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Advate (Antihemophilic Factor) - Warnings and Precautions

 
 



WARNINGS

None.

PRECAUTIONS

GENERAL

Identification of the clotting defect as Factor VIII deficiency is essential before the administration of ADVATE rAHF-PFM. No benefit may be expected from this product in treating other coagulation factor deficiencies.

FORMATION OF INHIBITORS TO FACTOR VIII

The formation of neutralizing antibodies to Factor VIII (Factor VIII inhibitors) is a known complication in the management of individuals with hemophilia A. The reported prevalence of these antibodies in previously-untreated patients who were administered rAHF products over several years is 20.7 to 31.7%. 3, 4, 5, 6, 7, 8 These inhibitors are invariably of the immunoglobulin G (IgG) isotype, and the Factor VIII inhibitory activity is expressed as BU per mL of plasma. Patients treated with AHF products should be carefully monitored for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests.

Factor VIII inhibitor testing was performed throughout all studies in the rAHF-PFM clinical program. Among 136 treated subjects >/= 10 years of age, all of whom had >/= 150 exposure days to Factor VIII products at study entry, 102 had at least 75 exposure days to ADVATE rAHF-PFM. None of these subjects developed an inhibitor. One subject who had < 50 exposure days to ADVATE rAHF-PFM while on study developed an inhibitor. This subject manifested a low titer inhibitor (2.0 BU by the Bethesda assay) after 26 ADVATE rAHF-PFM exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of RECOMBINATE rAHF. For the group comprising all subjects with at least 75 exposure days to ADVATE rAHF-PFM and the single subject who developed an inhibitor, the 95% confidence interval (Poisson distribution) for the risk of developing an inhibitor to Factor VIII was 0.02 to 5.4 %.

An interim analysis of inhibitor development in 15 of 50 planned pediatric subjects < 6 years of age who had at least 50 prior exposure days to factor VIII at study entry was conducted. No subject completed 50 exposure days to ADVATE rAHF-PFM. Ten of the 15 enrolled subjects completed at least 10 exposure days to ADVATE rAHF-PFM or 120 total days on study; among this subset, there were no inhibitors.

FORMATION OF ANTIBODIES TO MOUSE OR HAMSTER PROTEIN

ADVATE rAHF-PFM contains trace amounts of mouse immunoglobulin G (MuIgG; maximum of 0.1 ng/IU ADVATE rAHF-PFM) and hamster (CHO) proteins (maximum of 1.5 ng/IU ADVATE rAHF-PFM). As such, there exists a remote possibility that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

In the Phase 2/3 pivotal study of ADVATE rAHF-PFM, serum samples were tested by enzyme immunoassays at baseline and after every 15 ± 2 exposure days, for the presence of antibodies to CHO protein and MuIgG. Regression analysis of assay results was conducted to evaluate trends in levels of antibodies to heterologous proteins as a function of time on study. Four study subjects showed a statistically significant increasing trend in the levels of anti-CHO (n = 1) or anti-MuIgG (n = 3) antibody levels over the course of the study. A fifth study subject showed a marked increase in anti-MuIgG antibodies coincident with the 60 and 75 exposure day interval study visits. None of these subjects exhibited adverse experiences (AEs) or other study findings consistent with an allergic or hypersensitivity response.

INFORMATION FOR PATIENTS

Although allergic type hypersensitivity reactions were not observed in any study subjects receiving ADVATE rAHF-PFM, such reactions are theoretically possible. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician immediately if these symptoms occur.

LABORATORY TESTS

Although the dose can be estimated by the calculations that follow, it is highly recommended that, whenever possible, appropriate laboratory tests be performed on the patient's plasma at suitable intervals to assure that adequate Factor VIII levels have been reached and are maintained.

If the patient's plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after adequate dosing, the presence of an inhibitor should be suspected. By performing the appropriate laboratory procedures, the presence of an inhibitor can be demonstrated and quantified in terms of the number of BU per mL (i.e. the amount of Factor VIII activity neutralized by one mL of patient plasma). If the inhibitor is present at levels less than 10 BU per mL, the administration of additional AHF concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response. The close monitoring of plasma Factor VIII levels by laboratory assays is necessary in this situation.

Inhibitor titers above 10 BU per mL are likely to make the control of hemostasis with AHF concentrates either impossible or impractical because of the very large dose required. In addition, the inhibitor titer may rise following AHF 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.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

No studies were conducted with the active ingredient in ADVATE rAHF-PFM to assess its mutagenic or carcinogenic potential. The CHO cell line employed in the production of ADVATE rAHF-PFM is derived from that used in the biosynthesis of RECOMBINATE rAHF. ADVATE rAHF-PFM has been shown to be comparable to RECOMBINATE rAHF with respect to its biochemical and physicochemical properties, as well as its non-clinical in vivo pharmacology and toxicology.9 By inference, RECOMBINATE rAHF and ADVATE rAHF-PFM would be expected to have equivalent mutagenic and carcinogenic potential.

RECOMBINATE rAHF 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.

PEDIATRIC USE

Use of ADVATE rAHF-PFM is being examined in the context of an ongoing study of previously treated subjects under 6 years of age and in a planned study of previously untreated subjects with severe or moderately severe hemophilia A. In addition, pediatric subjects between 10 and 16 years of age were treated on the Phase 2/3 pivotal study, and those over 5 years of age were eligible for treatment on the ongoing Phase 2/3 surgery study.

A total of 54 subjects </= 16 years of age have been treated across all studies of ADVATE rAHF-PFM to date. Interim pharmacokinetic data for 34 subjects (per-protcol analysis population) </= 16 years of age were obtained from a combined dataset comprising subjects 10 to 16 years of age treated on the Phase 2/3 pivotal study and subjects enrolled and treated on the ongoing study of pediatric previously treated subjects < 6 years of age. Among these, 0 were neonates (birth to < 1 month of age), 2 were infants (1 month to < 2 years of age), 15 were children (2 to 12 years of age), and 17 were adolescents (12 to </= 16 years of age).

Pharmacokinetic parameters were not significantly different for the different age categories. A summary of the pharmacokinetic parameters for the 34 subjects </= 16 years of age in the per-protocol analysis population are shown in Table 5. The mean (± SD) plasma half-life was 11.21 ± 2.92 hours (range: 8.31-24.7 hours). The mean AUC0-48h was 1363 ± 440 IU·h/dL. The mean values for Cmax and adjusted recovery were 109 ± 23 IU/dL and 2.17 ± 0.44 IU/dL / IU/kg, respectively.

Table 5.
Pharmacokinetic Parameters with ADVATE rAHF-PFM in Pediatric Previously Treated Subjects
(Per-protocol Analysis)
N Mean SD Min Max
AUC0-48h(IU·h/dL) 34 1363 440 792 2398
Cmax(IU/dL) 34 109 23 51 181
Adjusted Recovery (IU/dL/IU/kg) 34 2.17 0.44 1.23 3.39
Total AUMC (IU·h2/dL) 34 36823 47250 9749 283097
Half-life (h) 34 11.21 2.92 8.31 24.7
Clearance (dL/(kg·h)) 34 0.04 0/01 0.01 0.06
Mean residence time (h) 34 19.79 9.92 10.70 66.66
Vss(dL/kg) 34 0.64 0.12 0.32 0.86

PREGNANCY

Pregnancy Category C. Animal reproduction studies have not been conducted with ADVATE rAHF-PFM. It is not known whether ADVATE rAHF-PFM can cause fetal harm when administered to a pregnant woman, or whether it can affect reproductive capacity. ADVATE rAHF-PFM should be given to a pregnant woman only if clearly needed.

Page last updated: 2006-02-18

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