1. FACTOR VII (NovoSeven)
A literature review of current dosing strategies

2. The main role of factor VII is to initiate the process of coagulation in conjunction with tissue factor.
Tissue factor is found on the outside of blood vessels - normally not exposed to the bloodstream.
Upon vessel injury, tissue factor is exposed to the blood and circulating factor VII.

3. NovoSeven® RT is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to FVIII or FIX, and in patients with acquired hemophilia; prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; treatment of bleeding episodes in patients with congenital Factor VII deficiency and prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency.

4. 2010 Sales of NovoSeven = $1.6 billion
Company claims that only 15% of sales are for
off-label use
NovoNordisk website

5. Nearly 90% of all NovoSeven usage is off-label
Magnetti S., Oinonen, M., An Evaluation of Of-Label Use of Recombinant Activated Human Factor VII (NovoSeven) P&T April Vol. 32 No. 4

6. Trends at Parkview Hospital
NovoSeven Usage
Trends at Parkview Hospital
NovoSeven usage is growing at 20% annualized rates worldwide.
~ $500,000
NovoSeven usage is growing at 20% annually worldwide.

7. NovoSeven
Cost per microgram
$1.34

8. Average Dose per Patient
NovoSeven
Average Dose per Patient
6,722 mcg
Parkview Pharmacy database

9. Average Cost per Patient
NovoSeven
Average Cost per Patient
$9,007

10. “There is significant regional variation in the administration of rFVIIa…..with little documentation of adherence to guidelines.”
Willis CD, Cameron PA, Phillips L. Variation in the use of Recombinant Activated Factor VII in critical bleeding. Intern Med J Aug 27
Magnetti S., Oinonen, M., An Evaluation of Of-Label Use of Recombinant Activated Human Factor VII (NovoSeven) P&T April Vol. 32 No. 4

11. NovoSeven Dosing
If NovoSeven is used off-label, the manufacturer provides no dosing guidelines.

12. NovoSeven Dosing
If NovoSeven is used off-label, the manufacturer provides no dosing guidelines.
If asked, pharmacists will probably dose NovoSeven at 90 mcg/kg

13. “optimal dose has not been established.”
Review: Off-Label Uses of Recombinant
Factor VIIa (NovoSeven® RT—Novo Nordisk)
February 2010
Authored by:
Michelle Wheeler, PharmD, Drug Information Specialist
An Vu, PharmD, Drug Information Specialist
University of Utah Hospitals & Clinics
Drug Information Center
421 Wakara Way, Suite 204
Salt Lake City, UT 84108
Meta-analysis. 173 references.
“It is unclear….”
“optimal dose has not been established.”

14. Review: Off-Label Uses of Recombinant
Factor VIIa (NovoSeven® RT—Novo Nordisk)
February 2010
“Due to the lack of strong clinical evidence, rFVIIa is not recommended as a first-line therapy for any unlabeled use.”

15. Dosing Variations at Parkview
Avg. dose of fVII if Pharmacy doses
8,395 mcg
$11,250
Avg. dose of fVII if MD orders specific dose
4,796 mcg
$6,426
Net Difference
3,599 mcg
$4,823
Parkview Hospital Database of NovoSeven usage in 2009

16. What dose should we give?

17. Serious Thrombotic Events and
NovoSeven Morbidity
Serious Thrombotic Events and
Off-Label Use
Postmarketing cases of arterial and venous thrombotic/thromboembolic events, incl. fatal, have been reported. Increased arterial thromboembolism risk when admin. outside approved indications.
Howles JL, Smith RS Complications of recombinant activated human coagulation factor VIIa Am J Surg 2009 Dec;198
Diringer MN, Skolnick BE Thromboembolic Events with recombinant activated factor VIIa in spontaneous intracerebral hemorrhage. Stroke Dec 3

18. NovoSeven Morbidity
An increasing volume of research suggest a dose-dependant incidence of thrombosis with the use of rFVIIa
Howles JL, Smith RS Complications of recombinant activated human coagulation factor VIIa Am J Surg 2009 Dec;198
Diringer MN, Skolnick BE Thromboembolic Events with recombinant activated factor VIIa in spontaneous intracerebral hemorrhage. Stroke Dec 3

19. NovoSeven Morbidity
An increasing volume of research suggests a dose-dependant incidence of thrombosis with the use of rFVIIa
Prudence dictates a conservative dosage strategy… at least initially!
Howles JL, Smith RS Complications of recombinant activated human coagulation factor VIIa Am J Surg 2009 Dec;198
Diringer MN, Skolnick BE Thromboembolic Events with recombinant activated factor VIIa in spontaneous intracerebral hemorrhage. Stroke Dec 3

20. Articles describing successful adoption of low-dose strategies.
Canadian study of 503 patients
Median total dose = 62 mcg/kg
“ …we found that rFVIIa is associated with a reduction in transfusion of blood products….”
Karkouti K, Beattie W Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery Circulation 2008;118;

21. Articles describing successful adoption of low-dose strategies.
Canadian study of 503 patients
Median total dose = 62 mcg/kg
Funded by Novo Nordisk
Karkouti K, Beattie W Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery Circulation 2008;118;

22. Articles describing successful adoption of low-dose strategies.
2005 Panel literature review
500,000 doses reviewed
“ Doses of 20 to 40 mcg/kg were recommended for non-emergent anticoagulant reversal. Doses of 41 to 90 mcg/kg were recommended for all other scenarios ”
40 patients – Italian study
Shander A, Goodnough L. Consensus Recommendations for Off-Label Use of Recombinant Human Factor VIIa (NovoSeven) Therapy P & T November Vol. 30 No 11

23. Articles describing successful adoption of low-dose strategies.
US study of 81 trauma patients
Total dose = 1.2 mg
40 patients – Italian study
“ Low dose FVIIa rapidly and effectively treats mild to moderate coagulaopathy following injury.”
Stein DM, Dutton RP Low-dose recombinant factor VIIa for trauma patients with coagulopathy Injury Sep;39(9)

24. Articles describing successful adoption of low-dose strategies.
Italian study of 15 CV patients
Total dose = 1.2 mg
40 patients – Italian study
“ Small-dose rFVIIa showed satisfactory results in cardiac patients with intractable bleeding.”
Romagnoli S, Bevilacqua S Small-Dose Recombinant Activated Factor VII (NovoSeven) in Cardiac Surgery Anesth Analg 2006;102:1320-6

25. Acute Hemorrhagic Stroke
Study of 841 patients with intracerebral hemorrhage randomized to:
NovoSeven 20 mcg/kg
NovoSeven 80 mcg/kg
Placebo
40 patients – Italian study
Mayer S., Brun N., Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NAJM volume 358:

26. Acute Hemorrhagic Stroke
“Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage.”
40 patients – Italian study
Mayer S., Brun N., Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NEJM volume 358:

27. Acute Hemorrhagic Stroke
Thromboembolic events were more frequent with higher doses.
40 patients – Italian study
Mayer S., Brun N., Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NEJM volume 358:

28. Acute Hemorrhagic Stroke
Thromboembolic events were more frequent with higher doses.
Study was funded by Novo Nordisk
40 patients – Italian study
Mayer S., Brun N., Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NEJM volume 358:

29. What dose should we give?

30. MASSIVE TRANSFUSION PROTOCOL
Definition: Expected transfusion of > 10 units RBC in 24 hours.
Indication: Exsanguinating and/or Hemodynamically Unstable
Shipment
RBC
Thawed Plasma
PLT
CRYO
NovoSeven*
Pharmacy to dispense 1
5 (O-neg)
2 If available 2 5 4
2 mg 3
1 (10) 6 7 8 9 10

31. NovoSeven Dosing
In accordance with Parkview’s Massive Transfusion Protocol, start with 2 mg.

32. NovoSeven Dosing
In accordance with Parkview’s Massive Transfusion Protocol, start with 2 mg.
DON’T ASK THE PHARMACY TO DOSE!

33. NovoSeven Dosing
In accordance with Parkview’s Massive Transfusion Protocol, start with 2 mg.
DON’T ASK THE PHARMACY TO DOSE!
Repeat dose as needed.

35. Parkview Pharmacy Dosing
77 kg x 90 mcg
= 6,930 mcg
X $1.34
=$9,286
Parkview Pharmacy Dosing

36. Parkview Pharmacy Dosing
2 mg (2,000mcg)
X $1.34
=$2,680
$6,606 savings
Parkview Pharmacy Dosing

37. NovoSeven usage is growing at 20% annualized rates worldwide.

38. NovoSeven usage is growing at 20% annualized rates worldwide.

39. NovoSeven usage is growing at 20% annualized rates worldwide.