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BRIEF SUMMARY OF PRESCRIBING INFORMATION INJECTAFER ® ( ferric carboxymaltose injection )
Forty-seven patients were included in the efficacy analysis ( this only included patients whose baseline anti-FXa activity was later determined to be ≥75 ng / mL , or < 0.5 IU / mL for enoxaparin ).
“ The clinical response 12 hours after the andexanet infusion was excellent or good in 79 percent of the patients ( n = 37 ) and was consistent across a variety of subgroups ( 95 % CI 64-89 ),” Dr . Connolly and colleagues reported .
“ Excellent ” clinical response was defined as
Rx Only
INDICATIONS AND USAGE : Injectafer ( ferric carboxymaltose injection ) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients :
• who have intolerance to oral iron or who have had unsatisfactory response to oral iron ,
• who have non-dialysis dependent chronic kidney disease .
DOSAGE AND ADMINISTRATION : For patients weighing 50 kg ( 110 lb ) or more : Give Injectafer in two doses separated by at least 7 days . Give each dose as 750 mg for a total cumulative dose not to exceed 1500 mg of iron per course .
For patients weighing less than 50 kg ( 110 lb ): Give Injectafer in two doses separated by at least 7 days . Give each dose as 15 mg / kg body weight for a total cumulative dose not to exceed 1500 mg of iron per course .
Injectafer treatment may be repeated if iron deficiency anemia reoccurs .
Administer Injectafer intravenously , either as an undiluted slow intravenous push or by infusion . When administering as a slow intravenous push , give at the rate of approximately 100 mg ( 2 mL ) per minute . When administered via infusion , dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9 % sodium chloride injection , USP , such that the concentration of the infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes .
Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration . The product contains no preservatives . Injectafer is a single-use vial . Discard unused portion .
Avoid extravasation of Injectafer since brown discoloration of the extravasation site may be long lasting . Monitor for extravasation . If extravasation occurs , discontinue the Injectafer administration at that site .
DOSAGE FORMS AND STRENGTHS : Single-use vials containing 50 mg elemental iron per mL in the following presentation : 750 mg iron / 15 mL
CONTRAINDICATIONS : Hypersensitivity to Injectafer or any of its inactive components . WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions : 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 not limited to , pruritus , rash , urticaria , wheezing , or hypotension were reported in 1.5 % ( 26 / 1775 ) of these subjects .
Hypertension : In clinical studies , hypertension was reported in 3.8 % ( 67 / 1,775 ) 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 / 1,775 ) 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 .
Laboratory Test Alterations : 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
Adverse Reactions in Clinical Trials : Because clinical trials are conducted under widely varying conditions , the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice .
In two randomized clinical studies , a total of 1,775 patients were exposed to Injectafer 15 mg / kg 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 . a cessation of bleeding within one hour after infusion for visible bleeding or pain relief , unequivocal improvement in objective signs of bleeding , and no increase in swelling within four hours after infusion for musculoskeletal bleeding ; “ good ” clinical response was defined as a cessation of bleeding within four hours after infusion and for visible bleeding or pain relief , unequivocal improvement in objective signs of bleeding , and no increase in swelling within one hour after infusion for
Adverse reactions reported by ≥ 1 % of treated patients are shown in the following table . Table 1 . Adverse reactions reported in ≥ 1 % of Study Patients in Clinical Trials 1 and 2
Term
Injectafer ( N = 1775 ) %
Pooled
Comparators a ( N = 1783 ) %
Oral iron ( N = 253 ) %
Nausea 7.2 1.8 1.2 Hypertension 3.8 1.9 0.4 Flushing / Hot Flush 3.6 0.2 0.0 Blood Phosphorus Decrease 2.1 0.1 0.0 Dizziness 2.0 1.2 0.0 Vomiting 1.7 0.5 0.4 Injection Site Discoloration 1.4 0.3 0.0 Headache 1.2 0.9 0.0 Alanine Aminotransferase Increase 1.1 0.2 0.0 Dysgeusia 1.1 2.1 0.0 Hypotension 1.0 1.9 0.0 Constipation 0.5 0.9 3.2 a
Includes oral iron and all formulations of IV iron other than Injectafer
Other adverse reactions reported by ≥ 0.5 % of treated patients include abdominal pain , diarrhea , gamma glutamyl transferase increased , injection site pain / irritation , rash , paraesthesia , sneezing .
Transient decreases in laboratory blood phosphorus levels (< 2 mg / dL ) have been observed in 27 % ( 440 / 1638 ) of patients in clinical trials .
Adverse Reactions from Post-marketing Experience : The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports with Injectafer : urticaria , dyspnea , pruritis , tachycardia , erythema , pyrexia , chest discomfort , chills , angioedema , back pain , arthralgia , and syncope . One case of hypophosphatemic osteomalacia was reported in a subject who received 500 mg of Injectafer every 2 weeks for a total of 16 weeks . Partial recovery followed discontinuation of Injectafer .
DRUG INTERACTIONS : Formal drug interaction studies have not been performed with Injectafer . USE IN SPECIFIC POPULATIONS
Pregnancy Pregnancy Category C : Adequate and well controlled studies in pregnant women have not been conducted . Injectafer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus .
Nursing Mothers : A study to determine iron concentrations in breast milk after administration of Injectafer ( n = 11 ) or oral ferrous sulfate ( n = 14 ) was conducted in 25 lactating women with postpartum iron deficiency anemia . Mean breast milk iron levels were higher in lactating women receiving Injectafer than in lactating women receiving oral ferrous sulfate .
Pediatric Use : Safety and effectiveness has not been established in pediatric patients .
Geriatric Use : Of the 1775 subjects in clinical studies of Injectafer , 50 % were 65 years and over , while 25 % were 75 years and over . No overall differences in safety or effectiveness were observed between these subjects and younger subjects , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out .
OVERDOSAGE : Excessive dosages of Injectafer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis . A patient who received Injectafer 18,000 mg over 6 months developed hemosiderosis with multiple joint disorder , walking disability and asthenia . Hypophosphatemic osteomalacia was reported in a patient who received Injectafer 4000 mg over 4 months . Partial recovery followed discontinuation of Injectafer .
CLINICAL STUDIES : The safety and efficacy of Injectafer for treatment of iron deficiency anemia were evaluated in two randomized , open-label , controlled clinical trials ( Trial 1 and Trial 2 ). In these two trials , Injectafer was administered at dose of 15 mg / kg 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 .
PATIENT COUNSELING INFORMATION
• Question patients regarding any prior history of reactions to parenteral iron products .
• Advise patients of the risks associated with Injectafer .
• Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Injectafer administration , such as rash , itching , dizziness , lightheadedness , swelling and breathing problems .
Injectafer is manufactured under license from Vifor ( International ) Inc , Switzerland .
This is not all the risk information for Injectafer . Please see www . injectafer . com for Full Prescribing Information . musculoskeletal bleeding .
The median reductions in anti-FXa activity ( the study ’ s primary endpoint ) from baseline until the end of bolus administration and the two-hour infusion are reported in TABLE 3 ( on page 50 ). Patients treated with apixaban had the greatest reduction in anti-FXa activity , with a relative decrease from baseline to infusion of 92 percent . “ Baseline anti-FXa activity was somewhat higher for patients receiving rivaroxaban than for those receiving apixaban , which may be related to a higher median daily dose of rivaroxaban ( 20 mg ) than of apixaban ( 5 mg ),” Dr . Connolly and authors noted . “ Rates of hemostatic efficacy were similar for patients who were receiving the two agents .”
The decreases in anti-FXa activity continued through four hours after andexanet administration :
• For patients treated with rivaroxaban , the relative decrease was 39 percent from baseline ( 95 % CI 27-45 ).
• For patients treated with apixaban , the relative decrease was 30 percent from baseline ( 95 % CI 23-46 ).
• For the patient treated with enoxaparin , the decrease was 25 % from baseline .
Anti-FXa activity levels also remained similar at eight and 12 hours after treatment with andexanet .
“ This finding supports the idea that prolonged reversal of FXa inhibition may not be necessary to achieve a good hemostatic response ,” the authors wrote .
All patients were included in the safety analysis , and no infusion reactions or development of antibodies to FXa or FX were reported . Eighteen percent of patients experienced thrombotic events ( n = 12 ), including myocardial infarction ( n = 1 ), stroke ( n = 5 ), deep-vein thrombosis ( n = 7 ), and pulmonary embolism ( n = 1 ). Ten patients died ( 15 %), with six deaths related to cardiovascular events . Anticoagulation was resumed in 18 patients ( 27 %) within 30 days .
The study is limited by its small patient population and its non-blinded , non-randomized design . The authors also noted that , “ a controlled study would be required to assess whether the frequency of these events exceeded that expected in patients at increased risk for thrombotic events .”
The study is ongoing and expected to enroll patients until there are 162 participants available for the efficacy analysis and 230 for the safety analysis . ●
IN0650BS Rev . 9 / 2015
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REFERENCE
Connolly SJ , Milling TJ , Eikelboom JW , et al . Andexanet alfa for acute major bleeding associated with factor Xa inhibitors . N Engl J Med . 2016 ; 375:1131-41 .
November 2016