RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

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DESCRIPTION SECTION

11 DESCRIPTION

Deferoxamine Mesylate for Injection, USP, is an iron-chelating agent, available in vials for injection via intramuscular, subcutaneous, and intravenous administration. Deferoxamine mesylate is supplied as vials containing 500 mg of deferoxamine mesylate USP (corresponding to 426.82 mg of deferoxamine as free base) and 2 g of deferoxamine mesylate USP (corresponding to 1707.28 mg of deferoxamine as free base) 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 is:

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

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DOSAGE FORMS & STRENGTHS SECTION

Highlight: For injection: 500 mg of deferoxamine mesylate as a lyophilized powder in single-dose fliptop vial for reconstitution. (3)

For injection: 2 g of deferoxamine mesylate as a lyophilized powder in single- dose fliptop vial for reconstitution. (3)

3 DOSAGE FORMS AND STRENGTHS

For injection: 500 mg of deferoxamine mesylate (corresponding to 426.82 mg of deferoxamine as free base) as a white to off-white lyophilized powder in single-dose fliptop vial for reconstitution.

For injection: 2 g of deferoxamine mesylate (corresponding to 1707.28 mg of deferoxamine as free base) as a white to off-white lyophilized powder in single-dose fliptop vial for reconstitution.

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CONTRAINDICATIONS SECTION

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Known hypersensitivity to the active substance. (4)

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Patients with severe renal disease or anuria. (4)

4 CONTRAINDICATIONS

Deferoxamine Mesylate for injection is contraindicated in patients with:

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A history of a hypersensitivity reaction to deferoxamine or any of its inactive ingredients [see Description (11)]. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].

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Severe renal disease or anuria since the drug and the iron chelate are excreted primarily by the kidney [see Warnings and Precautions (5.3)].

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USE IN SPECIFIC POPULATIONS SECTION

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Lactation: Advise not to breastfeed. (8.2)

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Geriatric Use: Increased risk of ocular disorders. (8.5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on Deferoxamine mesylate use in pregnant women to evaluate for a 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 a fetus. Consider the benefits and risks of Deferoxamine mesylate for the mother and possible risks to the fetus when prescribing Deferoxamine mesylate to a pregnant woman.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a 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 7 to gestation day 12 resulted in a 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 a 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 6 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 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 is relatively poor in patients under the age of 3 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., 1 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 3 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 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. 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.

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OVERDOSAGE SECTION

10 OVERDOSAGE

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 overdose. In case of overdose, discontinue Deferoxamine mesylate and provide symptomatic supportive care.

Deferoxamine mesylate is readily dialyzable.

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F) excursions permitted between 15°C and 30°C (59°F and 86°F).

Discard unused portion.

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