ASH Clinical News August 2015_updated | Page 16

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 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]. Exercise caution when administering NovoSeven® RT to patients with an
increased risk of thromboembolic complications. These include, but are not limited to, pat ients
with a history of coronary heart disease, liver disease, disseminated intravascular coagulation,
post-operative 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.
INR: NovoSeven® has demonPT (sec)
PT versus FVII:C
strated the ability to normalize
14
INR. However, INR values have
13
not been shown to directly
12
predict bleeding outcomes, nor
has it been possible to demon11
strate the impact of NovoSeven®
10
on bleeding times/volume in
9
models of clinically-induced
8
bleeding in healthy volunteers
who had received Warfarin, when
7
laboratory parameters (PT/INR,
6
aPTT, thromboelastogram) have
5
normalized. aPTT: While admin4
istration of NovoSeven® shortens
3
the prolonged aPTT in hemophilia
A/B patients with inhibitors,
2
normalization has usually not
1
been observed in doses shown to
0
30
40 induce clinical improvement. Data
0
10
20
indicate that clinical improvement
FVII:C (unit per mL)
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

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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
# of adverse reactions
# of patients
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. 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 peri-operative 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.
Table: Post Marketing Experience
MedDRA System Organ Preferred Term
Class
Immune system disorders
Hypersensitivity (including anaphylactic shock, flushing,
urticaria, rash, angioedema)
Vascular disorders
Thromboembolic events (including hepatic artery thrombosis,
myocardial infarction, cerebral infarction, intestinal infarction,
intracardiac thrombus, peripheral ischemia, portal vein
thrombosis, myocardial ischemia, renal artery thrombosis)
OVERDOSAGE: Dose limiting toxicities of NovoSeven® RT have not been investigated in clinical
trials. The following are examples of accidental overdose. One newborn female with congenital
factor VII deficiency was administered an overdose of NovoSeven® (single dose: 800 micrograms
per kg body weight). Following additional administration of NovoSeven® and various plasma
products, antibodies against rFVIIa were detected, but no thrombotic complications were reported.
One Factor VII deficient male (83 years of age, 111.1 kg) received two doses of 324 micrograms
per kg body weight (10-20 times the recommended dose) and experienced a thrombotic event
(occipital stroke). One hemophilia B patient (16 years of age, 68 kg) received a single dose of 352
micrograms per kg body weight and one hemophilia A patient (2 years of age, 14.6 kg) received
doses ranging from 246 micrograms per kg body weight to 986 micrograms per kg body weight
on five consecutive days. There were no reported complications in either case.
More detailed information is available upon request.
For information contact: Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536,
USA, 1-877-NOVO-777, www.NovoSevenRT.com
Manufactured by: Novo Nordisk A/S, 2880 Bagsvaerd, Denmark
Novo Nordisk® is a registered trademark of Novo Nordisk A/S.
NovoSeven® is a registered trademark of Novo Nordisk Health Care AG.
© 2014 Novo Nordisk 0614-00021853-1 7/14

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