A successful protocol for desensitization to iron salts.

Sir,

Iron deficiency is the most frequent nutritional disorder and accounts for about half of the anemia cases. Its treatment includes oral or intravenous iron replacement which is tolerated well by most of the patients. Hypersensitivity reactions against iron preparations have been seldom reported, and they were mostly attributed to dextran content of intravenous applications.[1]

We want to present a successful desensitization protocol with iron (III) hydroxide polymaltose complex (IPC) in a profound anemia patient who experienced anaphylactic reaction to an oral iron preparation. A 20-year-old female with no previous history of allergy and comorbidity had been diagnosed with iron deficiency anemia 2 years ago, resulting from excessive vaginal bleeding due to menometrorrhagia. Her main symptom had been fatigue; laboratory test results had been as follows: Hemoglobin 7.7 g/dL (12–15.5 g/dL), hematocrit 26.4% (37%–47%), mean corpuscular volume (MCV) 56.5 fL (88%–99 fL), iron 8 ug/dL (37–145 μg/dL), ferritin 2 μg/L (12–200 μg/L), and total iron-binding capacity 482 ug/dL (225–450 μg/dL). She had been started on daily oral ferrous sulfate (Oroferon®, Koçak Farma). After about 1 h following the administration of the second dose, she had experienced hives and tightness in the throat. She had been treated in an emergency room (ER) and stopped the drug. Six months later, she consulted her physician again for anemia and was started on IPC (Maltofer®, Abdi Ibrahim) treatment. After about 5 h following the drug, she had urticarial lesions all over the trunk. Later, oral treatment was changed to ferrous fumarate (Feramat ®, Abdi Ibrahim) which also resulted in similar symptoms about 5 h after administration. She was treated again in the ER and referred to the allergy department. A formal adverse drug reaction report was not prepared by the referring unit.

Skin tests with parenteral form of IPC and oral suspension form of ferrous sulfate were performed on the volar forearm according to the international guidelines. We used histamine (10 mg/mL) as positive control and 0.9% sterile saline as negative control. Prick tests were performed with undiluted drugs, intradermal tests with 10-fold dilutions. Prick tests with IPC was negative but resulted in a 2-mm wheal with ferrous sulfate. Intradermal tests were positive for both drugs.

Since the patient needed to receive treatment due to profound anemia, desensitization to an iron preparation was planned and IPC was chosen as being the one with least symptoms. The procedure was based on the dose protocol previously applied and reported to be successful by Demir et al. for ferrous sulfate and oral doses of IPC were revised accordingly (112.50/5 ml of ferrous sulfate complex being equivalent of 20 mg elemental iron and 357 mg/5 ml of IPC being equivalent of 100 mg elemental iron).[2] One milliliter of IPC (20 mg/ml) was combined with 4 ml of SS to obtain the first vial with a concentration of 4 mg/ml. This solution was further diluted 10 and a 100 fold to obtain two more vials [Table 1]. The solutions were reproduced as necessary. The doses were administered with 30-min intervals on day 1; vital signs were recorded after each dose. The dose intervals on the second and third days were 1 h except the last step. The full dose containing 5 ml of the original solution was given 6 h after the previous step and was tolerated successfully. The patient continued the treatment without problem for the subsequent 6 months.

Table 1

Protocol for desensitization to iron (III)-hydroxide polymaltose

	Dose number	Vials (n)	Volume given (ml)	Equivalent of elemental iron (mg)
Day 1	1	3a	0.1	0.004
	2	3	0.2	0.008
	3	3	0.25	0.01
	4	2b	0.25	0.1
	5	2	0.5	0.2
	6	2	1.0	0.4
	7	2	2.0	0.8
	8	2	2.5	1.0
	9	1c	1.0	4.0
	10	1	2.0	8.0
	11	1	2.5	10.0
	12	1	4.0	16.0
	13	OSd	1.0	20.0
	Daily cumulative dose			60.522
Day 2	1	OS	1.0	20.0
	2	OS	2.0	40.0
	3	OS	3.0	60.0
	Daily cumulative dose			120.0
Day 3	1	OS	3.0	60.0
	2	OS	3.0	60.0
	3	OS	5.0	100.0
	Daily cumulative dose			220.0

a Vial number 3 (1:100 dilution): 0.1 ml of vial number 2 + 0.9 ml NS=contains 0.04 mg elemental iron per ml, bVial number 2 (1:10 dilution): 0.1 ml of vial number 1 + 0.9 ml NS=contains 0.4 mg elemental iron per ml, cVial number 1: 1 ml of OS + 4 ml NS=contains 4 mg elemental iron per ml, dOS, 5 ml: contains 20 mg elemental iron per ml. NS= Normal saline, OS=Original solution

Although gastrointestinal side effects with oral iron preparations are frequent, allergic reactions are rare, including erythematous maculopapular eruption with ferrous sulfate, photodermatitis with sodium ferrous citrate, and anaphylactic reaction against the dextran content of intravenous iron preparations.[13]

Drug desensitization is a procedure aiming to administer a medication safely to a patient who is allergic to it; rapid or slow protocols can be chosen to perform for immediate-type and delayed-type hypersensitivity reactions, respectively. It is recommended to start the procedure with 1:1000–1:100 of the drug dose.[4]

A slow desensitization protocol lasting for 4 days for ferrous sulfate in a patient with delayed-type drug allergy had previously been reported.[3] de Barrio et al. reported another slow protocol lasting for 18 days for ferrous sulfate in an anaphylaxis patient; they completed the protocol with a drug dosage as high as 262.50 mg and observed urticarial lesions on four different days.[5]

Our desensitization protocol was based on a classically successful, three-vial, 10-fold dilution model applied previously for other drugs.[4] It was a revised version of the rapid protocol reported by Demir et al. to be used in two patients successfully.[2] It provided us to achieve tolerance induction in 3 days without adverse reactions.

Developing desensitization protocols for medications with no alternative provides an important clinical basis. We demonstrated the efficacy and safety of the 3-day protocol for IPC and believe that it can be instructive for future similar cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initial will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.