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EFFICACY & SAFETY
Review the data from pivotal trial 1: Injectafer vs oral iron and vs IV iron standard of care (SoC) in various etiologies
-
Study design for pivotal trial 11
A randomized, open-label, multicenter study evaluating the efficacy and safety of Injectafer in adult patients with IDA of any etiology.1
Primary
efficacy endpoint:Mean change in Hb from baseline to highest value between baseline and day 35 or time of intervention in Cohort 1.‡
Key secondary
efficacy endpoints:- Mean change from baseline to highest observed Hb at any time between baseline and day 35 or time of intervention in Cohort 2
- Proportion of subjects achieving a Hb level >12 g/dL at any time between baseline and day 35
- Mean change in Hb, ferritin, and TSAT from baseline to each scheduled visit
Primary
composite safety endpoint:Proportion of study participants experiencing at least one treatment-emergent adverse event included as components of a composite safety endpoint.§
- Treatment-emergent adverse events included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization, congestive heart failure, arrhythmias, and protocol-defined hypotension or hypertension
Pivotal trial 1 for Injectafer included subjects with iron intolerance, drug allergy, and hypotension1
*Participants who responded adequately to oral iron during run-in (Hb increase ≥1 g/dL) were not randomized. †Subjects inappropriate for oral iron were defined as either those who were intolerant of oral iron during the run-in phase or those in whom the baseline Hb measurement was sufficiently low as to require rapid repletion of iron stores to minimize the risk of eventual blood transfusion. These patients were not included in the indication for Injectafer. ‡The efficacy analyses were performed on the modified intent-to-treat (mITT) population, which included all patients who received at least 1 dose of randomized treatment and had at least 1 post-baseline Hb assessment. §The safety population consisted of all subjects who received a dose of randomized treatment. All safety analyses were performed with the safety population.
TRIAL 1, COHORT 1: INJECTAFER VS ORAL IRON IN VARIOUS ETIOLOGIES
Injectafer provided a significantly greater increase in Hb
- Cohort 1 consisted of patients with iron deficiency anemia who did not have a satisfactory response to oral iron in a 14-day run-in period1
- Injectafer was compared to oral iron in patients with IDA of various etiologies1
Greater increase in mean Hb1
Primary endpoint
Hb: Mean change in absolute value from baseline to highest value between baseline and day 35 or time of intervention
Injectafer helped more patients achieve a Hb target of >12 g/dL1,2
Secondary endpoint (secondary efficacy
endpoints were not powered for superiority)
Hb: Percentage of patients reaching Hb >12 g/dL between baseline and day 35 or time of intervention
Injectafer provided greater improvements in ferritin and TSAT1,2
Secondary endpoints (secondary efficacy endpoints were not powered for superiority)
Ferritin: Mean change from baseline to
day 35 or time of intervention
TSAT: Mean change from baseline to
day 35 or time of intervention
P=0.001
The diminished iron stores, as seen by ferritin and TSAT levels, in the oral iron arm of this study suggest that iron loss outpaced iron supplementation1
| Primary composite safety endpoint1 | ||
|---|---|---|
| Injectafer (n=246) | Oral iron (n=253) | |
| Patients meeting endpoint | 7 (2.9%) | 4 (1.6%) |
- The most commonly observed components of the composite safety endpoint were protocol-defined hypertension (4 participants in Cohort 1, Injectafer arm) and death due to any cause (2 participants in Cohort 1, oral iron arm).1
In pivotal trials 1 and 2 for Injectafer, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer3
TRIAL 1, COHORT 2: INJECTAFER VS IV IRON SoC IN VARIOUS ETIOLOGIES
Injectafer provided a significantly greater increase in Hb
- Cohort 2 consisted of patients who tolerated oral iron poorly or were inappropriate for treatment with oral iron1
- 90% of patients randomized to IV iron SoC received iron sucrose1
Injectafer provided a greater mean change from baseline in Hb vs IV iron SoC1
Secondary endpoint (secondary efficacy
endpoints were not powered for superiority)
Hb: Mean change in absolute value from baseline to highest value between baseline and day 35 or time of intervention
Injectafer helped patients achieve Hb target of >12 g/dL1
Secondary endpoint (secondary efficacy
endpoints were not powered for superiority)
Hb: Percentage of patients reaching Hb >12 g/dL between baseline and day 35 or time of intervention
Injectafer provided greater improvements in ferritin and TSAT1
Secondary endpoints (secondary efficacy endpoints were not powered for superiority)
Ferritin: Mean change from baseline to
day 35 or time of intervention
TSAT: Mean change from baseline to
day 35 or time of intervention
P=0.001
No significant difference was shown at the primary composite safety endpoint1
Primary composite safety endpoint
- The most commonly observed components of the composite safety endpoint were protocol-defined hypertension (7 participants in Cohort 2, Injectafer arm; 6 participants in Cohort 2, SoC IV iron arm)1
In pivotal trials 1 and 2 for Injectafer, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer3
||Post hoc comparison.
SD=standard deviation; SoC=standard of care.
References:
- Onken JE, Bregman DB, Harrington RA, et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion. 2014;54(2):306-315.
- Data on file. Daiichi Sankyo Inc., Basking Ridge, NJ.
- Injectafer [package insert]. Shirley, NY: American Regent, Inc.; February 2022.
-
IMPORTANT SAFETY INFORMATION
INDICATIONS
Injectafer® (ferric carboxymaltose injection) is indicated for the treatment of iron deficiency anemia (IDA) in adult and pediatric patients 1 year of age and older who have either intolerance to oral iron or an unsatisfactory response to oral iron, or adult patients who have non-dialysis dependent chronic kidney disease.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Injectafer is contraindicated in patients with hypersensitivity to Injectafer or any of its inactive components.
WARNINGS AND PRECAUTIONS
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.
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life- threatening and fatal, have been reported in patients receiving Injectafer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.
In clinical studies, hypertension was reported in 4% (67/1775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer administration.
In the 24 hours following administration of Injectafer, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer.
ADVERSE REACTIONS
Adults
In two randomized clinical studies [Studies 1 and 2], a total of 1775 patients were exposed to Injectafer, 15 mg/kg of body weight, up to a maximum single dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by >2% of Injectafer-treated patients were nausea (7.2%); hypertension (4%); flushing (4%); injection site reactions (3%); erythema (3%); hypophosphatemia (2.1%); and dizziness (2.1%).
The following adverse reactions have been identified during post approval use of Injectafer. Because these 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 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; pregnancy: fetal bradycardia.
Pediatric
The safety of Injectafer in pediatric patients was evaluated in Study 3. Study 3 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 1500 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 (≥4%) were hypophosphatemia, injection site reactions, rash, headache, and vomiting.
CLINICAL CONSIDERATIONS IN PREGNANCY
Untreated IDA in pregnancy is associated with adverse maternal outcomes such as postpartum anemia. Adverse pregnancy outcomes associated with IDA include increased risk for preterm delivery and low birth weight.
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.
You are encouraged to report Adverse Drug Events to American Regent, Inc. at 1-800-734-9236 or to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
IMPORTANT SAFETY INFORMATION
INDICATIONS
Injectafer® (ferric carboxymaltose injection) is indicated for the treatment of iron deficiency anemia (IDA) in adult and pediatric patients 1 year of age and older who have either intolerance to oral iron or an unsatisfactory response to oral iron, or adult patients who have non-dialysis dependent chronic kidney disease.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Injectafer is contraindicated in patients with hypersensitivity to Injectafer or any of its inactive components.
WARNINGS AND PRECAUTIONS
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.
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life- threatening and fatal, have been reported in patients receiving Injectafer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.
In clinical studies, hypertension was reported in 4% (67/1775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer administration.
In the 24 hours following administration of Injectafer, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer.
ADVERSE REACTIONS
Adults
In two randomized clinical studies [Studies 1 and 2], a total of 1775 patients were exposed to Injectafer, 15 mg/kg of body weight, up to a maximum single dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by >2% of Injectafer-treated patients were nausea (7.2%); hypertension (4%); flushing (4%); injection site reactions (3%); erythema (3%); hypophosphatemia (2.1%); and dizziness (2.1%).
The following adverse reactions have been identified during post approval use of Injectafer. Because these 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 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; pregnancy: fetal bradycardia.
Pediatric
The safety of Injectafer in pediatric patients was evaluated in Study 3. Study 3 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 1500 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 (≥4%) were hypophosphatemia, injection site reactions, rash, headache, and vomiting.
CLINICAL CONSIDERATIONS IN PREGNANCY
Untreated IDA in pregnancy is associated with adverse maternal outcomes such as postpartum anemia. Adverse pregnancy outcomes associated with IDA include increased risk for preterm delivery and low birth weight.
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.
You are encouraged to report Adverse Drug Events to American Regent, Inc. at 1-800-734-9236 or to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
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Click on your specialty for specific content tailored to your practice.