BeneFIX

Generic Name: Factor IX (Recombinant)
Class: Hemostatics
VA Class: BL500

Introduction

Biosynthetic preparation (recombinant DNA origin) of blood coagulation factor IX.^{1 7 21}

Uses for BeneFIX

Hemophilia B

Prevention and control of hemorrhagic episodes in patients with a deficiency of coagulation factor IX associated with hemophilia B (Christmas disease).^{1 4 6 9 14}

Because of a decreased risk of transmission of human viruses (e.g., HIV viruses, hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]) and other transmissible disease agents (e.g., agents for Creutzfeldt-Jakob disease [CJD], variant CJD [vCJD]) compared with plasma-derived factor IX preparations, the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation and other experts recommend factor IX (recombinant) as the preferred preparation when factor IX therapy is indicated in patients with hemophilia B.^{2 3 5 13 15 18} Recombinant and plasma-derived preparations of factor IX produce comparable hemostatic effects.^{2 7 9}

Maintenance of hemostasis in patients with hemophilia B undergoing surgery.^{1 6 9 14}

Also used for routine prophylaxis (i.e., administration at regular intervals) to reduce frequency of hemorrhagic events and preserve joint function.^{1 3 6 8 9 15 18} MASAC and the World Federation of Hemophilia recommend prophylaxis for patients with severe hemophilia B (factor IX activity <1%) after careful consideration of risks versus benefits.^{3 8}

Not indicated in the treatment of other coagulation factor deficiencies (e.g., factors II, VII, VIII, X).¹

Not indicated for the reversal of coumarin-induced anticoagulation or for treatment of bleeding associated with low levels of liver-dependent coagulation factors.¹

BeneFIX Dosage and Administration

General

• 
  

  Monitor factor IX activity during treatment to individualize dosage and assess response to therapy.¹ (See Laboratory Monitoring under Cautions.)

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow IV injection or IV infusion.¹

Has been given as a continuous infusion†, however manufacturer states safety and efficacy of continuous infusions of factor IX (recombinant) not established.^{1 7} Thromboembolic events reported in some patients receiving continuous infusion of factor IX (recombinant) during postmarketing surveillance of the drug.¹ (See Thromboembolic Events under Cautions and also see Pediatric Use under Cautions.)

Consult manufacturer's labeling for specific information on reconstitution and administration of factor IX (recombinant).¹

Reconstitution

Prior to reconstitution, allow injection concentrate and diluent to warm to room temperature (≤37°C).^{1 4}

Reconstitute and administer drug using administration set, syringe, and vial adapters provided by manufacturer.⁴

Reconstitute factor IX (recombinant) concentrate with diluent (sodium chloride 0.234%) supplied by the manufacturer.^{1 4}

Gently swirl vial to dissolve powder completely.^{1 4}

Administer immediately or within 3 hours after reconstitution.^{1 4} Discard any unused solution after 3 hours.^{1 4}

Carefully administer to prevent blood from entering tubing and syringe to minimize risk of RBC agglutination.^{1 4} If agglutination occurs, discard administration set, syringe, and remaining drug solution; restart using new materials.¹

Rate of Administration

Individualize infusion rates based on patient response and comfort.^{1 4} Slow infusion rate or discontinue therapy if any adverse reaction occurs.¹

Infuse over several minutes.^{1 4}

Dosage

Dosage (potency) expressed in terms of international units (IU, units) of factor IX activity.¹ One unit is approximately equivalent to amount of factor IX activity in 1 mL of pooled normal human plasma.¹

Individualize dosage and duration of therapy based on patient's age, severity and location of hemorrhage, degree of factor IX deficiency, desired factor IX levels, presence of factor IX inhibitors, clinical response, and pharmacokinetic parameters (e.g., half-life).^{1 4} (See Laboratory Monitoring under Cautions.)

If calculated dosage is ineffective in achieving appropriate factor IX levels, consider possibility that inhibitors to factor IX may have developed.^{1 8} (See Development of Inhibitors to Factor IX under Cautions.)

When switching from plasma-derived preparations of factor IX to factor IX (recombinant), may increase dosage of factor IX (recombinant) if needed.^{1 18 19} (See Plasma Concentrations under Pharmacokinetics.)

Administration of 1 unit/kg factor IX (recombinant) generally increases factor IX levels by approximately 0.8% in adults and 0.7% in children <15 years of age.^{1 8}

Calculate dosages of factor IX (recombinant) using the following formula:

Units required = body weight (in kg) x reciprocal of observed recovery (in units/kg per % of normal) × desired factor IX increase (in % of normal)²⁰

These calculations and suggested dosage regimens are only approximations and should not preclude appropriate laboratory determinations and individualization of dosage based on the hemostatic requirements of patients.¹ The manufacturer's dosage recommendations should be consulted for further information on dosage.¹

Pediatric Patients

Dosage required to achieve expected factor IX levels:

Units required = body weight (in kg) × 1.4 (units/kg per % of normal) × desired factor IX increase (in % of normal)

Hemophilia B

IV

Pediatric patients <15 years of age with minor hemorrhage (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue): Use appropriate dosage to achieve a factor IX level of 20–30% of normal; repeat every 12–24 hours for 1–2 days.¹

Pediatric patients <15 years of age with moderate hemorrhage (e.g., intramuscular, soft tissue with dissection, mucous membranes, tooth extraction, hematuria): Use appropriate dosage to achieve a factor IX level of 25–50% of normal; repeat every 12–24 hours until bleeding resolves or healing occurs, about 2–7 days.¹

Pediatric patients <15 years of age with major hemorrhage (e.g., pharynx, retropharynx, retroperitoneum, CNS): Use appropriate dosage to achieve a factor IX level of 50–100% of normal; repeat every 12–24 hours until bleeding resolves, about 7–10 days.¹

Pediatric patients <15 years of age undergoing surgery: Use appropriate dosage to achieve a factor IX level of 50–100% of normal; repeat every 12–24 hours until bleeding resolves, about 7–10 days.¹

Prophylaxis

IV

Optimum dosage regimen not yet established.^{8 18}

Adults

Hemophilia B

IV

Dosage required to achieve expected factor IX levels:

Units required = body weight (in kg) × 1.3 (units/kg per % of normal) × desired factor IX increase (in % of normal)

Minor hemorrhage (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue): Use appropriate dosage to achieve factor IX levels of 20–30% of normal; repeat every 12–24 hours for 1–2 days until bleeding resolves.¹

Moderate hemorrhage (e.g., intramuscular, soft tissue with dissection, mucous membranes, tooth extraction, hematuria): Use appropriate dosage to achieve factor IX levels of 25–50% of normal; repeat every 12–24 hours until bleeding resolves and healing occurs, about 2–7 days.¹

Major hemorrhage (e.g., pharynx, retropharynx, retroperitoneum, CNS): Use appropriate dosage to achieve factor IX levels of 50–100% of normal; repeat every 12–24 hours until bleeding resolves, about 7–10 days.¹

Surgery: Use appropriate dosage to achieve factor IX levels of 50–100% of normal; repeat every 12–24 hours until bleeding resolves, about 7–10 days.¹

Prophylaxis

IV

Optimum dosage regimen not yet established.⁸

Cautions for BeneFIX

Contraindications

• 
  

  Known hypersensitivity to hamster protein.^{1 4}

  
  

Warnings/Precautions

Warnings

Thromboembolic Events

Potential risk for thromboembolic events.^{1 4} Cases of peripheral thrombophlebitis and DVT reported in some patients receiving factor IX-containing preparations, including factor IX (recombinant); several patients received factor IX (recombinant) by continuous infusion†.¹ Increased risk in patients with preexisting thrombotic risk factors (e.g., liver disease, concomitant use of thrombogenic drugs, history of thrombosis, DIC) and those undergoing surgery.^{1 10 12 14 22} In addition, there have been postmarketing reports of thrombotic events, including life-threatening superior vena cava syndrome in critically ill neonates.¹ (See Pediatric Use under Cautions.)

Renal Effects

Nephrotic syndrome reported in patients undergoing immune tolerance induction who have inhibitors and/or a history of hypersensitivity reactions to factor IX.^{1 5 15 16 17} Safety and efficacy of factor IX products for immune tolerance induction not established.¹

Twelve days after administration of a dose of factor IX (recombinant), one patient with positive hepatitis C antibody developed renal infarct; however, a causal relationship to the drug not established.¹

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faintness, hypotension, tachycardia, anaphylaxis) reported with use of all factor IX products.^{1 5 11 12}

Increased risk in patients with certain genetic mutations of factor IX and those with inhibitors to factor IX.^{1 5 8 9 11 12 15 16 17 18 19} Up to 50% of patients with inhibitors to factor IX may experience severe hypersensitivity reactions, including anaphylaxis.⁸

In patients with inhibitors or with known genetic defects associated with inhibitor development, administer initial (e.g., approximately 10–20) infusions in a hospital setting where severe allergic reactions can be managed.^{1 4 8 16}

Closely observe for hypersensitivity reactions, especially during initial therapy in patients with a risk of inhibitor development.¹ If manifestations of hypersensitivity or anaphylaxis occur, discontinue drug immediately and initiate appropriate therapy.^{1 4}

Evaluate any patient who experiences a hypersensitivity reaction to factor IX for presence of inhibitors.¹ (See Development of Inhibitors to Factor IX under Cautions.)

Possible hypersensitivity reaction to hamster protein.¹ (See Contraindications.)

General Precautions

Development of Inhibitors to Factor IX

Risk for development of inhibitors (IgG antibodies) to factor IX following treatment with factor IX preparations.^{1 4 6 8 9 15 16 17 18 19 21} Reported in about 1–5% of patients with hemophilia B, usually within the first 10–20 days of treatment.^{6 8 9 15 17 19 21} Patients with certain genetic mutations of the factor IX gene may be at higher risk.^{1 5 8 9 14 15 16 17 18 19 21}

Consultation with a hemophilia treatment center strongly recommended for patients with inhibitors.^{2 8}

Laboratory Monitoring

Use under supervision of a qualified clinician experienced in treating hemophilia B.¹

Monitor factor IX levels to guide dosing and assess therapeutic response.^{1 8 21}

Monitor for development of inhibitors (with clinical observation and appropriate laboratory tests) during treatment and prior to surgery.^{1 4 8} (See Development of Inhibitors to Factor IX under Cautions.)

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether factor IX (recombinant) is distributed into human milk; use in nursing women only if clearly indicated.^{1 4}

Pediatric Use

Safety and efficacy evaluated in pediatric patients;¹ studies ongoing in previously treated, minimally treated, and previously untreated pediatric patients.¹

There have been rare postmarketing reports of critically ill neonates who have experienced thrombotic events, including life-threatening superior vena cava syndrome while receiving continuous infusions of factor IX (recombinant) through a central venous catheter.¹ Use with caution in neonates.¹ (See Thromboembolic Events under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.¹ Individualize dosage.¹

Common Adverse Effects

Headache,^{1 4} fever,^{1 4} chills,^{4 9} flushing,^{1 4} dizziness,¹ rash,^{1 9} injection site reaction/pain,¹ nausea,^{1 4} vomiting,^{1 4} lethargy,⁴ altered taste,¹ allergic rhinitis.¹

Interactions for BeneFIX

No formal drug interaction studies to date.²⁰

BeneFIX Pharmacokinetics

Absorption

Plasma Concentrations

In vivo recovery of the recombinant factor following IV administration of 50 units/kg factor IX (recombinant) approximately 28% lower than that achieved following administration of equivalent dose of plasma-derived factor IX; difference presumably due to structural modifications of factor IX (recombinant).^{1 5 7 9 18 19 21}

Decreased in vivo recovery in pediatric patients ≤15 years of age compared with those >15 years of age.¹⁹

Distribution

Extent

Readily diffuses through interstitial fluid; distributes through both intravascular and extravascular compartments.^{6 14 17}

Circulates in plasma as unbound drug.⁶

Binds rapidly and reversibly to vascular endothelium.⁶

Not known whether factor IX (recombinant) crosses the placenta or is distributed into milk.^{1 4 20}

Elimination

Elimination Route

Clearance correlates with body weight; generally increases through adolescence, then stabilizes during adulthood.⁶

Half-life

Biphasic.⁶

Adults: Terminal half-life approximately 19–23 hours (range: 10–37 hours).^{1 21}

Children ≤15 years of age: Approximately 20 hours (range: 10–37 hours).¹

Stability

Storage

Parenteral

Powder for Infusion

2–8°C; avoid freezing to prevent damage to diluent syringe.^{1 4}

May store at room temperature ≤25°C for up to 6 months.^{1 4}

May store reconstituted solution at room temperature prior to administration; use solution within 3 hours of reconstitution.^{1 4}

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible
Sodium chloride 0.234%1

ActionsActions

• 
  

  Factor IX is essential for blood clotting and maintenance of hemostasis.^{14 15}

  
  


• 
  

  Patients with hemophilia B (Christmas disease) have decreased levels of endogenous factor IX, resulting in a hemorrhagic tendency and clinical manifestations such as bleeding into soft tissues, muscles, joints, and internal organs.^{8 14 15 18}

  
  


• 
  

  The clinical severity and frequency of bleeding in patients with hemophilia B correlate with the degree of deficiency of factor IX activity.^{8 15 18} Patients with mild hemophilia B generally have >5% of normal activity, those with moderate disease generally have 1–5% of normal activity, and those with severe disease have <1% of normal activity.^{5 8 14 15 18}

  
  


• 
  

  Administration of factor IX (recombinant) to patients with hemophilia B results in increased plasma levels of factor IX and temporarily corrects coagulation defect.¹

  
  


• 
  

  Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by factor VII/tissue factor complex in the extrinsic coagulation pathway.^{1 14} Activated factor IX, in combination with activated factor VIII, activates factor X to Xa, resulting ultimately in the conversion of factor II (prothrombin) to thrombin and formation of a fibrin clot.^{1 14}

  
  


• 
  

  Similar in structure and function to plasma-derived factor IX, but associated with substantially reduced risk of transmission of bloodborne human viruses (e.g., HIV, HAV, HBV, HCV).^{1 4 6 7 9 13 15}

  
  

• 
  

  Produced by recombinant DNA technology in a mammalian cell expression system using chromatography and membrane filtration processes to isolate and purify factor IX.^{1 7 18 21} Manufactured without animal or human proteins.^{1 2 4 5 7 9 13 15 19 21}

  
  

Advice to Patients

• 
  

  Importance of discontinuing therapy and immediately informing clinician if hives, generalized urticaria, angioedema, chest tightness, difficulty in breathing, wheezing, faintness, rapid heart rate, low BP, swelling, or other manifestations of a hypersensitivity reaction or anaphylaxis occur or, alternatively, seeking immediate emergency care depending on severity of such reactions.^{1 4}

  
  


• 
  

  Advise patients to inform clinician if usual dosages of factor IX do not prevent or control bleeding; possible development of inhibitors.^{1 4}

  
  


• 
  

  Advise patients to inform clinician of current or previous DIC or if they have liver disease or recently underwent surgery, because of potential risk of thromboembolism.^{1 4}

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., liver disease).^{1 4}

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 4}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{1 4} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Factor IX (Recombinant)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use	number of units indicated on label	BeneFIX (with sodium chloride 0.234% diluent in a prefilled syringe or sterile disposable plastic syringe; available with infusion set and vial adapter)	Wyeth

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Wyeth. BeneFIX coagulation factor IX (recombinant) prescribing information. Philadelphia, PA; 2008 Jan.

2. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning the treatment of hemophilia and other bleeding disorders (revised October 2006). MASAC recommendation #177. From National Hemophilia Foundation website (). Accessed 15 November 2007.

3. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding) (June 3, 2006). MASAC recommendation #170. From National Hemophilia Foundation website (). Accessed 15 November 2007.

4. Wyeth. Information for patients: BeneFIX coagulation factor IX (recombinant). Philadelphia, PA; 2008 Jan.

5. Mannucci PM, Tuddenham EGD. The hemophilias—from royal genes to gene therapy. N Engl J Med. 2001; 344:1773-9. [PubMed 11396445]

6. Björkman S, Berntorp E. Pharmacokinetics of coagulation factor: clinical relevance for patients with haemophilia. Clin Pharmacokinet. 2001; 40: 815-32.

7. White GC II, Beebe A, Nielsen B. Recombinant factor IX. Thromb Haemost. 1997; 78:261-5. [PubMed 9198163]

8. World Federation of Hemophilia. Guidelines for the management of hemophilia. 2005. From World Federation of Hemophilia website (). Accessed 30 Oct 2007.

9. Shapiro AD, Di Paola J, Cohen A et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood. 2005; 105:518-25. [PubMed 15383463]

10. Grifols. Profilnine SD factor IX complex solvent detergent treated prescribing information. Los Angeles, CA; 2004 Jan.

11. Grifols. Alphanine SD coagulation factor IX (human) solvent detergent treated/virus filtered prescribing information. Los Angeles, CA; 2004 Jan.

12. ZLB Behring. Mononine coagulation factor IX (human) monoclonal antibody purified prescribing information. Kankakee, IL; 2006 May.

13. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding the use of recombinant clotting factor products with respect to pathogen transmission (June 3, 2006). MASAC recommendation #169. From National Hemophilia Foundation website ().

14. Shord SS, Lindley CM. Coagulation products and their uses. Am J Health Syst Pharm. 2000; 57:1403-17. [PubMed 10938981]

15. Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet. 2003; 361:1801-9.

16. Warrier I. Management of haemophilia B patients with inhibitors and anaphylaxis. Haemophilia. 1998; 4:574-6. [PubMed 9873797]

17. DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol. 2007; 138:305-15. [PubMed 17614818]

18. Giangrande P. Haemophilia B: Christmas disease. Expert Opin Pharmacother. 2005; 6:1517-24. [PubMed 16086639]

19. Poon MC, Lillicrap D, Hensman C et al. Recombinant factor IX recovery and inhibitor safety: a Canadian post-licensure surveillance study. Thromb Haemost. 2002; 87:431-5. [PubMed 11916075]

20. Wyeth, Philadelphia, PA: Personal communication.

21. Roth DA, Kessler CM, Pasi KJ et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood. 2001; 98:3600-6. [PubMed 11739163]

22. Köhler M, Helistern P, Lechler E et al. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost. 1998; 80:399-402.

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