Ferric Carboxymaltose Methemoglobinemia Study

NCT ID: NCT06958822

Last Updated: 2025-11-19

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 977 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2025-04-14
• Study Completion Date: 2025-09-30

Brief Summary

Anemia that develops due to iron deficiency is called iron deficiency anemia. This common condition is treated with iron supplements taken either orally or given through an intravenous (IV) infusion. Ferric carboxymaltose (FCM) is one of the widely used, comparably newer IV iron preparations. Recently, several publications have raised the possibility that FCM may be associated with mild elevations in methemoglobin (metHb), a form of hemoglobin that cannot effectively deliver oxygen to tissues.

Methemoglobinemia is a known, though uncommon, side effect of some drugs. While usually mild and self-limiting, in certain cases it can become clinically significant or even life-threatening. This observational study is being conducted across multiple centers to better understand how often methemoglobinemia occurs after administration of FCM. As part of routine care, venous blood samples will be used to measure metHb levels in patients receiving FCM, and these results will be compared with those from individuals not exposed to the drug.

Detailed Description

Methemoglobinemia, which results from the conversion of ferrous iron (Fe2+) to ferric iron (Fe3+) in hemoglobin (Hb), is a potentially life-threatening disorder resulting in functional anemia due to reduced oxygen-carrying capacity. Methemoglobin (metHb) levels above one percent (>1%) are considered abnormal, and ≥3% metHb is considered clinically significant methemoglobinemia. Severe elevation of this level (>20%) leads to more dangerous clinical manifestations such as shortness of breath, confusion, arrhythmias, and seizures. Cases are usually asymptomatic until metHb levels reach 20%, and only discoloration of the blood and/or skin can be detected. Levels exceeding 70 percent are fatal.

The more common acquired form of methemoglobinemia, which can be congenital or acquired, is often caused by the use of drugs or toxic substances. Exposure to certain compounds that exceed the enzymatic reduction capacity of erythrocytes causes signs/symptoms. Benzocaine, phenazopyridine, dapsone, and nitrates/nitrites are the substances most commonly associated with methemoglobinemia.

Ferric carboxymaltose (FCM) is a third-generation intravenous iron drug with a ferric iron (Fe³⁺) compound that is widely used in the intravenous treatment of iron deficiency anemia. There are only three studies on the relationship between FCM and metHb reflected in the literature, one as a case report and two as congress proceedings. Given the expanding clinical use of FCM and the potential implications of undetected methemoglobinemia, there is a need to evaluate this association in a structured and systematic manner under routine care conditions. This study is designed to contribute to pharmacovigilance efforts by generating incidence data and exploring potential patient-related or treatment-related risk factors. Therefore, the investigators plan to determine the incidence of this comparably rare adverse effect with a prospective multicenter observational study.

The primary objective is to estimate the incidence of methemoglobinemia - defined as venous blood methemoglobin (metHb) levels ≥3%-within 30 min. following intravenous administration of ferric carboxymaltose in adult patients receiving routine care.

Secondary objectives include (i) description of the full distribution of metHb values post-infusion (ii) determination of whether metHb levels remain elevated beyond 30 min. in affected individuals, (iii) estimation of the background distribution of metHb levels in an unexposed, healthy outpatient population (iv) comparison of the metHb levels between FCM-exposed patients and unexposed controls (v) identification of potential associations between methemoglobinemia and relevant covariates, including patient demographics, total iron dose administered, baseline hemoglobin and venous oxygen saturation, or other potential oxidant exposures.

This study is a multicenter, prospective observational study. Ferric carboxymaltose recipients are determined based on routine medical care practices; the researchers do not define which participants will receive ferric carboxymaltose. Patient recruitment will take place between April 14, 2025, and September 15, 2025, per protocol, in 21 different health institutions.

Statistical analysis:

Methemoglobinemia rates (≥3% metHb) between the exposed (FCM) and unexposed groups will be compared using Fisher's exact test. Subgroup differences in continuous metHb levels will be analyzed using analysis of variance (ANOVA) with appropriate post hoc comparisons. Correlations between metHb levels and continuous clinical variables will be evaluated using correlation tests. Independent predictors of methemoglobinemia will be assessed through multivariable regression modeling. A two-sided significance threshold of α = 0.05 will be used for all tests.

Conditions

Methemoglobinemia; Anemia, Iron-Deficiency; Parenteral Iron Therapy; Ferric Carboxymaltose

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

FCM Group

It will represent the group of patients who will be administered ferric carboxymaltose (FCM), i.e., the exposed group.

Ferric Carboxymaltose (FCM)

Intervention Type: DRUG

As this is an observational study, ferric carboxymaltose recipients are determined based on routine medical care practices. The researchers do not define which participants will receive ferric carboxymaltose.

Control Group

It will represent the control group of patients who do not receive FCM or any form of iron therapy, i.e., the unexposed group.

No interventions assigned to this group

Interventions

Ferric Carboxymaltose (FCM)

As this is an observational study, ferric carboxymaltose recipients are determined based on routine medical care practices. The researchers do not define which participants will receive ferric carboxymaltose.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

FCM Group:

1. Adults (≥18 years)

2. Presence of anemia (Hb <12 g/dl in women, <13 g/dl in men)

3. Low ferritin (<30 mcg/l)

4. Patients for whom FCM administration has been decided in routine medical care practice

Control Group:

Healthy adult (≥18 years) individuals who applied to the internal medicine outpatient clinic, who had no current or pre-existing chronic disease, who did not have anemia and iron deficiency (ferritin ≥30 mcg/L).

Exclusion Criteria

1. Known methemoglobinemia-related diseases (Hb M disease, cytochrome b5 reductase deficiency, etc.)

2. Use of drugs associated with methemoglobinemia (acetylsalicylic acid, dapsone, chloroquine, metoclopramide, benzocaine, lidocaine, prilocaine, rasburicase, primaquine, sulfonamide, nitric oxide)

3. Those with B12 and/or folate deficiency

4. Those with Charlson Comorbidity Index ≥3

5. Presence of advanced organ failure (Stage 4 and 5 chronic kidney disease, Child C cirrhosis, NYHA class 3 and 4 chronic heart failure, respiratory failure requiring oxygen supplementation and similar processes)

6. Presence of malignancy (with or without cure)

7. Presence of active infection (CRP > 5 mg/dL) and/or other acute disorder/disease

8. Pregnancy status

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Marmara University Pendik Training and Research Hospital

OTHER

Sponsor Role: collaborator

Ordu University

OTHER

Sponsor Role: lead

Responsible Party

Muhammet Özbilen, MD

Associate professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Muhammet Özbilen, MD

Role: STUDY_DIRECTOR

Ordu University Faculty of Medicine

Gökhan Tazegül, MD

Role: STUDY_DIRECTOR

Marmara University

Volkan Aydın, MD PhD

Role: STUDY_DIRECTOR

Marmara University School of Dentistry

Murat Bahadır, MD

Role: PRINCIPAL_INVESTIGATOR

Ordu University Faculty of Medicine, Department of Internal Medicine

Bilge Ada Özcan, MD

Role: PRINCIPAL_INVESTIGATOR

Marmara University Training and Research Hospital

Mehmet Bankir, MD

Role: PRINCIPAL_INVESTIGATOR

University of Health Sciences Adana City Health Application and Research Center

Mehmet Can Erişen, MD

Role: PRINCIPAL_INVESTIGATOR

University of Health Sciences Adana City Health Application and Research Center

Nurhayat Özkan Sevencan, MD

Role: PRINCIPAL_INVESTIGATOR

Karabuk University Training and Research Hospital

Ceren Çevik, MD

Role: PRINCIPAL_INVESTIGATOR

Karabuk University Training and Research Hospital

Aysel Toçoğlu, MD

Role: PRINCIPAL_INVESTIGATOR

Sakarya University Training and Research Hospital

Sümeyye Çekiç, MD

Role: PRINCIPAL_INVESTIGATOR

Sakarya University Training and Research Hospital

Arzu Denler Kılıç, MD

Role: PRINCIPAL_INVESTIGATOR

Çankırı State Hospital

Mehmet Selim Mamiş, MD

Role: PRINCIPAL_INVESTIGATOR

Siirt University Faculty of Medicine Training and Research Hospital

Necip Nas, MD

Role: PRINCIPAL_INVESTIGATOR

Siirt University Faculty of Medicine Training and Research Hospital

Teslime Ayaz, MD

Role: PRINCIPAL_INVESTIGATOR

Izmir Bakircay University Cigli Training and Research Hospital

Barış Emekdaş, MD

Role: PRINCIPAL_INVESTIGATOR

Izmir Bakircay University Cigli Training and Research Hospital

İhsan Solmaz, MD

Role: PRINCIPAL_INVESTIGATOR

University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital

Ömer Faruk Alakuş, MD

Role: PRINCIPAL_INVESTIGATOR

University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital

Kamil Konur, MD

Role: PRINCIPAL_INVESTIGATOR

Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital

Hasan Sözel, MD

Role: PRINCIPAL_INVESTIGATOR

Akdeniz University Hospital

Esin Avşar Küçükkurt, MD

Role: PRINCIPAL_INVESTIGATOR

Akdeniz University Hospital

Hacer Şen, MD

Role: PRINCIPAL_INVESTIGATOR

Balıkesir University Health Practice and Research Hospital

Özge Kama Başçı, MD

Role: PRINCIPAL_INVESTIGATOR

Balıkesir University Health Practice and Research Hospital

Nizameddin Koca, MD

Role: PRINCIPAL_INVESTIGATOR

Bursa City Hospital

Fatih İleri, MD

Role: PRINCIPAL_INVESTIGATOR

Bursa City Hospital

Banu Açmaz, MD

Role: PRINCIPAL_INVESTIGATOR

Kayseri City Hospital

Erdem Aydın, MD

Role: PRINCIPAL_INVESTIGATOR

Kayseri City Hospital

İdris Baydar, MD

Role: PRINCIPAL_INVESTIGATOR

Mardin Artuklu University Training and Research Hospital

Şengül Baran Yerlikaya, MD

Role: PRINCIPAL_INVESTIGATOR

Mardin Artuklu University Training and Research Hospital

Yıldız Okuturlar, MD

Role: PRINCIPAL_INVESTIGATOR

Mehmet Yılmaz Aydınlar Acıbadem University

Sibel Serin Ocak, MD

Role: PRINCIPAL_INVESTIGATOR

Umraniye Training and Research Hospita

Nur Düzen Oflas, MD

Role: PRINCIPAL_INVESTIGATOR

Van Yüzüncü Yıl University Training and Research Hospital

Abdullah Güneş, MD

Role: PRINCIPAL_INVESTIGATOR

Van Yüzüncü Yıl University Training and Research Hospital

Nazire Osmançelebioğlu, MD

Role: PRINCIPAL_INVESTIGATOR

Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital

Ant Uzay, MD

Role: PRINCIPAL_INVESTIGATOR

Mehmet Yılmaz Aydınlar Acıbadem University

Sevgi Gülşen Koç, MD

Role: PRINCIPAL_INVESTIGATOR

Antalya City Hospital

Ayşe Karaduru, MD

Role: PRINCIPAL_INVESTIGATOR

Antalya City Hospital

Gamze Kocaman, MD

Role: PRINCIPAL_INVESTIGATOR

Bursa Yuksek Ihtisas Training and Research Hospital

Ali Erol, MD

Role: PRINCIPAL_INVESTIGATOR

Bursa Yuksek Ihtisas Training and Research Hospital

Mehmet Biricik, MD

Role: PRINCIPAL_INVESTIGATOR

Mardin Kiziltepe State Hospital

Emine Binnetoğlu, MD

Role: PRINCIPAL_INVESTIGATOR

Çorlu Vatan Hospital

Muhammet Fatih Şahin, MD

Role: PRINCIPAL_INVESTIGATOR

Bursa Kestel State Hospital

Ebru Çağrı Çakır Özden, MD

Role: PRINCIPAL_INVESTIGATOR

Bursa Kestel State Hospital

Locations

University of Health Sciences Adana City Health Application and Research Center

Adana, Adana, Turkey (Türkiye)

Akdeniz University Hospital

Konyaalti, Antalya, Turkey (Türkiye)

Balıkesir University Health Practice and Research Hospital

Merkez, Balıkesir, Turkey (Türkiye)

Bursa City Hospital

Nilufer, Bursa, Turkey (Türkiye)

University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital

Kayapınar, Diyarbakır, Turkey (Türkiye)

Mehmet Yılmaz Aydınlar Acıbadem University

Ataşehir, Istanbul, Turkey (Türkiye)

Marmara University Training and Research Hospital

Pendik, Istanbul, Turkey (Türkiye)

Umraniye Training and Research Hospital

Ümraniye, Istanbul, Turkey (Türkiye)

Izmir Bakircay University Cigli Training and Research Hospital

Çiğli, İzmir, Turkey (Türkiye)

Karabuk University Training and Research Hospital

Karabük, Karabük Province, Turkey (Türkiye)

Kayseri City Hospital

Kocasinan, Kayseri, Turkey (Türkiye)

Antalya City Hospital

Antalya, Kepez, Turkey (Türkiye)

Bursa Kestel State Hospital

Bursa, Kestel, Turkey (Türkiye)

Mardin Kızıltepe State Hospital

Mardin, Kızıltepe, Turkey (Türkiye)

Mardin Artuklu University Training and Research Hospital

Merkez, Mardin, Turkey (Türkiye)

Ordu University Training and Research Hospital

Altinordu, Ordu, Turkey (Türkiye)

Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital

Rize, Rize Province, Turkey (Türkiye)

Sakarya University Training and Research Hospital

Adapazarı, Sakarya, Turkey (Türkiye)

Siirt University Faculty of Medicine Training and Research Hospital

Siirt, Siirt, Turkey (Türkiye)

Van Yüzüncü Yıl University Training and Research Hospital

Merkez, Van, Turkey (Türkiye)

Bursa Yuksek Ihtisas Training and Research

Bursa, Yıldırım, Turkey (Türkiye)

Çankırı State Hospital

Çankırı, Çankırı, Turkey (Türkiye)

Çorlu Vatan Hospital

Tekirdağ, Çorlu, Turkey (Türkiye)

Countries

Turkey (Türkiye)

References

Tazegul Gokhan, Kimyon Yusuf, Odabasi Zekaver. Ferric carboxymaltose induced methaemoglobinemia: Preliminary data of a novel side effect. 22nd European Congress of Internal Medicine , İstanbul, Turkey, 2024.

Reference Type: BACKGROUND

Özbilen M, Savrun ŞT, Aygün A, Kaya Y. P1492: A New Potential And Prevalent Side Effect of Ferric Carboxymaltose: Methemoglobinemia. A Case-Control Study. Hemasphere. 2023 Aug 8;7(Suppl 3):e825173f.

Reference Type: BACKGROUND

Ozbilen M, Savrun ST, Aygun A, Kaya Y. Ferric Carboxymaltose-mediated Methemoglobinemia. Curr Drug Saf. 2024;19(1):134-137. doi: 10.2174/1574886318666230213111038.

Reference Type: BACKGROUND

PMID: 36779493 (View on PubMed)

Other Identifiers

2024-KAEK-30 / 2025-43

Identifier Type: -

Identifier Source: org_study_id