ELOCTATE

• 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.
• 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.
• 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.
• 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)

• 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.
• 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.

1. Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.
2. Allow the vial of ELOCTATE and pre-filled diluent syringe to reach room temperature before use.
3. 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.

4. 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.

   Figure

5. 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.

   Figure

6. Lift the package cover away from the vial adapter and discard the cover.

   Figure

7. 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.

   Figure

8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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:
16. Remove the diluent syringe from the vial adapter by turning it counterclockwise until it is completely detached.
17. 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.
18. Attach a separate, large luer-lock syringe by turning clockwise until it is securely in place.
19. Slowly pull on the plunger rod to draw the solution into the syringe.
20. 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.

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.

Formation of neutralizing antibodies (inhibitors) to Factor VIII has been reported following administration of ELOCTATE, including in previously untreated patients. 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)]

• 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)]
• 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.

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 evaluated 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.

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

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 evaluable 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)]

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.

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.

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.

The pharmacokinetics (PK) of ELOCTATE (rFVIIIFc) were evaluated 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.

Long-term animal studies investigating the carcinogenic effects of ELOCTATE have not been conducted. In vitro and in vivo testing of ELOCTATE for mutagenicity or effects on fertility was not performed.

On-demand Treatment and Control of Bleeding Episodes

In the adult and adolescent study, a total of 757 bleeding episodes in 106 subjects were treated with ELOCTATE. The majority of the bleeding episodes were spontaneous and localized in joints. The median dose per injection used to treat a bleeding episode was 27.35 (IQR 22.73, 32.71) IU/kg. Assessment of response to each injection was recorded by subjects at 8-12 hours after treatment. A 4-point rating scale of excellent, good, moderate, and no response was used to assess response. Efficacy in control of bleeding episodes in subjects ≥12 years of age is summarized in Table 5.

In the pediatric study, a total of 86 bleeding episodes in 69 pediatric subjects were treated with ELOCTATE. Assessment of response to each injection was recorded by subjects at 8 to 12 hours post-treatment. A 4-point rating scale of excellent, good, moderate, and no response was used to assess response. Efficacy in control of bleeding episodes in subjects <12 years of age is summarized in Table 6.

The hemostatic efficacy in treatment of bleeds was rated excellent or good in 92.6% for all evaluable first injections.

Perioperative Management

Major Surgeries

Hemostatic efficacy was assessed in twenty-two (22) surgeries in twenty (20) subjects from the adult and adolescent study and the extension study. There were no major surgeries in the pediatric study. Most subjects (95.5%) received a single pre-operative dose to maintain hemostasis during surgery. The median dose per injection to maintain hemostasis during surgery was 57.4 IU/kg (range 45-102). On the day of surgery, most subjects received a second injection. The total dose on the day of surgery ranged from 50.8-126.6 IU/kg.

Hemostatic response was assessed by the investigator using ordinal scales as follows:

Excellent: Intraoperative and postoperative blood loss similar to (or less than) the nonhemophilic patient. No extra doses of rFVIIIFc needed and blood component transfusions required are similar to nonhemophilic patient

Good: Intraoperative and/or postoperative bleeding slightly increased over expectations for the nonhemophilic patient, but the difference was not clinically significant. Intraoperative blood loss no more than 250 mL greater than expected for a nonhemophilic patient and no extra doses of rFVIIIFc needed and blood component transfusions required are similar to nonhemophilic patient

Fair: Intraoperative and/or postoperative blood loss is increased over expectation for the nonhemophilic patient and additional treatment was needed. Intraoperative blood loss 250 to 500 mL greater than expected for person without hemophilia or extra dose of rFVIIIFc needed or increased blood component transfusion requirement

Poor/none: Significant intraoperative and/or postoperative bleeding that was substantially increased over expectations for the nonhemophilic patient, required intervention, and was not explained by a surgical/medical issue other than hemophilia: Intraoperative blood loss >500 mL greater than for the nonhemophilic patient or unexpected hypotension or unexpected transfer to intensive care unit due to bleeding or substantially increased blood component transfusion requirement

For twenty-two (22) major surgeries in twenty (20) subjects, hemostatic response was assessed and rated as excellent in 19 (86%) surgeries and good in 3 (14%) surgeries.

Types of surgeries assessed include major orthopedic procedures such as joint replacements (bilateral knee, as well as unilateral elbow, hip and knee replacements), ankle fusion and amputation. Other major surgeries include appendectomy, arthroscopy, spinal surgery, and inguinal hernia repair.

Minor Surgeries

A hemostatic assessment of 32 minor surgical procedures in 29 subjects from all three studies was conducted with a 100% excellent or good response.

Routine Prophylaxis

Adult and Adolescent Study

The efficacy of routine prophylaxis was evaluated against on-demand treatment. A total of 117 subjects received an individualized, twice weekly regimen, which started with 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. The dose and interval were adjusted within the range of 25 – 65 IU/kg every 3-5 days to maintain trough levels between 1% and 3% above baseline, or higher, as clinically indicated to prevent bleeding. The median dosing interval was 3.5 days. Among the 112 subjects treated for at least 6 months, 111 (99%) achieved a dosing interval of three days or longer, 39 (35%) achieved a dosing interval of 4 days or longer, and 33 (29%) achieved a dosing interval of 5 days or longer during the last 3 months on study. Twenty-three subjects received 65 IU/kg of ELOCTATE once weekly for a median period of 28 weeks. An additional 23 subjects received episodic (on-demand) doses of ELOCTATE for the treatment of bleeding episodes and were on study for a median period of 29 weeks. Using a negative binomial model to analyze the annualized bleeding rate (ABR), there was a statistically significant reduction in ABR of 92% (p<0.001) for subjects in the individualized prophylaxis arm and a statistically significant reduction of 76% (p<0.001) for subjects in the weekly prophylaxis arm compared to the episodic (on-demand) arm. Fifty-three (53) of 117 (45%) subjects experienced no bleeding episodes while on individualized prophylaxis and 4 of 23 (17%) subjects experienced no bleeding episodes while on weekly prophylaxis.

Median ABRs in subjects evaluable for efficacy is summarized in Table 7.

Pediatric Study

Sixty-nine (69) subjects received ELOCTATE on an individualized prophylactic dose regimen starting with a twice weekly regimen consisting of 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. The dose could be adjusted within the range of 25-80 IU/kg with a minimum dosing interval of every 2 days to maintain trough of 1% above baseline or as clinically indicated to prevent bleeding. The median dosing interval was 3.49 days (interquartile range, 3.46 to 3.51 days) with no difference in the median dosing interval between age cohorts. 89.9% of subjects remained on a twice weekly interval. The median weekly dose of ELOCTATE for subjects 1-5 years of age was 91.63 IU/kg (interquartile range (IQR), 84.72 to 104.56 IU/kg). For subjects in the 6 to 11 years of age cohort, the median weekly dose was 86.88 IU/kg (IQR, 79.12 to 103.08 IU/kg).

Of all subjects, 32 (46.4%) experienced no bleeding episodes (18 subjects (51.4%) 1-5 years of age and 14 subjects (41.2%) 6 to 11 years of age). A presentation of the median ABRs evaluable for efficacy is summarized in Table 8.

How Supplied

ELOCTATE is supplied in kits comprising a single use vial containing nominally, 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 5000 or 6000 international units (IU) of Factor VIII potency, a pre filled syringe with 3 mL sterile water for injection, and a sterile vial adapter (reconstitution device). The actual amount of ELOCTATE in IU is stated on the label and carton of each vial.

Components used in the packaging of ELOCTATE contain no natural rubber latex.

Storage and Handling

Prior to reconstitution:

• Store ELOCTATE in the original package to protect the ELOCTATE vials from light.
• Store ELOCTATE in powder form at 2°C to 8°C (36°F to 46°F). Do not freeze to avoid damage to the pre-filled diluent syringe.
• ELOCTATE may be stored at room temperature, not to exceed 30°C (86°F), for a single period of up to 6 months, within the expiration date printed on the label.
• If stored at room temperature, record the date that ELOCTATE is removed from refrigeration on the carton in the area provided. After storage at room temperature, do not return the product to the refrigerator.
• Do not use beyond the expiration date printed on the vial or 6 months after the date that was written on the carton, whichever is earlier.

After Reconstitution:

• The reconstituted product may be stored at room temperature, not to exceed 30°C (86°F), for up to 3 hours. Protect from direct sunlight. After reconstitution, if the product is not used within 3 hours, it must be discarded.
• Do not use ELOCTATE if the reconstituted solution is cloudy or has particulate matter.
• Discard any unused ELOCTATE.