advate ndc
(Baxter Healthcare)
Antihemophilic Factor (Recombinant)
Plasma/Albumin-Free Method (rAHF-PFM)
DESCRIPTION
Advate Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM)is a purified glycoprotein consisting of 2,332 amino acids that is synthesizedby a genetically engineered Chinese hamster ovary (CHO) cell line advate ndc. In culture,the CHO cell line expresses recombinant antihemophilic factor (rAHF) into thecell culture medium advate ndc. The rAHF is purified from the culture medium using a seriesof chromatography columns advate ndc. The cornerstone of the purification process is animmunoaffinity chromatography step in which a monoclonal antibody directed againstFactor VIII is employed to selectively isolate the rAHF from the medium advate ndc. Thecell culture and purification processes used in the manufacture of Advate rAHF-PFMemploy no additives of human or animal origin advate ndc. The production process includesa dedicated, viral inactivation solvent-detergent treatment step advate ndc. The rAHF synthesizedby the CHO cells has the same biological effects as Antihemophilic Factor (Human)[AHF (Human)] advate ndc. Structurally the recombinant protein has a similar combinationof heterogeneous heavy and light chains as found in AHF (Human) advate ndc.
Advate rAHF-PFM is formulated as a sterile, non-pyrogenic, white to off-whitepowder for intravenous injection advate ndc. Advate rAHF-PFM is available in single-dosevials that contain nominally 250, 500, 1000 and 1500 International Units (IU)per vial advate ndc. When reconstituted with the appropriate volume of diluent, the productcontains the following stabilizers in maximal amounts: 38 mg/mL mannitol, 10mg/mL trehalose, 108 mEq/L sodium, 12 mM histidine, 12 mM Tris, 1.9 mM calcium,0.17 mg/mL polysorbate-80, and 0.10 mg/mL glutathione advate ndc. Von Willebrand Factor(vWF) is co-expressed with FVIII, and helps to stabilize it in culture advate ndc. Thefinal product contains no more than 2 ng vWF/IU rAHF, which will not have anyclinically relevant effect in patients with von Willebrand's Disease advate ndc. The productcontains no preservative advate ndc. Each vial of Advate rAHF-PFM is labeled with the AHF activity expressed inIU per vial advate ndc. Biological potency is determined by an in vitro assay, which employsa Factor VIII concentrate standard that is referenced to a World Health Organization(WHO) International Standard for Factor VIII: C concentrates advate ndc. The specific activityof Advate rAHF-PFM is 4000 to 10,000 IU per milligram of protein advate ndc.
CLINICAL PHARMACOLOGY
The pharmacokinetics of Advate rAHF-PFM were investigated in a Phase 2/3 multicenterpivotal study of previously treated subjects advate ndc. In addition, an interim analysiscomparing the pharmacokinetics of Advate rAHF-PFM at the onset of treatmentand after a period of at least 75 exposure days was performed in the contextof an ongoing continuation study in subjects who completed treatment in themulticenter pivotal Phase 2/3 study advate ndc. Post-infusion levels and clearance of FactorVIII during the perioperative period were examined in an interim analysis ofsubjects from the pivotal and continuation studies who were enrolled in an ongoingPhase 2/3 surgical study advate ndc. Finally, the pharmacokinetics of Advate rAHF-PFM wereinvestigated in an interim analysis of an ongoing study of pediatric previouslytreated subjects < 6 years of age (see Pediatric Use subsection under "PRECAUTIONS ") advate ndc.
Pharmacokinetics
A randomized, crossover pharmacokinetic comparison of Advate rAHF-PFM producedat a pilot-scale facility in Orth, Austria (the test article) and RECOMBINATErAHF (the control article) was conducted in the context of the pivotal Phase2/3 study advate ndc. Study subjects were initially infused with one of the two preparationsat a dose of 50 ± 5 IU/kg body weight while in a non-bleeding state advate ndc. The second study preparation was infused in a non-bleeding state at 50 ±5 IU/kg after a washout period of 72 hours to 4 weeks following the first studyinfusion advate ndc. The order in which each study preparation was administered was assignedby randomization advate ndc. Pharmacokinetic parameters (area under the Factor VIII plasmaconcentration versus time curve [AUC], maximal post-infusion Factor VIII level[C max ], in vivo recovery, half-life, clearance [CL], mean residence time [MRT],and volume of distribution in steady-state [V ss ]) were calculated from FactorVIII activity measurements in blood samples obtained immediately before andat standardized time intervals up to 48 hours following each infusion advate ndc. A total of 56 study subjects were enrolled and randomized advate ndc. Of these, 50 (modifiedintent-to-treat population) received both infusions of study medication andhad sufficient pharmacokinetic data for the comparison of Advate rAHF-PFM andRECOMBINATE rAHF advate ndc. Thirty subjects (per-protocol population) received both pharmacokineticinfusions of study medication and had data for all pharmacokinetic time points advate ndc. Pharmacokinetic parameters for each study preparation in the per-protocol analysisare presented in Table 1 advate ndc. Table 1 advate ndc.
Pharmacokinetic Parameters for Advate rAHF-PFM and RECOMBINATE rAHF (Per-ProtocolAnalysis) Parameter RECOMBINATE rAHF Advate rAHF-PFM
N Mean ± SD N Mean a ± SD
AUC 0-48h (IU•h/dL) a 30 1530 ± 380 30 1534 ±436
In vivo recovery (IU/dL/IU/kg) b 30 2.59 ± 0.52 30 2.41 ± 0.50
Half-life (h) 30 11.24 ± 2.53 30 11.98 ± 4.28
C max (IU/dL) 30 129 ± 27 30 120 ± 26
MRT (h) 30 20.03 ± 7.80 30 22.82 ± 13.94
V ss (dL/kg) 30 0.58 ± 0.15 30 0.60 ± 0.15
CL (dL/kg/hr) 30 0.03 ± 0.01 30 0.03 ± 0.01
a Area under the plasma Factor VIII concentration ? time curve from 0 to 48hours post-infusion
b Calculated as (C max - baseline Factor VIII) divided by the dose in IU/kg,where C max is the maximal post-infusion Factor VIII measurement
For the pharmacokinetic parameters AUC 0-48h and in vivo recovery, the 90% confidenceintervals for the ratios of the mean values for the test and control articleswere within the pre-established limits of 0.80 and 1.25 for both the per-protocol(n = 30) and intent-to-treat study (n = 50) populations advate ndc. In addition, in vivorecovery at the onset of treatment and after 75 exposure days was compared for62 subjects advate ndc. Results of this analysis indicated no significant change in thein vivo recovery at the onset of treatment and after >/= 75 exposure days advate ndc.
Additionally, the pharmacokinetics of Advate rAHF-PFM produced at the Orthfacility were compared with those of Advate rAHF-PFM produced at a commercial-scalefacility in Neuchatel, Switzerland advate ndc. For the pharmacokinetic parameters AUC 0-48hand in vivo recovery, the 90% confidence intervals for the ratios of the meanvalues for the test and control articles were within the pre-established limitsof 0.80 and 1.25 for both the per-protocol and intent-to-treat study populations advate ndc. In an interim analysis of data from 10 of 25 planned subjects in the Phase2/3 surgery study, the target Factor VIII level was met or exceeded in all casesfollowing a single loading dose ranging from 48.0 to 69.8 IU/kg advate ndc. Hemostatic Efficacy
In the Phase 2/3 pivotal study, a global assessment of efficacy was renderedby the subject (for home treatment) or study site investigator (for treatmentunder medical supervision) using an ordinal scale of excellent, good, fair,or none, based on the quality of hemostasis achieved with Advate rAHF-PFM producedin the Orth facility for the treatment of each new bleeding episode advate ndc. A totalof 510 bleeding episodes were reported, with a mean (± SD) of 6.1 ±8.2 bleeding episodes per subject advate ndc. Of the 510 new bleeding episodes treatedwith Advate rAHF-PFM, 439 (86%) were rated excellent or good in their responseto treatment, 61 (12%) were rated fair, 1 (0.2%) was rated as having no response,and for 9 (2%), the response to treatment was unknown advate ndc. A total of 411 (81%)new bleeding episodes were managed with a single infusion, 62 (12%) required2 infusions, 15 (3%) required 3 infusions, and 22 (4%) required 4 or more infusionsof Advate rAHF-PFM for satisfactory resolution advate ndc. A total of 162 (32%) new bleedingepisodes occurred spontaneously, 228 (45%) were the result of antecedent trauma,and for 120 (24%) bleeding episodes, the etiology was unknown advate ndc. The rate of new bleeding episodes during the protocol-mandated 75 exposureday prophylactic regimen ( >/= 25 IU/kg body weight 3-4 times per week) wascalculated as a function of the etiology of bleeding episodes for 107 evaluablesubjects (n = 274 new bleeding episodes) advate ndc. These rates are presented in Table3 advate ndc. Table 3 advate ndc.
Rate of New Bleeding Episodes During Prophylaxis Bleeding Episode Etiology Mean(± SD) New Bleeding Episodes/Subject/Month
Spontaneous 0.34 ± 0.49
Post-traumatic 0.39 ± 0.46
Unknown a 0.33± 0.34
Overall 0.52 ± 0.71
a Etiology was indeterminate
In a post-hoc analysis, the overall rate of bleeding was correlated inverselywith the degree of compliance with the prescribed prophylactic regimen advate ndc. Subjectswho infused less than 25 IU Advate rAHF-PFM per kg per dose for more than 20%of prophylactic infusions or administered less than 3 infusions per week formore than 20% of study weeks (n = 37) experienced a 2.3-fold higher rate ofbleeding in comparison with subjects who complied with the prescribed prophylacticregimen at least 80% of the time and for >/= 80% of doses (n = 70) advate ndc.
The Phase 2/3 continuation study involved subjects previously treated on thepivotal Phase 2/3 study and provided additional efficacy data on Advate rAHF-PFM advate ndc. An interim analysis of efficacy was conducted for 27 of 82 enrolled subjectswho self-administered Advate rAHF-PFM produced in Neuchatel on a routine prophylacticregimen during a minimum period of 50 exposure days to Advate rAHF-PFM advate ndc. As inthe pivotal Phase 2/3 study, new bleeding episodes were treated with AdvaterAHF-PFM and the outcome of treatment was rated as excellent, good, fair, ornone, based on the quality of hemostasis achieved advate ndc. A total of 51 new bleedingepisodes occurred in 13 of the 27 subjects being treated with Advate rAHF-PFM advate ndc. By etiology, 53% of these bleeding events resulted from trauma and 27% occurredspontaneously; the other 20% had an undetermined etiology advate ndc. The response to treatmentwith Advate rAHF-PFM for the majority (63%) of all new bleeding episodes wasrated as excellent or good advate ndc. In addition, 86% of the bleeding episodes resolvedwith only 1 infusion and an additional 6% were resolved by a second infusion advate ndc. Thus, 92% of all bleeding episodes required 1 or 2 infusions of study product advate ndc. An interim analysis of the hemostatic efficacy of Advate rAHF-PFM during theperioperative management of subjects undergoing surgical procedures was conductedfor 10 of 25 planned subjects advate ndc. Ten subjects underwent 10 surgical procedureswhile receiving Advate rAHF-PFM advate ndc. Eight subjects received the test product byintermittent bolus infusion and 2 subjects received a combination of continuousand intermittent bolus infusion advate ndc. Nine of the 10 subjects completed the study advate ndc. Six of the surgical procedures were classified as major, and 4 were minor advate ndc. Ofthe 6 major surgeries, 5 were for orthopedic complications of hemophilia advate ndc. Abrief description of each surgical procedure, along with study duration andstudy medication exposure, are presented in Table 4 advate ndc. Table 4 advate ndc.
Surgical Procedures, Study Duration, and
Study Medication Exposure Surgery Type Days of Study Advate
rAHF-PFM
Exposure Days Cumulative Advate
rAHF-PFM
Exposure (IU)
Total hip replacement 16 15 61,600
Knee joint replacement 22 18 76,060
Knee arthrodesis 24 22 66,080
Transposition of the left ulnar nerve 5 3 14,560
Insertion of Mediport 28 8 a 46,893
Dental extraction 18 6 16,599
Left elbow synovectomy 43 32 102,180
Teeth extraction 2 2 10,350
Right knee arthroscopy, chondroplasty and synovectomy 13 10 a 32,334
Wisdom teeth extraction 14 5 15,357
a Advate rAHF-PFM was administered by continuous infusion for the first 48 hourspost-operatively, followed by bolus infusions for the remainder of study treatment advate ndc.
For each of the 10 subjects, intra- and post-operative quality of hemostasisachieved with Advate rAHF-PFM was assessed by the operating surgeon and studysite investigator, respectively, using an ordinal scale of excellent, good,fair, or none advate ndc. The same rating scale was used to evaluate control of hemorrhagefrom a surgical drain placed at the incision site in one subject advate ndc. The qualityof hemostasis achieved with Advate rAHF-PFM was rated as excellent or good forall assessments advate ndc.
INDICATIONS AND USAGE
Advate rAHF-PFM is indicated in hemophilia A (classical hemophilia) for theprevention and control of bleeding episodes advate ndc. Advate rAHF-PFM is also indicatedin the perioperative management of patients with hemophilia A advate ndc. Advate rAHF-PFMcan be of therapeutic value in patients with Factor VIII inhibitors not exceeding10 Bethesda Units (BU) per mL advate ndc. 1, 2 However, in patients with a known or suspectedinhibitor to Factor VIII, the plasma Factor VIII level should be monitored frequentlyand the dose of Advate rAHF-PFM should be adjusted accordingly advate ndc.
Advate rAHF-PFM is not indicated for the treatment of von Willebrand's disease advate ndc.
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