`
` 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-----------------------
`
`
`
`
`
`
`Indications and Usage (1)
`11/2021
`
`
`
`
`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:
`
`• Adults and pediatric patients 1 year of age and older who have either
`
`
`
`
`
`
`intolerance to oral iron or an unsatisfactory response to oral iron. (1)
`
`
`
`
`
`
`• Adult patients who have non-dialysis dependent chronic kidney disease.
`
`
`
`
`
`
`(1)
`
`
`
`
`
`•
`
`
`-------------------------------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 in adults (>2%) are nausea, hypertension,
`
`
`
`flushing, injection site reactions, erythema, hypophosphatemia, and dizziness.
`
`(6.1)
`
`
`
`
`
`The most common adverse reactions in pediatric patients (≥4%) are
`
`
`injection site reactions, rash, headache, and vomiting.
`hypophosphatemia,
`
`(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: 11/2021
`
`
`----------------------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. For adult patients weighing 50 kg or more,
`
`
`
`
`
`
`an alternative dose of 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 IDA 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
`•
`____________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4891843
`
`
`
` 1
`
`
`
`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
` Pregnancy
` 8.1
`
`
`
` 8.2
`
` Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`___________________________________________________________________________________________________________________________________
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`Injectafer is indicated for the treatment of iron deficiency anemia (IDA) in:
`
`
`
`• Adults and pediatric patients 1 year of age and older who have either intolerance to
`
`oral iron or an unsatisfactory response to oral iron.
`
`
`
`• Adult patients 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. For adult patients weighing 50 kg or more, an alternative
`
`dose of 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 1,000 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: 4891843
`
`
`
` 2
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`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)].
`
`
`5.4 Laboratory Test Alterations
`
`Reference ID: 4891843
`
`
`
` 3
`
`
`
`
`
`
`
`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)]
`
`
` 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.
`
`
`Adults
`
`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)
`
`
`
`
`
`
` %
` %
` %
` Nausea
`
`
` 7.2
`
` 2
`
` 1.2
` Hypertension*
`
` 2
`
` 0.4
`
` 4
`
` Flushing*
`
`
` 4
` 0.2
`
` 0
` Injection site reactions*
`
` 3.2
`
` 3
`
` 0
`
` Erythema*
`
` 3
`
` 0.6
`
` 0
` Hypophosphatemia
`
` 2.1
`
` 0.1
`
` 0
` Dizziness*
`
`
`
` 2.1
`
` 1.3
` 0.4
`
` Vomiting
`
` 0.4
`
`
` 2
` 1
` Injection Site Discoloration**
`
`
` 1.4
` 0.3
`
` 0
`
` Headache*
`
` 1.2
`
` 1.3
` 0.4
`
` Hepatic enzyme increased*
`
` 1.2
`
` 0.2
`
` 0
`
` Dysgeusia*
`
` 1.2
`
` 2.1
`
` 0
` Hypotension
`
`
` 0
`
`
` 1
` 2
`
` Rash*
`
`
` 1
` 0.3
`
` 0
` Constipation
`
` 0.9
` 0.5
` 3.2
`
`
`
`
`
` a Includes oral iron and all formulations of IV iron other than Injectafer
`
` *Grouped Terms:
`
`
` Hypertension includes hypertension, blood pressure increased, and hypertensive crisis.
`
`
` Flushing includes flushing and hot flush.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4891843
`
`
`
` 4
`
`
`
` 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 1VIT07017 (NCT00548860) and
`
`1VIT07018 (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
`
`
`
`Two Doses of 15 mg/kg to a Maximum of 750 mg to a Cumulative Dose of 1,500 mg
`
`
`
`or a Single Dose of Injectafer 15 mg/kg to a Maximum of 1,000 mg.
`
`
`
`
`Injectafer 15 mg/kg to a
`
`Injectafer 15 mg/kg to a
`
` maximum of 750 mg x 2
`
` maximum of 1,000 mg
` doses to a cumulative dose of
`
` single dose
`
`
` 1,500 mg
` IVIT09030 and IVIT09031b
`
` (n=1,775)
`
` %
`
` 24
`
` 3
` 0.2
`
`
` Any Adverse Reaction
`
` Injection site reactions*
`
` Injection site
` extravasation**
`
`Hepatic enzyme
`
` increased*
`
`Rash*
`
` Headache*
`
` Dizziness*
`Dysgeusia*
`
`Nausea
` Hypertension*
`
` Hypophosphatemia
`
`
`
`
`
`Reference ID: 4891843
`
`
`
`
`
`
`
`
`
`
`
` IVIT07017 and
`
` IVIT07018a(n=1,200)
`
` %
`
` 12
`
` 4
`
` 2
`
`
`
` 1.2
`
` 1
`
`
` 1.3
`
` 2.1
`
` 1.2
`
` 7.2
`
` 4
` 2.1
`
`
` 5
`
`
`
` 1.2
`
`
` 1.2
`
` 1
`
` 1
`
` 1
`
` 1
`
` 1
`
` 1
`
`
`
`
` 3
`
` 4
`
` 2
` 1.4
`
`
`
`
`
`
`
` 0.3
`
` 0.3
`
` 0.2
` <0.1
`
`
`
`
` <0.1
`
`
`
` Erythema*
`
`
` Flushing*
`
` Vomiting
` Injection site
`
` discoloration**
` 1
`
`
` Hypotension
` abIncluded 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.
`
`
`Pediatric Patients
`
`The safety of Injectafer in pediatric patients was evaluated in study 1VIT17044
`(NCT03523117; Study 3). Study 1VIT17044 was a randomized, active-controlled study
`
`
` in which 40 patients (1 to 12 years of age: 10 patients, 12 to 17 years of age: 30 patients)
` received Injectafer 15 mg/kg to a maximum single dose of 750 mg (whichever was
`
` smaller) on Days 0 and 7 for a maximum total dose of 1,500 mg; 38 patients evaluable
`
` for safety in the control arm received an age-dependent formulation of oral ferrous sulfate
`for 28 days. The median age of patients who received Injectafer was 14.5 years (range,
`
`
` 1-17); 83% were female; 88% White and 13% Black. The most common adverse
`reactions (≥4%) were hypophosphatemia, injection site reactions, rash, headache, and
`
` vomiting.
`
` Table 3 summarizes the adverse reactions in Study 3.
`
`
`
`
`
`
`
` Table 3. Adverse Reactions of any Grade in Pediatric Patients Receiving Injectafer
`
`
`
` in Study 3
`
`
`
`
`
`Injectafer
`
` (n=40)
`%
`
`
`
`
` Oral Ferrous
`
` Sulfate
`
` (n=38)
`%
`
`
` 26
`
` 0
`
` 0
`
` 0
`
` 3
`
` 3
`
` 5
`
` 0
`
` 0
`
` 0
`
` 0
`
` 0
`
`
`
`
`
`
`
`
`
`
`
`
` 35
`
` 13
`
` 8
`
` 8
`
` 5
`
` 5
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
` Any Adverse Reactions
`
`
` Hypophosphatemia*
` Injection site reactions*
`
` Rash*
` Headache
`
`
` Vomiting
` Nasopharyngitis
`
` Flushing
` Gastrointestinal infections
`
` Liver function test increased
`
` Platelet count decreased
` White blood cell count decreased
`
` *Grouped Terms
`
` Injection site reactions include infusion site hematoma, infusion site hypoesthesia and injection site pain.
`
`
` Hypophosphatemia includes hypophosphatemia and blood phosphorus decreased.
`
`
` Rash includes rash, exanthema and urticaria.
`
`
` 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
`
`
`
`Reference ID: 4891843
`
`
`
` 6
`
`
`
`
`
`
`
`
`
` 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
`
`
`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.
`
`
`
`Reference ID: 4891843
`
`
`
` 7
`
`
`
` 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.
`
`
`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.
`
`
`
`
`
`
`
`Reference ID: 4891843
`
`
`
` 8
`
`
`
`
`
`
`
` 8.4 Pediatric Use
`
`
`
`
`
`
` The safety and effectiveness of Injectafer for IDA in pediatric patients aged 1 year and
`
` older who have normal kidney function and have either intolerance to oral iron or have
`
`
`had unsatisfactory response to oral iron have been established. Use of Injectafer for this
`
`
`
`
`
`indication in this age group is supported by evidence from adequate and well-controlled
`
`studies of Injectafer in adults with additional pharmacodynamic and safety data in
`pediatric patients aged 1 year and older [see Adverse Reactions (6.1) and Clinical
`
`
`
`Pharmacology (12.3)].
`
`
`Safety and effectiveness of Injectafer have not been established in pediatric patients less
`
`
`
`
`than 1 year of age with IDA.
`
`
`
` 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.
`
` 10
` OVERDOSAGE
`
`
`
`
` 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(R),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: 4891843
`
`
`
` 9
`
`
`
`
`
`
`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 adult 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.
`
`
`
`
`
`
`Reference ID: 4891843
`
`
`
` 10
`
`
`
`
`
`
`
` After administration of a single dose of Injectafer 15 mg/kg in pediatric patients 1-17
`
`
`
`
`
` years of age, the maximum concentrations ranged between 124 and 418.1 µg/mL and the
`median time to maximum concentration was 7 minutes. The elimination half-life of
`Injectafer in pediatric patients was approximately 9.7 hours. The total median 72-hour
`
`exposure (AUC0-72h) after a single dose of Injectafer 15 mg/kg in pediatric patients was
`
`
`
`
`4529.7 µg∙h/mL while the median exposure after a single dose of 1000 mg in adults was
`
`5875.3 µg∙h/mL.
`
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenicity studies have not been performed with ferric carboxymaltose.
`
`
`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.
`
`CLINICAL STUDIES
`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%).
`
`
`
`
`Reference ID: 4891843
`
`
`
` 11
`
`
`
`
`
`
`
`
`
` Table 3 shows the baseline and the change in hemoglobin from baseline to highest value
`
`between baseline and Day 35 or time of intervention.
`
`
`
`Table 3. Mean Change in Hemoglobin From Baseline to the Highest Value
`
`Between Day 35 or Time of Intervention (Modified Intent-to-Treat Population)
` Cohort 2
`
`
` Hemoglobin (g/dL)
` Cohort 1
`
` Mean (SD)
` Oral Iron
`
`
` Injectafer
`
` Injectafer
`
`
` (N=251)
` (N=245)
`
` (N=244)
` 10.6 (1.0)
`
`
` 9.1 (1.6)
`
` 10.6 (1.0)
`
`
`
`
`
`
`11.4 (1.2)
`12.0 (1.2)
`12.2 (1.1)
`
`
`
`
`
`
`
`
`
`0.8 (0.8)
`2.9 (1.6)
`1.6 (1.2)
`
`
`
`
`
`
`
`
`
`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 Depend