NovoSeven RT

Contraindications

• Manufacturer states no known contraindications.1

Warnings/Precautions

Warnings

Risk of serious thromboembolic events.1 17 19 20 23 25 26 27 29 35 36 Adverse arterial and venous thromboembolic events reported in clinical studies and during postmarketing experience.1 17 19 20 23 25 26 27 29 35 36 Risk of thrombosis, particularly arterial thromboembolic events (e.g., myocardial ischemia, MI, cerebral ischemia and/or infarction), may be further increased in nonhemophilic patients who receive factor VIIa (recombinant) for non-FDA-labeled indications.19 35 36 37 38

Potentially greater risk in patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injuries, septicemia, or concomitant treatment with activated or nonactivated prothrombin complex concentrates (APCCs or PCCs) due to circulating tissue factor (TF) or predisposing coagulopathy.1 17 19

Weigh risk of thromboembolism against benefits of factor VIIa (recombinant) therapy.35 Use with caution, especially in patients with known risk factors for thromboembolism (e.g., elderly patients, neonates, those with a history of CHD, liver disease, DIC, or who require postoperative immobilization).1 19 20 25 27 29

Closely monitor for thrombosis or other signs of an activated coagulation system.1 25 27 39 Reduce dosage or discontinue therapy if thrombosis occurs or laboratory tests confirm presence of intravascular coagulation.1

Report thrombotic complications and other adverse effects associated with factor VIIa (recombinant) to the Hemophilia and Thrombosis Research Society (HTRS) Registry at 877-362-7355.1 13 36

Safety and efficacy of prolonged elevations of factor VIIa have not been evaluated, and most appropriate duration of posthemostatic therapy with factor VIIa (recombinant) is not known; exercise caution if factor VIIa (recombinant) used for extended periods to maintain hemostasis.1 Minimize duration of posthemostatic therapy and closely monitor patients (preferably by a clinician experienced in the posthemostatic management of hemophilia).1

Development of antibodies to factor VII reported rarely in patients with congenital factor VII deficiency receiving factor VIIa (recombinant).1 12 25 In some cases, inhibitory effects were demonstrated in vitro;1 clinical importance not established.12

Monitor PT and factor VII coagulant activity prior to and following drug administration in patients with factor VII deficiency.1 Suspect antibody formation if factor VIIa activity fails to reach the expected level, PT is not corrected, or bleeding is not controlled after treatment with recommended dosages of factor VIIa (recombinant) and perform appropriate screening tests.1 (See Adequate Patient Evaluation and Monitoring under Cautions.)

Monitor patients with congenital factor VII deficiency receiving factor VIIa (recombinant) for evidence of antibody development.1 (See Development of Antibodies to Factor VII under Cautions.)

Evaluate hemostasis to determine effectiveness of factor VIIa (recombinant) and need for dosage adjustments.1 Laboratory parameters (e.g., PT/INR, aPTT, plasma factor VII clotting activity) have not been shown to correlate directly with hemostasis; furthermore, coagulation assays may produce different results depending on the specific reagent used.1 25 26 27 31 42

Administration of factor VIIa (recombinant) generally shortens PT and aPTT and has been shown to rapidly normalize INR; however, clinical importance not known.1 20 25 31 42 43 44

Sensitivity Reactions

Hypersensitivity reactions (e.g., including anaphylactic shock, flushing, urticaria, rash, angioedema) reported.1 17 Administer with caution in patients with known hypersensitivity to factor VIIa (recombinant) or any ingredient in the formulation.1

Factor VIIa (recombinant) contains trace amounts of animal protein which may stimulate antibody production and cause hypersensitivity reactions.1 13 Use with caution in patients with known hypersensitivity to murine, hamster, or bovine proteins.1

If severe hypersensitivity or anaphylaxis occurs, discontinue drug immediately and initiate appropriate therapy.13

Specific Populations

Category C.1

Thrombotic events have been reported in women without a bleeding disorder receiving factor VIIa (recombinant) for uncontrolled postpartum hemorrhage.1 (See Thromboembolic Events under Cautions.)

Not known whether factor VIIa (recombinant) is distributed into human milk.1 Discontinue nursing or the drug.1

NovoSeven RT has not been evaluated in patients ≤16 years of age to determine if there are differences in safety and efficacy among various pediatric age groups.1 13 The predecessor product (NovoSeven) has been used in pediatric patients 0–16 years of age; no substantial differences in safety and efficacy relative to adults.1 7 13

In clinical trials, dosing in pediatric patients was determined according to body weight and not age.1

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 Potential risk of adverse thromboembolic events in geriatric patients; use with caution.1 17 19 26 (See Thromboembolic Events under Cautions.)

Common Adverse Effects

Fever,1 hemorrhage,1 injection site reaction,1 arthralgia,1 headache,1 BP changes (hypotension or hypertension),1 nausea,1 vomiting,1 pain,1 edema,1 rash.1

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Factor VIIa in children.

Geriatric

Adequate and well-controlled studies have not been done on the relationship of age to the effects of Factor VIIa in geriatric patients.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Factor XIII
• Prothrombin Complex

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood clots or a history of medical problems caused by blood clots or
• Heart disease (eg, coronary heart disease), history of or
• Infection or
• Injury (crush) or
• Liver disease—These conditions may increase the risk of developing blood clots.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Belly pain.
• Swelling of belly.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about NovoSeven RT, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about NovoSeven RT (factor VIIa (recombinant)). It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using NovoSeven RT.

Review Date: October 4, 2017

General

• NovoSeven RT is intended for intravenous bolus administration only.
• 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.
• NovoSeven RT should be administered to patients only under the supervision of a physician experienced in the treatment of bleeding disorders.

Hemophilia A or B with Inhibitors

Treatment of Acute Bleeding Episodes

Hemostatic Dosing

• 90 micrograms/kg 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/kg 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.

Congenital Factor VII deficiency

• 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/kg.
• Dose and frequency of injections should be adjusted to each individual.
• The minimum effective dose has not been determined.

Acquired Hemophilia

• The recommended dose range for the treatment of patients with acquired hemophilia is 70-90 micrograms/kg 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/kg; of the 15 treated, 10 (67%) were effective and 2 (13%) were partially effective.

Reconstitution

Calculate the NovoSeven RT dosage you will need and select the appropriate NovoSeven RT vial package. The selected package contains 1 vial of NovoSeven RT powder and 1 vial of histidine diluent required to prepare reconstituted NovoSeven RT solution. Reconstitute only with the histidine diluent provided with NovoSeven RT. Do not reconstitute with sterile water or other diluent.

Reconstitution should be performed using the following procedures:

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

After reconstitution with the specified volume of diluent, each vial contains approximately 1 mg/mL NovoSeven RT (1000 micrograms/mL).

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.

Administration

• NovoSeven RT is intended 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.

Administration should be performed using the following procedures:

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.
5. Administer as a slow bolus injection over 2 to 5 minutes, depending on the dose administered.
6. If line needs to be flushed before or after NovoSeven RT administration, use 0.9% Sodium Chloride Injection, USP.
7. Discard any unused reconstituted NovoSeven RT after 3 hours.

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:

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.

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).

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.

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 reports11, 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

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/kg NovoSeven12. The pharmacokinetics of rFVII were linear over the dose range of 40 to 180 micrograms/kg. Pharmacokinetics were similar across gender and ethnic groups. Mean steady state volume of distribution ranged from 130 to 165 mL/kg, mean values of clearance ranged from 33 to 37 mL/h 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/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/kg (range 78-139). Median clearance was 33 mL/kg/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/kg) and 10 male pediatric (2-12 years) patients (crossover, 90 and 180 micrograms/kg) with severe hemophilia A (10 of 18 subjects had inhibitors) received NovoSeven15. The PK of rFVII following 90 and 180 micrograms/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/hr (37.6 ± 13.1 mL/hr/kg) and 1375 ± 396 mL/hr (57.3 ± 9.5 mL/hr/kg), respectively. The volume of distribution at steady state (Vss) in adults and children was 121 ± 30 and 153 ± 29 mL/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/hr x kg), volume of distribution at steady state (280-290 mL/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/mL. Factor VII levels of 15-25% (0.075 – 0.125 micrograms/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/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/kg would be required to achieve sufficient FVII plasma levels for hemostasis, which is consistent with the recommended dose range.

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®

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®

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®