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Factor IX (Recombinant)

Pronunciation

(FAK ter nyne ree KOM be nant)

Index Terms

  • Factor IX Concentrate
  • Nonacog Alfa
  • Nonacog Gamma
  • 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]:

Ixinity: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea); 2000 units (1 ea); 3000 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.

  • 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

BeneFIX: Children <2 years of age: 252 ± 35 mL/kg; Children 2 to <6 years of age: 257 ± 25 mL/kg; Children 6 to <12 years of age: 303 mL/kg; Children ≥12 years of age, Adolescents, and Adults: 229 ± 57 mL/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

BeneFIX:

Children <2 years of age: Mean: 15.6 ± 1.2 hours.

Children 2 to <6 years of age: Mean: 16.7 ± 1.9 hours.

Children 6 to <12 years of age: Mean: 16.3 hours.

Children ≥12 years of age, Adolescents, and Adults: 23.1 ± 4.4 hours.

Ixinity: Children ≥12 years of age, Adolescents, and Adults: Mean: 24 ± 7 hours; range: 13 to 43 hours.

Rixubis:

Children <6 years of age: Mean: 27.7 ± 2.7 hours; range: 24 to 32.2 hours.

Children 6 to <12 years of age: 25.3 ± 1.8 hours; range: 23.7 to 30.3 hours.

Children ≥12 years of age, Adolescents, and Adults:

Single dose: Mean: 26.7 ± 9.6 hours; range: 15.8 to 52.3 hours.

Repeat dosing: Mean: 25.4 ± 6.9 hours; range: 16.2 to 42.2 hours.

Use: Labeled Indications

Factor IX deficiency: On-demand treatment and control of bleeding episodes in patients with factor IX deficiency (hemophilia B [Christmas disease]); perioperative management in patients with hemophilia B; routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia B.

Limitations of use: Not indicated for induction of immune tolerance in patients with hemophilia B.

Contraindications

Life-threatening, immediate hypersensitivity reactions (including anaphylaxis) to coagulation factor IX, hamster protein, 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, 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 0.8 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]); 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

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:

BeneFIX: 100 units/kg once weekly; may titrate dose or frequency based on patient’s clinical response.

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

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hemophilia B (Christmas disease): Individualize dosage based on clinical response and factor IX activity evaluated at baseline and at regular intervals during treatment.

General dosing for control or prevention of bleeding episodes or perioperative management: IV: Note: Dosage is expressed in units of factor IX activity and must be individualized based on formulation, severity of factor IX deficiency, extent and location of bleed, individualized incremental recovery using factor IX activity assays, and clinical situation of patient.

Infants, Children, and Adolescents (ages vary by product; see product-specific labeling for approved ages): IV:

Formula for units required to raise blood level:

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)

Reciprocal of average observed recovery (as units/kg per units/dL):

BeneFIX:

Infants, Children, and Adolescents <15 years: 1.4

Adolescents ≥15 years: 1.3

Ixinity: Children ≥12 years and Adolescents: 1.02

Rixubis:

Infants and Children <12 years: 1.4

Children ≥12 years and Adolescents: 1.1

For example for BeneFIX, for a 100% level in a 25 kg patient <15 years who has an actual level of 20%: Number of factor IX Units needed = 25 kg x 80% x 1.4 units/kg per units/dL = 2,800 units

Treatment recommendations (WFH [Srivastava 2013]): Note: Ages vary by product; see product-specific labeling for approved ages. Factor IX level may either be expressed as % or as units/dL.

Intermittent IV: The following recommendations reflect guideline recommendations for general dosing requirements; may vary from those found within prescribing information or practitioner preference. Frequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. If factor IX levels are available, subsequent doses should be based on the half-life of factor IX and on the recovery in an individual patient for a particular product.

Site of Hemorrhage/Clinical Situation

Desired Factor IX Peak Level

FrequencyA

Duration

AFrequency is based on type of bleed or surgery and varies by product; see specific product labeling for details.

Joint

40% to 60%

Every 12 to 24 hours

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

Superficial muscle/no neurovascular compromise

40% to 60%

Every 12 to 24 hours

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%

Every 12 to 24 hours

Initial: 1 to 2 days

Maintenance: 30% to 60%

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

CNS/Head

Initial: 60% to 80%

Every 12 to 24 hours

Initial: 1 to 7 days

Maintenance: 30%

Maintenance: 8 to 21 days

Throat and neck

Initial: 60% to 80%

Every 12 to 24 hours

Initial: 1 to 7 days

Maintenance: 30%

Maintenance: 8 to 14 days

Gastrointestinal

Initial: 60% to 80%

Every 12 to 24 hours

Initial: 7 to 14 days

Maintenance: 30%

Maintenance: Not specified

Renal

40%

Every 12 to 24 hours

3 to 5 days

Deep laceration

40%

Every 12 to 24 hours

5 to 7 days

Surgery (major)

Preop: 60% to 80%

Single dose

Postop: 40% to 60%

Every 8 to 24 hours

Postop: 1 to 3 days

Postop: 30% to 50%

Postop: 4 to 6 days

Postop: 20% to 40%

Postop: 7 to 14 days

Surgery (minor)

Preop: 50% to 80%

Single dose

Postop: 30% to 80%

Every 12 to 24 hours

Postop: 1 to 5 days depending on procedure type

Continuous IV infusion: Limited data available: Infants, Children, and Adolescents: Note: In general, administration of factor IX 7.5 units/kg/hour will increase circulating factor IX levels by 1 unit/mL (Prelog 2016).

Control and prevention of bleeding episodes and perioperative management: Note: 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; Prelog 2016; WFH [Srivastava 2013]). 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 (Poon 2012): Initial dosing: 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 Factor 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: Note: Adjust dose based on clinical response.

Product-specific dosing:

Rixubis:

Infants and Children <12 years: IV: 60 to 80 international units/kg/dose 2 times weekly.

Children ≥12 years and Adolescents: IV: 40 to 60 international units/kg/dose 2 times weekly.

Guideline dosing: IV: 15 to 30 units/kg/dose 2 times weekly (WFH [Srivastava 2013] [Utrecht protocol]) or 25 to 40 units/kg/dose 2 times weekly (WFH [Srivastava 2013] [Malmö protocol]); optimum regimen has yet to be defined.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Reconstitution

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

Administration

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

IV administration only:

Rixubis: For bolus infusion only; 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; 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 and Rixubis 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 [Srivastava 2013]).

Storage

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 250 unit strength at 2°C to 8°C (36°F to 47°F); store 500 unit, 1,000 unit, 1,500 unit, 2,000 unit, and 3,000 unit strength 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); do not freeze. May store at room temperature not to exceed 30°C (86°F) for up to 36 months; do not return to refrigerator. Infuse at room temperature and within 3 hours of reconstitution; 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%, postmarketing, and/or case reports: Anaphylaxis, angioedema, fatigue, halitosis, hypotension, nephrotic syndrome (associated with immune tolerance induction), obstructive uropathy, palpitations, peripheral thrombophlebitis, superior vena cava syndrome (neonates), therapeutic response unexpected (inadequate)

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 reactions (including anaphylaxis) may occur; 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 have frequently occurred in close temporal association with the development of factor IX inhibitors; patients experiencing allergic reactions should be evaluated for factor IX inhibitors. If hypersensitivity reactions occur, discontinue immediately; in the case of severe allergic reactions, consider the use of alternative hemostatic measures (WFH [Srivastava 2013]).

• Nephrotic syndrome: Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors and a history of allergic reactions. Safety and efficacy in this situation have not been established.

• Thrombotic events: Thromboembolism (eg, pulmonary embolism, venous/arterial thrombosis) may occur. Monitor for early signs of thromboembolism and coagulopathy in patients with hepatic disease, fibrinolysis, peri- and postoperative patients, or patients at risk for thromboembolic events or disseminated intravascular coagulation (DIC). The benefit of treatment should be weighed against the risk of complications in patients with DIC or those at risk for DIC or thromboembolic events. Reports of thrombotic events have also been reported in patients receiving continuous infusion through a central venous catheter, including life-threatening superior vena cava syndrome in critically ill neonates.

Disease-related concerns:

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

Dosage form specific issues:

• Hamster protein: May contain trace amounts of Chinese hamster proteins; hypersensitivity to these proteins may develop.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

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 Considerations

Pregnant hemophilia B carriers may have an increased bleeding risk following abortion, invasive procedures, miscarriage, and delivery; close surveillance is recommended. Factor IX levels should be monitored at the first antenatal visit, once or twice during the third trimester, prior to surgical or invasive procedures, and at delivery. Although factor IX levels remain stable during pregnancy, factor IX replacement is recommended if concentrations are <0.5 IU/mL and any of the following occur: need for invasive procedures (including delivery), spontaneous miscarriage, insertion and removal of epidural catheters, or active bleeding. Hemostatic factor IX concentrations should be maintained for at least 3 to 5 days following invasive procedures or postpartum. If replacement with a factor IX concentrate is indicated to increase factor IX during pregnancy, a recombinant product is preferred (NHF 2017; RCOG [Pavord 2017]; WFH [Srivastava 2013]).

Patient Education

What is this drug used for?

• It is used to treat hemophilia.

• It is used to treat or prevent bleeding.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Nausea

• Injection site pain or irritation

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Burning or numbness feeling

• Restlessness

• Flushing

• Dizziness

• Passing out

• Fast heartbeat

• Confusion

• Severe loss of strength and energy

• Cough

• Mouth discoloration

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.