RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS
Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving Feraheme. Initial symptoms may include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.
- Only administer Feraheme when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].
- Observe for signs or symptoms of hypersensitivity reactions during and for at least 30 minutes following Feraheme infusion including monitoring of blood pressure and pulse during and after Feraheme administration [see WARNINGS AND PRECAUTIONS].
- Hypersensitivity reactions have occurred in patients in whom a previous Feraheme dose was tolerated [see WARNINGS AND PRECAUTIONS].
Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.
Feraheme Injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme Injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
What are the possible side effects of ferumoxytol (Feraheme)?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; wheezing or difficult breathing; swelling of your face, lips, tongue, or throat.
Watch for signs of allergic reaction for at least 30 minutes after your injection.
Call your doctor at once if you have serious side effects such as:
- feeling like you might pass out;
- slow heart rate, weak pulse, fainting, slow breathing (breathing may stop);
- easy bruising;
- swelling where the medicine was injected; or
- worsening symptoms of kidney failure...
Feraheme is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).
DOSAGE AND ADMINISTRATION
The recommended dose of Feraheme is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. Administer Feraheme intravenously, either as an undiluted slow intravenous injection or by infusion.
|Administration||Rate of delivery||Dilution|
|Undiluted intravenous injection||1 mL/sec (30 mg/sec) At least 17 seconds||No Dilution|
|Diluted intravenous infusion||At least 15 minutes||Dilute in 50 to 200 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.|
Feraheme, when added to intravenous infusion bags containing either Sodium Chloride Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2-8 mg elemental iron per mL, should be used immediately, but may be stored at controlled room temperature (25°C ± 2°C) for up to 4 hours.
The dosage is expressed in terms of mg of elemental iron, with each mL of Feraheme containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin, iron and transferrin saturation) at least one month following the second Feraheme injection. The recommended Feraheme dose may be readministered to patients with persistent or recurrent iron deficiency anemia.
For patients receiving hemodialysis, administer Feraheme once the blood pressure is stable and the patient has completed at least one hour of hemodialysis. Monitor for signs and symptoms of hypotension following each Feraheme injection.
Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration.
Dosage Forms And Strengths
Feraheme Injection is available in single use vials. Each vial contains 510 mg of elemental iron in 17 mL.
Storage And Handling
Feraheme is available in single use vials in the following package sizes (Table 3).
Table 3: Feraheme Packaging Description
|NDC Code||Dose / Total volume per vial||Vials / Carton|
|NDC 59338-775-01||510 mg/ 17 mL||1|
|NDC 59338-775-10||510 mg/ 17 mL||10|
Stability And Storage
Store at 20° to 25°C (68°to 77°F). Excursions permitted to 15°– 30°C (59°– 86°F) [see USP controlled room temperature].
Distributed by: AMAG Pharmaceuticals, Inc. Waltham, MA 02451. Revised: December 2013
In clinical studies, 1,726 subjects were exposed to Feraheme; 1,562 of these had CKD and 164 did not have CKD. Of these subjects 46% were male and the median age was 63 years (range of 18 to 96 years).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.
Adverse Reactions In Clinical Studies
Across the three randomized clinical trials [Trial 1, 2, and 3, see Clinical Studies], a total of 605 patients were exposed to two injections of 510 mg of Feraheme and a total of 280 patients were exposed to 200 mg/day of oral iron for 21 days. Most patients received their second Feraheme injection 3 to 8 days after the first injection.
Adverse reactions related to Feraheme and reported by ≥ 1% of Feraheme-treated patients in the randomized clinical trials are listed in Table 1. Diarrhea (4.0%), constipation (2.1%) and hypertension (1.0%) have also been reported in Feraheme-treated patients.
Table 1: Adverse Reactions to Feraheme Reported in
≥ 1% of Patients with CKD
2 x 510 mg
(n = 605)
(n = 280)
In clinical trials, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 Feraheme-treated patients included hypotension, infusion site swelling, increased serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, pruritus, chronic renal failure, and urticaria.
Following completion of the controlled phase of the trials, 69 patients received two additional 510 mg intravenous injections of Feraheme (for a total cumulative dose of 2.04 g). Adverse reactions following this repeat Feraheme dosing were similar in character and frequency to those observed following the first two intravenous injections.
In a placebo-controlled, cross-over trial, 713 patients with CKD received a single 510 mg dose of Feraheme. Adverse reactions reported by these patients were similar in character and frequency to those observed in other clinical trials.
Because adverse 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 serious adverse reactions have been reported from the post-marketing experience with Feraheme: fatal, life-threatening, and serious anaphylactic-type reactions, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have usually occurred within 30 minutes after the administration of Feraheme. Reactions have occurred following the first dose or subsequent doses of Feraheme.
Drug-drug interaction studies with Feraheme were not conducted. Feraheme may reduce the absorption of concomitantly administered oral iron preparations.
Included as part of the PRECAUTIONS section.
Serious Hypersensitivity Reactions
Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness have occurred in patients receiving Feraheme [see BOXED WARNING]. Other adverse reactions potentially associated with hypersensitivity have occurred (pruritus, rash, urticaria, and wheezing). These reactions have occurred following the first dose or subsequent doses in patients in whom a previous Feraheme dose was tolerated.
Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.
Only administer Feraheme when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after Feraheme administration for at least 30 minutes and until clinically stable following completion of each infusion [see ADVERSE REACTIONS].
In clinical studies predominantly in patients with CKD, serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. In other trials excluding patients with Stages 4 and 5 CKD, moderate to severe hypersensitivity reactions were reported in 2.6% (26/1014) of patients treated with Feraheme.
In the post-marketing experience, fatal and serious anaphylactic type reactions presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes [see BOXED WARNING, ADVERSE REACTIONS and Use In Specific Populations].
Severe adverse reactions of clinically significant hypotension have been reported. In clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. Hypotension has also been reported in the post-marketing experience [see ADVERSE REACTIONS from Post-marketing Spontaneous Reports]. Monitor patients for signs and symptoms of hypotension following each Feraheme administration [see DOSAGE AND ADMINISTRATION and Serious Hypersensitivity Reactions above].
Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response during parenteral iron therapy [see DOSAGE AND ADMINISTRATION]. Do not administer Feraheme to patients with iron overload.
In the 24 hours following administration of Feraheme, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the Feraheme complex.
Magnetic Resonance (MR) Imaging
Administration of Feraheme may transiently affect the diagnostic ability of MR imaging. Anticipated MR imaging studies should be conducted prior to the administration of Feraheme. Alteration of MR imaging studies may persist for up to 3 months following the last Feraheme dose. If MR imaging is required within 3 months after Feraheme administration, use T1-or proton density-weighted MR pulse sequences to minimize the Feraheme effects; MR imaging using T2-weighted pulse sequences should not be performed earlier than 4 weeks after the administration of Feraheme. Maximum alteration of vascular MR imaging is anticipated to be evident for 1 – 2 days following Feraheme administration [see CLINICAL PHARMACOLOGY].
Patient Counseling Information
Refer patients to the FDA approved Patient Package Insert.
Prior to Feraheme administration:
- Question patients regarding a history of allergy to intravenous iron or any medications.
- Advise patients of the serious risks associated with Feraheme.
- Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems. Advise patients to seek immediate medical attention if these occur [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Ferumoxytol was not tested for carcinogenic effects. In standard genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.
No adverse effects on fertility or general reproductive performance were noted in animal studies. Ferumoxytol had no effect on male or female fertility or general reproductive function in rats.
Use In Specific Populations
Pregnancy Category C
There are no studies of Feraheme in pregnant women. In animal studies, ferumoxytol caused fetal malformations and decreased fetal weights at maternally toxic doses of 6 times the estimated human daily dose. Use Feraheme during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects. These doses are approximately 2 times the estimated human daily dose based on body surface area. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, caused a decrease in fetal weights. In rabbits, administration of ferumoxytol during organogenesis at a maternally toxic dose of 45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, was associated with external and/or soft tissue fetal malformations and decreased fetal weights.
It is not known whether Feraheme is present in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to avoid Feraheme, taking into account the importance of Feraheme to the mother and the known benefits of nursing.
The safety and effectiveness of Feraheme in pediatric patients (less than 18 years old) have not been established.
In controlled clinical trials, 330 patients ≥ 65 years of age were treated with Feraheme. No overall differences in safety and efficacy were observed between older and younger patients in these trials, but greater sensitivity of older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes. The potential risks and benefits of Feraheme administration should be carefully considered in these patients [see DOSAGE AND ADMINISTRATION, Serious Hypersensitivity Reactions and Clinical Studies].
Limited data are available regarding overdosage of Feraheme in humans.
Excessive dosages of Feraheme may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Feraheme to patients with iron overload [WARNINGS AND PRECAUTIONS].
Feraheme is contraindicated in patients with:
- Known hypersensitivity to Feraheme or any of its components
- History of allergic reaction to any intravenous iron product
Mechanism Of Action
Feraheme consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps to isolate the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and bone marrow. The iron is released from the iron-carbohydrate complex within vesicles in the macrophages. Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin.
In a randomized, positive-and placebo-controlled, parallel-group study, healthy subjects received a supratherapeutic regimen of Feraheme (1.02 g given as two 510 mg doses within 24 hours), placebo or a single dose of 400 mg moxifloxacin (positive control). Results demonstrated no effect of Feraheme on QT interval durations. No clinically meaningful effect of Feraheme on heart rate was observed.
The pharmacokinetic (PK) behavior of Feraheme has been examined in healthy subjects and in patients with CKD stage 5D on hemodialysis. Feraheme exhibited dose-dependent, capacity-limited elimination from plasma with a half life of approximately 15 hours in humans. The clearance (CL) was decreased by increasing the dose of Feraheme. Volume of distribution (Vd) was consistent with plasma volume, and the mean maximum observed plasma concentration (Cmax) and terminal half-life (t½) values increased with dose. The estimated values of CL and Vd following two 510 mg doses of Feraheme administered intravenously within 24 hours were 69.1 mL/hr and 3.16 L, respectively. The Cmax and time of maximum concentration (tmax) were 206 mcg/mL and 0.32 hr, respectively. Rate of infusion had no influence on Feraheme PK parameters. No gender differences in Feraheme PK parameters were observed. Feraheme is not removed by hemodialysis.
The safety and efficacy of Feraheme for the episodic treatment of iron deficiency anemia in patients with CKD were assessed in three randomized, open-label, controlled clinical trials (Trial 1, 2 and 3). These trials also included an uncontrolled, follow-up phase in which patients with persistent iron deficiency anemia could receive two additional 510 mg intravenous injections of Feraheme. The major efficacy results from the controlled phase of each study are shown in Table 2.
In all three trials, patients with CKD and iron deficiency anemia were randomized to treatment with Feraheme or oral iron. Feraheme was administered as two 510 mg intravenous single doses and oral iron (ferrous fumarate) was administered as a total daily dose of 200 mg elemental iron daily for 21 days. The major trial outcomes assessed the change in hemoglobin from baseline to Day 35. Trial 1 and 2 enrolled patients with non-dialysis dependent CKD and Trial 3 enrolled patients who were undergoing hemodialysis.
In Trial 1, the mean age of patients was 66 years (range, 23 to 95); 60% were female; 65% were Caucasian, 32% were Black, and 2% were other races. In the Feraheme and oral iron groups, 42% and 44% of patients, respectively, were receiving erythropoiesis stimulating agents (ESAs) at baseline.
In Trial 2, the mean age of patients was 65 years (range, 31 to 96); 61% were female; 58% were Caucasian, 35% were Black, and 7% were other races. In the Feraheme and oral iron groups, 36% and 43% of patients, respectively, were receiving ESAs at baseline.
In Trial 3, the mean age of patients was 60 years (range, 24 to 87); 43% were female; 34% were Caucasian, 59% were Black, and 7% were other races. All patients were receiving ESAs.
Table 2 shows the Baseline and mean change to Day 35 in hemoglobin (Hgb, g/dL), transferrin saturation (TSAT, %) and ferritin (ng/mL) in each treatment group for Trial 1, 2, and 3.
Table 2: Changes from Baseline to Day 35 in
Hemoglobin, Transferrin Saturation and Ferritin (Intent to Treat Population)
|ENDPOINT||Trial 1 Non-Dialysis CKD||Trial 2 Non-Dialysis CKD||Trial 3 CKD on Dialysis|
n = 226
n = 77
n = 228
n = 76
n = 114
n = 116
|Baseline Hgb (mean ± SD, g/dL)||9.9 ± 0.8||9.9 ± 0.7||10.0 ± 0.7||10.0 ± 0.8||10.6 ± 0.7||10.7 ± 0.6|
|Hgb change from Baseline at Day 35 (mean ± SD, g/dL)||1.2* ± 1.3||0.5 ± 1.0||0.8* ± 1.2||0.2 ± 1.0||1.0* ± 1.1||0.5 ± 1.1|
|Baseline TSAT (mean ± SD, %)||9.8 ± 5.4||10.4 ± 5.2||11.3 ± 6.1||10.1 ± 5.5||15.7 ± 7.2||15.9 ± 6.3|
|TSAT change from Baseline at Day 35 (mean ± SD, %)||9.2 ± 9.4||0.3 ± 4.7||9.8 ± 9.2||1.3 ± 6.4||6.4 ± 12.6||0.6 ± 8.3|
|Baseline ferritin (mean ± SD, ng/mL)||123.7 ± 125.4||146.2 ± 136.3||146.1 ± 173.6||143.5 ± 144.9||340.5 ± 159.1||357.6 ± 171.7|
|Ferritin change from Baseline at Day 35 (mean ± SD,ng/mL)||300.7 ± 214.9||0.3 ± 82.0||381.7 ± 278.6||6.9 ± 60.1||233.9 ± 207.0||-59.2 ± 106.2|
|* p ≤ 0.001 for main efficacy endpoint|
Following completion of the controlled phase of each of the Phase 3 trials, patients who were iron deficient and anemic could receive two additional 510 mg intravenous injections of Feraheme for a total cumulative dose of 2.04 g. Overall, 69 patients received two additional 510 mg intravenous injections of Feraheme, and on Day 35 following these additional injections, the majority of these patients (70%) experienced an increase in hemoglobin and iron parameters (TSAT and ferritin). The mean change (±SD) in hemoglobin level from the retreatment baseline for patients with an increase in hemoglobin was 0.86 (± 0.68) g/dL and was 0.5 (± 0.8) g/dL for all patients.
What is the most important information I should know about Feraheme?
Feraheme may cause serious side effects including:
- Serious allergic reactions
that can lead to death. Serious allergic reactions have happened in people after
receiving the first dose of Feraheme or after receiving additional doses in
people who did not previously have an allergic reaction. If you have a history
of allergies to many different medicines, you may have an increased risk of
serious allergic reactions to Feraheme. Tell your healthcare provider or get
medical help right away if you get any of these signs or symptoms:
- dizziness or lightheadedness
- swelling of the tongue or throat
- wheezing or trouble breathing
See “What are the possible side effects of Feraheme?” for more information about side effects.
What is Feraheme?
Feraheme is a prescription medicine used to treat iron deficiency anemia in adults with chronic kidney disease (CKD).
It is not known if Feraheme is safe and effective in children less than 18 years of age.
Who should not receive Feraheme?
You should not receive Feraheme if you:
- are allergic to Feraheme or any of the ingredients in Feraheme. See the end of this leaflet for a complete list of ingredients in Feraheme.
- have had an allergic reaction to any iron medicine given into your vein by intravenous (IV) infusion.
Before receiving Feraheme, tell your healthcare provider about all of your medical conditions, including if you:
- have allergies to many different medicines.
- have low blood pressure (hypotension).
- are pregnant or plan to become pregnant. It is not known if Feraheme will harm your unborn baby.
- are breastfeeding or plan to breastfeed. It is not known if Feraheme passes into your breast milk. You and your healthcare provider should decide if you will receive Feraheme or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive Feraheme?
Feraheme will be given to you into your vein by intravenous (IV) infusion over at least 15 minutes by your healthcare provider. Your healthcare provider will watch you during and for at least 30 minutes after you receive Feraheme.
What are the possible side effects of Feraheme?
Feraheme can cause serious side effects, including:
- See “What is the most important information I should know about Feraheme?”
- Low blood pressure (hypotension) is a common side effect of Feraheme and can sometimes be serious. Your healthcare provider will check you for signs and symptoms of hypotension after each Feraheme infusion.
- Iron overload. Your healthcare provider will do blood tests to check your iron levels during treatment with Feraheme.
The most common side effects of Feraheme include: diarrhea, nausea, dizziness, constipation, and swelling of your legs, feet, arms, or hands.
These are not all of the possible side effects of Feraheme. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Feraheme.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about Feraheme that is written for health professionals.
What are the ingredients in Feraheme?
Active ingredient: ferumoxytol
Inactive ingredient: mannitol
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.