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Rixubis

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Rixubis

CLINICAL PHARMACOLOGY

Mechanism Of Action

Patients with hemophilia B are deficient in coagulation factor IX, which is required for effective hemostasis. Treatment with RIXUBIS temporarily replaces the missing coagulation factor IX.

Pharmacodynamics

The administration of RIXUBIS increases plasma levels of factor IX, and can temporarily correct the coagulation defect in these patients by decreasing the aPTT.

Pharmacokinetics

A randomized, blinded, controlled, crossover pharmacokinetic study of RIXUBIS and another commercial recombinant factor IX product was conducted in non-bleeding subjects ( ≥ 15 years of age). The subjects received either of the products as an intravenous infusion. The dose range of RIXUBIS and the other recombinant factor IX product ranged from 71.3 to 79.4 international units/kg and 70.1 to 80 international units/kg, respectively. The pharmacokinetic parameters were calculated from factor IX activity measurements in blood samples obtained up to 72 hours following each infusion.

The pharmacokinetic evaluation was repeated for RIXUBIS in a prospective, open-label, uncontrolled study with RIXUBIS in subjects who participated in the initial crossover pharmacokinetic study and had then received RIXUBIS for 26 } 1 (mean } SD) weeks for routine prophylaxis, and accumulated at least 30 exposure days to RIXUBIS. The dose range of RIXUBIS in this repeat pharmacokinetic study was 64.5 to 79.2 international units/kg.

RIXUBIS was equivalent to the other recombinant factor IX product based on area under the plasma concentration-time curve (AUC). Table 4 presents the pharmacokinetic parameters for all evaluable subjects (per protocol analysis).

Table 4: Pharmacokinetic Parameters for RIXUBIS Following Single and Repeat Dosing

Parameter Initial Crossover Study
(N=25)
Repeat Evaluation
(N=23)
AUC0-jnf (IUhrs/dL)a
  Mean (SD) 1207 (242) 1305 (300)
  Min; Max 850; 1710 838; 1864
Incremental recovery at Cmax (IU/dL:IU/kg)b
  Mean (SD) 0.87 (0.22) 0.95 (0.25)
  Min; Max 0.53; 1.35 0.52; 1.38
Half-life (hrs)
  Mean (SD) 26.7 (9.6) 25.4 (6.9)
  Min; Max 15.8; 52.3 16.2; 42.2
Cmax(IU/dL)
  Mean (SD)  66.2 (15.8) 72.7 (19.7)
  Min; Max 41.7; 100.3 38.5; 106.3
Mean Residence Time (hrs)
  Mean (SD) 30.8 (7.3) 29.9 (4.2)
  Min; Max 22.3; 47.8 21.3; 37.5
Vssc (mL/kg)
  Mean (SD) 201.9 (77.4) 178.6 (45.2)
  Min; Max 110.0; 394.0 112.0; 272.0
Clearance [mL/(kg-hr)]
  Mean (SD) 6.4 (1.3) 6.0 (1.5)
  Min; Max 4.3; 9.1 4.1; 9.5
a Area under the plasma concentration-time curve from time 0 to infinity hours post-infusion.
b Calculated as (Cmax – baseline factor IX) divided by the dose in IU/kg, where Cmax is the maximum post-infusion factor IX measurement.
c Volume of distribution at steady state.

Data from PTPs who underwent repeat in vivo recovery testing for up to 26 weeks demonstrated that the incremental Factor IX recovery was consistent over time (Table 5).

Table 5: Incremental Recovery for RIXUBIS 30 Minutes After Infusion

  Day 1
(N=73)
Week 5
(N=71)
Week 13
(N=68)
Week 26
(N=55)
At study completion/ terminationb
(N=23)
Incremental recovery 30 min after infusion (IU/dL:IU/kg)a
Mean ± SD 0.79 ± 0.20 0.83 ± 0.21 0.85 ± 0.25 0.89 ± 0.12 0.87 ± 0.20
Median (range) 0.78 (0.26-1.35) 0.79 (0.46-1.48) 0.83 (0.14-1.47) 0.88 (0.52-1.29) 0.89 (0.52-1.32)
a Calculated as (C30min – baseline factor IX) divided by the dose in IU/kg, where C30min is the factor IX measurement 30 minutes after infusion.
b If not coinciding with week 26 visit.

Clinical Studies

The efficacy of RIXUBIS has been evaluated in a prospective, open-label, uncontrolled multicenter study, in which a total of 73 male PTPs between 12 and 65 years of age received RIXUBIS either for routine prophylaxis or on-demand treatment. In addition, there is an ongoing prospective, openlabel, uncontrolled, multicenter study where 14 PTPs underwent minor or major surgeries receiving RIXUBIS for perioperative management. PTPs were defined as subjects who were exposed to a factor IX containing product at ≥ 150 days. All subjects had severe (factor IX level < 1%) or moderately severe (factor IX level ≤ 2%) hemophilia B. The majority of subjects (88%) had arthropathy and/or target joints (66%) at screening. Subjects with history of a detectable factor IX inhibitor ≥ 0.6 BU, history of severe allergic reactions following exposure to factor IX containing products, evidence of severe chronic liver disease (INR > 1.4), impaired renal function, CD4 count < 200 cells/mm3, or any hemostatic defect other than hemophilia B, were excluded from the study.

Routine Prophylaxis

Of 59 subjects who received RIXUBIS for routine prophylaxis, 56 subjects received the product for a minimum of 3 months and were included in the efficacy evaluation. The prophylactic regimen consisted of 40 to 60 international units/kg RIXUBIS twice weekly. An additional 14 subjects received RIXUBIS on-demand for treatment of bleeding episodes only. These subjects had to have at least 12 documented bleeding episodes requiring treatment within 12 months prior to enrollment.

In the on-demand arm, the mean treatment duration was 3.5 } 1 months (median 3.4, ranging from 1.2 to 5.1 months) and the mean total annualized bleeding rate (ABR) was 33.9 } 17.37 with a median of 27 ranging from 12.9 to 73.1.

In the prophylaxis arm the mean ABR was 4.3 for all bleeds, 1.7 for spontaneous bleeds, and 2.9 for joint bleeds (Table 6).

Table 6 : Efficacy of Prophylaxis with RIXUBIS (N = 56)

Treatment duration (months)  
  Mean ± SD 6.0 ± 0.65
  Median (range) 6.0 (5.4-9.1)
Number of infusions per week
  Mean ± SD 1.8 ± 0.11
  Median (range) 1.8 (1.5-1.9)
Dose per infusion (IU/kg)
  Mean ± SD 49.4 ± 4.92
  Median (range) 50.5 (40.0-62.8)
Total ABR
  Mean ± SD 4.3 ± 5.80
  Median (range) 2.0 (0.0-23.4)
ABR for joint bleeds
  Mean ± SD 2.9 ± 4.25
  Median (range) 0.0 (0.0-21.5)
ABR for spontaneous bleeds
  Mean ± SD 1.7 ± 3.26
  Median (range) 0.0 (0.0-15.6)
Subjects with zero bleeding episodes
  % (n) 42.9% (24)

Treatment of Bleeding Episodes

A total of 249 bleeding episodes were treated with RIXUBIS, of which 115 bleeds were recorded for subjects treated on prophylaxis and 134 bleeds for those with the on-demand regimen. There were 197 joint bleeds and 52 non-joint bleeds (soft tissue, muscle, body cavity and other). Of the 249 bleeding episodes, 15 were major, 163 were moderate, and 71 were minor (see Table 1 for definitions of major, moderate and minor). Treatment was individualized based on the severity, cause, and site of bleed. The majority (211; 84.7%) were treated with 1 to 2 infusions. Of these, 153 (61.4%) were treated with 1 infusion and 58 (23.3%) were treated with 2 infusions. No nonresponders were reported.

Hemostatic efficacy at resolution of a bleed was rated excellent or good in 96% of all treated bleeding episodes (Excellent is defined as full relief of pain and cessation of objective signs of bleeding after a single infusion; no additional infusion is required for the control of bleeding; or Good is defined as definite pain relief and/or improvement in signs of bleeding after a single infusion; possibly requires more than one infusion for complete resolution).

Perioperative Management

The efficacy analysis of RIXUBIS in perioperative management included 14 surgeries performed in 14 PTPs between 19 and 54 years of age undergoing major or minor surgical (see Table 2 for definitions of major and minor), dental or other surgical invasive procedures. Eleven procedures (including 7 orthopedic and 1 dental surgeries) were major, 3 procedures (including 2 dental extractions) were minor.

Subjects undergoing major surgeries also underwent a pharmacokinetic evaluation. All patients were dosed based on their most recent individual incremental recovery. The recommended initial loading dose of RIXUBIS was used to ensure that during surgery factor IX activity levels of 80-100% for major surgeries and 30-60% for minor surgeries were maintained. RIXUBIS was administered by intravenous bolus infusions. Hemostasis was maintained throughout the study duration. The surgical procedures and the results of the assessment of the hemostatic response at various points in time are provided in Table 7.

Table 7 : Efficacy of RIXUBIS for Surgical Procedures

Procedure (category, number of subjects) Assessment of Response
Intra-operative At time of drain removal or on post-operative day 3* At time of discharge
Removal of intramedullary nail (Major, n=1) Excellent Good Excellent
Joint replacement (Major, n=5) Excellent Good (3) Excellent (2) Excellent (3) Good (2)
Open synovectomy (Major, n=1) Excellent Excellent Excellent
Excision neurofibroma (Major, n=1) Excellent Excellent Excellent
Hernioplastic (Major, n=2) Excellent Excellent Good (1) Excellent (1)
Tooth extraction (Major, n=1) Excellent Excellent Excellent
Tooth extraction (Minor, n=2) Excellent Excellent Excellent
Intra-articular injection (Minor, n=1) Excellent Not applicable Excellent
* Where no drain was employed, response was assessed on postoperative day 3.

REFERENCES

1. Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am. 1993;7(6):1269-1280.

Last reviewed on RxList: 3/25/2014
This monograph has been modified to include the generic and brand name in many instances.

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