Factor IX Complex (Human) [(Factors II, IX, X)]
(FAK ter nyne KOM pleks HYU man FAK ter too nyne ten)
- 3 Factor PCC
- 3-Factor PCC
- PCC (Caution: Confusion-prone synonym)
- Prothrombin Complex Concentrate (Caution: Confusion-prone synonym)
- Three-Factor PCC
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Bebulin: 200-1200 units (1 ea)
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]
Solution Reconstituted, Intravenous [preservative free]:
Profilnine: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea)
Brand Names: U.S.
- Profilnine SD
- Antihemophilic Agent
- Blood Product Derivative
- Prothrombin Complex Concentrate (PCC)
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.
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.
Off Label Uses
Factor IX deficiency (hemophilia B [Christmas disease]) (children and adolescents)
Based on the World Federation of Hemophilia, the use of factor IX concentrates is effective and recommended for the control and prevention of bleeding in children and adolescents with hemophilia B. However, the use of factor IX concentrates that also contain factors II, VII, IX, and X, also known as PCCs, are only rarely used and pure factor IX concentrations are preferred.
Intracranial hemorrhage associated with warfarin
Data from a prospective, observational study in patients presenting with warfarin-associated intracranial hemorrhage demonstrated that the use of factor IX complex (ie, 3-factor PCC) (in combination with vitamin K with or without FFP) adequately corrected INR without increased adverse events and suggested improvement in 3-month clinical outcomes as compared to FFP [Frontera 2014]. In one retrospective single-center study in patients presenting with warfarin-associated intracranial hemorrhage, the use of factor IX complex (with or without FFP) was associated with serious complications and was incompletely effective in reversing warfarin anticoagulation [Switzer 2012]. In another retrospective study with a lower number of patients, the use of factor IX complex suggested benefit when the time to INR normalization was shortened [Chong 2010]. Of note, morbidity and mortality were found to remain high in this population regardless of rate of INR reversal with PCC [Dowlatshahi 2012]. Additional data are necessary to further define the role of factor IX complex (human) in the management of this condition.
Based on the American Heart Association/American Stroke Association (AHA/ASA) Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, the use of factor IX complex (human) (ie, 3-factor PCC) may be considered for the treatment of intracranial hemorrhage associated with warfarin if it is readily available in the hospital. More recently, the Neurocritical Care Society and Society of Critical Care Medicine guidelines for the reversal of antithrombotics in intracranial hemorrhage suggests the use of 3-factor or 4-factor PCC (4-factor PCC preferred) for intracranial hemorrhage associated with warfarin when INR ≥1.4 (fresh frozen plasma may be used if PCC not available).
Life-threatening hemorrhage associated with warfarin
Clinical experience suggests the utility of factor IX complex (in combination with vitamin K) for the emergent correction of warfarin-induced coagulopathy (with clinically significant bleeding) [Liumbruno 2009]. Note: Products contain low or nontherapeutic levels of factor VII component; use of fresh frozen plasma (FFP) should be considered [Baker 2004], [Holland 2009].
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.
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:
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:
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.
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.
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
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
4 to 4.9
2.6 to 3.2
2.2 to 2.5
1.9 to 2.1
1.7 to 1.8
1.4 to 1.6
1 to 1.3
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: Factor IX complex (human) products contain low or nontherapeutic levels of factor VII component (ie, considered a 3-factor PCC). Four-factor PCC is preferred. Administer with vitamin K IV (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. For initial reversal, it is suggested to administer factor IX complex (PCC) alone rather than combined with FFP or recombinant factor VIIa (NCS/SCCM [Frontera 2016]).
Refer to adult dosing.
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.
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.
IV: 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.
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.
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
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)
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.
• 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.
• 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.
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
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).
• 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 or tingling. Have patient report immediately to prescriber signs of parvovirus B19 or hepatitis A infection (chills, severe fatigue, rhinorrhea, rash, joint pain, lack of appetite, nausea, vomiting, abdominal pain, or jaundice), 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), burning or numbness feeling, agitation, nausea, vomiting, shortness of breath, severe dizziness, severe headache, vision changes, abnormal heartbeat, passing out, tachycardia, angina, coughing up 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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- Drug class: miscellaneous coagulation modifiers
Other brands: Profilnine SD