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.

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.

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

Study participants will consist of persons admitted to a total of 21 different secondary or tertiary care hospitals in 16 different provinces across Turkey.

Age, gender, hemoglobin, MCV, MCHC, ferritin, CRP, transferrin saturation, ferric carboxymaltose (FCM) drug dose, FCM infusion concentration, infusion duration, methemoglobin levels

Beginning 3 months after publication with no end date

De-identified individual participant data (IPD) that underlie the results reported in this article (text, tables, figures, and appendices) will be made available to researchers who provide a methodologically sound proposal in order to achieve aims in the approved proposal.

Access to the IPD will require prior approval from the principal investigator. Researchers will need to submit a formal data access request including:

A detailed research protocol with clear objectives and statistical analysis plan,

A data use agreement,

Proof of institutional ethics approval (if applicable).

Decisions regarding data access will be made by the study's data sharing committee within a reasonable time frame, and applicants will be notified via email.

Requests should be directed to: drozbilen@gmail.com

Data will be shared via a secure data transfer system or repository, depending on the nature and size of the dataset.