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Drug Safety-related Labeling Changes (SrLC)

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INJECTAFER (NDA-203565)

(FERRIC CARBOXYMALTOSE)

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

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05/31/2023 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

Patients with Iron Deficiency and Heart Failure

The safety of Injectafer was evaluated in adult patients with iron deficiency and heart failure in randomized controlled trials FAIR-HF (NCT00520780), CONFIRM-HF (NCT01453608) and AFFIRM-AHF (NCT02937454) in which 1,016 patients received Injectafer versus 857 received placebo. The overall safety profile of Injectafer was consistent across the studied indications.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

Safety and effectiveness of Injectafer have not been established to improve exercise capacity in pediatric patients with ID and symptomatic heart failure.

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

PATIENT INFORMATION

Additions and/or revisions underlined

What is INJECTAFER?

INJECTAFER is a prescription iron replacement medicine used for the treatment of:

  • iron deficiency anemia (IDA) in:

    • adults and children 1 year of age and older who cannot tolerate iron taken by mouth (oral) or who have not responded well to oral iron.

    • adults who have chronic kidney disease who are not on dialysis (non-dialysis dependent chronic kidney disease).

  • iron deficiency in adults with mild to moderate heart failure to improve the ability to exercise (improve exercise capacity).

    It is not known if INJECTAFER is safe and effective in children with IDA who are under 1 year of age.

    It is not known if INJECTAFER is safe and effective in children with iron deficiency and mild to moderate heart failure to improve exercise capacity.

    How will I receive INJECTAFER?

  • INJECTAFER is given into your vein (intravenously) by your healthcare provider.

  • INJECTAFER is usually given in 2 doses at least 7 days apart for IDA, or 6 weeks apart for iron deficiency with mild to moderate heart failure to improve exercise capacity.

  • If your healthcare provider decides it is right for you, INJECTAFER may be given intravenously by your healthcare provider as a single-dose treatment.

    INJECTAFER treatment may be repeated if your healthcare provider decides it is needed.

    What are the possible side effects of INJECTAFER?

    INJECTAFER may cause serious side effects, including:

  • Allergic reactions. Serious life-threatening allergic reactions that can lead to death have happened in people who receive INJECTAFER and may include the following signs or symptoms:

    • low blood pressure   o cold or clammy skin

    • feeling dizzy or lightheaded          o feet or hands turn blue

    • loss of consciousness          o itching

    • trouble breathing    o rash

    • swelling      o hives

    • fast heartbeat          o wheezing

      The most common side effects of INJECTAFER in adults include:

  • dizziness

The most common side effects of INJECTAFER in children include:

  • low levels of phosphate in your blood

  • headache

  • injection site reactions  

  • vomiting

  • rash

05/31/2023 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Symptomatic Hypophosphatemia

Additions and/or revisions underlined

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 to Injectafer in patients with no reported history of renal impairment. However, symptomatic hypophosphatemia has been reported after one dose. Possible risk factors for hypophosphatemia include a history of gastrointestinal disorders associated with malabsorption of fat-soluble vitamins or phosphate, inflammatory bowel disease, concurrent or prior use of medications that affect proximal renal tubular function, hyperparathyroidism, vitamin D deficiency, and malnutrition. In most cases, hypophosphatemia resolved within three months. Correct pre-existing hypophosphatemia prior to initiating therapy with Injectafer. 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 [see Dosage and Administration (2.3)]. Treat hypophosphatemia as medically indicated.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

Symptomatic Hypophosphatemia

Advise patients to report any signs or symptoms of hypophosphatemia such as fatigue, muscle weakness or pain, bone and joint pain, or bone fractures [see Warnings and Precautions (5.2)].

PATIENT INFORMATION

Additions and/or revisions underlined

Before receiving INJECTAFER, tell your healthcare provider about all of your medical conditions, including if you:

  • have a history of trouble absorbing certain vitamins or phosphate in your body

  • have inflammatory bowel disease

  • have hyperparathyroidism

  • have low vitamin D levels

    What are the possible side effects of INJECTAFER?

    INJECTAFER may cause serious side effects, including:

  • Symptoms of low blood phosphate levels. INJECTAFER may cause low levels of phosphate in your blood that may be serious and can lead to softening of your bones and broken bones (fractures), especially in people who have received multiple INJECTAFER treatments. Your healthcare provider may check your blood phosphate levels before a repeat treatment with INJECTAFER if you are at risk for low blood phosphate levels. If a repeat treatment is needed within 3 months of your last treatment your healthcare provider should check your blood phosphate levels. Tell your healthcare provider if you develop any of the following signs or symptoms of low blood phosphate levels during treatment with INJECTAFER:

     

    • feeling very tired       o bone or joint pain

    • muscle weakness or pain      o broken bones

11/19/2021 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined: 

Pediatric Patients

The safety of Injectafer in pediatric patients was evaluated in study 1VIT17044 (NCT03523117; Study 3). Study 1VIT17044 was a randomized, active-controlled study in which 40 patients (1 to 12 years of age: 10 patients, 12 to 17 years of age: 30 patients) received Injectafer 15 mg/kg to a maximum single dose of 750 mg (whichever was smaller) on Days 0 and 7 for a maximum total dose of 1,500 mg; 38 patients evaluable for safety in the control arm received an age-dependent formulation of oral ferrous sulfate for 28 days. The median age of patients who received Injectafer was 14.5 years (range,

1-17); 83% were female; 88% White and 13% Black. The most common adverse reactions (greater than or equal to 4%) were hypophosphatemia, injection site reactions, rash, headache, and vomiting.

Table 3 summarizes the adverse reactions in Study 3

please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined: 

The safety and effectiveness of Injectafer for IDA in pediatric patients aged 1 year and older who have normal kidney function and have either intolerance to oral iron or have had unsatisfactory response to oral iron have been established. Use of Injectafer for this indication in this age group is supported by evidence from adequate and well-controlled studies of Injectafer in adults with additional pharmacodynamic and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

Safety and effectiveness of Injectafer have not been established in pediatric patients less than 1 year of age with IDA

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

17 PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined: 

Advise the patient to read the FDA-approved patient labeling (Patient Information) and discuss with the patient the etiology of the iron deficiency anemia and the patient’s iron deficiency anemia treatment options.

Patient Information

Additions and/or revisions underlined: 

What is INJECTAFER?

INJECTAFER is a prescription iron replacement medicine used to treat iron deficiency anemia (IDA) in:

  • Adults and pediatric patients 1 year of age and older who have normal kidney function and have either intolerance to oral iron or an unsatisfactory response to oral iron.

  • Adult patients who have non-dialysis dependent chronic kidney disease.

How will I receive INJECTAFER?

  • INJECTAFER is given intravenously (into your vein) by your healthcare provider in 2 doses at least 7 days apart.

If your healthcare provider decides it is right for you, INJECTAFER may be given intravenously to adults by your healthcare provider as a single dose treatment.

What are the possible side effects of INJECTAFER? INJECTAFER may cause serious side effects including:

  • Allergic (hypersensitivity) reactions. Serious life-threatening allergic reactions have happened in people who receive INJECTAFER. Other serious reactions including itching, hives, wheezing, and low blood pressure also have happened during treatment with INJECTAFER. Tell your healthcare provider if you have ever had any unusual or allergic reaction to any iron given by vein.

  • High blood pressure (hypertension). High blood pressure, sometimes with face flushing, dizziness, or nausea, has happened during treatment with INJECTAFER. Your healthcare provider will check your blood pressure and check for any signs and symptoms of high blood pressure after you receive INJECTAFER.

The most common side effects of INJECTAFER include:

    • nausea                                                   ·     high blood pressure

    • flushing                                                 ·     injection site reactions

    • skin redness (erythema)                         ·     low levels of phosphorous in your blood

    • rash                                                       ·      headache

    • vomiting

09/11/2020 (SUPPL-13)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

… There are risks to the mother and fetus associated with untreated 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 Injectafer) which may cause fetal bradycardia, especially during the second and third trimester.

8.2 Lactation

Additions and/or revisions underlined:

Clinical Considerations

Monitor breastfed infants for gastrointestinal toxicity (constipation, diarrhea).

02/19/2020 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Symptomatic Hypophosphatemia

(new subsection added)

Symptomatic hypophosphatemia requiring clinical intervention has been reported in patients at risk of low serum phosphate in the postmarketing setting. These cases have occurred mostly after repeated exposure to Injectafer in patients with no reported history of renal impairment. Possible risk factors for hypophosphatemia include a history of gastrointestinal disorders associated with malabsorption of fat-soluble vitamins or phosphate, concurrent or prior use of medications that affect proximal renal tubular function, hyperparathyroidism, vitamin D deficiency and malnutrition.  In most cases, hypophosphatemia resolved within three months.

 

Monitor serum phosphate levels in patients at risk for low serum phosphate who require a repeat course of treatment.

6 Adverse Reactions

(additions underlined)

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

  • Hypophosphatemia

 

6.2 Post-marketing Experience

(subsection revised, addition underlined)

The following adverse reactions have been reported from the post-marketing spontaneous reports with Injectafer:

 

  • Cardiac disorders: Tachycardia

  • General disorders and administration site conditions: Chest discomfort, chills, pyrexia

  • Metabolism and nutrition disorders:  Hypophosphatemia

  • Musculoskeletal and connective tissue disorders:  Arthralgia, back pain, hypophosphatemic osteomalacia (rarely reported event)

  • Nervous system disorders: Syncope

  • Respiratory, thoracic and mediastinal disorders: Dyspnea

  • Skin and subcutaneous tissue disorders: Angioedema, erythema, pruritus, urticaria

01/26/2018 (SUPPL-5)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Published studies on the use of ferric carboxymaltose in pregnant women have not reported an association with ferric carboxymaltose and adverse developmental outcomes. However, these studies cannot establish or exclude the absence of any drug-related risk during pregnancy because the studies were not designed to assess for the risk of major birth defects (see Data). There are risks to the mother and fetus associated with untreated iron deficiency anemia (IDA) in pregnancy.

In animal reproduction studies, administration of ferric carboxymaltose to rabbits during the period of organogenesis caused adverse developmental outcomes including fetal malformations and increased implantation loss at maternally toxic doses of approximately 12% to 23% of the human weekly dose of 750 mg (based on body surface area).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects 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

Human Data

Published data from randomized controlled studies, prospective observational studies and retrospective studies on the use of ferric carboxymaltose in pregnant women have not reported an association with ferric carboxymaltose and adverse developmental outcomes. However, these studies cannot establish or exclude the absence of any drug-related risk during pregnancy because of methodological limitations, including that the studies were not primarily designed to capture safety data nor designed to assess the risk of major birth defects. Maternal adverse events reported in these studies are similar to those reported during clinical trials in adult males and non-pregnant females.

 

Animal Data

Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to 30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryonic or fetal findings… Adverse embryonic or fetal effects were observed in the presence of maternal toxicity.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

The available published data on the use of ferric carboxymaltose in lactating women demonstrate that iron is present in breast milk. However, the data do not inform the full potential exposure of iron for the breastfed infant. Among the breastfed infants, there were no adverse events reported that were considered related to ferric carboxymaltose exposure through breastmilk. There is no information on the effects of ferric carboxymaltose on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Injectafer in addition to any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

 

Clinical Considerations

Monitor breastfed infants for gastrointestinal toxicity (constipation, diarrhea).

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

Patient Information

(Additions and/or revisions are underlined)

What is INJECTAFER?

INJECTAFER is a prescription iron replacement medicine used to treat iron deficiency anemia in adults who have:

  • intolerance to oral iron or who have not responded well to treatment with oral iron

  • non-dialysis dependent chronic kidney disease

It is not known if INJECTAFER is safe and effective for use in children.

Who should not receive INJECTAFER?

Do not receive INJECTAFER if you are allergic to ferric carboxymaltose or any of the ingredients in INJECTAFER. See the end of this leaflet for a complete list of ingredients in INJECTAFER.

Before receiving INJECTAFER, tell your healthcare provider about all of your medical conditions, including if you:

  • have had an allergic reaction to iron given into your vein

  • have high blood pressure

  • are pregnant or plan to become pregnant. It is not known if INJECTAFER will harm your unborn baby.

  • are breastfeeding or plan to breastfeed. INJECTAFER passes into your breast milk. It is unknown whether INJECTAFER would pose a risk to your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with INJECTAFER.

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 INJECTAFER?

INJECTAFER is given intravenously (into your vein) by your healthcare provider in 2 doses at least 7 days apart.

What are the possible side effects of INJECTAFER?

INJECTAFER may cause serious side effects, including:

  • Allergic (hypersensitivity) reactions. Serious life-threatening allergic reactions have happened in people who receive INJECTAFER. Other serious reactions including itching, hives, wheezing, and low blood pressure also have happened during treatment with INJECTAFER. Tell your healthcare provider if you have ever had any unusual or allergic reaction to any iron given by vein.

  • High blood pressure (hypertension). High blood pressure, sometimes with face flushing, dizziness, or nausea, has happened during treatment with INJECTAFER. Your healthcare provider will check your blood pressure and check for any signs and symptoms of high blood pressure after you receive INJECTAFER.

The most common side effects of INJECTAFER include:

  • nausea

  • flushing

  • dizziness

  • high blood pressure

  • low levels of phosphorous in your blood

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about INJECTAFER

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about INJECTAFER that is written for health professionals.

What are the ingredients in INJECTAFER?

Active ingredient: ferric carboxymaltose

Inactive ingredients: water for injection. Sodium hydroxide and/or hydrochloric acid may have been added to adjust pH to 5.0-7.0.