Coagulation Factor VIIa (Recombinant)
CATEGORIES:
Indications: Hemophilia A; Hemophilia B
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.
After reconstitution with the appropriate volume of sterile water for injection (not supplied), each vial contains approximately 0.6 mg/ml coagulation factor VIIa (recombinant) (corresponding to 600 mug/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: 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.
Pharmacokinetics: Single-dose pharmacokinetics of coagulation factor VIIa (recombinant) (17.5, 35, and 70 mug/kg) exhibited dose-proportional 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 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/h (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%).
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 coagulation factor VIIa (recombinant) during the investigational phase of product development were in an open protocol study3-5 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 the manufacturer, 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 1-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 coagulation factor VIIa (recombinant) was requested under the compassionate use program because it contained Factor VIIa and no other coagulation factors. Between the childs ages of 1-3, he was successfully treated with coagulation factor VIIa (recombinant) for 23 spontaneous joint, muscle, and oral bleeds. Coagulation factor VIIa (recombinant) was administered by intravenous bolus dosing at 90 Β΅g/kg every 2 hours. Hemostasis was achieved each time within 1-8 days therapy, without reported sequalae. Adverse events were infrequent, minor, and considered unrelated to coagulation factor VIIa (recombinant) 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 3 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 coagulation factor VIIa (recombinant), 90 Β΅g/kg every 2 (and later every 3) hours (Day 19 -36). Neurologic and symptomatic improvement was observed. On Day 29, the coagulation factor VIIa (recombinant) dose interval was increased to every 4 hours. On Day 31, the patient experienced a massive upper gastrointestinal bleed secondary to stress ulcers (likely dexamethasone induced). He was hypotensive for over 2 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 coagulation factor VIIa (recombinant) 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), coagulation factor VIIa (recombinant) investigational supplies were depleted, and the patient began receiving an aPCC (72 U/kg every 6 hours) and 4 units of packed red cells per day. During aPCC therapy, bleeding increased; there was coffee ground emesis in the naso-gastric tube. After 2 days (Day 38), additional coagulation factor VIIa (recombinant) was provided, but the patient was then experiencing severe adult respiratory distress syndrome (ARDS). Within 24 hours of resuming coagulation factor VIIa (recombinant) 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 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 coagulation factor VIIa (recombinant) as soon as they could be evaluated in the treatment centers (4-18 hours after experiencing a bleed). Thirty-five patients were treated at the 35 mug/kg dose (59 joint, 15 muscle and 5 mucocutaneous bleeding episodes) and 43 patients were treated at the 70 mug/kg dose (85 joint and 14 muscle bleeding episodes).
Dosing was to be repeated at 2.5 hour intervals but ranged up to 4 hours for some patients. Efficacy was assessed at 12 Β± 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 mug/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 mg/kg groups, respectively.
One patient in the 35 mug/kg group and 3 in the 70 mug/kg group experienced serious adverse events that were not considered related to coagulation factor VIIa (recombinant). Two unrelated deaths occurred; one patient died of AIDS and the other of intracranial hemorrhage secondary to trauma.
INDICATIONS AND USAGE:
Coagulation factor VIIa (recombinant) is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX. Coagulation factor VIIa (recombinant) should be administered to patients only under the direct supervision of a physician experienced in the treatment of hemophilia.
CONTRAINDICATIONS:
Coagulation factor VIIa (recombinant) should not be administered to patients with known hypersensitivity to coagulation factor VIIa (recombinant) or any of the components of coagulation factor VIIa (recombinant). Coagulation factor VIIa (recombinant) is contraindicated in patients with known hypersensitivity to mouse, hamster, or bovine proteins.
WARNINGS:
The extent of the risk of thrombotic adverse events after treatment with coagulation factor VIIa (recombinant) is not known, but is considered to be low. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, or septicemia may have an increased risk of developing thrombotic events due to circulating TF or predisposing coagulopathy. (See ADVERSE REACTIONS.)
Additional data on the adverse event profile in general and regarding the frequency of thrombotic events in particular is being collected through a postmarket surveillance program. The Coagulation Factor VIIa (recombinant) Cooperative Registry surveillance program is designed to collect data on all uses of coagulation factor VIIa (recombinant) to expand the base of experience regarding the use of coagulation factor VIIa (recombinant). All prescribers can obtain information regarding contribution of patient data to this program by calling 1-877-362-7355.
PRECAUTIONS:
General
Patients who receive coagulation factor VIIa (recombinant) should be monitored if they develop signs or symptoms of activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, the rFVIIa dosage should be reduced or the treatment stopped, depending on the patient's symptoms.
Due to limited clinical studies which clearly address the effect of post-hemostatic dosing, precautions should be exercised when coagulation factor VIIa (recombinant) is used for prolonged dosing. (See DOSAGE AND ADMINISTRATION.)
Information for the Patient
Patients receiving coagulation factor VIIa (recombinant) should be informed of the benefits and risks associated with treatment. Patients should be warned about the early signs of hypersensitivity reactions, including hives, urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.
Laboratory Tests
Laboratory coagulation parameters may be used as an adjunct to the clinical evaluation of hemostasis in monitoring the effectiveness and treatment schedule of coagulation factor VIIa (recombinant) although these parameters have shown no direct correlation to achieving hemostasis. Assays of prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma FVII clotting activity (FVII:C), may give different results with different reagents.
Treatment With Coagulation Factor VIIa (Recombinant) Has Been Shown to Produce the Following Characteristics:
PT: In patients with hemophilia A/B with inhibitors, the PT shortened to about a 7-second plateau at a FVII:C level of approximately 5 U/ml. For FVII:C levels >5 U/ml, there is no further change in PT.
aPTT: While administration of coagulation factor VIIa (recombinant) shortens the prolonged aPTT in hemophilia A/B patients with inhibitors, normalization has usually not been observed in doses shown to induce clinical improvement. Data indicate that clinical improvement was associated with a shortening of aPTT of 15-20 seconds.
FVIIa:C: FVIIa:C levels were measured 2 hours after coagulation factor VIIa (recombinant) administration of 35 mug/kg and 90 mug/kg following 2 days of dosing at 2 hour intervals. Average steady state levels were 11 and 28 U/ml for the 2 dose levels, respectively.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Two mutagenicity studies have given no indication of carcinogenic potential for coagulation factor VIIa (recombinant). The clastogenic activity of coagulation factor VIIa (recombinant) was evaluated in both in vitro studies (i.e., cultured human lymphocytes) and in vivo studies (i.e., mouse micronucleus test). Neither of these studies indicated clastogenic activity of coagulation factor VIIa (recombinant). Other gene mutation studies have not been performed with coagulation factor VIIa (recombinant) (e.g., Ames test). No chronic carcinogenicity studies have been performed with coagulation factor VIIa (recombinant).
A reproductive study in male and female rats at dose levels up to 3.0 mg/kg/day had no effect on mating performance, fertility, or litter characteristics.
Pregnancy Category C
Treatment of rats and rabbits with coagulation factor VIIa (recombinant) in reproduction studies has been associated with mortality at doses up to 6 mg/kg and 5 mg/kg. At 6 mg/kg in rats, the abortion rate was 0 out of 25 litters; in rabbits at 5 mg/kg, the abortion rate was 2 out of 25 litters. Twenty-three out of 25 female rats given 6 mg/kg of coagulation factor VIIa (recombinant) gave birth successfully, however, 2 of the 23 litters died during the early period of lactation. No evidence of teratogenicity was observed after dosing with coagulation factor VIIa (recombinant). There are no adequate and well-controlled studies in pregnant women. Coagulation factor VIIa (recombinant) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The patients in whom coagulation factor VIIa (recombinant) is indicated are male.
Labor and Delivery
Coagulation factor VIIa (recombinant) was administered to a FVII deficient patient (25 years of age, 66 kg) during a vaginal delivery (36 mug/kg) and during a tubal ligation (90 mug/kg). No adverse reactions were reported during labor, vaginal delivery, or the tubal ligation.
Nursing Mothers
It is not known whether coagulation factor VIIa (recombinant) is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of coagulation factor VIIa (recombinant) was not determined to be different in various age groups, from infants to adolescents (0-16 years of age). Clinical trials were conducted with dosing determined according to body weight and not according to age.
Geriatric Use
Clinical studies in hemophilia did not enroll geriatric patients.
DRUG INTERACTIONS:
The risk of a potential interaction between coagulation factor VIIa (recombinant) and coagulation factor concentrates has not been adequately evaluated in preclinical or clinical studies. Simultaneous use of activated prothrombin complex concentrates or prothrombin complex concentrates should be avoided.
Although the specific drug interaction was not studied in a clinical trial, there have been more than 50 episodes of concomitant use of antifibrinolytic therapies (i.e., tranexamic acid, aminocaproic acid) and coagulation factor VIIa (recombinant).
Coagulation factor VIIa (recombinant) should not be mixed with infusion solutions until clinical data are available to direct this use.
ADVERSE REACTIONS:
Coagulation factor VIIa (recombinant) has been generally well tolerated in clinical studies in 298 patients with hemophilia A or B with inhibitors treated for 1939 bleeding episodes. TABLE 2 lists adverse events that were reported in 2% of coagulation factor VIIa (recombinant) patients and were considered to be at least possibly related or of unknown relationship to coagulation factor VIIa (recombinant) administration.
Fever
Platelets, Bleeding, and Clotting
Hemorrhage
Fibrinogen Plasma Decreased
Skin and Musculoskeletal
Hemarthrosis
Cardiovascular
Hypertension
Events which were reported in 1% of patients and were considered to be at least possibly or of unknown relationship to coagulation factor VIIa (recombinant) administration were: allergic reaction, arthrosis, bradycardia, coagulation disorder, DIC, edema, fibrinolysis increased, headache, hypotension, injection site reaction, pain, pneumonia, prothrombin decreased, pruritus, purpura, rash, renal function abnormal, therapeutic response decreased, and vomiting.
In the 298 hemophilia patients, thrombosis was reported in 2 patients.
Serious adverse events that were probably or possibly related, or where the relationship to coagulation factor VIIa (recombinant) was not specified occurred in 14 of the 298 patients (4.7%). Six of these 14 patients died of the following conditions: Worsening of chronic renal failure, anesthesia complications during proctoscopy, renal failure complicating a retroperitoneal bleed, ruptured abscess leading to sepsis and DIC, pneumonia, and splenic hematoma and GI bleeding.
OVERDOSAGE:
Dose limiting toxicities of coagulation factor VIIa (recombinant) Coagulation Factor VIIa (Recombinant) have not been investigated in clinical trials. Two cases of accidental overdose by bolus administration have occurred in the clinical program. One hemophilia B patient (16 years of age, 68 kg) received a single dose of 352 mug/kg and one hemophilia A patient (2 years of age, 14.6 kg) received doses ranging from 246-986 mug/kg on 5 consecutive days. There were no reported complications in either case. The recommended dose schedule should not be intentionally increased, even in the case of lack of effect, due to the absence of information on the additional risk that may be incurred.
DOSAGE AND ADMINISTRATION:
Dosage
Coagulation factor VIIa (recombinant) is intended for intravenous bolus administration only. Evaluation of hemostasis should be used to determine the effectiveness of coagulation factor VIIa (recombinant) and to provide a basis for modification of the coagulation factor VIIa (recombinant) treatment schedule; coagulation parameters do not necessarily correlate with or predict the effectiveness of coagulation factor VIIa (recombinant).
The recommended dose of coagulation factor VIIa (recombinant) for hemophilia A or B patients with inhibitors is 90 Β΅g/kg given every 2 hours until hemostasis is achieved, or until the treatment has been judged to be inadequate. Doses between 35 and 120 Β΅g/kg have been used successfully in clinical trials, and both the dose and administration interval may be adjusted based on the severity of the bleeding and degree of hemostasis achieved.7 The minimal effective dose has not been established. For patients treated for joint or muscle bleeds, a decision on outcome was reached for a majority of patients within eight doses although more doses were required for severe bleeds. A majority of patients who reported adverse experiences received more than 12 doses.
Post-Hemostatic Dosing: The appropriate duration of post-hemostatic dosing has not been studied. For severe bleeds, dosing should continue at 3-6 hour intervals after hemostasis is achieved, to maintain the hemostatic plug. The biological and clinical effects of prolonged elevated levels of Factor VIIa have not been studied; therefore, the duration of post-hemostatic dosing should be minimized, and patients should be appropriately monitored by a physician experienced in the treatment of hemophilia during this time period.
Administration
Administration should take place within 3 hours after reconstitution. Any unused solution should be discarded. Do not store reconstituted coagulation factor VIIa (recombinant) in syringes. Coagulation factor VIIa (recombinant) is intended for intravenous bolus injection only and should not be mixed with infusion solutions. As with all parenteral drug products, reconstituted coagulation factor VIIa (recombinant) should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed.
REFERENCES:
1. Roberts, H.R.: Thoughts on the mechanism of action of FVIIa, 2nd Symposium on New Aspects of Hemophilia Treatment, Copenhagen, Denmark, 1991, pgs.153-156.
2. Lindley, C.M., et al. : Pharmacokinetics and pharmacodynamics of recombinant Factor VIIa, Clinical Pharmacology & Therapeutics, Vol. 55, No. 6, June 1994, pgs. 638-648.
3. Lusher, J., et al. : Clinical experience with recombinant Factor VIIa, Blood Coagulation and Fibrinolysis 1998, 9:119-128.
4. Bech, M.R.: Recombinant Factor VIIa in Joint and Muscle Bleeding Episodes, Haemostasis 1996;26(suppl 1):135-138.
5. Lusher, J.M.: Recombinant Factor VIIa (NovoSeven) in the Treatment of Internal Bleeding in Patients with Factor VIII and IX Inhibitors, Haemostasis 1996; 26(suppl 1):124-130.
6. Macik, B.G., et al. : Safety and initial clinical efficacy of three dose levels of recombinant activated Factor VII (rFVIIa): results of a Phase 1 study, Blood Coagulation and Fibrinolysis 1993, 4:521-527.
7. Hedner, U.: Dosing and Monitoring NovoSeven Treatment, Haemostasis 1996;26(suppl 1):102-108.