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. Discuss the
risks and explain the signs and symptoms of thrombotic and thromboembolic
events to patients who will receive NovoSeven ® RT. Monitor patients for signs
or symptoms of activation of the coagulation system and for thrombosis. [See
Warnings and Precautions]
INDICATIONS AND USAGE: NovoSeven® RT (Coagulation Factor VIIa
[Recombinant]) is a coagulation factor indicated for: Treatment of b leeding 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, thromboelas3
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)
NOSV15CDPR3303_Leadership_HCP_Journal_Ad_KING_BS_r2_FSU.indd 1
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 below).
Table: Adverse Reactions Reported in ≥2% of the 298 Patients with
Hemophilia A or B with Inhibitors
Body System
Reactions
Body as a whole
Fever
Platelets, Bleeding, and
Clotting
Fibrinogen plasma decreased
Cardiovascular
Hypertension
# of adverse
reactions
(n=1,939 treatments)
(n=298 patients)
16
13
10
5
9
6
# of patients
Serious adverse reactions included thrombosis, pain, thrombophlebitis deep,
pulmonary embolism, decreased therapeutic res ponse, 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.
There have been no confirmed reports of inhibitory antibodies against NovoSeven ®
or FVII in patients with congenital hemophilia A or B with alloantibodies. 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) 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). As
with all therapeutic proteins, there is a potential for immunogenicity. 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 identified during post approval use of NovoSeven®.
Because these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal
relationship.
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