May 26, 2016
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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

PTPs ≥ 12 Years of Age

A randomized, blinded, controlled pharmacokinetic trial of RIXUBIS was conducted in non-bleeding subjects ( ≥ 15 years of age). The subjects received RIXUBIS as an intravenous infusion. The infusion rate for the first administration during the trial was not to exceed 4 mL/minute with a maximum infusion rate of 10 mL/minute. The dose range of RIXUBIS was from 71.3 to 79.4 international units/kg (mean dose = 74.7 international units/kg). Blood samples for factor IX activity measurements were obtained up to 72 hours and a non-compartmental analysis was used to estimate pharmacokinetic parameters.

The pharmacokinetic evaluation was repeated for RIXUBIS in a prospective, open-label, uncontrolled trial with RIXUBIS in subjects who participated in the initial trial 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 trial was 64.5 to 79.2 international units/kg (mean dose = 74.6 international units/kg). Table 4 presents the pharmacokinetic parameters for all evaluable subjects (per protocol analysis).

Table 4 : Pharmacokinetic Parameters for RIXUBIS Following Single and Repeat Dosing ( ≥ 12 years of age)

Parameter First Dose
(N=25)
Repeat Dose
(N=23)
AUC0-inf (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/(kghr)]
  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 ( ≥ 12 years of age)

Incremental recovery 30 min after infusion (IU/dL:IU/kg)a Day 1
(N=73)
Week 5
(N=71)
Week 13
(N=68)
Week 26
(N=55)
At trial completion/ terminationb
(N=23)
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.

PTPs < 12 Years of Age

Twenty-three male subjects underwent a pharmacokinetic evaluation of RIXUBIS as part of the combined pediatric trial ( < 6 years and 6 - < 12 years). The mean (± SD) and median dose were 75.5 ± 3.0 and 75.3 international units/kg, respectively, with a range of 70.0 to 83.6 international units/kg. Non-linear mixed model (population PK) was used to estimate the pharmacokinetic parameters from factor IX activity measurements in blood samples obtained up to 60 hours following the infusion. Pharmacokinetic parameters for all subjects are presented in Table 6.

Table 6 : Pharmacokinetic Parameters for PTPs

Parameter ≥ 12 yearsa
(N=25)
6 - < 12 years (N=12) < 6 years
(N=11)
AUC0-inf (IUhr/dL)a
  Mean ± SD 1185±273 886 ± 134 864 724±119
  Median (range) 1197 (783-1780) (730-1138) 717 (488-947)
Half-life (hr)
  Mean ± SD 25.7 ± 1.5 23.2 ± 1.6 27.7 ± 2.7
  Median (range) 25.6 (22.8-29.0) 22.6 (21.8-27.4) 27.3 (24.0-32.2)
Mean residence time (hr)
  Mean ± SD 30.2    ± 2.2 25.3 ± 1.8 30.6 ± 3.3
  Median (range) 30.3    (25.9-33.9) 24.7 (23.7-30.3) 30.1 (26.2-36.2)
Vssb (mL/kg)
  Mean ± SD 201.5 ± 47.2 220.9 ± 31.7 322.5 ± 52.3
  Median (range) 190.2 (138-300) 218.5 (169.9-270.1) 315.7 (264.7-441.5)
Clearance (mL/[kghr])
  Mean ± SD 6.7 ± 1.5 8.7 ± 1.2 10.6 ± 1.7
  Median (range) 6.43 (4.1-9.9) 8.6 (6.9-10.8) 10.5 (8.1-14.4)
a Non-linear mixed model (population PK) was applied on the reduced 4 blood samples (30min, 6hr, 24hr, and 60hr).

Incremental recovery 30 minutes after infusion was determined for all subjects in the combined trial during the pharmacokinetic evaluation (exposure day 1), at week 5, 13, and 26 visits, and at the time of trial completion or termination, if it did not coincide with the week 26 visit. The data demonstrate that the incremental recovery is consistent over time across all pediatric age groups. (see Tables 7 and 8)

Table 7 : Incremental Recovery for RIXUBIS 30 Minutes After Infusion Ages < 6 Years

Incremental recovery 30 min after infusion (IU/dL-IU/kg)a PK (ED 1)
(N=10)
Week 5
(N=11)
Week 13
(N=10)
Week 26
(N=10)
  Mean ± SD 0.59 ± 0.13 0.63 ± 0.10 0.68 ± 0.12 0.65 ± 0.13
  Median (range) 0.59
(0.31-0.75)
0.6
(0.49-0.80)
0.66
(0.51-0.84)
0.61
(0.51-0.84)
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.

Table 8 : Incremental Recovery for RIXUBIS 30 Minutes After Infusion Ages 6 to < 12 Years

Incremental recovery 30 min after infusion PK (ED 1)
N=12)
Week 5
(N=12)
Week 13
(N=11)
Week 26
(N=11)
(IU/dL-IU/kg)a
  Mean ± SD 0.73 ± 0.16 0.73 ± 0.13 0.73 ± 0.14 0.8 ± 0.14
  Median (range) 0.71
(0.51 - 1.00)
0.70
(0.48-0.92)
0.70
(0.54-1.00)
0.78
(0.56-1.01)
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.

Clinical Studies

Prophylaxis and Control of Bleeding in PTPs ≥ 12 Years of Age

The efficacy of RIXUBIS has been evaluated in a prospective, open-label, uncontrolled multicenter trial, 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, open-label, uncontrolled, multicenter trial 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 for ≥ 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 trial.

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 9).

Table 9 : Efficacy of Prophylaxis with RIXUBIS (N = 56) ≥ 12 Years of Age

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)
* The prophylactic regimen consisted of 40 to 60 international units/kg RIXUBIS twice weekly.

Treatment of Bleeding Episodes in PTPs ≥ 12 Years of Age

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 non-responders 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; 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).

Prophylaxis and Control of Bleeding in PTPs < 12 Years of Age

The efficacy of RIXUBIS has been evaluated in a clinical trial, in which a total of 23 male, (PTPs) between 1.8 and 11.8 years (median age 7.10 years) with 11 subjects < 6 years, received RIXUBIS for prophylaxis and control of bleeding episodes. PTPs were defined as subjects who were exposed to a factor IX-containing product on ≥ 150 days for subjects aged 6 to < 12 years and on ≥ 50 days for subjects aged < 6 years. All subjects had severe (factor IX level < 1%) or moderately severe (factor IX level ≤ 2%) hemophilia B. Subjects with a history of or a detectable FIX inhibitor ≥ 0.6 BU, a history of severe allergic reactions following exposure to FIX, evidence of severe chronic liver disease (INR > 1.4), impaired renal function, a CD4 count < 200 cells/mm³ or any hemostatic effect other than hemophilia B were excluded from participation. All 23 subjects received prophylactic treatment with RIXUBIS for a minimum of 3 months and were included in the efficacy evaluation for prophylaxis (see Table 10).

Table 10 : Efficacy of Prophylaxis of RIXUBIS in 23 PTPs < 12 Years of Age

Total annualized bleeding rate (ABR)  
  Mean ± SD 2.7 ± 3.14
  Median (range) 2.0 (0.0-10.8)
ABR for joint bleeds
  Mean ± SD 0.8 ± 1.76
  Median (range) 0.0 (0.0-7.2)
ABR for spontaneous bleeds
  Mean ± SD 0.2 ± 0.66
  Median (range) 0.0 (0.0-2.0)
Subjects with zero bleeds
  % (n) 39.1.% (9)
* The prophylactic regimen consisted of 40 to 80 international units/kg RIXUBIS twice weekly.

Treatment of Bleeding Episodes in PTPs < 12 Years of Age

A total of 26 bleeding episodes were treated with RIXUBIS, of which 23 bleeds were due to injury, 2 spontaneous and 1 of unknown origin; 19 bleeds were non-joint (soft tissue, muscle, body cavity, intracranial and other) and 7 were joint bleeds of which 1 was a bleed into a target joint. Of the 26 bleeding episodes, 15 were minor, 9 moderate, and 2 major (Minor: little or no pain; little or no change in the range of motion of affected joint (if joint bleeding event); mild restriction of mobility and activity; Moderate: mild to moderate pain; some decrease in range of motion of affected joint (if joint bleeding event); moderate decrease in mobility and activity; Major/ life threatening: significant pain; substantial decrease in range of motion of affected joint (if joint bleeding event); incapacity; life threatening). Treatment was individualized based on the severity, cause and site of bleed. The majority (23; 88.5%) were treated with 1 to 2 infusions. Of the treated bleeding episodes 15 (57.7%) received 1 infusion, 8 (30.8%) received 2 infusions, and 3 (11.5%) were treated with 3 infusions. Hemostatic efficacy at resolution of a bleed was rated excellent or good in 96.2% of all treated bleeding episodes.

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 subjects 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 trial duration. The following are the surgical procedures and results of the assessment of the hemostatic response at various points.

Fourteen surgeries (11 major; 3 minor), included in the intraoperative assessment had a rating of 'excellent'. At discharge from hospital 11/14 surgeries (8 major) had a rating of 'excellent' and 3/14 (3 major) had a rating of 'good'.

The rating of excellent, good, fair and none at 72 hours post-surgery was based on the hemostasis achieved as compared to that expected in hemostatically normal subjects.

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: 2/29/2016
This monograph has been modified to include the generic and brand name in many instances.

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