditory and Ocular Toxicity: Have been reported when administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. (5.2)oRenal Toxicity: Cases of acute renal failure, renal tubular disorders and increase in serum creatinine have occurred. Monitor patients for changes in renal function. (5.3)oRespiratory Toxicity: Acute respiratory distress syndrome has occurred. Risk increased with high intravenous doses. Recommended daily dose should not be exceeded. (5.4)oGrowth Suppression: Has occurred in pediatric patients treated with high doses and concomitant low ferritin levels. Dose reduction may partially resume growth velocity to pre-treatment rates. (5.5) oSerious Infections: Cases of mucormycosis and Yersinia infections, some fatal, have occurred. Discontinue Deferoxamine mesylate and initiate appropriate treatment immediately. (5.6)oCardiac Dysfunction with Concomitant Use of Vitamin C: Avoid coadministration in patients with cardiac failure. Delay Vitamin for one month after start of Deferoxamine mesylate. Avoid exceeding 200 mg daily in adults. Monitor cardiac function with combined treatment. (5.7)oRisks of Deferoxamine mesylate Treatment in Patients with Aluminum Overload: Risks include neurological dysfunction (including seizures), dialysis dementia, and aggravation of hyperparathyroidism. (5.8)oEffects on Ability to Drive and Use Machines: May cause dizziness. (5.9)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use effective contraception. (5.10, 8.1, 8.3). oHypersensitivity Reactions: More common with rapid intravenous infusion. Administer intramuscularly or by slow subcutaneous or intravenous infusion. (5.1) oAuditory and Ocular Toxicity: Have been reported when administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. (5.2). oRenal Toxicity: Cases of acute renal failure, renal tubular disorders and increase in serum creatinine have occurred. Monitor patients for changes in renal function. (5.3). oRespiratory Toxicity: Acute respiratory distress syndrome has occurred. Risk increased with high intravenous doses. Recommended daily dose should not be exceeded. (5.4). oGrowth Suppression: Has occurred in pediatric patients treated with high doses and concomitant low ferritin levels. Dose reduction may partially resume growth velocity to pre-treatment rates. (5.5) oSerious Infections: Cases of mucormycosis and Yersinia infections, some fatal, have occurred. Discontinue Deferoxamine mesylate and initiate appropriate treatment immediately. (5.6). oCardiac Dysfunction with Concomitant Use of Vitamin C: Avoid coadministration in patients with cardiac failure. Delay Vitamin for one month after start of Deferoxamine mesylate. Avoid exceeding 200 mg daily in adults. Monitor cardiac function with combined treatment. (5.7). oRisks of Deferoxamine mesylate Treatment in Patients with Aluminum Overload: Risks include neurological dysfunction (including seizures), dialysis dementia, and aggravation of hyperparathyroidism. (5.8). oEffects on Ability to Drive and Use Machines: May cause dizziness. (5.9). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use effective contraception. (5.10, 8.1, 8.3). 5.1Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have occurred in deferoxamine mesylate-treated patients. Reactions have included flushing of the skin, urticaria, hypotension, and shock. These reactions typically occur when deferoxamine mesylate was administered by rapid intravenous injection. Therefore, administer deferoxamine mesylate intramuscularly or by slow subcutaneous or intravenous infusion.. 5.2Auditory and Ocular Toxicity Ocular and auditory toxicities have been reported in deferoxamine mesylate-treated patients. The ocular toxicities observed have included 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 toxicities reported have been tinnitus and hearing loss, including high frequency sensorineural hearing loss. Risk factors for both ocular and auditory disturbances include prolonged treatment duration, higher doses, or low ferritin levels. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment [see Adverse Reactions (6)].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.. 5.3Renal Toxicity Renal toxicity, including increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders has occurred in deferoxamine mesylate-treated patients. Deferoxamine mesylate is contraindicated in patients with severe renal disease [see Contraindications (4)]. Monitor serum creatinine to assess for changes in renal function.. 5.4Respiratory Toxicity Acute respiratory distress syndrome has occurred in deferoxamine mesylate-treated patients following treatment with excessively high intravenous doses of deferoxamine mesylate in patients with acute iron intoxication or thalassemia. The recommended daily doses should therefore not be exceeded.. 5.5Growth Suppression High doses of deferoxamine mesylate and concomitant low ferritin levels have also been associated with growth suppression in pediatric patients. After reduction of deferoxamine mesylate dose, growth velocity may partially resume to pre-treatment rates. Monitor growth (weight and height) in pediatric patients treated with deferoxamine mesylate every months.. 5.6Serious Infections Yersinia InfectionsDeferoxamine mesylate may increase the risk of Yersinia enterocolitica and Yersinia pseudotuberculosis infections. Avoid starting Deferoxamine mesylate treatment in patients with active Yersinia infections. Should Yersinia infection develop, interrupt deferoxamine mesylate treatment until the infection is resolved.MucormycosisCases of mucormycosis, some with fatal outcome, have occurred in deferoxamine mesylate-treated patients. Signs or symptoms are specific to the site of infection. If mucormycosis is suspected, discontinue deferoxamine mesylate, conduct mycological testing, and treat immediately.. 5.7Cardiac Dysfunction with Concomitant Use of Vitamin . Cardiac dysfunction has occurred in deferoxamine mesylate-treated patients with severe chronic iron overload following concomitant treatment with high doses of vitamin (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin was discontinued. The following precautions should be taken when vitamin and deferoxamine mesylate are to be used concomitantly:oVitamin supplements should not be given to patients with cardiac failure. oStart supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate.oGive vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.oDo not exceed daily vitamin dose of 200 mg in adults, given in divided doses. In general, 50 mg daily suffices for pediatric patients under 10 years old and 100 mg for older pediatric patients.oClinical monitoring of cardiac function is advisable during such combined therapy.. oVitamin supplements should not be given to patients with cardiac failure. oStart supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate.. oGive vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.. oDo not exceed daily vitamin dose of 200 mg in adults, given in divided doses. In general, 50 mg daily suffices for pediatric patients under 10 years old and 100 mg for older pediatric patients.. oClinical monitoring of cardiac function is advisable during such combined therapy.. 5.8Risks of Deferoxamine Mesylate Treatment in Patients with Aluminum Overload Deferoxamine mesylate may cause neurological dysfunction (including seizures) in patients with aluminum-related encephalopathy and receiving dialysis, possibly due to an acute increase in circulating aluminum [see Adverse Reactions (6)].Deferoxamine mesylate may precipitate the onset of dialysis dementia.Treatment with deferoxamine mesylate in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism.. 5.9Effects on Ability to Drive and Use Machines Deferoxamine mesylate may cause dizziness, which may impair the ability to drive car or operate machinery. Patients should not drive or operate machinery until they know how deferoxamine mesylate will affect their ability to engage in these activities.. 5.10Embryo-Fetal Toxicity Based on findings in animals, deferoxamine mesylate can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of deferoxamine to pregnant mice and rabbits during the period of organogenesis caused adverse developmental outcomes including decreased fetal body weights and malformations at maternal doses less than those in patients at maximum recommended human dose (MRHD). Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with deferoxamine mesylate and for one month after the last dose [see Use in Specific Populations (8.1 8.3), Nonclinical Toxicology (13.1)].