Medicines and Healthcare products Regulatory Agency (MHRA) announces that the risk of symptomatic hypophosphataemia leading to osteomalacia and fractures associated with the use of ferric carboxymaltose.
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.
As of 14 Feb 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 Feb 2020, the worldwide estimated exposure to ferric carboxymaltose was estimated to be 12,491,000 patient-years (168,632,771 defined daily doses). 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 United Kingdom up to 22 Oct 2020, MHRA has received 28 Yellow Card reports of hypophosphataemia and 2 reporting cases of hypophosphataemic osteomalacia with Ferinject. These cases in the United Kingdom were considered as part of the European review.
Hypophosphataemia (of uncommon frequency) is a listed adverse effect in association with Monofer▼ (iron isomaltoside, now known as ferric derisomaltose). Up to 1 Jan 2020, although cases have been reported of hypophosphatemia (including some serious cases), MHRA is not aware of any cases reported of hypophosphataemic osteomalacia in association with ferric derisomaltose worldwide. As of Feb 2020, ferric derisomaltose has a worldwide exposure of 3,216,000 patient-years (based on a defined daily dose of 100mg iron equivalent). Up to 22 Oct 2020, the Yellow Card scheme has received 2 reports of hypophosphataemia with Monofer and MHRA is 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), which can result in increased FGF23 activity and ultimately greater renal phosphate wasting.
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; and 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.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/ferric-carboxymaltose-ferinject-risk-of-symptomatic-hypophosphataemia-leading-to-osteomalacia-and-fractures
In Hong Kong, Ferinject Solution For Injection/Infusion 100mg/2ml (HK-64137) and Ferinject Solution For Injection/Infusion 500mg/10ml (HK-64138) are pharmaceutical products containing ferric carboxymaltose. These products are registered by Zuellig Pharma Ltd, and are prescription-only medicines. So far, the Department of Health (DH) has not received any case of adverse drug reaction related to ferric carboxymaltose.
Related news on the risk of hypophosphataemia associated with the use of ferric carboxymaltose was previously issued by Australia Therapeutic Goods Adminstration (TGA), and was posted on the Drug Office website on 28 Feb 2020. Letters to inform local healthcare professionals were issued by the DH on 28 Feb 2020. In light of the above MHRA’s announcement regarding the risk of hypophosphataemic osteomalacia and fractures, the matter together with the safety information issued previously by TGA, will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Tuesday, Nov 17, 2020
Issued at HKT 16:00
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