Ferrlecit

1 INDICATIONS AND USAGE Ferrlecit 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. Ferrlecit 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 )

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 Ferrlecit 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 Ferrlecit 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 Ferrlecit with other medications or add to parenteral nutrition solutions for intravenous infusion. The compatibility of Ferrlecit 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. Ferrlecit treatment may be repeated if iron deficiency reoccurs. 2.2 Adult Dosage and Administration The recommended dosage of Ferrlecit for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of Ferrlecit (125 mg of elemental iron). Ferrlecit may be diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session. Ferrlecit 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. Ferrlecit has been administered at sequential dialysis sessions by infusion or by slow intravenous injection during the dialysis session itself. Data from Ferrlecit 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 Ferrlecit for the repletion treatment of iron deficiency in hemodialysis patients is 0.12 mL/kg Ferrlecit (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.

3 DOSAGE FORMS AND STRENGTHS Injection: 62.5 mg/5 mL (12.5 mg/mL) clear, dark brown liquid in single-dose vial Injection: 62.5 mg/5 mL (12.5 mg/mL) in single-dose vial. ( 3 )

4 CONTRAINDICATIONS Ferrlecit 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 )

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 sanofi-aventis U.S. LLC at 1-800-633-1610 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 Ferrlecit 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 …

7 DRUG INTERACTIONS Drug-drug interactions involving Ferrlecit have not been studied. Ferrlecit may reduce the absorption of concomitantly administered oral iron preparations.

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 Ferrlecit use in pregnancy are insufficient to assess the risk of major birth defects and miscarriage. Ferrlecit 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, Ferrlecit 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 Ferrlecit 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. Ferrlecit 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 Ferrlecit 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 inf …

12.1 Mechanism of Action Ferrlecit 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.

11 DESCRIPTION Ferrlecit ® (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 0 11 )5] n≈200• Ferrlecit is supplied as a clear, dark brown liquid in colorless glass vials. Each sterile, single-dose vial of 5 mL of Ferrlecit 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.

10 OVERDOSAGE The Ferrlecit iron complex is not dialyzable. No data is available regarding overdose of Ferrlecit in humans. Excessive dosages of Ferrlecit may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Ferrlecit 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) ] . Ferrlecit 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Ferrlecit is a clear, dark brown liquid supplied in colorless glass vials. Each sterile, single-dose vial contains 62.5 mg of elemental iron in 5 mL for intravenous use. Discard unused portion. Carton containing 10 vials: NDC 0024-2794-10 Storage Store at 20°C–25°C (68°F–77°F); excursions permitted to 15°C–30°C (59°F–86°F). See USP Controlled Room Temperature. Do not freeze. Keep out of the reach of children.