Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia

Abstract

Oral iron is a standard treatment of iron deficient anemia despite high rates of intolerance and nonadherence and may not replenish iron stores rapidly enough to meet ongoing losses [1]. Intravenous (IV) iron has advantages but remains underutilized. Whereas most formulations of IV iron require multiple doses for replacement, low molecular weight iron dextran (LMW ID) may be administered as a total dose infusion, typically over a 4- to 6-hr period [2, 3]. A 4-hr infusion for doses up to 4 g was standard in our practice until 2 years ago. However, clinical studies suggest that 1 g of IV iron is an adequate dose for many patients [3-5], and it became apparent that we were frequently infusing doses of at least 1 g in 1 hr without evidence of significant adverse events [3]. Now, our clinical practice routinely infuses 1 g of LMW ID in 250 mL normal saline over 1 hr without premedication as our standard practice. We summarize our experience with the safety and efficacy of this method of administering IV iron in unselected patients with iron deficiency. From July 11, 2008 to February 25, 2010, a total of 396 consecutive iron deficient patients received 1g LMW ID infusions. The mean age was 50.7 years (range 14 to 90), 84.1% were women, 75.1% were white, and 14.4% had multiple documented drug allergies at baseline. The most common diagnoses were heavy uterine bleeding among women (43.5%) and gastrointestinal bleeding among men (33.3%). The majority (78.9%) included in this study had baseline transferrin saturation (TSAT) ≤ 20% (mean: 11.5 ± 8.7%) and serum ferritin ≤ 100 ng/mL (median: 11.0 ng/mL, range: <1–1,164 ng/mL). (Demographic characteristics and baseline laboratory parameters are further described in Supplemental Table I, available online.) A total of 570 infusions were administered over a median time of 63 min [interquartile range: 60–66 min (Fig. 1)]. INFeD administration–distribution of infusion time. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] A total of 41 adverse events (AEs) were reported in 22 patients (5.6%), with six patients requiring a decreased rate or temporary interruption of the infusion. One refused further treatment due to an AE (hives). There were no anaphylactoid reactions and no serious AEs (SAEs). All AEs were considered mild to moderate in severity, the most common being back pain, headache, myalgia, and nausea (Table I), all of which were self-limiting and completely resolved with no intervention in the majority of patients. A total of seven patients received treatment with methylprednisolone injection (n = 5) or acetaminophen (n = 2). Although AEs were relatively more common among female and black patients, these differences were not significant. An independent association was observed between multiple (>2) drug allergies and an increased likelihood of an AE [odds ratio (OR) = 3.40; 95% CI: 1.09–10.63; P= 0.036] when controlling for race, gender, and relative dose [estimated body surface area (BSA)] (Figure 2; Supplemental Table II, available online). However, this finding should be interpreted with caution due to the very low absolute incidence rate. Other variables, including baseline iron status and age, were not associated with the incidence of observed AEs. Adverse events by subgroup. When controlling for race, gender, and relative LMW ID dose, there was an independent association between number of drug allergies and the occurrence of adverse events (P = 0.036). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Premedication with 125 mg of IV methylprednisolone was administered to only 10 patients with a history of multiple drug allergies (4), asthma, active inflammatory bowel disease, and/or a previous reaction to IV iron. Three received granisetron premedication due to anticipatory nausea (n = 2) or nausea with prior IV iron therapy (n = 1). All premedicated patients subsequently received the infusion without AEs. No patient received premedication with antihistamines. Clinically significant hypophosphatemia, defined as a serum phosphate level < 2 mg/dL, was not observed. The mean change in serum phosphate level was monitored in a subset of patients (88 infusions in 87 patients). At preinfusion baseline, mean phosphate level was 3.6 ± 0.54 mg/dL (range: 2.0–5.1 mg/dL). After a median follow-up period of 2 weeks postinfusion, mean phosphate level was 3.6 ± 0.52 mg/dL (range: 2.4–5.3 mg/dL), with a mean change from baseline of 0.0 mg/dL (95% CI: −0.15 to 0.08; P= 0.58). Paired preinfusion and postinfusion hemoglobin (Hb) data were available for 434 infusions in 319 patients (Supplemental Table III, available online). Mean preinfusion Hb was 10.8 ± 1.6 g/dL. Treatment resulted in a significant increase in Hb (mean change from preinfusion baseline: +1.1 g/dL; P < 0.0001; 95% CI: 1.0–1.2 g/dL) over a median follow-up time of 4 weeks. An increase in Hb of ≥1 g/dL occurred following 222 infusions (51.2%) in 187 patients, and an increase in Hb of ≥2 g/dL occurred following 114 infusions (26.3%) in 108 patients. One patient received a blood transfusion following a severe gastrointestinal bleed secondary to angiodysplasia. Four patients received a dose of darbepoetin alfa within a week of the iron infusion, and the follow-up Hb data for these patients were excluded from the efficacy analyses. Although the majority of patients had preinfusion TSAT ≤20% and serum ferritin ≤100 ng/mL, 21.1% had TSAT >20% and/or serum ferritin >100 ng/mL. There was no significant difference in magnitude of Hb response between these two subsets (mean difference in Hb increase between patients with TSAT ≤ 20% and serum ferritin ≤ 100 ng/mL and the others was 0.3 g/dL; 95% CI: −0.0 to 0.5 g/dL; P = 0.08). When baseline TSAT ≤ 20% and serum ferritin ≤ 100 ng/mL, 54% of infusions led to an increase in Hb of at least 1 g/dL, while 37% of infusions when TSAT >20% or serum ferritin >100 ng/mL achieved an increase in Hb of at least 1 g/dL (Supplemental Table IV, available online). A total of 31 infusions in 43 women with pregnancy-related anemia (second and third trimester, or postpartum), for whom follow-up data were available, were included in the efficacy analysis. In this subgroup, the mean change in Hb from baseline was 1.2 g/dL (95% CI: 0.79–1.65 g/dL; P < 0.0001), and 25.8% resulted in an increase in Hb of >2 g/dL. Four of the patients with pregnancy-related anemia reported AEs. One resolved with a decreased rate and temporary interruption of the infusion and three received treatment with IV methylprednisolone. Although oral iron is a convenient and inexpensive therapy for iron deficient anemia, it has several important limitations. Even in patients who are not inflamed, and therefore have no problems with absorption, effective treatment requires a long course to correct anemia and completely replenish stores. Significant nonadherence and intolerance abound. While any of the available IV irons can infrequently cause acute reactions, the incidence and severity of these reactions are far less than perceived [6]. Whereas LMW ID, iron sucrose, ferric gluconate, and ferumoxytol can be administered safely and effectively, only LMW ID can be used to provide total dose repletion in a single setting (a method of administration approved in Europe but not the United States). This method of administration has typically been 2–6 hr in published reports. In some studies, doses of ≥3 g (and up to 4.5 g) were infused. Numerous clinical studies suggest that 1 g is an adequate dose for the majority of patients, and several support the use of 1 g/hr, providing a rationale for administering 1 g over 1 hr in this study [3, 7-11]. No prospective study has shown benefit of premedication with antihistamines, yet they are often administered empirically. A study of 135 iron deficient patients who received antihistamines before the administration of IV iron reported that the most frequent AE observed was sedation due to the antihistamine [1]. Antihistamines have been associated with flushing, hypotension, supraventricular tachycardia and somnolence, all of which may be misinterpreted as iron-related reactions. In contradistinction to the AEs just described, there is a syndrome occurring in ∼1:200 patients described by Fishbane, consisting of arthralgia and myalgia of the chest or flank, usually occurring with or after the test dose, without associated hypotension, tachypnea, tachycardia, wheezing, stridor, or periorbital edema. This reaction routinely abates without treatment and rarely recurs with rechallenge [6]. Inappropriate intervention with antihistamines or pressors can convert this minor reaction to one which is hemodynamically significant. On the basis of these observations, we avoid the use of antihistamine premedication. A history of multiple drug allergies has been associated with an increase in AEs to IV iron [12]. Our results were consistent with these observations in that AEs were relatively more common among those with more than two drug allergies. Four patients with multiple drug allergies received premedication with methylprednisolone, none of whom subsequently experienced an AE. Nonetheless, minor AEs were observed in 22 (5.6%) patients, and no SAEs were observed throughout this study. The reported AEs usually consisted of mild to moderate back pain, headache, and nausea. All AEs occurring during the infusion resolved within minutes, and all received the total planned dose, with the one exception who discontinued due to hives. Over the limited range of values observed in this study, we observed that Hb response, among these iron-deficient patients, was not associated with baseline iron status (TSAT ≤ 20% and serum ferritin ≤ 100 ng/mL vs. TSAT > 20% and/or serum ferritin > 100 ng/mL). This finding is consistent with that observed in anemia of chronic disease, where total iron binding capacity (TIBC, a negative acute phase reactant) is often depressed and serum ferritin (a positive acute phase reactant) can be increased. In fact, in hemodialysis- and chemotherapy-related anemias, serum ferritin has been shown to be a poor predictor of Hb responsivesness to IV iron [13, 14], particularly in settings of inflammation, infection, and chronic diseases. This study included 43 women who had pregnancy-related anemia. Anemia in pregnancy, a known risk factor for maternal and fetal morbidity and mortality, continues to be managed primarily with oral iron. However, gastrointestinal adverse effects and intolerance significantly limit the use of oral iron in pregnancy, as the effect of pregnancy on the gastrointestinal tract is often aggravated by the adverse effects of oral iron [15, 16]. These results are consistent with the study published by Ayub in 2008, where infusion of LMW ID was a safe and effective method of iron supplementation in pregnancy-related iron deficient anemia [17]. Ferric carboxymaltose has been given as a 1g infusion over 15 min to patients with chronic kidney disease, inflammatory bowel disease, and iron deficient anemia due to menorrhagia or pregnancy [18, 19]. However, in February 2008, the FDA delayed approval of ferric carboxymaltose for distribution in the United States, due to an increased number of adverse cardiac events, an imbalance in death rates in the treatment arm compared to the control arm, and hypophosphatemia, a marker of renal tubular injury, 2 weeks following administration [20]. As a result of these findings, we monitored serum phosphate levels prior to and 2 weeks following the infusion of 1 g LMW ID and found no decrease. Subsequent to this analysis, we have administered another 696 1-hr infusions of 1 g LMW ID in 492 consecutive, nonselected patients. The safety and efficacy data from these additional patients are consistent with the results reported in this study. Only one patient did not receive the planned dose due to refusal to be rechallenged after a transient myalgia of the chest. In the integrated safety analysis of 888 patients, no SAEs have been observed in a total of 1,266 infusions. However, this retrospective analysis is limited in its ability to detect serious events as the reported rate of SAEs is so rare that even if the underlying rate were as high as 1 in 1,000, we would need to study 3,000 infusions to have a 95% chance of detecting one such event. The data in this large population of consecutive, unselected patients with iron deficient anemia provide support for the safety and effectiveness of replacement doses of 1 g LMW ID given IV over 1 hr, without premedication. This method of administration has the advantages of a shorter treatment period and assured compliance compared to oral iron. While future prospective, randomized studies are needed to confirm these findings, the results of this study question the paradigm that oral iron should be standard first line therapy for all conditions associated with iron deficiency. Data were collected from consecutive, unselected patients with iron deficient anemia not actively receiving erythropoiesis-stimulating agents (ESAs) or chemotherapy, who were treated with 1 g LMW ID. All patients included were referred from internal medicine, family practice, obstetrics and gynecology, and gastroenterology practices. With the exception of patients with inflammatory bowel disease, where oral iron has been shown to exacerbate the inflammation of the intestinal epithelium [21], all had either previously failed or were intolerant of oral iron. After obtaining informed consent for data collection and treatment, patients underwent a baseline evaluation including medical history, physical examination, and laboratory testing (hematology and biochemistry profiles). Following initial consultation and confirmation of iron deficiency (TSAT ≤ 20% and/or serum ferritin ≤ 100 ng/mL), all patients received an infusion of 1 g LMW ID (INFeD, Watson Pharma, Morristown, NJ) diluted in 250 mL of normal saline. A test dose was administered to all IV iron-naïve patients by withdrawing 10 mL from the bag and administering it as a 5-min IV push. After a 15-min observation period, the remainder of the dose was administered at 300 mL/hr. If an adverse reaction occurred, the infusion was stopped, and the patient was observed for up to 1 hr. In these instances, the infusion was restarted at 100 mL/hr and adjusted as needed. Subsequent infusions, and those administered to non-IV iron-naïve patients, were administered at a rate to infuse the IV iron over a total of 1 hr. The primary outcome of this study was defined as the safety of administering 1 g LMW ID infusions over 1 hr. Safety was assessed by recording all signs or reports of AEs temporally associated with an infusion, and details of their treatment and resolution. AEs were categorized by Medical Dictionary for Regulatory Activities (MedDRA) preferred term. Additionally, due to concerns about hypophosphatemia observed with other IV iron formulations, mean change in phosphate level from baseline was evaluated in a subset of patients. The secondary efficacy variables were the mean change in Hb from preinfusion baseline, the proportion of patients achieving an increase in Hb ≥ 2g/dL, and number of transfusions administered. The following additional data were extracted from patients' charts: age, gender, height, weight, diagnosis, tests of iron status (serum ferritin, TIBC, serum iron, and TSAT), history of drug allergies and/or iron allergies, dose of iron dextran, and infusion rate. Demographic data, baseline laboratory values, and infusion data were summarized using descriptive statistics. Association between patient characteristics and the likelihood of experiencing an AE were explored using multiple logistic regression. Significance of change from baseline in Hb and serum phosphorus levels was analyzed using the paired student's t-test. The relationship between baseline iron status (preinfusion TSAT ≤ 20% and serum ferritin ≤ 100 ng/mL) and change in Hb was explored using analysis of covariance model including baseline value and length of follow-up period (<4 weeks or ≥4 weeks) as covariates. The authors thank Kristin Vaneekhoven for excellent editorial assistance. Financial Disclosures: Dr. Auerbach has not served as a paid consultant for any company manufacturing intravenous iron, been a member of any speaker bureau, or accepted honorarium since September 2007. Dr. Dahl and Dr. Pappadakis are salaried employees of Watson Pharmaceuticals. Drs. Bahrain, Ballard, and S. Auerbach have no financial disclosures to report. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Michael Auerbach MD* , Jennifer A. Pappadakis PhD , Huzefa Bahrain DO*, Sarah A. Auerbach BS*, Harold Ballard MD§, Naomi V. Dahl PharmD , * Auerbach Hematology-Oncology, Baltimore, Maryland, Clinical Professor of Medicine, Georgetown University School of Medicine, Washington, DC, Medical Affairs, Watson Laboratories, Inc., Parsippany, New Jersey, § Department of Medicine, New York University School of Medicine, NY, New York.