What Is Ferric Carboxymaltose (Inferject)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approval: Yes. Initial Approval Date: July 25, 2013
• Brand Names: Ferinject (former name), İnferject, Ferapplic
• Active Ingredient: Ferric carboxymaltose
• Route of Administration: Intravenous (IV) infusion
• Class: Parenteral iron preparation (IV iron supplement)
• Category: Supportive treatment
• Manufacturers:  Abdi İbrahiim, Sandoz İlaç.
• Availability in Turkey: Available and licensed. In Turkey, it is widely used as intravenous iron treatment under the name Ferinject in pharmacies and hospitals. Abdi İbrahim İlaç Sanayi ve Ticaret A.Ş.
• Approved Cancer Indications: It is not approved for cancer treatment itself. However, in cancer patients it is used as supportive treatment for chemotherapy-related anemia, functional iron deficiency, to reduce transfusion requirements.

What Is Ferric Carboxymaltose (İnferject)? How Does It Work?

Ferric carboxymaltose is an iron supplement administered intravenously (into a vein), most widely known by the brand name Ferinject. It was developed to meet systemic iron requirements in patients with iron deficiency anemia, particularly those who do not respond to oral iron or cannot tolerate it. It rapidly and effectively supplies the iron the bone marrow needs to produce healthy erythrocytes (red blood cells).

How Does It Work?

• Structure of the Complex: Ferric carboxymaltose has a colloidal nanoparticle structure with a core of trivalent ferric iron (Fe³⁺), stabilized by a surrounding carboxymaltose polysaccharide shell. This structure allows iron to be released slowly and absorbed without damaging tissue.
• Release Into Plasma: After intravenous administration, the complex is taken up by the reticuloendothelial system, particularly in the liver, spleen, and bone marrow. Lysosomal enzymes then gradually release ferric iron.
• Transferrin Binding and Transport: The released iron binds to transferrin in plasma and enters the circulation. The transferrin-iron complex is transported particularly to erythroid progenitor cells in the bone marrow.
• Hemoglobin Synthesis: In these cells, iron is used to synthesize hemoglobin, supporting red blood cell production and helping correct anemia.

FDA (US Food and Drug Administration) Approval History

• June 5, 2023: Injectafer received FDA approval in the US for treating iron deficiency in adults with heart failure.
• December 16, 2021: Injectafer (ferric carboxymaltose injection) was approved by the FDA for treating pediatric patients with iron deficiency anemia.
• May 6, 2021: Injectafer received FDA approval for a single-dose administration option in adults with iron deficiency anemia.
• July 26, 2013: The FDA approved Injectafer for treating iron deficiency anemia.
• July 26, 2012: Luitpold Pharmaceuticals Inc. announced that it had received a Complete Response Letter from the FDA regarding the application for Injectafer.
• October 13, 2011: Luitpold Pharmaceuticals Inc. announced that it had submitted a New Drug Application (NDA) for Injectafer to the US Food and Drug Administration.
• March 12, 2008: Luitpold Pharmaceuticals was reported to have received a non-approvable letter from the FDA for Injectafer (ferric carboxymaltose injection).
• February 4, 2008: Luitpold Pharmaceuticals Inc. issued a statement on the FDA Advisory Committee meeting evaluating Injectafer.
• May 14, 2007: Luitpold Pharmaceuticals Inc. announced that it had submitted a New Drug Application (NDA) for Injectafer, described as a next-generation intravenous iron product.

Licensing in Turkey

Ferric carboxymaltose, marketed as Ferinject, is licensed in Turkey by Abdi İbrahim İlaç Sanayi ve Ticaret A.Ş.

Therapeutic Indications

• When iron stores need to be replenished rapidly for clinical reasons,
• When oral iron preparations are ineffective or cannot be used,
• In patients with active inflammatory bowel disease who cannot adhere to oral iron treatment,
• In patients with chronic kidney disease, with or without erythropoietin treatment,

SGK Reimbursement

Ferinject (ferric carboxymaltose) is reimbursed by Turkey's Social Security Institution (SGK) for certain indications. In cancer patients, particularly those who develop chemotherapy-related anemia, a cancer diagnosis is sufficient for Ferinject use.

• Intestinal malabsorption syndromes
• Chronic inflammatory bowel diseases
• Patients with active gastrointestinal bleeding
• Patients on hemodialysis
• Patients who have undergone total or subtotal gastrectomy
• Patients with atrophic gastritis
• Pregnant patients who cannot tolerate oral iron
• Patients with stage III, IV, or V chronic kidney disease and iron deficiency anemia (saturation <20% and/or ferritin <100 mcg/l)
• Anemia in patients on peritoneal dialysis
• Anemia during the postpartum period,
• Preoperative and postoperative anemia,
• Cancer-related anemia,
• Anemia in patients with congestive heart failure,
• Anemia in predialysis patients [patients with end-stage (stage V) chronic renal failure before hemodialysis or peritoneal dialysis].

For treatment of iron deficiency in these circumstances, it is prescribed on the basis of a specialist physician's report.

Price: Inferject solution for IV injection/infusion, 500 mg/10 ml, 1x10 ml vial: 5769.29 Turkish lira.

Mechanisms of Resistance

• Functional Iron Deficiency: Although iron stores (ferritin) are normal or elevated, functional iron utilization is inadequate. The most common cause is inflammation and the associated increase in hepcidin levels. Hepcidin is a peptide hormone produced in the liver that inhibits iron absorption and release from macrophages by inhibiting ferroportin. As a result, iron remains "locked" inside cells, the bone marrow cannot use it adequately, and the Hb response is poor.
• Suppression by Inflammatory Cytokines: IL-6 and similar cytokines released in conditions such as cancer, infection, and autoimmune disease increase hepcidin. This may reduce the bioavailability even of intravenous iron.
• Inadequate Dose or Treatment Duration: Inadequate or single doses may fail to meet the body's actual iron requirements. Short courses or low doses may be insufficient, particularly in cancer patients with a high inflammatory burden.
• Erythropoietin (EPO) Deficiency or Inhibition: Ferric carboxymaltose supplies the iron needed for red blood cell production; however, if erythropoietin levels are inadequate, iron is not used and anemia does not improve. For this reason, some patients receive EPO and IV iron together.
• Iron Retention in Macrophages: Iron is retained in RES (reticuloendothelial system) cells but cannot be transferred adequately to the bone marrow. This creates a clinical situation in which "iron is present but cannot be used."

Absorption

• Ferric carboxymaltose is delivered directly into the systemic circulation by intravenous (IV) infusion.
• The conventional gastrointestinal (intestinal) absorption process is therefore bypassed, and bioavailability is considered to be 100%.
• Its principal advantage over oral iron is that it bypasses the gastrointestinal tract and does not cause gastrointestinal adverse effects.

Distribution

• The medicine consists of a ferric iron (Fe³⁺) core surrounded by a carboxymaltose polysaccharide complex.
• After administration, the complex circulates in plasma as a colloidal solution and rapidly moves to organs of the reticuloendothelial system (RES), particularly the liver, spleen, and bone marrow.
• Volume of distribution (Vd): Approximately 3 L (limited extravascular passage)
• This distribution directs iron to its target organs, particularly the bone marrow.

Metabolism

• Ferric carboxymaltose is not metabolized by liver enzymes (CYP450) in the conventional sense.
• Within RES cells, lysosomal enzymes gradually break it down:
• The polysaccharide shell is degraded.
• The released Fe³⁺ binds to transferrin and enters the circulation.
• Transferrin carries iron to erythropoietic tissues, particularly the bone marrow.
• Metabolism primarily involves enzymatic breakdown, storage, and directed transport.

Elimination

• Most of the released iron is used by the body in hemoglobin, myoglobin, cytochromes, and other structures.
• Unused iron is stored as ferritin or hemosiderin.
• A very small, trace amount is excreted in urine or bile.
• The polysaccharide carrier structures are broken down by macrophages and removed through natural pathways.
• Half-life (T½): An average of 7–12 hours (the time required for iron transfer to transferrin)

Dosing Schedule 

Iron Deficiency Anemia (General Use)

• Patients with Hb <10–11 g/dL require a total iron load of 1000–1500 mg.
• The dose may be divided into 1 or 2 sessions.

Chemotherapy-Related Anemia (Cancer Patients)

• It is generally given together with erythropoietin (ESA).
• A single 1000 mg dose is recommended; another dose may be given after 7 days if needed.

Chronic Kidney Disease (Patients Not on Dialysis)

• Initial dose: 1000 mg IV, either as a single administration or as 500 mg x 2 doses
• Maintenance dose: 200–500 mg may be administered at intervals according to Hb levels.

Anemia During Pregnancy (2nd and 3rd Trimesters)

• A single 1000 mg dose may be recommended, divided if necessary.
• IV treatment is preferred if oral iron is not tolerated or is inadequate.

Patients should be monitored carefully for signs and symptoms of hypersensitivity reactions during and after each administration.

It should be administered only where personnel trained to assess and manage anaphylactic reactions immediately are present and full resuscitation equipment is available. After every Ferinject administration, the patient should be observed for adverse effects for at least 30 minutes.

Drug Interactions

• Iron Chelators (e.g., Deferoxamine, Deferasirox): An antagonistic effect may occur. Iron chelators may reduce the effectiveness of iron carboxymaltose. They should not be used simultaneously. An interval should be left between administrations.
• Parenteral Iron and Oral Iron Preparations: Parenteral iron reduces the absorption of oral iron, and gastrointestinal adverse effects may increase. Oral iron is not recommended during IV iron use.
• ACE Inhibitors (e.g., Enalapril, Lisinopril): When used with parenteral iron, they may increase the risk of anaphylactic or allergic reactions. Caution is needed during administration, and the patient should be observed.
• Antibiotics (Tetracyclines, Quinolones): These generally interact with oral iron; interactions with IV formulations are minimal. These interactions apply mainly to oral iron.
• Levodopa and Levodopa Combinations: Iron may reduce the effects of some dopamine agonists. With IV formulations, this interaction may not be clinically significant, but monitoring is required.
• Precautions
• Risk of Iron Overload: Use is contraindicated in patients with elevated ferritin and transferrin saturation. Iron parameters should be monitored before and during treatment.
• Risk of Allergic and Anaphylactic Reactions: Parenteral iron preparations may rarely cause severe hypersensitivity reactions. Emergency equipment should be available during administration, and the patient should be observed for 30 minutes.
• Chronic Liver Disease: Iron metabolism may be impaired in these patients. Use cautiously and monitor liver function and iron accumulation.
• Presence of Infection: Ferric carboxymaltose may increase the severity of infections because microorganisms can use iron. It should be deferred in the presence of active infection; the decision should be based on the clinical situation.
• Pregnancy and Breastfeeding: The pregnancy category is generally C; adequate human data are lacking. A risk-benefit assessment should be performed in pregnant patients. It may be used during breastfeeding because systemic transfer is low.
• Hypophosphatemia: Serum phosphate levels may fall (hypophosphatemia), particularly with repeated doses. Phosphate levels should be monitored during prolonged treatment.
• Heart Failure: Careful dosing is needed in patients with both iron deficiency anemia and heart failure. Large-volume infusions should be avoided, and dosing should be individualized.
• Administration-Site Reactions: Local effects such as pain, edema, and discoloration may occur at the infusion site. Leakage outside the vein (extravasation) should be prevented by using the correct administration technique.

Adverse Effects

• Nausea 4.2%
• Headache 3.3%
• Hypophosphatemia (low serum phosphate) 2.1%
• Injection-site pain, swelling, and redness 2%
• Dizziness 1.9%
• Hypertension (increased blood pressure) 1.8%
• Flushing (a warm sensation or redness in the face) 1.6%
• Taste disturbance 1.5%
• Musculoskeletal pain (back, joints, muscles) 1.3%
• Itching (pruritus) 1.2%
• Rash 1.1%
• Injection-site discoloration (hyperpigmentation) 1%
• Injection-site extravasation <1%
• Anaphylactoid reactions / allergic reactions <1%
• Hypotension (low blood pressure) <1%
• Fever <1%
• Weakness / fatigue <1%