Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

Endpoint summary

Description of key information

Direct observations: clinical cases, poisoning incidents and other

Data on sodium ferric gluconate complex in sucrose injection

In a small pharmacokinetic study, 14 subjects were given either 62.5 mg or 125 mg of Ferrlecit at a “slow” infusion rate at approximately 2 mg/min and subsequently at a “fast” infusion rate at 15-18 mg/min.

Three adverse events (palpitation, shortness of breath and dizziness) were experienced by one subject during the administration of Ferrlecit under “fast” infusion conditions at a dose of 62.5 mg Ferrlecit over 4 minutes. The adverse events began just after initiation of the drug and were resolved just as the administration of the drug was completed. They did not correlate with the time of maximum concentration of Ferrlecit in the blood of the subject and were not correlated with dose. The study predicted that most patients can safely tolerate infusions of Ferrlecit at the fast infusion rate.

Sensitisation data in humans

Data on sodium ferric gluconate complex in sucrose injection

Various data is available for sodium ferric gluconate complex in sucrose injection (Ferrlecit).

First of all, serious hypersensitivity reactions have been reported from the spontaneous reporting system in the United States, however was observed rarely in patients receiving Ferrlecit.

From 1976 to 1996 where spontaneous reporting in Europe and U.S. can be reliably compared, there were only 74 allergic adverse events reported for Ferrlecit to the World Health Organization (WHO), German Health Bureau, and the manufacturer all combined. For Ferrlecit, there were no reports of deaths over the entire time period. However, for iron dextrans, there were 31 fatalities among 196 allergy/anaphylaxis cases reported in the U.S. yielding a case-fatality rate of 15.8%. The case fatality rate among iron dextran reports is similar to the case severity rates reported in the literature of 20 to 29% severe-to-total cases of anaphylaxis.

The estimated usage of Ferrlecit in Europe is about 2.7 million IV doses per year (1992 to 1996). For the same period, Ferrlecit had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for iron dextran in the U.S. in 1995. This difference is unlikely to be significant for epidemiologic studies. Case fatalities for Ferrlecit and iron dextran within these reports were also compared (see table below).

Allergy and Anaphylaxis Reporting From European and US Sources

Drug Rate	Number of Reports	Number of Deaths	Number of Unknown Outcomes	Case Fatality
Iron Dextrans	196	31	129	15.8%
Ferrlecit Injection	74	0	3	0%

Secondly, hypotension associated with light-headedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been associated with rapid administration of intravenous iron. This has also been reported following administration of Ferrlecit in European case reports. Of the 226 renal dialysis patients exposed to Ferrlecit and reported in the literature, 3 (1.3%) patients experienced hypotensive events which were accompanied by flushing in two. All completely reversed after one hour without sequelae. These hypotensive reactions are not associated with signs of drug hypersensitivity and have usually resolved within one or two hours. Successful treatment may consist of observation or, if the hypotension causes symptoms, volume expansion. Moreover, transient hypotension is a frequent concomitant event during hemodialysis.

The details of the studies with Ferrlecit in humans are described below.

In a small pharmacokinetic study, 14 subjects were given either 62.5 mg or 125 mg of Ferrlecit at a “slow” infusion rate at approximately 2 mg/min and subsequently at a “fast” infusion rate at 15-18 mg/min.

Three adverse events (palpitation, shortness of breath and dizziness) were experienced by one subject during the administration of Ferrlecit under “fast” infusion conditions at a dose of 62.5 mg Ferrlecit over 4 minutes. The adverse events began just after initiation of the drug and were resolved just as the administration of the drug was completed. They did not correlate with the time of maximum concentration of Ferrlecit in the blood of the subject and were not correlated with dose. The study predicted that most patients can safely tolerate infusions of Ferrlecit at the fast infusion rate.

Ferrlecit-associated hypersensitivity events in the multiple dose Study A resulting in premature study discontinuation occurred in three out of a total 88 (3.4%) Ferrlecit-treated patients. However, none of these was fatal. The first patient withdrew after the development of pruritus and chest pain following the test dose of Ferrlecit. The second patient, in the high-dose group, experienced nausea, abdominal and flank pain, fatigue and rash following the first dose of Ferrlecit. The third patient, in the low-dose group, experienced a “red blotchy rash” following the first dose of Ferrlecit.

Only a single patient was determined to have mast cell degranulation by pre-defined criteria in the entire study. This patient exhibited facial and upper body flushing when given 12.5 mg of Ferrlecit, which resolved without any treatment other than withdrawal of drug. The reaction was accompanied by a rise in tryptase from 2.1 to 4.9 ng/mL. The reaction was not considered life-threatening or even serious in the judgment of the clinical investigator.

Of the 38 patients exposed to Ferrlecit in the multiple dose Study B, none reported hypersensitivity reactions. No serum tryptase determinations were made in these studies.

It should be noted that many chronic renal failure patients experience cramps, pain, nausea, rash, flushing, and pruritus.

Most Frequent Adverse Reactions:

In multiple-dose Studies A and B, the most frequent adverse reactions following Ferrlecit were:

Body as a Whole: injection site reaction, chest pain, pain, asthenia, headache, abdominal pain, fatigue, fever, malaise, infection, abscess, back pain, chills, rigours, arm pain, carcinoma, flu-like syndrome, sepsis.

Nervous System: cramps, dizziness, paresthesias, agitation, somnolence.

Respiratory System: dyspnea, coughing, upper respiratory infections, rhinitis, pneumonia.

Cardiovascular System: hypotension, hypertension, syncope, tachycardia, bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema.

Gastrointestinal System: nausea, vomiting and/or diarrhea, anorexia, rectal disorder, dyspepsia, eructation, flatulence, gastrointestinal disorder, melena.

Musculoskeletal System: leg cramps, myalgia, arthralgia.

Skin and Appendages: pruritus, rash, increased sweating.

Genitourinary System: urinary tract infection.

Special Senses: conjunctivitis, abnormal vision, ear disorder.

Metabolic and Nutritional Disorders: hyperkalemia, generalized edema, leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia.

Hematologic System: abnormal erythrocytes, anemia, leukocytosis, lymphadenopathy.

Among the 126 patients who received Ferrlecit in Studies A and B, one patient experienced a transient decreased level of consciousness without hypotension. Another patient discontinued treatment prematurely because of dizziness, lightheadedness, diplopia, malaise, and weakness without hypotension that resulted in a 3-4 hour hospitalization for observation following drug administration. The syndrome resolved spontaneously.

In a post-market clinical study conducted in North America which included 2,534 Ferrlecit-naive patients who received a single-dose of Ferrlecit in a placebo-controlled, crossover, postmarketing safety study, undiluted Ferrlecit was administered over ten minutes (125 mg at 12.5 mg/min) during the first hour of hemodialysis. No test dose was used. Ferrlecit was well tolerated, with an overall incidence of all adverse events (12.3%, 310/2514) which compared favourably to placebo (9.8%, 245/2509), although with statistical significance (p<0.05 by McNemar’s test). Ferrlecit had a lower incidence of outcome (0.4%; 11/2493; confidence intervals 0.21, 0.71%) adverse events than reported historically with iron dextran (2.47%; 64/2589; confidence intervals 1.87, 3.07%). Ferrlecit also had a lower incidence of life-threatening (0.0%; 1/2493; confidence intervals 0.00, 0.22%) adverse events than reported historically with iron dextran (0.61%; 23/3768; confidence intervals 0.36, 0.86%). The cardiovascular system and the digestive system were the only two body systems for which adverse events occurred statistically (p<0.05 by McNemar’s test) more frequently among patients receiving Ferrlecit versus placebo. The percentage of patients who experienced at least one cardiovascular event was 5.4%, 136/2514 for Ferrlecit-treated patients and 4.1% 103/2509 for placebo-treated patients. The majority of the cardiovascular incidents were hypotension, hypertension and vasodilation. Within the digestive system, 2.5%, 64/2514 of patients experienced an event following Ferrlecit and 1.6%, 39/2509 of patients experienced an event after placebo. The majority of these events were diarrhea and nausea. No specific drug relationship of Ferrlecit to hypotension could be identified.

There was no difference in the incidence of life-threatening, outcome, suspected or confirmed allergic, or serious adverse events in patients with prior iron dextran sensitivity compared with patients without iron dextran sensitivity. Concomitant angiotensin converting enzyme (ACE) inhibitor use was also not a predisposing factor for adverse events with Ferrlecit.

No patients in Study C experienced an anaphylactic allergic adverse event as defined by the protocol.

One patient in this study experienced an immediate suspected hypersensitivity reaction which was considered to be life-threatening in the judgment of the clinical investigator. The patient’s reaction, while severe, was not confirmed by serum tryptase test to be a hypersensitivity reaction. It appeared to be an idiosyncratic drug intolerance reaction or anaphylactoid reaction (diaphoresis, dyspnea, and wheezing for 20 minutes) rather than a specific drug allergy.

Moreover, this patient had experienced prior sensitivities to iron dextran and other drugs and the reaction to Ferrlecit is best described as idiosyncratic.

Overall in Study C, 16 (0.6%; 16/2512) had 18 suspected allergic events according to the clinical investigator’s judgment. In only two (0.1%; 2/2512) of the 16 patients were the allergic events (facial redness and back pain) after Ferrlecit administration confirmed as drug intolerance events by a significant rise in serum tryptase levels. Serum tryptase data substantiated the lack of clinically significant immediate hypersensitivity to Ferrlecit.

There was no significant difference in the occurrence of suspected hypersensitivity reactions between Ferrlecit and placebo treatment. The study concluded that Ferrlecit is not an allergen.

Serious hypersensitivity reactions have been reported from the spontaneous reporting system in the United States. There have been eleven serious events which were described by the reporters as allergic or anaphylactoid since the product was introduced in the United States in June of 1999. All resolved without sequelae after withdrawal of Ferrlecit and administration of appropriate therapy.

A rise in serum tryptase is a marker for an immediate anaphylactic or anaphylactoid event or an allergic event.

Data on ferric gluconate

In 2011 the French medicines agency (ANSM) had concerns with regards to the risk of hypersensitivity reactions of intravenous iron containing products indicated in iron deficiency situations when the oral route is insufficient or poorly tolerated especially in chronic kidney disease (CKD) patients (haemodialysis), but also in pre- or post-operative situations, or in case of intestinal absorption disorders (CHMP, 2013).

In view of the above, on 7 December 2011 France requested the Committee for Medicinal Products for Human Use (CHMP) under Article 31 of Directive 2001/83/EC to assess the above concerns regarding hypersensitivity and its impact on the benefit-risk balance for iron intravenous containing medicinal products, and to give its opinion on measures necessary to ensure the safe and effective use, and on whether the marketing authorisation for these products should be maintained, varied, suspended or withdrawn.The iron complexes involved in this procedure are iron gluconate (sodium ferric gluconate), iron sucrose, iron dextran, ferric carboxymaltose, and iron (III) isomaltoside 1000.

The Committee reviewed all available data from pre-clinical, clinical studies, published literature, post-marketing experience on the safety of intravenous iron containing medicinal products with regards to hypersensitivity reactions.

For iron gluconate (sodium ferric gluconate) an overview of the toxicology program performed between 1970’s and 1996 to support registration of sodium ferric gluconate complex was submitted. In addition, clinical data was available. One pivotal and one supportive controlled studies were conducted in adults to assess the efficacy and safety of sodium ferric gluconate as first line treatment for iron deficiency anaemia in renal haemodialysis patients on supplemental recombinant human erythropoietin.

In the pivotal controlled study a total of 88 patients received sodium ferric gluconate. 3/88 experienced allergic reactions leading to product discontinuation. The most frequent AEs experienced by patients in all treatment groups were hypotension (48.7%), nausea (31.9%), vomiting (22.1%) and cramps. Of note, hypotension, nausea, vomiting and cramps are often symptoms associated with haemodialysis. 32/88 patients experienced a reaction at injection site.

Published literature was also provided. Among all studies provided, only one life-threatening reaction was reported (Michael,et al.,2002). This reaction occurred in a patient with a history of multiple drug allergies including anaphylaxis to iron dextran. Furthermore, only three patients with serious adverse events related to intravenous sodium ferric gluconate have been described. One of these cases was an anaphylactoid reaction, and another was a probable serious allergic reaction. It might be of interest to note, that these patients had penicillin allergy and latex allergy, respectively. The Committee for Medicinal Products for Human Use (CHMP) discussed the potential that patients with allergies (notably type 1-allergies) may have an increased risk of serious allergic reactions to intravenous iron.

Data provided regarding safety in pregnancy and intestinal absorption disorder was very limited. One study showed that slow administration of sodium ferric gluconate resulted in less allergic reactions than if this was done during a shorter period of time.

Moreover, post-marketing data for intravenously administered iron gluconate was available. A total of 1649 cases including 546 serious and 1103 non-serious cases corresponding to 6179 ADRs were recorded. Regarding allergic reactions, a total of 846 cases / 1524 ADRs/AEs were identified of which approximately half cases were serious and half were non-serious. Sodium ferric gluconate was mainly prescribed for the treatment of iron deficiency anaemia and rarely for the treatment of anaemia in pregnancy. 20 patients presented a reaction of grade IV. Amoung them 6 died, 5 died from a non-allergic reaction, 1 had previous allergies and severe complications NOS after administration of dextran - he received an overdose of sodium ferric gluconate and died from an acute myocardial infarction the day of sodium ferric gluconate infusion. Another 7/20 patients had a medical history of hypersensitivity reactions.

This supports the conclusion that in patients with known allergies and with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis) the risk of hypersensitivity reactions is enhanced.

In about one third of the total cases (223/846), the patients recovered after drug withdrawal. In the 3% of cases where sodium ferric gluconate was re-administered, the patients experienced the same type of ADRs, mainly allergic reactions without aggravation of the symptoms. Only 1 patient experienced an aggravation of symptoms at the sodium ferric gluconate re-introduction: minor skin reaction at infusion site then hypotension, syncope, nausea and vomiting at the 2nd administration. All these patients recovered after product withdrawal.

19 pregnant women presented at least one anaphylactic reaction. All of them recovered at sodium ferric gluconate withdrawal with or without corrective treatment.

The CHMP concluded that the benefit-risk balance of intravenous iron containing medicinal products is favourable as the benefits continue to outweigh the risks in the treatment of iron deficiency when the oral route is insufficient or poorly tolerated. Furthermore the CHMP agreed on other changes to the product information, additional pharmacovigilance activities and risk minimisation measures to address the risk of hypersensitivity events to all patients including administration in pregnancy. Patients with known allergies and with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis) may enhance their risk when given these products as their condition may worsen unless it is deemed that the benefit outweighs the risks for these patients. All administrations of these iron complexes should be given in an environment with staff able to recognise and treat hypersentitivity reactions and where resuscitation facilities are available. Close monitoring for signs of hypersensitivity during and for at least 30 minutes after each administration of an intravenous iron product is also recommended.

Data on Iron

A case is reported of allergic contact dermatitis due to iron in a toolmaker (Baer, 1973). The patient stated that he was a toolmaker who used the lathe and did bench work, such as machining, shaping, and cutting. He did no welding. In the course of these activities metal dust came off, which settled in his shoes and socks. The cutting oil used also became heavily contaminated with metal dust. In addition to cast iron, he used brass, aluminum, copper, and steel. He changed into his work clothes, which were washed only once a week, in the morning and back into other clothing in the afternoon.

A 66-year-old white man was first seen in March, 1972. He was in good general health and stated that in 1967 he had developed an itchy eruption on the ankles and legs. This subsequently spread to the upper parts of the legs, hands, arms, and trunk. He described the eruption, which was usually worse during the winter months, as occurring in patches and consisting of small water blisters. The eruption had not cleared completely at any time during this period, even though he had been treated with various topical medications and with systemic. corticosteroids. Examination showed a widespread eruption, consisting of moderately erythematous papular and papulovesicular lesions. Many of these occurred in ill-defined patches, and some were crusted. In healing areas slight scaling was noted. The lesions were distributed over the upper and lower extremities and the trunk. On the upper extremities, the dorsa of the hands, the radial aspects of the forearms, and the anterior aspects of the arms were principally involved, There was no involvement of the scalp, face, neck, axillae, palms, soles, and anogenital region.

On the basis of the clinical findings and the history, a preliminary diagnosis of allergic contact dermatitis was made. Nummular eczema was considered in differential diagnosis. Patch tests were performed with 11 different metals in appropriate dilutions. At the time of the 24 hour reading all tests were negative, but at the 72 hour reading a strongly positive reaction to ferric chloride 2 % aqueous solution was seen. The morphologic changes at this positive patch test site were identical with the lesions of the widespread clinical eruption. Because of the history, clinical changes, and patch test results, the diagnosis of allergic contact dermatitis due to iron was considered established. Treatment with betamethasone valerate cream and tar baths topically and promethazine 25 mg by mouth was instituted. A nonalkaline skin cleanser was prescribed. The patient was asked to have his work clothes laundered daily instead of weekly. Two weeks later there was almost complete clearing of the eruption. After 3 months, during which he continued his usual work, the patient reported that his skin had stayed clear with the exception of occasional mild localized eruptions.

This is only the second case of iron contact allergy published in the literature. The possible reasons for the rarity of contact allergy due to iron are considered, among them the development of tolerance due to exposure to iron-containing compounds during fetal life. 

Over a period of 2.5 years, 623 patients with suspected hypersensitivity to metals were patch tested with a series of 21 metal compounds, including ferric chloride 2% aq. and ferrous sulfate 5% pet. (Hemmer, 1996). Those positive to iron were further tested with ferrous (II) sulfate, ferrous (II) ammonium sulfate, ferric (III) ammonium sulfate, iron (III) oxide and ferric (III) chloride - applied in Finn Chambers on Scanpor tape. Readings were taken after 2 and 3-4 days and scored according to ihe recommendations of the ICDRD.

5 positive and 2 doubtful reactions to the initial 2 iron salts (ferric chloride 2 % aq. and ferrous sulfate 5% pet.) were recorded. No irritant reactions were observed. 6/7 patients were available for further testing. Only in 2/6 could the positive result be reconfirmed: both these patients were also positive to nickel and cobalt; nickel or cobalt sensitivity was not observed in the other subjects.

Case no. 1 was a 7-year-old boy tested for suspected nickel allergy. He had Legg-Perthes disease and an orthopedic prosthesis, made from a stainless steel (17% Cr. 13% Ni. 3% Mo, 66% FE), had been implanted 1 year ago. After severe local swelling, this implant had been removed a few weeks later.

Case no. 2 was a 38-year-old woman with a history of severe metal-induced eczema, though no particular history of iron contact.

The reactions to iron salts observed were only moderate in both subjects, mostly erythema and slight infiltration, but they were of crescendo type. In summary iron does not actually seem to play a role as a contact allergen. Positive results obtained on patch testing should be carefully re-investigated, since reactions frequently cannot be confirmed on retesting. In the material used in this investigation, reproducible reactivity was always associated with sensitivity to nickel and cobalt.

Exposure related observations in humans: other data

Data on Iron heptogluconate

Hypochromic anemia, the most common during pregnancy, deserve the attention of the practitioner as a simple treatment can reduce disease symptoms. Indeed iron treatment is, as in all hypochromic iron deficiency anemia, the specific therapeutic. In the experiment the therapeutic action of ferrous heptogluconate was studied in 25 patients with hypochromic pregnancy anemia (Dumont, 1965). This new salt caught attention because its intestinal absorption was experimentally found to be enhanced by the presence of sodium ascorbate. The administered dosage was 6 tablets per day in most cases and 9 tablets per day in 3 cases for an average of 30 to 45 days. Tolerance of Héliofer was perfect in all cases. The causative factors considered mostly responsible for pregnancy-related anemia, i.e. previous bleeding in the present pregnancy, the pregnancy-related bleeding, vomiting of pregnancy and unbalanced diets, multiparity were found in the present investigations. Several factors may be associated, thereby decreasing the iron stores of the woman in labor at a time when needs are growing as it has to support the fetus. The clinical symptomatology of hypochrome anemia is variable, however, several signs should alert the practitioner, especially the paleness of the skin and conjunctiva (noticed 22 times), asthenia (reported 20 times), anorexia (6 times),dyspnea (6 times), digestive troubles (3 cases) and hypotension (2 times). These symptoms are certainly not pathognomonic, but should lead to a hematology practice that will only allow confirmation of the diagnosis of hypochromic anemia. The first hematology (pre-treatment), among the 25 patients investigated revealed: 5 with a number of red cells less than 4 million per mL. In 8 cases this number was even lower at 3.5 million. The other patients had less severe anemia but with a clear hypochromia. Indeed globular value was decreased in all cases. The rate of serum iron, 20 times out of 23 (as in 2 cases the determination of serum iron was not done) it was below normal. In some cases hyposideremia was important, the lowest iron value found in serum was 18 micrograms per mL.

The 25 patients were treated with ferrous heptogluconate following dosage indicated above, and the therapeutic results were satisfactory. A significant increase in red blood cell count was observed (in 20 times out of 25 anemia was corrected in 80% of cases).The results are even clearer if the changes of the globular value and serum iron levels are considered as well. Indeed the globular value increased in 23 patients or in 92% of cases, and serum iron levels increased in 85% of cases. Finally clinically improvement was distinct in17 times, and moderate in 6 times. In 2 cases no change was noted in the condition of the patient. 

In conclusion, ferrous heptogluconate is an effective treatment of the anemia. Indeed, studied in 25 patients with gestational anemia, treatment with Héliofer gave very good results in most cases, since only two failures were observed. Correction of iron deficiency is easily achieved by ferrous heptogluconate. Furthermore, and this should be highlighted, the drug was always well tolerated.

 

Data on sodium ferric gluconate complex in sucrose injection

One study (study A, already specified partly under subsection sensitisation data (humans)) was a three-center, randomized, open-label study of the safety and efficacy of two doses of Ferrlecit administered intravenously to iron-deficient hemodialysis patients. The study included both a dose-response concurrent control and an historical control. Enrolled patients received a test dose of Ferrlecit (25 mg of elemental iron) and were then randomly assigned to receive Ferrlecit at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Ferrlecit was given to both dose groups in eight divided doses during sequential dialysis sessions (a period of 16 to 17 days). At each dialysis session, patients in the low-dose group received Ferrlecit 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received Ferrlecit 125 mg of elemental iron over 60 minutes. The primary endpoint was the change in hemoglobin from baseline to the last available observation through Day 40.

Eligibility for this study included chronic hemodialysis patients with a hemoglobin below 10 g/dL (or hematocrit at or below 32%) and either serum ferritin below 100 ng/mL or transferrin saturation below 18%. Exclusion criteria included significant underlying disease or inflammatory conditions or an epoetin requirement of greater than 10,000 units three times per week. Parenteral iron and red cell transfusion were not allowed for two months before the study. Oral iron and red cell transfusion were not allowed during the study for Ferrlecit® treated patients.

The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.

The evaluated population consisted of 39 patients in the lowdose Ferrlecit group, 44 patients in the high-dose Ferrlecit group, and 25 historical control patients.

The mean baseline hemoglobin and hematocrit were similar between treatment and historical control patients: 9.8 g/dL and 29% and 9.6 g/dL and 29% in low- and high-dose Ferrlecit treated patients, respectively, and 9.4 g/dL and 29% in historical control patients. Baseline serum transferrin saturation was 20% in the low-dose group, 16% in the high-dose group, and 14% in the historical control. Baseline serum ferritin was 106 ng/mL in the low-dose group, 88 ng/mL in the high-dose group, and 606 ng/mL in the historical control.

Patients in the high-dose Ferrlecit group achieved significantly higher increases in hemoglobin and hematocrit than either patients in the low-dose Ferrlecit group or patients in the historical control group (oral iron). Patients in the low-dose Ferrlecit group did not achieve significantly higher increases in hemoglobin and hematocrit than patients receiving oral iron.

 

Another study (study B, already specified partly under subsection sensitisation data (humans)) was a single-center, non-randomized, open-label, historically-controlled, study of the safety and efficacy of variable, cumulative doses of intravenous Ferrlecit in irondeficient hemodialysis patients. Enrolled patients received a test dose of Ferrlecit® (25 mg of elemental iron) and were then randomly assigned to receive Ferrlecit at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Ferrlecit was given to both dose groups in eight divided doses during sequential dialysis sessions (a period of 16 to 17 days). At each dialysis session, patients in the low-dose group received Ferrlecit 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received Ferrlecit 125 mg of elemental iron over 60 minutes. The primary efficacy variable was the change in hemoglobin from baseline to the last available observation through Day 50.

Inclusion and exclusion criteria were as follows: Eligibility for this study included chronic hemodialysis patients with a hemoglobin below 10 g/dL (or hematocrit at or below 32%) and either serum ferritin below 100 ng/mL or transferrin saturation below 18%. Exclusion criteria included significant underlying disease or inflammatory conditions or an epoetin requirement of greater than 10,000 units three times per week. Parenteral iron and red cell transfusion were not allowed for two months before the study. Oral iron and red cell transfusion were not allowed during the study for Ferrlecit treated patients. Sixty-three patients were evaluated in this study: 38 in the Ferrlecit-treated group and 25 in the historical control group. The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.

Ferrlecit-treated patients were considered to have completed the study per protocol if they received at least eight Ferrlecit doses of either 62.5 mg or 125 mg of elemental iron. A total of 14 patients (37%) completed the study per protocol. Twelve (32%) Ferrlecit®- treated patients received less than eight doses, and 12 (32%) patients had incomplete information on the sequence of dosing. Not all patients received Ferrlecit at consecutive dialysis sessions and many received oral iron during the study.

Baseline hemoglobin and hematocrit values were similar between the treatment and control groups, and were 9.1 g/dL and 27.3%, respectively, for Ferrlecit-treated patients. Serum iron studies were also similar between treatment and control groups, with the exception of serum ferritin, which was 606 ng/mL for historical control patients, compared to 77 ng/mL for Ferrlecit-treated patients.

In this patient population, only the Ferrlecit®-treated group achieved significant increase in hemoglobin and hematocrit from baseline. This increase was significantly greater than that seen in the historical oral iron treatment group.

 

A third study (study C, already specified partly under subsection sensitisation data (humans)) was a multicentre (n = 69), crossover, randomized, double-blind, prospective study of the safety of Ferrlecit in hemodialysis patients who required at least 125 mg of elemental intravenous iron.

A primary objective of the study was to compare outcome (drug intolerance) events and lifethreatening adverse events after Ferrlecit administration compared to placebo and an historical control. The historical control was based on a conservative analysis of exposure to iron dextran in defined patient populations from three independent publications which were combined by meta-analysis. The drugs were three different marketed formats of iron dextrans, used in three different populations. Two of the studies were retrospective and one study was prospective. Iron dextran was administered intravenously in doses which varied from 25 mg to 100 mg in these studies.

Another primary objective of this study was to assess the safety of Ferrlecit when administered undiluted at a rate of 12.5 mg/minute without a test dose in a large patient population. Each patient received a total of 125 mg of Ferrlecit® (10 mL undiluted) by slow injection via the venous return over 10 minutes. Treatment was administered during the first hour of hemodialysis. Patients received a course of four sequential dialysis sessions over a duration of approximately one week. At the first hemodialysis session, patients underwent screening procedures. If eligible to continue the study, patients were randomized to one of two crossover treatment schedules as follows: Ferrlecit at session 2 and placebo at session 3 or placebo at session 2 and Ferrlecit at session 3.

A third primary objective of this study was to compare the incidence of all immediate-type suspected and confirmed allergic reactions following Ferrlecit administration with those following placebo administration.

A rise in serum tryptase is a marker for an immediate anaphylactic or anaphylactoid event or an allergic event. The first 200 patients from selected centres had serum tryptase assays performed on samples obtained during dialysis. Blood from these patients was also drawn at session 2 prior to and 60 minutes after study drug administration, to define the normal range for changes in tryptase in this population, and to identify the effect of dialysis, Ferrlecit administration, and normal saline / benzyl alcohol solution (placebo) on circulating tryptase levels. In the event that one of these selected patients had a suspected allergic event, their blood was not included in the analysis defining the normal range, and a replacement was selected. A significant increase in tryptase level was defined as two standard deviations from the mean change defined in the reference (n = 200) population.

In all patients, a baseline blood sample was obtained at initiation of dialysis before study drug administration. In patients who had a suspected allergic event during administration of either study drug (Ferrlecit or placebo), then another blood sample was obtained one hour following the beginning of the event, and both samples for the patient were analyzed for serum tryptase levels. A confirmed allergic event was defined as one that had a post-event

increase in tryptase level that was at least two times greater than baseline (at or above 100% increase).

In the final analysis, 2512 patients were exposed to Ferrlecit and 2487 were exposed to placebo in the cross-over design for Study C. 2489 patients were evaluable for protocol events, having received both Ferrlecit and placebo infusions and having completed the study according to protocol.

Ferrlecit was well tolerated, with an overall incidence of all adverse events (12.3%, 310/2514) which compared favourably to placebo (9.8%, 245/2509), although with statistical significance (p < 0.05 by McNemar’s test). The safety of Ferrlecit was also demonstrated by the incidence of outcome (0.4%, 11/2493) and life-threatening (0.0%, 1/2493) adverse events which was not significantly different (McNemar’s test) than for the placebo treatment (outcome events 0.1%, 2/2487, lifethreatening events 0%, 0/2487). The incidence of adverse events for Ferrlecit was lower than reported historically with iron dextran (2.47%, 64/2589 for outcome events and 0.61%, 23/37684 for life-threatening events). The incidence of serious adverse events following Ferrlecit was 0.6%, 14/2514 while the incidence following placebo was 0.5%, 12/2509. The difference was not statistically significant by McNemar’s test.

Three of 11 outcome events after Ferrlecit were considered immediate serious adverse events (pruritus, hypotension and anaphylactoid reaction). Both the pruritus and the anaphylactoid reaction were also classified as clinically suspected allergic events; however both were subsequently confirmed by tryptase assay to be non-allergic. The third event (anaphylactoid reaction) was also considered by the investigator to be a life-threatening adverse event. The patient had a suspected anaphylactoid reaction (diaphoresis, dyspnea and wheezing for 20 minutes) immediately following administration of Ferrlecit. However the event was not anaphylactic per protocol because the patient’s serum tryptase level decreased from 11.7 ng/mL to 10.8 ng/mL. Additionally the patient had prior history of severe anaphylactoid reaction to iron dextran, had experienced rash when given penicillin and pruritus when given cephalosporin. This patient most probably had a high constitutive leak of tryptase with resultant drug idiosyncratic intolerance rather than a specific drug allergy.

Ferrlecit was not statistically different (by McNemar’s test) from placebo in suspected allergic reactions (rash, pruritus, nausea, dizziness, chills, dyspnea, chest pain, dry throat, vomiting, headache, malaise). The rate of reaction following Ferrlecit was 0.5% (12/2493) compared to 0.2% (5/2487) for placebo. For confirmed allergic events (based on tryptase assay), the rate following Ferrlecit was 0.1% (2/2493, facial redness with rise in serum tryptase from 2.1 to 4.9 ng/mL, and back pain with rise in serum tryptase from 3.8 to 7.8 ng/mL). No allergic events were confirmed by tryptase assay following placebo; calculated incidence 0% (0/2487). There were no patients in this study who experienced an anaphylactic event as defined by the protocol. The cardiovascular system and the digestive system were the only two body systems for which adverse events occurred statistically (p<0.05 by McNemar’s test) more frequently among patients receiving Ferrlecit versus placebo. The percentage of patients who experience at least one cardiovascular event was 5.4%, 136/2514 for Ferrlecit-treated patients and 4.1% 103/2509 for placebo-treated patients. The majority of the cardiovascular incidents were hypotension, hypertension and vasodilation. Hypotension is known to be a frequent concomitant event during hemodiaylsis and in fact, there was no statistically significant difference between Ferrlecit and placebo for this adverse event. Within the digestive system, 2.5%, 64/2514 of patients experienced an event following Ferrlecit and 1.6%, 39/2509 of patients experienced an event after placebo. The majority of these events were diarrhea and nausea. Prior iron dextran sensitivity and concomitant angiotensin converting enzyme (ACE) inhibitor therapy were monitored as secondary study objectives, and were found to be not predisposing factors for adverse events.

Finally, the overall low incidence of all adverse events, including allergic outcome, serious, and life-threatening events supports the safety of administering Ferrlecit at a rate of 12.5 mg/minutes without a test dose.

 

Data on ferrous gluconate

 

This investigation was designed to assess the efficacy of the fortification of powdered cow’s milk with ferrous gluconate, in combination with ascorbic acid, in reducing the prevalence of IDA in a sample of Mexican toddlers with a high prevalence of anemia (Villalpando, 2006).

Healthy children were randomly assigned to drink 400 mL/d of cow’s whole milk, either fortified milk (FM) with 5.8 mg/400 mL of iron as ferrous gluconate, 5.28 mg/400mL of zinc as zinc oxide, and 48 mg/400mL of ascorbic acid, or nonfortified milk (NFM) with 0.2 mg iron/400 mL, 1.9 mg zinc/400 mL, and 6.8 mg ascorbic acid/400 mL. Hemoglobin, serum ferritin, soluble transferrin receptors (TfR), and C-reactive protein concentrations were measured at baseline and 6 mo after intervention.

The prevalence of anemia declined from 41.4 to 12.1% (P < 0.001), or 29 percentage points, in the FM group; there was no change in the NFM group. Hemoglobin (coefficient = 0.22, P< 0.01) was positively and TfR (coefficient = 20.29, P < 0.001) negatively associated with treatment, controlling for their respective baseline values, age, and gender. Treatment with FM was negatively associated with the likelihood of being anemic (pseudo R² = 0.085, P < 0.03) after 6 mo of intervention. Ferrous gluconate added to whole cow’s milk as a fortificant along with ascorbic acid is efficacious in reducing the prevalence of anemia and in improving iron status of Mexican toddlers. The results of this study lead to broadening a subsidized FM distribution program to 4.2 million beneficiary children 1–11 y of age in Mexico.

In summary, ferrous gluconate added as fortificant to cow’s whole milk, along with ascorbic acid, is efficacious in reducing the prevalence of anemia and improving the iron status of Mexican preschoolers of 10 -30 month of age with a high prevalence of IDA. The results of this study led to the decision to scale-up an FM distribution program to 4.2 million beneficiary, low-income children, 1–11 y old in Mexico. Targeted beneficiaries are from families categorized in the food poverty range. This is an example of how the use of research can directly benefit the design of successful public nutrition programs.