antihaemorrhagics, blood coagulation factor VIII. ATC code:
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von Willebrand Factor) with different physiological functions. ADVATE contains recombinant coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII glycoprotein found in human plasma.
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand Factor in the patient's circulation. Activated factor VIII acts as a Cofactor for activated Factor IX, accelerating the conversion of Factor X to activated Factor X. Activated Factor X converts prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII activity and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are increased by replacement therapy, thereby enabling a temporary correction of the factor VIII deficiency and correction of the bleeding tendency.
The immunogenicity of ADVATE was evaluated in previously treated patients. During clinical trials with ADVATE in 233 paediatric and adult patients [paediatric patients (age 0-16 years) and adult patients (age over 16 years)] diagnosed with severe haemophilia A (factor VIII < 1%), with previous exposure to factor VIII concentrates ≥ 150 days for adults and older children and ≥ 50 days for children < 6 years of age, one patient developed a low-titre inhibitor (2.4 BU in the modified Bethesda assay) after 26 exposure days to ADVATE. Follow-up inhibitor tests in this patient after withdrawal from the study were negative. Across all studies, median exposure to ADVATE was 97.0 exposure days per subject (range 1 to 709) for previously treated patients. The overall incidence of any factor VIII inhibitor development (low or high) was 0.4% (1 of 233).
In the completed uncontrolled study 060103, 16 out of 45 (35.6%) of previously untreated patients with severe haemophilia A (FVIII < 1%) and at least 25 EDs to FVIII developed FVIII inhibitors: 7 (15.6%) subjects developed high-titre inhibitors and 9 (20%) subjects developed low-titre inhibitors, 1 of which was also classified as a transient inhibitor.
Risk factors related to inhibitor development in this study included non-Caucasian ethnicity, family history of inhibitors and intensive treatment at high dose within the first 20 EDs. In the 20 subjects who had none of these risk factors there was no inhibitor development.
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a sub‑study of PUP‑study 060103, ITI‑treatments in 11 PUPs were documented. Retrospective chart review was done for 30 subjects on ITI (study 060703) and collection of Registry data is on‑going.
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen (20 to 40 IU/kg every 48 ± 6 hours, n=30) . The pharmacokinetic guided dosing regimen (according to a specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval of 72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are comparable in terms of reduction of bleeding rate.
The European Medicines Agency has waived the obligation to submit the results of studies with ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (See Dosage & Administration for information on paediatric use).
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was conducted in a central laboratory using a one‑stage clotting assay.
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize PK parameters, where age was defined as age at time of PK infusion.
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The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of adult patients. Adjusted recovery and terminal half-life (t½
) was approximately 20% lower in young children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma volume per kilogram body weight in younger patients.
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available.
Toxicology: Preclinical safety data:
Non‑clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute toxicology, repeated dose toxicity, local toxicity and genotoxicity.