> Pharmacology

Designed for reliability with molecular precision.

Novoeight® offers consistency from batch to batch—measurable by a standard assay.1,2

Seven 250 mL Novoeight® purple topped vials
Seven 250 mL Novoeight® purple topped vials

Mechanism of action.

Novoeight® works by temporarily replacing the missing factor VIII protein that is needed for effective hemostasis.3

B-domain truncated.

Precisely B-domain truncated to obtain a well-defined product.4,5

Novoeigth® B-domain truncated heavy and light chain. Full-length FVIII B-domain heavy and light chain
Novoeigth® B-domain truncated heavy and light chain. Full-length FVIII B-domain heavy and light chain

Consistent heavy chain length.

FVIII analyzed by SDS-PAGE.4,a

Novoeight® SDS-Page precisely truncated B-domain length image compared to 2nd and 3rd generation (full length) with variable B-domain lengths image
Novoeight® SDS-Page precisely truncated B-domain length image compared to 2nd and 3rd generation (full length) with variable B-domain lengths image


SDS-PAGE gel comparison adapted from Thim et al.5 
HC=heavy chain; LC=light chain; SDS-PAGE=sodium dodecyl sulfate polyacrylamide gel electrophoresis.

aThis study compared turoctocog alfa with commercially available rFVIII products using SDS-PAGE and Western blotting.4 

Full Tyr-1680 sulfation.

Tyrosine sulfation supports high-affinity binding to vWF.4-6,b

  • Binding to vWF has been shown to protect FVIII from premature clearance and degradation4-6
  • Novoeight® is >99% sulfated at Tyr-16807 


bThe clinical significance of the degree of tyrosine sulfation has not been established.
vWF=von Willebrand factor.

Immunoaffinity chromatography.

  • Precise manufacturing process targets and selects molecules with fully intact A2 domains5,8 
  • Novoeight® is similar to endogenous FVIII in its active form, ensuring effective physiologic activity3,5
  • F25 is a recombinant mAB

Pharmacokinetics studies.3

All pharmacokinetic studies with Novoeight® were conducted in previously treated patients with severe hemophilia A (factor VIII ≤1%). Analysis of plasma samples was conducted using both the one-stage clotting assay and the chromogenic assay.3

In a multi-center, multi-national, open-label, single dose pharmacokinetic study, 23 patients with severe hemophilia A received 50 international units/kg of Novoeight® intravenously. Two patients were below the age of 18 years (13 and 17 years). The pharmacokinetic parameters for 20 patients who completed the study are summarized in the following table:3 

Pharmacokinetics of Novoeight® in 20 adult and adolescent patients with hemophilia A
Pharmacokinetics of Novoeight® in 20 adult and adolescent patients with hemophilia A

Pharmacokinetics of Novoeight® in 20 adult and adolescent patients with hemophilia A3

Parameters

Incremental Recovery
(IU/mL)/(IU/kg)
Clotting Assay: 0.020 (0.002)
Chromogenic Assay: 0.028 (0.006)

AUC (IU*h/mL)
Clotting Assay: 14.2 (3.8)
Chromogenic Assay: 18.7 (5.1)

CL (mL/h/kg)
Clotting Assay: 3.74 (0.95)
Chromogenic Assay: 2.87 (0.80)

t1/2 (h)
Clotting Assay: 10.8 (4.9)
Chromogenic Assay: 12.0 (9.3)

Vss (mL/kg)
Clotting Assay: 53.4 (10.9)
Chromogenic Assay: 44.3 (28.2)

Cmax (IU/mL)
Clotting Assay: 1.07 (0.16)
Chromogenic Assay: 1.54 (0.29)

MRT (h)
Clotting Assay: 15.4 (6.4)
Chromogenic Assay: 16.4 (10.1)


In a separate pharmacokinetic study, 28 pediatric patients with severe hemophilia A (14 patients were below 6 years of age and 14 patients were between 6 to <12 years of age) received a single dose of 50 international units/kg Novoeight®. The pharmacokinetic parameters of Novoeight® are summarized in the following table for both age groups.
 

Pharmacokinetics of Novoeight® in 28 pediatric patients with hemophilia A
Pharmacokinetics of Novoeight® in 28 pediatric patients with hemophilia A

Pharmacokinetics of Novoeight® in 28 pediatric patients with hemophilia A3

Parameters

Incremental Recovery
(IU/mL)/(IU/kg)
Clotting Assay 0 to <6 years: 0.018 (0.007); 6 to <12 years: 0.020 (0.004) 
Chromogenic Assay 0 to <6 years: 0.022 (0.006); 6 to <12 years: 0.025 (0.006)

AUC (IU*h/mL)
Clotting Assay 0 to <6 years: 9.9 (4.1); 6 to <12 years: 11.1 (3.7)
Chromogenic Assay 0 to <6 years: 12.2 (4.4); 6 to <12 years: 14.4 (3.5)

CL (mL/h/kg)
Clotting Assay 0 to <6 years: 6.26 (3.73); 6 to <12 years: 5.02 (1.67)
Chromogenic Assay 0 to <6 years: 4.60 (1.75); 6 to <12 years: 3.70 (1.00)

t1/2 (h)
Clotting Assay 0 to <6 years: 7.7 (1.8); 6 to <12 years: 8.0 (1.9)
Chromogenic Assay 0 to <6 years: 10.0 (1.7); 6 to <12 years: 9.4 (1.5)

Vss (mL/kg)
Clotting Assay 0 to <6 years: 57.3 (26.8); 6 to <12 years: 46.8 (10.6)
Chromogenic Assay 0 to <6 years: 55.8 (23.7); 6 to <12 years: 41.2 (6.0)

Cmax (IU/mL)
Clotting Assay 0 to <6 years: 1.00 (0.58); 6 to <12 years: 1.07 (0.35)
Chromogenic Assay 0 to <6 years: 1.12 (0.31); 6 to <12 years: 1.25 (0.27)

MRT (h)
Clotting Assay 0 to <6 years: 9.7 (2.5); 6 to <12 years: 9.9 (2.6)
Chromogenic Assay 0 to <6 years: 12.1 (1.9); 6 to <12 years: 11.6 (2.3)

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Selected Important Safety Information

Contraindications

  • Do not use in patients who have had life-threatening hypersensitivity reactions, including anaphylaxis, to Novoeight® or its components, including hamster proteins

Warnings and Precautions

  • Anaphylaxis and severe hypersensitivity reactions are possible. Patients may develop hypersensitivity to hamster proteins, which are present in trace amounts in the product. Should symptoms occur, discontinue Novoeight® and administer appropriate treatment

Indications and Usage

Novoeight® (antihemophilic factor, recombinant) is indicated for use in adults and children with hemophilia A for on-demand treatment and control of bleeding episodes, perioperative management, and routine prophylaxis to reduce the frequency of bleeding episodes.

  • Novoeight® is not indicated for the treatment of von Willebrand disease

Important Safety Information

Contraindications

  • Do not use in patients who have had life-threatening hypersensitivity reactions, including anaphylaxis, to Novoeight® or its components, including hamster proteins

Warnings and Precautions

  • Anaphylaxis and severe hypersensitivity reactions are possible. Patients may develop hypersensitivity to hamster proteins, which are present in trace amounts in the product. Should symptoms occur, discontinue Novoeight® and administer appropriate treatment
  • Development of activity-neutralizing antibodies (inhibitors) may occur. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all factor VIII products. Inhibitors have been reported following administration of Novoeight in PUPs. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform testing for factor VIII inhibitors

Adverse Reactions

  • The most frequently reported adverse reactions (≥1%) were inhibitors in Previously Untreated Patients (PUPs), injection site reactions, and pyrexia.

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References

  1. Christiansen ML, Balling KW, Persson E, Hilden I, et al. Functional characteristics of N8, a new recombinant FVIII. Haemophilia. 2010;16:878-887.
  2. Viuff D, Barrowcliffe T, Saugstrup T, Ezban M, Lillicrap D. International comparative field study of N8 evaluating factor VIII assay performance. Haemophilia. 2011; 17(4):695-702.
  3. Novoeight [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2020.
  4. Ezban M, Vaci K, Kjalke M. Turoctocog alfa (NovoEight®) - from design to clinical proof of concept. Eur J Haematol. 2014;93:369-376.
  5. Thim L, Vandahl B, Karlsson J, Klausen NK, et al. Purification And Characterization Of A New Recombinant Factor Viii (N8). Haemophilia. 2010; 16:349-359.
  6. Grancha S, Navajas R, Marali6n C, et al. Incomplete tyrosine 1680 sulphation in recombinant FVIII concentrates. Haemophilia. 2011;17(4):709-710.
  7. Nielsen PF, Bak S, Vanda hi B. Characterization of tyrosine sulphation in rFVIII (turoctocog alfa) expressed in CHO and HEK-293 cells. Haemophilia. 2012;18:e397-e398.
  8. Ahmadian H, Hansen EB, Faber JH, et al. Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule. Blood Coagul Fibrinolysis. 2016;27(5):568-575.