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Generic Name: Ferric Carboxymaltose
Proprietary Name: Injectafer (American Regent)
Approval Rating: 5S
Therapeutic Class: Iron, Parenteral
Similar Drugs: Ferumoxytol, Iron Dextran, Iron Sucrose, Sodium Ferric Gluconate Complex
Sound- or Look-Alike Names: Interferon
Ferric carboxymaltose received US Food and Drug Administration (FDA) approval for the treatment of iron deficiency anemia in adult patients who are intolerant of oral iron or have had an unsatisfactory response to oral iron and in adult patients with nondialysis-dependent chronic kidney disease (CKD).1
Table 1 compares the FDA-approved indications for parenteral iron products.
Ferric carboxymaltose does not contain dextran or modified dextran and does not react with dextran antibodies.2
Table 2 compares the available parental iron products.
Following intravenous (IV) administration of ferric carboxymaltose at single doses ranging from 100 to 1,000 mg, a rapid, dose-dependent increase in total serum iron was observed. Peak serum iron levels occurred within 0.3 to 1.2 hours. Mean maximum total serum iron levels were 36.9 mcg/mL following a 100 mg IV dose, 154.1 mcg/mL following a 500 mg IV dose, and 306.4 to 317.9 mcg/mL following a 1,000 mg IV dose.3,4
Iron administered as ferric carboxymaltose is rapidly distributed to the bone marrow, liver, and spleen. Peak serum ferritin levels occurred at 48 to 120 hours post infusion.3 The volume of distribution is about 3 L.1
Levels declined over 24 to 72 hours; total serum iron levels were below the limit of quantification in the majority of patients within 60 to 96 hours post dose.3 Ferric carboxymaltose has a terminal elimination half-life of 7.4 to 12.1 hours.1,3 Less than 0.1% of the administered dose is excreted in the urine.3,5
Guideline: KDIGO clinical practice guideline for anemia in chronic kidney diseases
Reference: Kidney Disease: Improving Global Outcomes Anemia Work Group, 20126
Comments: For adult CKD patients with anemia who are not receiving iron therapy, the guidelines advise a trial of IV iron if an increase in hemoglobin concentration without starting erythropoiesis-stimulating agent (ESA) treatment is desired, total saturation of transferrin is no greater than 30%, and ferritin is no greater than 500 ng/mL. For adult CKD patients receiving ESA therapy who are not receiving iron supplementation, the guidelines advise a trial of IV iron if an increase in hemoglobin concentration or a decrease in ESA dose is desired, total saturation of transferrin is no greater than 30%, and ferritin is no greater than 500 ng/mL. Alternatively, a 1- to 3-month trial of oral iron may be appropriate for adult CKD patients who are not receiving dialysis. For pediatric CKD patients with anemia who are on hemodialysis and not receiving iron or ESA therapy, the guidelines recommend oral or IV iron when total saturation of transferrin is 20% or lower and ferritin is 100 ng/mL or lower. For pediatric CKD patients on hemodialysis who are receiving ESA therapy and not receiving iron, the guidelines recommend oral or IV iron to maintain total saturation of transferrin greater than 20% and ferritin greater than 100 ng/mL. Regarding administration of the initial IV iron dose, the guidelines recommend monitoring the patient for 60 minutes after an initial iron dextran infusion and suggest monitoring for 60 minutes after initial administration of nondextran IV iron. The guidelines also recommend that IV iron be avoided in patients with active systemic infections.
Guideline: KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease
Reference: KDOQI, et al, 20067
Comments: Kidney Disease Outcomes Quality Initiative guidelines strongly recommend IV administration as the preferred route of iron administration for CKD patients on hemodialysis; IV or oral administration is an option in CKD patients not on dialysis or CKD patients receiving peritoneal dialysis. In CKD patients on hemodialysis who are receiving ESA treatment, sufficient iron should be administered to maintain serum ferritin greater than 200 ng/mL, total saturation of transferrin greater than 20%, or reticulocyte hemoglobin greater than 29 pg/cell; sufficient iron should be administered to maintain serum ferritin greater than 100 ng/mL and total saturation of transferrin greater than 20% in CKD patients not receiving dialysis or in CKD patients receiving peritoneal dialysis. The guidelines acknowledge there are no adequately powered studies directly comparing different IV iron agents.
Drug: Ferric Carboxymaltose vs Iron Sucrose
Drug: Ferric Carboxymaltose vs Oral Iron
Drug: Ferric Carboxymaltose vs IV Iron, Oral Iron, or No Iron (standard medical care)
Drug: Ferric Carboxymaltose
Guideline: Guidelines for the Management of Iron Deficiency Anemia
Reference: Goddard AF, et al, 201116
Comments: In patients with iron deficiency anemia, iron supplementation is necessary to correct anemia and replenish body stores. Parenteral iron is recommended when oral preparations are not tolerated or an adequate response is not achieved. The guidelines do not recommend one particular parenteral iron over others but do highlight the convenience of the shorter infusion duration with ferric carboxymaltose and the good tolerability of iron sucrose, both relative to iron dextran.
Guideline: ACOG Practice Bulletin No. 95: Anemia in Pregnancy
Reference: American College of Obstetricians and Gynecologists, 200817
Comments: The guidelines acknowledge that parenteral iron may be appropriate in pregnant patients who will not take modest doses of oral iron, patients not able to tolerate oral iron, patients with malabsorption syndrome, and patients with severe iron deficiency anemia. The guidelines do not recommend one particular parenteral iron over others but acknowledge the higher incidence of allergic reactions with iron dextran relative to iron sucrose.
Drug: Ferric Carboxymaltose vs IV Iron or Oral Iron
Drug: Ferric Carboxymaltose vs Iron Sucrose
Drug: Ferric Carboxymaltose vs Ferrous Sulfate
Drug: Ferric Carboxymaltose, Iron Dextrose, Iron Sucrose
The contraindications, warnings, and precautions of the available parenteral iron products are compared in Table 3.
Parenteral iron formulations, including ferric carboxymaltose, can cause hypersensitivity reactions, including potentially fatal anaphylactoid reactions. Facilities for cardiopulmonary resuscitation must be available during ferric carboxymaltose administration. Patients should be monitored for signs and symptoms of hypersensitivity during and for at least 30 minutes after administration and until clinically stable. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2 of 1,775) of patients receiving ferric carboxymaltose. Other serious reactions potentially related to hypersensitivity, including pruritus, rash, urticaria, wheezing, or hypotension, occurred in 1.5% (26 of 1,775) of patients.1
Hypertension was reported in 3.8% (67 of 1,775) of patients treated with ferric carboxymaltose in clinical trials, while transient elevations in systolic blood pressure sometimes accompanied by facial flushing, dizziness, or nausea occurred in 6% (106 of 1,775) of patients. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Patients should be monitored for hypertension following administration of each ferric carboxymaltose dose.1
Laboratory assays may overestimate serum iron and transferrin-bound iron in the 24 hours following ferric carboxymaltose administration by also measuring the iron in the product.1
Caution is necessary to avoid extravasation when administering ferric carboxymaltose. Leakage could result in brown discoloration and irritation of the skin. In the case of extravasation, ferric carboxymaltose administration should be immediately stopped.1
Safety and effectiveness have not been established in pediatric patients.1
Ferric carboxymaltose is assigned Pregnancy Category C. Fetal malformations and increased implantation losses were observed in animal studies at maternally toxic doses. Studies in pregnant women have not been conducted. Ferric carboxymaltose should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1
In 25 lactating women with postpartum iron deficiency, mean breast milk iron levels were higher in lactating women treated with ferric carboxymaltose than in lactating women receiving oral ferrous sulfate.1
Common adverse events include nausea, hypertension, flushing, dizziness, vomiting, injection-site discoloration, headache, dysgeusia, hypotension, constipation, abdominal pain, diarrhea, injection-site pain/irritation, rash, paresthesia, sneezing, increased gamma-glutamyl transferase, increased ALT, and blood phosphorus level reduction.1
Table 4 shows adverse reactions reported in clinical trials when comparing ferric carboxymaltose with oral and IV iron products.
Administration of ferric carboxymaltose 15 mg/kg (maximum, 1,000 mg) over 15 minutes as an IV infusion was not associated with an increased incidence of severe adverse events compared with placebo in a crossover study that included 559 patients with iron deficiency anemia. Rates of nausea, headache, and dizziness were slightly increased.7
For patients weighing 50 kg or more, ferric carboxymaltose is recommended in two 750 mg doses separated by at least 7 days, for a total cumulative dose not exceeding 1,500 mg of iron per course. For patients weighing less than 50 kg, ferric carboxymaltose is recommended in two 15 mg/kg doses separated by at least 7 days, for a total cumulative dose not exceeding 1,500 mg of iron per course. Treatment may be repeated if iron deficiency anemia recurs.1
Ferric carboxymaltose is administered IV as an undiluted slow IV push at a rate of approximately 100 mg (2 mL) per minute or as an IV infusion diluted in no more than 250 mL of sterile sodium chloride 0.9% injection administered over at least 15 minutes.1 In clinical trials, ferric carboxymaltose has been administered as 100 or 200 mg undiluted injections over 1 to 2 minutes, and at dosages of up to 1,000 mg as short infusions (10 to 30 minutes) in 100 to 250 mL of sodium chloride 0.9% solution.2-4,15,25,27,28 European labeling includes an IV bolus dosage of up to 200 mg/day no more than 3 times a week and an IV infusion dosage of up to 1,000 mg (not to exceed 15 mg/kg) no more than once a week.5
Table 5 compares the dosing and administration for the parental iron products.
Ferric carboxymaltose injection received FDA approval on July 25, 2013. It is available as an IV solution in single-use vials containing 750 mg of iron per 15 mL, supplied individually boxed and in packages of 2 vials.1 It should be stored at 20°C to 25°C (68°F to 77°F), with excursions permitted to 15°F to 30°C (59°F to 80°F). The product should not be frozen.1
Table 6 compares the dosage forms and strengths available for the parenteral iron products.
No REMS is required for ferric carboxymaltose or any other parenteral iron product.
Ferric carboxymaltose is effective for iron replacement in patients with iron deficiency anemia. Ferric carboxymaltose has efficacy comparable with or greater than IV iron sucrose and oral iron in patients with iron deficiency anemia associated with CKD, gynecologic bleeding, inflammatory bowel disease, and other medical conditions. It appears to be very well tolerated, permitting administration of dosages of up to 750 mg weekly, which results in rapid replacement of iron stores and a quick therapeutic response.