Joshua Strauss, MD
Advanced Care Oncology and Hematology Associates

Key Takeaways

  • Among the 3 widely used high-dose parental iron formulations, the risk for hypophosphatemia is significantly greater with ferric carboxymaltose than with ferumoxytol or ferric derisomaltose.
  • Patients receiving ferric carboxymaltose should have their serum phosphate levels monitored after treatment and take supplemental oral or intravenous phosphate as needed. These patients should also be monitored for clinical symptoms of low phosphate. 
  • For patients at high risk for hypophosphatemia, phosphate can also be monitored before repeat dosing of ferric carboxymaltose for iron repletion or switching to an alternate agent.

Joshua Strauss, MD, is a hematologist-oncologist with Advanced Care Hematology & Oncology Associates in New Jersey. His research focuses on gastrointestinal cancer, and his clinical areas of interest include anemia, hematology, colorectal cancer, gastrointestinal cancer, head and neck cancer, urologic cancer, leukemia, and lymphoma.

What formulations of parenteral iron are available and what are their respective risks for hypophosphatemia?

Several high-dose parenteral iron formulations are available for use, including ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. In the twin PHOSPHARE trials (ClinicalTrials.gov Identifiers: NCT03238911; NCT03237065), which compared ferric derisomaltose with ferric carboxymaltose with a primary endpoint of incidence of hypophosphatemia. In trial A (ClinicalTrials.gov Identifier: NCT03238911), the rates of hypophosphatemia were 7.9% in patients who received ferric derisomaltose vs 75.0% in patients who received ferric carboxymaltose. In trial B (ClinicalTrials.gov Identifier: NCT03237065), hypophosphatemia incidence was 8.1% in patients who received ferric derisomaltose vs 73.7% in patients who received ferric carboxymaltose. Overall, patients who received ferric derisomaltose had significantly less hypophosphatemia than did those who received ferric carboxymaltose.1
 
A post hoc analysis of data from a phase 3 clinical trial found that patients with cancer and concomitant anemia treated with ferric carboxymaltose experienced a significant decrease in serum phosphate, whereas patients treated with ferumoxytol did not.2 Overall, the risk for hypophosphatemia has been shown numerous times to be significantly higher with ferric carboxymaltose than with ferric derisomaltose or ferumoxytol.3


Ferric carboxymaltose adverse effects
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Adverse effects reported with ferric carboxymaltose include nausea, hypertension, flushing, injection site reaction, erythema, and hypophosphatemia.

In the PHOSPHARE trials and the HOMe aFers study (ClinicalTrials.gov Identifier: NCT02905539), the intravenous ferric derisomaltose resulted in a lower rate of treatment-associated hypophosphatemia compared with ferric carboxymaltose.1,4 Can you comment on risk for hypophosphatemia in adult patients receiving intravenous iron formulations?

Overall, ferric derisomaltose was associated with significantly less hypophosphatemia than was ferric carboxymaltose, which was also seen in the twin PHOSPHARE trials mentioned previously. 1

In the smaller HOMe aFers study,4 the results also showed that ferric carboxymaltose induced hypophosphatemia at a far greater rate than ferric derisomaltose (75% vs 8%). Overall, hypophosphatemia does not appear to be a class effect for high-dose parenteral iron. Rather, hypophosphatemia appears to be a risk specifically related to the use of ferric carboxymaltose.

Overall, hypophosphatemia does not appear to be a class effect for high-dose parenteral iron. Rather, hypophosphatemia appears to be a risk specifically related to the use of ferric carboxymaltose.

Are there any patient- and disease-related factors that should be considered when choosing an iron formulation to prevent hypophosphatemia?

Patients with borderline levels of serum phosphate at baseline or those who will require repeat dosing of parenteral iron may be most at risk for developing clinical sequelae related to hypophosphatemia from ferric carboxymaltose. Additionally, patients with cancer, who may already be at higher risk for hypophosphatemia because of bone metastasis or use of bone-modifying agents, may also be at increased risk. These patients may be better suited for treatment with an alternate product, such as ferumoxytol or ferric derisomaltose.

How are various iron replacement formulations administered in cases where patients are intolerant to oral therapy or experience a lack of efficacy with oral iron replacement?

If oral iron is ineffective or poorly tolerated, parenteral iron is a good way to replace iron stores. High-dose parenteral iron products — such as ferric carboxymaltose, ferric derisomaltose, and ferumoxytol — provide a convenient, effective, and safe way to replace iron in the outpatient setting in 1 to 2 doses. Low-dose parenteral iron, such as iron sucrose and ferric gluconate, are less expensive and equally effective ways to replace iron stores but are less convenient because they require more infusions.

Results of research show an association between intravenous ferric carboxymaltose and reduced mean serum phosphate levels in patients with cancer and concomitant anemia, whereas no such change was associated with ferumoxytol in this population.2 Why and how should clinicians monitor serum phosphate if intravenous ferric carboxymaltose is used in this setting?

As mentioned, these patients are most at risk for developing clinical sequelae related to hypophosphatemia and may already have a higher risk for hypophosphatemia because of bone metastasis or use of bone-modifying agents. Given these risks, if these patients receive ferric carboxymaltose, their serum phosphate levels should be monitored after treatment and phosphate repletion should be done as needed. Treatment is guided by the severity of the hypophosphatemia. Most patients with hypophosphatemia will require oral or intravenous replacement. These patients should also be monitored for clinical symptoms of low phosphate, such as generalized weakness and fatigue.


Current single-dose parenteral iron formulations for iron deficiency
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Single-dose parenteral iron formulations for iron deficiency include ferric derisomaltose, ferumoxytol, and low-molecular-weight iron dextran.

What role does monitoring play in patients at high risk for iron-induced hypophosphatemia?

In patients at high risk for iron-induced hypophosphatemia, clinicians can monitor their patients’ serum phosphate levels after treatment with ferric carboxymaltose so that phosphate repletion can be done if it is indeed low. Phosphate can also be monitored before repeat dosing of ferric carboxymaltose for the sake of repletion or switching to an alternate agent. These high-risk patients should also be monitored for clinical symptoms of low phosphate if they receive ferric carboxymaltose. I do not typically monitor phosphate levels in patients who receive non-ferric carboxymaltose parenteral iron.

This Q&A was edited for clarity and length.

Disclosures

Joshua Strauss, MD, reported affiliations with AbbVie Inc.; AstraZeneca Pharmaceuticals, LP; BeiGene, Ltd; Exelixis, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Incyte Corporation; Jazz Pharmaceuticals, Inc.; Pharmacosmos Therapeutics Inc.; and Servier Pharmaceuticals LLC.

References

1. Wolf M, Rubin J, Achebe M, et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials. JAMA. 2020;323(5):432-443. doi:10.1001/jama.2019.22450
 
2. Boccia RV, Dahl NV, Strauss WE. Severe hypophosphatemia in patients with cancer following IV iron treatment: results from a large comparative trial. Blood. 2019;134(suppl 1):2236. doi:10.1182/blood-2019-126149
 
3. Glaspy JA, Lim-Watson MZ, Libre MA, et al. Hypophosphatemia associated with intravenous iron therapies for iron deficiency anemia: a systematic literature review. Ther Clin Risk Manag. 2020;16:245-259. doi:10.2147/TCRM.S243462
 
4. Emrich IE, Lizzi F, Siegel JD, et al. Hypophosphatemia after high-dose iron repletion with ferric carboxymaltose and ferric derisomaltose-the randomized controlled HOMe aFers study. BMC Med. 2020;18(1):178. doi:10.1186/s12916-020-01643-5

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Reviewed October 2022