Published: 13 December 2018

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Infusing Iron? Consider Phosphate

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Prescriber Update 39(4): 54–55
December 2018

Background

Ferric carboxymaltose is a parenterally-administered iron preparation. Some patients may develop hypophosphatemia following its administration. In many cases the hypophosphatemia is mild, transient and asymptomatic.

More severe or prolonged cases may be associated with muscle weakness, pain, altered mental status and osteomalacia^1,2.

New Zealand reports

The Centre for Adverse Reactions Monitoring (CARM) has received five case reports of hypophosphatemia in association with parenteral iron treatment, reported between February 2016 and April 2018. All five cases reported ferric carboxymaltose as the suspect medicine, at a dose of 1,000 mg. All patients recovered after treatment with ferric carboxymaltose was stopped. Four of the patients had pre-existing renal disease (Table 1).

Table 1: Cases of hypophosphatemia associated with ferric carboxymaltose reported to the Centre for Adverse Reactions Monitoring between February 2016 and April 2018

CARM ID	Gender/Age	Duration of therapy	Time to onset (days)	Severity
119469	F 75	1 day	8 days	Severe
120170	F 39	1 day	7 days	Severe
126269	F 50	1 day	15 days	Not severe
127938	M 62	Every 3 months for 31 months	18 days	Severe
127939	F 44	1 day	32 days	Severe

Published cases

Symptomatic hypophosphatemia associated with the use of ferric carboxymaltose has been reported in the literature^3,4. Symptoms included vertigo, nausea, general weakness, tingling in the hands and depression-like symptoms. The authors highlight the importance of measuring pre-existing serum phosphate levels and renal function to evaluate the risk of developing hypophosphatemia, and continuing to monitor phosphate after the administration of ferric carboxymaltose.

Suggested mechanism

The mechanism for hypophosphatemia in relation to ferric carboxymaltose is unclear, however, the regulatory protein fibroblast growth factor 23 (FGF23) is believed to be involved^3,4,5. FGF23 is secreted by osteocytes and acts to increase the loss of phosphate through the kidneys. Administration of ferric carboxymaltose increases the amount of biologically active FGF23, thereby increasing renal phosphate losses³ .

Product information

Ferinject is the only ferric carboxymaltose product available in New Zealand. Hypophosphatemia is currently listed as a common adverse reaction in the Ferinject data sheet⁶ . Medsafe is working with the sponsor to include more information about hypophosphatemia in the data sheet.

Two other parenteral iron products are currently available in New Zealand. The data sheets for Venofer (iron sucrose)⁷ and Ferrum H (iron polymaltose)⁸ do not list hypophosphatemia as a possible adverse reaction.

A higher dose of iron can be administered over a shorter period of time with Ferinject, compared to the other parenteral iron products.

Management

Although mild hypophosphatemia after iron infusion is common and transient, symptomatic hypophosphatemia appears to be rare. Clinicians should remain alert to the possibility of hypophosphatemia after treatment with ferric carboxymaltose, particularly if patients present with symptoms such as weakness, bone pain, or a change in mental state⁹. In such patients, serum phosphate should be measured and hypophosphatemia corrected⁹. Consideration should also be given to the use of alternative parenteral iron products in patients who have risk factors for or a history of hypophosphatemia.

References

1. Schaefer B, Würtinger P, Finkenstedt A, et al. 2016. Choice of high-dose intravenous iron preparation determines hypophosphatemia risk. PLoS One 11(12): e0167146. URL: www.ncbi.nlm.nih.gov/pmc/articles/PMC5131956/pdf/pone.0167146.pdf (accessed 9 October 2018).
2. Yu ASL, Stubbs JR. 2018. Signs and symptoms of hyphosphatemia. In: UpToDate 9 March 2018. URL: www.uptodate.com/contents/signs-and-symptoms-of-hypophosphatemia (accessed 29 October 2018).
3. Anand G, Schmid C. 2017. Severe hypophosphataemia after intravenous iron administration. BMJ Case Reports (March 2017): bcr2016219160. URL: www.ncbi.nlm.nih.gov/pmc/articles/PMC5353490/pdf/bcr-2016-219160.pdf (accessed 9 October 2018).
4. Blazevic A, Hunze J, Boots JM. 2014. Severe hypophosphatemia after intravenous iron administration. Neth J Med. 72(1): 49–53. URL: www.njmonline.nl/getpdf.php?id=1406 (accessed 9 October 2018).
5. Zoller H, Schaefer B, Glodny B. 2017. Iron-induced hypophosphatemia: an emerging complication. Current Opinion in Nephrology and Hypertension 26(4): 266–75. DOI: 1097/MNH.0000000000000329 (accessed 29 October 2018).
6. Pharmacy Retailing (NZ) Ltd. 2016. Ferinject New Zealand Data Sheet 6 June 2016. URL: www.medsafe.govt.nz/profs/Datasheet/f/ferinjectinj.pdf (accessed 9 October 2018).
7. Pharmacy Retailing (NZ) Ltd. 2016. Venofer New Zealand Data Sheet 4 April 2016. URL: www.medsafe.govt.nz/profs/Datasheet/v/venoferinf.pdf (accessed 9 October 2018).
8. Pharmacy Retailing (NZ) Ltd. 2014. Ferrum H New Zealand Data Sheet February 2014. URL: www.medsafe.govt.nz/profs/Datasheet/f/FerrumHinj.pdf (accessed 9 October 2018).
9. BPAC NZ. 2017. Intravenous ferric carboxymaltose: now available for the treatment of iron deficiency. URL: https://bpac.org.nz/2017/docs/iron.pdf (accessed 23 October 2018).