NULOJIX Powder for concentrate for solution for infusion Ref.[6406] Active ingredients: Belatacept

Treatment should be prescribed and supervised by specialist physicians experienced in the management of immunosuppressive therapy and of renal transplant patients.

Belatacept has not been studied in patients with Panel Reactive Antibody (PRA) >30% (who often require increased immunosuppression). Because of the risk of a high total burden of immunosuppression, belatacept should only be used in these patients after consideration of alternative therapy (see section 4.4).

Posology

The recommended dose is based on patient body weight (kg). The dose and treatment frequency is given below.

Table 1. Dose of belatacept for renal transplant recipients:

For more details on the dose calculation, see section 6.6.

Patients do not require pre-medication prior to administration of belatacept.

NULOJIX should be administered in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. Corticosteroid tapering in patients taking belatacept should be implemented cautiously, particularly in patients with 4 to 6 human leukocyte antigen (HLA) mismatches (see sections 4.4 and 5.1).

Infusion-related reactions have been reported with belatacept administration in clinical studies. If any serious allergic or anaphylactic reaction occurs, belatacept therapy should be discontinued immediately and appropriate therapy initiated (see section 4.4).

Therapeutic monitoring of belatacept is not required.

During clinical studies, there was no dose modification of belatacept for a change in body weight of less than 10%.

Special populations

Elderly patients

No dose adjustment is required (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment is recommended in patients with renal impairment or undergoing dialysis (see section 5.2).

Hepatic impairment

No patients with hepatic impairment were studied in renal transplant protocols, therefore dose modification of belatacept in hepatic impairment can not be recommended.

Paediatric population

The safety and efficacy of belatacept in children and adolescents 0 to 18 years of age have not yet been established. No data are available.

Method of administration

NULOJIX is for intravenous use only.

The diluted solution must be administered as an intravenous infusion at a relatively constant rate over 30 minutes. Infusion of the first dose should be given in the immediate preoperative period or during surgery, but before completion of the transplant vascular anastomoses.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Single doses up to 20 mg/kg have been administered without apparent toxic effect. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

Shelf life

Unopened vials: 3 years.

After reconstitution: The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately.

After dilution: Chemical and physical in-use stability of the solution for infusion has been demonstrated for 24 hours when stored in a refrigerator (2°C-8°C). From a microbiological point of view, the product should be used immediately. If not used immediately, the solution for infusion may be stored in a refrigerator (2°C-8°C) for up to 24 hours. Out of these 24 hours, the solution for infusion may be stored below 25°C for a maximum of 4 hours. Do not freeze.

The NULOJIX infusion must be completed within 24 hours of reconstitution of the powder.

Store in a refrigerator (2°C-8°C).

Store in the original package in order to protect from light.

For storage conditions after reconstitution or dilution of the medicinal product, see section 6.3.

NULOJIX is supplied in a 20 ml vial (Type I flint glass) with a stopper (20 mm grey butyl rubber) and flip off seal (aluminum). Each vial is co-packaged with a disposable polypropylene syringe.

Pack sizes: 1 vial and 1 syringe or 2 vials and 2 syringes.

Not all pack-sizes may be marketed.

• Use aseptic technique to reconstitute the vials and dilute the solution for administration.
• Use the silicone-free disposable syringe provided to make up the vials and to add the solution to the infusion. This will avoid aggregate formation (see section 6.2).
• Do not shake the vials. This will avoid foam formation.
• The solution for infusion is to be used in conjunction with a sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 µm to 1.2 µm).

Dose selection and reconstitution of the vials

Calculate the dose and number of NULOJIX vials required. Each NULOJIX vial provides 250 mg of belatacept.

• Total dose of belatacept in mg equals the patient weight in kg times the belatacept dose in mg/kg (5 or 10 mg/kg, see section 4.2).
• Dose modification of NULOJIX is not recommended for a change in body weight of less than 10%.
• Number of vials required equals the belatacept dose in mg divided by 250 rounded up to the next full number of vials.
• Make up each vial with 10.5 ml reconstitution solution.
• Volume of the reconstituted solution required (ml) equals total belatacept dose in mg divided by 25.

Practical details on the reconstitution of vials

Using aseptic technique, make up each vial with 10.5 ml of one of the following solvents (sterile water for injections, sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for injection), using the co-packed disposable syringe (necessary to avoid aggregate formation) and an 18- 21 gauge needle. Syringes are marked in units of 0.5 ml; therefore, the calculated dose should be rounded to the nearest 0.5 ml.

Remove the flip off seal from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the centre of the rubber stopper. Direct the stream of fluid to the glass wall of the vial and not into the powder. Remove the syringe and needle after 10.5 ml of reconstitution fluid has been added to the vial.

To minimize foam formation, gently swirl and invert the vial for at least 30 seconds or until the powder is completely dissolved. Do not shake. Although some foam may remain on the surface of the reconstituted solution, a sufficient excess of belatacept is included in each vial to account for withdrawal losses. Thus, 10 ml of a 25 mg/ml belatacept solution can be withdrawn from each vial.

The reconstituted solution should be clear to slightly opalescent and colourless to pale yellow. Do not use if opaque particles, discolouration or other foreign particles are present. It is recommended to tranfer the reconstituted solution from the vial to the infusion bag or bottle immediately.

Practical details on the preparation of the solution for infusion

After reconstitution, dilute the product to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for injection. From a 100 ml infusion bag or bottle (typically, an infusion volume of 100 ml will be appropriate for most patients and doses, but total infusion volume ranging from 50 ml to 250 ml may be used), withdraw a volume of sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for injection equal to the volume (ml equals total dose in mg divided by 25) of the reconstituted belatacept solution required to provide the dose and discard it. Slowly add the required amount of reconstituted belatacept solution from each vial to the infusion bag or bottle using the same disposable syringe used for reconstitution of the powder. Gently mix the infusion container. The concentration of belatacept in the infusion should be between 2 mg and 10 mg belatacept per ml solution.

Any unused portion in the vials must be discarded in accordance with local requirements.

Administration

When reconstitution and dilution are performed under aseptic conditions, the NULOJIX infusion should be started immediately or must be completed within 24 hours of reconstitution of the powder. If not used immediately, the solution for infusion may be stored in the refrigerator (2°C-8°C) for up to 24 hours. Do not freeze. The solution for infusion may be stored for a maximum of 4 hours of the total 24 hours below 25°C. Infusion must be completed within 24 hours of reconstitution of the powder. Prior to administration, the solution for infusion should be inspected visually for particulate matter or discolouration. Discard the solution if any particulate matter or discolouration is observed. The entire, fully diluted infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 μm to 1.2 μm). Following administration, it is recommended that the intravenous line be flushed with infusion fluid to ensure administration of the complete dose.

Do not store any unused portion of the solution for infusion for reuse.

NULOJIX should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of NULOJIX with other agents.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.