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 6 9 14

Maintenance of hemostasis in patients with hemophilia B undergoing surgery.1 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 National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) 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

Slideshow: 18 Herbal Supplements with Risky Drug Interactions

Herbal and Dietary Supplements Deserve Your Attention

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

Not indicated for the treatment of other coagulation factor deficiencies (e.g., factors II, VII, VIII, X) or for management of hemophilia A patients with inhibitors to factor VIII.1

Not indicated for 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

  • Initiate therapy under supervision of a clinician experienced in the treatment of hemophilia B.1

  • Monitor factor IX activity when clinically indicated to individualize dosage and assess response to therapy.1 (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

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).1 (See Thromboembolic Events under Cautions and also see Pediatric Use under Cautions.)

Administer using the infusion set tubing and diluent syringe provided by the manufacturer, or a single sterile disposable plastic syringe.1 Carefully administer to prevent blood from entering tubing and syringe to minimize risk of RBC agglutination.1 If agglutination occurs, discard administration set, syringe, and remaining drug solution; restart using new materials.1

Do not administer in the same tubing or container with other drugs.1

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

Reconstitution

Reconstitute factor IX (recombinant) lyophilized powder with prefilled diluent syringe (sodium chloride 0.234%) provided by the manufacturer.1 Prior to reconstitution, allow drug vial and diluent to warm to room temperature.1

Gently swirl vial to dissolve powder completely.1

Administer immediately or within 3 hours after reconstitution.1 Discard any unused solution after 3 hours.1

The surfactant (polysorbate 80) contained in the reconstituted solution is known to increase the rate of extraction of diethylhexylphthalate (DEHP) from PVC; manufacturer states that this should be considered during the preparation and administration of the drug, including storage time elapsed in a PVC container following reconstitution.1

Rate of Administration

Infuse over several minutes; however, individualize infusion rates based on patient response and comfort.1 Slow infusion rate or discontinue therapy if any adverse reaction occurs.1

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 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

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 (See Laboratory Monitoring under Cautions.)

If calculated dose 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), it may be necessary to increase dosage of factor IX (recombinant).1 18 19 (See Plasma Concentrations under Pharmacokinetics.) Patients at the low end of the observed factor IX recovery may require an increase in dose to as much as twice the initial empirically calculated dose.1

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)1 20

These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and individualization of dosage based on the hemostatic requirements of patients.1 Perform serial assays of factor IX activity (by the one-stage clotting assay) whenever possible to ensure that adequate levels of factor IX have been attained and maintained.1

Pediatric Patients

Hemophilia B
IV

Dose 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)

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

Pediatric patients <15 years of age with moderate hemorrhage (e.g., intramuscular, soft tissue with dissection, mucous membranes, tooth extraction, hematuria): Administer appropriate dose 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): Administer appropriate dose 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: Administer appropriate dose to achieve a factor IX level of 50–100% of normal; repeat every 12–24 hours until bleeding resolves, about 7–10 days.1

Routine Prophylaxis
IV

Various dosing regimens have been recommended; optimal dosage remains to be established.3 6 8 18 23 24 Dosages of 25–40 units/kg twice a week commonly recommended.6 8 23 24 Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.3 18

Adults

Hemophilia B
IV

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

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

Routine Prophylaxis
IV

Various dosing regimens have been recommended; optimal dosage remains to be established.3 6 8 18 23 24 Dosages of 25–40 units/kg twice a week commonly recommended.6 8 23 24 Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.3 18

Cautions for BeneFIX

Contraindications

  • Life-threatening, immediate hypersensitivity reactions (e.g., anaphylaxis) to factor IX (recombinant) or any ingredient in the formulation, including hamster protein.1

Warnings/Precautions

Warnings

Thromboembolic Events

Potential risk for thromboembolic events.1 Peripheral thrombophlebitis and DVT reported in some patients receiving factor IX (recombinant); several patients received the drug by continuous infusion.1 Life-threatening superior vena cava syndrome reported in critically ill neonates who received factor IX (recombinant) via continuous infusion through a central venous catheter.1 (See Pediatric Use under Cautions.) Risk of thrombosis may be increased in patients with underlying risk factors (e.g., indwelling central venous catheters).1

Renal Effects

Nephrotic syndrome reported in hemophilia B patients with inhibitors and a history of hypersensitivity to factor IX undergoing immune tolerance induction with factor IX preparations.1 5 15 16 17 Safety and efficacy of factor IX (recombinant) 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, including bronchospastic reactions and anaphylaxis, reported.1 5 Manifestations have included pruritus, rash, urticaria, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, generalized discomfort, and fatigue.1

Increased risk in patients with certain genetic mutations of factor IX and/or those with inhibitors to factor IX.1 5 8 9 15 16 17 18 19 Up to 50% of hemophilia B patients with inhibitors to factor IX may experience a severe hypersensitivity reaction, including anaphylaxis, to factor IX concentrates.8

Closely observe for hypersensitivity reactions, especially during initial exposure to the drug.1 Administer initial (e.g., approximately 10–20) infusions in a hospital or clinic setting where severe allergic reactions can be managed.1 8 16 If manifestations of hypersensitivity or anaphylaxis occur, discontinue drug immediately and initiate appropriate therapy.1

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

Factor IX (recombinant) (BeneFIX) contains trace amounts of hamster proteins; possible hypersensitivity reaction to these nonhuman mammalian proteins.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 6 8 9 15 16 17 18 19 21 Inhibitors 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 of inhibitor development and of experiencing a hypersensitivity reaction.1 5 8 9 14 15 16 17 18 19 21 (See Hypersensitivity Reactions under Cautions.)

High-titer inhibitors observed in a few pediatric patients receiving factor IX (recombinant).1 Development of high-titer inhibitors may require use of an alternative treatment to factor IX replacement therapy.1

Carefully monitor patients, particularly those with known deletion mutations of the factor IX gene, for development of inhibitors with appropriate clinical observation and laboratory tests.1 Suspect presence of inhibitors if expected factor IX levels not achieved or bleeding is not controlled with a recommended dose.1 8

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

Laboratory Monitoring

Monitor factor IX levels whenever possible 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 8 (See Development of Inhibitors to Factor IX under Cautions.) If expected plasma factor IX levels are not attained or bleeding is not controlled with an expected dose, perform appropriate laboratory test (Bethesda assay) to detect presence of factor IX inhibitors.1

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

Pediatric Use

Safety and efficacy evaluated in pediatric patients <15 years of age;1 on average, in vivo recovery of factor IX is lower in pediatric patients than in adults and dosage adjustments may be necessary.1 19

In clinical studies, high-titer inhibitors were detected in several pediatric patients who had no prior exposure to factor IX preparations; these patients were withdrawn from study.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 dizziness,1 rash,1 9 hives,1 injection site reactions/pain,1 nausea.1 1

Interactions for BeneFIX

No formal drug interaction studies to date.1 20

BeneFIX Pharmacokinetics

Absorption

Plasma Concentrations

In vivo recovery of factor IX 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.1 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 20

Elimination

Elimination Route

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

Half-life

Biphasic.6

Adults: Approximately 17–30 hours.1

Pediatric patients: Approximately 16–24 hours in children 2 to <12 years of age and 17–26 hours in adolescents 12–15 years of age.1

Stability

Storage

Parenteral

Powder for Infusion

2–8°C; avoid freezing to prevent damage to diluent syringe.1

May be stored at room temperature (≤25°C) for up to 6 months.1 After end of 6-month period, do not return to refrigerator; use immediately or discard.1

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

Actions

  • 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 Treatment also may normalize aPTT, which is typically prolonged in patients with hemophilia B.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.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.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 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 components.1 2 5 7 9 13 15 19 21

Advice to Patients

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

  • Importance of patients informing a clinician if they experience a lack of response to factor IX (recombinant) therapy; possible development of inhibitors.1

  • Advise patients to always follow the specific instructions (e.g., for storage, reconstitution) given by their clinician.1

  • Importance of patients informing a clinician if they administer excessive amounts of the drug.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (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; available with infusion set and vial adapter device)

Wyeth

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 23, 2012. 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; 2010 Jun.

2. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (revised March 2009). MASAC recommendation #190. From National Hemophilia Foundation website. Accessed 24 February 2010.

3. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding) (November 7, 2007). MASAC recommendation #179. From National Hemophilia Foundation website. Accessed 24 February 2010.

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]

23. Carcao MD, Aledort L. Prophylactic factor replacement in hemophilia. Blood Rev. 2004; 18:101-13. [PubMed 15010149]

24. Nilsson IM, Berntorp E, Löfqvist T et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern med. 1992; 232:25-32. [PubMed 1640190]

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