Fatal anaphylactic reaction due to ferric carboxymaltose: A case report.

Introduction

Iron-deficiency anemia is most frequently related with insufficient nutrition. However, it is also encountered in chronic diseases including chronic renal failure (CRF) and congestive heart failure (CHF). Oral or intravenous (IV) iron replacement is recommended for its treatment (1, 2). IV administration is the preferred route in CRF and CHF, where intestinal mucosal edema and diminished gastrointestinal blood flow limit absorption of oral iron. Although IV route may cause hypersensitivity reaction (HSR), it is generally safe. The report of the European Medicines Agency declares that IV-iron treatment has a high benefit/risk ratio (3).

Ferric carboxymaltose (FCM) is a nondextran third-generation IV-iron preparation which has the advantage of normalizing hemoglobin and replenishing iron stores over a short period of time because it can be administered fast and in high doses (4). It has been approved and presented to the market in 2007 in Europe and in 2012 in Turkey (5). Clinical research has shown that it is generally well tolerated and has low serious HSR risk (≥1/10.000 to <1/1.000) (1, 4, 6, 7). Evaluation of safety reports discloses that there are four cases of death related to FCM (5, 8). To our knowledge, this is the first case of death related to FCM in Turkey and the fifth case of fatal anaphylactic reaction (AR) in the literature.

Case Report

A 74-year-old male patient who had a history of diabetes, hypertension, CRF, and coronary artery disease presented to the emergency service of our hospital with shortness of breath. On admission, since he had hypertension (190/110 mm Hg) and lung edema, he was given IV furosemide and nitrate infusion, and noninvasive ventilation was started. He was on long-acting insulin, lercanidipin, isosorbid mononitrate, and nebivolol due to his chronic diseases. The next day, he was moved to the coronary intensive care unit because of an increase in cardiac enzymes. Echocardiography showed a left ventricular ejection fraction of 40%, anterolateral hypokinesia, and slight mitral and tricuspid insufficiency. Angiography showed various stenoses in his coronary arteries and right renal artery, for which percutaneous intervention was planned.

IV-iron treatment was planned due to his iron-deficiency anemia (Table 1). After his signs of heart failure regressed and he became generally stable, FCM (Ferinject®, 1000 mg/15 min) infusion was started. He had no history of drug allergy or any allergic disease. Thirty seconds after the beginning of infusion, when the patient felt faint, infusion was stopped immediately. When respiratory distress (dyspnea and stridor) developed within a few minutes, IV prednisolone and an antihistaminic medication were administered. Despite treatment efforts, angioedema developed, which was followed by respiratory arrest. He was intubated using a video laryngoscope. When cardiac arrest developed shortly after, CPR was started, and IV atropine and IV adrenaline were given. CPR was stopped after 50 min of unresponsiveness.

Table 1

Various laboratory findings of our patient before ferric carboxymaltose infusion

	Patient values	Normal range
Hemoglobin (g/dL)	9.4	13.5-17.5
Transferrin saturation (%)	3.76	15.0-50.0
Iron (µg/dL)	12	70.0-180.0
BUN (mg/dL)	39.6	8.0-23.0
Serum creatinine (mg/dL)	2.05	0.67-1.17
e-GFR (CKD-EPI)	30.99	90.0
Uric acid (mg/dL)	9.61	3.5-7.2
Albumin (g/dL)	3.35	3.5-5.2
CRP (mg/L)	15.3	0.2-5.0
hs troponin I (ng/mL)	293.4	14.0-42.9
HbA1c (%)	9.0	4.0-6.0

BUN - blood urea nitrogen, e-GFR - estimated-glomerular filtration rate, CRP - C-reactive protein

Discussion

It is shown that iron deficiency worsens prognosis in patients with CRF and CHF. Therefore, IV FCM is recommended in the treatment of these symptomatic patients to decrease their symptoms and restore their exercise capacity (2, 4, 9).

IV-FCM treatment related fatal HSR is very rare, and the incidence is not increased in the presence of CHF or CRF (5, 8, 9). Retrospective evaluation of EudraVigilance drug safety database (2014–2017) revealed 121 FCM-related serious HSR, of which only one was fatal (5).

The factors which increase the incidence of HSR related to IV-iron administration are history of drug sensitivity, history of immune/inflammatory/allergic disease, mastocytosis, and high infusion rate (3). However, these factors were not present in our case. Causality relationship between the drug administration and AR was evaluated using the Naranjo Score (10), which was found to be “six” and interpreted as “probable” (Table 2). The presence of previous lung edema might have caused rapid decompensation after the occurrence of anaphylaxis. The presence of several comorbidities might have also influenced the development of serious HSR. Indeed, comorbidities have been reported to increase the risk of HSR by at least 2.8 times, regardless of the type of IV-iron formulations (6).

Table 2

The evaluation of causality relationship between the drug and anaphylactic reaction which developed after ferric carboxymaltose administration in our patient using the Naranjo Scale

Question	Yes	No	Do not know	Score
1. Are there previous conclusive reports on this reaction?	+1	0	0	+1
2. Did the adverse event appear after the suspected drug was administered?	+2	-1	0	+2
3. Did the adverse event improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	0
4. Did the adverse event reappear when the drug was readministered?	+2	-1	0	0
5. Are there alternative causes that could on their own have caused the reaction?	-1	+2	0	+2
6. Did the reaction reappear when a placebo was given?	-1	+1	0	0
7. Was the drug detected in blood or other fluids in concentrations known to be toxic?	+1	0	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
10. Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
	Total Score: 6

Total Score ≥9: definite; 5 to 8: probable; 1 to 4: possible; ≤0: doubtful

Conclusion

It should be kept in mind that fatal AR related to FCM administration may develop, although rare. Therefore, FCM should be administered in centers where emergency treatment can be delivered by healthcare personnel who can evaluate and manage AR. It should be known that every administration bears AR risk, even if the previous treatment was well tolerated.