Updates on Iron Deficiency: Gastroenterology article 2

Ferric carboxymaltose linked to higher incidence of hypophosphataemia

Anaemia has been acknowledged as a frequent systemic complication and/or extraintestinal manifestation in inflammatory bowel disease (IBD)¹ with iron deficiency (ID) being the primary cause of disease² with an estimated prevalence of iron deficiency anaemia (IDA) among patients with IBD at approximately 45 %.³ 

Considering the potential effect on hospitalization rates and consequences for patients quality of life, anaemia has been described as a significant and costly complication of IBD.⁴ However, ID and IDA are under-treated.⁵

The PHOSPHARE-IBD study is the first randomized double-blind clinical trial to compare the incidence of hypophosphataemia after treating inflammatory bowel disease (IBD) patients diagnosed with Iron deficiency anaemia (IDA) with intravenous irons; FCM¹ or FDI^2,3 The results substantiate previous findings showing that patients assigned to receive FCM¹ had a significantly higher incidence of hypophosphataemia compared to certain other iv iron compounds.^4–6

Hypophosphatemia: A challenging adverse effect

Even when IBD patients are screened, ID and IDA might be overlooked as commonly used laboratory tests may be compromised due to several pathophysiological mechanisms related to the inflammatory nature of IBD⁹ 

Consequently, when evaluating ID and IDA in IBD the following mechanisms should be taken into consideration: 

Hemoglobin: Iron deficiency should not be excluded despite normal Hb as Hb levels do not decline until a significant amount of iron is lost.¹⁰ 

• Iron deficiency without anaemia is possible in cases with normal Hb levels in the lower limit of normality, a low MHC, or an increase in RDW.¹⁰ 

Ferritin: Besides binding and storing iron in the liver, spleen, and reticuloendothelial system ferritin is also an acute-phase protein and can be increased in the presence of inflammation.¹¹ Following, the interpretation of serum ferritin in patients with inflammation is tricky.⁵ 

• In patients without clinical, endoscopic, or biochemical evidence of active disease, serum ferritin <30 μg/L is indicative of IDA. With concomitant inflammation, such as elevated serum C reactive protein, ferritin up to 100 ug/L may still be consistent with iron deficiency⁸ 

Hepcidin and ferroportin: The hepatic peptide hormone hepcidin functions as an important regulator of iron homeostasis by controlling ferroportin – the sole iron exporter. However, hepcidin also increases as a response to inflammation.¹³ The increased levels of hepcidin caused by inflammation will promote the degradation of ferroportin and subsequently impair the exportation of cellular iron into plasma.¹³ 

• Despite normal or high levels of serum ferritin, hepcidin might compromise iron uptake as it inhibits the iron flow from the cell to the bloodstream.¹³ 

Transferrin saturation: The main iron carrier protein is transferrin.⁶ In the presence of inflammation, a normal ferritin level does not exclude ID.¹⁴ In this case, testing TSAT provides an indication of the extent of iron utilization.¹⁰ 

• Absolute ID can be defined as a combination of ferritin <100 μg/L and a TSAT <20% whereas functional ID is defined as a ferritin level >100 μg/L and a TSAT <20%.¹⁰ 

Soluble transferrin saturation receptor: The TSAT level only indicates the extent of iron utilization.⁴ A more extensive workup should include soluble transferrin receptor (sTfR) testing.⁸ sTfR is a truncated form of the cellular transferrin receptor and circulates bound to transferrin.¹⁰ It is released in proportion to the expansion of erythropoiesis in the bone marrow and is not regulated by inflammation.⁵ As a reflector of erythropoiesis, sTfR correlates with the amount of iron available. 

• Increased sTfR is consistent with all cases of functional iron deficiency, its extent being entirely independent of chronic inflammation or hepatic damage⁴ – Hence, it is a reliable indicator of iron deficiency.¹⁵

Hypophosphatemia is characterized by low levels of phosphate in the blood. The divergence between FCM¹ and FDI² arises due to FCM¹ and FDI²’s different effects on fibroblast growth factor 23 (FGF23) affecting phosphate regulation.³ This occurs through the stimulation of renal phosphate excretion and downstream effects on 1,25-dihydroxy vitamin D and parathyroid hormone (PTH) that maintain hypophosphataemia.³

Symptoms of hypophosphataemia can be mild and are relatively non-specific, such as fatigue, which makes them challenging to differentiate from similar symptoms associated with IDA and IBD.⁷ However, the consequences of hypophosphatemia can extend beyond low phosphate levels with reports of complications such as severe muscle weakness and alterations in mineral and bone metabolism that can result in osteomalacia and fractures.⁸

PHOSPHARE-IBD further investigates hypophosphataemia related to FCM and FDI

The PHOSPHARE-IBD trial was conducted at 20 outpatient hospital clinics in Europe with a scope to explore the following endpoints:³ 

• Primary endpoint: incidence of hypophosphataemia (serum phosphate <2.0 mg/dL (<0.65 mmol/l)) at any time from baseline to Day 35 after all patients had received 1000 mg of either iron formulation^1,2, regardless of the degree of their iron deficiency.³
• Secondary endpoints: The study employed several secondary safety, exploratory, and efficacy endpoints. Including biomarkers of mineral and bone homeostasis, and patient-reported fatigue scores.³ 

Adults with IBD and IDA (haemoglobin (Hb) <130 g/L and serum ferritin ≤100 μg/L ) were randomized 1:1 to receive either FCM¹ or FDI² treatment.³ A total of 156 patients were screened and 97 (48 FDI², 49 FCM¹) were included to receive either one dose of FCM¹ or FDI² using identical haemoglobin- and weight-based dosing regimens at baseline and at Day 35.³

FCM displays a significant increase in hypophosphataemia compared to FDI

Exploring the primary endpoint using the safety analysis set (all patients who received at least one dose of the study drug) revealed comparable effects on haemoglobin (Hb) and iron stores after receiving either FCM¹ or FDI².³ On the contrary, hypophosphatemia (serum phosphate <2.0 mg/ dL (<0.65 mmol/l)) occurred in:³ 

• 3% of patients treated with FDI² 
• 0% of patients treated with FCM¹

(Figure 1)

When compared with FDI², FCM¹ treatment was associated with more pronounced changes in biomarkers showing increases in intact FGF23 and renal phosphate excretion, and PTH, and decreases in 1,25-dihydroxyvitamin D all related to an increased risk of hypophosphatemia.³ 

Analysis of patient-reported fatigue scores using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale was carried out within the intention-to-treat (ITT) population.³ The analysis aimed to explore the hypothesis of a potential relationship between phosphate level and fatigue.³ Results showed improved scores in both treatment groups. However, it is noteworthy that: 

• Improvement in patients treated with FDI² was faster and more substantial compared to those receiving FCM¹. Moreover, slower improvement in fatigue correlated with more severe hypophosphataemia (figure 2).³

Despite recovering from hypophosphataemia following their initial treatment, patients treated with FCM¹ still experienced prolonged biochemical changes linked to elevated FGF expression.³ Specifically, bone-specific ALP remained elevated on Day 70 and beyond implying a sustained impact on bone turnover.³

Shaping future treatment approaches

Based on the study design the results from the PHOSPHARE-IBD trial indicate that differences in hypophosphataemia are not a class or dose effect of IV iron or due to dosing, schedule, or patient factors but solely an adverse effect of FCM¹ driven by increases in FGF23.³ 

Furthermore, the discovery of significant differences in patient-reported fatigue and the link to hypophosphataemia severity offers valuable insights that advance the field.³ This information could assist in guiding future treatments by informing clinicians and patients about the short-term effects of hypophosphataemia on quality of life and the risk of long-term effects on mineral and bone metabolism increasing the risk of osteomalacia and fractures.³

Disclaimer
Despite the dramatically different effects on plasma phosphate homeostasis, FDI² and FCM¹ treatment have both been consistently shown to improve quality of life in patients with iron deficiency. The present trial confirms that both formulations effectively corrected IDA, as evidenced by almost identical Hb responses leading to a rise of 20–30 g/L in both groups as well as correction of serum iron parameters.³

References

1. Vifor Pharma. Ferinject (ferric carboxymaltose) 50 mg iron/mL dispersion for injection/infusion - Summary of Product Characteristics (SmPC) - (emc) [Internet]. [cited 2023 Nov 5]. Available from: https://www.medicines.org.uk/emc/product/5910/smpc
2. Pharmacosmos. Ferric derisomaltose Pharmacosmos 100 mg/ml solution for injection/infusion - Summary of Product Characteristics (SmPC) - (emc) [Internet]. [cited 2023 Nov 5]. Available from: https://www.medicines.org.uk/emc/product/5676/smpc
3. Zoller H, Wolf M, Blumenstein I, et al. Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial. Gut. 2023 Apr;72(4):644–653.
4. Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013 Aug;28(8):1793–803.
5. Wolf M, Chertow GM, Macdougall IC, et al. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight. 2018 Dec 6;3(23):e124486.
6. 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 Feb 4;323(5):432–43.
7. Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens. 2017 Jul;26(4):266–275.
8. Schaefer B, Tobiasch M, Viveiros A, et al. Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside-a systematic review and meta-analysis. Br J Clin Pharmacol. 2021 May;87(5):2256–2273.

Monofer®, järn(III)derisomaltos, Rx, F (subventioneras inte för patienter i hemodialys)

ATC: B03AC. Trevärt järn, parenteralt preparat. Injektions-/infusionsvätska 100 mg/ml. Injektionsflaska i förpackningsstorlekar: 1x5 ml, 1x10 ml, 5x1 ml, 5x5 ml och 2x10 ml.

För fullständig information och priser, se www.fass.se.

Indikation: Monofer är indicerat för behandling av järnbrist vid följande tillstånd: När perorala järnpreparat är ineffektiva eller inte kan användas. Vid kliniskt behov av snabb tillförsel av järn. Diagnosen järnbrist måste baseras på tillämpliga laboratorieprover. Kontraindikationer: Anemi som inte orsakas av järnbrist. Järnöverbelastning eller rubbning i kroppens användning av järn. Överkänslighet mot den aktiva substansen Monofer eller mot något hjälpämne. Konstaterad allvarlig överkänslighet mot andra parenterala järnprodukter. Dekompenserad leversjukdom. Särskilda varningar och försiktighetsmått: Parenteralt administrerade järnpreparat kan ge upphov till överkänslighetsreaktioner inklusive allvarliga och potentiellt dödliga anafylaktiska/anafylaktoida reaktioner. Överkänslighetsreaktioner har även rapporterats när tidigare doser av parenterala järnkomplex inte har resulterat i några oönskade effekter. Det har förekommit rapporter om överkänslighetsreaktioner som har utvecklats till Kounis syndrom. Risken är större för patienter med konstaterade allergier inklusive läkemedelsallergier, däribland patienter med svår astma, eksem eller andra atopiska allergier i anamnesen. Det finns även en ökad risk för överkänslighetsreaktioner mot parenterala järnkomplex hos patienter med immunologiska eller inflammatoriska tillstånd. Monofer ska endast administreras när personal som är utbildad i att bedöma och hantera anafylaktiska reaktioner finns tillhands, i en miljö där lokaler och utrustning för återupplivning garanterat finns tillgängliga. Varje patient ska observeras avseende biverkningar under minst 30 minuter efter varje injektion av Monofer. Om överkänslighetsreaktioner eller tecken på intolerans uppkommer under administrering måste behandlingen stoppas omedelbart. Lokaler för hjärt-lungräddning och utrustning för hantering av akuta anafylaktiska/anafylaktoida reaktioner ska finnas tillgängliga, inklusive en injicerbar 1:1 000 adrenalinlösning. Ytterligare behandling med antihistaminer och/eller kortikosteroider ges efter behov. Hos patienter med kompenserad leverdysfunktion ska parenteralt järn endast administreras efter noggrann nytta/riskbedömning. Administrering av parenteralt järn ska undvikas hos patienter med leverdysfunktion där järnöverskott är en förvärrande faktor, särskilt vid porfyria cutanea tarda (PCT). Noggrann övervakning av järnstatus rekommenderas för att undvika järnöverskott.  Parenteralt järn bör användas med försiktighet vid fall av akut eller kronisk infektion. Monofer bör inte användas för patienter med pågående bakteriemi. Hypotensiva reaktioner kan uppträda om den intravenösa injektionen ges för snabbt. Försiktighet bör vidtas för att undvika paravenöst läckage vid administrering av Monofer. Paravenöst läckage av Monofer kan leda till hudirritation och eventuellt långvarig brun missfärgning vid injektionsstället. Vid paravenöst läckage måste administreringen av Monofer stoppas omedelbart. Graviditet: Det finns endast begränsade data från användning av Monofer hos gravida kvinnor. En noggrann nytta/risk-bedömning krävs därför före användning under graviditet. Fosterbradykardi kan förekomma efter administrering av parenteralt järn. Tillståndet är vanligtvis övergående och är en följd av en överkänslighetsreaktion hos modern. Amning: Vid terapeutiska doser av Monofer förväntas inga effekter hos det ammade barnet. Produktresumé uppdaterad 2022-08-11

Pharmacosmos A/S
Roervangsvej 30
DK-4300 Holbaek, Danmark.

07-SCAN-11-09-2023.v1