Benefix

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BENEFIX (BeneFix®)

Composition:

Active substance: recombinant human coagulation factor IX (nonacog alfa);

One vial contains 250 IU, or 500 IU, or 1000 IU, or 2000 IU, or 3000 IU of nonacog alfa;

Excipients: L-histidine, glycine, sucrose, polysorbate 80.

Solvent: 0.234% sodium chloride solution in water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white lyophilisate, practically free from clearly visible foreign particles, moisture, and defects in vial stoppering. The reconstituted solution is clear, colorless, and practically free from visible particles.

Pharmacotherapeutic group. Antihemorrhagics. Coagulation factor IX.

ATC code B02BD04.

Pharmacological properties.

Pharmacodynamics.

Recombinant coagulation factor IX is a single-chain glycoprotein with an approximate molecular weight of 55 kDa, belonging to the family of vitamin K-dependent serine proteases involved in blood coagulation. Recombinant coagulation factor IX is a protein preparation synthesized using recombinant DNA technology, which has structural and functional characteristics similar to those of endogenous factor IX. Factor IX is activated by the factor VII/tissue factor complex (in the extrinsic pathway of the blood coagulation mechanism) or by factor XIa (in the intrinsic pathway of the blood coagulation mechanism). Activated factor IX, together with activated factor VIII, activates factor X. This ultimately leads to the conversion of prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin, after which a thrombus can form. In patients with hemophilia B, factor IX activity is absent or significantly reduced, therefore they may require replacement therapy.

Hemophilia B is an X-linked inherited blood coagulation disorder caused by decreased levels of factor IX, leading to spontaneous or trauma- (accidental or surgical) induced severe bleeding into joints, muscles, or internal organs. Replacement therapy increases factor IX levels in plasma, thereby temporarily correcting this deficiency and reducing the tendency toward hemorrhagic events.

Efficacy analysis in study 3090A1-301-WW was based on data from 22 children on prophylactic treatment, including 4 children who switched from on-demand to prophylactic treatment. Two patients underwent surgical procedures (circumcision and implantation of a port catheter system). The safety analysis, based on data from 25 patients, confirmed the expected safety profile. Only one serious adverse reaction was reported—hypersensitivity and development of inhibitors—related to the use of BeneFIX, occurring in a single previously untreated patient (PUP).

In two open-label studies, the safety of BeneFIX administered at a dose of 100 IU/kg once weekly was demonstrated. However, the elimination half-life of the drug (see section "Pharmacokinetics") and limited pharmacokinetic data for the once-weekly regimen generally do not support recommending this regimen for long-term prophylaxis in patients with severe hemophilia B.

Pharmacokinetics.

In a randomized, crossover pharmacokinetic study in which BeneFIX was reconstituted using 0.234% sodium chloride as diluent, the pharmacokinetic profile was shown to be equivalent to that of the marketed formulation of BeneFIX (reconstituted with sterile water) in 24 patients (aged ≥12 years) who had previously been treated with the drug at a dose of 75 IU/kg. Additionally, pharmacokinetic parameters were monitored in 23 of these patients after multiple administrations of BeneFIX over six months, and it was established that they did not differ from baseline values. Summary pharmacokinetic parameter estimates are presented in Table 1.

Table 1

Estimated pharmacokinetic parameter values for BeneFIX (75 IU/kg) at baseline and after 6 months in previously treated patients with hemophilia B

A population pharmacokinetic model was developed based on data collected from 73 patients aged from 7 months to 60 years. Parameters estimated using a final two-compartment model are presented in Table 2. Compared to adults and adolescents, infants and children have higher clearance, larger volume of distribution, shorter half-life, and lower recovery. The terminal phase was not adequately captured due to lack of data (beyond 24 hours) in children under 6 years of age.

Table 2

Mean value ± standard deviation of pharmacokinetic parameters based on individual Bayesian estimates from population pharmacokinetic analysis

Clinical characteristics.

Indications.

Treatment and prevention of bleeding episodes in patients with hemophilia B (congenital factor IX deficiency).

Benefix can be used in all age groups.

Contraindications.

The product is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients, as well as in patients with increased sensitivity to hamster proteins.

Interaction with other medicinal products and other forms of interaction

There have been no reports of interactions between human coagulation factor IX (recombinant DNA) and other medicinal products.

Special precautions for use.

Traceability

To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded. Patients may attach one of the peel-off labels from the vial to record the batch number in their diary or for reporting any adverse reactions.

Hypersensitivity

BeneFIX may cause allergic-type hypersensitivity reactions. The product contains trace amounts of hamster proteins. Potentially life-threatening anaphylactic/anaphylactoid reactions have been observed during treatment with factor IX-containing products, including BeneFIX. Patients should discontinue the product immediately and contact their physician if symptoms of hypersensitivity occur. Patients should be advised to report early signs of hypersensitivity reactions, such as dyspnea, wheezing, edema, urticaria (localized or generalized), pruritus, chest tightness, bronchospasm, laryngospasm, wheezing, hypotension, blurred vision, and anaphylaxis.

In some cases, these reactions may progress to severe anaphylaxis. If shock occurs, current medical standards for managing this condition should be followed. In the event of severe allergic reactions, consideration should be given to using alternative hemostatic therapies.

Inhibitors

Inhibitor development in previously treated patients (PTPs) receiving factor IX-containing products is infrequent. However, since clinically significant inhibitor development with inadequate response to treatment was observed in one PTP during clinical trials with BeneFIX, and considering the limited experience with antigenic properties of recombinant factor IX, patients receiving BeneFIX should be closely monitored for the development of factor IX inhibitors. Inhibitor titers in Bethesda units should be determined using appropriate biological assay methods.

Published data indicate a correlation between factor IX inhibitor development and allergic reactions. Therefore, patients who experience allergic reactions to the product should be evaluated for the presence of inhibitors. It should be noted that patients who have developed factor IX inhibitors may be at increased risk of anaphylaxis following factor IX administration. Previous data suggest a possible association between large deletion-type mutations in the factor IX gene and an increased risk of inhibitor development and acute hypersensitivity reactions to the product. Close monitoring for symptoms of acute hypersensitivity reactions, especially during initial stages of treatment, is required for patients with large deletion-type mutations in the factor IX gene.

Due to the risk of allergic reactions with factor IX concentrates, the first administration of BeneFIX as prescribed by a physician should be performed under medical supervision, with appropriate treatment for allergic reactions readily available.

Thrombosis

Although BeneFIX contains only factor IX, the risk of thrombosis and disseminated intravascular coagulation (DIC) should be considered. Historically, the use of factor IX-containing complex concentrates has been associated with thromboembolic complications. Therefore, administration of factor IX-containing products may pose a potential risk in patients with signs of fibrinolysis or DIC. Given the potential risk of thrombotic complications with this product, clinical monitoring for early signs of thrombotic events and consumption coagulopathy, using appropriate biological testing methods, is required in patients with liver disease, postoperative patients, neonates, patients at increased risk of thrombotic events, or those with DIC. In each of these situations, the benefit-risk balance of treatment with BeneFIX should be carefully evaluated.

The safety and efficacy of BeneFIX administered via continuous infusion have not been established. During post-marketing surveillance, thrombotic complications, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates, have been reported following continuous infusion of human coagulation factor IX via a central venous catheter (see section "Adverse reactions").

Cardiovascular events

Replacement therapy with factor IX may increase the risk of cardiovascular events in patients with predisposing risk factors for cardiovascular disease.

Nephrotic syndrome

Cases of nephrotic syndrome have been reported in patients with hemophilia B and factor IX inhibitors who have a history of allergic reactions, following attempts at immune tolerance induction therapy. The safety and efficacy of BeneFIX for immune tolerance induction have not been established.

Special patient populations

Sufficient data on the use of BeneFIX in previously untreated patients (PUPs) are not available from clinical trials.

Sodium content

After reconstitution, BeneFIX contains 0.2 mmol of sodium (4.6 mg) per vial, i.e., it is practically sodium-free. Depending on the patient's body weight and BeneFIX dosage, patients may receive several vials of the medicinal product in a single infusion. This should be taken into account if the patient is on a low-salt diet.

Use during pregnancy or breastfeeding

Studies on the effects of factor IX on reproductive function in animals have not been conducted. Since hemophilia B is rare in females, experience with factor IX use during pregnancy and breastfeeding is lacking. Therefore, factor IX should be administered to women during pregnancy and breastfeeding only if clearly needed.

The effect of the product on fertility has not been determined.

Ability to affect reaction speed when driving or operating machinery

BeneFIX does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

Treatment should be administered under the supervision of a physician experienced in the management of hemophilia.

Monitoring of Treatment

During the course of treatment, monitoring of Factor IX levels is recommended to determine the appropriate dosage and frequency of repeat infusions. Different patients may respond differently to Factor IX administration, reflected in varying half-lives and recovery levels. Dose calculations based on body weight may require adjustment in patients with underweight or overweight conditions. In the case of major surgical interventions, careful monitoring of replacement therapy through coagulation analysis (Factor IX activity in plasma) is essential.

If Factor IX activity in patient plasma samples is determined using a one-stage coagulation assay based on activated partial thromboplastin time (aPTT) in vitro, the assay results may be significantly influenced by both the type of aPTT reagent and the standard reference material used. This factor should be particularly considered when changing laboratories and/or reagents used for the analysis.

Dosage

The dosage and duration of replacement therapy depend on the severity of Factor IX deficiency, the location and severity of bleeding, and the patient's clinical condition.

The amount of administered Factor IX units is expressed in International Units (IU), referenced to the WHO standard for Factor IX-containing products. Factor IX activity in blood plasma is expressed as a percentage (relative to normal human plasma) or in International Units (relative to the international standard for plasma Factor IX).

1 IU of Factor IX activity is equivalent to the amount of Factor IX present in 1 mL of normal human plasma.

On-demand Treatment

The dose calculation for BeneFIX is based on empirical data indicating that 1 IU of Factor IX activity per kg of body weight increases Factor IX levels in blood plasma by an average of 0.8 IU/dL (ranging from 0.4 to 1.4 IU/dL) in patients aged 12 years and older (further information in the section "Pharmacokinetics").

The required dose is calculated using the following formula:

Required Factor IX units (IU) =
Body weight (kg) × Desired increase in Factor IX level (% or IU/dL) × Reciprocal of the observed incremental recovery after infusion;

For an incremental recovery of 0.8 IU/dL (average Factor IX increase), the following formula is used:

Required Factor IX units (IU) =
Body weight (kg) × Desired increase in Factor IX level (% or IU/dL) × 1.3 IU/kg.

The clinical response in each individual case should always be taken into account when determining the dose and frequency of administration.

In cases of hemorrhagic events, Factor IX activity in plasma should not fall below the levels indicated in Table 3 (% or IU/dL) during the respective time periods. The table below may be used as a guideline for determining the dosage of the drug in bleeding episodes and surgical interventions.

Table 3

Prophylaxis

BeneFIX can be used for long-term prevention of hemorrhagic episodes in patients with hemophilia B. In a clinical study, the mean dose for routine secondary prophylaxis in PTPs was 40 IU/kg (range 13 to 78 IU/kg) administered at intervals of 3 to 4 days.

In some cases, particularly in younger patients, it may be necessary to shorten the dosing intervals or increase the dose.

Geriatric patients

The number of patients aged 65 years and older included in clinical studies with BeneFIX is not sufficient to determine whether their response differs from that of younger patients. The dose of BeneFIX for elderly patients, as for other patients, should be individually determined.

Administration method

BeneFIX is administered by intravenous infusion after reconstitution of the injectable solution using sterile 0.234% sodium chloride solution.

BeneFIX should be administered slowly. In most cases, the infusion rate does not exceed 4 mL/min. The rate of administration should be based on patient comfort.

If a hypersensitivity reaction occurs that may be related to the use of BeneFIX, the infusion rate should be reduced or the infusion stopped altogether (see sections "Special precautions" and "Side effects").

Erythrocyte agglutination in the intravenous infusion set/syringe

Cases of erythrocyte agglutination in the intravenous infusion set/syringe have been reported during administration of BeneFIX. No clinical consequences associated with this observation have been reported. To minimize the risk of agglutination, it is important to limit the amount of blood entering the intravenous infusion set and to avoid blood entering the syringe. If erythrocyte agglutination is observed in the intravenous infusion set or syringe, all materials used for administration (infusion set, syringe, and BeneFIX solution) should be discarded and administration continued with a new kit.

Continuous infusion

Administration by continuous infusion is not approved and is not recommended (see section "Special precautions").

The lyophilized powder is reconstituted using a sterile adapter with the diluent provided in a pre-filled syringe. The vial should be gently swirled until the powder is completely dissolved. The powder and diluent should be warmed to room temperature prior to reconstitution. The resulting solution is then drawn back into the syringe. The solution should be clear and colorless. The solution should be discarded if foreign particles are observed or if there is a change in color.

The BeneFIX solution contains polysorbate 80, which may accelerate the extraction of di-(2-ethylhexyl) phthalate from polyvinyl chloride (PVC). This property should be taken into account during preparation and administration of the product.

Preparation of the solution

1. Allow the temperature of the lyophilized powder and the diluent in the pre-filled syringe to reach room temperature.
2. Remove the plastic flip-top cap from the BeneFIX vial to expose the center of the rubber stopper.
3. Wipe the top of the vial with the alcohol swab provided in the package or use another antiseptic solution, and allow it to dry. After cleaning, do not touch the rubber stopper with hands and avoid contact with any surfaces.
4. Peel back the protective cover of the clear plastic adapter packaging. Do not remove the adapter from the packaging.
5. Place the vial on a flat surface. Holding the packaging, place the adapter onto the vial. Press firmly until the adapter clicks into place on the top of the vial and the adapter's spike penetrates the vial stopper.
6. Remove the adapter packaging and discard it.
7. Attach the plunger rod to the diluent syringe: insert the rod into the syringe barrel stopper, press firmly, and rotate the rod until it is securely seated.
8. Snap off the plastic cap with the first-use indicator from the diluent syringe by breaking the perforation on the cap. This is done by wiggling the cap until the perforation breaks. Do not touch the inner surface of the cap or the tip of the syringe. If the prepared solution will not be used immediately, the cap may need to be replaced; therefore, set it aside with the opening facing upward.
9. Place the vial on a flat surface. Attach the diluent syringe to the vial adapter by inserting the syringe tip into the adapter opening, pressing firmly and rotating clockwise until a secure connection is achieved.
10. Slowly push the plunger to transfer all the diluent into the vial containing the drug.
11. Leaving the syringe attached to the adapter, gently swirl the vial until the powder is completely dissolved.
12. Before administration, visually inspect the reconstituted solution for foreign particles. The resulting solution should be clear or slightly opalescent and colorless.

If more than one vial of BeneFIX is used per infusion, each vial should be prepared according to the above instructions. Then, the diluent syringe should be discarded, leaving the vial adapter in place, and a single large syringe with a Luer lock can be used to withdraw the solution from each vial.

1. Ensuring the plunger remains fully inserted into the syringe barrel, invert the vial. Slowly withdraw the entire solution through the vial adapter into the syringe.
2. Disconnect the syringe from the vial adapter by gently pulling and rotating counterclockwise. Discard the vial with the attached adapter.

If the solution is not used immediately, the syringe cap should be carefully replaced. Do not touch the syringe tip or the inner surface of the cap.

The prepared solution should be used immediately or within 3 hours after reconstitution, stored at a temperature not exceeding 25°C.

Administration (intravenous injection)

BeneFIX should be administered using the pre-filled diluent syringe provided or a sterile disposable plastic syringe with a Luer lock. An adapter should be used to withdraw the solution from the vial.

Unused solution, empty vial(s), and used needles and syringes should be disposed of in an appropriate medical waste container, as these materials may pose a risk to others if not properly discarded.

Children

Limited data are available on on-demand treatment and surgical procedures in children under 6 years of age receiving BeneFIX.

The mean dose (± standard deviation) for prophylaxis was 63.7 (± 19.1) IU/kg administered at intervals of 3 to 7 days. For younger patients, it may be necessary to shorten the dosing intervals or increase the dose. The total amount of factor IX used for routine prophylaxis in 22 patients in the study was 4607 (± 1849) IU/kg per year and 378 (± 152) IU/kg per month.

For dose adjustment as needed, careful monitoring of factor IX activity and calculation of pharmacokinetic parameters (such as half-life and recovery level) are recommended based on clinical indications.

Overdose

No symptoms of overdose related to recombinant human coagulation factor IX products have been reported.

Adverse reactions.

Summary of safety.

Hypersensitivity reactions or allergic reactions have been observed (including angioedema, burning and stinging sensation at the infusion site, chills, facial flushing, ordinary and generalized urticaria, headache, arterial hypotension, lethargy, nausea, restlessness, tachycardia, chest tightness, ringing or buzzing in the ears, vomiting, wheezing), which in some cases may progress to severe anaphylaxis, including shock. In some instances, these reactions progressed to severe anaphylaxis and occurred in close temporal association with the development of factor IX inhibitors (see section "Special precautions"). Nephrotic syndrome has been reported following attempts to induce immune tolerance in patients with hemophilia B who have factor IX inhibitors and a history of allergic reactions.

Very rarely, formation of antibodies to hamster proteins with associated hypersensitivity reactions has been observed.

In patients with hemophilia B, neutralizing antibodies (inhibitors) to factor IX may develop. The formation of inhibitors may manifest as inadequate clinical response. In such cases, consultation with a specialized hemophilia treatment center is recommended.

There is a risk of thromboembolic events following administration of factor IX-containing products (see section "Special precautions").

List of adverse reactions.

The table below follows the MedDRA System Organ Class classification. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), unknown (cannot be estimated from available data). Table 4 lists adverse reactions observed during clinical trials in previously treated patients and those identified during post-marketing use of the product. Frequencies are based on all treatment-emergent adverse reactions from pooled clinical studies in 224 patients.

Within each group, adverse effects are listed in order of decreasing severity.

Table 4

Hypersensitivity reactions / allergic reactions

In case of hypersensitivity reactions, which may be related to the use of BeneFIX, see section "Special warnings and precautions for use" above.

Inhibitor development

Inhibitor development, which had minimal clinical significance and was manifested by an inadequate response to treatment, was observed in 1 out of 65 patients receiving BeneFIX (including 9 patients who participated only in the surgical study) who had previously been treated with plasma-derived products. This patient was able to continue treatment with BeneFIX without recurrence of inhibitor development or anaphylaxis (see sections "Dosage and administration" and "Special warnings and precautions for use").

Paediatric population

Allergic reactions may occur more frequently in children than in adults.

There is insufficient data to provide information on the frequency of inhibitor development in previously untreated patients (PUPs) (see section "Pharmacodynamics").

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

For the lyophilisate – 2 years.

For the solvent – 4 years.

(from manufacturer Wetter Pharma-Fertigung GmbH & Co. KG, Schuetzenstrasse 87 and 99-101, 88212 Ravensburg, Germany).

For the solvent – 5 years.

(from manufacturer Wetter Pharma-Fertigung GmbH & Co. KG, Eisenbahnstrasse 2-4, Langenargen, Baden-Wuerttemberg, 88085, Germany).

Storage conditions.

Store in the original packaging, protected from light and out of reach of children, at a temperature between 2 and 30 °C. Do not freeze, to avoid damage to the pre-filled syringe.

The reconstituted solution should be used immediately or within 3 hours after reconstitution, if stored at a temperature not exceeding 25 °C.

Incompatibilities.

The product must not be mixed with other medicinal products, including other infusion solutions. Only the infusion set supplied in the package should be used for administration, as nonacog alfa may adsorb onto the internal surfaces of other infusion equipment.

Packaging.

1 vial of lyophilisate, 1 pre-filled syringe with solvent, 1 vial adapter, 1 infusion set, 2 alcohol swabs, 1 plaster, 1 gauze pad in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Wyeth Farma S.A.

Manufacturer's name and address of the place of business.

Autovia del Norte A1, Km 23, desvio Algete, Km. 1, San Sebastian de los Reyes, 28700 Madrid, Spain / Autovia del Norte A1, Km 23, desvio Algete, Km. 1, San Sebastian de los Reyes, 28700 Madrid, Spain.