Deferoxamine

Deferoxamine belonging to pharmacology class of Iron Chelating Agent

Deferoxamine can be used in the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.

Deferoxamine is Poorly absorbed from the GI tract and get Metabolised mainly in the plasma and chelates with metal ions, which are then excreted in the urine.

Deferoxamine is available in the form of Powder for injections.

Deferoxamine mesylate 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 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 can be used in the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.

Deferoxamine, a pyridinyl bisphosphonate analogue, binds to hydroxyapatite and inhibits bone resorption via actions on osteoclast or osteoclast precursors. It reduces the increased rate of bone turnover while osteoblast activity and bone mineralization are preserved.

Deferoxamine is approved for use in the following clinical indications

Acute Iron Intoxication

• Deferoxamine mesylate is an adjunct to, and not a 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 a clear airway; control of shock with intravenous fluids, blood, oxygen, and vasopressors; and correction of acidosis.

Chronic Iron Overload

• Deferoxamine 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 3 years with relatively little iron overload. The drug should ordinarily not be given to such patients unless significant iron mobilization (e.g., 1 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.

Acute Iron Intoxication

• Intramuscular Administration:
• This 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 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4 to 12 hours. The total amount administered should not exceed 6000 mg in 24 hours.
• Intravenous Administration:
• This route should be used only for patients in a 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 a 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 Ringer’s lactate solution.
• An initial dose of 1000 mg should be administered at a rate NOT TO EXCEED 15 mg/kg/hr. This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4 to 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 OVERLOAD

• Subcutaneous Administration:
• A daily dose of 1000 to 2000 mg (20 to 40 mg/kg/day) should be administered over 8 to 24 hours, utilizing a 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 a short infusion of 8 to 12 hours as with the same dose given over 24 hours.
• . No data are available on more than 1 course of retreatment.
• Intravenous Administration

• The standard recommended method of deferoxamine mesylate administration is via slow subcutaneous infusion over 8 to 12 hours. In patients with intravenous access, the daily dose of deferoxamine mesylate can be administered intravenously. The standard dose is 20 to 40 mg/kg/day for children and 40 to 50 mg/kg/day over 8 to 12 hours in adults for 5 to 7 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.
• In patients who are poorly compliant, deferoxamine mesylate 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 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

• A daily dose of 500 to 1000 mg may be administered intramuscularly. The total daily dose should not exceed 1000 mg. The reconstituted deferoxamine mesylate for injection solution is an isotonic, clear and colorless to slightly yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Deferoxamine mesylate reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion.

Powder for injection

500 mg/vial, 2 g/vial

Powder for injection

Deferoxamine may be contraindicated in the following conditions:

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.

• 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.
• 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. 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.
• 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.

Precautions

General

• Flushing of the skin, urticaria, hypotension, and shock have occurred in a 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 a 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 a 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 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 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.
• Give vitamin C only if the patient is receiving deferoxamine mesylate 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.

There is no sufficient scientific evidence traceable regarding use and safety of Deferoxamine in concurrent use with alcohol.

It is not known if Deferoxamine is present in breast milk.

Pregnancy Category (FDA): C

• 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.

The adverse reactions related to Deferoxamine can be categorized as

Common Adverse effects:

Flushing, urticaria, hypotension and shock, Pruritus, erythema and swelling

Less Common Adverse effects:

Dysuria, Fever, Allergic Skin Rashes, Tachycardia, Cardiac Arrhythmias, Convulsions and Leg Cramps; Visual Disturbances, Cataract Formation

Rare Adverse effects:

Hearing Loss; May retard growth in very young child. Pulmonary syndrome with high IV doses.

The clinically relevant drug interactions of Deferoxamine is briefly summarized here:

Increased risk of neurological symptoms when used concurrently with phenothiazines.

Ascorbic acid improves Fe excretion but it should not be given during the 1st mth of starting deferoxamine treatment as it may worsen Fe toxicity.

May affect imaging results if given together with gallium-67.

The most common side effects of Deferoxamine includes: Flushing, urticaria, hypotension and shock, Pruritus, erythema and swelling.

Pregnancy Category (FDA): C

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.

Labor and Delivery

There is no FDA guidance on use of Deferoxamine during labor and delivery.

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 a nursing woman.

Pediatric Use

Pediatric patients receiving deferoxamine mesylate should be monitored for body weight and growth every 3 months.

Safety and effectiveness in pediatric patients under the age of 3 years have not been established.

Geriatic 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). 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.

Gender

There is no FDA guidance on the use of Deferoxamine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Deferoxamine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Deferoxamine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Deferoxamine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Deferoxamine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Deferoxamine in patients who are immunocompromised.

Acute Toxicity

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

Signs and Symptoms

• 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 in patients with acute iron intoxication and in patients with thalassemia.

Treatment

• There is no specific antidote. Deferoxamine mesylate should be discontinued and appropriate symptomatic measures undertaken.
• Deferoxamine mesylate is readily dialyzable.

Pharmacodynamics:

Deferoxamine mesylate 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 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.

Pharmacokinetics:

Absorption: Poorly absorbed from the GI tract.

Metabolism: Metabolized mainly in the plasma.

Excretion: Chelates with metal ions, which are then excreted in the urine. Nonclinical toxicology

1. https://www.uptodate.com/contents/ Deferoxamine -drug-information?search= Deferoxamine &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Deferoxamine _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Deferoxamine ?type=full&mtype=generic#mechanism-of-action