`•
`
`
`
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`Hypersensitivity to Injectafer or any of its inactive components. (4)
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`• Hypersensitivity Reactions: Observe for signs and symptoms of
`
`
`
`hypersensitivity during and after Injectafer administration for at least 30
`
`
`
`
`
`minutes and until clinically stable following completion of each
`
`
`
`
`
`administration. (5.1)
`
`Symptomatic Hypophosphatemia: Monitor serum phosphate levels in
`
`
`
`
`patients at risk for low serum phosphate who require a repeat course of
`
`
`
`
`treatment. (5.2)
`
`• Hypertension: Monitor patients closely for signs and symptoms of
`
`
`
`
`
`hypertension following each Injectafer administration. (5.3)
`
`---------------------------ADVERSE REACTIONS-------------------------­
`
`The most common adverse reactions (>2%) are nausea, hypertension, flushing,
`
`
`injection site reactions, erythema, hypophosphatemia, and dizziness. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact American
`
`Regent at 1-800-734-9236 or FDA at 1-800-FDA-1088 or
`
`
`
`www.fda.gov/medwatch.
`
`
`-------------------------USE IN SPECIFIC POPULATIONS---------------------­
`
`Pregnancy: Risk of hypersensitivity reactions which may have serious
`
`
`
`
`
`
`
`consequences for the fetus. (8.1)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`Revised: 04/2021
`
`
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use Injectafer
` safely and effectively. See full prescribing information for Injectafer.
`
`
`
`
`
` INJECTAFER® (ferric carboxymaltose injection), for intravenous use
`
`
` Initial U.S. Approval: 2013
`
`
`------------------------------RECENT MAJOR CHANGES-----------------------­
`
`
`
`
`
` Warnings and Precautions, Symptomatic Hypophosphatemia. (5.2) 02/2020
`
`
` Dosage and Administration, Recommended Dosage. (2.1) 04/2021
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Injectafer is an iron replacement product indicated for the treatment of iron
`
`
`
`deficiency anemia (IDA) in adult patients (1):
`
`
`• who have intolerance to oral iron or have had unsatisfactory response to
`
`
`
`
`
`
`oral iron, or
`
`
`• who have non-dialysis dependent chronic kidney disease.
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------­
`
`For patients weighing 50 kg or more, the recommended dosage is Injectafer
`
`
`
`
`750 mg intravenously in two doses separated by at least 7 days for a total
`
`
`
`
`
`
`
`cumulative dose of 1,500 mg of iron per course. Alternatively, for patients
`
`
`
`
`
`weighing 50 kg or more, Injectafer 15 mg/kg to a maximum of 1,000 mg may
`
`
`
`
`
`
`
`
`be administered as a single-dose treatment course.
`
`
`For patients weighing less than 50 kg, the recommended dosage is Injectafer
`
`
`
`
`15 mg/kg body weight intravenously in two doses separated by at least 7 days
`
`
`
`
`
`
`per course.
`
`
`Injectafer treatment may be repeated if iron deficiency anemia reoccurs. (2)
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Injection: 50 mg/mL (3)
`
`
`• 750 mg iron/15 mL single-dose vial
`
`
`
`• 1,000 mg iron/20 mL single-dose vial.
`
`
`
`____________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`
`10 OVERDOSAGE
`
`
` 11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Trial 1: Iron Deficiency Anemia in Patients Who are Intolerant to
`
`
`Oral Iron or Have Had Unsatisfactory Response to Oral Iron
`
`
`
`14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis
`
`Dependent Chronic Kidney Disease
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`2.2
`Preparation and Administration
`
`
` 2.3 Repeat Treatment Monitoring Safety Assessment
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
` 4 CONTRAINDICATIONS
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Hypersensitivity Reactions
`
`
` 5.2
`
` Symptomatic Hypophosphatemia
`
` 5.3 Hypertension
`
`
` 5.4
`
` Laboratory Test Alterations
` 6 ADVERSE REACTIONS
`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
`
` 6.2
` Post-marketing Experience
` 8 USE IN SPECIFIC POPULATIONS
`
` 8.1
`
`
` Pregnancy
`8.2
`Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`___________________________________________________________________________________________________________________________________
`
`
`* Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`listed.
`
`
`
`Reference ID: 4787071
`
`
`
` 1
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`
`Injectafer is indicated for the treatment of iron deficiency anemia (IDA) in adult patients:
`
`
`
`• who have intolerance to oral iron or have had unsatisfactory response to oral iron, or
`
`
`
`• who have non-dialysis dependent chronic kidney disease.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`2.1 Recommended Dosage
`
`
`For patients weighing 50 kg or more, the recommended dosage is Injectafer 750 mg
`
`intravenously in two doses separated by at least 7 days for a total cumulative dose of
`1,500 mg of iron per course. Alternatively, for patients weighing 50 kg or more,
`
`Injectafer 15 mg/kg body weight up to a maximum of 1,000 mg intravenously may be
`
`administered as a single dose treatment course.
`
`
`
`For patients weighing less than 50 kg, the recommended dosage is Injectafer 15 mg/kg
`
`
`body weight intravenously in two doses separated by at least 7 days per course.
`
`
`
`Each mL of Injectafer contains 50 mg of elemental iron.
`
`
`2.2 Preparation and Administration
`
`Administer Injectafer intravenously, either as an undiluted slow intravenous push or by
`
`infusion. When administered via infusion, dilute up to 1,000 mg of iron in no more than
`
`250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the
`
`
`infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes.
`
`
`When added to an infusion bag containing 0.9% sodium chloride injection, USP, at
`
`concentrations ranging from 2 mg to 4 mg of iron per mL, Injectafer solution is
`
`
`physically and chemically stable for 72 hours when stored at room temperature. To
`maintain stability, do not dilute to concentrations less than 2 mg iron/mL.
`
`
`
`
`Inspect parenteral drug products visually for the absence of particulate matter and
`
`discoloration prior to administration. The product contains no preservatives. Each vial of
`
`
`Injectafer is intended for single-dose only.
`
`
`
`When administering Injectafer 750 mg as a slow intravenous push, give at the rate of
`
`
`approximately 100 mg (2 mL) per minute. For Injectafer 1000 mg, administer as a slow
`
`
`intravenous push over 15 minutes. Avoid extravasation of Injectafer since brown
`
`discoloration of the extravasation site may be long lasting. Monitor for extravasation. If
`
`
`extravasation occurs, discontinue the Injectafer administration at that site.
`
`
`
`Discard unused portion.
`
`
`2.3 Repeat Treatment Monitoring Safety Assessment
`
`
`
`Injectafer treatment may be repeated if IDA reoccurs. Monitor serum phosphate levels in
`
`patients at risk for low serum phosphate who require a repeat course of treatment [see
`
`
`Warnings and Precautions (5.2)].
`
`Reference ID: 4787071
`
`
` 2
`
`
`
`

`

`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Injection: 50 mg/mL, dark brown, non-transparent, sterile, aqueous solution.
`
`
`
`• 750 mg iron/15 mL single-dose vial
`
`
`• 1,000 mg iron/20 mL single-dose vial
`
`
`
`CONTRAINDICATIONS
`4
`
`Injectafer is contraindicated in patients with a history of hypersensitivity to Injectafer or
`
`
`
`any of its components [see Warnings and Precautions (5.1)].
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`5.1 Hypersensitivity Reactions
`Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which
`have been life-threatening and fatal, have been reported in patients receiving Injectafer.
`
`Patients may present with shock, clinically significant hypotension, loss of
`
`
`
`consciousness, and/or collapse. Monitor patients for signs and symptoms of
`
`
`hypersensitivity during and after Injectafer administration for at least 30 minutes and
`
`
`until clinically stable following completion of the infusion. Only administer Injectafer
`
`when personnel and therapies are immediately available for the treatment of serious
`
`
`
`hypersensitivity reactions [see Adverse Reactions (6.1, 6.2)]. In clinical trials, serious
`
`anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1,775) of subjects
`
`
`receiving Injectafer. Other serious or severe adverse reactions potentially associated with
`
`hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or
`
`
`hypotension were reported in 1.5% (26/1,775) of these subjects.
`
`
`5.2 Symptomatic Hypophosphatemia
`Symptomatic hypophosphatemia requiring clinical intervention has been reported in
`
`patients at risk of low serum phosphate in the postmarketing setting. These cases have
`
`occurred mostly after repeated exposure to Injectafer in patients with no reported history
`
`
`of renal impairment. Possible risk factors for hypophosphatemia include a history of
`
`gastrointestinal disorders associated with malabsorption of fat-soluble vitamins or
`
`
`
`phosphate, concurrent or prior use of medications that affect proximal renal tubular
`
`
`function, hyperparathyroidism, vitamin D deficiency and malnutrition. In most cases,
`
`hypophosphatemia resolved within three months.
`
`
`Monitor serum phosphate levels in patients at risk for low serum phosphate who require a
`
`
`
`repeat course of treatment [see Dosage and Administration (2.3)].
`
`
`
`5.3 Hypertension
`
`
`
`In clinical studies, hypertension was reported in 4% (67/1,775) of subjects in clinical
`
`
`trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with
`
`
`facial flushing, dizziness, or nausea were observed in 6% (106/1,775) of subjects in these
`
`two clinical trials. These elevations generally occurred immediately after dosing and
`
`resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension
`
`
`
`following each Injectafer administration [see Dosage and Administration (2)].
`
`
`
`
`
`Reference ID: 4787071
`
`
` 3
`
`
`
`

`

` 5.4 Laboratory Test Alterations
`
`
` In the 24 hours following administration of Injectafer, laboratory assays may
`overestimate serum iron and transferrin bound iron by also measuring the iron in
`Injectafer.
`
`
` ADVERSE REACTIONS
` 6
`
`
` The following clinically significant adverse reactions are discussed in greater detail in
`
` other sections of the labeling:
`
`
`•
`
`•
`
`•
`
`•
`
`
`6.1 Clinical Trials Experience
`
`
`Because clinical trials are conducted under widely varying conditions, the adverse
`
`
`reaction rates observed cannot be directly compared to rates in other clinical trials and
`
`
`may not reflect the rates observed in clinical practice.
`
`
`In two randomized clinical studies [Studies 1 and 2, see Clinical Studies (14)], a total of
`
`
`1,775 patients were exposed to Injectafer 15 mg/kg body weight up to a maximum single
`
`dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative
`
`dose of 1,500 mg of iron.
`
`
`
`
`Adverse reactions reported by ≥1% of treated patients are shown in the following table.
`
` Table 1. Adverse reactions reported in ≥1% of Study Patients in Clinical Trials 1 and 2
`
`
`
`
`
` Injectafer
`
`
`
`
` Oral
` Pooled
`
`
` Comparatorsa
`
` iron
`
`
`
`
`(N=1,775)
`(N=1,783)
`(N=253)
`
`
`
`
`
`
` %
` %
` %
`
` 7.2
`
` 2
`
` 1.2
`
` 2
`
` 0.4
`
` 4
`
`
` 4
` 0.2
`
` 0
`
` 3.2
`
` 3
`
` 0
`
` 3
`
` 0.6
`
` 0
`
` 2.1
`
` 0.1
`
` 0
`
`
` 2.1
`
` 1.3
` 0.4
`
` 0.4
`
`
` 2
` 1
`
`
` 1.4
` 0.3
`
` 0
`
`
` 1.2
`
` 1.3
` 0.4
`
`
` 1.2
` 0.2
`
`
` 0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
`
`
`Hypophosphatemia [see Warnings and Precautions (5.2)]
`
`Hypertension [see Warnings and Precautions (5.3)]
`
`
`
`
`Laboratory Test Alterations [see Warnings and Precautions (5.4)]
`
`
`
`
`
`
` Nausea
`
` Hypertension*
`
` Flushing*
` Injection site reactions*
`
` Erythema*
` Hypophosphatemia
`
`
` Dizziness*
`
` Vomiting
` Injection Site Discoloration**
`
` Headache*
`
` Hepatic enzyme increased *
`
` 1.2
`
` Dysgeusia*
`
` 2.1
`
` 1
`
` Hypotension
`
` 2
`
` 1
`
` Rash*
`
` 0.3
` 0.5
` Constipation
`
` 0.9
`
`
`
` a Includes oral iron and all formulations of IV iron other than Injectafer
`
`
`
` *Grouped Terms:
`
` Hypertension includes hypertension, blood pressure increased, and hypertensive crisis.
`
`
`
` 0
`
` 0
`
` 0
` 3.2
`
`
`
`
`Reference ID: 4787071
`
`
` 4
`
`
`
`

`

` Flushing includes flushing and hot flush.
`
`
` Injection site reactions include injection site extravasation, injection site discoloration, injection site pain,
`
`
`
` injection site irritation, injection site bruising, injection site reaction, injection site discomfort, injection site
`
`
` erythema, injection site hematoma, injection site hemorrhage, injection site pruritus, injection site rash, and
`
`
` injection site swelling.
`
` Erythema includes erythema and injection site erythema.
`
`
`
`
` Dizziness includes dizziness, balance disorder, and vertigo.
`
`**Injection site discoloration was also included in the injection site local administration reactions grouped
`
`
` term.
`
` Headache includes headache and migraine.
`
`
`Hepatic enzyme increased includes alanine aminotransferase increased and aspartate aminotransferase
`
`
` increased.
`
` Dysgeusia includes dysgeusia and ageusia.
`
`
`
` Rash includes rash, urticaria, skin exfoliation, blister, erythema multiforme, injection site rash, rash
`
`
` maculo-papular, and rash pruritic.
`
`
`Other adverse reactions reported by ≥0.5% of treated patients include abdominal pain,
`
`
`
` diarrhea, gamma glutamyl transferase increased, paresthesia, and sneezing. Transient
`decreases in laboratory blood phosphorus levels (<2 mg/dL) have been observed in 27%
`
`(440/1,638) of patients in clinical trials.
`
`
`Pooled data from two Phase 3 studies 1VIT09030 (NCT00981045) and 1VIT09031
`(NCT00982007) with a dosing regimen of Injectafer 15 mg/kg up to a maximum of 750
`mg x 2 doses to a cumulative dose of 1,500 mg of iron were analyzed to compare rates of
`
`
`adverse reactions in two Phase 3 parallel group studies 1 VIT07017 (NCT00548860) and
`
`1 VIT07018 (NCT00548691) with a dosing regimen of Injectafer 15 mg/kg up to a
`
`maximum of 1,000 mg single dose (Table 2).
`
`
`Table 2. Adverse Reactions (≥1% in any Treatment Group) In Patients Receiving a
`
`
`
`Single dose of Injectafer 15 mg/kg to a Maximum of 1,000 mg or Two Doses of 15
`
`
`
`
`
`mg/kg to a Maximum of 750 mg to a Cumulative dose of 1,500 mg
`
`
`Injectafer 15 mg/kg to a
`
`Injectafer 15 mg/kg to a
` maximum of 1,000 mg
`
` maximum of 750 mg x 2
`
`
`
`doses to a cumulative dose of
` single dose
`
`
` 1,500 mg
` IVIT09030 and IVIT09031b
`
` (n=1,775)
`
` %
`
` 24
`
` 3
` 0.2
`
`
`
`
` IVIT07017 and
`
` IVIT07018a(n=1,200)
`
`
` %
`
` 12
`
` 4
`
` 2
`
`
`
` 1.2
`
` 1
`
`
` 1.3
`
` 2.1
`
` 1.2
`
` 7.2
`
` 4
`
`
` 5
`
`
`
`
`
` 1.2
`
`
` 1.2
`
` 1
`
` 1
`
` 1
`
` 1
`
` 1
`
`
`
` Any Adverse Reaction
`
` Injection site reactions*
`
`
` Injection site
` extravasation**
`
`Hepatic enzyme
`
` increased*
`
`Rash*
`
` Headache*
`
` Dizziness*
`Dysgeusia*
`
`Nausea
` Hypertension*
`
`
`
`
`
`Reference ID: 4787071
`
`

`

`
` 2.1
`
` 3
`
` 4
`
` 2
` 1.4
`
`
`
`
` 1
`
`
` 0.3
`
` 0.3
`
` 0.2
` <0.1
`
`
`
`
` <0.1
`
`
`
`Reference ID: 4787071
`
`
`
`
`
`
`
`
`
`
`
`
`
` Hypophosphatemia
`
`
` Erythema*
`
` Flushing*
`
` Vomiting
` Injection site
`
`
` discoloration**
` 1
`
`
` Hypotension
` ab Included studies 1VIT07017, 1VIT07018, 1VIT09030 and 1VIT09031
`
` *Grouped Terms
` **Injection site extravasation and injection site discoloration were also included in the injection site
`
` reactions grouped term.
`
` 6.2 Post- marketing Experience
`
`
`
` The following adverse reactions have been identified during post approval use of
`
` Injectafer. 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 adverse reactions have been reported from the post-marketing spontaneous
`
`
` reports with Injectafer:
`
` • Cardiac disorders: Tachycardia
`
`
` • General disorders and administration site conditions: Chest discomfort, chills,
`
`
`
`
` pyrexia
`
` • Metabolism and nutrition disorders: Hypophosphatemia
`
`
` • Musculoskeletal and connective tissue disorders: Arthralgia, back pain,
`
`
`
` hypophosphatemic osteomalacia (rarely reported event)
`
`
` • Nervous system disorders: Syncope
`
`
`
` • Respiratory, thoracic and mediastinal disorders: Dyspnea
`
` • Skin and subcutaneous tissue disorders: Angioedema, erythema, pruritus, urticaria
`
` • Pregnancy: Fetal bradycardia
`
`
`
`
` USE IN SPECIFIC POPULATIONS
` 8
`
`
`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 a fetus. Published studies and available data from postmarketing reports with
`
`
`intravenous Injectafer are insufficient to assess the risk of major birth defects and
`
`
`miscarriage.
`
`
`
`There are risks to the mother and fetus associated with untreated IDA in pregnancy as
`
`
`
`
`well as risks to the fetus associated with maternal severe hypersensitivity reactions (see
`
`
`Clinical Considerations).
`
`
`
`In animal reproduction studies, administration of ferric carboxymaltose to rabbits during
`
`the period of organogenesis caused adverse developmental outcomes including fetal
`
`
` 6
`
`

`

`malformations and increased implantation loss at maternally toxic doses of approximately
`12% to 23% of the human weekly dose of 750 mg (based on body surface area).
`
`
`The estimated background risk of major birth defects and miscarriage for the indicated
`populations is unknown. All pregnancies have a background risk of birth defect, 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% to 4%
`
`
`
`and 15% to 20%, respectively.
`
`
` Clinical Considerations
`
`
`Disease-associated maternal and/or embryo/fetal risk
`Untreated IDA in pregnancy is associated with adverse maternal outcomes such as post­
`
`partum 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
`
`parenteral iron products (such as Injectafer) which may cause fetal bradycardia,
`
`
`especially during the second and third trimester.
`
`
`Data
`
`Human Data
`
`Published data from randomized controlled studies, prospective observational studies and
`retrospective studies on the use of ferric carboxymaltose in pregnant women have not
`
`
`reported an association with intravenous ferric carboxymaltose and major birth defects
`
`and miscarriage. However, these studies cannot establish or exclude the absence of any
`
`
`
`drug-related risk during pregnancy.
`
`
`Animal Data
`
`Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to
`
`30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryonic or fetal
`
`
`
`findings. This daily dose in rats is approximately 40% of the human weekly dose of
`
`750 mg based on body surface area. In rabbits, ferric carboxymaltose was administered
`
`as a one-hour infusion on gestation days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18
`mg/kg/day. Malformations were seen starting at the daily dose of 9 mg/kg (23% of the
`
`human weekly dose of 750 mg Spontaneous abortions occurred starting at the daily iron
`dose of 4.5 mg/kg (12% of the human weekly dose of 750 mg based on body surface
`
`area). Pre-implantation loss was at the highest dose. Adverse embryonic or fetal effects
`
`were observed in the presence of maternal toxicity.
`
`
`A pre- and post-natal development study was conducted in rats at intravenous doses up to
`
`18 mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg based on
`
`
`body surface area). There were no adverse effects on survival of offspring, their
`
`behavior, sexual maturation or reproductive parameters.
`
`
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`Reference ID: 4787071
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`
` 7
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`

`

`
`
`
`
`
`
` 8.2 Lactation
`
`
` Risk Summary
`The available published data on the use of ferric carboxymaltose in lactating women
`
`demonstrate that iron is present in breast milk. Among the breastfed infants, adverse
`
`reactions included constipation and diarrhea but none of the adverse reactions reported
`
`were considered related to ferric carboxymaltose exposure through breastmilk. There is
`
`
`no information on the effects of ferric carboxymaltose on milk production. The
`
`
`developmental and health benefits of breastfeeding should be considered along with the
`
`mother’s clinical need for Injectafer in addition to any potential adverse effects on the
`
`
`breastfed child from the drug or from the underlying maternal condition.
`
`
`
` 8.4 Pediatric Use
`
` Safety and effectiveness have not been established in pediatric patients.
`
`
`8.5 Geriatric Use
`
`
`Of the 1,775 subjects in clinical studies of Injectafer, 50% were 65 years and over, while
`
`
`25% were 75 years and over. No overall differences in safety or effectiveness were
`
`
`observed between these subjects and younger subjects, and other reported clinical
`
`experience has not identified differences in responses between the elderly and younger
`
`patients, but greater sensitivity of some older individuals cannot be ruled out.
`
`
`
`OVERDOSAGE
`10
`
`
`Excessive dosages of Injectafer may lead to accumulation of iron in storage sites
`potentially leading to hemosiderosis. A patient who received Injectafer 18,000 mg over 6
`months developed hemosiderosis with multiple joint disorder, walking disability, and
`
`
`asthenia. Hypophosphatemic osteomalacia was reported in a patient who received
`
`
`
`Injectafer 4,000 mg over 4 months. Partial recovery followed discontinuation of Injectafer.
`
`
`
`DESCRIPTION
`11
`Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex
`
`
`
`with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(1→4)-O-α-D­
`
`glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative
`
`
`
`molecular weight of approximately 150,000 Da corresponding to the following empirical
`
`formula:
`
`
`
`[FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}l]k,
`
`where n ≈ 103, m ≈ 8, l≈ 11, and k ≈ 4
`
`
`
`
`
`
`
`
`
`(l represents the mean branching degree of the ligand).
`
`
`
`The chemical structure is presented below:
`
`
`
`
`
`
`
`Reference ID: 4787071
`
`
` 8
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`
`

`

`
`
`
`
` Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic
`
`colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric
`
`carboxymaltose in water for injection. Injectafer is available in 15 mL and 20 mL single-
`
`dose vials. Sodium hydroxide and/or hydrochloric acid may have been added to adjust
`
`the pH to 5.0-7.0.
`
`
`
`Vial closure is not made with natural rubber latex.
`
`
`
`CLINICAL PHARMACOLOGY
`12
`
`12.1 Mechanism of Action
`
`Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose,
`
`a carbohydrate polymer that releases iron.
`
`
`12.2 Pharmacodynamics
`
`Using positron emission tomography (PET) it was demonstrated that red cell uptake of
`59Fe and 52Fe from Injectafer ranged from 61% to 99%. In patients with iron deficiency,
`
`
`
`red cell uptake of radiolabeled iron ranged from 91% to 99% at 24 days after Injectafer
`
`dose. In patients with renal anemia, red cell uptake of radiolabeled iron ranged from 61%
`
`to 84% at 24 days after Injectafer dose.
`
`
`
`12.3 Pharmacokinetics
`
`After administration of a single dose of Injectafer of 100 to 1,000 mg of iron in iron
`
`
`
`deficient patients, maximum iron concentration of 37 µg/mL to 333 µg/mL were obtained
`
`respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was
`
`estimated to be 3 L.
`
`
`The iron injected or infused was rapidly cleared from the plasma, the terminal half-life
`
`
`ranged from 7 to 12 hours. Renal elimination of iron was negligible.
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenicity studies have not been performed with ferric carboxymaltose.
`
`
`
`
`Reference ID: 4787071
`
`
` 9
`
`
`
`

`

`CLINICAL STUDIES
`
`
`
` Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in
` vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human
`
`
`
`
`
` lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma
`
` L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to
`
`
`
`
`
`500 mg/kg.
`
`
`
`In a combined male and female fertility study, ferric carboxymaltose was administered
`intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg.
`Animals were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on
`mating function, fertility or early embryonic development. Based on body surface area,
`the dose of 30 mg/kg in animals is approximately 40% of the human dose of 750 mg.
`
`
`14
`
`
`The safety and efficacy of Injectafer for treatment of IDA were evaluated in two
`
`
`
`
`
`
`randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In these two trials,
`
`
`
`Injectafer was administered at a dose of 15 mg/kg body weight up to a maximum single
`
`
`dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative
`
`dose of 1,500 mg of iron.
`
`
`14.1 Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or
`Have Had Unsatisfactory Response to Oral Iron
`
`Trial 1: A Multi-center, Randomized, Active Controlled Study to Investigate the Efficacy
`and Safety of Intravenous Ferric Carboxymaltose (FCM) in Patients with Iron Deficiency
`
`
`Anemia (IDA), (NCT00982007) was a randomized, open-label, controlled clinical study
`
`in patients with IDA who had an unsatisfactory response to oral iron (Cohort 1) or who
`
`were intolerant to oral iron (Cohort 2) during the 14-day oral iron run-in period.
`Inclusion criteria prior to randomization included hemoglobin (Hb) <12 g/dL, ferritin
`
`≤100 ng/mL or ferritin ≤300 ng/mL when transferrin saturation (TSAT) ≤30%. Cohort 1
`subjects were randomized to Injectafer or oral iron for 14 more days. Cohort 2 subjects
`
`
`were randomized to Injectafer or another IV iron per standard of care [90% of subjects
`
`
`
`
`
`received iron sucrose]. The mean age of study patients was 43 years (range, 18 to 94);
`
`94% were female; 42% were Caucasian, 32% were African American, 24% were
`
`Hispanic, and 2% were other races. The primary etiologies of IDA were heavy uterine
`
`
`bleeding (47%) and gastrointestinal disorders (17%).
`
`
`
`Table 3 shows the baseline and the change in hemoglobin from baseline to highest value
`
`between baseline and Day 35 or time of intervention.
`
`
`
`Reference ID: 4787071
`
`
` 10
`
`
`
`

`

` Table 3. Mean Change in Hemoglobin From Baseline to the Highest Value
`
`
`
` Between Day 35 or Time of Intervention (Modified Intent-to-Treat Population)
`
`
` Hemoglobin (g/dL)
`
` Cohort 1
` Cohort 2
`
` Mean (SD)
`
` Oral Iron
`
` Injectafer
`
` Injectafer
`
`
` (N=244)
` (N=251)
`
` (N=245)
`
` 10.6 (1.0)
`
` 10.6 (1.0)
`
` 9.1 (1.6)
`
`
`
`
`
`
`
` 12.2 (1.1)
` 11.4 (1.2)
` 12.0 (1.2)
`
`
`
`
`
`
`
` 1.6 (1.2)
` 0.8 (0.8)
` 2.9 (1.6)
`
`
`
`
`
`
`IV SCa
`
`
` (N=237)
`
` 9.0 (1.5)
`
`
` 11.2 (1.3)
`
`
` 2.2 (1.3)
`
`
`
`
`
`
`
`
`
`
`
` Baseline
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 0.001
`
`
` Highest Value
`
`
`
`Change (from baseline to
`highest value)
`
`
` 0.001
`
` p-value
`
` SD=standard deviation; a: Intravenous iron per standard of care
`
`
`
`
`
`
`
` Increases from baseline in mean ferritin (264.2 ± 224.2 ng/mL in Cohort 1 and 218.2 ±
` 211.4 ng/mL in Cohort 2), and transferrin saturation (13 ± 16% in Cohort 1 and 20 ±
`
`
`
`
` 15% in Cohort 2) were observed at Day 35 in Injectafer-treated patients.
`
`
`
`
`
`
` 14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis Dependent
`
` Chronic Kidney Disease
`
` Trial 2: REPAIR-IDA, Randomized Evaluation of efficacy and safety of Ferric
`
`
`Carboxymaltose in Patients with Iron Deficiency Anemia and Impaired Renal function,
`
` (NCT00981045) was a randomized, open-label, controlled clinical study in patients with
`non-dialysis dependent chronic kidney disease. Inclusion criteria included hemoglobin
`(Hb) ≤11.5 g/dL, ferritin ≤100 ng/mL or ferritin ≤300 ng/mL when transferrin saturation
`
`(TSAT) ≤30%. Study patients were randomized to either Injectafer or Venofer. The
`
`
`mean age of study patients was 67 years (range, 19 to 101); 64% were female; 54% were
`
`
`
`
`Caucasian, 26% were African American, 18% Hispanics, and 2% were other races.
`
`
`Table 4 shows the baseline and the change in hemoglobin from baseline to highest value
`
`between baseline and Day 56 or time of intervention.
`
`
`Table 4. Mean Change in Hemoglobin From Baseline to the Highest Value
`
`Between Baseline and Day 56 or Time of Intervention (Modified Intent-to-Treat
`
`Population)
`
` Hemoglobin (g/dL)
`Mean (SD)
`
`
`
`Baseline
`
`
`
`
`
`
`
`
`
`
`
`
`
`Highest Value
`
`Change (from baseline to highest
`
` value)
`
`
`
`
`
`
`
`Reference ID: 4787071
`
`
` 11
`
`
`
`
` Injectafer
`
` (N=1,249)
`
` 10.3 (0.8)
`
`
` 11.4 (1.2)
`
` 1.1 (1.0)
`
`
`
`
` Venofer
`
` (N=1,244)
`
`
` 10.3 (0.8)
`
`
` 11.3 (1.1)
`
` 0.9 (0.92)
`
`
`
`
`
`
`

`

`
`
` Treatment Difference (95% CI)
`
`
`
` 0.21 (0.13, 0.28)
`
`
`750 mg iron/15 mL Single-Dose Vial
`
`
`Individually Boxed
`
`
`
`1,000 mg iron/20 mL Single-Dose Vial Individually Boxed
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Increases from baseline in mean f erritin (734.7 ± 337.8 ng/mL), and transferrin
`
`
`
`saturation (30 ± 17%) were observed prior to Day 56 in Injectafer-treated patients.
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`
`Injectafer (ferric carboxymaltose injection) is a dark brown, non-transparent, sterile,
`
`aqueous solution.
`
`
`NDC 0517-0650-01
`
`
`NDC 0517-0620-01
`
`
`
`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 the USP controlled room temperature.] Do not freeze.
`
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`
`Prior History of Reactions to Parenteral Iron Products
` Question patients regarding any prior history of reactions to parenteral iron products [see
`
` Warnings and Precautions (5.1)].
`
` Serious Hypersensitivity Reactions
`
`
`
` Advise patients to report any signs and symptoms of hypersensitivity that may develop
`
`during and following Injectafer administration, such as rash, itching, dizziness,
`
`
` lightheadedness, swelling, and breathing problems [see Warnings and Precautions (5.1)].
`
`
`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 [see Use in Specific
`
`
`Populations (8.1)].
`
`
`
`Injectafer is manufactured under license from Vifor (International) Inc, Switzerland.
`
`
`AMERICAN
`
`REGENT, INC.
`
`SHIRLEY, NY 11967
`
`
` RQ1052-D
`
`
`
`
`
`
`Reference ID: 4787071
`
`
` 12
`
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`
`

`

` Patient Information
`
`INJECTAFER (in-jekt-a-fer)
`
` (ferric carboxymaltose injection)
`
`
`
`
`
`What is INJECTAFER?
`
`
`
`
`
`INJECTAFER is a prescription iron replaceme