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NovoSeven

Novo Nordisk

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use NovoSeven RT safely and effectively. See full prescribing information for NovoSeven RT. NovoSeven RT, Coagulation Factor VIIa (Recombinant)For Intravenous Use Only. Lyophilized Powder for Solution for Injection Initial U.S. Approval: 1999RECENT MAJOR CHANGESDosage and AdministrationAdministration (2.6) 04/2014BOXED WARNINGWARNING: SERIOUS THROMBOTIC ADVERSE EVENTS ASSOCIATED WITH THE USE OF NovoSeven RT OUTSIDE LABELED INDICATIONS See full prescribing information for complete boxed warning  Arterial and venous thrombotic and thromboembolic events following administration of NovoSeven have been reported during postmarketing surveillance. Clinical studies have shown an increased risk of arterial thromboembolic adverse events with NovoSeven RT when administered outside the current approved indications. Fatal and non-fatal thrombotic events 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 (5.2). Safety and efficacy of NovoSeven RT has not been established outside the approved indications. INDICATIONS AND USAGE •Treatment of bleeding episodes in hemophilia A or B with inhibitors and in acquired hemophilia (1) •Prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B with inhibitors and in acquired hemophilia (1) •Treatment of bleeding episodes in congenital Factor VII (FVII) deficiency (1) •Prevention of bleeding in surgical interventions or invasive procedures in congenital FVII deficiency (1) DOSAGE AND ADMINISTRATION •For intravenous bolus injection only. •NovoSeven RT should be administered to patients only under the supervision of a physician experienced in the treatment of bleeding disorders (2.1) •After reconstitution, administer within 3 hours; do not freeze or store in syringes (2.6) Hemophilia A or B with Inhibitors - Bleeding Episodes (2.2) •90 micrograms/kg bolus injection every 2 hours until hemostasis is achieved •Post-hemostatic dosing every 3-6 hours for severe bleeds Hemophilia A or B with Inhibitors - Surgery (2.2) •90 micrograms/kg immediately before surgery and every 2 hours during surgery •Post-surgical dosing: •Minor surgery - 90 micrograms/kg every 2 hours for 48 hours and then every 2-6 hours, until healing has occurred •Major surgery - 90 micrograms/kg every 2 hours for the first 5 days and then every 4 hours, until healing has occurred Congenital FVII Deficiency - Bleeding Episodes or Surgery (2.3) •15-30 micrograms/kg every 4-6 hours until hemostasis is achieved Acquired Hemophilia - Bleeding Episodes or Surgery (2.4) •70-90 micrograms/kg every 2-3 hours until hemostasis is achieved DOSAGE FORMS AND STRENGTHS •Lyophilized powder in single-use vials of 1, 2, 5, or 8 mg recombinant coagulation factor VIIa (3) •After reconstitution with specified volume of histidine diluent, the final solution contains 1 mg per mL (1000 micrograms per mL) of recombinant FVIIa (3) CONTRAINDICATIONSNone (4) WARNINGS AND PRECAUTIONS •Thrombotic events of possible or probable relationship to NovoSeven occurred in 0.28% of bleeding episodes treated in clinical trials within the approved indications (5.1) •Increased risk of arterial thromboembolic adverse events with use of NovoSeven was demonstrated in 2 meta analyses of placebo-controlled clinical trials in populations outside the approved indications (5.2) •Thrombosis has occurred in women treated with NovoSeven to control post-partum hemorrhage (5.2) •Factor VII deficient patients should be monitored for prothrombin time (PT) and FVII coagulant activity, and for antibody formation to NovoSeven RT (5.4) •Administer with caution in patients with known hypersensitivity (5.5) Side EffectsThe most frequently reported adverse reactions in patients treated with NovoSeven are rash, pruritus, urticaria, pyrexia, therapeutic response decreased and venous thromboembolic events occurring in > 0.1% to < 1% of patients (6) . To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-668-6777 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •Avoid simultaneous use of NovoSeven RT and PCCs/aPCCs (7.1) •NovoSeven RT should not be mixed with infusion solutions (7.2) •Do not administer NovoSeven RT with recombinant coagulation factor XIII A-subunit (rFXIII) (7.3) USE IN SPECIFIC POPULATIONS •Pregnancy: No human or animal data. Use only if clearly needed. (8.1)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

WARNING: SERIOUS THROMBOTIC ADVERSE EVENTS ASSOCIATED WITH THE USE OF NovoSeven RT OUTSIDE LABELED INDICATIONS

Arterial and venous thrombotic and thromboembolic events following administration of NovoSeven have been reported during postmarketing surveillance. Clinical studies have shown an increased risk of arterial thromboembolic adverse events with NovoSeven RT when administered outside the current approved indications. Fatal and non-fatal thrombotic events 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 (5.2)]

Safety and efficacy of NovoSeven RT has not been established outside the approved indications.

1 INDICATIONS AND USAGE

NovoSeven RT, Coagulation Factor VIIa (Recombinant), is indicated for:

  • •Treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia.
  • •Prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia.
  • •Treatment of bleeding episodes in patients with congenital Factor VII (FVII) deficiency.
  • •Prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency.

2 DOSAGE AND ADMINISTRATION

For intravenous bolus administration only.

2.1 General

  • •NovoSeven RT should be administered to patients only under the supervision of a physician experienced in the treatment of bleeding disorders.
  • •Evaluation of hemostasis should be used to determine the effectiveness of NovoSeven RT and to provide a basis for modification of the NovoSeven RT treatment schedule.
  • •Coagulation parameters do not necessarily correlate with or predict the effectiveness of NovoSeven RT.

2.2 Hemophilia A or B with Inhibitors

Dosing for Treatment of Acute Bleeding Episodes

Hemostatic Dosing

  • •90 micrograms per kg body weight given every two hours by bolus infusion until hemostasis is achieved, or until the treatment has been judged to be inadequate.
  • •Doses between 35 and 120 micrograms per kg body weight have been used successfully in clinical trials for hemophilia A or B patients with inhibitors, and both the dose and administration interval may be adjusted based on the severity of the bleeding and degree of hemostasis achieved.1
  • •The minimum 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 twelve 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.
  • •Patients should be appropriately monitored by a physician experienced in the treatment of hemophilia during this time period.

Dosing for Surgical Interventions

Minor Surgery

  • •An initial dose of 90 micrograms per kg body weight should be given immediately before the intervention and repeated at 2-hour intervals for the duration of the surgery.
  • •For minor surgery, post-surgical dosing by bolus injection should occur at 2-hour intervals for the first 48 hours and then at 2- to 6-hour intervals until healing has occurred.

Major Surgery

  • •An initial dose of 90 micrograms per kg body weight should be given immediately before the intervention and repeated at 2-hour intervals for the duration of the surgery.
  • •For major surgery, post-surgical dosing by bolus injection should occur at 2 hour intervals for 5 days, followed by 4 hour intervals until healing has occurred. Additional bolus doses should be administered if required.

2.3 Congenital Factor VII Deficiency

  • •Dose and frequency of injections should be adjusted to each individual.
  • •The recommended dose range for treatment of bleeding episodes or for prevention of bleeding in surgical interventions or invasive procedures in congenital Factor VII deficient patients is 15-30 micrograms per kg body weight every 4-6 hours until hemostasis is achieved.
  • •Effective treatment has been achieved with doses as low as 10 micrograms per kg body weight.

    The minimum effective dose has not been determined.

2.4 Acquired Hemophilia

  • •The recommended dose range for the treatment of patients with acquired hemophilia is 70-90 micrograms per kg body weight repeated every 2-3 hours until hemostasis is achieved.
  • •The minimum effective dose in acquired hemophilia has not been determined.
  • •The majority of the effective outcomes were observed with treatment in the recommended dose range. The largest number of treatments with any single dose was 90 micrograms per kg body weight; of the 15 treated, 10 (67%) were effective and 2 (13%) were partially effective.

2.5 Reconstitution

  • •Patients should follow the specific reconstitution procedures provided by their physician. Instructions for Use are provided in the FDA-approved patient labeling accompanying NovoSeven RT. The procedures below are general guidelines for the preparation and reconstitution of NovoSeven RT. For questions regarding reconstitution, please contact Novo Nordisk at 1-877-NOVO-777.
  • •Calculate the NovoSeven RT dosage and select the appropriate NovoSeven RT package provided with either 1 histidine diluent vial or 1 pre-filled histidine diluent syringe.
  • •Reconstitute only with the histidine diluent provided with NovoSeven RT.

NovoSeven RT package containing 1 vial of NovoSeven RT powder and 1 vial of histidine diluent:

  • 1.Always use aseptic technique.
  • 2.Bring NovoSeven RT (white, lyophilized powder) and the specified volume of histidine (diluent) to room temperature, but not above 37° C (98.6° F). The specified volume of diluent corresponding to the amount of NovoSeven RT is as follows:

    1 mg (1000 micrograms) vial + 1.1 mL Histidine diluent

    2 mg (2000 micrograms) vial + 2.1 mL Histidine diluent

    5 mg (5000 micrograms) vial + 5.2 mL Histidine diluent

    8 mg (8000 micrograms) vial + 8.1 mL Histidine diluent

  • 3.Remove caps from the NovoSeven RT vials to expose the central portion of the rubber stopper. Cleanse the rubber stoppers with an alcohol swab and allow to dry prior to use.
  • 4.Draw back the plunger of a sterile syringe (attached to sterile needle) and admit air into the syringe. It is recommended to use syringe needles of gauge size 20-26.
  • 5.Insert the needle of the syringe into the Histidine diluent vial. Inject air into the vial and withdraw the quantity required for reconstitution.
  • 6.Insert the syringe needle containing the diluent into the NovoSeven RT vial through the center of the rubber stopper, aiming the needle against the side so that the stream of liquid runs down the vial wall (the NovoSeven RT vial does not contain a vacuum). Do not inject the diluent directly on the NovoSeven RT powder.
  • 7.Gently swirl the vial until all the material is dissolved. The reconstituted solution is a clear, colorless solution which may be stored either at room temperature or refrigerated for up to 3 hours after reconstitution. After reconstitution with the specified volume of diluent, each vial contains approximately 1 mg per mL NovoSeven RT (1000 micrograms per mL).

NovoSeven RT package containing 1 vial of NovoSeven RT powder and 1 pre-filled histidine diluent syringe with vial adapter for needleless reconstitution:

  • 1.Always use aseptic technique.
  • 2.Bring NovoSeven RT (white, lyophilized powder) and the specified volume of histidine (diluent) to room temperature, but not above 98.6° F (37° C). The specified volume of diluent corresponding to the amount of NovoSeven RT is as follows:

    1 mg (1000 micrograms) vial + 1 mL Histidine diluent in pre-filled syringe

    2 mg (2000 micrograms) vial + 2 mL Histidine diluent in pre-filled syringe

    5 mg (5000 micrograms) vial + 5 mL Histidine diluent in pre-filled syringe

    8 mg (8000 micrograms) vial + 8 mL Histidine diluent in pre-filled syringe

  • 3.Remove cap from the NovoSeven RT vial. Cleanse the rubber stopper with an alcohol swab and allow to dry prior to use.
  • 4.Peel back the protective paper from the vial adapter. Do not remove the vial adapter from the package.
  • 5.Place the NovoSeven RT vial on a flat surface. While holding the vial adapter package, place the vial adapter over the NovoSeven RT vial and press down firmly on the package until the vial adapter spike penetrates the rubber stopper.
  • 6.Attach the plunger rod to the syringe. Turn the plunger rod clockwise into the plunger inside the pre-filled diluent syringe until resistance is felt. Remove the syringe cap from the pre-filled diluent syringe and screw onto the vial adapter.
  • 7.Push the plunger rod to slowly inject all the diluent into the vial. Keep the plunger rod pressed down and swirl the vial gently until the powder is dissolved. The reconstituted solution is a clear, colorless solution which may be stored fully assembled either at room temperature or refrigerated for up to 3 hours after reconstitution. After reconstitution with the specified volume of diluent, each vial contains approximately 1 mg per mL NovoSeven RT (1000 micrograms per mL).

2.6 Administration

  • •NovoSeven RT is for intravenous bolus injection only and should not be mixed with infusion solutions.
  • •Reconstituted NovoSeven RT should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is observed.
  • •Administration should take place within 3 hours after reconstitution.
  • •Any unused solution should be discarded. Do not freeze reconstituted NovoSeven RT or store it in syringes.

Perform the following procedures immediately prior to administration:

NovoSeven RT package containing 1 vial of NovoSeven RT powder and 1 vial of histidine diluent:

1. Always use aseptic technique.

2. Draw back the plunger of a sterile syringe (attached to sterile needle) and admit air into the syringe.

3. Insert needle into the vial of reconstituted NovoSeven RT. Inject air into the vial and then withdraw the

appropriate amount of reconstituted NovoSeven RT into the syringe.

4. Remove and discard the needle from the syringe.

NovoSeven RT package containing 1 vial of NovoSeven RT powder and 1 pre-filled histidine diluent syringe with vial adapter for needleless reconstitution:

1. Always use aseptic technique.

2. Invert the NovoSeven RT vial. Stop pushing the plunger rod and let it move back on its own while the mixed

solution fills the syringe. Pull the plunger rod slightly downwards to draw the mixed solution into the syringe. Tap

the syringe to remove air bubbles and withdraw the required dose amount of reconstituted NovoSeven RT into the

syringe.

3. Unscrew the vial adapter with the vial. Discard the empty NovoSeven RT vial with the vial adapter attached.

Caution: The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector.

Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as Clave® /MicroClave®, InVision-Plus®, InVision-Plus CS®, InVision-Plus® Junior®, Bionector®), and their use can damage the connector and affect administration. To administer product through incompatible needleless connectors, withdraw reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe.

If you have encountered any problems with attaching the pre-filled histidine diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (877) 668-6777.

Administration should be performed using the following procedures:

1. Administer as a slow bolus injection over 2 to 5 minutes, depending on the dose administered.

2. If line needs to be flushed before or after NovoSeven RT administration, use 0.9% Sodium Chloride Injection,

USP.

3. Discard any unused reconstituted NovoSeven RT after 3 hours.

Note: Dispose of all unused solution and other used medical supplies in an appropriate container.

3 DOSAGE FORMS AND STRENGTHS

NovoSeven RT is available as a white lyophilized powder in single-use vials containing 1 mg (1000 micrograms), 2 mg (2000 micrograms), 5 mg (5000 micrograms), or 8 mg (8000 micrograms) recombinant coagulation Factor VIIa (rFVIIa) per vial.

The diluent for reconstitution of NovoSeven RT is a 10 mmol solution of L-histidine in water for injection. It is a clear colorless solution provided in a vial or a pre-filled diluent syringe and is referred to as the histidine diluent.

After reconstitution with the histidine diluent, the final solution contains approximately 1 mg per mL NovoSeven RT (1000 micrograms per mL).

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Thrombotic Events within the Licensed Indications

Clinical trials within the approved indications revealed that thrombotic events of possible or probable relationship to NovoSeven occurred in 0.28% of bleeding episodes treated, with the incidence within hemophilia patients with inhibitors to be 0.20%, and in acquired hemophilia an incidence of 4%. Thrombotic events have been identified through postmarketing surveillance following NovoSeven RT use for each of the approved indications.2 The incidence of thrombotic events can not be determined from postmarketing data. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) have an increased risk of developing thrombotic events due to circulating tissue factor (TF) or predisposing coagulopathy [See Adverse Reactions (6.1) and Drug Interactions (7.1)]. Caution should be exercised 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, 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.

Patients who receive NovoSeven RT should be monitored 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, the NovoSeven RT dosage should be reduced or the treatment stopped, depending on the patient's symptoms.

5.2 Thrombotic Events outside the Licensed Indications

NovoSeven has been studied in placebo controlled trials outside the approved indications to control bleeding in intracerebral hemorrhage, advanced liver disease, trauma, cardiac surgery, spinal surgery, and other therapeutic areas. Safety and effectiveness has not been established in these settings and the use is not approved by FDA. Two meta analyses of these pooled data indicate an increased risk of thrombotic events (10.0% in patients treated with NovoSeven versus 7.5% in placebo-treated patients). Arterial thromboembolic adverse events including myocardial infarction, myocardial ischemia, cerebral infarction and cerebral ischemia were statistically significantly increased with the use of NovoSeven compared to placebo (5.3 to 5.6% in subjects treated with NovoSeven versus 2.8 to 3.0% in placebo-treated patients). Other arterial thromboembolic events (such as retinal artery embolism, renal artery thrombosis, arterial thrombosis of limb, intracardiac thrombus, bowel infarction and intestinal infarction) have also been reported.3,4,5,6,7 While venous thromboembolic events such as deep venous thrombosis, portal vein thrombosis and pulmonary embolism have been reported in clinical trials, the meta analysis of these pooled data from placebo-controlled trials performed outside the currently approved indications did not suggest an increased risk of venous thromboembolic events in patients treated with NovoSeven versus placebo (4.8% in patients treated with NovoSeven versus 4.7% in placebo-treated patients).

In spontaneous reports of women without a prior diagnosis of bleeding disorders receiving NovoSeven for uncontrolled post-partum hemorrhage, thrombotic events were observed. During this period, patients are at increased risk for thrombotic complications.

5.3 Post-Hemostatic Dosing

Precautions should be exercised when NovoSeven RT is used for prolonged dosing [See Dosage and Administration (2.2)].

5.4 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.

5.5 Hypersensitivity Reactions

NovoSeven RT should be administered with caution 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.

5.6 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 demonstrated the ability to normalize INR. However, INR values have not been shown to directly predict bleeding outcomes, nor has it been possible to demonstrate the impact of NovoSeven on bleeding times/volume in models of clinically-induced bleeding in healthy volunteers who had received Warfarin, when laboratory parameters (PT/INR, aPTT, thromboelastogram) have normalized.

aPTT: While administration of NovoSeven 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 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.

6 ADVERSE REACTIONS

The most frequently reported adverse reactions in patients treated with NovoSeven are rash, pruritus, urticaria, pyrexia and venous thromboembolic events occurring in > 0.1% to < 1% of patients. Therapeutic response decreased has also been reported at a similar rate. It is important that the dosage regimen of NovoSeven is compliant with the recommended dosage in section 2.

6.1 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.

Thrombotic events following the administration of NovoSeven occurred in 0.3% of bleeding episodes treated, with the incidence in acquired hemophilia of 4% and in hemophilia patients of 0.2% in clinical trials within the approved indications [See Warnings and Precautions (5.1)].

Adverse reactions observed in clinical trials for all labeled indications of NovoSeven included pyrexia, injection site reaction, headache, hypertension, nausea, vomiting, pain, edema, rash (including allergic dermatitis and rash erythematous), pruritus, urticaria, hypersensitivity, cerebral artery occlusion, cerebrovascular accident, pulmonary embolism, deep vein thrombosis, angina pectoris, increased levels of fibrin degradation products, disseminated intravascular coagulation and related laboratory findings including elevated levels of D-dimer and AT-III, thrombosis at i.v. site, non-specified thrombosis, thrombophlebitis, superficial thrombophlebitis.

The following sections describe the adverse event profile observed during clinical studies for each of the labeled indications.

Hemophilia A or B Patients with Inhibitors

Two studies (Studies 1 and 2) are described for hemophilia A or B patients with inhibitors treated for bleeding episodes [See Clinical Studies (14.1)]. The table below lists adverse reactions that were reported in ≥2% of the 298 patients with hemophilia A or B with inhibitors that were treated with NovoSeven for 1,939 bleeding episodes.

Body System

Reactions

# of episodes reported

(n=1,939 treatments)

# of unique patients

(n=298 patients)

Body as a whole

Fever

16

13

Platelets, Bleeding, and Clotting

Fibrinogen plasma decreased

10

5

Cardiovascular

Hypertension

9

6

Other reactions reported in 1% of patients were: allergic reaction, coagulation disorder, DIC, edema, fibrinolysis increased, headache, injection site reaction, pain, pruritus, purpura, rash, thrombosis and therapeutic response decreased.

Serious adverse reactions occurred in approximately 3% of the patients and included thrombosis, pain, thrombophlebitis deep, pulmonary embolism, therapeutic response decreased, cerebrovascular disorder, angina pectoris, DIC, anaphylactic shock and hepatic function abnormal. The serious adverse reactions of DIC and therapeutic response decreased had a fatal outcome.

Surgery Studies

Two clinical trials (Studies 3 and 4) were conducted to evaluate the safety and efficacy of NovoSeven administration during and after surgery in hemophilia A or B patients with inhibitors [See Clinical Studies (14.1)].

In one study (Study 3), two patients had adverse reactions (acute post-operative hemarthrosis and internal jugular thrombosis). No deaths occurred during the study.

In another study (Study 4), four of 24 patients had serious adverse reactions, all being decreased therapeutic response. Two reactions were observed in each treatment arm (bolus injection and continuous infusion). No deaths occurred during the study period.

6.2 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.

These adverse reactions were reported following the use of NovoSeven in labeled and unlabeled indications that included individuals with and without coagulopathy: high D-dimer levels and coagulopathy, thrombosis, thrombophlebitis, arterial thrombosis, and thromboembolic events including myocardial ischemia, myocardial infarction, cerebral ischemia, cerebral infarction, renal artery thrombosis, intracardiac thrombus, portal vein thrombosis, thrombophlebitis, peripheral ischemia, deep vein thrombosis and related pulmonary embolism, injection site pain, headache, nausea and isolated cases of hypersensitivity/allergic reactions including anaphylactic shock, flushing, urticaria, rash, and angioedema [See Warnings and Precautions (5.1)].

Fatal and non-fatal thromboembolic events have been reported with use of NovoSeven when used for off-label or labeled indications.

There have been no confirmed reports on inhibitory antibodies against NovoSeven or FVII in patients with congenital hemophilia A or B with alloantibodies.

The Hemophilia and Thrombosis Research Society (HTRS) Registry surveillance program is designed to collect data on the treatment of congenital and acquired bleeding disorders.8 All prescribers can obtain information regarding contribution of patient data to this program by calling 1-877-362-7355 or at www.novosevensurveillance.com.

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 at least 75 patients with Factor VII deficiency had received NovoSeven - 70 patients for 124 bleeding episodes, surgeries, or prophylaxis regimens; 5 patients in the pharmacokinetics trial.

In the compassionate/emergency use programs, 1 non-serious adverse reaction (intracranial hypertension) and 1 serious adverse reaction (IgG antibody against rFVIIa and FVII) were reported. One adverse reaction (localized phlebitis) was reported in the literature. No adverse reactions were reported in the pharmacokinetics reports or for the HTRS registry. No thromboembolic complications were reported for the 75 patients included here.

As with all therapeutic proteins, there is a potential for immunogenicity. In compassionate/emergency use programs patients with factor VII deficiency formation of antibodies against NovoSeven and FVII (frequency: common (≥ 1/100 to < 1/10)) have been reported. In some cases, the antibodies showed inhibitory effect in vitro. Risk factors that may have contributed to antibody development including previous treatment with human plasma and/or plasma-derived factor VII, severe mutation of FVII gene, and overdose of NovoSeven, were present. Patients with factor VII deficiency treated with NovoSeven should be monitored for factor VII antibodies.

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 experienced 8 serious adverse reactions. Thrombotic serious adverse events included cerebral artery occlusion, cerebral ischemia, angina pectoris, myocardial infarction, pulmonary embolism and deep vein thrombosis. Additional serious adverse reactions included shock and cerebrovascular accident. Three of the serious adverse reactions had a fatal outcome (shock, cerebral artery occlusion and myocardial infarction).

7 DRUG INTERACTIONS

7.1 Coagulation Factor Concentrates

The risk of a potential interaction between NovoSeven RT 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.

7.2 Infusion Solutions

NovoSeven RT should not be mixed with infusion solutions.

7.3 Coagulation Factor XIII A-Subunit (Recombinant) (rFXIII)

Thrombosis may occur if NovoSeven RT is administered concomitantly with Coagulation Factor XIII A-Subunit (Recombinant) [See Nonclinical Pharmacology (13.2)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. NovoSeven RT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Treatment of rats and rabbits with NovoSeven in reproduction studies has been associated with mortality at doses up to 6 mg per kg body weight and 5 mg per kg body weight. At 6 mg per kg body weight in rats, the abortion rate was 0 out of 25 litters; in rabbits at 5 mg per kg body weight, the abortion rate was 2 out of 25 litters. Twenty-three out of 25 female rats given 6 mg per kg body weight of NovoSeven gave birth successfully, however, two of the 23 litters died during the early period of lactation. No evidence of teratogenicity was observed after dosing with NovoSeven.

8.2 Labor and Delivery

NovoSeven was administered to a FVII deficient patient (25 years of age, 66 kg) during a vaginal delivery (36 micrograms per kg body weight) and during a tubal ligation (90 micrograms per kg body weight). No adverse reactions were reported during labor, vaginal delivery, or the tubal ligation.

There are no adequate and well-controlled studies in labor, delivery, and postpartum periods. In spontaneous reports of women without a prior diagnosis of bleeding disorders receiving NovoSeven for uncontrolled post-partum hemorrhage, thrombotic events were observed. During this period, patients are at increased risk for thrombotic complications. It is not known to what extent NovoSeven contributed to the occurrence of these events.

8.3 Nursing Mothers

It is not known whether NovoSeven RT 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.

8.4 Pediatric Use

Clinical trials enrolling pediatric patients were conducted with dosing determined according to body weight and not according to age. The safety and effectiveness of NovoSeven RT has not been studied to determine if there are differences among various age groups, from infants to adolescents (0 to 16 years of age).

8.5 Geriatric Use

Clinical studies of NovoSeven in congenital factor deficiencies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

10 OVERDOSAGE

There are no adequate and well controlled studies to support the safety or efficacy of using higher than labeled doses in the indicated populations.

Dose limiting toxicities of NovoSeven RT have not been investigated in clinical trials. The following are examples of accidental overdose.

Congenital Factor VII Deficiency

A 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. A 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).

Hemophilia A or B with Inhibitors

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.

11 DESCRIPTION

NovoSeven RT is recombinant human coagulation Factor VIIa (rFVIIa), intended for promoting hemostasis by activating the extrinsic pathway of the coagulation cascade.9 NovoSeven RT is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues (MW 50 K Dalton). NovoSeven RT 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 RT.

NovoSeven RT is supplied as a sterile, white lyophilized powder of rFVIIa in single-use vials. Each vial of lyophilized drug contains the following:

Contents

1 mg Vial

2 mg Vial

5 mg Vial

8 mg Vial

rFVIIa

1000 micrograms

2000 micrograms

5000 micrograms

8000 micrograms

sodium chloride*

2.34 mg

4.68 mg

11.7 mg

18.72 mg

calcium chloride dihydrate*

1.47 mg

2.94 mg

7.35 mg

11.76 mg

glycylglycine

1.32 mg

2.64 mg

6.60 mg

10.56 mg

polysorbate 80

0.07 mg

0.14 mg

0.35 mg

0.56 mg

mannitol

25 mg

50 mg

125 mg

200 mg

Sucrose

10 mg

20 mg

50 mg

80 mg

Methionine

0.5 mg

1.0 mg

2.5 mg

4 mg

* per mg of rFVIIa: 0.4 mEq sodium, 0.01 mEq calcium

The diluent for reconstitution of NovoSeven RT is a 10 mmol solution of histidine in water for injection and is supplied as a clear colorless solution in a vial or pre-filled diluent syringe.

After reconstitution with the appropriate volume of histidine diluent, each vial contains approximately 1 mg/mL NovoSeven RT (corresponding to 1000 micrograms/mL). The reconstituted vials have a pH of approximately 6.0 in sodium chloride (2.3 mg/mL), calcium chloride dihydrate (1.5 mg/mL), glycylglycine (1.3 mg/mL), polysorbate 80 (0.1 mg/mL), mannitol (25 mg/mL), sucrose (10 mg/mL), methionine (0.5 mg/mL), and histidine (1.6 mg/mL).

The reconstituted product is a clear colorless solution which contains no preservatives. NovoSeven RT 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).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

NovoSeven RT 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. This process may also occur on the surface of activated platelets.

12.2 Pharmacodynamics

The effect of NovoSeven RT upon coagulation in patients with or without hemophilia has been assessed in different model systems. In an in vitro model of tissue-factor-initiated blood coagulation (Figure A),10 the addition of rFVIIa increased both the rate and level of thrombin generation in normal and hemophilia A blood, with an effect shown at rFVIIa concentrations as low as 10 nM. In this model, fresh human blood was treated with corn trypsin inhibitor (CTI) to block the contact pathway of blood coagulation. Tissue factor (TF) was added to initiate clotting in the presence and absence of rFVIIa for both types of blood.

In a separate model, and in line with previous reports,11 escalating doses of rFVIIa in hemophilia plasma demonstrate a dose-dependent increase in thrombin generation (Figure B). In this model, platelet rich normal and hemophilia plasma was adjusted with autologous plasma to 200,000 platelets/microliter. Coagulation was initiated by addition of tissue factor and CaCl2. Thrombin generation was measured in the presence of a thrombin substrate and various added concentrations of rFVIIa.

Figure A

Figure B

12.3 Pharmacokinetics

Healthy Subjects

The pharmacokinetics of NovoSeven was investigated in 35 healthy Caucasian and Japanese subjects in a dose-escalation study. Subjects were stratified according to gender and ethnic group and dosed with 40, 80 and 160 micrograms per kg NovoSeven.12 The pharmacokinetics of rFVII were linear over the dose range of 40 to 180 micrograms per kg. Pharmacokinetics were similar across gender and ethnic groups. Mean steady state volume of distribution ranged from 130 to 165 mL per kg, mean values of clearance ranged from 33 to 37 mL per hr x kg, and mean terminal half-life ranged from 3.9 to 6.0 hours.

Hemophilia A or B

Single‑dose pharmacokinetics of NovoSeven (17.5, 35, and 70 micrograms per kg) exhibited dose-proportional behavior in 15 subjects with hemophilia A or B.13 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 per kg (range 78-139). Median clearance was 33 mL per kg per hr (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%). The products NovoSeven RT and NovoSeven are pharmacokinetically equivalent.14

In a bolus single-dose pharmacokinetic study, 5 male adults (90 micrograms per kg) and 10 male pediatric (2-12 years) patients (crossover, 90 and 180 micrograms per kg) with severe hemophilia A (10 of 18 subjects had inhibitors) received NovoSeven.15 The PK of rFVII following 90 and 180 micrograms per kg IV dose in children indicated dose linearity. Based on the FVII:C assay, the terminal half-life of NovoSeven was 2.6 hrs in pediatric patients and 3.1 hrs in adults. Based on the 90 microgram/kg dose, the total clearance of NovoSeven in adults and children was 2767 ± 385 mL per hr (37.6 ± 13.1 mL per hr per kg) and 1375 ± 396 mL per hr (57.3 ± 9.5 mL per hr per kg), respectively. The volume of distribution at steady state (Vss) in adults and children was 121 ± 30 and 153 ± 29 mL per kg, respectively.

Congenital Factor VII deficiency

Single dose pharmacokinetics of NovoSeven in congenital Factor VII deficiency, at doses of 15 and 30 micrograms per kg body weight, showed no significant difference between the two doses used with regard to dose-independent parameters: total body clearance (70.8-79.1 mL per hr x kg), volume of distribution at steady state (280-290 mL per kg), mean residence time (3.75-3.80 hr), and half-life (2.82-3.11 hr). The mean in vivo plasma recovery was approximately 20% (18.9%-22.2%).

The normal Factor VII plasma concentration is 0.5 micrograms per mL. Factor VII levels of 15-25% (0.075 – 0.125 micrograms per mL) are generally sufficient to achieve normal hemostasis.16 For example, a 70 kg individual with FVII deficiency (plasma volume of approximately 3000 mL) would thus require 3.2 - 5.4 micrograms per kg of NovoSeven RT to secure hemostasis, assuming 100% recovery but, since the mean plasma recovery for NovoSeven is 20% for FVII-deficient patients, a NovoSeven RT dose range of 16-27 micrograms per kg would be required to achieve sufficient FVII plasma levels for hemostasis, which is consistent with the recommended dose range.

No adverse reactions were reported in the pharmacokinetics for congenital factor VII deficiency.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two mutagenicity studies have given no indication of carcinogenic potential for NovoSeven. The clastogenic activity of NovoSeven 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 NovoSeven. Other gene mutation studies have not been performed with NovoSeven RT (e.g., Ames test). No chronic carcinogenicity studies have been performed with NovoSeven RT.

A reproductive study in male and female rats at dose levels up to 3.0 mg per kg per day had no effect on mating performance, fertility, or litter characteristics.

Treatment of rats and rabbits with NovoSeven in reproduction studies has been associated with mortality at doses up to 6 mg per kg and 5 mg per kg. At 6 mg per kg in rats, the abortion rate was 0 out of 25 litters; in rabbits at 5 mg per kg, the abortion rate was 2 out of 25 litters. Twenty-three out of 25 female rats given 6 mg per kg of NovoSeven gave birth successfully, however, two of the 23 litters died during the early period of lactation. No evidence of teratogenicity was observed after dosing with NovoSeven.

13.2 Animal Toxicology and/or Pharmacology

In a monkey cardiovascular safety pharmacology model evaluating the combination of excessive doses of Coagulation Factor XIII A-Subunit (Recombinant) (585 IU/kg, 17 times the expected human dose) in combination with rFVIIa (1000 mcg/kg, 11 times the expected human dose), one of the twelve monkeys died 4 hours after treatment due to thrombosis. Procoagulant risk factors, including 6 indwelling catheters per monkey and the induction of anesthesia, may have complicated the study results. It is unclear whether the mortality was related to the overdose of one or both products, or a specific interaction between them. Nonclinical and clinical studies with the combination of rFXIII and NovoSeven RT at recommended human doses have not been performed.

14 CLINICAL STUDIES

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

14.1 Hemophilia A or B with Inhibitors

Open Protocol Use

The largest number of patients who received NovoSeven during the investigational phase of product development were in an open protocol study (Study 1)17,18,19 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 Study 1 are problematic for the evaluation of the safety and efficacy of the product by statistical methods.

Dosing Study

The dosing study (Study 2)20 was a double-blind, randomized comparison trial of two dose levels of NovoSeven in the treatment of joint, muscle and mucocutaneous hemorrhages 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 micrograms per kg dose (59 joint, 15 muscle and 5 mucocutaneous bleeding episodes) and 43 patients were treated at the 70 micrograms per 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 micrograms per 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 micrograms per kg groups, respectively.

One patient in the 35 micrograms per kg group and three in the 70 micrograms per 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.

Surgery Studies

Two clinical trials (Studies 3 and 4) were conducted to evaluate the safety and efficacy of NovoSeven administration during and after surgery in hemophilia A or B patients with inhibitors.

One study (Study 3) was a randomized, double-blind, parallel group clinical trial (29 patients with hemophilia A or B and inhibitors or acquired inhibitors to FVIII/FIX, undergoing major or minor surgical procedures).21 Patients received bolus intravenous NovoSeven (either 35 micrograms per kg, N=15; or 90 micrograms per kg, N=14) prior to surgery, intra-operatively as required, then every 2 hours for the following 48 hours beginning at closure of the wound. Additional doses were administered every 2 to 6 hours up to an additional 3 days to maintain hemostasis. After a maximum of 5 days of double-blind treatment, therapy could be continued in an open-label manner if necessary (90 micrograms per kg NovoSeven every 2-6 hours). Efficacy was assessed during the intra-operative period, and post-operatively from the time of wound closure (Hour 0) through Day 5.

When efficacy assessments at each time point were tabulated by a last value carried forward approach (patients who completed the study early having achieved effective hemostasis were counted as “effective” and those who discontinued due to treatment failure or adverse events were counted as “ineffective” at each time point thereafter), the results at the end of the 5-day double-blind treatment period were as summarized in the table below. Twenty-three patients successfully completed the entire study (including the open-label period after the 5-day double blind period) with satisfactory hemostasis.

Study 3: Dose Comparison of Efficacy in Major and Minor Surgery - Last Value Carried ForwardPatients who completed the study early having achieved effective hemostasis were counted as effective at subsequent time-points, and patients who discontinued due to treatment failure or adverse events were counted as ineffective at subsequent time-points. Only effective ratings were counted as successful hemostasis (ratings of “partially effective” were not counted). Ten patients completed the study by Day 5 because their bleeding had resolved and they were discharged from the hospital. Three patients dropped out of the study due to ineffective therapy and 1 patient left the study due to an adverse event.

Number of effective (E)/ineffective (I) responses in each dose group

Major Surgery

Minor Surgery

35 µg/kg µg/kg = micrograms/kg

(n = 5)

90 µg/kg

(n = 6)

35 µg/kg

(n = 10)

90 µg/kg

(n = 8)

Total

(n = 29)

E

I

E

I

E

I

E

I

E

I

Intraoperative

5

0

6

0

10

0

7

1

28

1

Post-Op Hour

0

5

0

6

0

8

2

6

2

25

4

8

4

1

5

1

9

1

7

1

25

4

24

4

1

6

0

9

1

6

2

25

4

48

3

2

6

0

8

2

8

0

25

4

Day

3

2

3

6

0

8

2

8

0

24

5

4

3

2

6

0

8

2

8

0

25

4

5

3

2

5

1

8

2

8

0

24

5

E: Number of patients where NovoSeven treatment was effective

I: Number of patients where NovoSeven treatment was ineffective
Study 3: Dosing by Surgery Category

Major Surgery

Minor Surgery

35 µg/kg*

(n = 5)

90 µg/kg

(n = 6)

35 µg/kg

(n = 10)

90 µg/kg

(n = 8)

Days of dosing, median (range)

15 (2-26)

9.5 (8-17)

4 (3-6)

6 (3-13)

No. injections, median (range)

135 (11-186)

81 (71-128)

29.5 (24-44)

39.5 (26-98)

Median total dose, mg (range)

656 (31-839)

569 (107-698)

45.5 (14-171)

67 (31-122)

* µg/kg = micrograms per kg body weight

Study 4 was an open-label, randomized, parallel trial conducted to compare the safety and efficacy of bolus intravenous injection (N=12) and continuous intravenous infusion (N=12) administration of NovoSeven in hemophilia A or B patients with inhibitors who were undergoing elective major surgery. The types of surgeries that were performed included knee (N=13), hip (N=3), abdomen/lower pelvis (N=2), groin/inguinal area (N=2), circumcision (N=1), eye (N=1), frontal/temporal region of cranium (N=1), and oral cavity (N=1).

Prior to surgery, a 90 micrograms per kg bolus dose of NovoSeven was administered to both bolus and continuous infusion groups. The bolus injection group then received 90 micrograms per kg NovoSeven by bolus intravenous injection every 2 hours during the procedure and for the first 5 days, then every 4 hours from Day 6 to Day 10. The continuous infusion group received 50 micrograms per kg per hr NovoSeven by continuous intravenous infusion for the first 5 days, and infusion of 25 micrograms per kg per hr from Day 6 to Day 10. For both NovoSeven-treated groups, two bolus rescue doses of 90 micrograms per kg were permitted during any 24-hour period.

The bolus injection (90 micrograms/kg) and continuous infusion (50 micrograms/kg/h) treatment groups showed comparable efficacy in achieving and maintaining hemostasis in major surgery from wound closure through Day 10. For the Global Hemostasis Treatment Evaluation for overall success in achieving and maintaining hemostasis at the end of the study period, treatment was rated as being effective in 9 patients (75%) and ineffective in 3 patients (25%) for both treatment groups.

When efficacy assessments at each time point were tabulated by a last value carried forward approach (patients who completed the study early having achieved effective hemostasis were counted as “effective” at each time point, and those who discontinued due to treatment failure counted as “ineffective” at each time point thereafter), the results were as summarized in the table below.

Study 4: Efficacy of Bolus Dosing vs. Continuous Infusion in Major Surgery - Last Value Carried ForwardPatients who completed the study early having achieved hemostasis counted as effective at subsequent time-points, and patients who discontinued due to treatment failure counted as ineffective at subsequent time-points. Eight patients completed the study early because their bleeding had resolved and they were discharged from the hospital. Four patients dropped out of the study due to ineffective therapy and 1 patient left the study due to a hemarthrosis that was described as an adverse event.

Number of effective (E)/ineffective (I) responses in each dose group

Bolus Injection

(NovoSeven 90 micrograms/kg)

n = 12

Continuous Infusion

(NovoSeven 50 micrograms/kg/h)

n = 12

E

I

E

I

Post-Op Hour

0

12

0

12

0

8

12

0

11

1

24

12

0

10

2

48

10

2

11

1

72

9

3

11

1

Day

4

11

1

10

2

5

11

1

10

2

6

11

1

10

2

7

9

3

10

2

8

10

2

10

2

9

9

3

10

2

10

9

3

10

2

E: Number of patients where NovoSeven treatment was effective

I: Number of patients where NovoSeven treatment was ineffective
Study 4: Dosing by Treatment Group

Bolus Injection

90 micrograms/kg

(n = 12)

Continuous Infusion

50 micrograms/kg/h

(n = 12)

Days of dosing, median (range)

10 (4-15)Includes dosing during the follow-up period after the 10-day study period.

10 (2-116)

No. bolus injections, median (range)

38 (36-42)

1.5 (0-7)

No. of additional bolus injections, median (range)

0 (0-3)

0 (0-4)

Mean total dose, mg

237.5

292.2

14.2 Congenital Factor VII Deficiency

Data were collected from the published literature and internal sources for 70 patients with Factor VII deficiency treated with NovoSeven for 124 bleeding episodes, surgeries, or prophylaxis regimens. Thirty-two of these patients were enrolled in emergency and compassionate use trials conducted by Novo Nordisk (43 non-surgical bleeding episodes, 26 surgeries); 35 were reported in the published literature (20 surgeries, 10 non-surgical bleeding episodes, 4 cases of caesarean section or vaginal birth, and 10 cases of long-term prophylaxis, and 1 case of on-demand therapy); and 3 were from a registry maintained by the Hemophilia and Thrombosis Research Society (9 bleeding episodes, 1 surgery). Dosing ranged from 6 to 98 micrograms per kg administered every 2-12 hours (except for prophylaxis, where doses were administered from 2 times per day up to 2 times per week). Patients were treated with an average of 1-10 doses. Treatment was effective (bleeding stopped or treatment was rated as effective by the physician) in 93% of episodes (90% for trial patients, 98% for published patients, 90% for HTRS registry patients).

14.3 Acquired Hemophilia

Data were collected from four studies in the compassionate use program conducted by Novo Nordisk and the Hemophilia and Thrombosis Research Society (HTRS) registry. A total of 70 patients with acquired hemophilia were treated with NovoSeven for 113 bleeding episodes, surgeries, or traumatic injuries. Sixty-one of these patients were from the compassionate use program with 100 bleeding episodes (68 non-surgical and 32 surgical bleeding episodes) and 9 patients were from the HTRS registry with 13 bleeding episodes (8 non-surgical, 3 surgical and 2 episodes classified as other). Concomitant use of other hemostatic agents occurred in 29/70 (41%); 13 (19%) received more than one hemostatic agent. The most common hemostatic agents used were antifibrinolytics, Factor VIII and activated prothrombin complex concentrates.

The compassionate use programs and the HTRS registry were not designed to select doses or compare first-line efficacy or efficacy when used after failure of other hemostatic agents (salvage treatment). A dose response was not seen in doses ranging from 70-90 micrograms per kg.

The mean dose of NovoSeven administered was 90 micrograms per kg (range: 31 to 197 micrograms per kg); the mean number of injections per day was 6 (range: 1 to 10 injections per day). Overall efficacy i.e., effective and partially effective outcomes, was 87/112 (78%); with 77/100 (77%) efficacy in the compassionate use programs and 10/12 (83%) efficacy in the HTRS registry. In the compassionate use programs, overall efficacy for the first-line treatment was 38/44 (86%) compared to 39/56 (70%) when used as salvage treatment.

Efficacy by Dose Group, for Patients Receiving Doses Ranging from <61 to >90 micrograms/kg NovoSeven, Compassionate Use Programs and HTRS Registry

NovoSeven Dose (micrograms/kg)

Outcome Outcome assessed at end of treatment, last observation carried forward.

Unknown

<61

61-69

70-80

81-89

90

>90

Total

Effective N (%)

1 (33)

3 (75)

5 (63)

10 (63)

12 (57)

10 (67)

26 (58)

67

Partial N (%)

1 (33)

0 (0)

0 (0)

3 (19)

3 (14)

2 (13)

11 (24)

20

Ineffective N (%)

0 (0)

1 (25)

3 (38)

2 (13)

2 (10)

2 (13)

7 (16)

17

Unknown N (%)

1 (33)

0 (0)

0 (0)

1 (6)

4 (19)

1 (7)

1 (2)

8

 

No. of Bleeding Episodes N (%) do not add up to 100 due to rounding.

3

4

8

16

21

15

45

112One patient in the HTRS registry was excluded from efficacy analysis since NovoSeven was used to maintain hemostasis after bleeding had been controlled.

15 REFERENCES

1. Hedner, U.: Dosing and Monitoring NovoSeven® Treatment, Haemostasis 1996; 26 (suppl 1): 102-108.

2. Girolami, B., et al.: Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review, Haemophilia (2006); 12, 345-351.

3. Mayer, S.A., et al.: Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage, New England Journal of Medicine 2005; 352: 777-785.

4. Mayer, S.A., et al.: Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage, New England Journal of Medicine 2008; 358:2127-37.

5. Thomas, R, et al: Thromboembolic complications associated with Factor VIIa administration, J Trauma 2007; 62:564-569.

6. Hsia, Cyrus C., et al., “Use of Recombinant Activated Factor VII in Patients Without Hemophilia, A Meta-Analysis of Randomized Control Trials,” Annals of Surgery, Vol 248, No. 1, July 2008.

7. Hardy, Jean-Francois, et al, “Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials,” Ann Thorac Surg 2008; 86: 1038-48.

8. Parameswaran, R., et al.: Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry, Haemophilia 2005; 11: 100-106.

9. 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.

10. Butenas, S., et al.: Mechanism of factor VIIa-dependent coagulation in hemophilia blood, Blood 2002; 99: 923-930. Figure A Copyright American Society of Hematology, used with permission.

11. Allen, G.A., et al.: The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation, Blood Coagulation and Fibrinolysis 2000; 11 (suppl 1): 3-7.

12. Fridberg M.J., et al.: A study of the pharmacokinetics and safety of recombinant activated factor VII in healthy Caucasian and Japanese subjects, Blood Coagulation and Fibrinolysis 2005; 16 (4): 259-266.

13. Lindley, C.M., et al.: Pharmacokinetics and pharmacodynamics of recombinant Factor VIIa, Clinical Pharmacology & Therapeutics 1994; 55 (6): 638-648.

14. Bysted B.V., et al.: A randomized double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25ºC stable formulation, Haemophilia 2007; 13, 527-532.

15. Villar, A., et al.: Pharmacokinetics of activated recombinant coagulation factor VIIa (NovoSeven®) in children vs. adults with haemophilia A, Haemophilia 2004; 10 (4):352-359.

16. Bauer, K.A.: Treatment of Factor VII deficiency with recombinant Factor VIIa, Haemostasis 1996; 26 (suppl 1): 155-158.

17. Lusher, J., et al.: Clinical experience with recombinant Factor VIIa, Blood Coagulation and Fibrinolysis 1998; 9: 119-128.

18. Bech, M.R.: Recombinant Factor VIIa in Joint and Muscle Bleeding Episodes, Haemostasis 1996; 26 (suppl 1): 135-138.

19. 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.

20. Lusher, J.M., et al.: A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with hemophilia A and B, with and without inhibitor, Haemophilia 1998; 4: 790-798.

21. Shapiro A.D., et al: Prospective, Randomised Trial of Two Doses of rFVIIa (NovoSeven®) in Haemophilia Patients with Inhibitors Undergoing Surgery, Thrombosis and Haemostasis 1998; 80: 773-778.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

NovoSeven RT, Coagulation Factor VIIa (Recombinant), is supplied as a room temperature stable, white, lyophilized powder in single‑use vials, one vial per carton. The diluent for reconstitution of NovoSeven RT is a 10 mmol solution of L-histidine in water for injection and is supplied as a clear colorless solution, and referred to as the histidine diluent. The histidine diluent is provided in either a vial or pre-filled diluent syringe.

The amount of rFVIIa in milligrams and in micrograms is stated on the label.

NovoSeven RT package containing 1 vial of NovoSeven RT powder and 1 vial of histidine diluent:

NovoSeven RT in a single-use vial
    • [NDC 0169-7010-01]
    Histidine diluent in vial, 1.1 mLNovoSeven RT in a single-use vial
    • [NDC 0169-7020-01]
    Histidine diluent in vial, 2.1 mLNovoSeven RT in a single-use vial

    [NDC 0169-7050-01]

    • Histidine diluent in vial, 5.2 mLNovoSeven RT in a single-use vial

    [NDC 0169-7040-01]

    • Histidine diluent in vial, 8.1 mL

    Presentation

    Carton NDC Number

    Components

    1 mg per vial

    (1000 micrograms/vial)

    NDC 0169 7010 01
    •   •

    2 mg per vial

    (2000 micrograms/vial)

    NDC 0169 7020 01
    •   •

    5 mg per vial

    (5000 micrograms/vial)

    NDC 0169 7050 01
    • •

    8 mg per vial

    (8000 micrograms/vial)

    NDC 0169 7040 01
    • •
    •  NovoSeven RT with MixPro® package containing 1 vial of NovoSeven RT powder and 1 pre-filled histidine diluent syringe with sterile vial adapter which serves as an alternative needleless reconstitution system:
    NovoSeven RT in a single-use vial
    • [NDC 0169-7211-11]
    Pre-filled histidine diluent in syringe, 1 mL
    • [NDC 0169-7011-98]
    Vial adapterNovoSeven RT in a single-use vial
    • [NDC 0169-7212-11]
    Pre-filled histidine diluent in syringe, 2 mL
    • [NDC 0169-7012-98]
    Vial adapterNovoSeven RT in a single-use vial
    • [NDC 0169-7215-11]
    Pre-filled histidine diluent in syringe, 5 mL
    • [NDC 0169-7015-98]
    Vial adapterNovoSeven RT in a single-use vial
    • [NDC 0169-7218-11]
    Pre-filled histidine diluent in syringe, 8 mL
    • [NDC 0169-7018-98]
    Vial adapter

    Presentation

    Carton NDC Number

    Components

    1 mg per vial

    (1000 micrograms/vial)

    NDC 0169 7201 01
    •   •   •

    2 mg per vial

    (2000 micrograms/vial)

    NDC 0169 7202 01
    •   •   •

    5 mg per vial

    (5000 micrograms/vial)

    NDC 0169 7205 01
    •   •   •

    8 mg per vial

    (8000 micrograms/vial)

    NDC 0169 7208 01
    •   •   •

    The NovoSeven RT and histidine diluent vials are made of glass, closed with a latex-free, chlorobutyl rubber stopper, and covered with an aluminum cap. The pre-filled diluent syringes are made of glass, with a latex-free siliconised bromobutyl rubber plunger. The closed vials and pre-filled diluent syringes are equipped with a tamper-evident snap-off cap which is made of polypropylene. A vial adapter with 25 micrometer filter is provided with the prefilled diluent syringe.

    16.2 Storage and Handling

    Prior to reconstitution, store NovoSeven RT powder and histidine diluent between 2-25°C (36-77°F). Do not freeze. Store protected from light. Do not use past the expiration date.

    After reconstitution, store NovoSeven RT either at room temperature or refrigerated for up to 3 hours. Do not freeze reconstituted NovoSeven RT or store in syringes.

    17 PATIENT COUNSELING INFORMATION

    See FDA-approved patient labeling (Instructions for Use)

    • •Inform patients receiving NovoSeven RT the benefits and risks associated with treatment.
    • •Advise patients about the early signs of hypersensitivity reactions, including hives, urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.
    • •Advise patients about the signs of thrombosis, including new onset swelling and pain in the limbs or abdomen, new onset chest pain, shortness of breath, loss of sensation or motor power, or altered consciousness or speech.
    • •Advise patients to immediately seek medical help if any of the above signs or symptoms occur.

    Version: 20140514-V11

    NovoSeven® RT is covered by US Patent No. 8,299,029, and other patents pending.

    Novo Nordisk® is a registered trademark of Novo Nordisk A/S.

    NovoSeven® is a registered trademark of Novo Nordisk Health Care AG.

    MixPro® is a registered trademark of Novo Nordisk A/S.

    Clave® and MicroClave® are registered trademarks of ICU Medical Inc.

    InVision-Plus®, InVision-Plus CS®, InVision-Plus® Junior® are registered trademarks of RyMed Technologies, Inc.

    Bionector® is a registered trademark of Vygon.

    © 1998-2014 Novo Nordisk

    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

    License Number: 1261

    FDA-approved patient labeling

    Instructions for Use

    NovoSeven RT

    Coagulation Factor VIIa (Recombinant)

    Instructions on how to use NovoSeven® RT

    READ THESE INSTRUCTIONS CAREFULLY BEFORE USING NOVOSEVEN® RT.

    NovoSeven® RT is supplied as a powder. Before injection (administration) it must be mixed (reconstituted) with the liquid diluent supplied in the syringe. The liquid diluent is a histidine solution. The mixed NovoSeven® RT must be injected into your vein (intravenous injection). The equipment in this package is designed to mix and inject NovoSeven® RT.

    You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads, and bandages.

    Don’t use the equipment without proper training from your doctor or nurse.

    Always use a clean and germ free (aseptic) technique. It is important that you wash your hands and ensure that the area around you is clean.

    Don’t open the equipment until you are ready to use it.

    The equipment is for single use only.

    Content

    The package contains:

    • Vial with NovoSeven® RT powder

    • Vial adapter

    • Pre-filled syringe with diluent

    • Plunger rod (placed under the syringe)

    •   Overview
    Take out the number of NovoSeven® RT packages you need. Check the expiry date.
    • Check the name and the color of the package, to make sure it contains the correct product.
    • Wash your hands and dry them properly using a clean towel or air dry.
    • Take the vial, the vial adapter and the pre-filled syringe out of the carton. Leave the plunger rod untouched in the carton.
    • Bring the vial and the pre-filled syringe to room temperature (not above 98.6°F (37°C)). You can do this by holding them in your hands until they feel as warm as your hands.Remove the plastic cap from the vial. If the plastic cap is loose or missing, don’t use the vial.
    • Wipe the rubber stopper on the vial with a sterile alcohol swab and allow it to dry for a few seconds before use. Don’t touch the rubber stopper after wiping it.Remove the protective paper from the vial adapter.

    Don’t take the vial adapter out of the protective cap.

    If the protective paper is not fully sealed or if it is broken, don’t use the vial adapter.

    Place the vial on a flat and solid surface.
    • Turn over the protective cap, and snap the vial adapter onto the vial.

    Don’t touch the spike on the vial adapter.

    Once attached, don’t remove the vial adapter from the vial.

    Lightly squeeze the protective cap with your thumb and index finger as shown.

    Remove the protective cap from the vial adapter.

    Don’t lift the vial adapter from the vial when removing the protective cap.

    Grasp the plunger rod by the wide top end and take it out of the carton. Be careful not to touch the sides or the thread of the plunger rod. Keep holding the plunger rod at the wide top end.
    • Immediately connect the plunger rod to the syringe by turning it clockwise into the rubber plunger inside the pre-filled syringe until resistance is felt. Remove the syringe cap from the pre-filled syringe by bending it down until the perforation breaks.

    Don’t touch the syringe tip under the syringe cap.

    If the syringe cap is loose or missing, don’t use the pre-filled syringe.

    Screw the pre-filled syringe securely onto the vial adapter until resistance is felt.

    Avoid touching the sides of the plunger rod at any time.

    Hold the pre-filled syringe slightly tilted with the vial pointing downwards.
    • Push the plunger rod to inject all the diluent into the vial.Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved.

    Don’t shake the vial as this will cause foaming.

    • Check the mixed solution. It must be clear and colorless. If you notice visible particles or discoloration, don’t use it. Use a new package instead.Keep the plunger rod pushed completely in.
    • Turn the syringe with the vial upside down.
    • Stop pushing the plunger rod and let it move back on its own while the mixed solution fills the syringe.
    • Pull the plunger rod slightly downwards to draw the mixed solution into the syringe. In case you only need part of the entire dose, use the scale on the syringe to see how much mixed solution you withdraw, as instructed by your doctor or nurse.
    • While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top.
    • Push the plunger rod slowly until all air bubbles are gone.Unscrew the vial adapter with the vial.Do not mix NovoSeven® RT with any other intravenous infusions or medications.
    • Inject the mixed solution slowly over 2 to 5 minutes as instructed by your doctor or nurse.

    Injecting the solution via a central venous access device (CVAD) such as a central venous catheter or subcutaneous port:

    Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your connector and central venous access device in consultation with your doctor or nurse.
    • Injecting into a CVAD may require using a sterile 10 mL plastic syringe for withdrawal of the mixed solution and injection.
    • If necessary, use 0.9% Sodium Chloride Injection, USP to flush the CVAD line before or after NovoSeven® RT injection. After injection, safely dispose of the syringe with the infusion set, the vial with the vial adapter, any unused NovoSeven ® RT and other waste materials as instructed by your doctor or nurse.

    Don’t throw it out with the ordinary household trash.

    1. Prepare the vial and the syringe

    • • • • •
    • •

    Don’t use the equipment if it has been dropped, or if it is damaged. Use a new package instead.

    Don’t use the equipment if it is expired. Use a new package instead. The expiration date is printed on the outer carton and on the vial, the vial adapter and the pre-filled syringe.

    Don’t dispose of any of the items until after you have injected the mixed solution.

    2. Attach the vial adapter

    •
    • •
    •

    3. Attach the plunger rod and the syringe

    • •
    •
    •

    4. Mix the powder with the diluent

    • •
    • •

    NovoSeven® RT is recommended to be used immediately after it is mixed.

    If you cannot use the mixed NovoSeven® RT solution immediately, it can be kept in the vial, still with the vial adapter and the syringe attached, at room temperature or refrigerated for no longer than 3 hours.

    Do not freeze mixed NovoSeven® RT solution or store it in syringes.

    Keep mixed NovoSeven® RT solution out of direct light.

    If your dose requires more than one vial, repeat step A to J with additional vials, vial adapters and pre-filled syringes until you have reached your required dose.
    • • • • • •
    •

    Caution: The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector.

    Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as Clave® /MicroClave®, InVision-Plus®, InVision-Plus CS®, InVision-Plus Junior®, Bionector®), and their use can damage the connector and affect administration. To administer product through incompatible needleless connectors, withdraw reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe.

    If you have encountered any problems with attaching the pre-filled histidine diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (877) 668-6777.

    5. Inject the mixed solution

    NovoSeven® RT is now ready to inject into your vein.

    • • • • •

    Disposal

    •

    Don’t disassemble the vial and vial adapter before disposal.

    Don’t reuse the equipment.

    Important information

    Indications and Usage

    NovoSeven® RT, Coagulation Factor VIIa [Recombinant] is room temperature stable and is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; treatment of bleeding episodes in patients with congenital Factor VII deficiency and prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency.

    Safety Information

    Serious thrombotic side effects are associated with the use of NovoSeven® RT outside of the uses approved by the FDA. These thrombotic side effects are blood clots that form in arteries and veins and can cause harm and may lead to death. Your doctor should discuss the risks and explain the signs and symptoms of thrombotic side effects to you. Your doctor should monitor you for blood clots during treatment with NovoSeven® RT.

    Thrombotic side effects following the use of NovoSeven ® RT occurred in 0.3% of all bleeds that were treated for FDA-approved uses. The rate of 0.2% was observed in hemophilia patients with inhibitors, and the rate was higher in patients with acquired hemophilia (4%). Thrombotic events (fatal and non-fatal) have been reported following use of NovoSeven® RT for all FDA-approved uses.

    Some patients have conditions that may increase the risk of thrombotic side effects. These include clogged arteries, blood clots that form throughout the body instead of at the place of injury (called disseminated intravascular coagulation), a type of blood poisoning called septicemia, and crush injury, which is when a body part is crushed or squeezed between heavy or immobile objects.

    Also, people taking aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) at the same time that they are taking NovoSeven® RT may be at increased risk for thrombotic side effects. NovoSeven® RT should be used with caution in patients who have an increased risk for thrombotic side effects. These include, but are not limited to, patients with a history of heart disease, liver disease, patients who have limited movement following surgery, elderly patients, and neonates (babies who are four weeks old or younger). In each of these situations, the potential benefit of treatment with NovoSeven® RT should be weighed against the risk of these complications.

    Some patients with Factor VII deficiency have developed resistance (antibodies) to Factor VII after treatment with NovoSeven® RT. Factor VII deficient patients should be monitored for antibody formation before and after administration of NovoSeven® RT.

    People who have ever had a bad reaction to NovoSeven® RT or to proteins from mice, hamsters, or “bovines” (such as an ox or cow) should consult their physician prior to using NovoSeven® RT.

    The most common side effects in patients treated with NovoSeven® RT are rash, itch, hives, fever, decreased effectiveness of NovoSeven® RT and blood clots occurring in > 0.1% to < 1% of patients.

    For full Prescribing Information please read the other insert included in this package.

    Revised: 05/2014

    NovoSeven® RT is covered by US Patent No. 8,299,029, and other patents pending.

    Novo Nordisk® is a registered trademark of Novo Nordisk A/S.

    NovoSeven® is a registered trademark of Novo Nordisk Health Care AG.

    Clave® and MicroClave® are registered trademarks of ICU Medical Inc.

    InVision-Plus®, InVision-Plus CS®, InVision-Plus® Junior® are registered trademarks of RyMed Technologies, Inc.

    Bionector® is a registered trademark of Vygon.

    © 2012-2014 Novo Nordisk

    Manufactured by:

    Novo Nordisk A/S

    2880 Bagsvaerd, Denmark

    License Number: 1261

    Version: 20140514-v5

    Principal Display Panel 1 mg

    NDC 0169 7010 01

    List: 701001

    NovoSeven® RT

    Coagulation Factor VIIa

    (Recombinant)

    Room Temperature Stable

    1 mg

    For IV administration only

    For human use only

    Single dose vial

    Administer within 3 hours of reconstitution

    Contains no preservative

    Rx only

    novo nordisk®

    Principal Display Panel 2mg

    NDC 0169 7020 01

    List: 702001

    NovoSeven® RT

    Coagulation Factor VIIa

    (Recombinant)

    Room Temperature Stable

    2 mg

    For IV administration only

    For human use only

    Single dose vial

    Administer within 3 hours of reconstitution

    Contains no preservative

    Rx only

    novo nordisk®

    Principal Display Panel 5 mg

    NDC 0169 7050 01

    List: 705001

    NovoSeven® RT

    Coagulation Factor VIIa

    (Recombinant)

    Room Temperature Stable

    5 mg

    For IV administration only

    For human use only

    Single dose vial

    Administer within 3 hours of reconstitution

    Contains no preservative

    Rx only

    novo nordisk®

    Principal Display Panel 8 mg

    NDC 0169 7040 01

    List: 704001

    NovoSeven® RT

    Coagulation Factor VIIa

    (Recombinant)

    Room Temperature Stable

    8 mg

    For IV administration only

    For human use only

    Single dose vial

    Administer within 3 hours of reconstitution

    Contains no preservative

    Rx only

    novo nordisk®

    Principal Display Panel 1 mg

    NDC 0169 7201 01

    List: 720101

    •   NovoSeven® RT
    •  Coagulation Factor VIIa (Recombinant)

    Room Temperature Stable

    For bolus intravenous administration. For human use only.

    Single dose vial. Administer within 3 hours of reconstitution

    Contains no preservative

    Rx Only

    •  1 mg

    Principal Display Panel 2 mg

    NDC 0169 7202 01

    List: 720201

    •   NovoSeven® RT
    •  Coagulation Factor VIIa (Recombinant)

    Room Temperature Stable

    For bolus intravenous administration. For human use only.

    Single dose vial. Administer within 3 hours of reconstitution

    Contains no preservative

    Rx Only

    2 mg

    Principal Display Panel 5 mg

    NDC 0169 7205 01

    List: 720501

    •   NovoSeven® RT
    •  Coagulation Factor VIIa (Recombinant)

    Room Temperature Stable

    For bolus intravenous administration. For human use only.

    Single dose vial. Administer within 3 hours of reconstitution

    Contains no preservative

    Rx Only

    5 mg

    Principal Display Panel 8 mg

    NDC 0169 7208 01

    List: 720801

    •   NovoSeven® RT
    •  Coagulation Factor VIIa (Recombinant)

    Room Temperature Stable

    For bolus intravenous administration. For human use only.

    Single dose vial. Administer within 3 hours of reconstitution

    Contains no preservative

    Rx Only

    8 mg

    Principal Display Panel 1 mL Histidine Label

    Principal Display Panel 2 mL Histidine Label

    Principal Display Panel 5 mL Histidine

    Principal Display Panel 8 mL Histidine

    Principal Display Panel 1 mg. Vial

    Principal Display Panel 2 mg. Vial

    Principal Display Panel 5 mg. Vial

    Principal Display Panel 8 mg. Vial

    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7010
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7010-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2008-04-30


    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7020
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7020-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2008-04-30


    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7050
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7050-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2008-04-30


    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7040
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7040-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2010-08-06


    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7201
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7201-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2012-10-29


    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7202
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7202-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2012-10-29


    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7205
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7205-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2012-10-29


    NovoSeven

    Coagulation Factor VIIa (Recombinant) KIT

    Product Information

    Product Type Plasma derivative Item Code (Source) NDC:0169-7208
    Route of Administration DEA Schedule

    Packaging

    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0169-7208-01 1 in 1 KIT

    Marketing Information

    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103665 2012-10-29


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