Factor IX (Recombinant)

Dosage Forms & 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

Control and prevention of bleeding episodes (Rebinyn; nonacog beta pegol)

• Minor and moderate: 40 IU/kg IV as a single dose is typically sufficient; additional doses can be give if needed
• Major: 80 IU/kg IV; additional doses of 40 IU/kg can be given

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

Perioperative management (Rebinyn)

• Minor: 40 IU/kg IV as a single preoperative dose is typically sufficient; additional doses can be give if needed
• Major: 80 IU/kg IV as a single preoperative dose

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)

Rebinyn: Conjugated to a 40-kDa polyethylene glycol molecule, which slows down its removal from the blood circulation; each vial is labeled with the actual Factor IX potency in IU

Dosage Forms & 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

Control and prevention of bleeding episodes (Rebinyn; nonacog beta pegol)

• Minor and moderate: 40 IU/kg IV as a single dose is typically sufficient; additional doses can be give if needed
• Major: 80 IU/kg IV; additional doses of 40 IU/kg can be given

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

Perioperative management (Rebinyn)

• Minor: 40 IU/kg IV as a single preoperative dose is typically sufficient; additional doses can be give if needed
• Major: 80 IU/kg IV as a single preoperative dose

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

Rebinyn: Conjugated to a 40-kDa polyethylene glycol molecule, which slows down its removal from the blood circulation; each vial is labeled with the actual Factor IX potency in IU

Contraindications

• Life-threatening, immediate hypersensitivity (e.g., anaphylaxis) or known hypersensitivity to factor IX (recombinant) or any ingredient in the formulation, including hamster protein.1 25

• Rixubis also contraindicated in patients with disseminated intravascular coagulation (DIC) or signs of fibrinolysis.25

Warnings/Precautions

Warnings

Risk of thromboembolic complications.1 25 Peripheral thrombophlebitis, DVT, and life-threatening superior vena cava syndrome (in critically ill neonates) reported with at least one preparation of factor IX (recombinant); in several cases, patients received the drug by continuous infusion† sometimes via a central venous catheter.1 (See Pediatric Use under Cautions.)

Monitor for early manifestations of thromboembolic and consumptive coagulopathy in patients with hepatic disease, signs of fibrinolysis, or other risk factors for thromboembolism or DIC.25 (See Contraindications under Cautions.) Also monitor during perioperative or postoperative period for such events.25 Weigh risk of thromboembolism against benefits of therapy in patients with (or at risk of) DIC or thromboembolism.25

Nephrotic syndrome reported following immune tolerance induction with factor IX-containing preparations in patients with hemophilia B who have factor IX inhibitors and a history of hypersensitivity to factor IX.1 5 15 16 17 25

Safety and efficacy of factor IX (recombinant) for immune tolerance induction not established.1 25

Sensitivity Reactions

Hypersensitivity reactions, including bronchospastic reactions and anaphylaxis, reported.1 5 25 Manifestations have included pruritus, rash, urticaria, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, generalized discomfort, and fatigue.1

Increased risk in patients with certain genetic mutations of factor IX and/or those with inhibitors to factor IX.1 5 9 15 16 17 18 19 25 171 Up to 50% of hemophilia B patients with inhibitors to factor IX may experience a severe hypersensitivity reaction, including anaphylaxis, to factor IX concentrates.171

Closely observe for hypersensitivity reactions, especially during initial exposure to the drug.1 25 Administer initial (e.g., approximately 10–20) infusions in a hospital or clinic setting where severe allergic reactions can be managed.1 16 171 If manifestations of hypersensitivity or anaphylaxis occur, discontinue drug immediately and initiate appropriate therapy.1 25

Evaluate any patient who experiences a hypersensitivity reaction to factor IX (recombinant) for presence of inhibitors.1 (See Development of Inhibitors to Factor IX under Cautions.)

Commercially available preparations of factor IX (recombinant) (BeneFIX, Rixubis) contain trace amounts of hamster proteins; possibility of hypersensitivity reactions to these nonhuman mammalian proteins.1 25 (See Contraindications.)

General Precautions

Risk for development of neutralizing antibodies (inhibitors) to factor IX following treatment with factor IX preparations.1 6 9 15 16 17 18 19 21 25 171 Inhibitors reported in about 1–5% of patients with hemophilia B, usually within the first 10–20 days of treatment.6 9 15 17 19 21 171 Patients with certain genetic mutations of the factor IX gene may be at higher risk of inhibitor development and of experiencing a hypersensitivity reaction.1 5 9 14 15 16 17 18 19 21 171 (See Hypersensitivity Reactions under Cautions.)

High-titer inhibitors observed in a few previously untreated pediatric patients receiving BeneFIX; may require use of an alternative treatment to factor IX replacement therapy.1

Neutralizing antibodies to factor IX not reported to date with Rixubis;25 however, inhibitor formation is a concern with any clotting factor therapy.27 171

Monitor regularly for development of inhibitors with appropriate clinical observation and laboratory tests.1 Suspect presence of inhibitors if expected factor IX levels not achieved or bleeding is not controlled with a recommended dose.1 25 171

Patients who develop inhibitors may be at increased risk of anaphylaxis following re-exposure to factor IX (recombinant).25 (See Hypersensitivity Reactions under Cautions.)

Consultation with a hemophilia treatment center strongly recommended for patients with inhibitors.25

Monitor factor IX levels to guide dosing and assess therapeutic response.1 21 25 171 Use of one-stage clotting assay recommended.1 25

Monitor for development of inhibitors (with clinical observation and appropriate laboratory tests).1 25 171 (See Development of Inhibitors to Factor IX under Cautions.) If expected plasma factor IX levels are not attained or bleeding is not controlled with the recommended dose, perform appropriate laboratory test (Bethesda assay) to detect presence of factor IX inhibitors.1 25

Specific Populations

Category C.1 25

Not known whether distributed into human milk; use with caution.1 25

Safety, efficacy, and pharmacokinetics of BeneFIX evaluated in previously treated and previously untreated pediatric patients <15 years of age;1 on average, in vivo recovery of factor IX is lower in such pediatric patients than in older individuals and dosage adjustments may be necessary.1 19

Safety, efficacy, and pharmacokinetics of Rixubis evaluated in previously treated pediatric patients <12 years of age; on average, in vivo recovery of factor IX is lower in such pediatric patients than in older individuals and dosage adjustments may be necessary.25

High-titer inhibitors detected in several pediatric patients receiving BeneFIX who had no prior exposure to factor IX preparations; these patients were withdrawn from study.1

Rare postmarketing reports of critically ill neonates who experienced thrombotic events, including life-threatening superior vena cava syndrome, while receiving continuous infusions of BeneFIX through a central venous catheter.1 (See Thromboembolic Events under Cautions.)

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 25 Individualize dosage.1 25

Common Adverse Effects

BeneFIX: Headache,1 dizziness,1 nausea,1 9 injection site reactions/pain,1 skin-related hypersensitivity reactions (e.g., rash, hives).1

Rixubis: Dysgeusia, pain in extremity, positive furin antibody test.25

• Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX.1 7 21 25

• Factor IX is essential for blood clotting and maintenance of hemostasis.14 15

• Patients with hemophilia B (Christmas disease) have decreased levels of endogenous factor IX, resulting in a hemorrhagic tendency and clinical manifestations such as bleeding into soft tissues, muscles, joints, and internal organs.14 15 18 171

  Clinical severity and frequency of bleeding in patients with hemophilia B correlate with the degree of deficiency of factor IX activity.15 18 171 Patients with mild hemophilia B generally have >5% of normal activity, those with moderate disease generally have 1–5% of normal activity, and those with severe disease have <1% of normal activity.5 14 15 18 171

• Administration of factor IX (recombinant) to patients with hemophilia B results in increased plasma levels of factor IX and temporarily corrects coagulation defect.1 25 Treatment also may normalize aPTT, which is typically prolonged in patients with hemophilia B.1 25

• Similar in structure and function to plasma-derived factor IX, but associated with substantially reduced risk of transmission of bloodborne human viruses (e.g., HIV, HAV, HBV, HCV).1 6 7 9 13 15 25

• Produced by recombinant DNA technology in a mammalian cell expression system using several purification and virus-inactivating/removal processes (e.g., chromatography, nanofiltration, solvent/detergent).1 7 18 21 25 Manufactured without animal or human components.1 5 7 9 13 15 19 21 25

• If you have an allergy to Factor IX or any other part of factor IX (recombinant).
• If you are allergic to hamsters, talk with the doctor.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Store in a refrigerator or at room temperature.
• Do not freeze.
• Be sure you know how long you can store factor IX if stored in a refrigerator or at room temperature.
• If stored at room temperature, make a note of the date it was placed at room temperature.
• Do not put this medicine back in the refrigerator after it has been stored at room temperature.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Refer to adult dosing.

Note: Contains only factor IX. Therefore, NOT INDICATED for the treatment of other factors deficiencies (eg, factors II, VII, VIII, and X), hemophilia A patients with inhibitors to factor VIII, reversal of coumarin-induced anticoagulation, and bleeding due to low levels of liver-dependent clotting factors.

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B or Christmas disease): IV: Dosage is expressed in units of factor IX activity; dosing must be individualized based on severity of factor IX deficiency, extent and location of bleeding, clinical status of patient, and recovery of factor IX. Refer to product information for specific manufacturer recommended dosing. Alternatively, the World Federation of Hemophilia (WFH) has recommended general dosing for factor IX products.

Formula for units required to raise blood level %: Note: If patient has severe hemophilia (ie, baseline factor IX level is or presumed to be <1%), then may just use “desired factor IX level” instead of “desired factor IX level increase”. On average, the observed recovery for BeneFix is 0.7 units/dL per units/kg in children <15 years of age.

Infants, Children, and Adolescents: IV: Number of factor IX units required = patient weight (in kg) x desired factor IX level increase (as % or units/dL) x reciprocal of observed recovery (as units/kg per units/dL)

Alternative recommendations (off label): Infants, Children, and Adolescents:

Prophylaxis: Refer to adult dosing.

Treatment: Refer to adult dosing.

Routine prophylaxis to prevent bleeding episodes in patients with factor IX deficiency (hemophilia B or Christmas disease): IV: Rixubis:

Children <12 years: 60 to 80 units/kg twice weekly; may titrate dose depending upon age, bleeding pattern, and physical activity.

Children ≥12 years and Adolescents: 40 to 60 units/kg twice weekly; may titrate dose depending upon age, bleeding pattern, and physical activity.

Refer to instructions provided by the manufacturer. Diluent and factor IX should come to room temperature (if refrigerated) before combining.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, injection site pain or irritation, or numbness or tingling in mouth. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), burning or numbness feeling, nausea, vomiting, agitation, shortness of breath, flushing, dizziness, passing out, tachycardia, angina, confusion, coughing up blood, severe loss of strength and energy, cough, or mouth discoloration (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.