Factor IX (Recombinant [Fc Fusion Protein])

Dosage Forms

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

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)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss: ~0.3 L/kg

Half-Life Elimination

Children: 66 to 72 hours

Children ≥12 years and Adolescents ≤17 years: ~84 hours

Adults: ~87 hours

Use: Labeled Indications

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

Hypersensitivity (eg, anaphylaxis) to factor IX (recombinant [Fc fusion protein]) or any component of the formulation (ie, sucrose, mannitol, sodium chloride, L-histidine, and polysorbate 20).

Dosage and Administration

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, pharmacokinetic profile, 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".

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:

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.

Routine prophylaxis to prevent bleeding episodes in patients with factor IX deficiency (hemophilia B or Christmas disease): IV: 50 units/kg once weekly or 100 units/kg once every 10 days; adjust dose based on individual response

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, pharmacokinetic profile, 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".

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:

Infants and Children <12 years of age: Initial: 60 units/kg once weekly; adjust dose based on individual response. More frequent or higher doses may be needed, especially in children <6 years of age.

Children ≥12 years of age and Adolescents: Refer to adult dosing.

Reconstitution

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

Administration

IV: Administer by IV bolus infusion; maximum rate of administration: 10 mL/minute.

Solution should be infused at room temperature. Safety and efficacy of continuous infusion administration have not been determined. Do not infuse via the same tubing as other medications.

Per the WFH, infuse by slow IV injection at a rate not to exceed 3 mL/minute. With patients who have had allergic reactions during factor IX infusion, administration of hydrocortisone prior to infusion may be necessary (WFH [Srivstava 2013]).

Storage

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.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

1% to 10%:

Central nervous system: Headache (1%)

Gastrointestinal: Oral paresthesia (1%)

Genitourinary: Obstructive uropathy (1%)

<1%, postmarketing, and/or case reports: Anaphylaxis, decreased appetite, dizziness, dysgeusia, factor IX inhibitor development in hemophilia B, fatigue, halitosis, hematuria, hypersensitivity reaction, hypotension, infusion-site pain, palpitations, renal colic

Warnings/Precautions

Concerns related to adverse effects:

• 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 has been associated with the presence of factor IX inhibitors; 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]). Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge.
• 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.
• Neutralizing 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]).
• 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 a validated one-stage clotting assay (measure 15 minutes after infusion) to verify calculated doses (WFH [Srivastava 2013]), activated partial thromboplastin time (aPTT), blood pressure, heart rate, signs/symptoms of hypersensitivity reactions, disseminated intravascular coagulation (DIC), and thrombosis; monitor all patients regularly for the development of inhibitors; screen for factor IX inhibitors if the patient experiences hypersensitivity reaction or when patient is to undergo surgery, if suboptimal response for treatment of bleeding 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.

Note: Factor IX one-stage clotting assays using a kaolin-based aPTT reagent may underestimate factor IX levels

Pregnancy

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.

Frequently reported side effects of this drug

• Headache
• Numbness or tingling in the mouth

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Swelling
• Burning or numbness feeling
• Nausea
• Vomiting
• Shortness of breath
• Dizziness
• Passing out
• Restlessness
• 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
• Signs of a significant reaction like 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. 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.