Pill Identifier App

NovoSeven

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

Warning(s)

  • Risk of serious arterial and venous thromboembolic adverse events, particularly when factor VIIa (recombinant) is used outside FDA-labeled indications.1 29 36 37 39 (See Thromboembolic Events under Cautions.)

  • Both fatal and nonfatal thromboembolic events have been reported in clinical studies and during postmarketing experience.1 19 35 36 38

  • Discuss risk of thromboembolism with patient.1 Monitor for signs and symptoms of coagulation system activation and thrombosis during therapy.1

Introduction

Biosynthetic preparation (recombinant DNA origin) of blood coagulation factor VIIa.1

Uses for NovoSeven

Hemophilia A or B with Inhibitors

Treatment and prevention of hemorrhagic episodes in patients with hemophilia A (antihemophilic factor [factor VIII] deficiency; classic hemophilia) or hemophilia B (factor IX deficiency; Christmas disease) who have developed inhibitors (alloantibodies) to factor VIII or factor IX, respectively;1 11 21 22 25 26 designated an orphan drug by FDA for this use.2

Prevention of bleeding in patients with hemophilia A or B with inhibitors to factor VIII or factor IX, respectively, undergoing surgery or invasive procedures;1 21 22 25 26 designated an orphan drug by FDA for this use.2

Management of hemophilia in patients with inhibitors may be difficult and consultation with a hemophilia treatment center is strongly recommended.11 21

The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation and other experts state that factor VIIa (recombinant) is one of several therapeutic options for the management of hemophilic patients with inhibitors.6 11 21 Treatment of choice depends on several factors (e.g., severity and location of bleeding, type [low- or high-responding] and titer of inhibitor, history of anamnestic response, previous response to these preparations).5 6 11 21

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Patients with low titers (e.g., <5–10 Bethesda units/mL) of inhibitors may be effectively treated with high dosages of coagulation factor concentrates (factor VIII or factor IX).21 23 33 34 48 49 Bypassing agents (e.g., factor VIIa [recombinant]) generally are used when a response to specific factor replacement therapy has not been obtained or is unlikely.21 23 MASAC recommends use of a bypassing agent in hemophilia A or hemophilia B patients with inhibitors in settings where clotting factor preparations would otherwise be used, including before and after surgery and physical therapy.22

Acquired Hemophilia

Treatment and prevention of bleeding in patients with acquired hemophilia (i.e., those with acquired inhibitor antibodies [autoantibodies] to factor VIII);1 20 26 designated an orphan drug by FDA for this use.2

Prevention of bleeding in patients with acquired hemophilia undergoing surgery or invasive procedures;1 20 21 25 26 designated an orphan drug by FDA for this use.2

One of several options used to control bleeding in patients with acquired hemophilia.20

Factor VII Deficiency

Management of hemorrhagic episodes in patients with congenital factor VII deficiency; 1 11 12 16 24 26 designated an orphan drug by FDA for this use.2

Prevention of bleeding in patients with congenital factor VII deficiency undergoing surgery or invasive procedures;1 designated an orphan drug by FDA for this use.2

MASAC recommends use of factor VIIa (recombinant) for management of bleeding in patients with congenital factor VII deficiency.11

Nonhemophilic Hemorrhage

Has been used in nonhemophilic patients in a variety of clinical settings (e.g., intracranial hemorrhage [ICH], advanced liver disease, liver surgery, trauma, cardiac surgery, spinal surgery, GI bleeding, reversal of warfarin anticoagulation) to control or prevent excessive or life-threatening hemorrhage.1 19 25 26 35 36 38 39 41 42 43 44 45 However, efficacy and safety of the drug in these settings not established.1 36 42 43 45 Additional randomized controlled studies are needed to establish the role of factor VIIa (recombinant) as a general hemostatic agent in patients without hemophilia.26 27 36 40 41 42

NovoSeven Dosage and Administration

General

  • Administer only under direct supervision of a clinician experienced in the management of bleeding disorders.1

  • Adjust dose and dosing interval based on severity of bleeding and hemostatic response.1

  • Coagulation parameters (e.g., PT/INR, aPTT, plasma factor VII clotting activity [FVII:C]) have not been shown to directly correlate with hemostatic response.1 20 25 26 27 31 42 (See Adequate Patient Evaluation and Monitoring under Cautions.)

Administration

IV Administration

Administer by slow (over 2–5 minutes) IV injection.1

Has been given as a continuous IV infusion;7 8 9 10 25 26 28 42 however, manufacturer states that the drug should not be admixed with any IV infusion solutions.1 13 If flushing of the line is necessary prior to and following drug administration, use 0.9% sodium chloride injection.1

Reconstitution

Select appropriate vial size and diluent based on indicated dosage.1 Prior to reconstitution, allow lyophilized powder and diluent supplied by manufacturer (histidine diluent) to warm to room temperature (≤37°C).1

Reconstitute vials containing 1, 2, or 5 mg of lyophilized factor VIIa (recombinant) with 1.1, 2.1, or 5.2 mL of histidine diluent, respectively, to provide a solution containing approximately 1 mg/mL (1000 mcg/mL).1 Reconstitute only with the histidine diluent provided by manufacturer; do not use sterile water for injection or any other diluent.1

Direct diluent toward side of vial; do not inject directly onto powder.1

Gently swirl solution until all the powder is dissolved.1

May store reconstituted solutions under refrigeration or at room temperature, but administer within 3 hours after reconstitution; discard any unused solution after 3 hours.1

Dosage

Pediatric Patients

Hemophilia A or B with Inhibitors
Hemorrhagic Episodes
IV

90 mcg/kg every 2 hours until hemostasis achieved or response to drug is inadequate; doses of 35–120 mcg/kg have been used successfully in clinical studies.1 4 5

For severe bleeding episodes, continue treatment every 3–6 hours after hemostasis is achieved to prevent recurrence of bleeding.1 Optimum duration of therapy not established; minimize duration of posthemostatic dosing.1 (See Posthemostatic Dosing under Cautions.)

Surgical Prophylaxis
IV

Minor surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure.1 Continue every 2 hours postoperatively for 48 hours, then every 2–6 hours until healing achieved.1

Major surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure.1 Continue every 2 hours postoperatively for 5 days, then every 4 hours until healing achieved.1 Administer additional doses, if required.1

Acquired Hemophilia
IV

70–90 mcg/kg every 2–3 hours until hemostasis achieved.1

Factor VII Deficiency
Hemorrhagic Episodes and Surgical Prophylaxis
IV

15–30 mcg/kg every 4–6 hours until hemostasis achieved.1 Although minimum effective dose not established, manufacturer states that doses as low as 10 mcg/kg have been effective.1

Individualize dose and dosing frequency.1 Monitor PT and plasma factor VII clotting activity (FVII:C) prior to and following administration.1 Consider possibility that antibodies to factor VII may have developed if therapeutic response or expected factor VII levels are not achieved with calculated dosages.1 (See Development of Antibodies to Factor VII under Cautions.)

Adults

Hemophilia A or B with Inhibitors
Hemorrhagic Episodes
IV

90 mcg/kg every 2 hours until hemostasis achieved or response to drug is inadequate; doses of 35–120 mcg/kg have been used successfully in clinical studies.1 4 5

For severe bleeding episodes, continue treatment every 3–6 hours after hemostasis is achieved to prevent recurrence of bleeding.1 Optimum duration of therapy not established; minimize duration of posthemostatic dosing.1 (See Posthemostatic Dosing under Cautions.)

Surgical Prophylaxis
IV

Minor surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure.1 Continue every 2 hours for 48 hours postoperatively, then every 2–6 hours until healing achieved.1

Major surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure.1 Continue every 2 hours postoperatively for 5 days, then every 4 hours until healing achieved.1 Administer additional doses, if required.1

Acquired Hemophilia
IV

70–90 mcg/kg every 2–3 hours until hemostasis achieved.1

Factor VII Deficiency
Hemorrhagic Episodes and Surgical Prophylaxis
IV

15–30 mcg/kg every 4–6 hours until hemostasis achieved. Although minimum effective dose not established, manufacturer states that doses as low as 10 mcg/kg have been effective.1

Individualize dose and dosing frequency.1 Consider possibility that antibodies to factor VII may have developed if therapeutic response or expected factor VII levels are not achieved with calculated dosages.1 (See Development of Antibodies to Factor VII under Cautions.)

Cautions for NovoSeven

Contraindications

  • Manufacturer states no known contraindications.1

Warnings/Precautions

Warnings

Thromboembolic Events

Risk of serious thromboembolic events.1 17 19 20 23 25 26 27 29 35 36 Adverse arterial and venous thromboembolic events reported in clinical studies and during postmarketing experience.1 17 19 20 23 25 26 27 29 35 36 Risk of thrombosis, particularly arterial thromboembolic events (e.g., myocardial ischemia, MI, cerebral ischemia and/or infarction), may be further increased in nonhemophilic patients who receive factor VIIa (recombinant) for non-FDA-labeled indications.19 35 36 37 38

Potentially greater risk in patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injuries, septicemia, or concomitant treatment with activated or nonactivated prothrombin complex concentrates (APCCs or PCCs) due to circulating tissue factor (TF) or predisposing coagulopathy.1 17 19

Weigh risk of thromboembolism against benefits of factor VIIa (recombinant) therapy.35 Use with caution, especially in patients with known risk factors for thromboembolism (e.g., elderly patients, neonates, those with a history of CHD, liver disease, DIC, or who require postoperative immobilization).1 19 20 25 27 29

Closely monitor for thrombosis or other signs of an activated coagulation system.1 25 27 39 Reduce dosage or discontinue therapy if thrombosis occurs or laboratory tests confirm presence of intravascular coagulation.1

Report thrombotic complications and other adverse effects associated with factor VIIa (recombinant) to the Hemophilia and Thrombosis Research Society (HTRS) Registry at 877-362-7355.1 13 36

Posthemostatic Dosing

Safety and efficacy of prolonged elevations of factor VIIa have not been evaluated, and most appropriate duration of posthemostatic therapy with factor VIIa (recombinant) is not known; exercise caution if factor VIIa (recombinant) used for extended periods to maintain hemostasis.1 Minimize duration of posthemostatic therapy and closely monitor patients (preferably by a clinician experienced in the posthemostatic management of hemophilia).1

Development of Antibodies to Factor VII

Development of antibodies to factor VII reported rarely in patients with congenital factor VII deficiency receiving factor VIIa (recombinant).1 12 25 In some cases, inhibitory effects were demonstrated in vitro;1 clinical importance not established.12

Monitor PT and factor VII coagulant activity prior to and following drug administration in patients with factor VII deficiency.1 Suspect antibody formation if factor VIIa activity fails to reach the expected level, PT is not corrected, or bleeding is not controlled after treatment with recommended dosages of factor VIIa (recombinant) and perform appropriate screening tests.1 (See Adequate Patient Evaluation and Monitoring under Cautions.)

Adequate Patient Evaluation and Monitoring

Monitor patients with congenital factor VII deficiency receiving factor VIIa (recombinant) for evidence of antibody development.1 (See Development of Antibodies to Factor VII under Cautions.)

Evaluate hemostasis to determine effectiveness of factor VIIa (recombinant) and need for dosage adjustments.1 Laboratory parameters (e.g., PT/INR, aPTT, plasma factor VII clotting activity) have not been shown to correlate directly with hemostasis; furthermore, coagulation assays may produce different results depending on the specific reagent used.1 25 26 27 31 42

Administration of factor VIIa (recombinant) generally shortens PT and aPTT and has been shown to rapidly normalize INR; however, clinical importance not known.1 20 25 31 42 43 44

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., including anaphylactic shock, flushing, urticaria, rash, angioedema) reported.1 17 Administer with caution in patients with known hypersensitivity to factor VIIa (recombinant) or any ingredient in the formulation.1

Factor VIIa (recombinant) contains trace amounts of animal protein which may stimulate antibody production and cause hypersensitivity reactions.1 13 Use with caution in patients with known hypersensitivity to murine, hamster, or bovine proteins.1

If severe hypersensitivity or anaphylaxis occurs, discontinue drug immediately and initiate appropriate therapy.13

Specific Populations

Pregnancy

Category C.1

Thrombotic events have been reported in women without a bleeding disorder receiving factor VIIa (recombinant) for uncontrolled postpartum hemorrhage.1 (See Thromboembolic Events under Cautions.)

Lactation

Not known whether factor VIIa (recombinant) is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

NovoSeven RT has not been evaluated in patients ≤16 years of age to determine if there are differences in safety and efficacy among various pediatric age groups.1 13 The predecessor product (NovoSeven) has been used in pediatric patients 0–16 years of age; no substantial differences in safety and efficacy relative to adults.1 7 13

In clinical trials, dosing in pediatric patients was determined according to body weight and not age.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 Potential risk of adverse thromboembolic events in geriatric patients; use with caution.1 17 19 26 (See Thromboembolic Events under Cautions.)

Common Adverse Effects

Fever,1 hemorrhage,1 injection site reaction,1 arthralgia,1 headache,1 BP changes (hypotension or hypertension),1 nausea,1 vomiting,1 pain,1 edema,1 rash.1

Interactions for NovoSeven

Specific Drugs

Drug

Interaction

Comments

Antifibrinolytic agents (e.g., aminocaproic acid, tranexamic acid)

No specific interaction reported with concomitant use21

May be used concomitantly to enhance hemostasis21

Anti-inhibitor coagulant complex (Activated Prothrombin Complex Concentrate; APCC)

Potential additive thrombotic effects1

Avoid concomitant use1

Factor IX Complex (Prothrombin Complex Concentrate; PCC)

Potential additive thrombotic effects1

Avoid concomitant use1

NovoSeven Pharmacokinetics

Absorption

Bioavailability

Circulating factor VIIa concentrations increase approximately 1000-fold following administration of factor VIIa (recombinant).25 26

Onset

Mean maximum factor VII activity observed approximately 10 minutes following single IV infusion in one study.30

Duration

Factor VII activity decreases rapidly and returns to baseline within 24 hours following IV infusion.30

Distribution

Extent

Distributes into a volume 2–3 times that of plasma.31

Not known whether distributed into human milk.1

Elimination

Half-life

2.3 hours (range: 1.7–2.7 hours) in patients with hemophilia A or B and 2.8–3.1 hours in patients with congenital factor VII deficiency.1

Special Populations

Clearance in children is increased compared with adolescents and adults.25 28

Half-life in children is shorter than that observed in adolescents and adults.25 28

Stability

Storage

Parenteral

Powder for Injection

2–25°C; do not freeze.1 Protect from light.1 13 Do not use beyond expiration date.1

Store reconstituted solutions of the drug at room temperature or under refrigeration; do not freeze or store in syringes.1 13 Use solution within 3 hours of reconstitution.1

Compatibility

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

Parenteral

Do not mix with other infusion solutions.1

Actions

  • Factor VIIa (recombinant), a hemostatic agent, is structurally nearly identical to human plasma-derived coagulation factor VIIa.1 29

  • Promotes hemostasis through activation of the extrinsic blood coagulation pathway.1

  • Following injury to vessel wall, tissue factor (TF) is exposed to circulating blood; TF-FVIIa complexes are formed on TF-bearing cells, where they activate factor X to factor Xa and factor IX to factor IXa.1 25 26 29

  • Factor Xa, in complex with factor V, calcium, and phospholipids, converts prothrombin to thrombin and subsequently activates fibrinogen to fibrin to form a hemostatic plug that provides local hemostasis.1 29 This process also may occur on the surface of activated platelets.1 26 29

  • Produces hemostasis in the absence of factor VIII or factor IX by binding to activated platelets and directly activating factor X to generate thrombin independently of TF.1 11 22 25 26 27 29

  • Produces circulating concentrations of factor VIIa that are approximately 1000-fold higher than physiologic levels.25 26 32

Advice to Patients

  • Importance of understanding risks and benefits associated with therapy.1

  • Importance of discontinuing therapy and immediately informing clinician if hives, urticaria, chest tightness, hypotension, wheezing, or anaphylaxis occurs.1

  • Importance of warning patients about the possibility of thromboembolism and advising them to monitor for signs of thrombosis, including new-onset swelling and pain in the limbs or abdomen, new-onset chest pain, shortness of breath, loss of sensation or motor skills, or altered consciousness or speech.1 Advise patients to immediately seek medical attention if any manifestations of thromboembolism occur.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., diabetes, cancer, cardiovascular disease, thromboembolic disease, liver disease).1 25

  • 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 VIIa (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

1 mg

NovoSeven RT

Novo Nordisk

2 mg

NovoSeven RT

Novo Nordisk

5 mg

NovoSeven RT

Novo Nordisk

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2011. 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. Novo Nordisk. NovoSeven RT (coagulation factor VIIa [recombinant] room temperature stable) prescribing information. Princeton, NJ; 2010 15 Jan.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2001 June. From FDA web site ()

3. Arkin S, Blei F, Fetten J et al. Human coagulation factor FVIIa (recombinant) in the management of limb-threatening bleeds unresponsive to alternative therapies: results from the NovoSeven emergency-use programme in patients with severe haemophilia or with acquired inhibitors. Blood Coag Fibrino. 2000; 11:255-9.

4. Shirahata A, Kamiya T, Takamatsu J et al. Clinical trial to investigate the pharmacokinetics, pharmacodynamics, safety, and efficacy of recombinant factor VIIa in Japanese patients with hemophilia with inhibitors. Int J Hematol. 2001; 73:517-25. [PubMed 11503968]

5. Ingerslev J. Efficacy and safety of recombinant factor VIIa in the prophylaxis of bleeding in various surgical procedures in hemophilic patients with factor VIII and factor IX inhibitors. Semin Thromb Hemost. 2000; 26:425-32. [PubMed 11092219]

6. Kulkarni R, Aledort LM, Berntorp E et al. Therapeutic choices for patients with hemophilia and high-titer inhibitors. Am J Hematol. 2001; 67:240-6. [PubMed 11443636]

7. Shapiro AD. Recombinant factor VIIa in the treatment of bleeding in hemophilic children with inhibitors. Semin Thromb Hemost. 2000; 26:413-9. [PubMed 11092217]

8. Schulman S for the rFVIIa-CI Group. Continuous infusion of recombinant factor VIIa in hemophilic patients with inhibitors: safety, monitoring, and cost effectiveness. Semin Thromb Hemost. 2000; 26:421-4. [PubMed 11092218]

9. Chuansumrit A, Isarangkura P, Angchaisuksiri P et al. Controlling acute bleeding episodes with recombinant factor VIIa in haemophiliacs with inhibitor: continuous infusion and bolus injection. Haemophilia. 2000; 6:61-5. [PubMed 10781189]

10. Baudo F, Redaelli R, Caimi TM et al. The continuous infusion of recombinant activated factor VIIa (rFVIIa) in patients with factor VIII inhibitors activates the coagulation and fibrinolytic systems without clinical complications. Thromb Res. 2000; 99:21-4. [PubMed 10904100]

11. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (revised April 2010). MASAC recommendation #195. From National Hemophilia Foundation website ().Accessed 17 August 2010.

12. Hunault M, Bauer KA. Recombinant factor VIIa for the treatment of congenital factor VII deficiency. Semin Thromb Hemost. 2000; 26:401-5. [PubMed 11092215]

13. Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ: Personal communication.

14. Shapiro AD, Gilchrist GS, Hoots WK et. al. Prospective, randomized trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors of undergoing surgery. Thromb Haemost. 1998; 80:773-8. [IDIS 417591] [PubMed 9843170]

15. Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (NovoSeven) in haemophiliacs with inhibitors. Thromb Haemost. 1998;80:912-8.

16. Mariani G, Testa MG, Paolantonio TD, et al. Use of recombinant, activated factor VII in the treatment of congenital factor VII deficiencies. Vox Sang.1999;77:131-6.

17. NovoNordisk. Dear Health Care Professional letter regarding new warnings and adverse reactions added to NovoSeven coagulation factor VIIa (recombinant). Princeton, NJ; 2005 Nov.

19. Mayer SA, Brun NC, Begtrup K et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005; 352:777-85. [IDIS 531825] [PubMed 15728810]

20. Giangrande P. Acquired hemophilia. Treatment of Hemophilia. 2005. From World Federation of Hemophilia website (). Accessed 2006 Nov 16.

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

22. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors) (June 3, 2006). MASAC recommendation #167. From National Hemophilia Foundation website ().

23. Mathew P. Current opinion on inhibitor treatment options. Semin Hematol. 2006; 43 (Suppl 4):S8-13. [PubMed 16690374]

24. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding rare coagulation factor disorders. MASAC recommendation #174. From National Hemophilia Foundation website ().Accessed 25 October 2007.

25. Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood. 2004; 104:3858-64. [PubMed 15328151]

26. Franchini M, Zaffanello M, Veneri D. Recombinant factor VIIa: an update on its clinical use. Thromb Haemost. 2005; 93:1027-35. [PubMed 15968384]

27. Lam MSH, Sims-McCallum RP. Recombinant factor VIIa in the treatment of non-hemophiliac bleeding. Ann Pharmacother 2005; 39:885-91. [PubMed 15784806]

28. Stachnik JM, Gabay MP. Continuous infusion of coagulation factor products. Ann Pharmacother. 2002; 36:882-91. [PubMed 11978168]

29. O’Connell KA, Wood JJ, Wise RP et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA.. 2006; 295:293-8.

30. Shirahata A, Kamiya T, Takamatsu J et al. Clinical trial to investigate the pharmacokinetics, pharmacodynamics, safety, and efficacy of recombinant factor VIIa in Japanese patients with hemophilia with inhibitors. Int J Hematol. 2001; 73:517-25. [PubMed 11503968]

31. Lindley CM, Sawyer WT, Macik BG et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther. 1994; 55:638-48. [PubMed 8004880]

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

33. Baxter. Feiba VH anti-inhibitor coagulant complex, vapor heated prescribing information. Westlake Village, CA; 2005 Apr.

34. White GC II, Rosendaal F, Aledort LM et al. Definitions in hemophilia: recommendations of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the international society on thrombosis and haemostasis. Thromb Haemost. 2001; 85:560. [PubMed 11307831]

35. Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg. 2008; 248:61-8. [PubMed 18580208]

36. Hardy JF, Bélisle S, Van der Linden P. Efficacy and safety of recombinant activated factor VII to control bleeding in nonhemophiliac patients: a review of 17 randomized controlled trials. Ann Thorac Surg. 2008; 86:1038-48. [PubMed 18721620]

37. Gill R, Herbertson M, Vuylsteke A et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation. 2009; 120:21-7. [PubMed 19546387]

38. Mayer SA, Brun NC, Begtrup K et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008; 358:2127-37. [PubMed 18480205]

39. Patanwala AE. Factor VIIa (recombinant) for acute traumatic hemorrhage. Am J Health Syst Pharm. 2008; 65:1616-23. [PubMed 18714107]

40. Ranucci M, Isgrò G, Soro G et al. Efficacy and safety of recombinant activated factor vii in major surgical procedures: systematic review and meta-analysis of randomized clinical trials. Arch Surg. 2008; 143:296-304; discussion 304. [PubMed 18347278]

41. Johnson SJ, Ross MB, Moores KG. Dosing factor VIIa (recombinant) in nonhemophiliac patients with bleeding after cardiac surgery. Am J Health Syst Pharm. 2007; 64:1808-12. [PubMed 17724361]

42. Levi M, Peters M, Büller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med. 2005; 33:883-90. [PubMed 15818119]

43. Rosovsky RP, Crowther MA. What is the evidence for the off-label use of recombinant factor VIIa (rFVIIa) in the acute reversal of warfarin? ASH evidence-based review 2008. Hematology Am Soc Hematol Educ Program. 2008; :36-8. [PubMed 19074054]

44. Aguilar MI, Hart RG, Kase CS et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc. 2007; 82:82-92. [PubMed 17285789]

45. Lin Y, Stanworth S, Birchall K et al. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without hemophilia (review). Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD005011. DOI: 10.1002/14651858.CD005011.pub2.

46. Marti-Carvajal AJ, Salanti G, Mari-Carvajal PI. Human recombinant activated factor VII for upper gastrointestinal bleeding in patients with liver diseases (review). Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD004887. DOI: 10.1002/14651858.CD004887.pub2.

47. Novo Nordisk. NovoSeven (coagulation factor VIIa [recombinant]) prescribing information. Princeton, NJ; 2006 13 Oct.

48. Baxter Healthcare Corporation. Recombinate antihemophilic factor (recombinant) prescribing information. Westlake Village, CA; 2009 Jul.

49. CSL Behring. Helixate FS antihemophilic factor (recombinant) formulated with sucrose prescribing information. Kankakee, IL; 2009 Aug.

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