Hypophosphatemia Following IV Iron Administration: An Emerging Safety Concern
By Courtney Lamontagne, BSN, RN, OCN®, and Chelsea Backler, MSN, APRN, AGCNS-BC, AOCNS®, VA-BC
Used since the early 20th century to treat iron-deficiency anemia (https://www.nhlbi.nih.gov/health/anemia/iron-deficiency-anemia) for a wide range of patient populations and therapeutic indications (e.g., oncology conditions, nephrology, women’s health), IV iron formulations have become safer over time. However, emerging data (https://doi.org/10.1080/14740338.2021.1912010) have identified post-infusion hypophosphatemia as a safety concern.
Incidence, Risk Factors, and Early Diagnosis
The greatest risk is associated with ferric carboxymaltose (FCM), with several studies reporting (https://doi.org/10.1001/jama.2019.22450) that more than 70% of patients (https://doi.org/10.1186/s12916-020-01643-5) experienced hypophosphatemia in two to five weeks (https://doi.org/10.1080/14740338.2021.1912010) after administration. Symptomatic hypophosphatemia can occur (https://doi.org/10.1007/s12325-021-01770-2) after just a single dose of FCM, according to case reports. In comparison, the risk of hypophosphatemia following ferric deisomaltose (FDI) (https://doi.org/10.1080/14740338.2021.1912010) or ferumoxytol (FER) (https://doi.org/10.1002/ajh.27220) is significantly lower (less than 10%).
Mild to moderate hypophosphatemia can be asymptomatic and self-limiting. The most common symptom is mild to moderate generalized weakness, which often mirrors the primary symptom of iron-deficiency anemia, making it even more challenging to assess. More severe symptoms include altered mental status, seizures, and muscle weakness and pain. Severe or chronic hypophosphatemia can cause (https://doi.org/10.1001/jama.2019.22450) complications such as heart failure, respiratory failure, rhabdomyolysis, osteomalacia, and fractures. Advise patients to contact their care team if they experience worsening fatigue with myalgias or bone pain (https://doi.org/10.1002/ajh.27220).
The Science Behind the Adverse Event
FCM has been shown to increase intact fibroblast growth factor-23 (iFGF23), the main regulator of phosphate concentration in plasma. Increased levels of iFGF23 result in (https://doi.org/10.1080/14740338.2021.1912010) reductions of 1,25-dihydroxyvitamin D, hypocalcemia, and the development of secondary hyperparathyroidism, which maintains the elevated phosphate secretion even after iFGF23 levels return to normal.
Hypophosphatemia is classified as mild (with phosphate levels less than lower limit of normal to 2.5 mg/dl), moderate (less than 2.5–2 mg/dl), severe (less than 2–1 mg/dl) or potentially life-threatening (less than 1 mg/dl). Treatment-emergent hypophosphatemia’s onset is within two weeks (https://doi.org/10.1002/ajh.27220) of iron administration, but hypophosphatemia can also be prolonged, presenting up to six months following administration.
The Oncology Nurse’s Role in Hypophosphatemia
Identifying patients at risk is the best way to optimize outcomes. Patients who are experiencing recurrent blood loss (e.g., abnormal uterine bleeding, gastrointestinal bleeding) and iron malabsorption (e.g., bariatric surgery, celiac disease, inflammatory bowel disease) that necessitate repeated infusions are at greatest risk. Patients with (https://doi.org/10.1002/ajh.27220) lower body weight, low baseline serum phosphate, higher serum parathyroid hormone levels—and, although it seems counterintuitive, normal renal function (phosphorus excretion is correlated to higher glomerular filtration rate [GFR], so patients with reduced GFR because of kidney dysfunction that filters less phosphate and limits the amount excreted in the urine may appear to have normal renal function in the presence of hypophosphatemia)—are at increased risk.
Universally monitoring phosphorus levels following iron infusions is not currently recommended (https://doi.org/10.1002/ajh.27220). However, FCM’s prescribing information recommends (https://injectaferhcp.com/iron-injection-administration) assessing baseline serum phosphate levels prior to repeat infusions in patients who are at increased risk for hypophosphatemia or are receiving a second infusion within three months, correcting preexisting hypophosphatemia prior to initiating therapy, and monitoring phosphate levels in patients who are at risk for chronic low serum phosphate.
There is no standard of care for the management of treatment-emergent hypophosphatemia because it is refractory to phosphate supplementation. Vitamin D supplementation can aid in mitigating secondary hyperparathyroidism, but FCM cessation may be (https://doi.org/10.1002/ajh.27220) the most effective management approach.