2.1 Dose

• Dosage and duration of treatment depend on the severity of factor VIII deficiency, the location and extent of the bleeding, and the patient's clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.
• Each vial of ADVATE has the recombinant factor VIII potency in International Units (IU) stated on the label. The expected in vivo peak increase in factor VIII level expressed as IU/dL of plasma or percent of normal can be estimated using the following formulas:

  IU/dL (or % of normal) = [total dose (IU)/body weight (kg)] × 2 [IU/dL]/[IU/kg]

  OR

  Required dose (International Units) = body weight (kg) × desired factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)

Examples (assuming patient's baseline factor VIII level is < 1% of normal):

1. A dose of 1750 IU ADVATE administered to a 70 kg patient should be expected to result in a peak post-infusion factor VIII increase of 1750 IU × {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of normal).
2. A peak level of 70% is required in a 40 kg child. In this situation, the appropriate dose would be 40 kg × 70 IU/dL/{[2 IU/dL]/[IU/kg]} = 1400 IU.

• Base the dose and frequency on the individual clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to ADVATE. Although the dose can be estimated by the calculations above, whenever possible, perform appropriate laboratory tests including serial factor VIII activity assays. [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]

2.2 Preparation and Reconstitution

2.3 Administration

ADVATE is for intravenous use after reconstitution only.

• Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear and colorless in appearance. If not, do not use the solution and notify Baxalta immediately.
• Administer ADVATE at room temperature within 3 hours of reconstitution.
• Use plastic syringes with this product because proteins in the product tend to stick to the surface of glass syringes.

1. Use aseptic technique.
2. Remove the blue cap from the BAXJECT II device. Connect the syringe to the BAXJECT II device (Figure E). Do not inject air.
3. Turn the system upside down (factor concentrate vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly (Figure F).
4. Disconnect the syringe; attach a suitable needle and inject intravenously as instructed. If a patient is to receive more than one vial of ADVATE, the contents of multiple vials may be drawn into the same syringe. Note: the BAXJECT II device is intended for use with a single vial of ADVATE and Sterile Water for Injection, USP only; therefore, reconstituting and withdrawing a second vial into the syringe requires a second BAXJECT II device.
5. Administer ADVATE over a period of ≤ 5 minutes (maximum infusion rate 10 mL/min). Determine the pulse rate before and during administration of ADVATE. Should a significant increase in pulse rate occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.

5.1 Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Symptoms include dizziness, paresthesia, rash, flushing, facial swelling, urticaria, dyspnea, pruritus, and vomiting.

ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG) ≤0.1 ng/IU ADVATE, and hamster proteins ≤1.5 ng/IU ADVATE. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.

5.2 Neutralizing Antibodies

Neutralizing antibodies (inhibitors) have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration. [see Warnings and Precautions (5.3)]

5.3 Monitoring Laboratory Tests

• Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained when clinically indicated. [see Dosage and Administration (2.1)]
• Monitor for development of factor VIII inhibitors. Perform the Bethesda assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of ADVATE, use Bethesda Units (BU) to titer inhibitors.
  • If the inhibitor titer is less than 10 BU per mL, the administration of additional antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.
  • If the inhibitor titer is above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise following ADVATE infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

ADVATE has been evaluated in eleven clinical trials in previously treated patients (PTPs) and one trial in previously untreated patients (PUPs) with severe to moderately severe hemophilia A (factor VIII ≤2% of normal). A total of 418 subjects have been treated with ADVATE as of January 2012. Total exposure to ADVATE was 63,188 infusions. The median duration of participation per subject was 397 (min-max: 2 −1620) days and the median number of exposure days to ADVATE per subject was 97 (min-max: 1−709).

The summary of adverse reactions with a frequency >5% are shown in Table 3 below.

No subject was withdrawn from a clinical trial due to an adverse reaction.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ADVATE. 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.

Table 4 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms.

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with ADVATE. It is not known whether ADVATE can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. Prescribe ADVATE only if clinically needed.

8.2 Labor and Delivery

There are no adequate and well-controlled human studies that have investigated the effects of ADVATE during labor and delivery. Prescribe ADVATE only if clinically needed.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ADVATE is administered to a nursing woman. Prescribe ADVATE only if clinically needed.

8.4 Pediatric Use

Pharmacokinetic studies in children have demonstrated higher clearance, a shorter half-life and lower recovery of factor VIII compared to adults. [see Clinical Pharmacology (12.3)] This may be explained by differences in body composition and should be taken into account when dosing or following factor VIII levels in the pediatric population.4 Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric population, dose adjustment or more frequent dosing based on per kg body weight may be needed in this population. [see Clinical Pharmacology (12.3)] In the ADVATE routine prophylaxis clinical trial, 3 children aged 7 to <12 and 4 adolescents aged 12 to < 16 were included in the per-protocol analysis. The reductions in annualized bleeding rate per subject per year during any prophylaxis regimen as compared to during on-demand therapy were similar among children, adolescents, and adults. [see Clinical Studies (14)]

8.5 Geriatric Use

Clinical studies of ADVATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Individualize dose selection for geriatric patients.

12.1 Mechanism of Action

ADVATE temporarily replaces the missing coagulation Factor VIII that is needed for effective hemostasis.

12.2 Pharmacodynamics

The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of Factor VIII. Treatment with ADVATE normalizes the aPTT over the effective dosing period.

12.3 Pharmacokinetics

A randomized, crossover pharmacokinetic trial of ADVATE (test) and RECOMBINATE [Antihemophilic Factor (Recombinant)] (reference) was conducted in 56 non-bleeding subjects. The subjects received either of the products as an IV infusion (50 ± 5 IU/kg body weight) and there was a washout period of 72 hours to 4 weeks between the two infusions. The pharmacokinetic parameters were calculated from factor VIII activity measurements in blood samples obtained up to 48 hours following each infusion.3 The per-protocol analysis included 30 patients (20 adults and 10 children). Pharmacokinetic parameters for the 20 adults for each trial are presented in Table 6.

The 90% confidence intervals for the ratios of the mean AUC(0-48h) and in vivo recovery values for the test and control products were within the pre-established limits of 0.80 and 1.25. In addition, in vivo recoveries at the onset of treatment and after 75 exposure days were compared for 62 subjects. Results of this analysis indicated no significant change in the in vivo recovery at the onset of treatment and after ≥ 75 exposure days.

In an analysis of data from 58 subjects with 65 surgical procedures in the perioperative management trial, the target factor VIII level was met or exceeded in all cases following a single loading dose ranging from 29 to 104 IU/kg.

Pharmacokinetic parameters calculated from 98 subjects less than 16 years of age (intent-to-treat analysis) are available for 7 infants (1 month to less than 2 years), 32 children (2 to less than 5 years), 24 older children (5 to less than 12 years), and 35 adolescents (12 to less than 16 years), as shown in Table 7. The mean clearance (based on body weight) of ADVATE in infants, children, older children, and adolescents was higher than adults (3.6 mL/kg*hr). The mean half-life of ADVATE in infants, children, older children, and adolescents was lower than adults (12 hours). The extent to which these differences may be clinically significant is not known.

In a crossover pharmacokinetic trial of rAHF-PFM reconstituted in 2 mL versus 5 mL Sterile Water for Injection, USP (sWFI) in previously treated severe hemophilia A adult and adolescent patients, the AUCs of the two formulations were comparable and the 90% confidence interval ranged from 90.4 to 102.6, indicating that the two formulations are pharmacokinetically equivalent.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with the active ingredient in ADVATE to assess its mutagenic or carcinogenic potential.

RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations in vitro, and at doses up to ten times the expected maximal clinical dose in vivo. At that concentration, it did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei formation in bone marrow polychromatic erythrocytes. Studies in animals have not been performed to evaluate carcinogenic potential.

13.2 Animal Toxicology and/or Pharmacology

Single doses up to 4,750 IU/kg did not demonstrate any acute or toxic effect for ADVATE in laboratory animals (rat and rabbit).

Original Safety and Efficacy Study

A safety and efficacy trial evaluated the pharmacokinetics (double-blinded, randomized, cross-over), safety, immunogenicity, and hemostatic efficacy (open-label) of ADVATE in 111 subjects. The trial was conducted in the US and Europe with 103 Caucasian, 7 Black, and 1 Asian previously treated subjects (PTPs with ≥ 150 exposure days) diagnosed with moderate to severe hemophilia A (FVIII level ≤ 2% of normal) who were ≥10 years of age (20 were 10 to <13, 22 were 13 to <16, and 69 were 16 years and older). Subjects with a history of, or a detectable FVIII inhibitor were excluded.

Subjects self-administered ADVATE for routine prophylaxis (≥25 IU/kg body weight 3-4 times per week) and for the on-demand treatment of bleeding episodes. A global assessment of efficacy was rendered by the subject (for home treatment) or study site investigator (for treatment under medical supervision) using a scale of excellent, good, fair, or none, based on the quality of hemostasis achieved with ADVATE for the treatment of each new bleeding episode.

A total of 510 bleeding episodes were reported, with a mean (± SD) of 6.1 ± 8.2 bleeding episodes per subject. Of these 510 episodes, 439 (86%) were rated excellent or good in their response to treatment with ADVATE, 61 (12%) were rated fair, 1 (0.2%) was rated as having no response, and for 9 (2%), the response to treatment was unknown. A total of 411 (81%) bleeding episodes were managed with a single infusion, 62 (12%) required 2 infusions, 15 (3%) required 3 infusions, and 22 (4%) required 4 or more infusions of ADVATE for satisfactory resolution. A total of 162 (32%) bleeding episodes occurred spontaneously, 228 (45%) were the result of antecedent trauma, and for 120 (24%) bleeding episodes, the etiology was unknown.3

The rate of new bleeding episodes during the 75-exposure-day prophylactic regimen was calculated as a function of the etiology of bleeding episodes for 107 evaluable subjects (n = 274 bleeding episodes).3 These rates are presented in Table 8. The overall rate of new bleeding episodes in the prophylaxis study was 0.52 ± 0.71.

The pharmacokinetic properties of ADVATE were investigated at the beginning of treatment in a multicenter trial of previously treated subjects and at the end of treatment in a subset of subjects (N=34) who had completed at least 75 exposure days of treatment with ADVATE. [Clinical Pharmacology (12.3)]

Continuation Study

Additional (open-label) safety and efficacy data were collected on 82 subjects who continued with treatment following participation in the original safety and efficacy study. Bleeding episodes were treated with ADVATE and the outcome of treatment was rated as excellent, good, fair, or none, based on the quality of hemostasis achieved. Final analysis of efficacy was conducted for 81 subjects who self-administered ADVATE on a routine prophylactic regimen for a minimum period of 75 exposure days.

A total of 837 bleeding episodes occurred in 70 of the 81 subjects. The other 11 subjects experienced no bleeding episodes. The response to treatment with ADVATE was rated as excellent or good for 80.4% of all bleeding episodes. Most (88%) bleeding episodes required only 1 or 2 infusions to obtain hemostasis. Among the 837 bleeding episodes, 2 (0.3%) did not require treatment (0 infusions), 521 (62.2%) required 1 infusion, 216 (25.8%) required 2 infusions, 23 (2.7%) required 3 infusions, and 75 (9.0%) required 4 or more infusions. By etiology, 45.3% of these bleeding events were secondary to trauma and 27.7% occurred spontaneously; the other 27% had an undetermined etiology.

In vivo recoveries at the onset of treatment and after 75 exposure days were compared for 62 subjects and there were no significant differences.

Perioperative Management Study

The safety and efficacy of ADVATE for perioperative management was investigated in 59 subjects with severe or moderately severe hemophilia A (factor VIII ≤ 2%). They were between the ages of 7 to 65 years of age (3 were 7 to <13, 6 were 13 to < 16, and 50 were ≥ 16). Fifty-five were Caucasian, 3 were Black, and 1 was Asian. One subject elected not to undergo the planned surgery. Thus, 58 subjects underwent 65 surgical procedures, among which, 6 subjects underwent more than 1 procedure each. One subject withdrew during the postoperative period; thus, 57 subjects completed the study. Of the 65 procedures, 22 in 22 subjects were classified as major, 35 in 28 subjects were classified as minor, and 8 in 8 subjects were dental. (See Table 2 for definitions of major and minor)

Prior to surgery, subjects received a pre-operative loading dose aimed at increasing the plasma factor VIII level to 60% to 100% of normal for dental procedures or 80% to 120% of normal for all other surgical procedures. During the surgery, subjects received replacement therapy by either bolus (47 procedures) or continuous infusion (18 procedures). For continuous infusion, the initial rate was 4 IU/kg/hr for subjects >12 years of age and 5 IU/kg/hr for subjects 5 to 12 years of age. After discharge, subjects continued to receive ADVATE for control of hemostasis as prescribed by the investigator for up to 6 weeks for major orthopedic procedures and up to 2 weeks for all other procedures.

Intraoperative efficacy was rated as excellent or good (Excellent intraoperative blood loss was less than expected for the type of procedure performed; Good intraoperative blood loss was as expected for the type of procedure performed.) for 61 (93.9%) of the 65 procedures; the rating was not done for 3 procedures and unknown for 1 procedure. Postoperative efficacy was rated as excellent or good for 62 (95.4%) of the 65 procedures; the rating was unknown for 2 procedures and not done for 1 procedure. Of the 24 procedures requiring surgical drains, efficacy assessments at the time of drain removal were rated as excellent or good for 20 (83.3%) procedures and fair (Fair intraoperative blood loss was more than expected for the type of procedure performed) for 2 (8.3%) procedures; the rating was unknown for 1 procedure and not done for 1 procedure. Both procedures requiring surgical drains with fair ratings were major orthopedic surgeries.

Routine Prophylaxis Study

In a multicenter, open-label, prospective, randomized, controlled postmarketing clinical trial of ADVATE use in two prophylactic treatment regimens compared to that of on-demand treatment, 53 PTPs with severe to moderately severe hemophilia A (FVIII level ≤ 2 IU/dL) were analyzed in the per-protocol group. Subjects were initially treated for 6 months of on-demand therapy and then randomized to 12 months of either a standard prophylaxis regimen (20-40 IU/kg every 48 hours) or PK-driven prophylaxis regimen (20-80 IU/kg every 72 hours). All subjects had a history of at least 8 joint bleeding episodes per year upon entering the trial. Each subject in the per-protocol group was adherent to > 90% of the prescribed number of prophylactic infusions; no subject in the trial surpassed the upper boundary of 110% of the prescribed number of prophylactic infusions.

The equation used to determine the weight-adjusted dose of the product used in the PK-driven prophylaxis arm, as calculated from the individual subject's incremental recovery and half-life values to achieve a trough level of ≥ 1 IU/dL at the inter-dosing interval of 72 hours is defined as follows:

 

Di = (2)72/ti / ri (i is the subject)

 

D = target FVIII dose (IU/kg) that ensures that a trough level of ≥1 IU/dL is achieved after 72 hours

 

r = FVIII incremental recovery (IU/dL / IU/kg) as determined by the subject's PK analysis

 

t = FVIII half-life (hrs) as determined by the subject's PK analysis

The median annual bleed rate during the on-demand therapy period was 44 bleeds per subject per year compared to 1 bleed per subject per year while on either prophylaxis regimen, which was a statistically significant difference (p<0.0001). Twenty-two of 53 (42%) subjects experienced no bleeding episodes while on prophylaxis for one year. While there was no statistically significant difference in bleeding frequency observed between the two prophylaxis regimens studied, the trial was not powered to demonstrate equivalence in bleeding rate between the two prophylaxis arms.

The annualized bleed rates by age category during on-demand and either standard or PK-driven prophylaxis regimens are shown in Table 10.

As a secondary endpoint, the study assessed all Short Form Health Survey (SF-36v1) domains. The SF-36v1 is a valid and reliable measure of health-related quality of life that is comprised of 8 domain and 2 summary scores (Table 13).

Human Factors Usability Study

A human factors study was performed with 44 participants to evaluate the usability of the ADVATE in the BAXJECT III reconstitution system. Participants in the study included 15 patients, 16 caregivers, and 13 healthcare providers.

During the study, participants viewed an instructional video then performed the reconstitution steps utilizing the instructions for use (IFU). Objective performance data were collected and evaluated. Participants' comments from a post-evaluation interview were reviewed for their appropriateness and applicability. As a result, the content of the package insert was revised to clarify the instructions for use.

How Supplied

ADVATE is packaged with 5 mL or 2 mL of Sterile Water for Injection, USP, a BAXJECT II Needleless Transfer Device, one Terumo Microbore Infusion set (2 mL only), one full prescribing physician insert, and one patient insert.

ADVATE is available in single-dose vials that contain the following nominal product strengths:

Actual Factor VIII activity in International Units is stated on the label of each ADVATE carton and vial.

Storage and Handling

• Refrigerate ADVATE in powder form at 2° - 8°C (36° - 46°F).
• Store at room temperature up to 30°C (86°F) for a period of up to 6 months not to exceed the expiration date.
• Record on the carton the date ADVATE is removed from refrigeration. The product must not be returned to refrigerated temperature.
• Do not use beyond the expiration date printed on the ADVATE label or carton.
• Do not freeze.