Deferoxamine - Fresenius Kabi USA, LLC

Deferoxamine Mesylate for Injection is indicated as an adjunct to standard measures for the treatment of acute iron intoxication.

Deferoxamine Mesylate for Injection is indicated for the treatment of transfusional iron overload in patients with chronic anemia.

Deferoxamine Mesylate for Injection is not indicated for the treatment of primary hemochromatosis (since phlebotomy is the method of choice for removing excess iron in this disorder).

Reconstitute Deferoxamine Mesylate for Injection prior to administration. Deferoxamine Mesylate for Injection should be further diluted for intravenous infusion. Use appropriate aseptic technique.

Reconstitute each vial of Deferoxamine Mesylate for Injection with Sterile Water for Injection, USP per Table 1. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if visibly opaque particles, discoloration or foreign particles are observed. The reconstituted Deferoxamine Mesylate for Injection solution is an isotonic, clear and colorless to slightly-yellowish solution. Discard unused portion.

If not used immediately, store at room temperature between 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F), for a maximum period of 24 hours. Do not refrigerate reconstituted solution.

Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with Deferoxamine Mesylate for Injection [see Warnings and Precautions (5.7)]. Vitamin C increases availability of iron for chelation. In general, 50 mg daily suffices for pediatric patients under 10 years old and 100 mg daily for older pediatric patients. Larger doses of vitamin C fail to produce any additional increase in excretion of iron complex.

Hypersensitivity reactions, including anaphylaxis, have occurred in Deferoxamine Mesylate for Injection-treated patients. Reactions have included flushing of the skin, urticaria, hypotension, and shock. These reactions typically occur when Deferoxamine Mesylate for Injection was administered by rapid intravenous injection. Therefore, administer Deferoxamine Mesylate for Injection intramuscularly or by slow subcutaneous or intravenous infusion.

Ocular and auditory toxicities have been reported in Deferoxamine Mesylate for Injection-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.

Renal toxicity, including increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders has occurred in Deferoxamine Mesylate for Injection-treated patients. Deferoxamine Mesylate for Injection is contraindicated in patients with severe renal disease [see Contraindications (4)]. Monitor serum creatinine to assess for changes in renal function.

Acute respiratory distress syndrome has occurred in Deferoxamine Mesylate for Injection-treated patients following treatment with excessively high intravenous doses of Deferoxamine Mesylate for Injection in patients with acute iron intoxication or thalassemia. The recommended daily doses should therefore not be exceeded.

High doses of Deferoxamine Mesylate for Injection and concomitant low ferritin levels have also been associated with growth suppression in pediatric patients. After reduction of Deferoxamine Mesylate for Injection dose, growth velocity may partially resume to pre-treatment rates. Monitor growth (weight and height) in pediatric patients treated with Deferoxamine Mesylate for Injection every 3 months.

Cardiac dysfunction has occurred in Deferoxamine Mesylate for Injection-treated patients with severe chronic iron overload following concomitant treatment with high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Deferoxamine Mesylate for Injection are to be used concomitantly:

• Vitamin C supplements should not be given to patients with cardiac failure.
• Start supplemental vitamin C only after an initial month of regular treatment with Deferoxamine Mesylate for Injection.
• Give vitamin C only if the patient is receiving Deferoxamine Mesylate for Injection regularly, ideally soon after setting up the infusion pump.
• Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses. 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.

Deferoxamine Mesylate for Injection 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 for Injection may precipitate the onset of dialysis dementia.

Treatment with Deferoxamine Mesylate for Injection in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism.

Deferoxamine Mesylate for Injection may cause dizziness, which may impair the ability to drive a car or operate machinery. Patients should not drive or operate machinery until they know how Deferoxamine Mesylate for Injection will affect their ability to engage in these activities.

Based on findings in animals, Deferoxamine Mesylate for Injection can cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Deferoxamine Mesylate for Injection and for one month after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

The following adverse reactions associated with the use of deferoxamine mesylate for injection were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

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

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

Infections: Yersinia, mucormycosis

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)

Nervous System: Neurological disturbances, including dizziness, peripheral sensory, motor, or mixed neuropathy, paresthesias, seizures; exacerbation or precipitation of aluminum-related dialysis encephalopathy

Special Senses: High-frequency sensorineural hearing loss, tinnitus visual disturbances including acuity, blurred vision, loss of vision, dyschromatopsia, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts

Respiratory: Acute respiratory distress syndrome (with dyspnea, cyanosis, and/or interstitial infiltrates)

Skin: Generalized rash

Urogenital: Dysuria, acute renal failure, increased serum creatinine and renal tubular disorders

Concurrent treatment with Deferoxamine Mesylate for Injection and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness.

Imaging results may be distorted because of the rapid urinary excretion of Deferoxamine Mesylate for Injection-bound gallium-67. Discontinue Deferoxamine Mesylate for Injection 48 hours prior to scintigraphy.

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 for Injection, and for one week after the last dose.

Based on animal data, Deferoxamine Mesylate for Injection can cause malformations at doses less than the human dose [see Use in Specific Populations (8.1)].

Safety and effectiveness in pediatric patients 3 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 3 years have not been established.

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

High doses of Deferoxamine Mesylate for Injection and concomitant low ferritin levels have been associated with growth suppression in pediatric patients. Monitor weight and height in pediatric patients receiving Deferoxamine Mesylate for Injection every 3 months [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

Clinical Studies of Deferoxamine Mesylate for Injection 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 a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of color blindness, maculopathy, and scotoma.

However, it is unclear if these eye disorders were dose related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking Deferoxamine Mesylate for Injection. 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.

Deferoxamine Mesylate for Injection 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.

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

Acute Toxicity

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

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

Acute respiratory distress syndrome has been reported following treatment with excessively high intravenous doses of Deferoxamine Mesylate for Injection in patients with acute iron intoxication and in patients with thalassemia.

There is no specific antidote for Deferoxamine Mesylate for Injection overdose. In case of overdose, discontinue Deferoxamine Mesylate for Injection and provide symptomatic supportive care.

Deferoxamine Mesylate for Injection is readily dialyzable.

Deferoxamine Mesylate for Injection chelates iron by forming a 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 for Injection does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of Deferoxamine Mesylate for Injection is capable of binding approximately 8.5 parts by weight of ferric iron.

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

Long-term carcinogenicity studies in animals have not been performed with Deferoxamine Mesylate for Injection. Cytotoxicity may occur, since Deferoxamine Mesylate for Injection has been shown to inhibit DNA synthesis in vitro.

Deferoxamine Mesylate for Injection 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.

How Supplied

Deferoxamine Mesylate for Injection, USP is supplied in single-dose vials containing 500 mg and 2 g of deferoxamine mesylate (corresponding to 426.82 mg and 1.707 g of deferoxamine as free base) as a sterile, white to off-white lyophilized powder.

Storage and Handling

STORE AT: 20ºC to 25°C (68ºF to 77°F) [see USP Controlled Room Temperature].

The container closure is not made with natural rubber latex.

Embryo-fetal Toxicity:

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a 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)].

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

451101F