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Novoseven

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Novoseven

CLINICAL PHARMACOLOGY

Pharmacodynamics

NovoSeven (coagulation factor viia (recombinant)) is recombinant Factor VIIa and, when complexed with tissue factor can activate coagulation Factor X to Factor Xa, as well as coagulation Factor IX to Factor IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may also occur on the surface of activated platelets.

The effect of NovoSeven (coagulation factor viia (recombinant)) upon coagulation in patients with or without hemophilia has been assessed in different model systems. In an in vitro model of tissue-factor-initiated blood coagulation (Figure A)2, the addition of NovoSeven (coagulation factor viia (recombinant)) increased both the rate and level of thrombin generation in normal and hemophilia A blood, with an effect shown at NovoSeven (coagulation factor viia (recombinant)) concentrations as low as 10 nM. In this model, fresh human blood was treated with corn trypsin inhibitor (CTI) to block the contact pathway of blood coagulation. Tissue factor (TF) was added to initiate clotting in the presence and absence of NovoSeven (coagulation factor viia (recombinant)) for both types of blood.

In a separate model, and in line with previous reports3, escalating doses of NovoSeven (coagulation factor viia (recombinant)) in hemophilia plasma demonstrate a dose-dependent increase in thrombin generation (Figure B). In this model, platelet rich normal and hemophilia plasma was adjusted with autologous plasma to 200, 000 platelets/μl. Coagulation was initiated by addition of tissue factor and CaCl2. Thrombin generation was measured in the presence of a thrombin substrate and various added concentrations of rFVIIa.

Figure A

An in vitro model of tissue-factor-initiated blood coagulation - Illustration

Figure B

Dose-dependent increase in thrombin generation - Illustration

TF-initiated clotting of normal and hemophilia A platelet rich plasma in the presence of rFVIIa.

Pharmacokinetics

Hemophilia A or B

Single-dose pharmacokinetics of NovoSeven (coagulation factor viia (recombinant)) (17.5, 35, and 70 μg/kg) exhibited dose-proportional behavior in 15 subjects with hemophilia A or B.4 Factor VII clotting activities were measured in plasma drawn prior to and during a 24-hour period after NovoSeven (coagulation factor viia (recombinant)) administration. The median apparent volume of distribution at steady state was 103 mL/kg (range 78-139). Median clearance was 33 mL/kg/hr (range 27-49). The median residence time was 3.0 hours (range 2.4-3.3), and the t1/2 was 2.3 hours (range 1.7-2.7). The median in vivo plasma recovery was 44% (30-71%).

Congenital Factor VII deficiency

Single dose pharmacokinetics of NovoSeven (coagulation factor viia (recombinant)) in congenital Factor VII deficiency, at doses of 15 and 30 μg per kg body weight, showed no significant difference between the two doses used with regard to dose-independent parameters: total body clearance (70.8-79.1 mL/hr x kg), volume of distribution at steady state (280-290 mL/kg), mean residence time (3.75-3.80 hr), and half-life (2.82-3.11 hr). The mean in vivo plasma recovery was approximately 20% (18. 9%-22. 2%).

The normal Factor VII plasma concentration is 0. 5 μg/mL. Factor VII levels of 15-25% (0.075 – 0.125 μg/mL) are generally sufficient to achieve normal hemostasis. 5 A 70 kg individual with FVII deficiency (plasma volume of approximately 3000 mL) would thus require 3.2 - 5.4 μg/kg of NovoSeven (coagulation factor viia (recombinant)) to secure hemostasis, assuming 100% recovery. Since the mean plasma recovery for NovoSeven (coagulation factor viia (recombinant)) is 20% for FVII-deficient patients, a NovoSeven (coagulation factor viia (recombinant)) dose range of 16-27 μg/kg would be required to achieve sufficient FVII plasma levels for hemostasis.

Clinical Studies

No direct comparisons to other coagulation products have been conducted, therefore no conclusions regarding the comparative safety or efficacy can be made.

Hemophilia A or B with Inhibitors to Factor VIII or Factor IX

Open Protocol Use

The largest number of patients who received NovoSeven (coagulation factor viia (recombinant)) during the investigational phase of product development were in an open protocol study (Study A)6,7,8 that began enrollment in 1988, shortly after the completion of the pharmacokinetic study. These patients included persons with hemophilia types A or B (with or without inhibitors), persons with acquired inhibitors to Factor VIII or Factor IX, and a few FVII deficient patients. The clinical situations were diverse and included muscle/joint bleeds, mucocutaneous bleeds, surgical prophylaxis, intracerebral bleeds, and other emergent situations. Dose schedules were suggested by Novo Nordisk, but they were subject to the option of the investigator. Clinical outcomes were not reported in a standardized manner. Therefore, the clinical data from Study A are problematic for the evaluation of the safety and efficacy of the product by statistical methods.

Dosing Study

A double-blind, randomized comparison trial (Study B)9 of two dose levels of NovoSeven (coagulation factor viia (recombinant)) in the treatment of joint, muscle and mucocutaneous hemorrhages was conducted in hemophilia A and B patients with and without inhibitors. Patients received NovoSeven (coagulation factor viia (recombinant)) as soon as they could be evaluated in the treatment centers (4 to 18 hours after experiencing a bleed). Thirty-five patients were treated at the 35 μg/kg dose (59 joint, 15 muscle and 5 mucocutaneous bleeding episodes) and 43 patients were treated at the 70 μg/kg dose (85 joint and 14 muscle bleeding episodes). Dosing was to be repeated at 2.5 hour intervals but ranged up to four hours for some patients. Efficacy was assessed at 12 ± 2 hours or at end of treatment, whichever occurred first. Based on a subjective evaluation by the investigator, the respective efficacy rates for the 35 and 70 μg/kg groups were: excellent 59% and 60%, effective 12% and 11%, and partially effective 17% and 20%. The average number of injections required to achieve hemostasis was 2.8 and 3.2 for the 35 and 70 μg/kg groups, respectively.

One patient in the 35 μg/kg group and three in the 70 μg/kg group experienced serious adverse events that were not considered related to NovoSeven (coagulation factor viia (recombinant)) . Two unrelated deaths occurred; one patient died of AIDS and the other of intracranial hemorrhage secondary to trauma.

Surgery Studies

Two clinical trials (Studies C and D) were conducted to evaluate the safety and efficacy of rFVIIa administration during and after surgery in hemophilia A or B patients with inhibitors.

Study C was a randomized, double-blind, parallel group clinical trial (29 patients with hemophilia A or B and inhibitors or acquired inhibitors to FVIII/FIX, undergoing major or minor surgical procedures). 10 Patients received bolus intravenous rFVIIa (either 35 μg/kg, N=15; or 90 μg/kg, N=14) prior to surgery, intra-operatively as required, then every 2 hours for the following 48 hours beginning at closure of the wound. Additional doses were administered every 2 to 6 hours up to an additional 3 days to maintain hemostasis. After a maximum of 5 days of double-blind treatment, therapy could be continued in an open-label manner if necessary (90 μg/kg rFVIIa every 2-6 hours). Efficacy was assessed during the intra-operative period, and postoperatively from the time of wound closure (Hour 0) through Day 5.

When efficacy assessments at each time point were tabulated by a last value carried forward approach (patients who completed the study early having achieved effective hemostasis were counted as “effective”and those who discontinued due to treatment failure or adverse events were counted as “ineffective”at each time point thereafter), the results at the end of the 5-day double-blind treatment period were as summarized in the table below. Twenty-three patients successfully completed the entire study (including the open-label period after the 5-day double blind period) with satisfactory hemostasis.

Study C: Dose Comparison of Efficacy in Major and Minor Surgery -LastValue Carried Forward*

Number of effective (E)/ineffective (I) responses in each dose group
  Major Surgery Minor Surgery
35 μg/kg
(n= 5)
90 μg/kg
(n= 6)
35 μg/kg
(n =10)
90 μg/kg
(n= 8)
Total
(n =29)
  E I E I E I E I E I
Intraoperative   5 0 6 0 10 0 7 1 28 1
Post-Op
Hour 0 5 0 6 0 8 2 6 2 25 4
  8 4 1 5 1 9 1 7 1 25 4
  24 4 1 6 0 9 1 6 2 25 4
  48 3 2 6 0 8 2 8 0 25 4
Day 3 2 3 6 0 8 2 8 0 24 5
  4 3 2 6 0 8 2 8 0 25 4
  5 3 2 5 1 8 2 8 0 24 5
*Patients who completed the study early having achieved effective hemostasis were counted as effective at subsequent time-points, and patients who discontinued due to treatment failure or adverse events were counted as ineffective at subsequent time-points. Only effective ratings were counted as successful hemostasis (ratings of “partially effective” were not counted). Ten patients completed the study by Day 5 because their bleeding had resolved and they were discharged from the hospital. Three patients dropped out of the study due to ineffective therapy and 1 patient left the study due to an adverse event.

E: Number of patients where rFVIIa treatment was effective; I: Number of patients where rFVIIa treatment was ineffective

Study C: Dosing by Surgery Category

  Major Surgery Minor Surgery
35 μg/kg
(n = 5)
90 μg/kg
(n = 6)
35 μg/kg
(n = 10)
90 μg/kg
(n = 8)
Days of dosing, median (range) 15 (2-26) 9.5 (8-17) 4 (3-6) 6 (3-13)
No.injections, median (range) 135 (11-186) 81 (71-128) 29.5 (24-44) 39.5 (26-98)
Median total dose, mg (range) 656 (31-839) 569 (107-698) 45.5 (14-171) 67 (31-122)

Study D was an open-label, randomized, parallel trial conducted to compare the safety and efficacy of i. v. bolus (N=12) and i. v. continuous infusion (N=12) administration of rFVIIa in hemophilia A or B patients with inhibitors who were undergoing elective major surgery. The types of surgeries that were performed included knee (N=13), hip (N=3), abdomen/lower pelvis (N=2), groin/inguinal area (N=2), circumcision (N=1), eye (N=1), frontal/temporal region of cranium (N=1), and oral cavity (N=1).

Prior to surgery, a 90 μg/kg bolus dose of rFVIIa was administered to both bolus and continuous infusion groups. The bolus injection group then received 90 μg/kg rFVIIa by i. v. bolus injection every 2 hours during the procedure and for the first 5 days, then every 4 hours from Day 6 to Day 10. The continuous infusion group received 50 μg/kg/h rFVIIa by i. v. continuous infusion for the first 5 days, and infusion of 25 μg/kg/h from Day 6 to Day 10. For both rFVIIa-treated groups, two bolus rescue doses of 90 μg/kg were permitted during any 24-hour period.

The bolus injection (90 μg/kg) and continuous infusion (50 μg/kg/h) treatment groups showed comparable efficacy in achieving and maintaining hemostasis in major surgery from wound closure through Day 10. For the Global Hemostasis Treatment Evaluation for overall success in achieving and maintaining hemostasis at the end of the study period, treatment was rated as being effective in 9 patients (75%) and ineffective in 3 patients (25%) for both treatment groups.

When efficacy assessments at each time point were tabulated by a last value carried forward approach (patients who completed the study early having achieved effective hemostasis were counted as “effective” at each time point, and those who discontinued due to treatment failure counted as “ineffective” at each time point thereafter), the results were as summarized in the table below.

Study D: Efficacy of Bolus Dosing vs. Continuous Infusion in Major Surgery - Last Value Carried Forward*

  Number of effective (E)/ineffective (I)
responses in each dose group
Bolus Injection
(rFVIIa 90μg/kg)
n = 12
Continuous Infusion
(rFVIIa 50μg/kg/h)
n =12
E I E I
Post-Op
Hour 0 12 0 12 0
  8 12 0 11 1
  24 12 0 10 2
  48 10 2 11 1
  72 9 3 11 1
Day 4 11 1 10 2
  5 11 1 10 2
  6 11 1 10 2
  7 9 3 10 2
  8 10 2 10 2
  9 9 3 10 2
  10 9 3 10 2
*Patients who completed the study early having achieved hemostasis counted as effective at subsequent time-points, and patients who discontinued due to treatment failure counted as ineffective at subsequent time-points. Eight patients completed the study early because their bleeding had resolved and they were discharged from the hospital. Four patients dropped out of the study due to ineffective therapy and 1 patient left the study due to a hemarthrosis that was described as an adverse event.

E: Number of patients where rFVIIa treatment was effective; I: Number of patients where rFVIIa treatment was ineffective

Study D: Dosing by Treatment Group

  Bolus Injection
90 μg/kg
(n = 12)
Continuous Infusion
50 μg/kg/h
(n = 12)
Days of dosing, median (range) 10 (4-15)a 10 (2-116)
No.bolus injections, median (range) 38 (36-42) 1.5 (0-7)
No.of additional bolus injections, median (range) 0 (0-3) 0 (0-4)
Mean total dose,mg 237.5 292.2
a Includes dosing during the follow-up period after the 10-day study period

Congenital Factor VII Deficiency

Data were collected from the published literature and internal sources for 70 patients with Factor VII deficiency treated with NovoSeven (coagulation factor viia (recombinant)) for 124 bleeding episodes, surgeries, or prophylaxis regimens. Thirty-two of these patients were enrolled in emergency and compassionate use trials conducted by Novo Nordisk (43 non-surgical bleeding episodes, 26 surgeries); 35 were reported in the published literature (20 surgeries, 10non-surgical bleeding episodes, 4 cases of caesarean section or vaginal birth, and 10 cases of long-term prophylaxis, and 1 case of on-demand therapy); and 3 were from a registry maintained by the Hemophilia and Thrombosis Research Society (9 bleeding episodes, 1 surgery). Dosing ranged from 6-98 μg/kg administered every 2-12 hours (except for prophylaxis, where doses were administered from 2 times per day up to 2 times per week). Patients were treated with an average of 1-10 doses. Treatment was effective (bleeding stopped or treatment was rated as effective by the physician) in 93% of episodes (90% for trial patients, 98% for published patients, 90% for HTRS registry patients).

Acquired Hemophilia

Data were collected from four studies in the compassionate use program conducted by Novo Nordisk and the Hemophila and Thrombosis Research Society (HTRS) registry. A total of 70 patients with acquired hemophilia were treated with NovoSeven (coagulation factor viia (recombinant)) for 113 bleeding episodes, surgeries, or traumatic injuries. Sixty-one of these patients were from the compassionate use program with 100 bleeding episodes (68 non-surgical and 32 surgical bleeding episodes) and 9 patients were from the HTRS registry with 13 bleeding episodes (8 non-surgical, 3 surgical and 2 episodes classified as other). Concomitant use of other hemostatic agents occurred in 29/70 (41%); 13 (19%) received more than one hemostatic agent. The most common hemostatic agents used were antifibrinolytics, Factor VIII and activated prothrombin complex concentrates.

The compassionate use programs and the HTRS registry were not designed to select doses or compare first-line efficacy or efficacy when used after failure of other hemostatic agents (salvage treatment). A dose response was not seen in doses ranging from 70-90 μg/kg.

The mean dose of rFVIIa administered was 90 μg/kg (range: 31 to 197 μg/kg); the mean number of injections per day was 6 (range: 1 to 10 injections per day). Overall efficacy i. e. , effective and partially effective outcomes, was 87/112 (78%);with 77/100 (77%) efficacy in the compassionate use programs and 10/12 (83%) efficacy in the HTRS registry. In the compassionate use programs, overall efficacy for the first-line treatment was 38/44 (86%) compared to 39/56 (70%) when used as salvage treatment.

Efficacy by Dose Group, for Patients Receiving Doses Ranging from < 61 to > 90 μg/kg rFVIIa, Compassionate Use Programs and HTRS Registry

  rFVIIa Dose (μg/kg)
Outcomea Unknown < 61 61-69 70-80 81-89 90 > 90 Total
Effective N (%) 1 (33) 3 (75) 5 (63) 10 (63) 12 (57) 10 (67) 26 (58) 67
Partial N (%) 1 (33) 0 (0) 0 (0) 3 (19) 3 (14) 2 (13) 11 (24) 20
Ineffective N (%) 0 (0) 1 (25) 3 (38) 2 (13) 2 (10) 2 (13) 7 (16) 17
Unknown N (%) 1 (33) 0 (0) 0 (0) 1 (6) 4 (19) 1 (7) 1 (2) 8
No.of Bleeding Episodesc 3 4 8 16 21 15 45 112b
a Outcome assessed at end of treatment, last observation carried forward
b One patient in the HTRS registry was excluded from efficacy analysis since rFVIIa was used to maintain hemostasis after bleeding had been controlled.
c N (%) do not add up to 100 due to rounding.

REFERENCES

2. Butenas, S. , et al. : Mechanism of factor VIIa-dependent coagulation in hemophilia blood, Blood 2002; 99: 923-930. Figure A Copyright American Society of Hematology, used with permission.

3. Allen, G. A. , et al. : The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation, Blood Coagulation and Fibrinolysis 2000;11 (suppl 1): 3-7.

4. Lindley, C. M. , et al. : Pharmacokinetics and pharmacodynamics of recombinant Factor VIIa, Clinical Pharmacology & Therapeutics 1994; 55 (6): 638-648.

5. Bauer, K. A. : Treatment of Factor VII deficiency with recombinant Factor VIIa, Haemostasis 1996; 26 (suppl 1):155-158.

6. Lusher, J. , et al. :Clinical experience with recombinant Factor VIIa, Blood Coagulation and Fibrinolysis 1998; 9: 119-128.

7. Bech, M. R. : Recombinant Factor VIIa in Joint and Muscle Bleeding Episodes, Haemostasis 1996; 26 (suppl 1): 135-138.

8. Lusher, J. M. : Recombinant Factor VIIa (NovoSeven (coagulation factor viia (recombinant)) ®) in the Treatment of Internal Bleeding in Patients with Factor VIII and IX Inhibitors, Haemostasis 1996; 26 (suppl 1): 124-130.

9. Lusher, J. M. , et al. : A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with hemophilia A and B, with and without inhibitor, Haemophilia 1998; 4: 790-798.

10. Shapiro A. D. , et al: Prospective, Randomised Trial of Two Doses of rFVIIa (NovoSeven (coagulation factor viia (recombinant)) ) in Haemophilia Patients with Inhibitors Undergoing Surgery, Thrombosis and Haemostasis 1998; 80: 773-778.

Last reviewed on RxList: 1/12/2009
This monograph has been modified to include the generic and brand name in many instances.

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