Factor IX, recombinant (Rixubis, BeneFIX, Alprolix, Ixinity)

Dosing and uses of Rixubis, BeneFIX (Factor IX, recombinant)

• Adult
• Pediatric

 

Adult dosage forms and strengths

lyophilized powder for reconstitution

• 250 IU
• 500 IU
• 1000 IU
• 1500 IU
• 2000 IU
• 3000 IU

 

Hemophilia B, Bleeding Episodes

Indicated for control and prevention of bleeding episodes and perioperative management

Initial dose

• Initial dose = body weight (kg) x desired factor IX increase (% or IU/dL) x reciprocal of observed recovery (IU/dL per IU/kg)

Incremental recovery in previously treated patients (Rixubis)

• For incremental recovery of 0.9 IU/dL, the dose is calculated as follows:
• Dose (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x 1.1 dL/kg

Incremental recovery in previously treated patients (BeneFIX)

• For incremental recovery of 0.8 IU/dL, the dose is calculated as follows:
• Dose (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x 1.3 dL/kg

Incremental recovery in previously treated patients (Ixinity)

• For incremental recovery of 0.98 IU/dL, the dose is calculated as follows:
• Dose (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x 1.02 dL/kg

Control and prevention of bleeding episodes (Rixubis, BeneFIX)

• Minor: Circulating factor IX level required = 20-30 IU/dL; dosing interval 12-24 hr; treatment duration at least 1 day until healing achieved
• Moderate: Circulating factor IX level required = 25-50 IU/dL; dosing interval 12-24 hr; treatment duration 2-7 days until bleeding stops and healing achieved
• Major: Circulating factor IX level required = 50-100 IU/dL; dosing interval 12-24 hr; treatment duration 7-10 days until bleeding stops and healing achieved

Control and prevention of bleeding episodes (Alprolix)

• Minor and moderate: Circulating factor IX level required = 30-60 IU/dL; dosing interval 24 hr prn
• Major: Circulating factor IX level required = 80-100 IU/dL; consider repeating dose after 6-10 hr, then q24hr x3 days, then q48hr until healing achieved

Control and prevention of bleeding episodes (Ixinity)

• Minor: Circulating factor IX level required = 30-60 IU/dL; dosing interval 24 hr prn; 1-3 days until healing achieved
• Moderate: Circulating factor IX level required = 40-80 IU/dL; dosing interval 24 hr prn; 2-7 days until healing achieved
• Major: Circulating factor IX level required = 60-100 IU/dL; dosing interval 12-24 hr prn; 2-14 days until healing achieved

Perioperative management (Rixubis)

• Minor (eg, tooth extraction): Circulating factor IX level required = 30-60 IU/dL; dosing interval 24 hr; treatment duration at least 1 day until healing achieved
• Major: Circulating factor IX level required = 80-100 IU/dL; dosing interval 8-24 hr; treatment duration 7-10 days until bleeding stops and healing achieved

Perioperative management (BeneFIX)

• Minor: Circulating factor IX level required = 20-30 IU/dL; dosing interval 12-24 hr; treatment duration at least 1 day until healing achieved
• Moderate: Circulating factor IX level required = 25-50 IU/dL; dosing interval 12-24 hr; treatment duration 2-7 days until bleeding stops and healing achieved
• Major: Circulating factor IX level required = 50-100 IU/dL; dosing interval 12-24 hr; treatment duration 7-10 days until bleeding stops and healing achieved

Perioperative management (Alprolix)

• Minor and moderate: Circulating factor IX level required = 50-80 IU/dL; a single infusion may be sufficient, may repeat as needed after 24-48 hr until bleeding stopped and healing achieved
• Major: Circulating factor IX level required = 60-100 IU/dL (initial level); consider repeating dose after 6-10 hr, then q24hr x3 days, may then reduce dose and extend dosing interval to q48hr (or longer) until bleeding stopped and healing achieved

Perioperative management (Ixinity)

• Minor, pre-op: Circulating factor IX level required = 50-80 IU/dL
• Minor, post-op: Circulating factor IX level required = 30-80 IU/dL; dosing interval 24 hr; treatment duration 1-5 days depending on type of procedure
• Major, pre-op: Circulating factor IX level required = 60-80 IU/dL
• Major, post-op
  • Dosing interval 8-24 hr
  • Days 1-3: Circulating factor IX level required = 40-60 IU/dL
  • Days 4-6: Circulating factor IX level required = 30-50 IU/dL
  • Days 7-14: Circulating factor IX level required = 20-40 IU/dL

 

Hemophilia B, Routine Prophylaxis

Indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes

Rixubis

• 40-60 IU/kg IV bolus 2x/week; not to exceed infusion rate of 10 mL/min
• Dose titration may be needed depending on patient’s age, bleeding pattern, and physical activity

Alprolix

• Long-acting recombinant Factor IX Fc fusion protein allows for less frequent dosing
• Initial: 50 IU/kg IV once weekly OR 100 IU/kg q10days
• Adjust dose based on individual response

 

Dosing Considerations

Rixubis: 1 IU/kg is expected to increase circulating level of Factor IX by 0.9 IU/dL of plasma

BeneFIX (adults): 1 IU/kg is expected to increase circulating level of Factor IX by 0.8 IU/dL (range 0.4-1.2 IU/dL)

Alprolix: 1 IU/kg is expected to increase circulating level of Factor IX by 1% (IU/dL)

 

Pediatric dosage forms and strengths

lyophilized powder for reconstitution

• 250 IU
• 500 IU
• 1000 IU
• 1500 IU
• 2000 IU
• 3000 IU

 

Hemophilia B, Bleeding Control

BeneFIX: Approved for children <15 yr; indicated for control and prevention of bleeding episodes and perioperative management

Ixinity: Approved for children ≥12 yr; indicated for control and prevention of bleeding episodes and perioperative management

Alprolix, Rixubix: Approved for children; indicated for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent/reduce frequency of bleeding episodes

Initial dose

• Initial dose = body weight (kg) x desired factor IX increase (% or IU/dL) x reciprocal of observed recovery (IU/dL per IU/kg)

Incremental recovery in previously treated patients (BeneFIX)

• For incremental recovery of 0.7 IU/dL, the dose is calculated as follows:
• Dose (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x1.4 dL/kg

Incremental recovery in previously treated patients (Ixinity)

• For incremental recovery of 0.98 IU/dL, the dose is calculated as follows:
• Dose (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x 1.02 dL/kg

Control and prevention of bleeding episodes (BeneFIX)

• Minor: Circulating factor IX level required = 20-30 IU/dL; dosing interval 12-24 hr; treatment duration at least 1 day until healing achieved
• Moderate: Circulating factor IX level required = 25-50 IU/dL; dosing interval 12-24 hr; treatment duration 2-7 days until bleeding stops and healing achieved
• Major: Circulating factor IX level required = 50-100 IU/dL; dosing interval 12-24 hr; treatment duration 7-10 days until bleeding stops and healing achieved

Control and prevention of bleeding episodes (Alprolix)

• Minor and moderate: Circulating factor IX level required = 30-60 IU/dL; dosing interval 24 hr prn
• Major: Circulating factor IX level required = 80-100 IU/dL; consider repeating dose after 6-10 hr, then q24hr x3 days, then q48hr until healing achieved

Control and prevention of bleeding episodes (Ribuxis)

• Minor: Circulating factor IX level required = 20-30 IU/dL; dosing interval 12-24 hr prn; at least 1 day until healing achieved
• Moderate: Circulating factor IX level required = 25-50 IU/dL; dosing interval 12-24 hr prn; at least 2-7 days until healing achieved
• Major: Circulating factor IX level required = 50-100 IU/dL; dosing interval 12-24 hr prn; at least 7-10 days until healing achieved

Control and prevention of bleeding episodes (Ixinity)

• Minor: Circulating factor IX level required = 30-60 IU/dL; dosing interval 24 hr prn; 1-3 days until healing achieved
• Moderate: Circulating factor IX level required = 40-80 IU/dL; dosing interval 24 hr prn; 2-7 days until healing achieved
• Major: Circulating factor IX level required = 60-100 IU/dL; dosing interval 12-24 hr prn; 2-14 days until healing achieved

Perioperative management (BeneFIX)

• Minor: Circulating factor IX level required = 20-30 IU/dL; dosing interval 12-24 hr; treatment duration at least 1 day until healing achieved
• Moderate: Circulating factor IX level required = 25-50 IU/dL; dosing interval 12-24 hr; treatment duration 2-7 days until bleeding stops and healing achieved
• Major: Circulating factor IX level required = 50-100 IU/dL; dosing interval 12-24 hr; treatment duration 7-10 days until bleeding stops and healing achieved

Perioperative management (Alprolix)

• Minor and moderate: Circulating factor IX level required = 50-80 IU/dL; a single infusion may be sufficient, may repeat as needed after 24-48 hr until bleeding stopped and healing achieved
• Major: Circulating factor IX level required = 60-100 IU/dL (initial level); consider repeating dose after 6-10 hr, then q24hr x3 days, may then reduce dose and extend dosing interval to q48hr (or longer) until bleeding stopped and healing achieved

Perioperative management (Rixubis)

• Minor: Circulating factor IX level required = 30-60 IU/dL; dosing interval 24 hr; at least 1 day until healing achieved
• Major: Circulating factor IX level required = 80-100 IU/dL; dosing interval 8-24 hr; at least 7-10 days until healing achieved

Perioperative management (Ixinity)

• Minor, pre-op: Circulating factor IX level required = 50-80 IU/dL
• Minor, post-op: Circulating factor IX level required = 30-80 IU/dL; dosing interval 24 hr; treatment duration 1-5 days depending on type of procedure
• Major, pre-op: Circulating factor IX level required = 60-80 IU/dL
• Major, post-op
  • Dosing interval 8-24 hr
  • Days 1-3: Circulating factor IX level required = 40-60 IU/dL
  • Days 4-6: Circulating factor IX level required = 30-50 IU/dL
  • Days 7-14: Circulating factor IX level required = 20-40 IU/dL

 

Hemophilia B, Routine Prophylaxis

Indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes

Alprolix

• Long-acting recombinant Factor IX Fc fusion protein allows for less frequent dosing
• Initial: 50 IU/kg IV once weekly OR 100 IU/kg q10days
• Adjust dose based on individual response

Rixubis

• <12 years: 60-80 IU/kg IV 2x/week
• ≥12 years: 40-60 IU/kg IV 2x/week
• Maximum infusion rate is 10 mL/min
• Adjust the dose based on the individual patient’s age, bleeding pattern, and physical activity

 

Dosing Considerations

BeneFIX (children <15 years): 1 IU/kg is expected to increase circulating level of Factor IX by 0.7 IU/dL (range 0.2-2.1 IU/dL)

Alprolix: 1 IU/kg is expected to increase circulating level of Factor IX by 1% (IU/dL)

Alprolix (<12 years): May have higher Factor IX bodyweight-adjusted clearance, shorter half-life, and lower recovery; therefore, higher dose/kg or more frequent dosing may be needed

Rixubis (<12 years): 1 IU/kg is expected to increase circulating level of Factor IX by 0.7 IU/dL

Rixubis (≥12 years): 1 IU/kg is expected to increase circulating level of Factor IX by 0.9 IU/dL

 

Rixubis, BeneFIX (Factor IX, recombinant) adverse (side) effects

>10% (BeneFIX)

Headache (10.8%)

 

1-10% (BeneFIX)

Dizziness (7.7%)

Injection site reaction (7.7%)

Injection site pain (6.2%)

Nausea (6.2%)

Rash (6.2%)

Taste perversion (4.6%)

Hives (3.1%)

Flushing (3.1%)

Fever (3.1%)

Factor IX inhibition (1.5%)

Blurred vision (1.5%)

Vomiting (1.5%)

Cellulitis at IV site (1.5%)

Phlebitis at IV site (1.5%)

Shaking (1.5%)

Drowsiness (1.5%)

Renal infarct (1.5%)

Dry cough (1.5%)

Hypoxia (1.5%)

Chest tightness (1.5%)

 

1-10% (Rixubis)

Factor IX or furin antibodies (7.7%)

Dysgeusia (1.1%)

Pain in extremity (1.1%)

Positive furin antibody test (1.1%)

 

1-10% (Alprolix)

Headache (1.7%)

Oral paresthesia (1.7%)

 

<1% (Alprolix)

Dizziness

Dysgeusia

Breath odor

Fatigue

Infusion site pain

Palpitations

Obstructive uropathy

Hypotension

 

Warnings

Contraindications

Hypersensitivity to product or its excipients including hamster protein

Disseminated intravascular coagulation (DIC)

Signs of fibrinolysis

 

Cautions

Hypersensitivity reactions including anaphylaxis reported, particularly with initial exposure in previously untreated patients Factor IX inhibitors may develop

Nephrotic syndrome reported

Thromboembolic complications may occur (eg, PE, venous or arterial thrombosis); monitor for thrombotic and consumptive coagulopathy, especially in patients with liver disease, signs of fibrinolysis, peri- and post-operatively, or at risk for thrombotic events or DIC

Monitor Factor IX activity plasma levels by the one-stage clotting assay to confirm factor IX levels achieved and maintained

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Unknown if distributed in human breast milk

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Rixubis, BeneFIX (Factor IX, recombinant)

Mechanism of action

Temporarily replaces missing clotting factor IX which corrects and/or prevents bleeding

 

Absorption

Rixubis

• Peak plasma concentration: 66.2-72.7 IU/dL
• AUC: 1207-1305 IU•hr/dL

BeneFIX

• Peak plasma concentration: 54.5 IU/dL
• AUC: 548-940 IU•hr/dL

Alprolix

• Peak plasma concentration: 46 IU/dL
• 1619 IU•hr/dL

 

Distribution

Rixubis

• Vd: 201.9-178.6 mL/kg

Alprolix

• Vd: 327 mL/kg

 

Elimination

Rixubis

• Half-life: 25.4-26.7 hr
• Clearance: 6-6.4 mL/kg/hr

BeneFIX

• Half-life: 18.1-22.4 hr (adults); 19.8 hr (children 2-12 years); 21.1 hr (children 12-15 years)
• Clearance: ~8.5 mL/kg/hr

Alprolix

• Half-life: 86.52 hr
• Clearance: 3.3 mL/kg/hr

 

Administration

IV Preparation

BeneFIX, Alprolix: Use the adapter and supplied diluent syringe to reconstitute each vial (see package instructions)

Rixubis: Use the Baxject II device and sterile water for injection provided in each kit to reconstitute each vial (see package instructions)

 

IV Administration

Safety and efficacy of administration by continuous infusion has not been established

BeneFIX: Administer IV over several minutes

Rixubis, Alprolix: Administer by IV bolus at rate not to exceed 10 mL/min

 

Storage

Unopened vials

• Refrigerated: Store between 2-8°C (35-46°F) in original carton for up to 18 months; do not freeze
• Room temperature: May store at room temperature, not to exceed 30°C (86°F) for up to 6 months within the 18 month time period (mark carton on date removed from refrigerator)
• After storage at room temperature, do not return the product to the refrigerator

Reconstituted vials

• Use within 3 hr following reconstitution
• Do not refrigerate after reconstitution
• Discard partially used vials