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® (ferriderisomaltose) forkortet produktresumé

Note: Vennligst se den fullstendige preperatomtalen før produktet forskrives.

Legemiddelform: Infusjons-/injeksjonsvæske, jern(III)derisomaltose, oppløsning 100 mg/ml. Tilgjengelig som hetteglass: 5 x 1 ml, 5 x 5 ml og 2 x 10 ml. Indikasjoner: Behandling av jernmangel ved følgende indikasjoner: Ved klinisk behov for hurtig tilførsel av jern. Når orale jernpreparater ikke kan benyttes pga. manglende effekt eller ikke kan brukes av andre årsaker. Diagnosen må baseres på laboratorieprøver. Dosering: Doseringen gjøres trinnvis: [1] bestemmelse av det individuelle jernbehovet, og [2] utregning og administrasjon av jerndosen(e). Trinnene kan gjentas etter [3] vurdering av jernoppfylling etter jerntilskudd. Jernbehovet er uttrykt i mg elementært jern. Jernbehovet kan bestemmes enten ved en forenklet tabell basert på Hb-verdi og kroppsvekt eller ved Ganzoni-formelen (se preparatomtalen). For å vurdere effekten av Monofer skal Hb-nivået revurderes tidligst 4 uker etter siste administrering. Ved ytterligere behov for jern, må dette utregnes på nytt. Administrasjon: Preparatet gis som i.v. bolusinjeksjon, som i.v. infusjon eller som en injeksjon direkte i veneslangen ved hemodialyse. I.v. bolusinjeksjon: Doser opptil 500 mg pr. injeksjon opptil 3 ganger ukentlig og med injeksjonshastighet på opptil 250 mg jern/minutt kan tilføres. Dosen kan gis ufortynnet eller fortynnes. I.v. infusjon: Hele jerndosen, opptil 20 mg jern/kg kroppsvekt, kan gis som én engangsinfusjon eller som ukentlige infusjoner til det kumulative jernbehovet er gitt. Dersom jernbehovet overstiger 20 mg jern/kg kroppsvekt, må dosen deles opp i 2 administreringer med minst 1 ukes mellomrom. Det anbefales, når det er mulig, å gi 20 mg jern/kg i 1. administrering. Avhengig av klinisk skjønn kan 2. administrering avvente oppfølgende laboratorieprøver. Skal infunderes ufortynnet eller fortynnet, med steril 9mg/ml natriumkloridoppløsning, i maksimalt 500 ml. Kontraindikasjoner: Overfølsomhet for innholdsstoffene eller kjent overfølsomhet for andre parenterale jernpreparater. Anemi uten at det foreligger jernmangel (f.eks. hemolytisk anemi). For høyt jernnivå eller forstyrrelser i kroppens utnyttelse av jern (f.eks. hemokromatose, hemosiderose). Dekompensert leversykdom. Forsiktighetsregler: Parenteralt administrerte jernpreparater kan gi overfølsomhetsreaksjoner, inkl. alvorlige og potensielt dødelige anafylaktiske/anafylaktoide reaksjoner. Overfølsomhetsreaksjoner er også sett etter tidligere bivirkningsfrie doser av parenterale jernkomplekser. Overfølsomhetsreaksjoner som har utviklet seg til Kounis syndrom er sett. Risikoen er økt ved kjente allergier. Pasienten bør observeres for bivirkninger i minst 30 minutter etter hver administrasjon. Behandlingen må stoppes umiddelbart ved overfølsomhetsreaksjoner eller tegn på intoleranse under administrering. Parenteralt jern bør brukes med forsiktighet til pasienter med akutt eller kronisk infeksjon. Bør ikke gis til pasienter med aktiv bakteriemi. Overfølsomhets-reaksjoner kan oppstå, hvis IV injeksjonen gis for hurtig. Bivirkninger: Akutte, alvorlige overfølsomhetsreaksjoner kan forekomme ved administrering av parenterale jernpreparater. De opptrer vanligvis i løpet av de første minuttene etter infusjonsoppstart og er karakterisert ved plutselig innsettende pustebesvær og/eller sirkulatorisk kollaps. Vanlige: Kvalme, utslett, reaksjoner på injeksjonsstedet. Vennligst se den komplette preperatomtale for opplysninger om alle bivirkninger. Graviditet: Det er begrenset data på bruk av Monofer hos gravide kvinner, dette fra en studie med 100 behandlede gravide kvinner. En grundig nytte/risiko-vurdering er påkrevd før bruk under graviditet. Behandling med Monofer bør begrenses til andre og tredje trimester.

Ytterligere sikkerhetsinformasjon: Bør ikke brukes til barn og ungdom <18 år. Kan gi overfølsomhetsreaksjoner, inkl. alvorlige og potensielt dødelige anafylaktiske/anafylaktoide reaksjoner. De opptrer vanligvis i løpet av de første minuttene etter infusjonsoppstart og er karakterisert ved plutselig innsettende pustebesvær og/eller sirkulasjonssvikt. Overfølsomhetsreaksjoner som har utviklet seg til Kounis syndrom er sett. Risikoen er økt ved kjente allergier og ved autoimmune eller inflammatoriske tilstander. Behandlingen må stoppes umiddelbart ved overfølsomhetsreaksjoner eller tegn på intoleranse under administrering. 

Pakninger og priser (per 09/22): ATC: B03AC. Hetteglass: 5 x 1 ml kr 1532,40. 5 x 5 ml kr 7203,10. 2 x 10 ml kr 5770,60.

Reseptgruppe C

Basert på SPC godkjent 11.08.2022.

For ytterligere informasjon om Monofer^®, se SPC. www.felleskatalogen.no

Innehaver av markedsføringstilatelsen: Pharmacosmos A/S, Rørvangvej 30, DK- 4300 Holbæk, Danmark www.pharmacosmos.com.

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