Nurses need to understand that iron overload is a consequence

of chronic blood transfusion, and they need to know what

effects it has on end-organs and what treatment options are available.

Under normal conditions, the human body stores approximately 3.5 g of iron. Most of this iron is distributed within the RBC (a component of hemoglobin), with the remainder being stored in muscle fibres, macrophages, the liver, and bone marrow. On average, 1–2 mg of iron is absorbed daily via the duodenum, with the same amount being excreted through sloughing of mucosal cells, desquamation of epithelial cells, and blood loss during menstruation. Because the same amount of iron is absorbed and eliminated on a daily basis, the iron pool represents a closed system (Shah et al., 2012). Therefore, the human body has no effective means of naturally disposing of excess iron.

Iron-binding proteins

Heme: Found in red blood cells (RBC)

Ferritin: • Intracellular protein that functions as

the primary form of iron storage

• Provides an indirect measure of the

amount of iron stored in the body

Transferrin: • Responsible for iron transport

• Provides a measure of iron

circulation

Ferroportin: • Transmembrane protein that

transports iron from inside to outside

the cell

Although iron is physiologically

critical, excess iron is toxic.Due to its ability to donate and

accept electrons, iron can

catalyze the conversion of

hydrogen peroxide into free

radicals if it is left unbound within cells. These free radicals,

in turn, can cause damage to a

number of cellular structures

and processes, leading to cell

death. To prevent this free radical formation, iron must be

bound to. It is important to note

that 80% of the body’s daily iron

needs are used for the

production of new RBC, which requires only 20–25 mg of iron

Iron overload is the result of chronic blood transfusions of red blood cells

(RBC) for various blood disorders.

Transfusions are needed because of a

decrease in RBC production,

an increase in cell destruction,

chronic blood loss.

β-Thalassemia Major

Sickle-Cell Disease

Myelodysplasia

Other Anemias

β-Thalassemia Major

β-thalassemia major is a group of inherited blood disorders affecting the formation of the hemoglobin molecule. Diagnosed in early infancy, patients exhibit signs and symptoms of severe anemia, ineffective erythropoiesis, and increased iron absorption…

Transfusion therapy is necessary to sustain life, promote growth until adolescence, improve overall quality of life, and decrease end-organ abnormalities…

Chronic transfusion therapy may lead to cardiac iron overload, a major cause of mortality and morbidity.Hepatic cirrhosis and primary liver cancer are also common, especially in the presence of a hepatitis C infection, as well as various endocrinopathies such as diabetes.

Sickle-Cell Disease

A second blood disorder that requires chronic transfusion therapy is sickle-cell disease.

Sickle-cell disease is composed of a heterogeneous group of mutations including at least 1 copy of the sickle (HbS) mutation, which alters the form of red blood cells into sickleshaped crescents. This common genetic blood disease is most often in the form of sickle-cell anemia where a patient has 2 genes for sickle cell (HbSS). Other forms of sickle-cell disease include 1 copy of HbS combined with either an HbC (hemoglobin C) or a β-thalassemia allele. Sickle-cell disease is characterized by chronic anemia due to intravascular malformation or sickling of red blood cells during stress or infection.

Administration of blood transfusions is used to alleviate the anemia and other complications identified with sickle-cell disease.

Iron overload is an important cause of morbidity and mortality of these patients, especially those who are treated with monthly chronic red cell transfusions for sickle-cell complications like stroke.

Myelodysplasia

Myelodysplasia, another disease requiring chronic transfusions, is a

heterogenous group of blood disorders characterized by

hemocytopenias, dysmorphic and genetically abnormal bone marrow

and blood cells of the myeloid type…These patients also have an

increased risk of acute leukemia. The majority of patients with this

disorder are 60–80 years old.

%8 of individuals diagnosed with this disorder have anemia and are

transfusion dependent.

There are additional disorders that cause iron overload but are not due to

chronic transfusion therapy.

Hemochromatosis is an autosomal recessive disorder causing abnormal

absorption of iron. African iron overload,

fatty liver,

viral hepatitis,

nonalcoholic fatty liver,

and metabolic syndrome

are examples of other disorders that can exhibit iron overload.

Other Anemias

Besides myelodysplastic anemia, other anemias require chronic blood

transfusions.

Aplastic anemia

A few of these are the bone marrow failure syndromes of Diamond-

Blackfan and Fanconi anemia.

Both syndromes are congenital and cause a failure of blood cell

components to mature or function properly.

As blood levels of NTBI (Non-transferrin-bound serum iron) increase, tissue absorption of toxic NTBI results in iron deposits in various organs including the

heart,

liver, and

endocrine glands.

Elevated levels of iron in the liver leads to an increased risk of hepatic dysfunction and cirrhosis,

While excess iron in the heart is associated with an increased risk of cardiac-related events including myocardial infarction, congestive heart failure, and arrhythmias.

Excess iron in the endocrine system can lead to gonadal and thyroid dysfunction, as well as diabetes.

AIRWAYS AND LUNGS Buildup of fluids in the lungs

STOMACH AND INTESTINES

Black, and possibly bloody stools

Diarrhea

Liver damage

Metallic taste in mouth

Nausea

Vomiting blood

HEART AND BLOOD Dehydration

Low blood pressure

Fast and weak pulse

Shock

NERVOUS SYSTEM Chills

Coma (decreased level of consciousness and lack of responsiveness, may occur within 1/2 hour to 1 hour after overdose)

Convulsions

Dizziness

Drowsiness

Fever

Headache

Lack of desire to do anything

SKIN Bluish-colored lips and fingernails

Flushing

Loss of color from the skin (pallor)

Each unit of blood transfused contains 200–250 mg of iron. With an average transfusion

of 2 units, a patient could receive as much as 500 mg of iron with each episode of

transfusion. Iron is an essential element within the body, and its quantity is tightly

regulated physiologically.

The body has no mechanism to excrete excess iron.

For the individual receiving an occasional transfusion, the slight increase in iron would

not be a problem. However, what happens to that individual who receives 2–4 units of

blood every month over a 20-year span?

Two transfused units of blood per month over 1 year would equate to 24 units of blood infused. As noted above, there is 250 mg of iron per unit of blood, which would result in accumulation

of 6000 mg of iron within 1 year.

Consider that patient receiving 2 units of transfused blood over a 20-year span of time; he or she will have taken in 120 000 mg of iron just from the blood transfused.

Because the body has no means to deal with a large amount of excess iron, it deposits iron

into end-organs such as the heart, liver, and endocrine organs, which leads to the dysfunction of these end-organs.

Any individual who is receiving blood

transfusions and has received greater

than 20 units during his or her lifetime is

considered to have iron overload.

Evaluation of Iron Overload

Method* Advantages Disadvantages Count erythrocyte

transfusions

Reflects total iron burden; noninvasive,

universally available; prospective; inexpensive

Not organ specific

Count phlebotomy units Reflects total iron burden; noninvasive,

universally available; inexpensive

Not organ specific; retrospective

Assess serum ferritin concentration

Widely available; noninvasive; inexpensive Not organ specific; altered by inflammation, liver disease, recent chelation, alcohol consumption, ascorbate nutriture

Evaluate bone marrow Detects abnormal erythroblast iron (“ringed

sideroblasts”); permits estimate of

macrophage iron

Invasive; usually not helpful in hemochromatosis or in

absence of undiagnosed anemia

Perform liver biopsy Major target organ; “gold standard”; liver

histology Invasive; sampling errors; expensive

Perform endomyocardial

biopsy

Major target organ; organ specific; heart

histology

Invasive; correlation with functional studies fair

Scan by CT Noninvasive; widely available Involves radiation exposure; insensitive to early iron

overload; common liver disorders may yield false-positive readings; expensive

Scan by MRI (T2-

weighted)

Adaptable to multiple target organs;

noninvasive; can detect small primary liver

cancers; widely available

Sensitivity, specificity must be evaluated for each machine;

various scanning, interpretation routines; expensive

Scan by MRI (T2*-

weighted) Major target organs; noninvasive; adaptable

to multiple organs; greater sensitivity than T2 methods; may become preferred method for

cardiac iron

Largely investigational

Once iron overload is identified in a patient, chelation therapy can be

initiated to remove iron from the patient’s body.

Through the medications currently available, it is possible to bind with

Fe+ molecules from the end-organs and eliminate them either through

urine or feces. The molecules of chelating drugs create an attraction

and compete with the parenchymal tissues in binding with the iron.

There are 2 specific aims for chelation therapy.

reduction therapy or maintenance therapy.

protection from the effects of toxic iron and reduced end-organ

damage.

The first aim of chelation therapy is to

bind excess iron within the system and remove it

from the body.

This occurs when iron is bound at equal or

greater amounts than iron intake from transfusions

through either reduction therapy or maintenance

therapy.

Reduction therapy is when chelation is

used at rates to decrease iron levels from

the present state to a more acceptable level.

Depending on the source, acceptable levels

are less than 1000– 2500 ng/mL.

Maintenance therapy is used to prevent further iron, over the established acceptable

level for that patient, from being stored.

Once an individual is established on iron chelation therapy, there is a

decreased risk of developing comorbidities and an improved survival rate.

A secondary aim of therapy is to afford

the individual 24-hour protection from

the effects of toxic iron and reduced end-organ damage. If there are any

gaps in therapy, iron will reinsert itself into

the tissue cells, and further tissue

damage occurs.

There are studies that have suggested

that the relationship of iron burden in

various organs may be patient-specific,

making it difficult to evaluate the

efficacy/ effectiveness of the chelation

treatment between patients.

Drug

Deferoxamine

(DFO) Deferiprone (DFP) Deferasirox Iron chelator

complex

1:1 1:3 1:2

Plasma clearance

half-life

20–30 minutes 53–240 minutes 1–16 hours

Oral absorption Negligible Peak 45 minutes Peak 1–2.9 hours

Iron excretion Urine and fecal Urine Fecal

Therapeutic daily

dose; route;

schedule

25-50 mg/kg Maximum dose: 6g in

24 hours

75 mg/kg 20 mg/kg (maximum 30 mg/kg)

Route SQ, IV,IM Oral Oral

Frequency 8–12 hours nightly for 5–7 nights weekly

3 times daily Once daily

Advantages Widely available;

much clinical experience;

inexpensive

Good chelation of cardiac, hepatic iron;

much clinical experience;

inexpensive

Good chelation of cardiac, hepatic iron;

no growth abnormalities in children;

no agranulocytosis

Disadvantages Inadequate chelation of

cardiac iron

Inadequate chelation of cardiac iron in

some cases

Limited clinical experience

Adverse effects Reactions at infusion sites;

hearing, vision, growth,

skeletal abnormalities; zinc deficiency;

Yersinia infection

Agranulocytosis; transient neutropenia;

arthralgias; zinc deficiency;

mild gastrointestinal symptoms; mild aminotransferase elevations

Skin rash; nonprogressive elevation of

serum creatinine;

mild gastrointestinal symptoms; mild aminotransferase elevations;

rare hearing, vision abnormalities

Acute Iron Poisoning IM administration is indicated for all patients NOT in shock; administer 1g IM initially and then

500mg Q4hr for 2 doses

Depending upon clinical response, subsequent doses of 500mg Q4-12hr can be administered

Maximum dose: 6g in 24 hours

IV administration should be reserved for patients in a state of cardiovascular collapse or shock; 1g slow IV infusion

Rate of infusion should not exceed 15mg/kg/hr for the first dose; subsequent doses should not be infused at a faster rate than 125mg/hr

Chronic Iron Overload SC administration: 1-2g (20-40mg/kg/day) SC over 8-24 hours using a small portable pump

capable of providing continuous mini-infusion; individualize infusion duration

IV administration in patients with IV access: 40-50mg/kg/day over 8-12 hours for 5-7 days/ week (maximum of < 60mg/kg/day and an IV infusion rate of <15mg/kg/hr)

IM administration: 0.5-1g QD (maximum of 1g QD)

Additional Information

Can be administered prior to or following same day blood transfusion in patients that are poorly compliant; should not be administered concurrently as this can lead to errors in interpretation of ADRs

DESFERAL

Injection site reactions (eg, localized irritation, induration, infiltration, pain,

erythema, wheal formation, eschar, burning, swelling, pruritus, crust, vesicles, local

edema); these may be associated with systemic allergic reactions

• Ensure:

• Patient is rotating administration sites (lateral arms, legs and abdomen)

• Correct dilution and rate of infusion

• Patient is not experiencing a reaction/allergy to dressing or adhesives used to

secure needle

• If reactions persist despite the above, consider diluting the drug or adding 1 mg of

hydrocortisone to the infusion.

• Advise patient on the use of Thalaset needles which have a small gauge and needle

size.

Systemic reactions (eg, abdominal pain, arthralgia, asthma, fever, headache,

myalgia, nausea, vomiting)

DESFERAL

Special Senses reactions

(eg, high-frequency sensorineural hearing loss and/or tinnitus are uncommon if dosage

guidelines are not exceeded and if dose is reduced when ferritin levels decline;

• Baseline auditory assessment to rule out sensorineural hearing loss.

• If tinnitus occurs, hold drug and refer for repeat audiology assessment (monthly) until

hearing stabilized.

• Reinitiate treatment at a lower dose once complaints have resolved, and monitor hearing

closely.

Visual disturbances inlcuding decreased acuity, blurred vision, loss of vision, dyschromatopsia,

night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts are rare if dosage guidelines are not exceeded)

• Baseline ophthalmological assessment to rule out macular or retinal pigment epithelial

disease.

• If ocular events occur, hold drug and refer patient for repeat ophthalmological

assessment.

• Re-initiate drug at lower dose once visual complaints have resolved, and monitor vision

closely.

DESFERAL

Cardiovascular reactions (eg, hypotension with too rapid IV infusion, tachycardia,

shock)

Hypersensitivity reactions (eg, anaphylactic reaction with or without shock,

angioedema, generalized rash, urticaria)

Digestive reactions (eg, abdominal discomfort, diarrhea, nausea, vomiting)

Hematologic reactions (eg, blood dyscrasia including thrombocytopenia and

leucopenia)

Hepatic reactions (eg, increased transaminases, hepatic dysfunction)

Musculoskeletal reactions (eg, muscle spasms, growth retardation and bone changes

including metaphyseal dysplasia are common in doses ≥ 60 mg/kg, especially those

who begin iron chelation in the first three years of life; reduced risk if doses are kept to ≤

40 mg/kg)

Nervous System reactions (eg, neurological disturbances including dizziness, peripheral

sensory, motor, or mixed neuropathy, paresthesias, seizures; exacerbation or

precipitation of aluminum-related dialysis encephalopathy)

DESFERAL

Respiratory reactions (eg, acute respiratory distress syndrome with dyspnea,

cyanosis, and/or interstitial infiltrates)

Very rare generalized rash

Urogenital reactions including dysuria, acute renal failure, increased serum

creatinine and renal tubular disorders

Obtain baseline measurements of serum creatinine and aminotransferases.

• If serum transaminase elevations occur, consider other possible causes (e.g.,

viral hepatitis, increasing hepatic hemosiderosis, inadequate chelation, or

concomitant medications).

• If renal toxicity suspected due to increasing creatinine levels, interrupt therapy

or reduce dose.

• Inform patients that their urine may show a reddish discoloration.

DESFERAL

Renal Failure

Exjade can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders.

Measure serum creatinine and determine creatinine clearance in duplicate prior to initiation of therapy and monitor renal function at least monthly thereafter.

For patients with baseline renal impairment or increased risk of acute renal failure, monitor creatinine weekly for the first month, then at least monthly.

Consider dose reduction, interruption, or discontinuation based on increases in serum creatinine

Hepatic Failure

Exjade can cause hepatic injury including hepatic failure and death.

Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter.

Avoid use of Exjade in patients with severe (Child-Pugh C) hepatic impairment and reduce the dose in patients with moderate (Child Pugh B) hepatic impairment

exjade

Gastrointestinal Hemorrhage

Exjade can cause gastrointestinal (GI) hemorrhages, which may be fatal,

especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts. Monitor patients and discontinue Exjade for

suspected GI ulceration or hemorrhage

Change timing of administration (evening administration, with or without food,

may significantly improve GI tolerability).

• Diarrhea: Advise patient to take antidiarrheals for up to 2 days, and keep

hydrated. If patient is lactose intolerant, advise on lactase supplementation (e.g.,

Lactaid) and/or avoidance of dairy.

• Abdominal pain: Advise patient to sip water or other clear fluids and avoid solid

food for the first few hours.

Avoid narcotic pain medication and NSAIDs.

• Nausea/vomiting: Drink small, steady amounts of clear liquids, such as electrolyte

solutions, and keep hydrated.

exjade

Skin rash

• Mild-to-moderate: Continue therapy without dose adjustment as rash likely to

resolve spontaneously.

• Severe: Interrupt treatment; reintroduce at a lower dose and gradually escalate

dose. Consider long-acting antihistamines and/or short-course of low-dose oral

corticosteroids if required.

Exjade

Exjade is contraindicated in patients with:

Serum creatinine greater than 2 times the age-appropriate ULN or creatinine clearance less than 40 mL/min

Poor performance status;

High-risk myelodysplastic syndromes;

Advanced malignancies;

Platelet counts less than 50 x 109/L;

Known hypersensitivity to deferasirox or any component of Exjade

Deferasirox can harm your liver or kidneys. Stop using Exjade and call your doctor at once if you have swelling, rapid weight gain, shortness of breath, pain in your upper stomach, loss of appetite, pain in your side or lower back, little or no urinating, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Exjade

Take this medicine at the same time every day.

Take Exjade on an empty stomach at least 30 minutes before eating.

While using Exjade, you may need frequent blood tests. Your kidney or liver function may also need to be checked every 6 months, and you may need a liver biopsy.

Store at room temperature, away from moisture and heat.

Do not chew or crush the Exjade dispersible tablet and do not swallow it whole.

Place the tablet into a glass of apple juice, orange juice, or water and allow the tablet to disperse in the liquid. The tablet will not dissolve completely. Drink this mixture right away. To make sure you get the entire dose, add a little more liquid to the same glass, swirl gently and drink right away.

If you take less than 1000 milligrams (1 gram) daily, dissolve the tablet in about one-half cup of apple juice, orange juice, or water. If you take more than 1000 milligrams daily, dissolve the tablet in about 1 cup of apple juice, orange juice, or water.

Exjade

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is

almost time for your next scheduled dose. Do not take extra medicine to

make up the missed dose.

While you are taking Exjade, do not take antacids that contain aluminum,

such as Amphojel, Gaviscon, Maalox, Mi-Acid, Mylanta, Rulox, and others.

Exjade

Adverse Event Management Approach

Agranulocytosis Stop the drug immediately and consider use of G-CSF.

• Do not rechallenge in the future.

Neutropenia Temporarily discontinue drug until resolved.

Arthropathy • Monitor for signs/symptoms and consider referring patient for X-ray of ultrasound or joint.

• Consider dose reductions and/or analgesics (NSAIDs).

• If symptoms become debilitating, refer to rheumatology and/or orthopedic surgery.