Injectafer, an injectable iron replacement product, has been linked in clinical studies with a condition called “hypophosphatemia” (HPP). What is this condition, and is it serious?

Hypophosphatemia Linked with Injectafer

Several studies have found that Injectafer (ferric carboxymaltose or FCM), when used to treat patients with iron deficiency anemia (IDA), can increase the risk of hypophosphatemia (HPP). This is a condition in which the body becomes deficient in phosphate, an important nutrient for a number of bodily functions.

When we consume phosphorus in foods like meat, dairy, beans, lentils, and nuts, the body absorbs the phosphorus, combines it with oxygen, and produces phosphate. The body then uses that phosphate to produce energy, build bones and teeth, regulate pH levels, and to make up DNA.

Without enough phosphate, the body can’t carry on some of its most essential functions. Though mild levels of phosphate deficiency are unlikely to cause symptoms, moderate levels may cause symptoms like the following:

  • Generalized muscle weakness
  • Fatigue
  • Irritability
  • Confusion

Symptoms at mild and moderate levels are often nonspecific, however, and may be detected only if doctors are monitoring phosphate levels. Treatment involves phosphate supplementation.

Severe Hypophosphatemia, a More Dangerous Condition

When HPP becomes severe, symptoms get a lot more serious. This occurs when blood phosphate levels in adults drop below 2.5 mg/dL, with the most severe at levels below 1.5 mg/dL. Symptoms may include:

  • Pins and needles feeling
  • Slurred speech
  • Seizures
  • Nerve pain
  • Bone pain
  • Acute muscle pain or muscle wasting
  • Respiratory failure
  • Enlarged heart or heart failure
  • Abnormal heart rhythms
  • Death

Treatment for moderate HPP generally includes oral phosphate supplements given over a period of 7-10 days. Treatment for severe HPP usually includes intravenous (IV) administration of phosphate over a period of about six hours. Treatment has its own risks, so patients have to be watched closely.

What Causes Severe Hypophosphatemia?

There are a number of things that can cause HPP. These include:

  • Poor phosphorus absorption
  • Inflammatory bowel diseases
  • Severe malnutrition
  • Vitamin D deficiency
  • Kidney dysfunction
  • Thyroid disorders
  • Alcoholism
  • Rickets
  • Poorly controlled diabetes
  • Some medications, including antacids and diuretics

In some cases, Injectafer may also cause severe HPP.

Injectafer Linked with Severe Hypophosphatemia

In 2017, scientists called iron-induced HPP “an emerging complication.” They looked at several clinical trials, and found that the highest risk of developing HPP was associated with three types of iron:

  • Ferric carboxymaltose (FCM, the iron in Injectafer)
  • Iron polymaltose
  • Saccharated iron oxide

Why would this happen? Scientists aren’t sure, but they believe that some forms of iron such as those listed above encourage the kidneys to flush away more phosphate. That’s one of the reasons why Injectafer is indicated for patients who have non-dialysis chronic kidney disease—reduced kidney function reduces risk of the kidneys flushing away too much phosphate. Therefore, the risk of HPP goes down in these patients.

What might cause the kidneys to get rid of more phosphate? Certain types of iron, like FCM, inhibit a type of hormone called “FGF-23 (fibroblast growth factor 23).” As noted in a 2013 study, this hormone regulates phosphate and vitamin D levels in the body by reducing phosphate when needed. It seems that certain IV iron preparations like FCM increase levels of this hormone in the body, which causes a depletion in phosphate. In other words, the more FGF-23, the less phosphate.

The scientists tested treatment with FCM against treatment with another form of iron called “iron dextran” in 55 women. They found that within 24 hours of administration, levels of FGF-23 increased only in those treated with FCM, and was followed by a reduction in blood levels of phosphate in 10 of the women in the FCM group, and none of those in the iron dextran group.

In an earlier study, scientists looked at the medical records from patients who were treated either with the iron in Injectafer (FCM) or the iron in a comparable product, Monofer (IIM). The risk of HPP was substantially greater after FCM (45.5 percent) compared with IIM (4 percent). Severe HPP occurred only after treatment with FCM (32.7 percent).

How long did it take for the HPP to develop? The median time was 41 days, but in some patients, it took as long as nearly two months. The scientists noted that a “significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation.” In other words, the FCM altered hormone function, thereby increasing the risk of HPP.

The researchers noted that HPP risk “appears to be substantially lower with IIM.” They also stated in their introduction to the study that after excluding patients with chronic kidney disease, “the reported incidence of hypophosphatemia after FCM treatment is 41-70%, as compared to 5-8% after IIM treatment.”

Injectafer Side Effects Can Have Severe Consequences

Other studies have shown similar results, connecting FCM to HPP. In 2015, scientists looked at medical records for patients who received iron injections between 2012 and 2014. Among 130 patients included in the study, 52 received iron sucrose (FS), and 78 received FCM. Among those receiving FS, 22 percent developed HPP, versus 51 percent for FCM-treated patients, including 13 percent who developed profound or severe HPP.

The researchers concluded that HPP was “frequent after parenteral FCM injection” and that more studies were needed to determine the long-term consequences.

In yet another study, researchers looked at data from 231 patients treated with IV iron infusions between 2011 and 2014. They found more HPP events when patients received FCM as opposed to isomaltoside, noting the “most marked decrease” in phosphate occurring with FCM.

A group of Austrian doctors submitted a letter to the editor, published in the journal Alimentary Pharmacology & Therapeutics in 2017, in which they stated that study results so far suggest that HPP occurs more frequently than it is reported, and has “indeed been described to occur in up to 70 percent of patients treated with ferric carboxymaltose [FCM].” The doctors added that while the condition is considered a “transient” event (meaning that it will pass), it “can have severe and debilitating consequences.”

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