Deferoxamine (DFO) is FDA approved to treat iron overload, either acute or chronic. The definition of iron overload is serial ferritin levels above 800 to 3000 ng/mL . The FDA has not approved DFO as first-line therapy for hereditary hemochromatosis unless there is a contraindication to phlebotomy. Clinicians can also use DFO is also used as an off-label treatment for aluminum toxicity in chronic kidney disease (CKD) patients.
Transfusion-related iron overload occurs in patients that require frequent transfusions throughout their life. These patients include those affected by Thalassemia, Sickle cell disease, myelodysplastic syndromes, ineffective hematopoiesis, and other inherited anemic disorders. In this population, chelation should begin two years after transfusions start, serum ferritin levels greater than 1000 mcg/L, or when liver iron concentration (LIC) is greater than 3 mg Fe/g. Another indication for iron chelation is a cardiac T2* <20 milliseconds found on cardiac magnetic resonance. Cardiac MRI’s can measure proton relaxation times (T2*) in the cardiac nuclei. Excess iron within these cells speeds the rate of proton relaxation. This reduced cardiac T2* time is associated with cardiomyopathy, which dramatically increases mortality. Chelation therapy improves overall survival in these patients and should not be delayed.
The use of DFO in acute ingestion of iron is an indication when patients present with systemic toxicity, hemodynamic instability, lethargy, persistent vomiting, metabolic acidosis, or toxic serum iron levels. Iron levels >500 mcg/dL are considered hazardous, and chelation should be initiated. Signs and symptoms of systemic toxicity include coagulopathy, cardiomyopathy, hepatic and renal failure. Acute iron toxicity progresses through five clinical stages, with the most deadly consequences occurring within the first four days. Thus, rapid progression through these stages is another indicator that chelation may be required.
Aluminum toxicity is an off-label use for DFO chelation therapy. Aluminum toxicity can occur in patients with chronic kidney disease who undergo bladder irrigation with aluminum-containing products, use phosphate binders that contain aluminum, or receive hemodialysis with a water source contaminated with aluminum. Its use is an indication in those patients that exhibit signs and symptoms associated with chronic aluminum levels greater than >20 mcg/L, such as osteomalacia, anemia hypercalcemia, and dialysis dementia. It is also an indicated use in acute toxicity, which results from exposure to >200 mcg/L of aluminum resulting in acute encephalopathy.
Iron is an essential part of human physiology. It is a vital element in proteins such as hemoglobin, myoglobin, cytochrome, and also functions as a cofactor for many enzymes. It is stored by ferritin and transferred throughout the serum by transferrin. No physiological mechanism exists to excrete iron. Instead, humans regulate GI uptake by altering hepcidin levels. When iron storing proteins become saturated, free iron species accumulate in the plasma. These include non-transferable bound iron (NTBI) and Labile Plasma Iron (LBI). Free iron is also taken up by cells to form Labile Iron Pools (LIP) within them. This excess iron within cells catalyzes the production of free radicals via the Fenton reaction. Free radicals lead to DNA destruction and cellular damage. Free iron also precipitates acidosis by inhibiting oxidative phosphorylation in mitochondria. Deferoxamine is a molecule produced by the fermentation of Streptomyces pilosus. It binds free plasma iron and excess iron within cells. DFO is a hexadentate molecule and able to bind iron at a 1 to 1 ratio. The bound form of DFO is then excreted via the urine or bile. DFO chelates non-transferrin bound iron (free iron), iron in transit between transferrin and ferritin (labile chelating iron pool), hemosiderin and ferritin. Although DFO can directly bind and remove iron from myocardial cells, it will not bind iron that is already bound to molecules such as in transferrin, hemoglobin, or cytochromes. Thus, only a small amount of iron is available for chelation at any given time. Although this is a small fraction of total body iron, it has a profound effect. When bound, the resultant ferrioxamine is very water-soluble. If chelation occurs in hepatocytes, the compound will be excreted in bile, and when chelation occurs with free iron in plasma or other tissues, it is excreted by the kidneys.
DFO can also bind aluminum within the plasma to form aluminoxamine, which is renally excreted. In the case of CKD/ESRD patients, the product is dialyzable with the use of a high-flux membrane. DFO can draw aluminum deposited in tissues into the plasma. For this reason, patients with a measured serum aluminum concentration >200 mcg/L should not be treated with DFO as it may lead to severely high levels of aluminum and fatal neurotoxicity. The recommended administration will be discussed in the following section.
Deferoxamine is poorly absorbed from the GI tract when taken orally. For this reason, it must be given intramuscularly, subcutaneously, or intravenously. The subcutaneous route is preferable for those patients with chronic iron overload. Intravenous DFO is reserved for those with acute ingestion and life-threatening symptoms. Figure 1 is a summary of recommended dosages and administration times for DFO in iron toxicity.
A 25 gauge or smaller butterfly needle is used for the SQ route. The abdomen is generally the safest and most common area to avoid important vessels and nerves. A 10% deferoxamine solution is administered subcutaneously over 8 to 12 hours using a slow infusion pump. The dose is dependent on the patient's age and weight. In general, approximately 40 to 60 mg/kg/day is given for 4 to 5 days per week. The total dose should not exceed 2.5g daily.
Intravenous administration is reserved for those patients in severe acute iron toxicity with Iron levels >500 mcg/dL, severe cardiac disease (dysrhythmias, LV dysfunction, severe heart iron loading (T2*<6 ms on MRI)), or those who cannot tolerate the subcutaneous infusion. The standard dose of 50 to 60 mg/kg/day or 5 to 15 mg/kg/h is given as a 24-hour infusion using an indwelling catheter. Patients should not receive DFO for more than 24 hours intravenously as this can increase the risk of developing ARDS and other complications.
The dose of deferoxamine may be reduced or increased by using clinical judgment, decreasing liver ion concentrations, or calculating the therapeutic index, which divides the daily dose of DFO by the serum ferritin levels. The Therapeutic index should be <.025 at all times to avoid serious adverse effects.
Vitamin C can potentiate the therapeutic effect of DFO by mobilizing iron stores, subsequently increasing the concentration of chelatable iron. On the other hand, this increase in free iron can potentiate iron toxicity leading to impaired cardiac function and worsening overload. For this reason, the FDA advises that supplemental vitamin C should be avoided in patients with cardiac failure and should only start after an initial one month of standard DFO treatment has been completed. Furthermore, its use is only indicated in those patients receiving regular DFO therapy and should not exceed 200 mg/day. Close evaluation of the patient's cardiac function is of the utmost importance when using this combined therapy.
In aluminum toxicity, the appropriate dosing and therapy duration of DFO is uncertain and should be tailored by serum aluminum levels, symptoms, and response. The National Kidney Foundation has listed specific guidelines for the use of DFO in aluminum toxicity, which this article will cover. A proposed mechanism by the Kidney Disease Outcomes Quality Initiative states that symptomatic patients with serum aluminum levels >60 μg/L but <200 μg/L or a rise in aluminum after DFO >50 μg/L, DFO should be given to treat the aluminum overload. DFO's ability to draw aluminum out of tissues and into the plasma makes its use very dangerous in those patients with serum aluminum level >200 μg/L. To avoid DFO-induced neurotoxicity in these patients, its use should delay until completion of intensive dialysis (6 days per week) with a high-flux dialysis membrane, a dialysate aluminum level of <5 μg/L and until the pre-dialysis serum aluminum level has reduced to <200 μg/L.
When giving chronic deferoxamine therapy, it can lead to sensorineural hearing loss and retinopathy. Though the mechanism of ocular injury is not well understood, it appears to partially occur as a result of damage to the retinal pigment epithelium, which can lead to decreased visual acuity, visual field defects, and color vision defects. Hearing and vision loss can be reversible if the patient discontinues DFO early in the course. Growth retardation can also occur in children receiving DFO treatment, and clinicians should monitor patients over time for appropriate growth velocity. Administering less than 2.5g of DFO per day and monitoring the therapeutic index is the best way to avoid such complications. Acute side effects can include GI complaints, anaphylaxis, skin discoloration, skin irritation, and anaphylaxis. Chelation of iron and formation of the water-soluble compound, ferioxamine, may lead to vine rose-colored urine. DFO can increase the risk of infection by specific pathogens and invasive fungi such as mucormycosis, Yersinia, and Vibrio. ARDS is another potential and rare complication that occurs most often when giving the drug via intravenous infusion for more than 24 hours.
DFO is relatively safe and well-tolerated by patients. Its use is contraindicated in patients with previous hypersensitivity reactions to the drug and those with renal disease or anuria. DFO is a pregnancy category C drug and usually reserved for those women who are at high risk of cardiac disease or have severe symptoms from acute ingestion. Although there is no evidence to indicate that DFO is a teratogen, animal studies have shown adverse fetal effects. Clinicians should be cautious in using during pregnancy, and the risks vs. benefits must merit consideration in each case. It is unknown if DFO is excreted in breast milk.
The therapeutic index is a crucial measurement when it comes to DFO therapy, and the provider should calculate it regularly. It can be calculated by dividing the mean daily dose over seven days by the measured ferritin levels. Complication risk can be mitigated while using DFO by keeping the therapeutic index below 0.025, and the patient's daily dose requires adjustment for the alternating ferritin levels. Other than monitoring the patient's iron stores, it is also advisable to regularly screen for adverse effects. A screening hearing exam should be performed in the clinic every six months and a formal audiogram every 12 months. An evaluation by an ophthalmologist should take place in children every six months and annually in adults. Since the kidneys excrete the majority of the chelation byproduct ferrioxamine, it is essential to monitor the patient's renal function. The patient's chemistry, BUN/Cr, and urine protein/Cr ratios should be measured at least four times a year, and the dose of DFO should be reduced with worsening renal function.
Patients tolerate DFO well, and there is no specific antidote for the medication. The precautions and dose reductions are described elsewhere in this paper.
DFO treatment can be a tedious and painful process, with local skin reactions being common. To maximize compliance, the patient will require strong supportive relationships with several providers, nurses, and family. To provide safe chelation therapy, a patient must be compliant with their primary care doctor, ophthalmologist, endocrinologist, nephrologist, and hematologist. These interprofessional teams are vital to successful outcomes that decrease mortality and complications. Many of those who require chelation begin at a young age due to hereditary disease. Compliance in this age group is usually high when compared to others due to parental support. Compliance with the strict regimen can become problematic in adolescence or when life burdens become too cumbersome for a patient to manage. One multicenter study in Germany found that patients had more misery from chelation treatment than from the disease requiring it. Patient involvement, education, and behavioral support are of utmost importance. A systematic review from the Agency for Healthcare Research and Quality on interventions to improve adherence to self-administered medications found that reduced out-of-pocket expenses, case management, and patient education with behavioral support all improved medication adherence. Shared decision making also has an important role. There are a variety of chelators available for Iron overdose, and providers should seek the option with the lowest burden to the patient. Allowing patients to change the chelator for various reasons helped to increases compliance with the regiment. We must remember that chelation will be a life-long therapy for the majority of these patients. It is thus critical for providers to be empathetic, educational, and inspiring.
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