Injectafer (Ferric Carboxymaltose)
ferric carboxymaltose injection, for intravenous use
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Iron deficiency anemia — oral iron intolerance or unsatisfactory response | Adults and pediatric ≥1 year | Iron replacement | FDA Approved |
| Iron deficiency anemia in non-dialysis-dependent CKD | Adults | Iron replacement | FDA Approved |
| Iron deficiency in heart failure (NYHA class II/III) — to improve exercise capacity | Adults | Iron replacement / functional improvement | FDA Approved |
Ferric carboxymaltose is the first non-dextran IV iron approved in the United States for a broad IDA population regardless of underlying cause, and is the only IV iron with an FDA-approved indication for iron deficiency in heart failure. The IDA indication covers patients who have failed or cannot tolerate oral iron and those with NDD-CKD; it does not extend to dialysis-dependent CKD, where iron sucrose and ferric gluconate remain established options. The heart failure indication (approved 2021) is based on the CONFIRM-HF trial, which demonstrated improved 6-minute walk distance in patients with LVEF <45% and NYHA class II/III. Pediatric approval for IDA (ages ≥1 year) was granted based on adult efficacy data and supplementary pediatric PK/safety data.
Iron deficiency anemia in pregnancy (2nd/3rd trimester) — Widely used when oral iron fails; supported by multiple RCTs. However, FDA PI notes animal teratogenicity at high doses and advises patients of potential fetal risk. Evidence quality: Moderate
Perioperative iron deficiency anemia — Used to optimise haemoglobin before elective surgery (patient blood management). Supported by guidelines from NICE and NATA. Evidence quality: Moderate
Iron deficiency anemia in IBD — ECCO guidelines endorse IV iron for IDA in IBD when oral iron is ineffective or exacerbates symptoms. Note: IBD patients are at higher risk for ferric carboxymaltose-induced hypophosphatemia. Evidence quality: Moderate
Chemotherapy-associated iron-restricted erythropoiesis — May augment ESA response in functional iron deficiency. Evidence quality: Low–Moderate
Dosing
Iron Deficiency Anemia — Adults and Pediatrics ≥1 Year
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| IDA, weight ≥50 kg — standard 2-dose course | 750 mg IV (Day 1) | 750 mg IV (≥Day 8) | 1500 mg per course | Two doses separated by at least 7 days. IV push at ~100 mg/min or infusion in ≤250 mL NS over ≥15 min. Repeat course if IDA recurs |
| IDA, adults ≥50 kg — single-dose alternative | 15 mg/kg up to 1000 mg | Single dose per course | 1000 mg per course | IV push 1000 mg over 15 min, or infusion in ≤250 mL NS over ≥15 min. Adults only. Lower total iron delivery than 2-dose regimen |
| IDA, weight <50 kg (adults or pediatrics ≥1 yr) | 15 mg/kg IV (Day 1) | 15 mg/kg IV (≥Day 8) | 750 mg per single dose | Two weight-based doses ≥7 days apart. In pediatrics, max single dose is the lesser of 15 mg/kg or 750 mg. Not studied in children <1 year |
Iron Deficiency in Heart Failure (NYHA II/III) — Weight- and Hb-Based Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| HF, weight <70 kg, Hb <10 g/dL | 1000 mg (Day 1) | 500 mg (Week 6) | 1500 mg initial | Maintenance: 500 mg at weeks 12, 24, 36 if ferritin <100 ng/mL, or ferritin 100–300 ng/mL with TSAT <20%. No data beyond 36 weeks or with Hb ≥15 g/dL. Based on CONFIRM-HF dosing protocol |
| HF, weight <70 kg, Hb 10–14 g/dL | 1000 mg (Day 1) | No Week 6 dose | 1000 mg initial | |
| HF, weight <70 kg, Hb >14 to <15 g/dL | 500 mg (Day 1) | No Week 6 dose | 500 mg initial | |
| HF, weight ≥70 kg, Hb <10 g/dL | 1000 mg (Day 1) | 1000 mg (Week 6) | 2000 mg initial | Same maintenance schedule as <70 kg. Separate initial doses by 6 weeks (not 7 days as in IDA dosing). Hb ≥15 g/dL excluded from trials |
| HF, weight ≥70 kg, Hb 10–14 g/dL | 1000 mg (Day 1) | 500 mg (Week 6) | 1500 mg initial | |
| HF, weight ≥70 kg, Hb >14 to <15 g/dL | 500 mg (Day 1) | No Week 6 dose | 500 mg initial |
For IV push of 500 mg or 750 mg, administer at approximately 100 mg (2 mL) per minute. For 1000 mg doses, administer as a slow IV push over 15 minutes. For infusion, dilute up to 1000 mg in a maximum of 250 mL NS (concentration ≥2 mg/mL) and infuse over at least 15 minutes. Diluted solutions are stable for 72 hours at room temperature. Avoid extravasation — brown skin discoloration at the extravasation site may be long-lasting. Each vial is single-use; discard any unused portion.
Pharmacology
Mechanism of Action
Ferric carboxymaltose is a colloidal iron (III) hydroxide complexed with carboxymaltose, a carbohydrate polymer shell. After intravenous administration, the complex is taken up intact by macrophages of the reticuloendothelial system, where the iron core is released in a controlled manner. Released iron enters the physiological iron pool, binding to transferrin for transport to erythroid precursors in bone marrow and to ferritin for storage. PET studies using radiolabelled iron show that 91–99% of administered iron is incorporated into red blood cells within 24 days in iron-deficient patients, and 61–84% in patients with renal anaemia. The carboxymaltose shell confers high structural stability, enabling safe delivery of large single doses (up to 1000 mg) with a low labile (free) iron release profile, which distinguishes it from older iron preparations.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | 100% bioavailable (IV); Tmax 15 min–1.2 hr; Cmax 37–333 µg/mL (100–1000 mg doses) | Dose-proportional peak levels; rapid uptake enables single-visit high-dose delivery |
| Distribution | Vd ~3 L; distributes to blood, liver, spleen, bone marrow | Small Vd indicates initial confinement to vascular/RES compartments |
| Metabolism | RES dissociation; no CYP involvement; iron enters normal physiological pool | No hepatic drug-drug interactions via CYP enzymes |
| Elimination | t½ = 7–12 h (adults), ~9.7 h (peds); renal elimination negligible | Lab assays may overestimate serum iron and TSAT for up to 24 h post-dose (FDA PI) |
Side Effects
Adverse reaction data are from two pivotal randomised trials (N=1,775 adults receiving ferric carboxymaltose up to 1500 mg per course) and one pediatric study (N=40). The overall adverse reaction rate was 24% with the 750 mg x 2 regimen. Hypophosphatemia is a distinctive safety signal: while reported as an adverse reaction in only 2.1% of patients, transient laboratory phosphorus levels below 2.0 mg/dL were observed in 27% (440/1,638) of patients in clinical trials, and up to 50.8% in a head-to-head trial against ferumoxytol.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypophosphatemia (serum phosphorus <2.0 mg/dL) | 27% (lab finding); 2.1% (reported AE) | FGF23-mediated renal phosphate wasting. Usually asymptomatic and transient (resolves within ~3 months). Higher risk with repeated courses, IBD, vitamin D deficiency, and malabsorption disorders. See monitoring. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 7.2% | Most common clinical AE; usually self-limiting; may be reduced by slower infusion rate |
| Hypertension (including BP increased, hypertensive crisis) | 4% | Transient systolic BP elevation with flushing/dizziness/nausea in 6% (106/1,775); usually resolves within 30 min. Monitor BP post-dose. |
| Flushing (including hot flush) | 4% | Often accompanies transient hypertension; self-resolving. Distinguish from anaphylaxis. |
| Injection site reactions (grouped) | 3% | Includes pain, bruising, extravasation, swelling, erythema. Ensure stable IV access. |
| Erythema (including injection site erythema) | 3% | Skin reddening at or distal to the infusion site; typically transient |
| Dizziness (including balance disorder, vertigo) | 2.1% | May relate to transient BP changes; assess haemodynamics before attributing to other causes |
| Vomiting | 2% | Less frequent than nausea; generally self-limiting |
| Injection site discoloration | 1.4% | Brown staining may be long-lasting or permanent after extravasation |
| Headache (including migraine) | 1.3% | Usually self-limiting; higher rate (5%) in pediatric patients |
| Hepatic enzyme increased (ALT/AST) | 1.2% | Transient elevations; typically resolve without intervention |
| Dysgeusia (including ageusia) | 1.2% | Metallic taste; self-resolving within minutes to hours |
| Hypotension | 1% | Less common than with iron sucrose; monitor in patients on antihypertensives |
| Rash (including urticaria, erythema multiforme) | 1% | May indicate early hypersensitivity; stop infusion if progressive |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylactic/anaphylactoid reactions | 0.1% (2/1,775) | Within 30 min of infusion | Stop infusion immediately. Administer epinephrine, IV fluids, corticosteroids. Permanent discontinuation. |
| Serious hypersensitivity (pruritus, rash, urticaria, wheezing, hypotension) | 1.5% (26/1,775) | During or within 30 min of infusion | Stop infusion; treat symptomatically. Reassess risk-benefit before re-challenge. |
| Symptomatic hypophosphatemia (osteomalacia, fractures) | Uncommon (post-marketing); lab HPP in up to 50.8% | Nadir ~2 weeks post-dose; symptomatic cases over weeks–months | Check serum phosphate before repeat courses. Treat with oral/IV phosphate. Avoid repeated courses in high-risk patients without phosphate monitoring. |
| Hypertensive crisis | Rare (grouped within hypertension 4%) | Immediately after dosing | Standard acute hypertension management. Monitor BP after each administration. |
| Fetal bradycardia (in pregnant women) | Rare (post-marketing) | During or after infusion | Fetal monitoring during and after infusion in pregnant patients. Usually in context of maternal hypersensitivity reaction. |
Ferric carboxymaltose triggers a rapid increase in biologically active FGF23 (fibroblast growth factor 23), which causes renal phosphate wasting, reduced calcitriol synthesis, and secondary hyperparathyroidism. In a head-to-head RCT (Wolf et al., JCI Insight 2018), 50.8% of ferric carboxymaltose patients developed phosphorus levels below 2.0 mg/dL versus 0.9% with ferumoxytol. Phosphate levels typically reach a nadir at approximately 2 weeks post-infusion and recover within 3 months. Symptomatic cases — including osteomalacia, fractures, and severe fatigue — have been reported in post-marketing surveillance, predominantly after repeated high-dose courses. Risk factors include IBD, vitamin D deficiency, malabsorption, hyperparathyroidism, and hereditary haemorrhagic telangiectasia (HHT). The November 2024 FDA label update strengthened the hypophosphatemia warning.
Drug Interactions
Ferric carboxymaltose has a limited interaction profile as it does not undergo hepatic CYP metabolism. The primary clinical concern is co-administration with oral iron (additive iron load and reduced oral absorption) and the pharmacodynamic interaction with phosphate homeostasis affecting vitamin D metabolism.
Monitoring
-
Haemoglobin / Haematocrit
Baseline, then 2–4 weeks post-course
Routine Expect Hb increase of 1–3 g/dL within 2–5 weeks. In Trial 1, mean Hb rise was 1.6 g/dL (Cohort 1) and 2.9 g/dL (Cohort 2). Reassess iron status and bleeding if response is inadequate. -
Serum Ferritin and TSAT
Baseline, then ≥24 h post-dose for accuracy
Routine Iron studies drawn within 24 hours of dosing will be artificially elevated (FDA PI). For heart failure dosing, reassess ferritin and TSAT at weeks 12, 24, 36 to guide maintenance doses. -
Serum Phosphate
Before repeat courses; in at-risk patients before and 2 wk after
Routine Check before any repeat course within 3 months (FDA PI). Correct pre-existing hypophosphatemia before initiating. Monitor in patients with IBD, vitamin D deficiency, malabsorption, hyperparathyroidism, or HHT. Nadir typically at ~2 weeks post-dose. -
Blood Pressure
During and for ≥30 min after each infusion
Routine Transient hypertension occurred in 4% of trial patients. Usually resolves within 30 minutes. Monitor closely in patients with pre-existing hypertension or heart failure. -
Signs of Hypersensitivity
During and for ≥30 min after each infusion
Routine Serious anaphylactic reactions occurred in 0.1% (2/1,775). Ensure resuscitation equipment and trained personnel are immediately available. Most reactions occur within 30 minutes. -
Liver Function Tests
If symptoms develop
Trigger-based Transient ALT/AST elevations reported in 1.2%. Check if signs of hepatotoxicity appear, though clinically significant liver injury has not been a major concern.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to ferric carboxymaltose or any of its inactive components
Relative Contraindications (Specialist Input Recommended)
- Pre-existing hypophosphatemia — Must be corrected before initiating FCM (FDA PI). Risk of severe symptomatic worsening via FGF23-mediated phosphate wasting.
- First trimester of pregnancy — Animal studies showed fetal malformations at maternally toxic doses. Insufficient human data in first trimester; defer to 2nd/3rd trimester with risk-benefit discussion.
- Active systemic infection — Iron may promote microbial growth; defer treatment until infection is controlled.
- Known iron overload or haemochromatosis — Parenteral iron will exacerbate storage iron excess.
Use with Caution
- Patients at high risk for hypophosphatemia — IBD, vitamin D deficiency, malabsorption, hyperparathyroidism, HHT, or concurrent proximal tubular toxins. Monitor phosphate closely.
- Patients requiring repeated FCM courses — Risk of symptomatic hypophosphatemic osteomalacia with cumulative exposure. Check phosphate before each repeat course, especially within 3 months.
- Pre-existing hypertension — Transient BP elevation in 4–6% of patients. Monitor closely during and after administration.
- Dialysis-dependent CKD — Not specifically studied in this population; iron sucrose and ferric gluconate are established alternatives.
Symptomatic hypophosphatemia with serious outcomes including osteomalacia and fractures requiring clinical intervention has been reported in patients treated with Injectafer in the post-marketing setting. These cases have occurred mostly after repeated exposure in patients with no reported history of renal impairment. However, symptomatic hypophosphatemia has been reported after one dose. Correct pre-existing hypophosphatemia prior to initiating therapy. Monitor serum phosphate levels in patients at risk for chronic low serum phosphate. Check serum phosphate levels prior to a repeat course of treatment in patients at risk for low serum phosphate and in any patient who receives a second course of therapy within three months.
Patient Counselling
Purpose of Therapy
Ferric carboxymaltose delivers iron directly into the bloodstream when iron tablets have not worked well enough or have caused intolerable side effects. It is also used to replenish iron stores in patients with heart failure to improve the ability to exercise. The treatment works by providing the body with the iron it needs to make healthy red blood cells and restore energy levels. Most patients complete treatment in just 1–2 visits.
How to Receive Treatment
Ferric carboxymaltose is typically given as two infusions at least 7 days apart, or as a single infusion depending on the dose. Each infusion takes 15 minutes or more. For heart failure patients, infusions are spaced 6 weeks apart, with possible maintenance doses every 12 weeks. Patients must remain under observation for at least 30 minutes after each infusion.
Sources
- Injectafer (ferric carboxymaltose injection) — Full Prescribing Information. American Regent, Inc. Revised 01/2025. NDA 203565. FDA Label (2025) Primary source for all dosing, adverse reactions, PK, and contraindication data in this monograph. Includes the November 2024 hypophosphatemia warning update.
- American Regent, Inc. Injectafer Dosing and Administration. injectaferhcp.com Manufacturer resource with dosing tables and administration guidance for IDA and HF indications.
- Onken JE, Bregman DB, Engert RA, et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion. 2014;54(2):306–315. doi:10.1111/trf.12289 Trial 1 (NCT00982007) in FDA PI. FCM raised Hb by 1.6 g/dL vs 0.8 g/dL oral iron in Cohort 1 (oral non-responders) and by 2.9 g/dL vs 2.2 g/dL IV SOC in Cohort 2 (oral-intolerant); both p=0.001.
- Charytan C, Bernardo MV, Koch TA, et al. Intravenous ferric carboxymaltose versus standard of care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multi-center study. Nephrol Dial Transplant. 2013;28(4):953–964. doi:10.1093/ndt/gfs528 REPAIR-IDA trial (Trial 2 / NCT00981045); FCM vs iron sucrose in NDD-CKD. Treatment difference in Hb: 0.21 g/dL (95% CI 0.13, 0.28).
- Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657–668. doi:10.1093/eurheartj/ehu385 CONFIRM-HF trial (Trial 3 / NCT01453608). 6MWD improvement of 25 m vs placebo (p=0.007) at 24 weeks. Basis for the heart failure indication.
- Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436–2448. doi:10.1056/NEJMoa0908355 FAIR-HF trial (NCT00520780). Landmark study demonstrating improved self-reported patient global assessment and NYHA class with FCM in iron-deficient HF patients.
- Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396(10266):1895–1904. doi:10.1016/S0140-6736(20)32339-4 AFFIRM-AHF trial (NCT02937454). Reduced the composite of HF hospitalisations and cardiovascular death (rate ratio 0.79, 95% CI 0.62–1.01).
- McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. doi:10.1093/eurheartj/ehab368 Class IIa recommendation for IV FCM in symptomatic HF with iron deficiency (ferritin <100 or ferritin 100–299 with TSAT <20%) to improve symptoms and exercise capacity.
- Dignass AU, Gasche C, Bettenworth D, et al. European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. J Crohns Colitis. 2015;9(3):211–222. doi:10.1093/ecco-jcc/jju009 ECCO consensus supporting IV iron (including FCM) for IDA in IBD. Notes IBD as a risk factor for FCM-associated hypophosphatemia.
- Wolf M, Chertow GM, Macdougall IC, et al. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight. 2018;3(23):e124486. doi:10.1172/jci.insight.124486 Demonstrated FCM-induced FGF23 elevation (+303% from baseline at week 2) with phosphorus <2.0 mg/dL in 50.8% vs 0.9% with ferumoxytol. Defines the FGF23-mediated mechanism.
- Schaefer B, Tobiasch M, Wagner S, et al. Hypophosphatemia after intravenous iron therapy: comprehensive review of clinical findings and recommendations for management. Bone. 2022;154:116202. doi:10.1016/j.bone.2021.116202 Comprehensive review of FCM-associated hypophosphatemia including mechanism, clinical manifestations, risk factors, and management recommendations.
- Geisser P, Burckhardt S. The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011;3(1):12–33. doi:10.3390/pharmaceutics3010012 Comparative PK analysis of IV iron formulations; positions FCM as having a stable iron-carbohydrate complex with low labile iron release.
- Breymann C, Honegger C, Hösli I, Surbek D. Diagnosis and treatment of iron-deficiency anaemia in pregnancy and postpartum. Arch Gynecol Obstet. 2017;296(6):1229–1234. doi:10.1007/s00404-017-4526-2 Reviews evidence for IV iron including FCM in pregnancy-associated IDA; supports use from the second trimester with appropriate monitoring.