Advate

— THERAPEUTIC CATEGORIES —
  • Bleeding disorders
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Advate Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU, 4000 IU; per vial; pwd for IV inj after reconstitution; albumin- and preservative-free.

    Pharmacological Class

    Clotting factor.

    How Supplied

    Single-dose vial—1 (w. diluent, Baxject II needleless transfer device)

    Storage

    Refrigerate Advate in powder form at 2° - 8°C (36° - 46°F); do not freeze. 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.

    Manufacturer

    Takeda Pharmaceutical Company

    Generic Availability

    NO

    Advate Indications

    Indications

    In patients with Hemophilia A: to control and prevent hemorrhagic episodes, for perioperative management, and routine prophylaxis to prevent or reduce the frequency of hemorrhagic episodes.

    Advate Dosage and Administration

    Prior to Treatment Evaluations

    Determine pulse rate before administration and during administration.

    Adults and Children

    Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Infuse over ≤5 minutes (max infusion rate 10mL/min); monitor pulse; if increased significantly, reduce infusion rate or hold. Hemorrhage: Mild: obtain 20–40% FVIII increase; give every 12–24hrs for 1–3 days until resolved. Moderate: obtain 30–60% FVIII increase; give every 12–24hrs for 3 days or until pain or disability resolved. Major: obtain 60–100% FVIII increase; give every 8–24hrs until resolved. Perioperative: Minor: obtain 60–100% FVIII increase; give single bolus infusion within 1 hour of surgery, then every 12–24hrs as needed to control bleeding; Major: pre- and post-op: obtain 80–120% FVIII increase; give 1 dose preoperative to achieve 100% activity, then repeat every 8–24hrs based on healing. Routine prophylaxis: give 20–40 IU/kg every other day (3–4 times weekly). Or, alternatively, an every 3rd day dosing regimen may be followed. Adjust based on response.

    Advate Contraindications

    Contraindications

    Hypersensitivity reactions to mouse or hamster protein or other constituents of the product (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and/or glutathione).

    Advate Boxed Warnings

    Not Applicable

    Advate Warnings/Precautions

    Warnings/Precautions

    Not for von Willebrand's disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

    Warnings/Precautions

    Hypersensitivity Reactions

    Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with Advate. 

    • Contains trace amounts of mouse immunoglobulin G (MuIgG) ≤0.1 ng/IU Advate, and hamster proteins ≤1.5 ng/IU Advate.
    • Patients may develop hypersensitivity to these non-human mammalian proteins.
    • Discontinue treatment if hypersensitivity occurs and administer appropriate emergency treatment.

    Neutralizing Antibodies

    Neutralizing antibodies (inhibitors) have been reported following administration of Advate predominantly in previously untreated patients  and previously minimally treated patients.

    • Monitor for the development of factor VIII inhibitors.
    • Perform an assay that measures factor VIII inhibitor concentration if expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose.

    Monitoring Laboratory Tests

    Patients may vary in their pharmacokinetic (eg, 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.

    • 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.
    • 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, use Bethesda Units (BU) to titer inhibitors.
    • If inhibitor titer <10 BU per mL: administration of additional antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.
    • If inhibitor titer >10 BU per mL: , adequate hemostasis may not be achieved. The inhibitor titer may rise following infusion as a result of an anamnestic response to factor VIII. In such patients, alternative therapeutic approaches and agents are required to prevent bleeding.

    Pregnancy Considerations

    It is not known whether Advate can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity.

    Nursing Mother Considerations

    There is no information regarding the presence of Advate in human milk, the effect on the breastfed infant, or the effects on milk production. Assess clinical need vs risks.

    Pediatric Considerations

    Pharmacokinetic studies in children have demonstrated higher clearance, a shorter half-life and lower recovery of factor VIII compared with adults. Dose adjustment or more frequent dosing based on per kg body weight may be needed in this population.

    Geriatric Considerations

    Clinical trials did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection should be cautious, reflecting the greater frequency of comorbid conditions.

    Advate Pharmacokinetics

    Elimination

    Half-life: ~12 hours.

    Advate Interactions

    Not Applicable

    Advate Adverse Reactions

    Adverse Reactions

    Pyrexia, headache, cough, nasopharyngitis, arthralgia,
    vomiting, upper respiratory tract infection, limb injury, nasal congestion, diarrhea; antibody formation, hypersensitivity reactions.

    Advate Clinical Trials

    Clinical Trials

    Safety and Efficacy Study

    Safety and efficacy trial evaluated the pharmacokinetics (double-blinded, randomized, cross-over), safety, immunogenicity, and hemostatic efficacy (open-label) of Advate in 111 patients.

    • The trial included previously treated patients (PTPs with ≥150 exposure days) diagnosed with moderate to severe hemophilia A (FVIII level ≤2% of normal) who were ≥10 years of age.
    • Patients self-administered Advate for routine prophylaxis (≥25 IU/kg body weight 3-4 times per week) and for on-demand treatment of bleeding episodes.
    • A total of 510 bleeding episodes were reported; 439 (86%) were rated excellent or good in their response to treatment with Advate.
    • A total of 411 (81%) bleeding episodes were managed with a single infusion.
    • 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 patients (n=274 bleeding episodes).
    • The overall rate of new bleeding episodes in the prophylaxis study was 0.52 ± 0.71.

    Perioperative Management Study

    Safety and efficacy of Advate for perioperative management was investigated in 59 patients (7-65 years old) with severe or moderately severe hemophilia A (factor VIII ≤2%).

    • 57 patients completed the study.
    • Patients 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, patients received replacement therapy by either bolus or continuous infusion.
    • After discharge, patients continued to receive Advate for control of hemostasis 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 for 61 (93.9%) of the 65 procedures.
    • Postoperative efficacy was rated as excellent or good for 62 (95.4%) of the 65 procedures.

    Routine Prophylaxis Study

    In a multicenter, open-label, prospective, randomized, controlled postmarketing clinical trial of Advate use in 2 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. 

    • Patients were initially treated for 6 months of on-demand therapy and then randomly assigned 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).
    • The median annual bleed rate during the on-demand therapy period was 44 bleeds per patients per year compared with 1 bleed per patient per year while on either prophylaxis regimen, which was a statistically significant difference (P <.0001).
    • 42% of patients experienced no bleeding episodes while on prophylaxis for 1 year.

    Advate Note

    Not Applicable

    Advate Patient Counseling

    Patient Counseling

    Allergic-type hypersensitivity reactions have been reported with Advate. Early signs of hypersensitivity reactions include hives, pruritus, generalized urticaria, angioedema, hypotension, shock, anaphylaxis and acute respiratory distress. Discontinue treatment and seek immediate emergency treatment.

    Inhibitor formation may occur with treatment; report a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

    While traveling, patients should bring an adequate supply of Advate based on their current regimen of treatment.

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