BENEFIX Powder and solvent for solution for injection Ref.[9440] Active ingredients: Nonacog alfa

Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.

Treatment monitoring

During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor IX activity in patients' blood samples, plasma factor IX activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

Posology

Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of bleeding, and on the patient’s clinical condition.

The number of units of factor IX administered is expressed in International Units (IU), which is related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for factor IX in plasma).

One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one mL of normal human plasma.

On demand treatment

The calculation of the required dose of BeneFIX can be based on the finding that one unit of factor IX activity per kg body weight is expected to increase the circulating level of factor IX, an average of 0.8 IU/dL (range from 0.4 to 1.4 IU/dL) in patients ≥12 years (further information in section 5.2).

The required dose is determined using the following formula:

Number of factor IX IU required = body weight (in kg) X desired factor IX increase (%) or (IU/dL) X reciprocal of observed recovery

Example: For a recovery of 0.8 IU/dL, the formula reads:

Number of factor IX IU required = body weight (in kg) X desired factor IX increase (%) or (IU/dL) X 1.3 IU/kg

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity levels (in % of normal or in IU/dL) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

Prophylaxis

BeneFIX may be administered for long term prophylaxis against bleeding in patients with severe haemophilia B. In a clinical study for routine secondary prophylaxis the average dose for previously treated patients (PTP) was 40 IU/kg (range 13 to 78 IU/kg) at intervals of 3 to 4 days.

In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

Paediatric population

There is limited documentation of on-demand treatment and surgery in paediatric patients less than 6 years of age treated with BeneFIX.

Mean dosage (± standard deviation) for prophylaxis was 63.7 (± 19.1) IU/kg at intervals of 3 to 7 days. In younger patients, shorter dosage intervals or higher doses may be necessary. FIX consumption for routine prophylaxis in 22 evaluable patients was 4607 (± 1849) IU/kg per year and 378 (± 152) IU/kg per month.

Close monitoring of factor IX plasma activity should be performed as clinically indicated, as well as calculation of pharmacokinetic parameters such as recovery and half-life, in order to adjust doses as appropriate.

Elderly population

Clinical studies of BeneFIX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any patient receiving BeneFIX, dose selection for an elderly patient should be individualised.

Method of administration

BeneFIX is administered by intravenous infusion after reconstitution of the lyophilised powder for solution for injection with sterile 0.234% sodium chloride solution (see section 6.6).

BeneFIX should be administered at a slow infusion rate. In most of the cases, an infusion rate of up to 4 mL per minute has been used. The rate of administration should be determined by the patient’s comfort level.

If any suspected hypersensitivity reaction takes place that is thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped (see sections 4.4 and 4.8).

Agglutination of red blood cells in the tube/syringe

There have been reports of agglutination of red blood cells in the tube/syringe with the administration of BeneFIX. No adverse events have been reported in association with this observation. To minimize the possibility of agglutination, it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe. If agglutination of red blood cells in the tubing/syringe is observed, discard all this material (tubing, syringe and BeneFIX solution) and resume administration with a new package.

Continuous infusion

Administration by continuous infusion has not been approved and is not recommended (see also sections 4.4 and 6.6). For instructions on reconstitution of the medicinal product before administration, see section 6.6.

No symptoms of overdose have been reported with recombinant coagulation factor IX products.

2 years.

The reconstituted product does not contain a preservative and should be used immediately, but no longer than 3 hours after reconstitution. Chemical and physical in-use stability has been demonstrated for 3 hours at temperatures up to 25°C.

Store below 30°C. Do not freeze.

BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU powder and solvent for solution for injection:

BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU of powder in a 10 mL vial (type 1 glass) with a stopper (chlorobutyl) and a flip-off seal (aluminium) and 5 mL of clear, colourless solvent in a prefilled syringe (type 1 glass) with a plunger stopper (bromobutyl), a tip-cap (bromobutyl) and a sterile vial adapter reconstitution device, a sterile infusion set, two alcohol swabs, a plaster, and a gauze pad.

BeneFIX is administered by intravenous infusion after reconstitution of the lyophilised powder for injection with the supplied solvent (0.234% w/v sodium chloride solution) in the pre-filled syringe (see also section 3 of the package leaflet for reconstitution instructions).

BeneFIX, when reconstituted, contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of BeneFIX. It is important that the recommendations in section 4.2 be followed closely.

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

Because the use of BeneFIX by continuous infusion has not been evaluated, BeneFIX should not be mixed with infusion solutions or be given in a drip.