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Drug Safety-related Labeling Changes (SrLC)

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FERAHEME (NDA-022180)

(FERUMOXYTOL)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/16/2022 (SUPPL-25)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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, acute myocardial ischemia with or without myocardial infarction or with in-stent thrombosis in the context of a hypersensitivity reaction, 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.

09/11/2020 (SUPPL-24)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Limited available data with ferumoxytol use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with untreated iron deficiency anemia (IDA) in pregnancy as well as risks to the fetus associated with maternal severe hypersensitivity reactions (see Clinical Considerations)

Clinical Considerations

Newly added information:

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 Feraheme) which may cause fetal bradycardia, especially during the second and third trimester.

02/02/2018 (SUPPL-9)

Approved Drug Label (PDF)

Boxed Warning

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS

(Additions and/or revisions are underlined)


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 as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

5 Warnings and Precautions

5.1 Serious Hypersensitivity Reactions

(Additions and/or revisions are underlined)

Only administer Feraheme as an intravenous infusion over at least 15 minutes and only 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.


In a clinical study in patients with IDA, regardless of etiology, hypersensitivity reactions were reported in 0.4% (4/997) of subjects receiving Feraheme administered as intravenous infusion over at least 15 minutes. These included one patient with severe hypersensitivity reaction and three patients with moderate hypersensitivity reactions.


In clinical studies predominantly in patients with IDA and CKD, serious hypersensitivity reactions were reported in 0.2% (4/1,806) of subjects receiving Feraheme (administered as a rapid intravenous injection prior method of administration no longer approved).

Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.5% (63/1,806) of these subjects.


...

5.2 Hypotension

(Additions and/or revisions are underlined)


Feraheme may cause clinically significant hypotension.


In a clinical study with Feraheme in patients with IDA, regardless of etiology, moderate hypotension was reported in 0.2% (2/997) of subjects receiving Feraheme administered as intravenous infusion over at least 15 minutes.


In clinical studies in patients with IDA and CKD, hypotension was reported in 1.9% (35/1,806) of subjects, including three patients with serious hypotensive reactions, who had received Feraheme as a rapid intravenous injection (prior method of administration no longer approved).

5.4 Magnetic Resonance (MR) Imaging Test Interference

(Subsection title has been revised; additions and/or revisions are underlined)

Magnetic Resonance (MR) Imaging Test Interference

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)


Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


In clinical studies, 3,968 subjects were exposed to Feraheme. Of these subjects 31% were male and the median age was 54 years (range of 18 to 96 years).



The data described below reflect exposure to Feraheme in 997 patients exposed to a 1.02 g course of ferumoxytol administered as two 510 mg intravenous (IV) doses: 992 subjects (99.5%) received at least 1 complete dose of ferumoxytol and 946 subjects (94.9%) received 2 complete doses. The mean cumulative IV Iron exposure was 993.80 ±119.085 mg.


The safety of Feraheme was studied in a randomized, multicenter, double-blind clinical trial in patients with IDA (IDA Trial 3), [see Clinical Studies (14.1)]. In this trial, patients were randomized to two intravenous infusions of 510 mg (1.02 g) of Feraheme (n=997), or two intravenous infusions of 750 mg (1.500 g) of ferric carboxymaltose (FCM) (n=1000). Both intravenous irons were infused over a period of at least 15 minutes. Most patients received their second infusion of Feraheme and FCM 7(+1) days after Dose 1.


The mean (SD) age of the study population (N=1997) was 55.2 (17.16) years. The majority of patients were female (76.1%), white (71.4%) and non-Hispanic (81.8%). The mean (SD) hemoglobin at baseline for all patients was 10.4 (1.5) g/dl.


Serious adverse events were reported in 3.6% (71/1997) of ferumoxytol- and FCM- treated patients. The most common (greater than or equal to 2 subjects) serious AEs reported in Feraheme-treated patients were syncope, gastroenteritis, seizure, pneumonia, hemorrhagic anemia, and acute kidney injury. In FCM-treated patients the most common (greater than or equal to 2 subjects) serious AEs were syncope, cardiac failure congestive, angina pectoris, and atrial fibrillation.


Adverse reactions related to Feraheme and reported by greater than or equal to 1% of Feraheme-treated patients in IDA Trial 3 are listed in Table 1.

 

 (Table has been added; please refer to label)

Table 1: Adverse Reactions to Feraheme Reported in greater than or equal to 1% of IDA Patients in IDA Trial 3


In IDA Trial 3, adverse reactions leading to treatment discontinuation and occurring in greater than or equal to 2 Feraheme-treated patients included arthralgia (0.3%), dyspnea (0.3%), flushing (0.2%), chest discomfort (0.2%), chest pain (0.2%), nausea (0.2%), back pain (0.2%), dizziness (0.2%) and headache (0.2%).


Across two clinical trials in patients with IDA (IDA Trial 1 and 2), [see Clinical Studies (14.1)], patients were randomized to: two injections (rapid intravenous injection - prior method of administration no longer approved) of 510 mg of Feraheme (n=1,014), placebo (n=200), or five injections/infusions of 200 mg of iron sucrose (n=199). Most patients received their second Feraheme injection 3 to 8 days after the first injection. Adverse reactions related to Feraheme and reported by greater than or equal to 1% of Feraheme-treated patients in these trials were similar to those seen in Trial 3.


In Trials 1 and 2, adverse reactions leading to treatment discontinuation and occurring in greater than or equal to 2 Feraheme-treated patients included hypersensitivity (0.6%), hypotension (0.3%), and rash (0.2%).


In addition, a total of 634 subjects enrolled in and completed participation in a Phase 3 open label extension study. Of these, 337 subjects met IDA treatment criteria and received Feraheme. Adverse reactions following this repeat Feraheme dosing were generally similar in type and frequency to those observed after the first two intravenous injections.

 

Across three randomized clinical trials in patients with IDA and CKD (CKD Trials 1, 2, and 3), 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 greater than or equal to 1% of Feraheme-treated patients in the CKD randomized clinical trials are listed in Table 2. Diarrhea (4%), constipation (2.1%) and hypertension (1%) have also been reported in Feraheme-treated patients.


(Table has been revised; please refer to label)

Table 2: Adverse Reactions to Feraheme Reported in greater than or equal to 1% of Patients with IDA and CKD Trials 1, 2 and 3

 

In these clinical trials in patients with IDA and CKD, adverse reactions leading to treatment discontinuation and occurring in greater than or equal to 2 Feraheme-treated patients included hypotension (0.4%), chest pain (0.3%), and dizziness (0.3%).

 

ADVERSE REACTIONS

(Additions and/or revisions are underlined)


The following serious adverse reactions are described elsewhere in the labeling:

  • Serious Hypersensitivity Reactions
  • Hypotension
  • Iron Overload
  • Magnetic Resonance (MR) Imaging Test Interference

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)     

     

Risk Summary

Limited available data with ferumoxytol use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with untreated iron deficiency anemia (IDA) in pregnancy (see Clinical Considerations). In animal studies, administration of ferumoxytol to pregnant rabbits during organogenesis caused adverse developmental outcomes including fetal malformations and decreased fetal weights at maternally toxic doses of 6 times the estimated human daily dose.

 

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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.



Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Untreated iron deficiency anemia (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.



Data

Animal Data

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….

8.2 Lactation

(Newly added subsection)

 

Risk Summary

 

There are no data on the presence of ferumoxytol in human milk, the effects on the breastfed child, or the effects on milk production. Ferumoxytol has been detected in the milk of lactating rats. However, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Feraheme and any potential adverse effects on the breastfed child from Feraheme or from the underlying maternal condition.

 

8.5 Geriatric Use

(Additions and/or revisions are underlined)


In controlled clinical trials, 833 patients ? 65 years of age were treated with Feraheme….

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information) Prior History of Allergies to Parenteral Iron Products

Question patients regarding any prior history of allergies to parenteral iron products.

Hypersensitivity Reactions

Advise patients to immediately report any symptoms of hypersensitivity that may develop during and following Feraheme administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems.

Medication Guide

(Medication Guide Table has been added; please refer to label)