Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and/or bleeding disorders.

Posology

Haemophilia A or B with inhibitors or expected to have a high anamnestic response

Dose

NovoSeven should be given as early as possible after the start of a bleeding episode. The recommended initial dose, administered by intravenous bolus injection, is 90 μg per kg body weight. Following the initial dose of NovoSeven further injections may be repeated. The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or surgery being performed.

Paediatric population

Current clinical experience does not warrant a general differentiation in dosing between children and adults, although children have faster clearance than adults. Therefore, higher doses of rFVIIa may be needed in paediatric patients to achieve similar plasma concentrations as in adult patients (see section 5.2).

Dose interval

Initially 2–3 hours to obtain haemostasis.

If continued therapy is needed, the dose interval can be increased successively once effective haemostasis is achieved to every 4, 6, 8 or 12 hours for as long as treatment is judged as being indicated.

Mild to moderate bleeding episodes (including home therapy)

Early intervention has been shown to be efficacious in the treatment of mild to moderate joint, muscle and mucocutaneous bleeds. Two dosing regimens can be recommended:

1. Two to three injections of 90 μg per kg body weight administered at three-hour intervals. If further treatment is required, one additional dose of 90 μg per kg body weight can be administered.
2. One single injection of 270 μg per kg body weight.

The duration of home therapy should not exceed 24 hours. Only after consultation with the haemophilia treatment centre can continued home treatment be considered.

There is no clinical experience with administration of a single dose of 270 μg per kg body weight in elderly patients.

Serious bleeding episodes

An initial dose of 90 μg per kg body weight is recommended and could be administered on the way to the hospital where the patient is usually treated. The following dose varies according to the type and severity of the haemorrhage. Dosing frequency should initially be every second hour until clinical improvement is observed. If continued therapy is indicated, the dose interval can then be increased to 3 hours for 1–2 days. Thereafter, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged as being indicated. A major bleeding episode may be treated for 2–3 weeks but can be extended beyond this if clinically warranted.

Invasive procedure/surgery

An initial dose of 90 μg per kg body weight should be given immediately before the intervention. The dose should be repeated after 2 hours and then at 2–3 hour intervals for the first 24–48 hours depending on the intervention performed and the clinical status of the patient. In major surgery, the dose should be continued at 2–4 hour intervals for 6–7 days. The dose interval may then be increased to 6–8 hours for another 2 weeks of treatment. Patients undergoing major surgery may be treated for up to 2 – 3 weeks until healing has occurred.

Acquired Haemophilia

Dose and dose interval

NovoSeven should be given as early as possible after the start of a bleeding episode. The recommended initial dose, administered by intravenous bolus injection, is 90 μg per kg body weight. Following the initial dose of NovoSeven further injections may be given if required. The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or the surgery being performed. The initial dose interval should be 2–3 hours. Once haemostasis has been achieved, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged to be indicated.

Factor VII deficiency

Dose, dose range and dose interval

The recommended dose range in adults and children for treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 15–30 μg per kg body weight every 4–6 hours until haemostasis is achieved. Dose and frequency of injections should be adapted to each individual.

Paediatric population

Limited clinical experience in long term prophylaxis has been gathered in the paediatric population below 12 years of age, with a severe clinical phenotype (see section 5.1).

Dose and frequency of injections for prophylaxis should be based on clinical response and adapted to each individual.

Glanzmann’s thrombasthenia

Dose, dose range and dose interval

The recommended dose for treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 90 μg (range 80–120 μg) per kg body weight at intervals of two hours (1.5–2.5 hours). At least three doses should be administered to secure effective haemostasis. The recommended route of administration is bolus injection as lack of efficacy may appear in connection with continuous infusion.

For those patients who are not refractory, platelets is the first line treatment for Glanzmann’s thrombasthenia.

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6. Administer the solution as an intravenous bolus injection over 2–5 minutes.

Monitoring of treatment – laboratory tests

There is no requirement for monitoring of NovoSeven therapy. Severity of bleeding condition and clinical response to NovoSeven administration must guide dosing requirements.

After administration of rFVIIa, prothrombin time (PT) and activated partial thromboplastin time (aPTT) have been shown to shorten, however no correlation has been demonstrated between PT and aPTT and clinical efficacy of rFVIIa.

Dose limiting toxicities of NovoSeven have not been investigated in clinical trials.

Four cases of overdose have been reported in patients with haemophilia in 16 years. The only complication reported in connection with an overdose was a slight transient increase in blood pressure in a 16 year-old patient receiving 24 mg rFVIIa instead of 5.5 mg.

No cases of overdose have been reported in patients with acquired haemophilia or Glanzmann’s thrombasthenia.

In patients with factor VII deficiency, where the recommended dose is 15–30 µg/kg rFVIIa, one episode of overdose has been associated with a thrombotic event (occipital stroke) in an elderly (>80 year) male patient treated with 10 – 20 times the recommended dose. In addition, the development of antibodies against NovoSeven and FVII has been associated with overdose in one patient with factor VII deficiency.

The dose schedule should not be intentionally increased above the recommended doses due to the absence of information on the additional risk that may be incurred.

Shelf life: The shelf life for the product packed for sale is 3 years when the product is stored below 25°C.

In vial: After reconstitution, chemical and physical stability has been demonstrated for 6 hours at 25°C and 24 hours at 5°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, storage time and storage conditions prior to use are the responsibility of the user, and should not be longer than 24 hours at 2°C–8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. The reconstituted solution should be stored in the vial.

In syringe (50 ml polypropylene) in hospital settings only: Reconstitution must take place in controlled and validated aseptic conditions by adequately trained staff. Under these conditions, chemical and physical stability has been demonstrated for 24 hours at 25°C when stored in a 50 ml syringe (polypropylene). If not used immediately, the conditions prior to use are the responsibility of the user and the in-use storage time must not be longer than as stated above.

Store powder and solvent below 25°C.

Store powder and solvent protected from light.

Do not freeze.

For storage conditions of the reconstituted medicinal product, see section 6.3.

The solvent of NovoSeven is provided in either a vial or in a pre-filled syringe. Not all presentations may be marketed.

The NovoSeven 1 mg (50 KIU)/NovoSeven 2 mg (100 KIU) package contains either:

• 1 vial (2 ml) with white powder for solution for injection
• 1 vial (2 ml) with solvent for reconstitution

or

• 1 vial (2 ml) with white powder for solution for injection
• 1 pre-filled syringe (3 ml) with solvent for reconstitution
• 1 plunger rod
• 1 vial adapter, with an integrated particle filter with a pore size of 25 micrometer.

The NovoSeven 5 mg (250 KIU)/NovoSeven 8 mg (400 KIU) package contains either:

• 1 vial (12 ml) with white powder for solution for injection
• 1 vial (12 ml) with solvent for reconstitution

or

• 1 vial (12 ml) with white powder for solution for injection
• 1 pre-filled syringe (10 ml) with solvent for reconstitution
• 1 plunger rod
• 1 vial adapter, with an integrated particle filter with a pore size of 25 micrometer.

Vial: Type I glass vial closed with a chlorobutyl rubber stopper, covered with an aluminium cap. The closed vial is equipped with a polypropylene tamper-evident snap-off cap.

Pre-filled syringe: Type I glass barrel with a polypropylene backstop and bromobutyl rubber plunger. The syringe cap consists of bromobutyl rubber and polypropylene tamper evident seal.

Plunger rod: made of polypropylene.

The solvent of NovoSeven is provided in either a vial or in a pre-filled syringe. Not all presentations may be marketed. Handling procedures for both presentations are described below.

Powder in vial and solvent in vial

Always use an aseptic technique.

Reconstitution:

• NovoSeven powder and solvent vials should be at room temperature at reconstitution. Remove the plastic caps from the two vials. If the caps are loose or missing, do not use the vials. Clean the rubber stoppers on the vials with alcohol swabs and allow them to dry before use. Use a disposable syringe of an appropriate size and a vial adapter, transfer needle (20–26G) or other suitable device. If devices other than those supplied by Novo Nordisk are used, ensure the use of an adequate filter with a pore size of 25 micrometer.
• Attach the vial adapter to the solvent vial. If using a transfer needle, screw the transfer needle tightly onto the syringe.
• Pull the plunger to draw in a volume of air that is equal to the amount of solvent in the solvent vial (ml equals cc on the syringe).
• Screw the syringe tightly onto the vial adapter on the solvent vial. If using a transfer needle, insert the transfer needle into the rubber stopper of the solvent vial. Inject air into the vial by pushing the plunger until you feel a clear resistance.
• Hold the syringe with the solvent vial upside down. If using a transfer needle, make sure the transfer needle tip is in the solvent. Pull the plunger to draw the solvent into the syringe.
• Remove the empty solvent vial. If using a vial adapter, tip the syringe to remove it from the vial.
• Attach the syringe with the vial adapter or transfer needle to the powder vial. If using a transfer needle, make sure to penetrate the centre of the rubber stopper. Hold the syringe slightly tilted with the vial facing downwards. Push the plunger slowly to inject the solvent into the powder vial. Make sure not to aim the stream of solvent directly at the NovoSeven powder as this will cause foaming.
• Gently swirl the vial until all the powder is dissolved. Do not shake the vial as this will cause foaming.

NovoSeven reconstituted solution is colourless and should be inspected visually for particulate matter and discolouration prior to administration.

Do not store reconstituted NovoSeven in plastic syringes, unless as described in section 6.3.

It is recommended to use NovoSeven immediately after reconstitution, unless as described in section 6.3.

Administration:

• Ensure that the plunger is pushed all the way in before turning the syringe upside down (it may have been pushed out by the pressure in the syringe). If using a transfer needle, make sure the transfer needle tip is in the solution. Hold the syringe with the vial upside down and pull the plunger to draw all the solution into the syringe.
• If using a vial adapter, unscrew the vial adapter with the empty vial. If using a transfer needle, remove the transfer needle from the vial, replace the transfer needle cap, and twist the transfer needle off the syringe.
• NovoSeven is now ready for injection. Locate a suitable site, and slowly inject NovoSeven into a vein over a period of 2–5 minutes without removing the needle from the injection site.

Safely dispose of the syringe, vials and any unused product. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Powder in vial and solvent in pre-filled syringe

Always use an aseptic technique.

Reconstitution:

• The NovoSeven powder vial and pre-filled syringe with solvent should be at room temperature at reconstitution. Remove the plastic cap from the vial. If the cap is loose or missing, do not 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. Do not touch the rubber stopper after wiping it.
• Remove the protective paper from the vial adapter. Do not take the vial adapter out of the protective cap. If the protective paper is not fully sealed or it is broken do not use the vial adapter. Turn over the protective cap, and snap the vial adapter onto the vial. Lightly squeeze the protective cap with the thumb and index finger. Remove the protective cap from the vial adapter.
• Screw the plunger rod clockwise into the 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. Do not touch the syringe tip under the syringe cap. If the syringe cap is loose or missing, do not use the pre-filled syringe.
• Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. Hold the pre- filled syringe slightly tilted with the vial pointing downwards. Push the plunger rod to inject all the solvent into the vial. Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved. Do not shake the vial as this will cause foaming.

If a larger dose is needed, repeat the procedure with additional vials, pre-filled syringes and vial adapters.

The NovoSeven reconstituted solution is colourless and should be inspected visually for particulate matter and discolouration prior to administration.

It is recommended to use NovoSeven immediately after reconstitution. For storage conditions of the reconstituted medicinal product, see section 6.3.

Administration:

• 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 reconstituted solution fills the syringe. Pull the plunger rod slightly downwards to draw the mixed solution into the syringe.
• 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. If the entire dose is not required, use the scale on the syringe to see how much mixed solution is withdrawn.
• Unscrew the vial adapter with the vial.
• NovoSeven is now ready for injection. Locate a suitable site, and slowly inject NovoSeven into a vein over a period of 2–5 minutes without removing the needle from the injection site.

Safely dispose of the used materials. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Procedure for pooling of vials for hospital use only

During in vitro studies, the chemical and physical in-use stability has been demonstrated for 24 hours at 25°C in a 50 ml syringe (polypropylene). Compatibility with the product was demonstrated for the system consisting of a 50 ml syringe (polypropylene), a 2 m infusion tube (polyethylene) and an in-line filter with a 5 micrometer pore size.

Pooling of vials (hospital use only):

• All steps should be completed under controlled and validated aseptic conditions by adequately trained staff.
• If not reconstituted, pooled or used as recommended the in-use times and conditions prior to use are the responsibility of the user.
• Ensure that a vial adapter is used irrespective of presentation.
• Reconstitute the product as described above under Reconstitution for relevant product presentation. Unscrew the empty syringe from the vial adapter and for both presentations ensure that a vial adapter is attached to the vial containing reconstituted product.
• Repeat the procedure with the appropriate number of additional vials, solvent vials/pre-filled syringes and vial adapters.
• Draw approximately 5 ml of sterile air into the 50 ml syringe (polypropylene). Screw the syringe securely onto the vial adapter until resistance is felt. Hold the syringe slightly tilted with the vial pointing downwards. Push the plunger rod gently to inject a little air into the vial. Turn the syringe with the vial upside down and withdraw the contents of the vial into the syringe.
• Repeat the above procedure with the remaining vials with reconstituted product, to obtain the desired volume in the syringe.
• An in-line filter with a 5 micrometer pore size must be ensured for administration. Ensure that the syringe, the infusion tube and the in-line filter are primed and free of air before administration.
• The syringe with adequately reconstituted product is now ready for administration in a CE-marked infusion pump (accepting a 50 ml syringe).
• The infusion pump must only be operated by trained hospital personnel.