Novoseven (Coagulation Factor Viia (Recombinant, Human)) - Description and Clinical Pharmacology

DESCRIPTION

NovoSeven® is recombinant human coagulation Factor VIIa (rFVIIa), intended for promoting hemostasis by activating the extrinsic pathway of the coagulation cascade.¹ NovoSeven is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues (MW 50 K Dalton). NovoSeven is structurally similar to human plasma-derived Factor VIIa.

The gene for human Factor VII is cloned and expressed in baby hamster kidney cells (BHK cells). Recombinant FVII is secreted into the culture media (containing newborn calf serum) in its single-chain form and then proteolytically converted by autocatalysis to the active two-chain form, rFVIIa, during a chromatographic purification process. The purification process has been demonstrated to remove exogenous viruses (MuLV, SV40, Pox virus, Reovirus, BEV, IBR virus). No human serum or other proteins are used in the production or formulation of NovoSeven.

NovoSeven is supplied as a sterile, white lyophilized powder of rFVIIa in single-use vials.

Each vial of lyophilized drug contains the following:

After reconstitution with the appropriate volume of Sterile Water for Injection, USP (not supplied), each vial contains approximately 0.6 mg/mL NovoSeven (corresponding to 600 µg/mL). The reconstituted vials have a pH of approximately 5.5 in sodium chloride (3 mg/mL), calcium chloride dihydrate (1.5 mg/mL), glycylglycine (1.3 mg/mL), polysorbate 80 (0.1 mg/mL), and mannitol (30 mg/mL).

The reconstituted product is a clear colorless solution which contains no preservatives. NovoSeven contains trace amounts of proteins derived from the manufacturing and purification processes such as mouse IgG (maximum of 1.2 ng/mg), bovine IgG (maximum of 30 ng/mg), and protein from BHK-cells and media (maximum of 19 ng/mg).

CLINICAL PHARMACOLOGY

PHARMACODYNAMICS

NovoSeven 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.

PHARMACOKINETICS

Single-dose pharmacokinetics of NovoSeven (17.5, 35, and 70 µg/kg) exhibited dose-porportional behavior in 15 subjects with hemophilia A or B.² Factor VII clotting activities were measured in plasma drawn prior to and during a 24-hour period after NovoSeven 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 t_1/2 was 2.3 hours (range 1.7-2.7). The median in vivo plasma recovery was 44% (30-71%).

CLINICAL STUDIES

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

OPEN PROTOCOL USE

The largest number of patients who received NovoSeven during the investigational phase of product development were in an open protocol study^3,4,5 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 the Open Protocol is problematic for the evaluation of the safety and efficacy of the product by statistical methods. The following two cases describe the extremes of the clinical outcomes that were observed under the Open Protocol:

Case #1: A one-year-old hemophilia B patient had both an inhibitor to Factor IX and would experience severe anaphylactic reactions to any product containing Factor IX. His life threatening hypersensitivity reaction to Factor IX precluded the use of other coagulation products and NovoSeven was requested under the compassionate use program because it contained Factor VIIa and no other coagulation factors. Between the child's ages of one to three, he was successfully treated with NovoSeven for 23 spontaneous joint, muscle, and oral bleeds. NovoSeven was administered by intravenous bolus dosing at 90 µg/kg every two hours. Hemostasis was achieved each time within one to eight days therapy, without reported sequelae. Adverse events were infrequent, minor, and considered unrelated to NovoSeven treatment.

Case #2: A 36-year-old hemophilia A patient with long standing inhibitors experienced pain between his shoulderblades (DAY 0); he treated himself at home for three days with an activated Prothrombin Complex Concentrate (aPCC). From DAY 16-DAY 18, the patient treated himself at home with another aPCC. On DAY 18, he awoke with paraparesis of the lower extremities and was hospitalized. A large epidural hematoma (C6 to T12) was seen on MRI.

The following day (DAY 19), the patient began treatment with NovoSeven, 90 µg/kg every 2 (and later every 3) hours (DAY 19-36). Neurologic and symptomatic improvement was observed. On DAY 29, the NovoSeven dose interval was increased to every four hours. On DAY 31, the patient experienced a massive upper gastrointestinal bleed secondary to stress ulcers (likely dexamethasone induced). He was hypotensive for over two hours, and by the next day, he was requiring large volumes of fluid support and developed abdominal pain. A laparotomy on DAY 32 revealed necrotic large bowel which required resection. Intraoperative and post operative hemostasis was satisfactory on NovoSeven and there was no evidence of thrombosis of the larger mesenteric vessels either at surgery or in the pathologic specimen. On the fourth day post-op (DAY 36), NovoSeven investigational supplies were depleted, and the patient began receiving an aPCC (72 U/kg every 6 hours) and four units of packed red cells per day. During aPCC therapy, bleeding increased; there was coffee ground emesis in the naso-gastric tube. After two days (DAY 38), additional NovoSeven was provided, but the patient was then experiencing severe adult respiratory distress syndrome (ARDS). Within 24 hours of resuming NovoSeven treatment (DAY 40), the patient's life support was voluntarily removed. An autopsy noted the history of bleeding ulcer, ischemic colon, thrombocytopenia, diffuse hemorrhage, lung changes consistent with ARDS, history of epidural hemorrhage, arthropathy, and generalized edema. His stomach had no signs of the ulcers seen the week before on endoscopy indicating healing. On gross neuropathologic exam, his epidural hematoma had resolved.

DOSING STUDY

A double-blind, randomized comparison trial⁶ of two dose levels of NovoSeven in the treatment of joint, muscle and mucocutaneous hemorrhages was conducted in hemophilia A and B patients with and without inhibitors. Patients received NovoSeven 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. Two unrelated deaths occurred; one patient died of AIDS and the other of intracranial hemorrhage secondary to trauma.