Deferoxamine Mesylate Drug Information

Acute Iron Intoxication

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

Chronic Iron Overload

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

Limitations of Use

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).

Recommended Dosage for Treatment of Acute Iron Intoxication for Adults and Pediatric Patients Intramuscular (IM) Administration Use for all patients not in shock. The initial recommended dose of deferoxamine mesylate for injection is 1,000 mg intramuscularly (IM) once. If needed based on the clinical response, administer subsequent doses of 500 mg every 4 hours to 12 hours.

The maximum recommended daily dose is 6,000 mg in 24 hours. Intravenous (IV) Administration Administer deferoxamine mesylate for injection intravenously (IV) to patients in a state of cardiovascular collapse and then only by slow infusion. As soon as the clinical condition of the patient permits, intravenous administration should be discontinued, and the drug should be administered intramuscularly.

The initial recommended IV dose of deferoxamine mesylate for injection is 1,000 mg administered at an infusion rate of up to 15 mg/kg/hr.

Recommended Dosage for Treatment of Chronic Iron Overload for Adults and Pediatric Patients Subcutaneous Infusion Administration The average daily dose of deferoxamine mesylate for injection is usually between 20 and 60 mg/kg. In general patients with serum ferritin level below 2,000 ng/mL require about 25 mg/kg/day. Patients with serum ferritin level between 2,000 and 3,000 ng/mL require about 35 mg/kg/day.

Patients with higher serum ferritin may require up to 55 mg/kg/day. It is not advisable to regularly exceed an average daily dose of 50 mg/kg/day except when very intensive chelation is needed in patients who have completed growth. If ferritin levels fall below 1,000 ng/mL, the risk of deferoxamine mesylate for injection toxicity increases; it is important to monitor these patients particularly carefully and perhaps to consider lowering the total weekly dose.

The doses specified here are the average daily doses. Since most patients use deferoxamine mesylate for injection less than 7 days a week, the actual dose per infusion usually differs from the average daily dose; e.g. if an average daily dose of 40 mg/kg/day is required and the patient wears the pump 5 nights a week, each infusion should contain 56 mg/kg. Slow subcutaneous infusion using a portable, light-weight infusion pump over a period of 8 to 12 hours is regarded as effective and especially convenient for ambulatory patients, but may also be given over a 24-hour period.

Deferoxamine mesylate for injection should normally be used with the pump 5 to 7 times a week. Deferoxamine mesylate for injection is not formulated to support subcutaneous bolus injection. Intravenous Administration Deferoxamine mesylate for injection can be administered intravenously if needed in patients with intravenous access.

Maximum dose is 60 mg/kg/day. The maximum recommended daily dose is 40 mg/kg/day until growth (body weight and linear growth) has ceased. In case of missed doses, deferoxamine mesylate for injection may be administered prior to or following same day blood transfusion (for example, 1 gram over 4 hours on the day of transfusion); however, the contribution of this mode of administration to iron balance is limited.

Deferoxamine mesylate for injection 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 Administration If given intramuscularly, the recommended dose of deferoxamine mesylate for injection is 500 mg to 1,000 mg per day. The maximum recommended daily dose is 1,000 mg per day.

Preparation

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. Table 1.

Do not refrigerate reconstituted solution.

Management of Vitamin C Deficiency 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. 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.

Clinical Trials Experience

The following adverse reactions associated with the use of deferoxamine mesylate 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 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

Prochlorperazine

Concurrent treatment with deferoxamine mesylate and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness.

Gallium-67

Imaging results may be distorted because of the rapid urinary excretion of deferoxamine mesylate-bound gallium-67. Discontinue deferoxamine mesylate 48 hours prior to scintigraphy.

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 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).

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).

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.

• Deferoxamine mesylate for injection is contraindicated in patients with:
• A history of a hypersensitivity reaction to deferoxamine or any of its inactive ingredients. Reactions have included anaphylaxis.
• Severe renal disease or anuria since the drug and the iron chelate are excreted primarily by the kidney.
• Known hypersensitivity to the active substance.
• Patients with severe renal disease or anuria.

Acute Toxicity Intravenous LD 50 s (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.