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Factor IX (Recombinant)

Pronunciation

(FAK ter nyne ree KOM be nant)

Index Terms

  • Factor IX Concentrate
  • rFIX

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Kit, Intravenous [preservative free]:

BeneFIX: 250 units, 500 units, 1000 units, 2000 units, 3000 units [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Alprolix: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea); 3000 units (1 ea); 4000 units (1 ea)

Ixinity: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea) [contains mouse (murine) and/or hamster protein, polysorbate 80]

Rixubis: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea); 3000 units (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • Alprolix
  • BeneFIX
  • Ixinity
  • Rixubis

Pharmacologic Category

  • Antihemophilic Agent

Pharmacology

Replaces deficient clotting factor IX. Hemophilia B, or Christmas disease, is an X-linked inherited disorder of blood coagulation characterized by insufficient or abnormal synthesis of the clotting protein factor IX. Factor IX is a vitamin K-dependent coagulation factor which is synthesized in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway. Activated factor IX (IXa) in combination with factor VII:C activates factor X to Xa, resulting ultimately in the conversion of prothrombin to thrombin and the formation of a fibrin clot. The infusion of exogenous factor IX to replace the deficiency present in hemophilia B temporarily restores hemostasis.

Distribution

Alprolix ~0.3 L/kg

Ixinity: 102 to 314 mL/kg

Rixubis: Children <6 years: ~0.3 L/kg; Children ≥6 years, Adolescents, and Adults: ~0.2 L/kg

Half-Life Elimination

Children: BeneFIX: 14 to 28 hours; Alprolix: 66 to 72 hours; Rixubis: 23 to 28 hours

Children ≥ 12 years, Adolescents ≤ 17 years: Alprolix: ~84 hours

Children ≥12 years, Adolescents, and Adults: Ixinity: 13 to 43 hours

Children ≥12 years, Adolescents, and Adults: Rixubis: ~26 hours

Adolescents >15 years and Adults: BeneFIX: 11 to 36 hours

Adults: Alprolix: ~87 hours

Note: Since Alprolix contains the Fc region of human IgG1, which binds to the neonatal Fc receptor (FcRn), delaying lysosomal degradation, and cycling factor IX back into the circulation, the plasma half-life is prolonged as compared to other recombinant factor IX products.

Use: Labeled Indications

Factor IX deficiency: Prevention and control of bleeding in patients with factor IX deficiency (hemophilia B [Christmas disease]); perioperative management in patients with hemophilia B.

Alprolix and Rixubis: Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia B

Limitations of use: 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.

Contraindications

Life-threatening, immediate hypersensitivity reactions (including anaphylaxis) to factor IX, hamster protein (BeneFix, Ixinity, and Rixubis), or any component of the formulation; disseminated intravascular coagulation (Rixubis); signs of fibrinolysis (Rixubis)

Dosing: Adult

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. As compared to Benefix, Ixinity, and Rixubis, Alprolix displays a longer half-life. Therefore, Alprolix dosing and frequency may differ. 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 0.8 units/dL per units/kg in adults.

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 dosing (off-label): Note: The following recommendations may vary from those found within prescribing information or practitioner preference.

Prophylaxis: 15 to 30 units/kg/dose twice weekly (Utrecht protocol; WFH [Srivastava 2013]) or 25 to 40 units/kg/dose twice weekly (Malmö protocol; WFH [Srivastava 2013]) or 40 to 100 units/kg/dose 2 to 3 times weekly (National Hemophilia Foundation, MASAC recommendation 2007); optimum regimen has yet to be defined.

Treatment:

2013 World Federation of Hemophilia Treatment Recommendations (When No Significant Resource Constraint Exists):

Site of Hemorrhage/Clinical Situation

Desired Factor IX Level to Maintain

Duration

Note: Factor IX level may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor IX but should be determined based on an assessment of factor IX levels before the next dose.

Joint

40-60 units/dL

1-2 days, may be longer if response is inadequate

Superficial muscle/no neurovascular compromise

40-60 units/dL

2-3 days, sometimes longer if response is inadequate

Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss

Initial: 60-80 units/dL

Maintenance: 30-60 units/dL

Initial: 1-2 days

Maintenance: 3-5 days, sometimes longer as secondary prophylaxis during physiotherapy

CNS/head

Initial: 60-80 units/dL

Maintenance: 30 units/dL

Initial: 1-7 days

Maintenance: 8-21 days

Throat and neck

Initial: 60-80 units/dL

Maintenance: 30 units/dL

Initial: 1-7 days

Maintenance: 8-14 days

Gastrointestinal

Initial: 60-80 units/dL

Maintenance: 30 units/dL

Initial: 7-14 days

Maintenance: Not specified

Renal

40 units/dL

3-5 days

Deep laceration

40 units/dL

5-7 days

Surgery (major)

Preop: 60-80 units/dL

Postop:

40-60 units/dL

30-50 units/dL

20-40 units/dL

Postop:

1-3 days

4-6 days

7-14 days

Surgery (minor)

Preop: 50-80 units/dL

Postop: 30-80 units/dL

Postop: 1-5 days depending on procedure type

Table has been converted to the following text.

2013 World Federation of Hemophilia Treatment Recommendations (When No Significant Resource Constraint Exists):

Desired Factor IX Level to Maintain and Duration Based on Site of Hemorrhage/Clinical Situation:

Joint: 40 to 60 units/dL for 1 to 2 days, may be longer if response is inadequate

Superficial muscle (no neurovascular compromise): 40 to 60 units/dL for 2 to 3 days, sometimes longer if response is inadequate

Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss: Initial: 60 to 80 units/dL for 1 to 2 days; Maintenance: 30 to 60 units/dL for 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy

CNS/head: Initial: 60 to 80 units/dL for 1 to 7 days; Maintenance: 30 units/dL for 8 to 21 days

Throat and neck: Initial: 60 to 80 units/dL for 1 to 7 days; Maintenance: 30 units/dL for 8 to 14 days

Gastrointestinal: Initial: 60 to 80 units/dL for 7 to 14 days; Maintenance: 30 units/dL (duration not specified)

Renal: 40 units/dL for 3 to 5 days

Deep laceration: 40 units/dL for 5 to 7 days

Surgery (major): Preop: 60 to 80 units/dL; Postop: 40 to 60 units/dL for 1 to 3 days; then 30 to 50 units/dL for 4 to 6 days; then 20 to 40 units/dL for 7 to 14 days

Surgery (minor): Preop: 50 to 80 units/dL; Postop: 30 to 80 units/dL for 1 to 5 days depending on procedure type

Note: Factor IX level may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor IX but should be determined based on an assessment of factor IX levels before the next dose.

Continuous infusion (For patients who require prolonged periods of treatment [eg, intracranial hemorrhage or surgery] to avoid peaks and troughs associated with intermittent infusions) (Batorova 2002; Poon 2012; Rickard, 1995; WFH [Srivastava 2013]): Note: Evidence supporting the use of continuous infusion is primarily with BeneFix (Chowdary 2001); however manufacturer’s labeling states that safety and efficacy of BeneFIX administration by continuous infusion has not been established: Following initial bolus to achieve the desired factor IX level, initiate 4 to 6 units/kg/hour; adjust dose based on frequent factor assays and calculation of factor IX clearance at steady-state using the following equations:

Factor IX clearance (mL/kg/hour) = (current infusion rate in units/kg/hour)/(plasma level in units/mL)

New infusion rate (units/kg/hour) = (factor IX clearance in mL/kg/hour) x (desired plasma level in units/mL)

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

Alprolix: 50 units/kg once weekly or 100 units/kg once every 10 days; adjust dose based on individual response

Rixubis: 40 to 60 units/kg twice weekly; may titrate dose depending upon age, bleeding pattern, and physical activity

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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. As compared to Benefix, Ixinity, and Rixubis, Alprolix displays a longer half-life. Therefore, Alprolix dosing and frequency may differ. 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:

Alprolix: 50 units/kg once weekly or 100 units/kg once every 10 days; adjust dose based on individual response

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.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; monitor factor IX levels.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; monitor factor IX levels. Use with caution due to the risk of thromboembolic complications.

Reconstitution

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

Administration

Solution should be infused at room temperature. Safety and efficacy of continuous infusion administration have not been determined.

IV administration only:

Alprolix, Rixubis: Bolus infusion; maximum rate of administration is 10 mL/minute

BeneFIX: Should be infused slowly over several minutes. Rate of administration should be determined by the response and comfort of the patient. Do not administer as a continuous infusion.

Ixinity: Rate of administration should be determined by the comfort of the patient; maximum rate of administration is 10 mL/minute

Per the WFH, infuse by slow IV injection at a rate not to exceed 3 mL/minute (adults) or 100 units/minute (young children); may also administer as a continuous infusion in select patients. Evidence supporting the use of continuous infusion is primarily with BeneFix (Chowdary 2001); however, the safety and efficacy of BeneFIX, Rixubis and Alprolix administration by continuous infusion has not been established. With patients who have had allergic reactions during factor IX infusion, administration of hydrocortisone prior to infusion may be necessary (WFH [Srivstava 2013]).

Storage

Alprolix: Store at 2°C to 8°C (36°F to 46°F); do not freeze. May be stored at room temperature (not to exceed 30°C [86°F]) for up to 6 months. After removal from refrigeration, do not return to refrigerator. Store in the original package to protect from light. Following reconstitution, may be stored at room temperature (not to exceed 30°C [86°F]) for no longer than 3 hours. Protect from direct sunlight. Do not refrigerate after reconstitution.

BeneFIX: Store at 2°C to 30°C (36°F to 86°F). Avoid freezing which may damage the diluent syringe. Reconstituted solution should be at room temperature and used within 3 hours of preparation. Do not refrigerate after reconstitution.

Ixinity: Store at 2°C to 25°C (36°F to 77°F). Do not freeze. Keep vial in the carton and protect from light. Infuse reconstituted solution immediately or within 3 hours when stored at room temperature. Do not refrigerate after reconstitution.

Rixubis: Store at 2°C to 8°C (36°F to 46°F) for up to 24 months; do not freeze. May store at room temperature not to exceed 30°C (86°F) for up to 12 months within the 24-month time period; do not return to refrigerator. Infuse reconstituted solution immediately or within 3 hours when stored at room temperature. Do not refrigerate after reconstitution

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Frequency not always defined.

Cardiovascular: Flushing (3%), chest tightness (2%), thromboembolic complications, thromboembolism

Central nervous system: Headache (2% to 11%), dizziness (≤8%), chills (2%), drowsiness (2%), apathy (1%), depression (1%), lethargy (1%)

Dermatologic: Skin rash (2% to 6%), urticaria (3% to 5%), pruritic rash (1%)

Gastrointestinal: Nausea (6%), dysgeusia (≤5%), oral paresthesia (2%), vomiting (2%)

Hematologic & oncologic: Hemophilia (lack of efficacy; 1% to 2%)

Hypersensitivity: Hypersensitivity reaction

Immunologic: Antibody development (≤30%; non-neutralizing)

Infection: Influenza (1%)

Local: Injection site reaction (2% to 8%), pain at injection site (≤6%), cellulitis at injection site (2%), injection site phlebitis (2%), discomfort at injection site (1%)

Neuromuscular & skeletal: Tremor (2%), limb pain (1%), weakness (1%)

Ophthalmic: Blurred vision (2%)

Renal: Renal infarction (2%)

Respiratory: Dyspnea (3%), cough (2%, dry), hypoxia (2%)

Miscellaneous: Fever (3%)

<1% (Limited to important or life-threatening): Anaphylaxis, hypotension, nephrotic syndrome (associated with immune tolerance induction), obstructive uropathy, palpitations, superior vena cava syndrome (neonates)

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: The development of factor IX antibodies (or inhibitors) has been reported with factor IX therapy (usually occurs within the first 10 to 20 exposure days); the risk of severe hypersensitivity reactions occurring may be greater in these patients. When clinical response is suboptimal, the patient has reached a specified number of exposure days, or patient is to undergo surgical procedure, screen for inhibitors. Patients with severe hemophilia compared to those with mild or moderate hemophilia are more likely to develop inhibitors (WFH [Srivastava 2013]).

• Hypersensitivity reactions: Hypersensitivity and anaphylactic reactions have been reported with use. Risk is highest during the early phases of initial exposure in previously untreated patients, especially those with high-risk gene mutations. Delayed reactions (up to 20 days after infusion) in previously untreated patients may also occur. Due to potential for allergic reactions, the initial ~10 to 20 administrations should be performed under appropriate medical supervision. Hypersensitivity reactions may be associated with factor IX inhibitor development; patients experiencing allergic reactions should be evaluated for factor IX inhibitors. If hypersensitivity reactions occur, discontinue immediately and consider the use of alternative hemostatic measures (WFH [Srivastava 2013]).

• Nephrotic syndrome: Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX.

• Thrombotic events: Observe closely for signs or symptoms of intravascular coagulation or thrombosis; risk is generally associated with the use of factor IX complex concentrates (containing therapeutic amounts of additional factors); however, potential risk exists with use of factor IX products (containing only factor IX) especially when administered as a continuous infusion through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome. Use with caution when administering to patients with liver disease, postoperatively, neonates, patients at risk of thromboembolic phenomena or disseminated intravascular coagulation, or patients with signs of fibrinolysis due to the potential risk of thromboembolic complications.

Disease-related concerns:

• Hepatic impairment: Use with extreme caution in patients with hepatic impairment due to the risk of thromboembolic complications.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Clinical response: Response to factor IX administration may vary. If bleeding is not controlled with the recommended dose, determine plasma level of factor IX and follow with a sufficient dose to achieve satisfactory clinical response. If plasma levels of factor IX fail to increase as expected or bleeding continues, suspect the presence of an inhibitor; test as appropriate.

Monitoring Parameters

Factor IX levels by the one-stage clotting assay (measure 15 minutes after infusion to verify calculated doses (WFH [Srivastava 2013]), aPTT, BP, HR, signs of hypersensitivity reactions, DIC, and thrombosis; screen for factor IX inhibitors if the patient experiences hypersensitivity reaction or when patient is to undergo surgery, if suboptimal response to treatment occurs, if patient is being intensively treated for >5 days within 4 weeks of the last infusion, or at the following intervals ( WFH [Srivastava 2013]):

Children: Screen for inhibitors every 5 exposure days until 20 exposure days, every 10 exposure days between 21 to 50 exposure days, and at a minimum of twice a year until 150 exposure days is reached.

Adults (with >150 exposure days apart from a 6 to 12 monthly review): Screen for inhibitors when suboptimal response occurs.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Factor IX concentrations do not change significantly in pregnant women with coagulation disorders and women with factor IX deficiency may be at increased risk of postpartum hemorrhage. Pregnant women should have clotting factors monitored, particularly at 28 and 34 weeks gestation and prior to invasive procedures. Prophylaxis may be needed if factor IX concentrations are <50 units/mL at term and treatment should continue for 3 to 5 days postpartum depending on route of delivery. Because parvovirus infection may cause hydrops fetalis or fetal death, a recombinant product is preferred if prophylaxis or treatment is needed. The neonate may also be at an increased risk of bleeding following delivery and should be tested for the coagulation disorder (Chi 2012; Kadir 2009; Lee 2006).

Patient Education

• 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.

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