NovoSeven ® RT
Coagulation Factor VIIa (Recombinant)
Rx only
BRIEF SUMMARY. Please consult package insert for full prescribing
information.
WARNING: THROMBOSIS: Serious arterial and venous thrombotic events
following administration of NovoSeven® RT have been reported. [See Warnings
and Precautions] Discuss the risks and explain the signs and symptoms of
thrombotic and thromboembolic events to patients who will receive NovoSeven ®
RT. [See Warnings and Precautions] Monitor patients for signs or symptoms
of activation of the coagulation system and for thrombosis. [See Warnings and
Precautions]
INDICATIONS AND USAGE: Indicated for: Treatment of bleeding episodes and
peri-operative management in adults and children with hemophilia A or B with
inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia
with refractoriness to platelet transfusions, with or without antibodies to platelets.
Treatment of bleeding episodes and peri-operative management in adults with
acquired hemophilia.
CONTRAINDICATIONS: None known.
WARNINGS AND PRECAUTIONS: Thrombosis: Serious arterial and
venous thrombotic events have been reported in clinical trials and postmarketing
surveillance. Patients with disseminated intravascular coagulation (DIC), advanced
atherosclerotic disease, crush injury, septicemia, or concomitant treatment with
aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates)
and uncontrolled post-partum hemorrhage have an increased risk of developing
thromboembolic events due to circulating tissue factor (TF) or predisposing
coagulopathy [See Adverse Reactions and Drug Interactions]. Exercise caution when
administering NovoSeven® RT to patients with an increased risk of thromboembolic
complications. These include, but are not limited to, patients with a history of
coronary heart disease, liver disease, disseminated intravascular coagulation, postoperative immobilization, elderly patients and neonates. In each of these situations,
the potential benefit of treatment with NovoSeven® RT should be weighed against
the risk of these complications. Monitor patients who receive NovoSeven® RT
for development of signs or symptoms of activation of the coagulation system or
thrombosis. When there is laboratory confirmation of intravascular coagulation or
presence of clinical thrombosis, reduce the dose of NovoSeven® RT or stop the
treatment, depending on the patient’s condition. Hypersensitivity Reactions:
Hypersensitivity reactions, including anaphylaxis have been reported with
NovoSeven® RT. Administer NovoSeven® RT only if clearly needed in patients
with known hypersensitivity to NovoSeven® RT or any of its components, or in
patients with known hypersensitivity to mouse, hamster, or bovine proteins. Should
symptoms occur, discontinue NovoSeven® RT, administer appropriate treatment
and weigh the benefit/risks prior to restarting treatment with NovoSeven ® RT.
Antibody Formation in Factor VII Deficient Patients: Factor VII deficient
patients should be monitored for prothrombin time (PT) and factor VII coagulant
activity before and after administration of NovoSeven® RT. If the factor VIIa activity
fails to reach the expected level, or prothrombin time is not corrected, or bleeding is
not controlled after treatment with the recommended doses, antibody formation may
be suspected and analysis for antibodies should be performed. Laboratory Tests:
Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) have shown no direct
correlation to achieving hemostasis. Assays of prothrombin time (PT/INR), activated
partial thromboplastin time (aPTT), and plasma FVII clotting activity (FVII:C), may
give different results with different reagents. Treatment with NovoSeven® has been
shown to produce the following characteristics: PT: As shown below, 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 units per mL. For FVII:C levels > 5 units per
mL, there is no further change in PT. The clinical relevance of prothrombin time
shortening following NovoSeven® RT administration is unknown.
PT (sec)
PT versus FVII:C
INR: NovoSeven® has demonstrated the ability to
14
normalize INR. However, INR
13
values have not been shown
12
to directly predict bleeding
11
outcomes, nor has it been
10
possible to demonstrate the
9
impact of NovoSeven® on
8
bleeding times/volume in
7
models of clinically-induced
6
bleeding in healthy volunteers
who had received Warfarin,
5
when laboratory parameters
4
(PT/INR, aPTT, throm boelas3
togram) have normalized.
2
aPTT: While administration of
1
NovoSeven® shortens the
0
30
40 prolonged aPTT in hemo0
10
20
philia A/B patients with
FVII:C (unit per mL)
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 to 20 seconds. FVIIa:C: FVIIa:C levels were measured two
hours after NovoSeven® administration of 35 micrograms per kg body weight and
90 micrograms per kg body weight following two days of dosing at two hour intervals. Average steady state levels were 11 and 28 units per mL for the two dose levels,
respectively.
ADVERSE REACTIONS: The most common and serious adverse reactions in
clinical trials are thrombotic events. Thrombotic adverse reactions following the
administration of NovoSeven® in clinical trials occurred in 4% of patients with
acquired hemophilia and 0.2% of bleeding episodes in patients with congenital
hemophilia. Clinical Trials Experience: Because clinical studies are conducted
under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug product cannot be directly compared to rates in clinical trials of another
drug, and may not reflect rates observed in practice. Adverse reactions outlined
below have been reported from clinical trials and data collected in registries.
Hemophilia A or B Patients with Inhibitors: In two studies for hemophilia A or B
patients with inhibitors treated for bleeding episodes (N=298), adverse reactions
were reported in ≥2% of the patients that were treated with NovoSeven® for 1,939
bleeding episodes (see Table Table below).
Table: Adverse Reactions Reported in ≥2% of the 298 Patients with
Hemophilia A or B with Inhibitors
# of adverse
Body System
# of patients
reactions
Reactions
(n=1,939 treatments) (n=298 patients)
Body as a whole
Fever
16
13
Platelets, Bleeding, and Clotting
Fibrinogen plasma decreased
10
5
Cardiovascular
Hypertension
9
6
Serious adverse reactions included thrombosis, pain, thrombophlebitis deep,
pulmonary embolism, decreased therapeutic response, cerebrovascular disorder,
angina pectoris, DIC, anaphylactic shock and abnormal hepatic function. The serious
adverse reactions of DIC and therapeutic response decreased had a fatal outcome.
In two clinical trials evaluating safety and efficacy of NovoSeven® administration
in the perioperative setting in hemophilia A or B patients with inhibitors (N=51),
the following serious adverse reactions were reported: acute post-operative
hemarthrosis (n=1), internal jugular thrombosis adverse reaction (n=1), decreased
therapeutic response (n=4). Immunogenicity: There have been no confirmed reports
of inhibitory antibodies against NovoSeven® or FVII in patients with congenital
hemophilia A or B with alloantibodies. The incidence of antibody formation is
dependent on the sensitivity and specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity in an assay may be
influenced by several factors including assay methodology, sample handling, timing
of sample collection, concomitant medications, and underlying disease. For these
reasons, comparison of the incidence of antibodies to NovoSeven ® RT with the
incidence of antibodies to other products may be misleading. Congenital Factor VII
Deficiency: Data collected from the compassionate/emergency use programs, the
published literature, a pharmacokinetics study, and the Hemophilia and Thrombosis
Research Society (HTRS) registry showed that 75 patients with Factor VII deficiency
had received NovoSeven® : 70 patients for 124 bleeding episodes, surgeries, or
prophylaxis; 5 patients in the pharmacokinetics trial. The following adverse reactions
were reported: intracranial hypertension (n=1), IgG antibody against rFVIIa and FVII
(n=1), localized phlebitis (n=1). Immunogenicity: In 75 patients with factor FVII
deficiency treated with NovoSeven® RT, one patient developed IgG antibody against
rFVIIa and FVII. Patients with factor VII deficiency treated with NovoSeven® RT
should be monitored for factor VII antibodies. The incidence of antibody formation is
dependent on the sensitivity and specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity in an assay may
be influenced by several factors including assay methodology, sample handling,
timing of sample collection, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies to NovoSeven® RT
with the incidence of antibodies to other products may be misleading. Acquired
Hemophilia: Data collected from four compassionate use programs, the HTRS
registry, and the published literature showed that 139 patients with acquired
hemophilia received NovoSeven® for 204 bleeding episodes, surgeries and
traumatic injuries. Of these 139 patients, 6 patients experienced 8 serious adverse
reactions. Serious adverse reactions included shock (n=1), cerebrovascular
accident (n=1) and thromboembolic events (n=6) which included cerebral artery
occlusion, cerebral ischemia, angina pectoris, myocardial infarction, pulmonary
embolism and deep vein thrombosis. Three of the serious adverse reactions had a
fatal outcome. Glanzmann’s Thrombasthenia: Data collected from the Glanzmann’s
Thrombasthenia Registry (GTR) and the HTRS registry showed that 140 patients with
Glanzmann’s thrombasthenia received NovoSeven® RT for 518 bleeding episodes,
surgeries or traumatic injuries. The following adverse reactions were reported: deep
vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea
(n=1). Postmarketing Experience: The following adverse reactions have been