Sodium Ferric Gluconate Complex in Sucrose

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ] Hypotension [see Warnings and Precautions ( 5.2 ) ] The most commonly reported adverse reactions (≥10%) in adult patients were nausea, vomiting and/or diarrhea, injection site reaction, hypotension, cramps, hypertension, dizziness, dyspnea, chest pain, leg cramps, and pain. In patients 6 to 15 years of age the most common adverse reactions (≥10%) were hypotension, headache, hypertension, tachycardia and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The most commonly reported adverse reactions (≥10%) in adult patients were nausea, vomiting and/or diarrhea, injection site reaction, hypotension, cramps, hypertension, dizziness, abnormal erythrocytes (e.g., changes in morphology, color, or number of red blood cells), dyspnea, chest pain, leg cramps and pain. In patients 6 to 15 years of age the most common adverse reactions (≥10%) were hypotension, headache, hypertension, tachycardia and vomiting. Studies A and B In multiple dose Studies A and B (total 126 adult patients), the most frequent treatment emergent adverse reactions following sodium ferric gluconate complex in sucrose injection were: Body as a Whole: injection site reaction (33%), chest pain (10%), pain (10%), asthenia (7%), headache (7%), fatigue (6%), fever (5%), malaise, infection, abscess, chills, rigors, carcinoma, flu-like syndrome, sepsis, lightheadedness, weakness. Nervous System: cramps (25%), dizziness (13%), paresthesias (6%), agitation, somnolence, decreased level of consciousness. Respiratory System: dyspnea (11%), coughing (6%), upper respiratory infections (6%), rhinitis, pneumonia. Cardiovascular System: hypotension (29%), hypertension (13%), syncope (6%), tachycardia (5%), bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema. Gastrointestinal System: nausea, vomiting and/or diarrhea (35%), anorexia, abdominal pain (6%), rectal disorder, dyspepsia, eructation, flatulence, gastrointestinal disorder, melena. Musculoskeletal System: leg cramps (10%), myalgia, arthralgia, back pain, arm pain. Skin and Appendages: pruritus (6%), rash, increased sweating. Genitourinary System: urinary tract infection, and menorrhagia. Special Senses: conjunctivitis, rolling of the eyes, watery eyes, puffy eye lids, arcus senilis, redness of the eye, diplopia, and deafness. Metabolic and Nutritional Disorders: hyperkalemia (6%), generalized edema (5%), leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia. Hematologic System: abnormal erythrocytes (11%) (changes in morphology, color, or number of red blood cells), anemia, leukocytosis, lymphadenopathy. Study C – Pediatric Pediatric Patients: In a clinical trial of 66 iron-deficient pediatric hemodialysis patients, 6 to 15 years of age, inclusive, who were receiving a stable erythropoietin dosing regimen, the most common adverse reactions, occurring in ≥5%, regardless of treatment dosage, were: hypotension (35%), headache (24%), hypertension (23%), tachycardia (17%), vomiting (11%), fever (9%), nausea (9%), abdominal pain (9%), pharyngitis (9%), diarrhea (8%), infection (8%), rhinitis (6%), and thrombosis (6%). More patients in the higher dose group (3.0 mg/kg) than in the lower dose group (1.5 mg/kg) experienced the following adverse events: hypotension (41% vs. 28%), tachycardia (21% vs. 13%), fever (15% vs. 3%), headache (29% vs. 19%), abdominal pain (15% vs. 3%), nausea (12% vs. 6%), vomiting (12% vs. 9%), pharyngitis (12% vs. 6%), and rhinitis (9% vs. 3%). 6.2 Postmarketing Experience In the single-dose, postmarketing, safety study, 11% of patients who received sodium ferric gluconate complex in sucrose injection and 9.4% of patients who received placebo reported adverse reactions. The most frequent adverse reactions following sodium ferric gluconate complex in sucrose injection administration were: hypotension (2%), nausea, vomiting and/or diarrhea (2%), pain (0.7%), hypertension (0.6%), allergic reaction (0.5%), chest pain (0.5%), pruritus (0.5%), and back pain (0.4%). The following additional events were reported in two or more patients: hypertonia, nervousness, dry mouth, and hemorrhage. In the multiple-dose, open-label surveillance study, 28% of the patients received concomitant angiotensin-converting enzyme inhibitor (ACEI) therapy. The incidences of both drug intolerance and suspected allergic events following first dose sodium ferric gluconate complex in sucrose injection administration were 1.6% in patients with concomitant ACEI use compared to 0.7% in patients without concomitant ACEI use. The patient with a life-threatening event was not on ACEI therapy. One patient had facial flushing immediately on sodium ferric gluconate complex in sucrose injection exposure. No hypotension occurred and the event resolved rapidly and spontaneously without intervention other than drug withdrawal. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified with the use of sodium ferric gluconate complex in sucrose injection from postmarketing spontaneous reports: Cardiovascular System: shock, fetal bradycardia, injection site superficial thrombophlebitis, phlebitis, acute myocardial ischemia with or without myocardial infarction or with in-stent thrombosis in the context of a hypersensitivity reaction. Gastrointestinal System: dysgeusia. Immune System: anaphylactic-type reactions. Nervous System: loss of consciousness, generalized convulsion, hypoesthesia. Skin and Appendages: skin discoloration, pallor. Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events based on information from postmarketing spontaneous reports. These adverse events included hypotension, nausea, vomiting, abdominal pain, diarrhea, dizziness, dyspnea, urticaria, chest pain, paresthesia, and peripheral swelling.

4 CONTRAINDICATIONS Sodium ferric gluconate complex in sucrose injection is contraindicated in patients with known hypersensitivity to sodium ferric gluconate or any of its components. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.1 ) ]. Known hypersensitivity to sodium ferric gluconate or any of its inactive components. ( 4 )

11 DESCRIPTION Sodium ferric gluconate complex in sucrose injection, an iron replacement product, is a stable macromolecular complex with an apparent molecular weight on gel chromatography of 289,000 – 440,000 daltons. The macromolecular complex is negatively charged at alkaline pH and is present in solution with sodium cations. The product has a deep red color indicative of ferric oxide linkages. The chemical name is D-Gluconic acid, iron (3+) sodium salt. The structural formula is considered to be [NaFe 2 O 3 (C 6 H 11 O 7 )(C 12 H 22 O 11 )5] n≈200 . Each sterile, single dose vial of 5 mL of sodium ferric gluconate complex in sucrose injection for intravenous injection contains 62.5 mg (12.5 mg/mL) of elemental iron as the sodium salt of a ferric ion carbohydrate complex in an alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in water for injection, pH 7.7 - 9.7. Each mL contains 9 mg of benzyl alcohol as an inactive ingredient.

2 DOSAGE AND ADMINISTRATION Adult Patients - The recommended adult dosage is 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 of up to 12.5 mg/min) per dialysis session. ( 2.2 ) Pediatric Patients - The recommended pediatric dosage is 0.12 mL/kg (1.5 mg/kg of elemental iron) diluted in 25 mL 0.9% sodium chloride and administered by intravenous infusion over 1 hour per dialysis session. ( 2.3 ) Do not mix sodium ferric gluconate complex in sucrose injection with other medications or add to parenteral nutrition solutions for intravenous infusion. Administer in 0.9% saline. ( 2 ) 2.1 Important Administration Instructions The dosage of sodium ferric gluconate complex in sucrose injection is expressed in terms of mg of elemental iron. Each 5 mL sterile, single dose vial contains 62.5 mg of elemental iron (12.5 mg/mL). Do not mix sodium ferric gluconate complex in sucrose injection with other medications or add to parenteral nutrition solutions for intravenous infusion. The compatibility of sodium ferric gluconate complex in sucrose injection with intravenous infusion vehicles other than 0.9% sodium chloride has not been evaluated. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever the solution and container permit. If diluted, use immediately. Sodium ferric gluconate complex in sucrose injection treatment may be repeated if iron deficiency reoccurs. 2.2 Adult Dosage and Administration The recommended dosage of sodium ferric gluconate complex in sucrose injection for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of sodium ferric gluconate complex in sucrose injection (125 mg of elemental iron). Sodium ferric gluconate complex in sucrose injection may be diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session. Sodium ferric gluconate complex in sucrose injection may also be administered undiluted as a slow intravenous injection (at a rate of up to 12.5 mg/min) per dialysis session. For repletion treatment most patients may require a cumulative dose of 1000 mg of elemental iron administered over 8 dialysis sessions. Sodium ferric gluconate complex in sucrose injection has been administered at sequential dialysis sessions by infusion or by slow intravenous injection during the dialysis session itself. Data from sodium ferric gluconate complex in sucrose injection postmarketing spontaneous reports indicate that individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events [see Adverse Reactions ( 6.2 ) ]. 2.3 Pediatric Dosage and Administration The recommended pediatric dosage of sodium ferric gluconate complex in sucrose injection for the repletion treatment of iron deficiency in hemodialysis patients is 0.12 mL/kg sodium ferric gluconate complex in sucrose injection (1.5 mg/kg of elemental iron) diluted in 25 mL 0.9% sodium chloride and administered by intravenous infusion over 1 hour per dialysis session. The maximum dosage should not exceed 125 mg per dose.

1 INDICATIONS AND USAGE Sodium ferric gluconate complex in sucrose injection is indicated for the treatment of iron deficiency anemia in adult patients and in pediatric patients age 6 years and older with chronic kidney disease receiving hemodialysis who are receiving supplemental epoetin therapy. Sodium ferric gluconate complex in sucrose injection is an iron replacement product for treatment of iron deficiency anemia in adult patients and in pediatric patients age 6 years and older with chronic kidney disease receiving hemodialysis who are receiving supplemental epoetin therapy. ( 1 )

10 OVERDOSAGE The sodium ferric gluconate complex in sucrose injection iron complex is not dialyzable. No data is available regarding overdose of sodium ferric gluconate complex in sucrose injection in humans. Excessive dosages of sodium ferric gluconate complex in sucrose injection may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer sodium ferric gluconate complex in sucrose injection to patients with iron overload [see Warnings and Precautions ( 5.3 ) ]. Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events [see Adverse Reactions ( 6.2 ) ] . Sodium ferric gluconate complex in sucrose injection at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg caused deaths in mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

7 DRUG INTERACTIONS Drug-drug interactions involving sodium ferric gluconate complex in sucrose injection have not been studied. Sodium ferric gluconate complex in sucrose injection may reduce the absorption of concomitantly administered oral iron preparations.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sodium ferric gluconate complex in sucrose injection is used to replete the body content of iron. Iron is critical for normal hemoglobin synthesis to maintain oxygen transport. Additionally, iron is necessary for metabolism and various enzymatic processes. 12.3 Pharmacokinetics Multiple sequential single-dose intravenous pharmacokinetic studies were performed on 14 healthy iron-deficient volunteers. Entry criteria included hemoglobin ≥10.5 gm/dL and transferrin saturation ≤15% (TSAT) or serum ferritin value ≤20 ng/mL. In the first stage, each subject was randomized 1:1 to undiluted sodium ferric gluconate complex in sucrose injection of either 125 mg/hr or 62.5 mg/0.5 hr (2.1 mg/min). Five days after the first stage, each subject was re-randomized 1:1 to undiluted sodium ferric gluconate complex in sucrose injection of either 125 mg/7 min or 62.5 mg/4 min (>15.5 mg/min). Peak drug levels (C max ) varied significantly by dosage and by rate of administration with the highest C max observed in the regimen in which 125 mg was administered in 7 minutes (19.0 mg/L). The terminal elimination half-life for drug bound iron was approximately 1 hour. Half-life varied by dose but not by rate of administration. Half-life values were 0.85 and 1.45 hours for the 62.5 mg/4 min and 125 mg/7 min regimens, respectively. Total clearance of sodium ferric gluconate complex in sucrose injection was 3.02 to 5.35 L/h. The AUC for sodium ferric gluconate complex in sucrose injection bound iron varied by dose from 17.5 mg-h/L (62.5 mg) to 35.6 mg-h/L (125 mg). Approximately 80% of drug bound iron was delivered to transferrin as a mononuclear ionic iron species within 24 hours of administration in each dosage regimen. Direct movement of iron from sodium ferric gluconate complex in sucrose injection to transferrin was not observed. Mean peak transferrin saturation returned to near baseline by 40 hours after administration of each dosage regimen. Pediatrics: Single dose intravenous pharmacokinetic analyses were performed on 48 iron-deficient pediatric hemodialysis patients. Twenty-two patients received 1.5 mg/kg sodium ferric gluconate complex in sucrose injection and 26 patients received 3.0 mg/kg sodium ferric gluconate complex in sucrose injection (maximum dose 125 mg). The mean C max , AUC 0-∞ , and terminal elimination half-life values following a 1.5 mg/kg dose were 12.9 mg/L, 95.0 mg•hr/L, and 2.0 hours, respectively. The mean C max , AUC 0-∞ , and terminal elimination half-life values following a 3.0 mg/kg dose were 22.8 mg/L, 170.9 mg•hr/L, and 2.5 hours, respectively. In vitro experiments have shown that less than 1% of the iron species within sodium ferric gluconate complex in sucrose injection can be dialyzed through membranes with pore sizes corresponding to 12,000 to 14,000 daltons over a period of up to 270 minutes. Human studies in renally competent patients suggest the clinical insignificance of urinary excretion.

12.1 Mechanism of Action Sodium ferric gluconate complex in sucrose injection is used to replete the body content of iron. Iron is critical for normal hemoglobin synthesis to maintain oxygen transport. Additionally, iron is necessary for metabolism and various enzymatic processes.

12.3 Pharmacokinetics Multiple sequential single-dose intravenous pharmacokinetic studies were performed on 14 healthy iron-deficient volunteers. Entry criteria included hemoglobin ≥10.5 gm/dL and transferrin saturation ≤15% (TSAT) or serum ferritin value ≤20 ng/mL. In the first stage, each subject was randomized 1:1 to undiluted sodium ferric gluconate complex in sucrose injection of either 125 mg/hr or 62.5 mg/0.5 hr (2.1 mg/min). Five days after the first stage, each subject was re-randomized 1:1 to undiluted sodium ferric gluconate complex in sucrose injection of either 125 mg/7 min or 62.5 mg/4 min (>15.5 mg/min). Peak drug levels (C max ) varied significantly by dosage and by rate of administration with the highest C max observed in the regimen in which 125 mg was administered in 7 minutes (19.0 mg/L). The terminal elimination half-life for drug bound iron was approximately 1 hour. Half-life varied by dose but not by rate of administration. Half-life values were 0.85 and 1.45 hours for the 62.5 mg/4 min and 125 mg/7 min regimens, respectively. Total clearance of sodium ferric gluconate complex in sucrose injection was 3.02 to 5.35 L/h. The AUC for sodium ferric gluconate complex in sucrose injection bound iron varied by dose from 17.5 mg-h/L (62.5 mg) to 35.6 mg-h/L (125 mg). Approximately 80% of drug bound iron was delivered to transferrin as a mononuclear ionic iron species within 24 hours of administration in each dosage regimen. Direct movement of iron from sodium ferric gluconate complex in sucrose injection to transferrin was not observed. Mean peak transferrin saturation returned to near baseline by 40 hours after administration of each dosage regimen. Pediatrics: Single dose intravenous pharmacokinetic analyses were performed on 48 iron-deficient pediatric hemodialysis patients. Twenty-two patients received 1.5 mg/kg sodium ferric gluconate complex in sucrose injection and 26 patients received 3.0 mg/kg sodium ferric gluconate complex in sucrose injection (maximum dose 125 mg). The mean C max , AUC 0-∞ , and terminal elimination half-life values following a 1.5 mg/kg dose were 12.9 mg/L, 95.0 mg•hr/L, and 2.0 hours, respectively. The mean C max , AUC 0-∞ , and terminal elimination half-life values following a 3.0 mg/kg dose were 22.8 mg/L, 170.9 mg•hr/L, and 2.5 hours, respectively. In vitro experiments have shown that less than 1% of the iron species within sodium ferric gluconate complex in sucrose injection can be dialyzed through membranes with pore sizes corresponding to 12,000 to 14,000 daltons over a period of up to 270 minutes. Human studies in renally competent patients suggest the clinical insignificance of urinary excretion.

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3 DOSAGE FORMS AND STRENGTHS Injection: 62.5 mg/5 mL (12.5 mg/mL) in single dose vial Injection: 62.5 mg/5 mL (12.5 mg/mL) in single dose vial. ( 3 )

Sodium Ferric Gluconate Complex in Sucrose Sodium Ferric Gluconate Complex in Sucrose SODIUM FERRIC GLUCONATE COMPLEX FERRIC CATION SUCROSE BENZYL ALCOHOL WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term carcinogenicity studies of sodium ferric gluconate in animals were not performed. Sodium ferric gluconate was not genotoxic in the Ames test or the rat micronucleus test. Sodium ferric gluconate produced a clastogenic effect in an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Studies to assess the effects of sodium ferric gluconate on fertility were not conducted.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term carcinogenicity studies of sodium ferric gluconate in animals were not performed. Sodium ferric gluconate was not genotoxic in the Ames test or the rat micronucleus test. Sodium ferric gluconate produced a clastogenic effect in an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Studies to assess the effects of sodium ferric gluconate on fertility were not conducted.

ANDA078215

Sodium Ferric Gluconate Complex in Sucrose

Sodium Ferric Gluconate Complex in Sucrose

0143-9298

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL NDC 0143- 9298 -01 5 mL Single Dose Vial Rx ONLY Sodium Ferric Gluconate Complex in Sucrose Injection 62.5 mg elemental iron per 5 mL (12.5 mg/mL) For Intravenous use ONLY PLB110

17 PATIENT COUNSELING INFORMATION Prior to sodium ferric gluconate complex in sucrose injection administration: Question patients regarding any prior history of reactions to parenteral iron products. Advise patients of the risks associated with sodium ferric gluconate complex in sucrose injection. Advise patients to report adverse reactions associated with the use of sodium ferric gluconate complex in sucrose injection, including hypersensitivity, allergic reactions, chest pain, dizziness, lightheadedness, swelling, and breathing problems [see Warnings and Precautions ( 5.1 , 5.2 ) and Adverse Reactions ( 6.1 , 6.2 ) ]. Advise patients that sodium ferric gluconate complex in sucrose injection may reduce the absorption of concomitantly administered oral iron preparations [see Drug Interactions ( 7 ) ]. Pregnancy Advise pregnant women about the risk of hypersensitivity reactions which may have serious consequences for the fetus. Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy (contains benzyl alcohol) [see Use in Specific Populations ( 8.1 ) ]. Lactation Advise patients that treatment with sodium ferric gluconate complex in sucrose injection is not recommended for use while breastfeeding [see Use in Specific Populations ( 8.2 ) ]. Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A. Estrada do Rio da Mó, nº 8, 8A e 8B – Fervença – 2705 - 906 Terrugem SNT, PORTUGAL Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Novaplus is a registered trademark of Vizient, Inc. novaplus+ Revised July 2022 PIN473-NOV/4

14 CLINICAL STUDIES Two clinical studies (Studies A and B) were conducted in adults and one clinical study was conducted in pediatric patients (Study C) to assess the efficacy and safety of sodium ferric gluconate complex in sucrose injection. Study A Study A was a three-center, randomized, open-label study of the safety and efficacy of two doses of sodium ferric gluconate complex in sucrose injection 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 sodium ferric gluconate complex in sucrose injection (25 mg of elemental iron) and were then randomly assigned to receive sodium ferric gluconate complex in sucrose injection at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Sodium ferric gluconate complex in sucrose injection 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 sodium ferric gluconate complex in sucrose injection 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received sodium ferric gluconate complex in sucrose injection 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 sodium ferric gluconate complex in sucrose injection-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 low-dose sodium ferric gluconate complex in sucrose injection group (50% female, 50% male; 74% white, 18% black, 5% Hispanic, 3% Asian; mean age 54 years, range 22-83 years), 44 patients in the high-dose sodium ferric gluconate complex in sucrose injection group (50% female, 48% male, 2% unknown; 75% white, 11% black, 5% Hispanic, 7% other, 2% unknown; mean age 56 years, range 20-87 years), and 25 historical control patients (68% female, 32% male; 40% white, 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25-84 years). 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 sodium ferric gluconate complex in sucrose injection-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 sodium ferric gluconate complex in sucrose injection group achieved significantly higher increases in hemoglobin and hematocrit than patients in the low-dose sodium ferric gluconate complex in sucrose injection group. See Table 1. Table 1: Study A: Hemoglobin, Hematocrit, and Iron Studies Mean Change from Baseline to Two Weeks after Cessation of Therapy Sodium Ferric Gluconate Complex in Sucrose Injection 1000 mg IV (N=44) Sodium Ferric Gluconate Complex in Sucrose Injection 500 mg IV (N=39) Historical Control Oral Iron (N=25) Hemoglobin (g/dL) 1.1 p<0.01 versus the 500 mg group. 0.3 0.4 Hematocrit (%) 3.6 1.4 0.8 Transferrin Saturation (%) 8.5 2.8 6.1 Serum Ferritin (ng/mL) 199 132 NA Study B Study B was a single-center, non-randomized, open-label, historically controlled, study of the safety and efficacy of variable, cumulative doses of intravenous sodium ferric gluconate complex in sucrose injection in iron-deficient hemodialysis patients. Sodium ferric gluconate complex in sucrose injection administration was identical to Study A. The primary efficacy variable was the change in hemoglobin from baseline to the last available observation through Day 50. Inclusion and exclusion criteria were identical to those of Study A as was the historical control population. Sixty-three patients were evaluated in this study: 38 in the sodium ferric gluconate complex in sucrose injection-treated group (37% female, 63% male; 95% white, 5% Asian; mean age 56 years, range 22-84 years) and 25 in the historical control group (68% female, 32% male; 40% white, 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25-84 years). Sodium ferric gluconate complex in sucrose injection-treated patients were considered to have completed the study per protocol if they received at least eight sodium ferric gluconate complex in sucrose injection 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%) sodium ferric gluconate complex in sucrose injection-treated patients received less than eight doses, and 12 (32%) patients had incomplete information on the sequence of dosing. Not all patients received sodium ferric gluconate complex in sucrose injection at consecutive dialysis sessions and many received oral iron during the study. Cumulative Sodium Ferric Gluconate Complex in Sucrose Injection Dose (mg of elemental iron) 62.5 250 375 562.5 625 750 1000 1125 1187.5 Patients (#) 1 1 2 1 10 4 12 6 1 Baseline hemoglobin and hematocrit values were similar between the treatment and control groups, and were 9.1 g/dL and 27.3%, respectively, for sodium ferric gluconate complex in sucrose injection-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 sodium ferric gluconate complex in sucrose injection-treated patients. In this patient population, only the sodium ferric gluconate complex in sucrose injection-treated group achieved increase in hemoglobin and hematocrit from baseline. See Table 2. Table 2: Study B: Hemoglobin, Hematocrit, and Iron Studies Mean Change from Baseline to One Month after Treatment Sodium Ferric Gluconate Complex in Sucrose Injection (N=38) Oral Iron (N=25) Change Change Hemoglobin (g/dL) 1.3 0.4 Hematocrit (%) 3.8 0.2 Transferrin Saturation (%) 6.7 1.7 Serum Ferritin (ng/mL) 73 -145 Study C Study C was a multicenter, randomized, open-label study of the safety and efficacy of two sodium ferric gluconate complex in sucrose injection dose regimens (1.5 mg/kg or 3.0 mg/kg of elemental iron) administered intravenously to 66 iron-deficient (transferrin saturation <20% and/or serum ferritin <100 ng/mL) pediatric hemodialysis patients, 6 to 15 years of age, inclusive who were receiving a stable erythropoietin dosing regimen. Sodium ferric gluconate complex in sucrose injection at a dose of 1.5 mg/kg or 3.0 mg/kg (up to a maximum dose of 125 mg of elemental iron) in 25 mL 0.9% sodium chloride was infused intravenously over 1 hour during each hemodialysis session for eight sequential dialysis sessions. Thirty-two patients received the 1.5 mg/kg dosing regimen (47% male, 53% female; 66% Caucasian, 25% Hispanic, and 3% Black, Asian, or Other; mean age 12.3 years). Thirty-four patients received the 3.0 mg/kg dosing regimen (56% male, 44% female; 77% Caucasian, 12% Hispanic, 9% Black, and 3% Other; mean age 12.0 years). The primary endpoint was the change in hemoglobin concentration from baseline to 2 weeks after last sodium ferric gluconate complex in sucrose injection administration. There was no significant difference between the treatment groups. Improvements in hematocrit, transferrin saturation, serum ferritin, and reticulocyte hemoglobin concentrations compared to baseline values were observed 2 weeks after the last sodium ferric gluconate complex in sucrose injection infusion in both the 1.5 mg/kg and 3.0 mg/kg treatment groups (Table 3). Table 3: Study C: Hemoglobin, Hematocrit, and Iron Status Mean Change from Baseline to Two Weeks after Cessation of Therapy in Patients Completing Treatment 1.5 mg/kg Sodium Ferric Gluconate Complex in Sucrose Injection (N=25) 3.0 mg/kg Sodium Ferric Gluconate Complex in Sucrose Injection (N=32) Hemoglobin (g/dL) 0.8 0.9 Hematocrit (%) 2.6 3.0 Transferrin Saturation (%) 5.5 10.5 Serum Ferritin (ng/mL) 192 314 Reticulocyte Hemoglobin Content (pg) 1.3 1.2 The increased hemoglobin concentrations were maintained at 4 weeks after the last sodium ferric gluconate complex in sucrose injection infusion in both the 1.5 mg/kg and the 3.0 mg/kg sodium ferric gluconate complex in sucrose injection dose treatment groups.

8.5 Geriatric Use Clinical studies of sodium ferric gluconate complex in sucrose injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.2. Lactation Risk Summary Sodium ferric gluconate complex in sucrose injection contains benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low-birth-weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.4 ) ].Consider alternative iron replacement therapies without benzyl alcohol for use during lactation. There are no available data on the presence of sodium ferric gluconate complex in sucrose injection in human or animal milk, the effects on milk production, or the effects on the breastfed child.

8.4 Pediatric Use The safety and effectiveness of sodium ferric gluconate complex in sucrose injection have been established in pediatric patients 6 to 15 years of age [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 ) ]. Safety and effectiveness in pediatric patients younger than 6 years of age have not been established. Benzyl Alcohol Toxicity and Pediatrics Sodium ferric gluconate complex in sucrose injection is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Benzyl alcohol contained in sodium ferric gluconate complex in sucrose injection may cause serious and anaphylactoid reactions in infants and children up to 3 years old. The administration of medications containing benzyl alcohol to newborns or premature neonates has been associated with a fatal "gasping syndrome" (symptoms include a striking onset of gasping syndrome, hypotension, bradycardia, and cardiovascular collapse). Preterm, low-birth-weight infants may be more likely to develop these reactions because they could be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Sodium ferric gluconate complex in sucrose injection contains 9 mg of benzyl alcohol per mL) [see Warnings and Precautions ( 5.4 ) ].

8.1 Pregnancy Risk Summary Parenteral iron administration may be associated with hypersensitivity reactions [see Warnings and Precautions ( 5.1 ) ], which may have serious consequences, such as fetal bradycardia (see Clinical Considerations ). Advise pregnant women of the potential risk to the fetus. Available data from postmarketing reports with sodium ferric gluconate complex in sucrose injection use in pregnancy are insufficient to assess the risk of major birth defects and miscarriage. Sodium ferric gluconate complex in sucrose injection contains benzyl alcohol as a preservative. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low-birth-weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.4 ) ]. Consider alternative iron replacement therapies without benzyl alcohol. There are risks to the mother and fetus associated with untreated iron deficiency anemia in pregnancy (see Clinical Considerations ). In the absence of maternal toxicity, sodium ferric gluconate complex in sucrose injection was not teratogenic to offspring of pregnant mice or rats at clinically relevant exposures (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Untreated iron deficiency anemia (IDA) in pregnancy is associated with adverse maternal outcomes such as postpartum anemia. Adverse pregnancy outcomes associated with IDA include increased risk for preterm delivery and low-birth-weight. Fetal/Neonatal Adverse Reactions Severe adverse reactions including circulatory failure (severe hypotension, shock including in the context of anaphylactic reaction) may occur in pregnant women with intravenous iron administration, which may have serious consequences on the fetus such as fetal bradycardia, especially during the second and third trimesters. Data Animal Data Sodium ferric gluconate complex in sucrose injection was administered intravenously to pregnant mice during gestation days 6 to 15 at doses of 5, 30, and 100 mg Fe/kg/day to assess embryofetal development. No teratogenic effects were seen in offspring at the highest dose, representing maternal exposure of approximately 4 times maximum human exposure based on body surface area. There were increased fetal resorptions and decreased fetal weights at doses that caused maternal toxicity as evidenced by decreased body-weight gain and decreased food consumption. Sodium ferric gluconate complex in sucrose injection was administered intravenously to pregnant rats during gestation days 6 to 15 at doses of 4 and 20 mg Fe/kg/day to assess embryofetal development. No teratogenic effects were seen in offspring at the highest dose, representing maternal exposure of approximately 1.5 times maximum human exposure based on body surface area. There were decreases in gestation index and litter size, increased fetal resorptions, and decreased fetal weights at doses that caused maternal toxicity as evidenced by decreased body-weight gain and decreased food consumption.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Risk of hypersensitivity reaction which may have serious consequences for the fetus. Use only if clearly needed (contains benzyl alcohol). ( 8.1 ) Lactation: Not recommended when breastfeeding. ( 8.2 ) Pediatric Use: Safety and effectiveness have not been established in pediatric patients <6 years of age. ( 8.4 ) 8.1 Pregnancy Risk Summary Parenteral iron administration may be associated with hypersensitivity reactions [see Warnings and Precautions ( 5.1 ) ], which may have serious consequences, such as fetal bradycardia (see Clinical Considerations ). Advise pregnant women of the potential risk to the fetus. Available data from postmarketing reports with sodium ferric gluconate complex in sucrose injection use in pregnancy are insufficient to assess the risk of major birth defects and miscarriage. Sodium ferric gluconate complex in sucrose injection contains benzyl alcohol as a preservative. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low-birth-weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.4 ) ]. Consider alternative iron replacement therapies without benzyl alcohol. There are risks to the mother and fetus associated with untreated iron deficiency anemia in pregnancy (see Clinical Considerations ). In the absence of maternal toxicity, sodium ferric gluconate complex in sucrose injection was not teratogenic to offspring of pregnant mice or rats at clinically relevant exposures (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Untreated iron deficiency anemia (IDA) in pregnancy is associated with adverse maternal outcomes such as postpartum anemia. Adverse pregnancy outcomes associated with IDA include increased risk for preterm delivery and low-birth-weight. Fetal/Neonatal Adverse Reactions Severe adverse reactions including circulatory failure (severe hypotension, shock including in the context of anaphylactic reaction) may occur in pregnant women with intravenous iron administration, which may have serious consequences on the fetus such as fetal bradycardia, especially during the second and third trimesters. Data Animal Data Sodium ferric gluconate complex in sucrose injection was administered intravenously to pregnant mice during gestation days 6 to 15 at doses of 5, 30, and 100 mg Fe/kg/day to assess embryofetal development. No teratogenic effects were seen in offspring at the highest dose, representing maternal exposure of approximately 4 times maximum human exposure based on body surface area. There were increased fetal resorptions and decreased fetal weights at doses that caused maternal toxicity as evidenced by decreased body-weight gain and decreased food consumption. Sodium ferric gluconate complex in sucrose injection was administered intravenously to pregnant rats during gestation days 6 to 15 at doses of 4 and 20 mg Fe/kg/day to assess embryofetal development. No teratogenic effects were seen in offspring at the highest dose, representing maternal exposure of approximately 1.5 times maximum human exposure based on body surface area. There were decreases in gestation index and litter size, increased fetal resorptions, and decreased fetal weights at doses that caused maternal toxicity as evidenced by decreased body-weight gain and decreased food consumption. 8.2. Lactation Risk Summary Sodium ferric gluconate complex in sucrose injection contains benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low-birth-weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.4 ) ].Consider alternative iron replacement therapies without benzyl alcohol for use during lactation. There are no available data on the presence of sodium ferric gluconate complex in sucrose injection in human or animal milk, the effects on milk production, or the effects on the breastfed child. 8.4 Pediatric Use The safety and effectiveness of sodium ferric gluconate complex in sucrose injection have been established in pediatric patients 6 to 15 years of age [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 ) ]. Safety and effectiveness in pediatric patients younger than 6 years of age have not been established. Benzyl Alcohol Toxicity and Pediatrics Sodium ferric gluconate complex in sucrose injection is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Benzyl alcohol contained in sodium ferric gluconate complex in sucrose injection may cause serious and anaphylactoid reactions in infants and children up to 3 years old. The administration of medications containing benzyl alcohol to newborns or premature neonates has been associated with a fatal "gasping syndrome" (symptoms include a striking onset of gasping syndrome, hypotension, bradycardia, and cardiovascular collapse). Preterm, low-birth-weight infants may be more likely to develop these reactions because they could be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Sodium ferric gluconate complex in sucrose injection contains 9 mg of benzyl alcohol per mL) [see Warnings and Precautions ( 5.4 ) ]. 8.5 Geriatric Use Clinical studies of sodium ferric gluconate complex in sucrose injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied NDC 0143-9298-10 Sodium ferric gluconate complex in sucrose injection is supplied in colorless glass vials. Each sterile, single dose vial contains 62.5 mg of elemental iron in 5 mL for intravenous use, packaged in cartons of 10 vials. Discard unused portion. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Do not freeze. Keep out of the reach of children.