Sodium Ferric Gluconate Complex Research Articles

Iron Deficiency Anemia: The Impact of Intravenous Iron Replacement Treatment on Health Care Costs

INTRODUCTION: An estimated 5 million patients in the United States have iron deficiency anemia (IDA). Although most patients with IDA initiate treatment with oral iron therapy, IV iron replacement therapy is often required in patients with chronic inflammatory diseases such as cancer, heart failure (HF) or chronic kidney disease (CKD). The 2022 AHA/ACC/HFSA recommends IV iron as a treatment option for patients with HF with reduced ejection fraction and iron deficiency with or without anemia. There is limited real-world data on the economic value of IV iron treatment. This study examined health care costs for patients treated with ferric carboxymaltose (FCM) and patients treated with low-dose IV iron therapy in the populations with cancer, HF or CKD. METHODS: This study included commercial and Medicare Advantage patients from the Optum Research Database, a large, national United States administrative claims database. Patients were included if they were treated with IV iron therapy from 2017 to 2019; the first treatment date was the index date. Patient were required to have cancer, HF, or CKD in addition to an IDA diagnosis. Continuous enrollment was required for a 6-month baseline and 12-month follow-up period (with patients retained if they had <12 months due to death). Cohorts were classified based on index date treatment: FCM patients received ferric carboxymaltose; low-dose IV iron patients were treated with iron sucrose, iron dextran, or sodium ferric gluconate complex in sucrose. Follow-up all-cause total costs were compared using generalized linear models, and inpatient costs estimated with 2-part models to account for patients with no hospitalizations. Models adjusted for age, gender, geographic region, plan type, index year, comorbidity score, and baseline health care cost. Sensitivity analyses compared FCM with the subgroup treated with iron sucrose. RESULTS: Cancer population: Of 10,763 cancer patients meeting eligibility criteria, 5,892 patients received FCM, and 4,871 patients received low-dose IV iron. Within the low-dose IV iron cohort, 3,040 patients (62%) received iron sucrose. The meanadjusted all-cause total cost was similar between FCM and low-dose IV iron (cost ratio 0.97; p=0.182) and significantly lower for FCM vs. iron sucrose (cost ratio 0.92; p=0.001). Adjusted all-cause inpatient costs for FCM were lower compared to low-dose IV iron due to lower risk of hospitalization (odds ratio 0.79, p<0.001) and reduced inpatient costs if hospitalized (cost ratio 0.88; p<0.001); results were similar versus iron sucrose (p<0.001). HF population: Of 8,337 HF patients, 3,364 patients received FCM, and 4,973 patients received low-dose IV iron therapy. Within the low-dose IV iron cohort, 3,471 patients (70%) received iron sucrose. All-cause total cost for FCM was similar to low-dose IV iron (cost ratio 0.97, p=0.198) but significantly lower for iron sucrose (0.95, p=0.024) during follow-up period. All-cause inpatient cost was also lower for FCM compared to lose-dose IV iron (odds ratio 0.76; cost ratio 0.88; p<0.001) and iron sucrose (odds ratio 0.79; cost ratio 0.85; p<0.001). CKD population: Of 10,617 CKD patients, 4,377 patients received FCM, and 6,240 patients received low-dose IV iron. Within the low-dose IV iron cohort, 4,584 patients (73%) received iron sucrose. During the follow-up period, the mean adjusted all cause total cost was significantly lower for FCM compared to low-dose IV iron (cost ratio 0.94; p=0.006) and iron sucrose (cost ratio 0.93; p=0.004). All-cause inpatient cost was also lower for FCM compared to low-dose IV iron (odds ratio 0.75; cost ratio 0.84; p<0.001) and iron sucrose (odds ratio 0.75; cost ratio 0.89; p<0.001). CONCLUSIONS: Despitethe higher drug acquisition cost ofFCM relative to low-dose IV iron, the drug price differential was offset by lower inpatient cost incurred in the FCM group. This resulted in similar all-cause total health care costs between FCM and low-dose IV iron in cancer and heart failure patients and lower total cost for FCM compared to low-dose IV iron in CKD patients. These results were more pronounced when comparing FCM with iron sucrose; the FCM group consistently had statistically lower total costs than iron sucrose in patients with cancer, HF and CKD. These findings suggest FCM's potential economic benefit in reducing in inpatient utilization and associated costs to patients and health plans than the low-dose IV iron products.

Iron Infusions, Their Reactions and Efficacy Related to Dosing - a Single Center Retrospective Study

Background: Intravenous (IV) iron infusions are associated with a variety of adverse drug reactions (ADRs) including anaphylactic reactions. The Commonly used IV iron formulations are Iron sucrose (Venofer), Ferric carboxymaltose (Injectafer), Sodium ferric gluconate complex (Ferrlecit), and others. Iron sucrose has been approved by the FDA (Food and Drug Administration) for patients with iron deficiency who also have kidney disease. It is also often used off-label for iron deficiency anemia on its own. In our facility, multiple ADRs were noted with Venofer compared to other formulations. Hence, we aimed to study: 1. If altering the dose of Venofer will result in a lesser incidence of allergic reactions. 2. To determine if one preparation of IV iron has a higher incidence of adverse events than another. 3. To evaluate the efficacy after 6 to 8 weeks of completion of iron infusions, by comparing the response to various dosages and formulations. Methods: This is a retrospective chart review of 274 patients ages 18-92 who received at least one dose of Intravenous Iron at Einstein Medical Center Montgomery Outpatient Infusion Center from 01/01/21 to 10/31/21. Patients were divided into two groups based on the Venofer dosing schedule. Group D1 included patients that received any IV iron formulation from January to May 2021. In this group, Venofer dosing was 400mg x 1 followed by 300mg x2. Multiple ADRs were noticed in group D1 hence Group D2 was created. This group included patients that received any IV iron formulation from June to October 2021, where Venofer dosing was changed to 300mg x 3 doses or 300mg x 2 followed by 400mg. We collected data on age, gender, race, preparation, strength, pregnancy status, prior history of allergies and transfusion reactions, adverse drug reactions, the timing of reaction, total doses received, pre/post-medications provided to prevent or treat a reaction, outcomes of reaction, hemoglobin, iron studies before and after the infusions. Patient characteristics in both D1 and D2 groups were well balanced. Data were analyzed and summarized in descriptive measures. Efficacy of intravenous iron treatment was measured as a rise in Hemoglobin by 2gm/dl. Results: Out of 120 patients in group D1, 71 patients (59.2%) received Injectafer, out of these, 12 patients (16.9%) had ADRs, the most common reaction was hypotension, and 1 patient had an anaphylactic reaction requiring Emergency Room (ER) visit. Responders in this group were 28/71(39.4%). 10/71 (14.1%) were lost to follow-up. 48 patients (40%) received Venofer, out of which 11 patients (22.9%) had ADRs, the most common being pain in the back, and 2 patients required ER visits. Responders to the infusion in this group were 11/48 (22.9%) with 10/48 (20%) lost to follow-up. 1 patient (0.8%) received ferumoxytol, with no ADRs to report. In the D2 group, which involved a total of 154 patients, 76 patients (49.3%) received Injectafer, out of which 14 patients (18.4%) had ADRs, again the most common being hypotension, and 2 patients required an ER visit. Responders in this group were 29/76 (38.1%) and 10/76 (13.2%) were lost to follow-up. 77 patients (50%) received Venofer, out of which 9 patients (11.7%) had ADRs, the most common being hypotension and this group has not had any ER visits. Responders to the infusion in this group were 36/77(46.8%) and 9/77 (11.7%) were lost to follow-up. 1 patient (0.6%) received Ferumoxytol with no ADRs. [See Table 1]. Conclusions: Injectafer was overall the most used iron formulation in our institution. It was associated with more ADRs when compared to Venofer, including anaphylactic reactions. The most common ADR was hypotension with Injectafer, and back pain with Venofer. We found that Venofer dosing with 400mg x 1 followed by 300mg x2 was associated with the highest incidence of ADRs. Both strategies of Venofer dose modification with 300mg x 3 and schedule modification, 300x 2 followed by 400mg had greater efficacy and lesser frequency of ADRs as compared to Venofer 400mg followed by 300mg x2. Other studies have shown the benefit of Venofer in non-renal disease patients with iron deficiency. Although our study was not planned to demonstrate this outcome, our data may suggest that Venofer is beneficial for this group of patients. This should be looked into with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Retrospective Assessment of Total Cost of Care in Non-Dialysis Dependent Chronic Kidney Disease Patients Receiving Parenteral Iron Therapy for Iron Deficiency Anemia

Introduction Iron deficiency anemia (IDA) is a common comorbidity among patients with chronic kidney disease. Iron deficiency occurs in 15% to 48% of non-dialysis dependent chronic kidney disease (ND-CKD) patients with anemia. Parenteral iron therapy is often required in ND-CKD patients with IDA who cannot tolerate or are nonresponsive to oral iron. Available IV iron treatments vary in the amount of iron dose per administration, the number of infusions required to achieve complete iron repletion and drug acquisition cost. The objective of this study was to compare healthcare costs between ferric carboxymaltose (FCM) and low dose IV iron (LDI) for the treatment of IDA in ND-CKD patients. Methods Medical and pharmacy claims from IQVIA PharMetrics® Plus data were analyzed. Adult patients who received first (index) dose of FCM or LDI (i.e., iron sucrose, iron dextran, sodium ferric gluconate complex in sucrose) from 2017 to 2019 were included. Eligible patients were required to be continuously eligible 6 months before (baseline) and 12 months after index IV iron infusion and had medical claims associated with diagnosis of chronic kidney disease (ICD-10: N18.1 to N18.5) and IDA (ICD-10: D50.x) anytime during the 18-month study observation period. In addition, eligible FCM patients were required to receive a second dose of FCM within 21 days of index date. Patients who had claims associated with end stage renal disease (ICD-10: N18.5 and N18.6) or dialysis (HCPCS CPT code: 90935-90999) and patients who had received other IV iron products in the 6-month baseline period were excluded. Unadjusted mean number of IV iron infusions, outpatient visits and hospital admissions in the 6 months before and 12 months following index IV iron dose were summarized on a per-patient-per-month basis. Post-index monthly inpatient, outpatient, and total healthcare costs for FCM and LDI were compared using generalized linear model with gamma log-link adjusting for pre-index monthly cost, age, gender, year of index treatment and the Charlson Comorbidity Index (CCI). Sensitivity analyses comparing FCM versus iron sucrose were performed. Results Data from 3,727 FCM patients [mean (SD) age= 67.9 (13.8) years, 61% females, CCI (SD)=1.9 (2.5)] and 5,068 LDI patients [mean (SD) age=64.8 (15.0) years, 60% females, CCI (SD)=1.6 (2.4)] were analyzed. Within the LDI cohort, 3,489 patients received index iron sucrose treatment [mean (SD) age=64.6 (15.1) years, 60% females, CCI (SD)=1.5(2.4)]. Mean (SD) number of IV iron infusions was 0.24 (0.26) for FCM, 0.43 (0.52) for LDI and 0.46 (0.52) for iron sucrose during the post-index period. During the post-index period, FCM has a smaller increase in the number of outpatient visits (mean change from baseline=0.13) than LDI (mean change from baseline=0.64) and iron sucrose (mean change from baseline=0.70). The number of hospital admissions in the post-index period were numerically lower for FCM (mean change from baseline=-0.05) but numerically higher for LDI (mean change from baseline=0.04) and iron sucrose (mean change from baseline=0.05). Mean total health care cost increased during the 12-month period after IV iron treatment compared to baseline in all treatment groups. After adjusting for pre-index cost and other covariates, FCM treatment was associated with significantly lower post-index inpatient costs [adjusted cost ratio (ACR)= 0.73, p<0.0001], ER costs (ACR=0.76, p<0.0001), outpatient costs (ACR=0.73, p<0.0001) and total costs (including IV iron) (ACR = 0.81, p<0.0001) than LDI. Similar results were observed in the comparisons between FCM and iron sucrose. Conclusion Higher drug acquisition cost of FCM compared to LDI was primarily offset by lower inpatient and outpatient costs during the 12 months after FCM treatment for IDA in ND-CKD patients than LDI, resulting in significantly lower overall total health care cost for FCM compared to LDI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 11358: Total Cost of Care in Heart Failure Patients Receiving Parenteral Iron Therapy for Iron Deficiency Anemia: A Retrospective Analysis

Introduction: Iron deficiency (ID) is a common comorbidity in heart failure (HF) patients. This study compared healthcare costs between treatment with ferric carboxymaltose (FCM) and low dose IV iron (LDI) in HF patients with iron deficiency anemia (IDA). Methods: Medical and pharmacy claims from IQVIA PharMetrics ® Plus data were analyzed. Adult patients who received FCM or LDI (i.e iron sucrose, iron dextran, sodium ferric gluconate complex in sucrose) from 2017 to 2019, who had HF and IDA medical claims and were continuously eligible 6 months before (baseline) and 12 months after first (index) IV iron infusion were included. Patients with chronic kidney disease who required dialysis were excluded. Eligible FCM patients were required to receive 2 FCM doses within 21 days of index date. Healthcare resource use and costs for pre- and post-index periods were summarized descriptively. Post-index monthly inpatient, outpatient (excluding IV iron), and total costs for FCM and LDI were compared using generalized linear model with gamma log-link adjusting for pre-index monthly cost, age, gender, year of index treatment and Charlson Comorbidity Index. Results: Data from 3,153 FCM patients and 3,971 LDI patients were analyzed. Unadjusted mean number of outpatient visits increased numerically in the LDI group and unchanged for FCM, whereas ER visits and inpatient admissions decreased numerically for both treatment groups in the post-index period compared to baseline. After adjusting for covariates, post-index monthly inpatient costs [adjusted cost ratio (ACR)= 0.70, p &lt;0.001], outpatient costs (ACR=0.74, p &lt;0.001) and total costs (including IV iron) (ACR = 0.81, p &lt;0.001) were significantly lower for FCM than LDI. Conclusion: Higher acquisition cost of FCM was offset by lower inpatient and outpatient costs in HF patients with IDA receiving FCM than LDI during the 12 months after IV iron treatment, resulting in significantly lower total healthcare costs for FCM compared to LDI.

Case Findings: Sodium Ferric Gluconate Complex and Fetal Bradycardia

Abstract Anemia in pregnancy is a significant event that often requires treatment to prevent long term effects in the mother and the fetus. Many factors determine which iron preparation to use, including route and ease of administration, patient tolerability, safety, and cost. This case report summarizes two separate patient cases where sodium ferric gluconate complex was administered intravenously to pregnant women, resulting in fetal bradycardia and emergent cesarean procedures.

IV Sodium Ferric Gluconate Complex in Patients With Iron Deficiency Hospitalized due to Acute Heart Failure-Investigator Initiated, Randomized Controlled Trial.

Patients with heart failure (HF) with iron deficiency (ID) have worse New York Heart Association class and are at a higher risk of recurrent hospitalizations. Intravenous (IV) iron has been shown to improve exercise ability and reduce hospitalizations. IV sodium ferric gluconate complex (SFGC) has been found to be safe and affordable but has not been studied in this population in a randomized trial. This was a prospective, single-blind, investigator-initiated, randomized controlled trial. Patients admitted for acute heart failure with ID were randomly assigned 1:1 to receive IV SFGC on top of optimal medical treatment. The primary outcome was the change in the 6-minute walk test (6MWT) from baseline to 3 and 6 months. Between September 2019 and May 2021, 34 patients were randomized. 19 patients (55%) were randomized to the treatment arm receiving 125 mg of IV SFGC per day for 3-5 days. COVID-19 was a major barrier to the implementation of the study follow-up protocol, which caused the study to end early. Both groups of patients had similar clinical characteristics, comorbidities, median left ventricular ejection fraction, and rate of death and readmissions due to HF. A higher level of NT-proBNP was observed in patients treated with IV iron (7902 pg/mL vs. 3158, P = 0.04). There was no difference in 6MWT change between groups at 3 months (improvement of 21.6 vs. 24.1 meters) or 6 months (-5 meters vs. 46 meters). In conclusion, IV SFGC-treated patients had a comparable 6-minute walk at 3 and 6 months despite suffering from more severe HF with higher baseline NT-proBNP (NCT04063033).

Intravenous sodium ferric gluconate complex for pediatric inpatients with iron deficiency anemia or after acute blood loss

Background: Iron deficiency anemia (IDA) is a frequent finding in hospitalized pediatric patients. Sodium ferric gluconate complex (SFGC) has been in use at our institution for rapid replenishment of iron in patients unable to take or tolerate oral iron. Objective: Evaluate efficacy of SFGC, and incidence of adverse drug reactions (ADRs). Methods: Retrospective review of SFGC infusions in hospitalized patients &lt;18 years with IDA, or after acute blood loss between January 1st 2008 and April 20th 2015. Results: Sixty-five inpatients received 1586 infusions in 738 courses of daily 1-3 mg/kg infusions followed by laboratory tests within 2-4 days. Mean number of infusions per course was 2.06±1.08, mean dose per course 4.6±3.1 mg/kg, and mean age was 8.43±6.64 years. 18.4% of the courses were administered to infants, and 24.4% to children 1-&lt;7 years. The largest patient diagnoses group was gastrointestinal diseases (175 of 738, 23.7%), of those 64.6% (113) were inflammatory bowel disease. Comparing pre to post infusion values, there were significant increases in iron saturation, ferritin, reticulocyte count, and hemoglobin in all diagnoses and age groups. 85.8% of the courses were accompanied by erythropoietin injections. Those who received erythropoietin had higher reticulocyte count and lower ferritin levels compared to those who did not receive it (59.16±70.75 vs. 8.32±75.11, p=.005 and 81.61±179.01 vs. 134.84±117.87, p=.027 respectively). Two patients had transient hypotension but completed the infusions. Conclusion: SFGC infusions rapidly improved iron studies, and induced hematopoiesis in all age and diagnoses groups, and without significant ADRs. Safety in neonates needs further examination.

IV Sodium Ferric Gluconate Complex in Patients Hospitalized Due to Acute Decompensated Heart Failure and Iron Deficiency.

Background: Patients suffering from heart failure (HF) and iron deficiency (ID) have worse outcomes. Treatment with intra-venous (IV) ferric carboxymaltose has been shown to reduce HF rehospitalizations and to improve functional capacity and symptoms in patients with HF and reduced ejection fraction (HFrEF). However, IV ferric carboxymaltose is significantly more expensive than IV sodium ferric gluconate complex (SFGC) limiting its availability to most HF patients around the globe. Methods: A retrospective analysis comparing patients admitted to internal medicine or cardiology departments between January 2013 to December 2018 due to acute decompensated HF (ADHF) and treated with or without IV SFGC on top of standard medical therapy. Results: During the study period, a total of 1863 patients were hospitalized due to ADHF with either HFrEF or HF with preserved ejection fraction (HFpEF). Among them, 840 patients had laboratory evidence of iron deficiency (absolute or functional) and met the inclusion criteria. One hundred twenty-two of them (14.5%) were treated with IV SFGC during the index hospitalization. Patients treated with IV iron were more likely to have history of ischemic heart disease, atrial fibrillation, and chronic kidney disease. The rate of readmissions due to ADHF was similar between the groups at 30 days, 3 months, and 1 year. Conclusion: High risk patient hospitalized to ADHF and treated with IV SFGC showed comparable ADHF readmission rates, compared to those who did not receive iron supplementation.

IV sodium ferric gluconate complex in patients admitted due to acute decompansated heart failure and iron deficiency

Abstract Introduction Patients suffering from heart failure (HF) and iron deficiency (ID) have worse outcomes. Intra-venous (IV) ferric carboxymaltose has been shown to reduce HF readmissions and improve symptoms in patients with HF with reduced ejection fraction. However, IV ferric carboxymaltose is significantly more expensive than IV Sodium Ferric Gluconate Complex limiting its availability to most HF failure patients around the globe. Methods This is a retrospective analysis comparing patients admitted due to acute decompensated HF (ADHF) and treated with or without IV sodium ferric gluconate complex on top of standard medical therapy. The study included all patients admitted due to ADHF, with either reduced or preserved EF between January 2013 to December 2018. Results During the study period, a total of 1856 patients were admitted due to ADHF. Among them 840 patients had an indication for IV iron therapy. Among them 122 (14.5%) patients were treated with IV Sodium Ferric Gluconate during hospitalisation. When comparing the group that was treated with IV iron compared to standard HF treatment no difference was found at one year after the hospitalization regarding reduction in readmissions due to ADHF (27.9% vs 24.8% respectively P=0.54), nor in all-cause mortality (25.4% vs. 25.6% respectively, P=0.99). Conclusion Treatment with IV Sodium ferric gluconate complex during hospitalization due to ADHF did not show any advantage in reduction of readmission due to heart failure after 1 year follow up. Funding Acknowledgement Type of funding sources: None.

Safety and Effectiveness of an Accelerated Intravenous Iron Administration Protocol in Hospitalized Patients With Heart Failure.

The ACC/AHA heart failure (HF) guidelines include a class IIb recommendation for intravenous (IV) iron replacement in patients with iron deficiency and New York Heart Association class II or III to improve functional status and quality of life. Several studies have addressed the use of IV iron formulations such as ferric carboxymaltose or iron sucrose in HF population; however, few studies focused on sodium ferric gluconate complex (SFGC). To assess the safety and effectiveness of an IV SFGC administration protocol in patients hospitalized with HF. A retrospective cohort study was conducted. We included patients admitted to the HF service from September 2017 to March 2018. The primary outcome was the frequency of adverse reactions. The secondary outcome was the odds of HF readmissions between the 2 groups (IV SFGC vs. control). Of the 123 patients, 70 received IV iron (SFGC group) and 53 did not receive IV iron (control group). Five (7%) patients of the 70 in the SFGC group experienced adverse events, which included hypotension (n = 2, 2.8%), fever (n = 2, 2.8%) and myalgia (n = 2, 2.8%). Nine (12.8%) and 18 (25.7%) were readmitted within 30 days and 6 months respectively. In the control arm, 5 (9.4%) and 14 (26.4%) were admitted within 30 days and 6 months respectively. The odds of HF readmission at 30 days [OR 1.4 (95% CI: 0.45, 4.5)] and at 6 months [OR 0.96 (95% CI: 0.43, 2.2)] were similar in those who did not receive IV iron compared to those who received IV iron. Sodium ferric gluconate complex given at an accelerated dosing schedule appears to provide a more efficient means to prescribe IV iron in the inpatient setting and is safe with a low frequency of hypotension, fevers, and myalgias.

Intravenous Sodium Ferric Gluconate Complex And Iron Dextran Are Safe For Administration During Hospitalization For Heart Failure With Reduced Ejection Fraction

Introduction Iron deficiency (ID) with or without anemia is common in patients who have heart failure with reduced ejection fraction (HFrEF). Several trials have demonstrated improvement in symptoms and exercise tolerance in response to IV iron in patients with chronic HFrEF. To date, no large randomized trials evaluating the impact of IV iron on mortality and hospitalization in acutely decompensated HFrEF patients have been published. In addition, the interchangeability of IV iron preparations in this population is unknown. Currently, our institution has only sodium ferric gluconate complex (SFGC) and iron dextran on inpatient formulary. Hypothesis Administration of IV SFGC or iron dextran during hospitalization for acute decompensated HFrEF reduces mortality and cardiovascular (CV) hospitalization with a low rate of adverse events. Methods Single-center, retrospective cohort study of adult patients with a primary discharge diagnosis of heart failure, a reduced EF ( Results Of the 141 patients included in the efficacy analysis, 33 were in the intervention group and 108 were in the control group. Groups were generally well-matched. Hemoglobin, ferritin, and iron saturation were significantly lower in the intervention group at baseline. The primary outcome occurred in 45.5% of intervention group patients and 62% of controls (p=0.091). Among the safety population (N=82), 45 patients received IV SFGC, 37 iron dextran, and one both agents. One AE (nausea) was reported. Conclusion Administration of IV SFGC or iron dextran was associated with a non-significant reduction in 90-day CV hospitalization or mortality. The low incidence of reported AEs supports safety of these IV iron formulations in the study population. Results from large randomized trials regarding morbidity and mortality are eagerly anticipated.

Cyclic voltammetry: a simple method for determining contents of total and free iron ions in sodium ferric gluconate complex

&lt;p class="PaperAbstract"&gt;Sodium ferric gluconate complex (SFGC) is the third generation of iron supplement of polysaccharide iron (III) complex (PIC). For evaluation of technological level and application value of the prepared SFGC, it would be of great significance to determine the iron content in SFGC in a simple but effective way. This paper introduces the cyclic voltammetry (CV) method for determination of iron content in SFGC. Under established optimal experimental conditions, the content of free iron ions can be directly scanned and calculated, while the total iron content can also be determined by completely acidifying SFGC into Fe&lt;sup&gt;3+&lt;/sup&gt; ions. After optimizing and screening, the optimal scanning conditions are determined as pH 3 and 0.05 V/s of the scanning rate. Prior CV measurements, 0.4 V of the enrichment potential, and 3 min of the enrichment time are found optimal. It has also been verified that CO&lt;sub&gt;3&lt;/sub&gt;&lt;sup&gt;2-&lt;/sup&gt; ions present in the solution show little interference in the system within the experimental range of investigation. The contents of free Fe&lt;sup&gt;3+&lt;/sup&gt;, Fe&lt;sup&gt;2+&lt;/sup&gt; ions and the total iron determined after acid-hydrolysis of SFGC can be accurately calculated according to the corresponding linear relationships between peak currents and iron concentrations. In this paper, the repeatability and accuracy of the method are verified, and its feasibility as a convenient and effective method to determine the iron supplements is confirmed.&lt;/p&gt;

Impact of Parenteral Iron Therapy on Hemoglobin Normalization: A Retrospective Analysis

Introduction Parenteral iron therapy is often necessary for patients with iron deficiency anemia who cannot tolerate or are nonresponsive to oral iron. Parenteral iron therapy is also used in patients with chronic diseases when oral iron is poorly absorbed or when rapid iron repletion is desirable. Several parenteral iron therapies are currently available in the US. They vary in the amount of iron dose per administration and the number of infusions required to achieve complete iron repletion. The objective of this analysis was to evaluate complete repletion of iron deficit and its effect on the likelihood of serum hemogloblin (Hgb) normalization among patients receiving various parenteral iron therapies in real world clinical practice. Methods Data was obtained from the Decision Resources Group (DRG) Real World Evidence US Data Repository. Patients (≥18 years) who were treated with parenteral iron therapy from 3/1/2015-2/28/2017 were included. Patients were required to have their most recent baseline Hgb level recorded &amp;lt;30 days prior to or on the date of their index (first) parenteral iron therapy claim and below the normal Hgb level (&amp;lt;12 g/dL for females and &amp;lt;13.5 g/dL for males). Patients were excluded if they received parenteral iron therapy 6 weeks prior to the date of their index iron injection (index date); received dialysis or had insufficient data to identify comorbidities 1 year prior to index date. Iron deficit was calculated using the modified Ganzoni equation. The proportion of patients receiving parenteral iron dose required for complete repletion during the 3 weeks after index date, and the proportion of patients achieving normalized Hgb levels within 1 year after index date were summarized for patients receiving ferric carboxymaltose (FCM), ferumoxytol (FM) and other parenteral iron products (OTH). Multivariable logistic regression was used to assess the likelihood of complete iron repletion within 3 weeks of index date while controlling for gender, age, comorbidities, prescription oral iron use and iron deficit level. The likelihood of Hgb normalization within 1 year of index date was assessed using multivariable logistic regression while controlling for gender, age, comorbidities, prescription oral iron use, baseline Hgb and if the patient received the complete iron repletion dose within 3 weeks of index date. Results A total of 2,966 patients were included (female [68.2%], ≥65 years [58.4%]; CKD [60.1%], congestive heart failure [50.1%], IBD [64.4%], and cancer [59.5%]). Most (95%) patients did not receive prescription oral iron therapy within 3 months before or after index date. Iron sucrose was the most commonly used parenteral therapy (46.2%), followed by FCM (23.1%), FM (13.7%), iron dextran (13.6%), and sodium ferric gluconate complex in sucrose (3.4%). Mean (SD) iron deficit in mg was 966 (303) for FCM, 1007 (317) for FM and 1011 (313) for OTH patients. FCM had the highest proportion of patients received the full iron repletion dose within the 3 weeks after index date (73.1%), followed by FM (41.4%) and OTH (18.0%). Mean (SD) total iron dose in mg received by FCM, FM and OTH patients within 3 weeks of index date was 1277.1 (446.9), 842.5 (357.6), and 534.2 (584.8), respectively. The proportion of patients who had normalized Hgb within 1 year of index date was 66.6%, 40% and 51.9% for FCM, FM and OTH, respectively. Patients treated with FCM were significantly more likely to have received their full repletion dose within 3 weeks of index date than patients treated with FM [adjusted odds ratio (AOR)] (95% CI) = 5.10 (3.66, 7.11)] or OTH [AOR (95% CI) = 17.46 (13.59, 22.42)] after adjusting for differences in iron deficit level and other covariates. Patients treated with FM also had higher likelihood of receiving full repletion dose within 3 weeks compared to OTH [AOR (95% CI) = 3.71 (2.82, 4.88)]. After adjusting for full repletion dose and other covariates, patients treated with FCM were significantly more likely to have normalized Hgb within 1 year of index date than patients treated with FM [AOR (95% CI) = 1.88 (1.38, 2.56) or OTH [AOR (95% CI) = 1.40 (1.11, 1.77). However, patients treated with FM had lower likelihood to have normalized Hgb within 1 year of index date than patients treated with OTH [AOR (95% CI) = 0.69 (0.53, 0.89)]. Conclusion The results of this analysis suggest that the choice of iron replacement product may affect the likelihood of Hgb normalization for some patients in real world practice. Disclosures Kwong: Daiichi Sankyo, Inc.: Employment. Boccia:Bristol Myers Squibb: Consultancy, Speakers Bureau; SecuraBio: Consultancy; Rigel: Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; AMAG: Consultancy.

Comparative Physicochemical Characterization between Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection

Oral iron supplementation is commonly used to treat iron anemia. However, some iron anemia associated diseases, such as chronic kidney disease, are only receptive to intravenous (IV) therapies. In the US, there are six reference and one generic colloidal IV iron nanoparticle type formulations approved clinically. The product for which both an innovator and generic are available in the US is sodium ferric gluconate (SFG) (brand - Ferrlecit, generic - Sodium Ferric Gluconate). These formulations function by delivering iron to a protein in the plasma called transferrin. Transferrin subsequently delivers iron to cells to be used for cellular processes. If too much iron is released into the blood plasma, transferrin becomes saturated with iron, and the remaining iron is delivered non-specifically to the cells resulting in toxicity. Compared to conventional small molecule drugs, an extensive functional regulatory standard for generic nanoparticle drug approval has yet to be fully established. Given the complex nature of nanotechnology, the regulatory agencies may require analysis of nanoparticle-based drug products using state-of-the-art tools. It is important to understand which in vitro measures are most appropriate for in vivo predictive during generic drug approval. To attempt to fill these gaps, we have conducted a comprehensive suite of physicochemical measures of brand and generic SFG including total iron content, hydrodynamic diameter, acid solubility, molecular weight distribution, iron core oxidation state, and crystalline order and structure. We have employed a variety of techniques including inductively coupled plasma mass spectrometry, dynamic light scattering, gel permeation chromatography, analytical ultracentrifugation, mössbauer, electron paramagnetic resonance, and x-ray powder diffraction to characterize and compare the physicochemical properties of brand and generic SFG. Our findings will be presented in light of their application to interpret clinical data.

In vitro and in vivo DFO-chelatable labile iron release profiles among commercially available intravenous iron nanoparticle formulations

Intravenous (IV) iron formulations are complex colloidal suspensions of iron oxide nanoparticles. Small changes in formulation can allow more labile iron to be released after injection causing toxicity. Thus, bioequivalence (BE) evaluation of generic IV iron formulations remains challenging. We evaluated labile iron release in vitro and in vivo using a high performance liquid chromatography chelatable iron assay to develop a relational model to support BE. In vitro labile iron release and in vivo labile iron pharmacokinetics were evaluated for Venofer®, Ferrlecit®, generic sodium ferric gluconate complex, InFeD®, Feraheme® and a pre-clinical formulation GE121333. Labile iron release profiles were studied in vitro in 150 mM saline and a biorelevant matrix (rat serum) at 0.952 mgFe/mL. In vivo plasma labile iron concentration-time profiles (t0-240 min) were studied in rats after a 40 mgFe/kg IV dose. In vitro labile iron release in saline was significantly higher compared to rat serum, especially with InFeD®. An in vitro release constant (iKr) was calculated which correlated well with maximal plasma concentrations in the in vivo rat PK model (R2 = 0.711). These data suggest an in vitro to in vivo correlation model of labile iron release kinetics could be applied to BE. Other generic IV iron formulations need to be studied to validate this model.

Determination of Non-Transferrin Bound Iron, Transferrin Bound Iron, Drug Bound Iron and Total Iron in Serum in a Rats after IV Administration of Sodium Ferric Gluconate Complex by Simple Ultrafiltration Inductively Coupled Plasma Mass Spectrometric Detection.

A rapid, sensitive and specific ultrafiltration inductively-coupled plasma mass spectrometry method was developed and validated for the quantification of non-transferrin bound iron (NTBI), transferrin bound iron (TBI), drug bound iron (DI) and total iron (TI) in the same rat serum sample after intravenous (IV) administration of iron gluconate nanoparticles in sucrose solution (Ferrlecit®). Ultrafiltration with a 30 kDa molecular cut-off filter was used for sample cleanup. Different elution solvents were used to separate each form of iron from sample serum. Isolated fractions were subjected to inductively-coupled mass spectrometric analysis after microwave digestion in 4% nitric acid. The reproducibility of the method was evaluated by precision and accuracy. The calibration curve demonstrated linearity from 5–500 ng/mL with a regression (r2) of more than 0.998. This method was effectively implemented to quantify rat pharmacokinetic study samples after intravenous administration of Ferrlecit®. The method was successfully applied to a pharmacokinetic (PK) study of Ferrlecit in rats. The colloidal iron followed first order kinetics with half-life of 2.2 h and reached background or pre-dose levels after 12 h post-dosing. The drug shown a clearance of 0.31 mL/min/kg and volume of distribution of 0.05 L/kg. 19.4 ± 2.4 mL/h/kg.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Physicochemical Characterization.

The objective of this study was to evaluate physicochemical equivalence between brand (i.e., Ferrlecit) and generic sodium ferric gluconate (SFG) in sucrose injection by conducting a series of comparative in vitro characterizations using advanced analytical techniques. The elemental iron and carbon content, thermal properties, viscosity, particle size, zeta potential, sedimentation coefficient, and molecular weight were determined. There was no noticeable difference between brand and generic SFG in sucrose injection for the above physical parameters evaluated, except for the sedimentation coefficient determined by sedimentation velocity analytical ultracentrifugation (SV-AUC) and molecular weight by asymmetric field flow fractionation-multi-angle light scattering (AFFF-MALS). In addition, brand and generic SFG complex products showed comparable molecular weight distributions when determined by gel permeation chromatography (GPC). The observed minor differences between brand and generic SFG, such as sedimentation coefficient, do not impact their biological activities in separate studies of in vitro cellular uptake and rat biodistribution. Coupled with the ongoing clinical study comparing the labile iron level in healthy volunteers, the FDA-funded post-market studies intended to illustrate comprehensive surveillance efforts ensuring safety and efficacy profiles of generic SFG complex in sucrose injection, and also to shed new light on the approval standards on generic parenteral iron colloidal products.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Biodistribution after Intravenous Dosing in Rats.

Relative biodistribution of FDA-approved innovator and generic sodium ferric gluconate (SFG) drug products was investigated to identify differences in tissue distribution of iron after intravenous dosing to rats. Three equal cohorts of 42 male Sprague-Dawley rats were created with each cohort receiving one of three treatments: (1) the innovator SFG product dosed intravenously at a concentration of 40 mg/kg; (2) the generic SFG product dosed intravenously at a concentration of 40 mg/kg; (3) saline dosed intravenously at equivalent volume to SFG products. Sampling time points were 15 min, 1 h, 8 h, 1 week, two weeks, four weeks, and six weeks post-treatment. Six rats from each group were sacrificed at each time point. Serum, femoral bone marrow, lungs, brain, heart, kidneys, liver, and spleen were harvested and evaluated for total iron concentration by ICP-MS. The ICP-MS analytical method was validated with linearity, range, accuracy, and precision. Results were determined for mean iron concentrations (µg/g) and mean total iron (whole tissue) content (µg/tissue) for each tissue of all groups at each time point. A percent of total distribution to each tissue was calculated for both products. At any given time point, the overall percent iron concentration distribution did not vary between the two SFG drugs by more than 7% in any tissue. Overall, this study demonstrated similar tissue biodistribution for the two SFG products in the examined tissues.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: In Vitro Cellular Uptake.

Iron deficiency anemia is a common clinical consequence for people who suffer from chronic kidney disease, especially those requiring dialysis. Intravenous (IV) iron therapy is a widely accepted safe and efficacious treatment for iron deficiency anemia. Numerous IV iron drugs have been approved by U.S. Food and Drug Administration (FDA), including a single generic product, sodium ferric gluconate complex in sucrose. In this study, we compared the cellular iron uptake profiles of the brand (Ferrlecit®) and generic sodium ferric gluconate (SFG) products. We used a colorimetric assay to examine the amount of iron uptake by three human macrophage cell lines. This is the first published study to provide a parallel evaluation of the cellular uptake of a brand and a generic IV iron drug in a mononuclear phagocyte system. The results showed no difference in iron uptake across all cell lines, tested doses, and time points. The matching iron uptake profiles of Ferrlecit® and its generic product support the FDA’s present position detailed in the draft guidance on development of SFG complex products that bioequivalence can be based on qualitative (Q1) and quantitative (Q2) formulation sameness, similar physiochemical characterization, and pharmacokinetic bioequivalence studies.

Equivalence and regulatory approaches of nonbiological complex drug products across the United States, the European Union, and Turkey.

Regulatory agencies around the world may have different standards and approaches to evaluate and approve drug products and biological products. We describe the U.S. Food and Drug Administration's (FDA) Generic Drug User Fee Act program, as well as their approach to complex products. We discuss regulatory approaches for the development of nonbiological complex drug follow-ons and approval pathways in the United States. We compare FDA policies with other regulatory agencies (i.e., the European Medicines Agency and the Turkish Medicines and Medical Devices Agency). In particular, we describe the policies/pathways across these three agencies to assess equivalence of glatiramer acetate, enoxaparin sodium, and sodium ferric gluconate complex products. We also examine the Turkish market for these selected nonbiological complex drugs.