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Factor IX Complex (Human)

Pronunciation

(FAK ter nyne KOM pleks HYU man FAKter too nyne ten)

Index Terms

  • 3 Factor PCC
  • 3-Factor PCC
  • PCC (Caution: Confusion-prone synonym)
  • Prothrombin Complex Concentrate (Caution: Confusion-prone synonym)
  • Three-Factor PCC

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intravenous:

Bebulin: 200-1200 units (1 ea)

Bebulin VH: 200-1200 units (1 ea [DSC])

Profilnine: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea) [contains polysorbate 80]

Profilnine SD: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • Bebulin
  • Bebulin VH [DSC]
  • Profilnine
  • Profilnine SD

Pharmacologic Category

  • Antihemophilic Agent
  • Blood Product Derivative
  • Prothrombin Complex Concentrate (PCC)

Pharmacology

Replaces deficient clotting factor including factor X; hemophilia B, or Christmas disease, is an X-linked recessively 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.

Half-Life Elimination

IX component: ~19 to 25 hours

Use: Labeled Indications

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

Limitations of use: Not indicated for the treatment of other factor deficiencies (eg, factor II, VII, VIII, X), treatment of hemophilia A patients with inhibitors to factor VIII, or treatment of bleeding caused by low levels of liver-dependent coagulation factors.

Use: Unlabeled

Emergent correction of warfarin-induced coagulopathy (with clinically significant bleeding); Note: Products contain low or nontherapeutic levels of factor VII component; use of fresh frozen plasma (FFP) should be considered

Contraindications

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

Bebulin: Hypersensitivity reactions to factor IX complex or any component of the formulation; known allergy to heparin; history of heparin-induced thrombocytopenia.

Dosing: Adult

Note: Factor IX complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) contains low or nontherapeutic levels of factor VII component and should not be confused with Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Kcentra, Octaplex) which contains therapeutic levels of factor VII.

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B [Christmas disease]): Dosage is expressed in units of factor IX activity and must be individualized based on severity of factor IX deficiency, extent and location of bleeding, and clinical status of patient. Close laboratory monitoring of the factor IX level is required to determine proper dosage, particularly with severe hemorrhage and major surgery. Larger doses than those derived from the formula below may be required, especially if treatment is delayed. When multiple doses are required, administer at 24-hour intervals unless otherwise specified.

Formula for units required to raise blood level %:

Bebulin: In general, factor IX 1 unit/kg will increase the plasma factor IX level by 0.8%

Number of Factor IX units required = body weight (kg) x desired factor IX increase (as % of normal) x 1.2 units/kg

Profilnine: In general, factor IX 1 unit/kg will increase the plasma factor IX level by 1%:

Number of factor IX units required = bodyweight (kg) x desired factor IX increase (as % of normal) x 1 unit/kg

For example, to increase factor IX level to 25% of normal in a 70 kg patient: Number of factor IX units needed = 70 kg x 25 x 1 unit/kg = 1,750 units

As a general rule, the level of factor IX required for treatment of different conditions is listed below:

Hemorrhage: IV:

Minor bleeding (early hemarthrosis, minor epistaxis, gingival bleeding, mild hematuria):

Bebulin: Raise factor IX level to 20% of normal (typical initial dose: 25 to 35 units/kg); average duration of treatment is 1 day. A single dose is usually sufficient or a second dose may be given after 24 hours.

Profilnine: Raise factor IX level to 20% to 30% of normal (initial dose: 20 to 30 units/kg) every 16 to 24 hours for 1 to 2 days for minor hemorrhage or until hemorrhage stops and healing has been achieved.

Moderate bleeding (severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, hematemesis, melena, major hematuria):

Bebulin: Raise factor IX level to 40% of normal (typical initial dose: 50 to 65 units/kg); average duration of treatment is 2 days or until adequate wound healing.

Profilnine: Raise factor IX level to 20% to 30% of normal (initial dose: 20 to 30 units/kg) every 16 to 24 hours for 2 to 7 days for moderate hemorrhage or until hemorrhage stops and healing has been achieved.

Major bleeding (severe hematoma, major trauma, severe hemoptysis, hematemesis, melena):

Bebulin: Raise factor IX level to ≥60% of normal (typical initial dose: 75 to 90 units/kg); average duration of treatment is 2 to 3 days or until adequate wound healing.

Profilnine: Raise factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg) every 16 to 24 hours; following this treatment period, maintain factor IX levels at 20% of normal (maintenance dose: 20 units/kg) for 3 to 10 days or until healing has been achieved.

Surgical procedures: IV:

Dental surgery:

Bebulin: Raise factor IX level to 40% to 60% of normal on day of surgery (typical dose: 50 to 75 units/kg). One infusion, administered 1 hour prior to surgery, is generally sufficient for the extraction of one tooth; for the extraction of multiple teeth, replacement therapy may be required for up to 1 week (See dosing guidelines for Minor Surgery).

Profilnine: Raise factor IX level to 50% of normal immediately prior to procedure; maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg) every 16 to 24 hours for 7 to 10 days following surgery or until healing has been achieved.

Minor surgery:

Bebulin: Raise factor IX level to 40% to 60% of normal on day of surgery (typical initial dose: 50 to 75 units/kg). Decrease factor IX level from 40% to 60% of normal to 20% to 40% of normal during initial postoperative period (1 to 2 weeks or until adequate wound healing) [typical dose: 26 to 65 units/kg]. The preoperative dose should be given 1 hour prior to surgery. The average dosing interval may be every 12 hours initially, then every 24 hours later in the postoperative period.

Profilnine: Raise factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg) prior to surgery (Note: Surgery type not specified by the manufacturer); maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg) every 16 to 24 hours for 7 to 10 days following surgery or until healing is achieved.

Major surgery:

Bebulin: Raise factor IX level to ≥60% of normal on day of surgery (typical initial dose: 75 to 90 units/kg). Decrease factor IX level from ≥60% of normal to 20% to 60% of normal during initial postoperative period (1 to 2 weeks) [typical dose: 25 to 75 units/kg]; further decrease to maintain a factor IX level of 20% of normal during late postoperative period (≥3 weeks) and continuing until adequate wound healing is achieved [typical dose: 25 to 35 units/kg]. The preoperative dose should be given 1 hour prior to surgery. The average dosing interval may be every 12 hours initially, then every 24 hours later in the postoperative period.

Profilnine: Raise Factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg) prior to surgery (Note: Surgery type not specified by the manufacturer); maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg) every 16 to 24 hours for 7 to 10 days following surgery or until healing is achieved.

Life-threatening hemorrhage associated with warfarin (off-label use): IV: Note: Products contain low or nontherapeutic levels of factor VII component; therefore, additional fresh frozen plasma (FFP) or factor VIIa may be considered (Masotti 2011). When immediate INR reversal is required, concomitant use of 1 to 2 units of FFP should be considered to ensure acute INR reversal (Baker 2004; Holland 2009). Coadminister vitamin K (phytonadione) 5 to 10 mg by slow IV infusion (ACCP [Guyatt 2012]); vitamin K may be repeated every 12 hours if INR is persistently elevated. Factor IX complex (human) dosing has not been established in this setting; the following regimens have been used with some success.

The following 2 methods have been suggested, but are not product specific:

Adjusted-dose regimen, weight based (Liumbruno 2009):

INR <2: 20 units/kg

INR 2 to 4: 30 units/kg

INR >4: 50 units/kg

Note: If after administration, INR remains >1.5 consider repeating dose appropriate for INR.

May also determine dose based on presenting INR and estimated functional prothrombin complex (PC) expressed as percentage of normal plasma levels (see table; Masotti 2011):

Units needed to be infused = (target % of functional PC to be reached – current estimated % of functional PC) x kg of body weight

Example:

Patient (weight: 70 kg) presents with INR of 4.5 which corresponds to an estimated % functional PC of 10% (see table). Target INR of 1.4 corresponds to an estimated target % functional PC of 40%.

Units needed to be infused = (40 - 10) x 70 kg = 2,100 units

Conversion of the INR to Estimated Functional Prothrombin Complex (PC)

INR Value

Estimated

Functional PC

≥5

5%

4 to 4.9

10%

2.6 to 3.2

15%

2.2 to 2.5

20%

1.9 to 2.1

25%

1.7 to 1.8

30%

1.4 to 1.6

40%

1 to 1.3

100%

Table has been converted to the following text.

Conversion of the INR to Estimated Functional Prothrombin Complex (PC)

If INR ≥5, then estimated functional PC is 5%

If INR 4 to 4.9, then estimated functional PC is 10%

If INR 2.6 to 3.2, then estimated functional PC is 15%

If INR 2.2 to 2.5, then estimated functional PC is 20%

If INR 1.9 to 2.1, then estimated functional PC is 25%

If INR 1.7 to 1.8, then estimated functional PC is 30%

If INR 1.4 to 1.6, then estimated functional PC is 40%

If INR 1 to 1.3, then estimated functional PC is 100%

Intracranial hemorrhage associated with warfarin (off-label use): IV: Note: Products contain low or nontherapeutic levels of factor VII component. Four-factor PCC (prothrombin complex concentrate [human]) is preferred. Administer concomitantly with one dose of vitamin K 10 mg IV (repeated if INR still ≥1.4 within the first 24 to 48 hours) (NCS/SCCM [Frontera 2016]).

Fixed-dose regimen, weight based: INR ≥1.4: 50 units/kg; repeat INR within 15 to 60 minutes and serially every 6 to 8 hours for the next 24 to 48 hours. If INR remains ≥1.4 within the first 24 to 48 hours after initial dose, use FFP (alone) for further correction (Frontera 2014, NCS/SCCM [Frontera 2016]). For initial reversal, the Neurocritical Care Society and Society of Critical Care Medicine suggests administering factor IX complex (PCC) alone rather than combined with FFP or recombinant factor VIIa (NCS/SCCM [Frontera 2016]).

Life-threatening hemorrhage associated with non-vitamin K antagonist anticoagulation (off-label use): IV: Initial: 50 units/kg; although there are no data, the European Heart Rhythm Association (EHRA) suggests that an additional dose of 25 units/kg may be administered if clinically indicated (EHRA [Heidbuchel 2015]). Note: If hemorrhage associated with dabigatran, consider the use of idarucizumab instead of factor IX complex.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B [Christmas disease]) (off-label use): IV: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

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

Prior to reconstitution, bring diluent (sterile water for injection) and factor IX concentrate to room temperature (but not above 37°C [98.6°F]); gently rotate or agitate to dissolve, do not shake. Following reconstitution, do not refrigerate and use as soon as possible within 3 hours. Do not mix with other drugs or solvents. Vials are intended for single use (does not contain preservative); discard unused portion of the vial.

Bebulin: The reconstituted product should be a colorless to slightly yellowish and clear to slightly turbid solution.

Profilnine: A few particles may remain in solution following reconstitution; the Mix2Vial set will remove the particles and the labeled potency will not be reduced.

Administration

Solution should be infused at room temperature. Rate should not exceed 2 mL/minute for Bebulin or 10 mL/minute for Profilnine. Vasomotor reactions may result from rapid administration; do not exceed the recommended infusion rates. Slowing the rate of infusion, changing the lot of medication, or administering antihistamines may relieve some adverse reactions.

Storage

Bebulin: Store undiluted vials at 2°C to 8°C (35°F to 46°F); do not freeze.

Profilnine: Storage temperature should not exceed 25°C (77°F); do not freeze.

Drug Interactions

Aminocaproic Acid: May enhance the adverse/toxic effect of Factor IX Complex (Human) [(Factors II, IX, X)]. Specifically, use of this combination may increase the risk of thrombosis. Avoid combination

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing, thrombosis (sometimes fatal)

Central nervous system: Chills, drowsiness, headache, lethargy, paresthesia

Dermatologic: Skin rash, urticaria

Gastrointestinal: Nausea, vomiting

Hematologic & oncologic: Disseminated intravascular coagulation, heparin-induced thrombocytopenia (with products containing heparin)

Hypersensitivity: Anaphylactic shock

Immunologic: Antibody development (to clotting factor)

Respiratory: Dyspnea

Miscellaneous: Fever

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/anaphylactoid 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. If severe hypersensitivity reactions occur, consider the use of alternative hemostatic measures (WFH [Srivastava 2013]).

• Thrombotic events: Thrombotic events (eg, deep vein thrombosis, pulmonary embolism, thrombotic strokes) as well as disseminated intravascular coagulation (DIC) have occurred. Monitor closely for signs or symptoms of intravascular coagulation or thrombosis; risk is higher in patients with congenital or acquired coagulation disorders, and with repeated dosing or high doses. Use with caution when administering to patients with liver disease, history of coronary artery disease, pre- or 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. Discontinue infusion immediately if signs or symptoms of thrombosis or embolism occur.

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:

• Heparin: Some products may contain heparin. Use with caution in patients with a history of heparin-induced thrombocytopenia (use of Bebulin is contraindicated).

• Human plasma: Product of human plasma; may potentially contain infectious agents 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.

• Latex: Some product packaging may contain natural rubber latex.

Other warnings/precautions:

• Appropriate use: Factor IX Complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) contains low or nontherapeutic levels of factor VII component and should not be confused with Prothrombin complex concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Kcentra, Octaplex) which contains therapeutic levels of factor VII. Factor IX Complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) should not be used for the treatment of factor VII deficiency. When treating warfarin-associated hemorrhage (off-label use), administration of additional fresh frozen plasma (FFP) or factor VIIa should be considered.

• 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 hemophilia B with factor IX inhibitors receiving factor IX products.

Monitoring Parameters

Levels of factor IX; PT, PTT; INR (when used for warfarin reversal); signs and symptoms of hypersensitivity reactions, DIC, thrombosis, especially in patients with liver disease, surgical patients, and patients with known risk factors predisposing to thrombosis

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 flushing, headache, tingling, vomiting, or nausea. Have patient report immediately to prescriber signs of infection, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), shortness of breath, dizziness, arrhythmia, passing out, tachycardia, angina, vomiting blood, cough, or bleeding (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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