Factor IX (Human)

Dosage Forms

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

Solution Reconstituted, Intravenous [preservative free]:

AlphaNine SD: 500 units (1 ea) [contains heparin, polysorbate 80]

AlphaNine SD: 500 units (1 ea) [contains polysorbate 80]

AlphaNine SD: 1000 units (1 ea) [contains heparin, polysorbate 80]

AlphaNine SD: 1000 units (1 ea) [contains polysorbate 80]

AlphaNine SD: 1500 units (1 ea) [contains heparin, polysorbate 80]

Mononine: 1000 units (1 ea) [contains polysorbate 80]

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

Half-Life Elimination

IX component: ~21 to 25 hours

Use: Labeled Indications

Factor IX deficiency: Prevention and control of bleeding in patients with hemophilia B (congenital factor IX deficiency or Christmas disease)

Limitations of use: Contains nondetectable levels of factors II, VII, and X. Therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX or for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), for hemophilia A patients with factor VIII inhibitors, or for patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).

Contraindications

AlphaNine SD: There are no contraindications listed in the manufacturer's labeling.

Mononine: Hypersensitivity to mouse protein

Immunine VH [Canadian product]: Hypersensitivity to factor IX or any component of the formulation; known allergy to heparin; history of heparin-induced thrombocytopenia; disseminated intravascular coagulation (DIC) and/or hyperfibrinolysis

Dosage and Administration

Dosing: Adult

NOTE: Contains nondetectable levels of factors II, VII, and X. Therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX or for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), for hemophilia A patients with factor VIII inhibitors, or for patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B or Christmas disease): IV: AlphaNine SD, Mononine: 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, and clinical status of patient. 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 to determine units required to obtain desired factor IX 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 1 unit/kg

For example, to attain an 80% level in a 70 kg patient who has a baseline level of 20%: Number of factor IX units needed = 70 kg x 60% x 1 unit/kg = 4200 units

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:

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) (Holme 2018; Poon 2012; Rickard 1995; WFH [Srivastava 2013]): 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) divided by (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)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

NOTE: Contains nondetectable levels of factors II, VII, and X; therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX or for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), for hemophilia A patients with factor VIII inhibitors, or for patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B or Christmas disease): Infants, Children, and Adolescents: IV: 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, and clinical situation of patient.

Formula for units required to raise blood level:

Number of Factor IX Units Required = body weight (in kg) x desired Factor IX level increase (% or units/dL) x 1 unit/kg

For example, for a 100% level in a 25 kg patient who has an actual level of 20%: Number of Factor IX Units needed = 25 kg x 80% x 1 unit/kg = 2000 units

Manufacturer's labeling: AlphaNine SD, Mononine: Infants, Children, and Adolescents: Intermittent IV:

Desired Factor IX Level, Dosing Interval and Duration based on Hemorrhage Type:

Minor hemorrhage (eg, bruising, cuts/scrapes, uncomplicated joint hemorrhage):

Desired factor IX levels (% or units/dL): 15 to 30

Frequency of dosing: Every 12 to 24 hours

Duration of treatment: 1 to 2 days

Moderate hemorrhage (eg, epistaxis, oropharyngeal bleeds, dental extractions, hematuria):

Desired factor IX levels (% or units/dL): 25 to 50

Frequency of dosing: Every 12 to 24 hours

Duration of treatment: 2 to 7 days

Major hemorrhage [eg, joint and muscle (especially large muscles) hemorrhage, intracranial or intraperitoneal hemorrhage], major trauma, or surgical prophylaxis:

Desired factor IX levels (% or units/dL): 50 to 100 (depending on the clinical situation, desired Factor IX level may be reduced following active treatment period for hemorrhage or >48 hours postop)

Frequency of dosing: Every 12 to 24 hours (AlphaNine SD) or 18 to 30 hours (Mononine), interval dependent upon product used, half-life, and measured factor IX levels (after 3 to 5 days, maintain at least 20% activity)

Duration of treatment: 7 to 10 days, depending upon nature of insult

Alternate dosing: Note: The following recommendations reflect general dosing requirements; may vary from those found within prescribing information or practitioner preference:

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

Hemorrhage, treatment (when no significant resource constraints exist) [WFH guidelines (Srivastava 2013)]: 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. Infants, Children, and Adolescents:

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

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

Superficial muscle (no neurovascular compromise): 40 to 60 units/dL for 2-3 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

Continuous IV infusion: Very limited data available; only data with Mononine product available: Note: Used for patients who require prolonged periods of treatment (eg, intracranial hemorrhage or surgery) to avoid peaks and troughs associated with intermittent infusions [Batorova 2002; Hoots 2003; Morfini 2008; Poon 2012; WFH guidelines (Srivastava 2013)]:

Following initial bolus to achieve the desired factor IX level: Initial dosing: 4 to 6 units/kg/hour; adjust dose based on frequent factor IX 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 IX level in units/mL)

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

The median reported dose in post-operative patients (7-85 years) was 3.84 units/kg/hour (range: 1.74 to 7.3 units/kg/hour) (Hoots 2003)

Reconstitution

Refer to instructions for individual products. Exact potency labeled on each vial. Diluent and factor IX should come to room temperature before combining.

Administration

IV: IV administration only: Should be infused slowly over several minutes: Rate of administration should be determined by the response and comfort of the patient. Solution should be infused at room temperature.

AlphaNine SD: Administer IV at a rate not exceeding 10 mL/minute

Mononine: Administer IV at a rate of ~2 mL/minute (when reconstituted as directed to ~100 units/mL). Administration rates of up to 225 units/minute have been regularly tolerated without incident.

World Federation of Hemophilia recommendations: Infuse by slow IV injection at a rate not to exceed 3 mL/minute; may also administer as a continuous infusion in select patients. With patients who have anti-factor IX inhibitors who have had allergic reactions during factor IX infusion, administration of hydrocortisone prior to infusion may be necessary (WFH [Srivastava 2013]).

Storage

When stored at refrigerator temperature, 2°C to 8°C (36°F to 46°F), factor IX is stable for the period indicated by the expiration date on its label. Avoid freezing which may damage container for the diluent.

AlphaNine SD: May also be stored at room temperature not to exceed 30°C (86°F) for up to 1 month. Reconstituted solution should be used within 3 hours of preparation.

Mononine: May also be stored at room temperature not to exceed 25°C (77°F) for up to 1 month. Reconstituted solution should be at room temperature and used within 3 hours of preparation.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing, thrombosis

Central nervous system: Burning sensation (in jaw/skull), chills, headache, lethargy, paresthesia, rigors

Dermatologic: Skin photosensitivity, urticaria

Gastrointestinal: Diarrhea, nausea, vomiting

Hematologic & oncologic: Disseminated intravascular coagulation

Hepatic: Increased serum alkaline phosphatase, increased serum ALT, increased serum AST

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Local: Discomfort at injection site (stinging, burning), injection site reaction, pain at injection site

Neuromuscular & skeletal: Neck tightness

Ophthalmic: Visual disturbance

Respiratory: Allergic rhinitis, asthma, laryngeal edema, pulmonary disease

Miscellaneous: Fever (including transient fever following rapid administration)

Postmarketing and/or case reports: Angioedema, cerebral hemorrhage (intrathalamic [Douvas, 2004]), cyanosis, decreased therapeutic response, dyspnea, factor IX inhibitor development, hypotension, myocardial infarction (high doses), pulmonary embolism (high doses), superior vena cava syndrome (neonates [Douvas, 2004])

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. 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 (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). Use with caution when administering to patients with liver disease, postoperatively, neonates, or patients at risk of thromboembolic phenomena, 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.

Dosage form specific issues:

• Human plasma: Product of human plasma. Despite purification methods (AlphaNine SD - solvent detergent treated/virus filtered; Mononine - virus filtered); products may potentially contain infectious agents (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD] agent and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.
• 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:

• Appropriate use: Contains nondetectable levels of factors II, VII, and X. Therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX. In addition, factor IX concentrate is NOT INDICATED for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), hemophilia A patients with factor VIII inhibitors, or patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).
• 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.
• Immune tolerance induction: Safety and efficacy have not been established in immune tolerance induction with factor IX products. Nephrotic syndrome has occurred following immune tolerance induction in patients with factor IX inhibitors and a history of allergic reactions to therapy.

Monitoring Parameters

Factor IX levels (measure 15 minutes after infusion to verify calculated doses) (WFH [Srivastava] 2013), aPTT, BP, HR, signs of hypersensitivity reactions; 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

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
• Nausea
• Vomiting
• Flushing
• Loss of strength and energy
• Tingling
• Injection site burning, stinging, or redness
• Chills

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

• Parvovirus B19 or hepatitis A infection like chills, severe fatigue, runny nose, rash, joint pain, lack of appetite, nausea, vomiting, abdominal pain, or yellow skin
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• 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
• Severe dizziness
• Passing out
• Fast heartbeat
• 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.