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ELOCTATE ® [Antihemophilic Factor (Recombinant), Fc Fusion Protein]
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ELOCTATE ® safely and effectively. See full prescribing information for ELOCTATE.
ELOCTATE ® [Antihemophilic Factor (Recombinant), Fc Fusion Protein]
Lyophilized Powder for Solution for Intravenous Injection
Initial U.S. Approval: 2014
INDICATIONS AND USAGE
ELOCTATE, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, antihemophilic factor indicated in adults and children with Hemophilia A (congenital Factor VIII deficiency) for:
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On-demand treatment and control of bleeding episodes
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Perioperative management of bleeding
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Routine prophylaxis to reduce the frequency of bleeding episodes.
Limitation of Use
ELOCTATE is not indicated for the treatment of von Willebrand disease. (1)
DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only.
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Each vial of ELOCTATE is labeled with the amount of recombinant Factor VIII in international units (IU or unit). One unit per kilogram body weight will raise the Factor VIII level by 2% (IU/dL). (2.1)
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For on-demand treatment and control of bleeding episodes and perioperative management, calculate dose using the following formulas:
Estimated Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg)
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Required Dose (IU) = Body Weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)
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For routine prophylaxis: 50 IU/kg every 4 days. Adjust dose based on patient response with dosing in the range of 25-65 IU/kg at 3-5 day intervals.
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For routine prophylaxis in children less than 6 years of age: 50 IU/kg twice weekly. Adjust dose based on patient response with dosing in the range of 25-65 IU/kg at 3-5 day intervals. More frequent or higher doses up to 80 IU/kg may be required. (2.1)
DOSAGE FORMS AND STRENGTHS
For injection: nominally 250, 500, 750, 1000, 1500, 2000 or 3000 IU, lyophilized powder in single-use vials for reconstitution. ( 3)
CONTRAINDICATIONS
Do not use in patients who have had life-threatening hypersensitivity reactions, including anaphylaxis, to ELOCTATE. ( 4) WARNINGS AND PRECAUTIONS
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Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, immediately discontinue ELOCTATE and initiate appropriate treatment. (5.1)
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Development of Factor VIII neutralizing antibodies (inhibitors) may occur. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor VIII inhibitor concentration. (5.2, 5.3)
ADVERSE REACTIONS
The most frequently occurring adverse reactions (>0.5% of subjects) in clinical trials were arthralgia, malaise, myalgia, headache, and rash. (6)
To report SUSPECTED ADVERSE REACTIONS, contact BIOGEN at 1-855-693-5628 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pediatric: Clearance (based on per kg body weight) is higher (75%) in pediatric patients 1 to 5 years of age. Higher or more frequent dosing may be needed. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 1/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ELOCTATE, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, antihemophilic factor indicated in adults and children with Hemophilia A (congenital Factor VIII deficiency) for:
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On-demand treatment and control of bleeding episodes,
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Perioperative management of bleeding,
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Routine prophylaxis to reduce the frequency of bleeding episodes.
Limitation of Use
ELOCTATE is not indicated for the treatment of von Willebrand disease.
2 DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only.
2.1 Dose
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Dose and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition. Careful monitoring of replacement therapy is necessary in cases of major surgery or life-threatening bleeding episodes.
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Each vial label of ELOCTATE states the Factor VIII potency in international units (IU). One IU corresponds to the activity of Factor VIII contained in one milliliter of normal human plasma.
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Potency assignment is determined using a chromogenic substrate assay. A field study1 has indicated that plasma Factor VIII levels can be monitored using either a chromogenic substrate assay or a one stage clotting assay routinely used in US clinical laboratories.
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Calculation of the required dose of Factor VIII is based on the empirical finding that 1 IU of Factor VIII per kg body weight raises the plasma Factor VIII level by 2 IU/dL.
The expected in vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) is estimated using the following formula:
Estimated Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg)
The dose to achieve a desired in vivo peak increase in Factor VIII level may be calculated using the following formula:
Dose (IU) = body weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)
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Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Base the dose and frequency of ELOCTATE on the individual clinical response.
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Dose adjustment may be necessary in pediatric patients under six years of age [see Use in Specific Populations (8.4)]. For patients six years of age or older, dose adjustment is not usually required.
On-demand Treatment and Control of Bleeding Episodes
A guide for dosing ELOCTATE for the on-demand treatment and control of bleeding episodes is provided in Table 1. Consideration should be given to maintaining a Factor VIII activity at or above the target range.
Perioperative Management
A guide for dosing ELOCTATE during surgery (perioperative management) is provided in Table 2. Consideration should be given to maintaining a Factor VIII activity at or above the target range.
Routine Prophylaxis
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The recommended starting regimen is 50 IU/kg of ELOCTATE administered every 4 days. Adjust the regimen based on patient response with dosing in the range of 25-65 IU/kg at 3-5 day intervals.
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For children <6 years of age, the recommended starting regimen is 50 IU/kg of ELOCTATE administered twice weekly. Adjust the regimen based on patient response with dosing in the range of 25-65 IU/kg at 3-5 day intervals. More frequent or higher doses up to 80 IU/kg may be required. [see Use In Specific Populations (8.4), Clinical Pharmacology (12.3)]
2.2 Preparation and Reconstitution
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Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.
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Allow the vial of ELOCTATE and pre-filled diluent syringe to reach room temperature before use.
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Remove the plastic cap from the vial and wipe the rubber stopper of the vial with an alcohol wipe. Allow the rubber stopper to dry.
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Completely remove the backing from the vial adapter package by peeling back the lid. Do not remove the vial adapter from the package or touch the inside of the package of the adapter.
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Place the vial on a flat and solid surface and use one hand to hold the vial steady. Use the other hand to place the vial adapter over the vial. Place the adapter spike directly above the center of the rubber stopper and push the adapter straight down until the spike punctures the center of the vial stopper and is fully inserted.
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Lift the package cover away from the vial adapter and discard the cover.
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Hold the plunger rod at the circular disk. Place the tip of the plunger rod into the end of the syringe. Turn clockwise until it is securely attached. Only use the diluent syringe provided in the ELOCTATE package.
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With one hand, hold the diluent syringe by the ridged part directly under the cap, with the cap pointing up. Do not use if the cap has been removed or is not securely attached.
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With your other hand, grasp the cap and bend it at a 90° angle until it snaps off. After the cap snaps off, you will see the glass tip of the syringe. Do not touch the glass tip of the syringe or the inside of the cap.
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With the vial sitting on a flat surface, insert the tip of the syringe into the adapter opening. Turn the syringe clockwise until it is securely attached to the adapter.
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Slowly depress the plunger rod to inject all of the diluent into the vial. The plunger rod may rise slightly after this process. This is normal.
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With the syringe still connected to the adapter, gently swirl the vial until the product is completely dissolved. Do not shake. The reconstituted solution should be clear to slightly opalescent and colorless. Do not use the reconstituted ELOCTATE if it contains visible particles or is cloudy.
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Make sure the plunger rod is completely depressed. Turn the vial upside-down. Slowly pull on the plunger rod to draw the solution into the syringe. Be careful not to pull the plunger rod completely out of the syringe.
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Gently unscrew the syringe from the vial adapter and dispose of the vial with the adapter still attached. Do not touch the syringe tip or the inside of the cap.
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Use the reconstituted ELOCTATE as soon as possible, but no later than 3 hours after reconstitution. Do not touch the glass tip of the syringe if not used immediately after reconstitution. Protect from direct sunlight. Do not refrigerate after reconstitution.
To combine two or more vials of ELOCTATE, after step 12 above, follow these pooling steps:
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Remove the diluent syringe from the vial adapter by turning it counterclockwise until it is completely detached.
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Leave the vial adapter attached to the vial, as it is needed for attaching a large luer lock syringe (not included in kit). Do not detach the diluent syringe until ready to attach the large luer-lock syringe.
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Attach a separate, large luer-lock syringe by turning clockwise until it is securely in place.
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Slowly pull on the plunger rod to draw the solution into the syringe.
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Repeat this pooling procedure with each vial that is needed to obtain the required dose. When pooling, do not detach the large luer-lock syringe until ready to attach it to the next vial (with vial adapter attached). Once you have pooled the required dose, proceed to administration using the large luer-lock syringe.
2.3 Administration
For intravenous injection only
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Inspect the reconstituted ELOCTATE solution visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed.
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Do not administer reconstituted ELOCTATE in the same tubing or container with other medications.
Administration Steps:
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Attach the syringe to the connector end of the infusion set tubing by turning clockwise until it is securely in place.
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Depress the plunger until all air is removed from the syringe and ELOCTATE has reached the end of the infusion set tubing. Do not push ELOCTATE solution through the needle.
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Remove the protective needle cover from the infusion set tubing.
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Perform intravenous bolus infusion. The rate of administration should be determined by the patient's comfort level, and no faster than 10 ml per minute. After infusing ELOCTATE, remove and properly discard the infusion set.
3 DOSAGE FORMS AND STRENGTHS
ELOCTATE is available as a lyophilized powder in single use vials containing nominally 250, 500, 750, 1000, 1500, 2000, or 3000 international units (IU) per vial. The actual Factor VIII potency is labeled on each ELOCTATE vial.
4 CONTRAINDICATIONS
ELOCTATE is contraindicated in patients who have had life-threatening hypersensitivity reactions to ELOCTATE or other constituents of the product. [see Description (11)]
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, are possible with ELOCTATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
5.2 Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to Factor VIII can occur following administration of ELOCTATE. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after ELOCTATE administration, suspect the presence of an inhibitor (neutralizing antibody). [see Warnings and Precautions (5.3)]
5.3 Monitoring Laboratory Tests
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Monitor plasma Factor VIII activity by performing a validated test (e.g., one stage clotting assay), to confirm that adequate Factor VIII levels have been achieved and maintained. [see Dosage and Administration (2)]
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Monitor for the development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained, or if bleeding is not controlled with the expected dose of ELOCTATE. Use Bethesda Units (BU) to report inhibitor levels.
6 ADVERSE REACTIONS
The most frequently occurring adverse reactions (incidence >0.5% of subjects) reported in clinical trials were arthralgia, malaise, myalgia, headache, and rash.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
ELOCTATE has been eva luated in 233 subjects in two completed studies and one ongoing extension study in previously treated patients (PTPs) with severe Hemophilia A (<1% endogenous FVIII activity or a genetic mutation consistent with severe Hemophilia A) who received at least one dose of ELOCTATE as part of either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management. Sixty-nine (29.6%) were pediatric subjects <12 years of age, 13 (5.6%) were adolescents (12 to <18 years of age), and 151 (64.8%) were adults (18 years of age and older). There were 136 subjects treated for at least 104 weeks. The total number of exposure days (EDs) was 34,746 with a median of 129 (range 1-326) exposure days per subject. The subjects received a total of 35,248 injections with a median of 136 injections of ELOCTATE (range 1-328) per subject.
Adverse reactions (ARs) were reported for 11 of 233 (4.7 %) subjects treated with routine prophylaxis or episodic (on-demand) therapy. No age-specific differences in ARs were observed between pediatric and adult subjects. Table 3 summarizes the most frequently occurring adverse reactions. Additional adverse reactions, each occurring in a single subject (incidence 0.4%), include dizziness, dysgeusia, bradycardia, hypertension, hot flush, angiopathy (investigator term: vascular pain after injection of study drug), cough, lower abdominal pain, back pain, joint swelling, chest pain, feeling cold, feeling hot, and procedural hypotension. Two subjects were withdrawn from study due to adverse reactions of rash and arthralgia. In the studies, no inhibitors were detected and no events of anaphylaxis were reported.
Immunogenicity
Clinical trial subjects were monitored for neutralizing antibodies to Factor VIII. No subjects developed confirmed neutralizing antibodies to Factor VIII. One 25 year old subject had a transient, positive, neutralizing antibody of 0.73 BU at week 14, which was not confirmed upon repeat testing 18 days later and thereafter.
The detection of antibodies that are reactive to Factor VIII is highly dependent on many factors, including the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. Therefore, it may be misleading to compare of the incidence of antibodies to ELOCTATE with the incidence of antibodies to other products.
6.2 Postmarketing Experience
The following adverse reaction has been identified during the post-approval use of ELOCTATE. 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.
Blood and lymphatic system disorders: Factor VIII inhibitor development
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no studies of ELOCTATE use in pregnant women to inform a drug-associated risk. The background risk of major birth defects and miscarriage in the indicated population is unknown; however, the background risk of major birth defects in the U.S. general population is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Animal reproductive and developmental toxicity studies have not been conducted with ELOCTATE. In a placental transfer study, ELOCTATE was detected in murine fetal blood samples at approximately 1% of the maternal blood levels (range, 0.2% to 1.9%), 3 to 4 hours following dosing of pregnant mice with 260 to 650 times the clinical dose of 20 to 50 IU/kg ELOCTATE [see Data].
It is not known whether ELOCTATE can cause fetal harm when administered to a pregnant woman, or whether it can affect reproduction capacity. If ELOCTATE is clearly needed to treat a pregnant woman, advise the patient that the risks to the mother and to the fetus are unknown.
Animal Data
Pregnant, genetically-modified, FVIII-deficient mice (Hem A mice) were injected intravenously with a single dose of 400 IU (approximately 13,000 IU/kg) ELOCTATE at the end of pregnancy on Gestation Day 19. Blood samples were collected from the maternal mice and the fetuses 3 to 4 hours after dosing, and FVIII activity was measured in both maternal and fetal plasma using a FVIII chromogenic assay. After dosing pregnant HemA mice with ELOCTATE, FVIII activity in fetal blood was approximately 1% of the maternal blood levels, suggesting that placental transfer of ELOCTATE may occur. The relevance of these data to humans is unknown.
8.2 Lactation
Risk Summary
There is no information regarding the presence of ELOCTATE in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ELOCTATE and any potential adverse effects on the breastfed infant from ELOCTATE or from the underlying maternal condition.
8.4 Pediatric Use
Safety and efficacy studies have been performed in 82 previously treated, pediatric patients <18 years of age who received at least one dose of ELOCTATE as part of routine prophylaxis, on-demand treatment of bleeding episodes, or perioperative management. Adolescent subjects were enrolled in the adult and adolescent safety and efficacy trial, and subjects <12 were enrolled in a pediatric trial.
Pharmacokinetic data from a pediatric study of the 54 eva luable subjects <12 years of age showed that no dose adjustment was required for patients ≥6 years old. Children age 1 to 5 years had a shorter half-life and higher clearance (adjusted for body weight); therefore, a higher dose or more frequent dosing may be needed in this age group. [see Clinical Pharmacology (12.3)]
8.5 Geriatric Use
Clinical studies of ELOCTATE did not include sufficient numbers of subjects aged 65 and over to determine whether or not they respond differently from younger subjects.
11 DESCRIPTION
ELOCTATE, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a sterile, non-pyrogenic, lyophilized powder for reconstitution for intravenous injection. The product is supplied in single use vials containing nominal potencies of 250, 500, 750, 1000, 1500, 2000 or 3000 international units (IU). Each vial of ELOCTATE is labeled with the actual content in IU. The powder for injection is reconstituted with 3 mL sterile water for injection (SWFI) supplied in a sterile prefilled syringe. The reconstituted product contains the excipients: sucrose, sodium chloride, L-histidine, calcium chloride and polysorbate 20. ELOCTATE contains no preservatives.
B-domain deleted recombinant Factor VIII, Fc fusion protein (BDD-rFVIIIFc) is the active ingredient in ELOCTATE. BDD-rFVIIIFc is a recombinant protein consisting of a B-domain deleted analogue of human Coagulation Factor VIII covalently linked to the human immunoglobulin G1 (IgG1) Fc domain sequence. The Factor VIII portion of the molecule has a 90 kDa heavy chain and an 80 kDa light chain (similar to endogenous Factor VIII), which are linked by 14 (of 908) amino acids from the central B-domain. The FVIII portion has post-translational modifications comparable to endogenous Factor VIII. The Fc domain of the molecule contains the hinge, CH2, and CH3 regions of IgG1. BDD-rFVIIIFc contains 1890 amino acids with an apparent molecular weight of 220 kDa. The majority of the expressed protein is proteolytically processed to a two chain molecule; however ELOCTATE may also contain up to 39% of a single chain, non-processed form. Both molecules have been shown to have comparable Factor VIII activity.
BDD-rFVIIIFc is produced by recombinant DNA technology from a human embryonic kidney (HEK) cell line, which has been extensively characterized. The HEK cell line expresses BDD-rFVIIIFc into a defined, cell culture medium that does not contain any proteins derived from animal or human sources. BDD-rFVIIIFc is purified using a series of chromatography steps, including affinity capture with a recombinant, single chain antibody fragment produced in a yeast expression system. No human or animal derived proteins are used in the purification or formulation processes. The production process also incorporates two dedicated viral clearance steps - a detergent treatment step for inactivation and a 15 nm filtration step for removal of viruses.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ELOCTATE is a recombinant fusion protein that temporarily replaces the missing Coagulation Factor VIII needed for effective hemostasis. ELOCTATE contains the Fc region of human immunoglobulin G1 (IgG1), which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation and prolonging their plasma half-life.
12.2 Pharmacodynamics
Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation Factor VIII, resulting in a prolonged, patient plasma clotting time as measured by the activated partial thromboplastin time (aPTT) assay. Treatment with ELOCTATE normalizes the aPTT over the effective dosing period.
12.3 Pharmacokinetics
The pharmacokinetics (PK) of ELOCTATE (rFVIIIFc) were eva luated in 28 subjects following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters were based on plasma FVIII activity measured by the one-stage clotting assay. The PK profile obtained at week 14, after repeated dosing, was comparable with the PK profile obtained after the first dose. The PK data demonstrate that ELOCTATE has a prolonged circulating half-life. Time to 1% was 5.10 days (95% CI: 4.54, 5.66). The terminal plasma half-life of ELOCTATE when compared against a currently marketed recombinant Factor VIII (ADVATE®) was 1.5 fold longer.
Pediatric and Adolescent Pharmacokinetics
Pharmacokinetic (PK) parameters of ELOCTATE were determined for adolescents (ages 12 to 17 years) in the adult and adolescent study and for children (ages 1 to 5 years and 6 to 11 years) in the pediatric study. Table 4 presents the PK parameters calculated from the pediatric data of 65 subjects, less than 18 years of age, after receiving a single 50 IU/kg dose.
Compared to adults and adolescents, body weight adjusted clearance was 75% higher in children 1 to 5 years of age. These results indicate a need for dose adjustments in children 1 to 5 years of age. [see Use in Specific Populations (8.4)]
The PK eva luation of pediatric subjects, ages 6 to 17 years, showed that their PK profiles and arithmetic means of PK parameters are similar to those of adults. Therefore, for subjects 6 years and older, an age-based dose adjustment is not required. [see Use in Specific Populations (8.4)]
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