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

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.

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.

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

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 2007 Vol. 32 No. 4

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.

NovoSeven Cost per microgram $1.34

Average Dose per Patient NovoSeven Average Dose per Patient 6,722 mcg Parkview Pharmacy database - 2009

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

“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 2009 Aug 27 Magnetti S., Oinonen, M., An Evaluation of Of-Label Use of Recombinant Activated Human Factor VII (NovoSeven) P&T April 2007 Vol. 32 No. 4

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

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

“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.”

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.”

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

What dose should we give?

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 2009 Dec 3

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 2009 Dec 3

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 2009 Dec 3

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;331-338

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;331-338

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 2005 Vol. 30 No 11

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 2008 Sep;39(9) 1054-61

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

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 2008 volume 358:2127-2137

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 2008 volume 358:2127-2137

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 2008 volume 358:2127-2137

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 2008 volume 358:2127-2137

What dose should we give?

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

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

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

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.

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

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

NovoSeven usage is growing at 20% annualized rates worldwide.

NovoSeven usage is growing at 20% annualized rates worldwide.

NovoSeven usage is growing at 20% annualized rates worldwide.