Iron Infusions

Iron is an essential micronutrient that is required for the production of haemoglobin and a range of other proteins, including enzymes. This makes iron important in the transport of oxygen, oxidative metabolism, cellular proliferation, and many catalytic reactions. Iron is obtained from the diet, with the average adult absorbing around 1-2mg per day from an average daily intake of 10-15mg. Iron is highly conserved in the body, and daily losses are small in the absence of bleeding or pregnancy.

However, iron deficiency is common in Australia and may be related to:

• Inadequate dietary intake;
• Malabsorption; and
• Increased iron requirements (e.g. pregnancy or breastfeeding, rapid growth, heavy menstrual loss, chronic gastrointestinal loss).

Iron deficiency can lead to iron deficiency anaemia. While some patients may be asymptomatic, symptoms can include breathlessness, angina, claudication, and fatigue.

Iron deficiency

The cause of iron deficiency should be treated as appropriate. Supplementation should be initiated for patients with iron deficiency anaemia. An iron supplement may also be considered to improve symptoms for patients with iron deficiency without anaemia.

Iron supplements may be administered orally or parenterally. Oral iron is more commonly used and is effective at increasing haemoglobin levels. Oral iron has the advantage of being a cheap and convenient option for patients, and is safe when taken as recommended. However, gastrointestinal adverse effects are common and may affect adherence. These adverse effects may be minimised by starting with a low dose and gradually increasing, dosing on alternate days, or taking the supplement with food (although this may reduce absorption from ferrous salts).

Intravenous iron supplementation may be more appropriate in some cases, including:

• When rapid replacement is required (e.g. highly symptomatic patients or patients scheduled for elective surgery that is associated with significant blood loss);
• Anaemia associated with malignancy;
• When oral iron is not tolerated or absorbed effectively (e.g. following gastrectomy);
• Chronic kidney disease; and
• Inflammatory bowel disease.

When iron is administered intravenously, the absorption from oral iron products is significantly reduced. Therefore, it is not recommended to take oral iron supplements with intravenous iron. Oral iron is generally not required after an infusion as the infusion is intended to replete iron stores. However, if oral iron is considered necessary, it should be started at least a week after the last IV iron dose.

Intravenous iron preparations

There has been a significant increase in the use of iron infusions in the last decade, largely due to the introduction of newer iron salts that are better tolerated and faster to administer.

There are four iron salts available in Australia for parenteral use:

• Ferric carboxymaltose;
• Ferric derisomaltose;
• Iron polymaltose; and
• Iron sucrose.

While oral iron may require a course of around six months, intravenous iron supplementation may allow iron levels to be corrected with a single infusion (depending on the severity of iron deficiency).

Ferric carboxymaltose (Ferinject^®)

Ferric carboxymaltose has some advantages over other salts. It can be infused rapidly, making it more attractive for use in the primary care setting. In many cases, the total iron requirement can be given as a single dose (up to 1,000mg of elemental iron can be given in one infusion over 15 minutes). If repeat doses are required, it is recommended to wait at least seven days between doses.

Ferric carboxymaltose may be administered undiluted for IV injection, but must be diluted in 0.9% sodium chloride when administered via IV infusion. To ensure stability, the final concentration should not be less than 2mg iron/mL. Doses of 200-500mg are usually diluted in a maximum of 100mL, and doses of 500-1000mg are diluted in a maximum of 250mL.

Ferric derisomaltose (Monofer^®)

Ferric derisomaltose may also allow the total iron requirement to be given as a single dose. Up to 20mg of iron per kg body weight can be given at once, although single doses over 1,500mg are not recommended. If the total iron dose exceeds this, the dose can be split into two and given at least a week apart. Administration is also reasonably fast, with doses less than 1,000mg able to be given over 20 minutes and higher doses given over at least 30 minutes.

Ferric derisomaltose may be diluted in 0.9% sodium chloride. To ensure stability, it should not be diluted to less than 1mg iron/mL and never diluted in more than 500mL.

Ferric derisomaltose may also be given as an IV injection, either undiluted or diluted in up to 20mL of 0.9% sodium chloride.

Iron polymaltose (Ferrosig^®)

Iron polymaltose allows the total iron requirement to be given as a single dose. Up to 2,500mg can be given in 500mL of 0.9% sodium chloride.

A potential disadvantage of iron polymaltose is the longer infusion time. The product information recommends slow infusion (5-10 drops/minute) for the first 50mL, increased to 30 drops/minute if well tolerated. Therefore, an infusion may take around five hours, making this a very resource intensive option. However, there is some evidence to support a rapid infusion for doses up to 1,500mg.

Iron polymaltose is approved for intramuscular injection. However, this is not generally recommended as iron is poorly absorbed by this route, can be painful, and increases the risk of permanent skin staining.

Iron sucrose (Venofer^®)

Iron sucrose is indicated for use in patients undergoing chronic haemodialysis who are also receiving supplemental erythropoietin therapy. The recommended dose for these patients is 100mg of iron (one 5mL ampoule) given intravenously during the dialysis session up to three times per week. In most cases, patients require at least 1,000mg iron, which can be administered over ten consecutive dialysis sessions. Following this, dosing may continue at the lowest dose required to maintain target haemoglobin, haematocrit, and iron storage parameters.

Iron sucrose can be administered by intravenous drip infusion or by slow injection directly into the venous line of the dialysis machine. The solution is strongly alkaline and must not be administered by the intramuscular or subcutaneous route.

When given by infusion, the ampoules are diluted in 0.9% sodium chloride up to a maximum of 100mL. It is then infused at a rate of 100mg of iron over at least 15 minutes. When injected into the venous line of the dialysis machine, it can be used undiluted. An ampoule can be given over five minutes, i.e. 1mL (equivalent to 20mg iron) per minute.

Table 1. Summary of IV iron preparations

*Rates given per manufacturer’s recommendations. Local protocols may differ.

Adverse effects

Iron infusions are generally well tolerated but can cause minor adverse events such as headache and taste disturbance. The following adverse effects may also occur.

Flushing

Some patients may experience flushing or feel dizzy or light-headed during the first few minutes of the infusion. This is thought to be caused by unbound labile iron interacting with the endothelium. Preparing the infusion according to directions helps minimise this effect. Changes in pH and concentration during dilution can destabilise iron complexes, potentially increasing the amount of labile iron. Therefore, it is important not to dilute iron further than what is recommended.

These reactions may occur less frequently when the iron complex binds the elemental iron more strongly, as is the case with ferric carboxymaltose and ferric derisomaltose. Iron sucrose does not bind elemental iron as strongly and releases larger amounts of labile iron into the blood. Therefore, the maximum single dose is considerably lower for iron sucrose compared to the other IV iron salts.

If these effects occur, the infusion can be stopped until the symptoms subside and then restarted at a slower rate or as advised by the prescriber.

Skin staining

Iron can stain the skin if extravasation occurs during administration. This is not a common event; clinical trials have reported rates of 0.68% to 1.3%.

Skin discolouration that occurs as a result of iron can be long-lasting and potentially even permanent. Patients should be informed of the risk of skin staining prior to receiving an iron infusion and advised to report any adverse reactions during the infusion.

The general principles of minimising the risk of iron stains are to ensure that there is an appropriate indication for parenteral iron, ensure the correct injection site and administration technique is used, and monitor the patient closely for signs and symptoms of extravasation (e.g. pain, swelling, feelings of pressure at the infusion site). If extravasation occurs, the infusion should be stopped immediately to minimise the amount of solution entering the tissues and the prescriber contacted for assessment.

If skin staining occurs, it may be localised around the injection site or extend along the length of the arm. It is typically brownish in colour, but may also appear black, bluish, purple, or grey. While this discolouration is often permanent, it can fade with time. Some patients have also achieved good cosmetic results from laser therapy.

Hypersensitivity

All iron infusions can cause hypersensitivity, including anaphylactic and anaphylactoid reactions. Severe reactions have been reported, even in patients who tolerated a previous dose. Therefore, infusions should only be administered by staff trained in the management of anaphylaxis, and adrenaline should be on hand. The number of infusions administered to a patient should also be kept to a minimum. Severe reactions are rare. Studies suggest that the rate of anaphylaxis to currently used IV iron products is around 1 in 200,000.

It is recommended that patients be monitored during each infusion and for at least 30 minutes after.

Factors that may increase the risk of allergic reactions include a history of asthma, eczema, or other atopic allergy, or a previous allergic reaction to another parenteral iron preparation. The concomitant use of beta-blockers or angiotensin-converting enzyme (ACE) inhibitors may also increase the risk of hypersensitivity reactions. Beta-blockers include atenolol, bisoprolol, and metoprolol; ACE inhibitors include enalapril, perindopril, ramipril, and trandolapril.

Influenza-like symptoms

Patients should be advised that they may develop influenza-like symptoms a few days after their iron infusion. This may include body aches and raised temperature that typically subsides within 24-48 hours. These reactions are common, with some studies suggesting up to a third of patients may be affected to some degree. Patients should be reassured that this is not an allergic reaction.

Hypophosphataemia

Hypophosphataemia has been reported in patients receiving ferric carboxymaltose and ferric derisomaltose. This may be asymptomatic or present with fatigue, muscular weakness, bone pain, breathlessness, and tachycardia.

The incidence, severity and duration of this adverse effect is highest with ferric carboxymaltose. A large meta-analysis found a pooled incidence of 47% in patients treated with ferric carboxymaltose compared to 4% in patients receiving ferric derisomaltose. Only ferric carboxymaltose was associated with severe hypophosphataemia (11% of patients); evidence suggests that hypophosphataemia can persist for six months in around 5% of patients.

This adverse effect is related to an increased urinary excretion of phosphate. Patients with impaired renal function are at a significantly lower risk of developing this adverse effect. Patients at higher risk of this effect include those receiving multiple high doses who also have risk factors for hypophosphataemia (e.g. vitamin D deficiency, calcium and phosphate malabsorption, secondary hypoparathyroidism, inflammatory bowel disease, and osteoporosis).

Summary

There are four different formulations available for the intravenous administration of iron. The dosage and rate of administration are not interchangeable between these products. The product information provides dosing information, although local protocols may also be in place.

While intravenous iron is generally well tolerated, it is associated with serious adverse effects. Therefore, it is important that patients only receive intravenous iron when oral supplementation is inappropriate.