What data is available on dosing Ferrlecit (sodium ferric gluconate complex) at a 375mg IV daily dose?

Comment by InpharmD Researcher

There are limited data on high-dose (≥ 250 mg) sodium ferric gluconate infusions. The current evidence consists of small, observational studies with non-standardized dosing regimens that seem to support higher doses of sodium ferric gluconate (see Tables 1-3).

Background

Both the KDIGO Clinical Practice Guidelines for Anemia in Chronic Kidney Disease (2012) and the NCCN Clinical Practice Guidelines in Oncology Cancer and Chemotherapy-Induced Anemia (2018) do not recommend single ferric gluconate doses exceeding 125 mg. A test dose prior to treatment is not required but recommended if the patient has a history of drug allergies. [1], [2]

In a 2017 clinical review, ferric gluconate was considered superior to iron dextran in efficacy and safety in CKD patients with anemia EPO patients with chemotherapy-induced anemia. However, its formulation releases large amounts of labile free iron into circulation, an event that is historically linked to life-threatening iron toxicity reactions. Therefore ferric gluconate (and molecularly-similar iron sucrose) is not recommended to be administered as a single, total-dose infusion; rather, it's pharmacodynamically best to be given over multiple infusions (eg., concurrently with dialysis sessions). This may explain the lack ferric gluconate studies investigating high dose/frequently administered regimens. [3]

Relevant Prescribing Information

Ferrlecit® (sodium ferric gluconate complex in sucrose injection), for intravenous use
FDA-Approved Dose (adults): 10 ml (125 mg of elemental iron) diluted in 100 ml of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session or undiluted as a slow intravenous injection (at a rate up to 12.5 mg/ml) per dialysis session. Available in 12.5 mg/ml (5 ml vials).

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Can you summarize any literature on Ferrlecit (sodium ferric gluconate complex) 250 mg BID dosing?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-3 for your response.

Chronic use of sodium ferric gluconate complex in hemodialysis patients: safety of higher-dose (> or =250 mg) administration
Design	Prospective, open-label, surveillance study N= 144
Objective	To assess the safety of high-dose (≥250 mg) sodium ferric gluconate infusions in hemodialysis patients
Study Groups	High-Dose Patients: received at least one dose ≥250 mg (n= 144) Safety Study (n= 2,534)
Inclusion Criteria	Adults with end stage renal disease undergoing hemodialysis (HD), completion of previous safety study, previous tolerance of at least one dose of 125 mg sodium ferric gluconate complex (SGFC)
Exclusion Criteria	Anemia unrelated to iron deficiency, development of clinical instability, hypersensitivity to treatment components
Methods	Participants followed an individualized regimen (based on physician discretion) resulting in a total of 1.25 g of sodium ferric gluconate administered over 9 months. The one-hour infusions aimed to replete or maintain iron levels during the study interval (mean infusion rate: 4.17 mg/min, range 1 - 25 mg/min). Safety assessments were measured during and up to 72 hours after the infusion, and any adverse events occurring between treatments were reported at the next session. Patients who received high-dose sodium ferric gluconate (at least one dose ≥250 mg) were compared to a larger cohort of patients from a single-dose safety study.
Duration	9 months
Outcome Measures	Proportion of patients experiencing a drug-related adverse event, an outcome adverse event (an event that in investigator opinion would warrant treatment discontinuation), and serious adverse events
Baseline Characteristics		High-Dose Patients (n = 144)	Safety Study (n = 2,534)
	Age, years	56 ± 12.8	55.9 ± 15
	Female	46%	45%
	Race Black White	70.8% 13.2%	58% 22%
	Body mass index, kg/m²	25.4 ± 5.6	26.8 ± 7.4
	Prior iron dextran exposure Iron dextran allergy	93% 5.2%	92% 6.2%
	Sodium ferric gluconate dose 250 mg 312.5 mg 375 mg 500 mg	N=590 571 (96.8%) 1 (0.2%) 14 (2.4%) 4 (0.7%)
Results		Number of infusions within the High-Dose Group (n = 590)
	Drug-related adverse events*	4 (0.7%)
	Outcome Adverse Events†	1 (0.2%)
	Serious Adverse Events	0
	*One patient had diarrhea, two patients had transient edema of the hands, and one patient had pruritus †One patient experienced pruritus after the second 250mg dose All adverse events occurred with the 250 mg infusions; no adverse events were reported after the 19 sodium ferric gluconate doses >250 mg.
Study Author Conclusions	Administration of 250 mg sodium ferric gluconate over 1 hour is safe and well tolerated. Individual doses of 375 mg and 500 mg sodium ferric gluconate also were well tolerated, but further research and experience are needed to confirm the safety and tolerance of these doses.
InpharmD Researcher Critique	This was an observational, single-arm study that evaluated non-standardized and undisclosed dosing regimens. Additionally, the low number of patients receiving sodium ferric gluconate doses >250 mg makes it difficult to draw conclusions about the safety of these higher doses.

References:

Folkert VW, Michael B, Agarwal R, et al. Chronic use of sodium ferric gluconate complex in hemodialysis patients: safety of higher-dose (> or =250 mg) administration. Am J Kidney Dis. 2003;41(3):651-657. doi:10.1053/ajkd.2003.50141

Effects of an Accelerated Intravenous Iron Regimen in Hospitalized Patients with Advanced Heart Failure and Iron Deficiency
Design	Prospective, single-arm, open-label, descriptive study N= 13
Objective	To investigate the short-term efficacy and safety of an accelerated intravenous regimen of sodium ferric gluconate in hospitalized heart failure patients with iron deficiency
Study Groups	Sodium ferric gluconate (n= 13)
Inclusion Criteria	Hospitalized adults with heart failure (New York Heart Association class III-IV, ejection fraction < 40%), anemia (hemoglobin ≤ 12.0 g/dl), iron deficiency (ferritin < 100 ng/ml, or ferritin level of 100 to 300 ng/ml with transferrin saturation < 20%)
Exclusion Criteria	Anemia of other known etiology, active bleeding, infection, immunosuppression therapy, renal replacement therapy, pregnancy; receipt of IV or oral iron therapy, erythropoietin-stimulating agents, or blood transfusions within 12 weeks prior
Methods	All participants received sodium ferric gluconate 250 mg in 100 mL of normal saline twice daily (each intravenously infused over 2 hours) until normalization of iron levels or discharge. No test doses were administered. Safety assessments were taken during and for 2 hours after the infusion, and weekly thereafter.
Duration	1 to 4 weeks post-iron therapy or discharge (mean follow-up: 13.1 days +/- 5.6)
Outcome Measures	Primary Endpoint: Change in serum hemoglobin (Hgb) level from baseline to follow up (1-4 weeks after iron therapy completion) Secondary Endpoints: Changes in serum ferritin level and transferrin saturation (TSAT), changes in blood pressure (SBP, DBP), heart rate (HR), adverse events
Baseline Characteristics	Characteristic
	Age, years	58.9 ±12.8
	Female	46.2%
	White	38.5%
	African American	61.5%
	Ejection fraction (%)	20.2 ± 8.4
	Hgb concentration (g/dl)	10.6 ± 1.4
	Ferritin concentration (ng/ml)	86.4 ± 61.4
	Transferrin saturation (%)	11.7 ± 4.6
	Serum creatinine concentration (mg/dl)	1.2 ± 0.4
Results	Efficacy Endpoint	Sodium ferric gluconate (n= 11)	Versus baseline
	Change in serum Hgb, g/dl	+ 1.2	95% CI 0.45–1.9; p= 0.005
	Change in ferritin, ng/ml	+ 364.2	95% CI 129.7–598.7; p= 0.007
	Change in TSAT	+ 10.5%	95% CI 6.5%–14.6%; p< 0.001
	Safety Endpoint	Sodium ferric gluconate (n= 13)	Versus baseline
	Change in SBP, mmHg	+ 1.5 +/- 5.2	95% CI 1.6–4.6, p= 0.31
	Change in DBP, mmHg	+ 1.0	CI: not reported, p= 0.62
	Change in HR, bpm	- 0.5	CI: not reported, p= 0.36
	One patient was withdrawn from study treatment early (after two of four doses) due to deterioration of clinical condition secondary to hypovolemia and aggressive vasodilator titration. Results from this patient were included in the safety analyses only. One patient was readmitted (12 days after final iron infusion, 7 days after discharge) for bleeding from a femoral access site from the previous admission; thus, the last Hgb level prior to this event (6 days after final iron infusion) was carried forward for the efficacy analysis. Two additional patients were lost to follow-up.
Adverse Events	Nausea (n = 3), constipation (n =3), abdominal discomfort (n =3); injection site reactions (discomfort, itching, [n = 3], thrombophlebitis [n = 1], cellulitis [n = 1]). Other reports included headache, dyspnea, back pain, leg cramps, bladder discomfort, fatigue, and chills. One patient developed hemodynamic instability (hypovolemia, vasodilator use) which led to treatment discontinuation; the event was considered unrelated to iron administration.
Study Author Conclusions	An accelerated intravenous iron regimen improved hematologic parameters and was well tolerated in hospitalized patients with advanced heart failure. A randomized multicenter trial comparing this regimen with placebo is warranted
InpharmD Researcher Critique	This study was small with two patients lost to follow-up and an additional two did not complete the full duration of trial. Because of this, only nine patients were available for follow up with only eight patients no longer meeting the definition of iron deficiency.

References:

Reed BN, Blair EA, Thudium EM, et al. Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency. Pharmacotherapy. 2015;35(1):64-71. doi:10.1002/phar.1525

Weekly administration of high-dose sodium ferric gluconate is safe and effective in peritoneal dialysis patients
Design	Retrospective cohort; descriptive study N = 18
Objective	To describe the safety and efficacy of high-dose sodium ferric gluconate in dialysis patients
Study Groups	Low-dose (125 mg) (n= 9) High-dose (250 mg) (n= 9)
Inclusion Criteria	Adult patients receiving peritoneal dialysis, hemoglobin (Hgb) < 11 g/dl, transferrin saturation (TSAT) approximately 20%, serum ferritin < 250 ng/ml, receiving erythropoietin (EPO) twice weekly
Exclusion Criteria	N/A
Methods	Patients in the low-dose group received once-weekly treatments of ferric gluconate 125 mg IV in 100 ml of 0.9% normal saline (NS) infused over 45 to 60 minutes (total dose over 8 weeks: 1000 mg). Patients in the high-dose group received once-weekly ferric gluconate 250 mg IV in 250 ml in NS over 90 minutes (total dose over 4 weeks: 1000 mg). After the treatment period, both the low-dose and high-dose groups were given maintenance doses (125 mg and 250mg, respectively) once every 4 weeks thereafter. Test doses (25 mg ferric gluconate in 50 ml NS) were performed for all patients prior to study treatment.
Duration	8 weeks (low-dose group) and 4 weeks (high-dose group) treatment period, followed by maintenance period of at least 4 weeks
Outcome Measures	Endpoints: Hgb, ferritin, TSAT, adverse reactions, vital signs Stated goals: From baseline, increase Hgb to 11 g/dl and TSAT to > 200 ng/ml
Baseline Characteristics	Baseline Measurements	Low-dose (n= 9)		High-dose (n= 9)
	Hgb, g/dl	9.7 ± 1.0		9.2 ± 3.0
	TSAT, %	19.6 ± 3.8		19.5 ± 6.7
	Ferritin, ng/ml	204 ± 180		247 ± 198
	*No age, gender, or race data reported
Results	Endpoint Measurements	Low-dose (n= 9)	p-Value*	High-dose (n= 9)	p-Value*
	Hgb, g/dl	11.0 ± 1.3	p= 0.11	11.0 ± 2.1	p= 0.09
	TSAT, %	33.5 ± 6.9	p= 0.002	35.0 ± 25.77	p= 0.01
	Ferritin, ng/ml	465 ± 292	p= 0.02	622 ± 339	p= 0.03
	* Compared to baseline measurements
Adverse Events	No adverse events were observed in either group, and transferrin oversaturation was not noted in the high-dose group. All vitals were within normal range after infusions.
Study Author Conclusions	The results of this retrospective clinical analysis indicate that the administration of high-dose sodium ferric gluconate is safe, convenient, and effective in treating iron deficiency in peritoneal dialysis patients.
InpharmDResearcher Critique	This study was published as a letter to the author with only limited details

References:

Javier AM. Weekly administration of high-dose sodium ferric gluconate is safe and effective in peritoneal dialysis patients. Nephrol Nurs J. 2002 Apr;29(2):183-6. PMID: 11997953.