Efficacy and tolerability of oral iron protein succinylate: a systematic review of three decades of research.

Objective: Oral supplementation with iron is a standard intervention for treating or preventing iron deficiency with or without anemia. Over the last few decades, various forms of oral iron have been developed to improve treatment tolerability and iron bioavailability. In this review, we gathered research data regarding the use of iron protein succinylate since it was first marketed in the 1980s.Methods: Electronic databases - PubMed and the Cochrane Library - were searched for studies published up to March 2019. Clinical or observational studies reporting data on the tolerability of oral iron protein succinylate were included. Results were statistically described to evaluate and compare the efficacy and safety of iron protein succinylate with the comparators under study.Results: Iron protein succinylate was investigated in 54 studies: 38 randomized clinical trials and 16 observational studies, with a total of 8454 subjects. Of them, 8142 were included in the efficacy analysis: patients were divided into three population subtypes: general (n = 1899), gynecological/obstetric (n = 5283), and pediatric (n = 960). In total, 6450 patients received iron protein succinylate, experiencing a significant change in hemoglobin and ferritin in all populations. The change in all parameters was similar or higher with iron protein succinylate compared to other iron treatments evaluated. Overall, study groups receiving iron protein succinylate reported the lowest rate of adverse events.Conclusions: Although all iron treatments analyzed are effective and safe, our results suggest that iron protein succinylate may be an excellent choice to treat iron deficiency and anemia due to its superior effectiveness and tolerability.

[Clinical study of iron protein succinylate oral solution for preventing and treating anemia of prematurity].

OBJECTIVE: To evaluate the efficacy and safety of iron protein succinylate (IPS) oral solution in preventing and treating anemia of prematurity (AOP). METHODS: Sixty premature infants less than 35 weeks of gestation were randomly divided into IPS (n=30) and polysaccharide iron complex (PIC) groups(n=30). Treatment began at two weeks after birth. The infants received IPS or PIC in addition to recombinant human erythropoietin. On days 14, 28, 42, and 60 after treatment, hemoglobin (Hb), red blood cell count(RBC), hematocrit (HCT), percentage of reticulocytes, serum iron, and serum ferritin were determined. Liver and renal functions were evaluated before and after treatment. RESULTS: There were significant differences in the changing trends of RBC and HCT between the two groups (P<0.05). In the IPS group, RBC and HCT gradually decreased after birth, but began to rise gradually on days 28 and 42 of treatment; in the PIC group, RBC and HCT kept decreasing from birth to day 60 of treatment. On day 60 of treatment, the IPS group had significantly higher levels of Hb, RBC, HCT, serum iron, and serum ferritin than the PIC group (P<0.05). No notable adverse events occurred in either group. CONCLUSIONS: IPS oral solution has good efficacy and tolerability in preventing and treating AOP.

Tolerability of different oral iron supplements: a systematic review.

OBJECTIVE: A systematic review was conducted to analyze the tolerability of several oral iron supplements based on data obtained in available publications and to report the incidence of adverse effects (AEs) for each supplement both overall and gastrointestinal. METHODS: Electronic databases - Medline, the Cochrane Library, and Embase were searched for studies published up to January 2009. Clinical or observational studies reporting data on the tolerability of oral iron supplements were included. Results were described statistically and a quasi-binomial logistic regression model was developed to evaluate and compare the tolerability of the supplements studied. RESULTS: For this review 111 studies were included, with data on 10,695 patients. Ferrous sulfate with mucoproteose had the lowest incidence of AEs (4.1% for overall AEs, 3.7% for gastrointestinal AEs [GAEs]) and was used as the reference supplement in the regression model. Incidence rates of overall AEs for the other supplements were 7.3% for iron protein succinylate [GAEs: 7%; OR for AE compared to the reference supplement, 1.96], 23.5% for ferrous glycine sulfate [GAEs: 18.5%; OR: 5.90], 30.9% for ferrous gluconate [GAEs: 29.9%; OR: 11.06], 32.3% for ferrous sulfate without mucoproteose [GAEs: 30.2%; OR: 11.21], and 47.0% for ferrous fumarate [GAEs: 43.4%; OR: 19.87]. The differences in incidence of AEs between extended-release ferrous sulfate with mucoproteose and all other supplements except iron protein succinylate were statistically significant at p < 0.001. These findings are subject to some limitations as the designs and methodologies of the studies included show heterogeneity among them that has partially been counteracted by the large sample size provided by the substantial number of trials, which is considered a strength in tolerability studies. CONCLUSION: Extended-release ferrous sulfate with mucoproteose appears to be the best tolerated of the different oral iron supplements evaluated.

Iron complex, dabigatran and toxic epidermal necrolysis syndrome: a case-report.

WHAT IS KNOWN AND OBJECTIVE: Toxic Epidermal Necrolysis Syndrome falls in the spectrum of acute idiosyncratic bullous disorders with medications being the major aetiological factor. The authors review the relevant literature and report a case of Toxic Epidermal Necrolysis Syndrome where two medications, iron protein succinylate and dabigatran, not previously associated with the disorder might have acted as precipitants to it. CASE SUMMARY: An 86-year-old female recently introduced to iron protein succinylate and dabigatran, presented with a widespread rash consisting of erythematous macules symmetrically distributed on her torso and both upper and lower limbs, down to her extremities. She was diagnosed with Toxic Epidermal Necrolysis Syndrome. None of the drugs previously implicated with the disorder were listed in her recent prescriptions. It was therefore concluded that the two most recently initiated medications, iron protein succinylate and dabigatran, might have been the cause. They were both discontinued to good effect for our patient. WHAT IS NEW AND CONCLUSION: Although neither iron protein succinylate nor dabigatran has been incriminated as causative of Toxic Epidermal Necrolysis Syndrome, we believe that either one of these or their interaction might have acted as the precipitant to this condition. We suggest that the possibilities of the above associations should be further explored.

Acute allergic reaction to an iron compound in a milk-allergic patient.

A child allergic to cow's milk developed a mild systemic allergic reaction after the first dose of Ferplex 40 (iron proteinsuccinylate). Skin tests and in vitro studies were performed in the child, in three cow's milk-allergic controls and in a non-allergic control. Milk, casein and iron proteinsuccinylate (Ferplex 40) were used for skin tests, specific immunoglobulin E (IgE) determination, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting and enzyme allergo sorbent test (EAST) inhibition. A review of the drug information sheet and contact with the manufacturer were also performed. Although proteinsuccinylate is indeed a succinylated casein (each dose containing about 575 mg of casein) there was no indication of the milk protein content in the prescribing information provided by the manufacturer. Skin tests and specific IgE were positive in the case and in all allergic controls, except for EAST to iron proteinsuccinylate in one control. In EAST, iron proteinsuccinylate in solid phase was 100% inhibited by casein and casein in solid phase was inhibited 74% by iron proteinsuccinylate. SDS-PAGE of iron proteinsuccinylate showed a broad 46 kDa band and a blur of aggregated material. On immunoblot, the patient's IgE reacted to this heavily aggregated material and in the native casein extract recognized a 35-kDa band. The allergenicity of succinylated casein (proteinsuccinylate) among milk-allergic children is demonstrated. The protein source used in drug-protein conjugates should always be indicated by the manufacturer (as it should be in foods) to avoid potential risks to allergic patients.

The efficacy and tolerability of iron protein succinylate in the treatment of iron-deficiency anemia in pregnancy.

The aim of this study was to evaluate the efficacy and tolerability of iron protein succinylate in the treatment of iron-deficiency anemia in pregnancy. One hundred and thirty anemic pregnant women were studied. Inclusion criteria were iron-deficiency type of anemia, and hemoglobin levels below of 11.5, 10.9 and 10.3 g/dl for the three trimesters of pregnancy, respectively. Twenty-five women who presented pregnancy-related complications were excluded during treatment. The remaining 105 were treated with 1600-mg iron protein succinylate per os daily for a period of four months. A group of anemia-related clinical signs and symptoms, and hematological parameters were recorded at the beginning of treatment, as well as two and four months later. They included epidermis and mucosal paleness, skin and nail lesions, glossitis, heart pulse, sickness, anorexia, apathy, ataxia, polypnea, insomnia, nervousness, paresthesias and other neurological symptoms; the hematological parameters included Hgb, hct, RBCs, WBCs, MCV, MCH, MCHC, PLTs, serum Fe and ferritin. Possible side or adverse effects were considered during treatment. The majority of symptoms and signs of anemia were gradually improved. There was a statistically significant increase in the means of Hgb, hct, WBCs, MCV, MCH, PLTs and serum ferritin (p < 0.05). Anemia was effectively treated in 100/105 (95.2%) women, but not in five patients (4.8%) who displayed poor compliance to the therapeutic protocol. There were transient and mild side-effects in seven (6.6%) treated women, namely diarrhea, epigastralgia, vomiting, and nausea, which however, did not necessitate discontinuation of the therapeutic protocol. Iron protein succinylate is an effective and well tolerated treatment of iron-deficiency anemia in pregnancy.

A comparative study on the gastroduodenal tolerance of different antianaemic preparations.

The most significant adverse effect of repeated oral administration of iron-containing antianaemic preparations is the gastroduodenal toxicity, attributable to a direct toxic effect of iron on the glandular epithelium. To assess gastroduodenal mucosal damage and the potential protective effect of different antianaemic preparations, a study was carried out to compare the gastroduodenal toxicity caused by three different types of antianaemic drugs in normal and anaemic rats administered at repeated therapeutic doses. Histological damage to the gastroduodenal mucosa was evaluated using light and electron microscopy. In both normal and anaemic rats, pathological changes were less marked in animals treated with ferrimannitol-ovoalbumin (TM/FMOA) than in those treated with iron protein succinylate or ferrous sulphate. Electron microscopic studies of duodenal mucosa in normal rats treated with iron protein succinylate and ferrous sulphate confirmed a severe ultrastructural alteration, whereas no changes were detected in animals treated with TM/FMOA. In anaemic rats, slight duodenal ultrastructural changes were noted with all three types of treatment. The effectiveness of the preparations in resolving the anaemia was similar in the three groups. It was concluded that TM/FMOA exerts a protective effect against the toxicity normally observed of the iron in other formulations in normal and anaemic rats, which was attributed to the fact that administration of iron bound to a protein core allows for gradual release of iron.

Aerosol orgotein (Ontosein) for the prevention of radiotherapy-induced adverse effects in head and neck cancer patients: a feasibility study.

Orgotein is an anti-inflammatory superoxide dismutase agent successfully used in treating several inflammatory diseases. It is also used in treating radiation-induced adverse effects in difference malignancies, notably breast, lung, bladder, prostate, cervix, and head and neck cancers. It is administered either topically or parenterally. To our knowledge, it has never been used before for prophylaxis of radiation-induced adverse effects or in aerosol form. Here we report on the results from a feasibility study on aerosol orgotein (Ontosein) for prevention of acute and deferred radiation-induced adverse effects in patients treated for head and neck malignancies. Our results show that aerosol orgotein administered before each radiation therapy session may impart some benefits in both incidence and severity of acute and deferred radiation-induced adverse effects in head and neck cancer patients, when compared with historical controls. In addition, aerosol orgotein administration is easy and convenient for both the patient and the radiotherapist.

Anaphylactic shock caused by impurities in orgotein preparations.

Previously reported allergic reactions to orgotein (superoxide dismutase) injections has assigned responsibility to this molecule, which is obtained from bovine liver. We report an anaphylactic shock probably caused by impurities contained in an orgotein preparation. Prick test to Peroxinorm (orgotein), BSA, and cow liver extract were positive but resulted negative with chymotrypsin, milk, meat and cow epithelium extracts. Tryptase levels determined 3, 24 hours and 15 days after the shock measured 6.32, 0.81 and 0.84 U/L respectively. Detection of specific IgE to Peroxinorm, BSA and chymotrypsin by ELISA was negative and positive to cow liver. Specific IgE to milk and cow epithelium by Pharmacia CAP system was negative. Immunoblotting with Peroxinorm revealed IgE specific bands at an apparent M.W of 67, 51, 56 and 16 kDa; immunoblotting with cow liver revealed bands at 72, 56, 50 and 36 kDa; immunoblotting with BSA and chymotypsin were negative. This case emphasises the role that 20 % of impurities of the pharmaceutical preparation may have in immediate hypersensitivity reactions.

Comparative study of tolerability and efficacy of iron protein succinylate versus iron hydroxide polymaltose complex in the treatment of iron deficiency in children.

One-hundred children, 48 males and 52 females, mean age +/- SD 39.9 +/- 28.2 months (range 12 to 113) with sideropenia or sideropenic anemia were randomly divided into 2 groups of 50 patients each (groups A and B) and were treated with iron protein succinylate (group A) or iron hydroxide polymaltose complex (group B). Patients of both groups received 4 mg/kg elemental iron, maximally 80 mg daily, for 2 months. Side-effects of therapy and laboratory values (RBC, hematocrit, hemoglobin, MCV, serum iron, total iron binding capacity, and ferritin) were registered before treatment, 30 days after the beginning of therapy as well as after 60 days in order to evaluate tolerability and efficacy of the drugs. Both drugs were well tolerated and showed only few adverse reactions, which were comparable in severity and frequency. Iron protein succinylate led not only to a faster increase of hemoglobin, hematocrit, MCV, serum iron, and ferritin than iron hydroxide polymaltose complex, but the laboratory values remained higher in group A than in B even after 2 months of treatment.

Prevention of radioinduced cystitis by orgotein: a randomized study.

On the basis of previous experiences indicating that the anti-oxidant agent Cu/Zn superoxide dismutase (SOD) is an effective drug in reducing acute and late radiation-induced tissue injury, in the Center of Radiotherapy and Oncology of Catalonia, Barcelona, Spain in 1990 we implemented a randomized prospective study to analyze the incidence and grade of side effects in a group of bladder cancer patients. After surgery patients were randomly allocated to receive either: Option A: Radiotherapy or Option B: Radiotherapy + SOD 8 mgr/IM/day, after each radiotherapeutic application. Between January 1990 and January 1995 a total of 448 patients were included (226 A/ 222 B). Apart from cutaneous side effects, a highly significant incidence of radioinduced acute cystitis and rectitis was detected in patients not treated by SOD. Which was similar to the delayed side effects. From our data we can conclude that SOD is effective in decreasing acute radioinduced damage, and also in preventing the appearance of more delayed disorders.

Meta-analysis of efficacy and tolerability data on iron proteinsuccinylate in patients with iron deficiency anemia of different severity.

Iron proteinsuccinylate (ITF 282, CAS 93615-44-2) is an iron derivative for the oral treatment of iron deficiency anemia. Its efficacy and tolerability have been proved in about 1800 patients, enrolled in 3 multicenter clinical trials. The first aim of this meta-analysis is to verify the increase of hemoglobin (Hb) in these patients (891 treated with ITF282, 644 treated with iron sulphate and 236 treated with iron-polysterene sulphonate). The 3 studies show homogeneous Hb increases. ITF 282 appeared to provide, from time 0 to the 30th day of treatment, a similar or lesser increase in Hb in comparison to the reference drugs, while from the 30th day of treatment to the 60th day its efficacy was always greater than that of the reference medications. The data have been further analyzed by subdividing the patients in three classes, according to the severity of the anemia: basal Hb < or = 9 g/dl, > 9 < or = 11 g/dl, > g/dl. During the 60-day treatment, both ITF 282 and the reference drugs induced the most significant increase in Hb in the patients affected by the most severe anemia. The meta-analytic evaluation of the 3 trials results has been extended to tolerability data. Most side effects were related to the gastrointestinal tract. Their incidence resulted signficantly lower for ITF 282 than that for the reference drugs (9.4% vs. 20.4%, p < 0.01). The comparative sub-analysis of the side effect distribution into the patients populations shows that ITF 282 is definitely better tolerated in pregnant women (relative risk 0.321, p < 0.01). The time course of Hb increases and the tolerability data suggest a different mechanism by which ITF 282 and the reference drugs are effective. Since the main difference between ITF 282 and the reference drugs is the form in which the iron is presented to the gastrointestinal mucosa, it may be supposed that the reference drugs, providing free divalent iron ions for absorption, could induce some kind of irritative condition of the gastrointestinal mucosa, which results in a reduced long-term absorption capacity, as well as in a higher incidence of gastroenteric adverse events. ITF 282, providing protein-bound iron, would not permit the process supposed with divalent iron, thus resulting in prolonged absorption capacity (that is higher hemoglobin recovery) and higher gastrointestinal tolerability.

Iron protein succynilate in the treatment of iron deficiency: potential interaction with H2-receptor antagonists.

A prospective, open, multicenter clinical trial was set up to evaluate the potential interaction of ITF 282 with H2-receptor antagonists in patients affected with iron deficiency. Patients treated with H2 blockers and affected with iron deficiency or iron deficient anemia were given one tablet of ITF 282 (60 mg iron) twice daily for 60 days. A second group of iron deficient patients with no anti H2 concurrent treatment were admitted to the same iron treatment, lasting 60 days. To evaluate the outcome of the iron treatment, a comprehensive assessment of laboratory and clinical determinations was adopted in all the patients: special hematology, symptomatology, safety hematology and hematochemistry, urinalysis. Fifty-three patients with iron deficiency and 47 patients affected with overt iron deficient anemia entered the study. After treatment, a significant trend toward the normalization of the main hematologic parameters in both groups was detected. The general tolerability was apparently more favorable in the patients who had also the antiulcer (1 event of diarrhoea) than in those who had ITF 282 alone (2 heartburn, 3 constipation, 2 abdominal pain). There were no indications of subgroups of patients particularly at risk of adverse events, all of which resulted reversible without the need to reduce the dose of medication or to take other medical action. ITF 282 resulted, also when administered together with H2-receptor antagonists, in the expected therapeutic efficacy, with the expected clinical tolerability and biological safety, without signs of possible interaction, negative or positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic anaphylaxis following parenteral orgotein administration.

We present a patient displaying a systemic anaphylactic reaction after local infiltration of orgotein. An IgE-mediated mechanism was demonstrated with skin tests and specific IgE measurement. It is concluded that orgotein can rarely cause IgE-mediated anaphylaxis.

Iron protein succinylate: preclinical safety assessment.

In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF 282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopathological findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rat and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.

Hypersensitivity reaction after orgotein (superoxide dismutase) administration.

Orgotein is being increasingly used in the treatment of some inflammatory disorders. Up to now no hypersensitivity reaction has been reported. We present the case of an allergic reaction demonstrated by both, "in vivo" and "in vitro" tests. This finding further supports the need for an adequate control during and after orgotein administration.