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, leucopenia).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).

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.. Deferoxamine01.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE ADMINISTRATION. Acute Iron IntoxicationIntramuscular AdministrationThis 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 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.Intravenous AdministrationTHIS 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 1000 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 1000 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 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. CHRONIC IRON OVERLOADSubcutaneous AdministrationA daily dose of 1000-2000 mg (20-40 mg/kg/day) should be administered over 8-24 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 8-12 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 administration is via slow subcutaneous infusion over - 12 hours. In patients with intravenous access, the daily dose of deferoxamine mesylate can be administered intravenously. The standard dose is 20 40 mg/kg/day for children and 40 50 mg/kg/day over - 12 hours in adults for - 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 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 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 500-1000 mg may be administered intramuscularly. The total daily dose should not exceed 1000 mg. For reconstitution instructions for intramuscular administration see Table 1.Reconstitution and PreparationTable 1: Preparation for Intramuscular Administration RECONSTITUTE DEFEROXAMINE MESYLATE WITH STERILE WATER FOR INJECTION Vial Size Amount of SterileWater for InjectionRequired forReconstitution Total Drug Contentafter Reconstitution Final Concentration per mL after Reconstitution 500 mg mL 500 mg/2.35 mL 213 mg/mL grams mL grams/9.4 mL 213 mg/mL Table 2: Preparation for Intravenous AdministrationsRECONSTITUTE DEFEROXAMINE MESYLATE WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required forReconstitution Total Drug Contentafter Reconstitution Final Concentration per mL after Reconstitution 500 mg mL 500 mg/5.3 mL 95 mg/mL grams 20 mL grams/21.1 mL 95 mg/mL Table 3: Preparation for Subcutaneous AdministrationRECONSTITUTE DEFEROXAMINE MESYLATE WITH STERILE WATER FOR INJECTION Vial Size Amount of SterileWater for InjectionRequired forReconstitution Total Drug Contentafter Reconstitution Final Concentration per mL after Reconstitution 500 mg mL 500 mg/5.3 mL 95 mg/mL grams 20 mL grams/21.1 mL 95 mg/mL The 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 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 in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Vials each containing 500 mg of sterile, lyophilized deferoxamine mesylateCartons of vials...................................................NDC 68083-172-04Vials each containing g of sterile, lyophilized deferoxamine mesylateCartons of vials...................................................NDC 68083-173-04Each vial is for single use only. Discard unused portion.Store at 20o to 25oC (68o to 77 oF) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

INDICATIONS 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.

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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Package Label 500 mg per vialRx Only NDC 68083-172-01Deferoxamine mesylate for injection, USP500 mg per vialEach vial contains Deferoxamine mesylate USP, 500 mg in lyophilized form.For subcutaneous intramuscular or intravenous administration.4 vials Package Label 2 per vialRx Only NDC 68083-173-01Deferoxamine mesylate for injection, USP2 per vialEach vial contains Deferoxamine mesylate USP, g in lyophilized form.For subcutaneous intramuscular or intravenous administration.4 vials. image02. image2g.

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralFlushing of the skin, urticaria, hypotension, and shock have 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:o Vitamin supplements should not be given to patients with cardiac failure.o Start supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate.o Give vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump.o Do not exceed daily vitamin dose of 200 mg in adults, given in divided doses.o Clinical 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.Drug InteractionsVitamin 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 PatientsPatients 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 FertilityLong-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.Pregnancy Category CDelayed 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 MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted inhuman milk, caution should be exercised when deferoxamine mesylate is administered to nursing woman.Pediatric UsePediatric 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 UseClinical 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 ImpairmentNo studies have been performed in patients with hepatic impairment.

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 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 deferoxamine mesylate in patients with acute iron intoxication or thalassemia.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

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) and grams of deferoxamine mesylate (corresponding to 1.707 grams of deferoxamine as free base) as white to off-white lyophilized powder in single-dose vial for reconstitution.. For injection: 500 mg and grams of deferoxamine mesylate as lyophilized powder in single-dose vial for reconstitution (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Concurrent treatment with prochlorperazine may lead to temporary impairment of consciousness. (7.1) Imaging results may be distorted due to rapid urinary excretion of deferoxamine mesylate bound gallium-67. Discontinue deferoxamine mesylate 48 hours prior to scintigraphy. (7.2). 7.1 Prochlorperazine. Concurrent treatment with deferoxamine mesylate and prochlorperazine, phenothiazine derivative, may lead to temporary impairment of consciousness. 7.2 Gallium-67. Imaging results may be distorted because of the rapid urinary excretion of deferoxamine mesylate-bound gallium-67. Discontinue deferoxamine mesylate 48 hours prior to scintigraphy.

GERIATRIC USE SECTION.

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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Caution patients about the potential allergic reactions associated with rapid intravenous administration of deferoxamine mesylate for injection and the need for monitoring allergic reactions during treatment [see Warnings and Precautions (5.1)]. Caution patients about the potential auditory and ocular toxicities due to prolonged use of deferoxamine mesylate for injection, conduct auditory testing and ophthalmic testing at regular intervals. Advise patients to contact their healthcare provider if they develop visual or auditory changes during treatment [see Warnings and Precautions (5.2)]. Caution patients about the potential for kidney toxicity when taking deferoxamine mesylate for injection and the need for kidney function test to monitor for increase in serum creatinine [see Warnings and Precautions (5.3)]. Inform patients that if they have difficulty in breathing during treatment, they should inform the healthcare provider as this is symptom of acute respiratory distress syndrome which can occur with excessively high intravenous doses of deferoxamine mesylate for injection [see Warnings and Precautions (5.4)]. Caution pediatric patients and their caregivers that child treated with deferoxamine mesylate for injection could have slower than normal growth and the need to monitor for body weight and height every months [see Warnings and Precautions (5.5)]. Caution patients about the increased risk of bacterial infections (Yersinia enterocolitica and Yersinia pseudotuberculosis) with deferoxamine mesylate for injection treatment and the need for treatment discontinuation until the infection is resolved [see Warnings and Precautions (5.6)]. Caution patients about the potential risk of fungal infections (Mucormycosis) when receiving deferoxamine mesylate for injection treatment and the need for treatment discontinuation, mycological tests and required treatment for treating the infection [see Warnings and Precautions (5.6)]. Caution patients about the potential impairment of cardiac function when taking deferoxamine mesylate for injection concomitantly with high doses of Vitamin (more than 500 mg daily in adults). Inform adult patients not to exceed daily Vitamin dose of 200 mg given in divided doses. Inform pediatric patients under 10 years of age and older pediatric patients or their care takers not to exceed daily Vitamin of 50 mg and 100 mg, respectively [see Dosage and Administration (2.4) and Warnings and Precautions (5.7)]. Inform patients with cardiac failure not to take Vitamin supplements when on treatment with deferoxamine mesylate for injection [see Dosage and Administration (2.4) and Warnings and Precautions (5.7)]. Caution patients with aluminum-related encephalopathy and receiving dialysis about potential neurological dysfunction [see Warnings and Precautions (5.8)]. Cautions patients that treatment with deferoxamine mesylate for injection in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism [see Warnings and Precautions (5.8)]. Inform patients that they should refrain from driving or operating potentially hazardous machines if they experience dizziness or other nervous system disturbances, or impairment of vision or hearing [see Warnings and Precautions (5.9)]. Advise patients to inform the healthcare provider if they have received prochlorperazine prior to deferoxamine mesylate for injection treatment as this may lead to temporary impairment of consciousness [see Drug Interactions (7.1)]. Inform patients that if they are going for any imaging tests while receiving Gallium-67 and deferoxamine mesylate for injection concomitantly it can result in reports with distorted images [see Drug Interactions (7.2)]. Inform patients that their urine may occasionally show reddish discoloration. Embryo-fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraceptive during treatment with deferoxamine mesylate for injection and for one month after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise patients to avoid breastfeeding while taking deferoxamine mesylate for injection and for one week after the final dose [see Use in Specific Populations (8.2)]. Manufactured by: Gland Pharma Limited Hyderabad 500043, India. Revised: 07/2023.

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.

PEDIATRIC USE SECTION.

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)].

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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There 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. Data Animal 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).

SPL UNCLASSIFIED SECTION.

1.1 Acute Iron Intoxication. Deferoxamine mesylate for injection is indicated as an adjunct to standard measures for the treatment of acute iron intoxication.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed (8.2) Geriatric Use: Increased risk of ocular disorders (8.5). 8.1 Pregnancy. Risk Summary There 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. Data Animal 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)]. Contraception Females Deferoxamine 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. Hypersensitivity Reactions: More common with rapid intravenous infusion. Administer intramuscularly or by slow subcutaneous or intravenous infusion. (5.1) Auditory 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) Renal 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) Respiratory Toxicity: Acute respiratory distress syndrome has occurred. Risk increased with high intravenous doses. Recommended daily dose should not be exceeded. (5.4) Growth 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) Serious Infections: Cases of mucormycosis and Yersinia infections, some fatal, have occurred. Discontinue deferoxamine mesylate and initiate appropriate treatment immediately. (5.6) Cardiac 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) Risks of Deferoxamine Mesylate Treatment in Patients with Aluminum Overload: Risks include neurological dysfunction (including seizures), dialysis dementia, and aggravation of hyperparathyroidism. (5.8) Effects on Ability to Drive and Use Machines: May cause dizziness. (5.9) Embryo-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). 5.1 Hypersensitivity 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.. 5.2 Auditory 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.. 5.3 Renal 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. 5.4 Respiratory 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.. 5.5 Growth 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. 5.6 Serious Infections. Yersinia Infections Deferoxamine 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. Mucormycosis Cases 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.. 5.7 Cardiac Dysfunction with Concomitant Use of Vitamin C. 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: Vitamin supplements should not be given to patients with cardiac failure. Start supplemental vitamin only after an initial month of regular treatment with deferoxamine mesylate. Give vitamin only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump. Do 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. Clinical monitoring of cardiac function is advisable during such combined therapy. 5.8 Risks 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. 5.9 Effects 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. 5.10 Embryo-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)].