Ferric carboxymaltose (Ferinject▼): risk of symptomatic hypophosphataemia leading to osteomalacia and fractures
Monitor serum phosphate levels in patients treated with multiple high-dose administrations, or those on long-term treatment, and in those with pre-existing risk factors for hypophosphataemia. Re-evaluate ferric carboxymaltose treatment in patients with persistent hypophosphataemia.
Advice for healthcare professionals:
- ferric carboxymaltose is known to be commonly associated with hypophosphatemia
- cases have been reported of symptomatic hypophosphataemia leading to infrequent reports of hypophosphataemic osteomalacia and fractures in patients with existing risk factors and following prolonged exposure to high doses – some cases required clinical intervention, including surgery
- monitor serum phosphate levels in patients:
- requiring multiple administrations of ferric carboxymaltose at higher doses
- on long-term treatment with ferric carboxymaltose
- with pre-existing risk factors for hypophosphataemia such as vitamin D deficiency, calcium and phosphate malabsorption, secondary hyperparathyroidism, inflammatory bowel disease, and osteoporosis
- advise patients to seek medical advice if they experience symptoms indicative of hypophosphataemia, including new musculoskeletal symptoms or worsening of tiredness – be aware these symptoms may be confused with those of iron deficiency anaemia
- if hypophosphataemia persists, re-evaluate treatment with ferric carboxymaltose
- report all suspected adverse drug reactions to ferric carboxymaltose to the Yellow Card scheme without delay
Review of risk of hypophosphataemia and osteomalacia
Ferric carboxymaltose (Ferinject▼) is indicated for the treatment of iron deficiency when oral iron preparations are ineffective or cannot be used and there is a clinical need to deliver iron rapidly.
Ferinject has been associated with common cases of hypophosphatemia (low blood phosphate).
A recent European review concluded that ferric carboxymaltose is associated with hypophosphataemic osteomalacia (inadequate mineralisation of the bone matrix leading to softening of the bones). The review recommended strengthened advice to make healthcare professionals aware that osteomalacia can be a consequence of hypophosphataemia and to ensure early detection and effective management of hypophosphataemic osteomalacia.
Based on the available data, it is difficult to estimate the magnitude of the risk of hypophosphataemic osteomalacia with ferric carboxymaltose, therefore the risk of this adverse reaction is included in the product information with a frequency category of not known.
Cases of osteomalacia in post-marketing use
As of 14 February 2020, the review considered 36 spontaneous cases worldwide in patients with concurrent hypophosphataemia associated with ferric carboxymaltose. Osteomalacia was reported in 28 cases and hypophosphataemic osteomalacia in 6 cases, with 2 cases reporting both terms. As of February 2020, the worldwide estimated exposure to ferric carboxymaltose was estimated to be 12,491,000 patient-years (168,632,771 defined daily doses).[footnote 1]
In most cases (30 [83%]) hypophosphataemia was reported as medically significant (moderate to severe) using a phosphate cut-off of lower than 2.0 milligram per decilitre.
Where reported the patient age was 26–39 years in 8 cases, 40–56 years in 12 cases, 57–68 years in 4 cases, and 73–81 years in 3 cases.
Where dosing information was reported, 13 patients had been given doses of 1000mg per infusion of ferric carboxymaltose for an average of 19 infusions over a period of 5–24 months. The time to onset of osteomalacia after starting treatment with ferric carboxymaltose at 1000mg dose was reported in 6 cases and ranged from 3 months to 5 years (median 14.5 months).
Of the 36 cases, 24 cases reported one or more reliable diagnostic criteria for osteomalacia: alkaline phosphatase (12 cases), parathyroid hormone (12 cases), magnetic resonance imagery (11 cases), bone scan (5 cases), bone biopsy (3 cases), and bone densitometry (2 cases).
All 36 cases presented with one or more risk factors for osteomalacia, namely inflammatory bowel disease (14 cases), vitamin D deficiency (9 cases), osteoporosis (8 cases), malabsorption (6 cases), Rendu-Osler disease (6 cases), hyperparathyroidism (6 cases), long-term steroid use (6 cases), and chronic use of antacid therapies (3 cases).
Approximately half of the patients (19 of 36; 53%) developed one or more fractures (where reported, femoral neck fracture or pelvic or hip fracture) in conjunction with osteomalacia.
Where reported, the outcome for the patient was recovered in 7 cases and recovering in 9 cases. The patients were treated with phosphate, calcium and/or vitamin D supplements. Where required, surgical treatment was provided for fractures.
In the UK up to 22 October 2020, we have received 28 Yellow Card reports of hypophosphataemia and 2 reporting cases of hypophosphataemic osteomalacia with Ferinject. These UK cases were considered as part of the EU review.
Mechanisms and risk with other irons
Intravenous iron products are indicated for the treatment of iron deficiency and anaemia when oral iron supplements cannot be given or have not worked.
Hypophosphataemia (of uncommon frequency) is a listed adverse effect in association with Monofer▼ (iron isomaltoside, now known as ferric derisomaltose) - .
Up to 1 January 2020, although cases have been reported of hypophosphatemia (including some serious cases), we are not aware of any cases reported of hypophosphataemic osteomalacia in association with ferric derisomaltose worldwide. As of February 2020, ferric derisomaltose has a worldwide exposure of 3,216,000 patient-years (based on a defined daily dose of 100mg iron equivalent).[footnote 2] Up to 22 October 2020, the Yellow Card scheme has received 2 reports of hypophosphataemia with Monofer and we are not aware of any cases of osteomalacia.
The risk of persistent hypophosphatemia and osteomalacia may be higher with ferric carboxymaltose than with other intravenous iron formulations. A key mechanism postulated is that the carbohydrate moieties in ferric carboxymaltose may disproportionately inhibit degradation of fibroblast growth factor 23 (FGF23),[footnote 3] [footnote 4] which can result in increased FGF23 activity and ultimately greater renal phosphate wasting.[footnote 5]
Report any suspected adverse reactions
Intravenous iron medicines are black triangle medicines (▼) and any suspected adverse drug reactions (ADRs) should be reported to the Yellow Card scheme.
Reporting suspected ADRs, even those known to occur, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
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the Yellow Card app; download from the Apple App Store or Google Play Store
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some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting please provide as much information as possible, including information about medical history, any concomitant medication, onset, treatment dates, and product brand name.
Article citation: Drug Safety Update volume 14, issue 4: November 2020: 3.
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Exposure data provided to the MHRA by the Marketing Authorisation Holder. November 2020 ↩
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Exposure data provided to the MHRA by the Marketing Authorisation Holder. November 2020. ↩
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Wolf M and others. ‘Effects of iron deficiency anaemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women’. Journal of Bone and Mineral Research 2013: volume 28, pages 1793–803. ↩
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Wolf M and others. ‘Coupling FGF23 Production and Cleavage: Iron Deficiency, Rickets and Kidney Disease’. Current Opinion in Nephrology and Hypertension 2014; volume 23, pages 411–19. ↩
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Fang W and others. ‘Symptomatic severe hypophosphatemia after intravenous ferric carboxymaltose’. JGH Open 2019: volume 3, pages 438–40. ↩
Updates to this page
Published 16 November 2020Last updated 16 November 2020 + show all updates
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Added to DSU November
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First published.