Benefix (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Wyeth LLC (Russia)

Manufactured By

Wyeth Pharma, S.A. (Spain)

Packaged By

VETTER PHARMA-FERTIGUNG, GmbH & Co.KG (Germany)

ATC Code

B02BD04 (Blood coagulation factor IX)

Active Substance

Nonacog alfa (Rec.INN registered by WHO)

Dosage Forms

	Benefix	Lyophilisate for preparation of solution for intravenous administration 250 IU: vial 1 pc. in a set with a syringe with solvent
		Lyophilisate for preparation of solution for intravenous administration 500 IU: vial 1 pc. in a set with a syringe with solvent
		Lyophilisate for preparation of solution for intravenous administration 1000 IU: vial 1 pc. in a set with a syringe with solvent
		Lyophilisate for preparation of solution for intravenous administration 2000 IU: vial 1 pc. in a set with a syringe with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous administration as a white lyophilized mass.

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injections q.s. 5 ml.

Vials (1) made of clear glass (type I) in a set with a syringe with 5 ml of solvent, plunger, microinfusion set, adapter with filter, plaster, gauze pad and 2 alcohol wipes – plastic packs (1) with a cap – cardboard boxes.

Lyophilisate for preparation of solution for intravenous administration as a white lyophilized mass.

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injections q.s. 5 ml.

Vials (1) made of clear glass (type I) in a set with a syringe with 5 ml of solvent, plunger, microinfusion set, adapter with filter, plaster, gauze pad and 2 alcohol wipes – plastic packs (1) with a cap – cardboard boxes.

Lyophilisate for preparation of solution for intravenous administration as a white lyophilized mass.

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injections q.s. 5 ml.

Vials (1) made of clear glass (type I) in a set with a syringe with 5 ml of solvent, plunger, microinfusion set, adapter with filter, plaster, gauze pad and 2 alcohol wipes – plastic packs (1) with a cap – cardboard boxes.

Lyophilisate for preparation of solution for intravenous administration as a white lyophilized mass.

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injections q.s. 5 ml.

Vials (1) made of clear glass (type I) in a set with a syringe with 5 ml of solvent, plunger, microinfusion set, adapter with filter, plaster, gauze pad and 2 alcohol wipes – plastic packs (1) with a cap – cardboard boxes.

Clinical-Pharmacological Group

Blood coagulation factor IX preparation

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

Recombinant blood coagulation factor IX is a glycoprotein expressed by genetically modified Chinese hamster ovary cells.

Benefix contains recombinant blood coagulation factor IX (Nonacog alfa). Recombinant blood coagulation factor IX is a single-chain glycoprotein containing 415 amino acid residues, with an approximate molecular mass of 55,000 daltons, belonging to the serine protease family and being a vitamin K-dependent blood coagulation factor.

Recombinant blood coagulation factor IX is a protein produced using recombinant DNA technology, structurally and functionally similar to endogenous blood coagulation factor IX. The latter is activated by blood coagulation factor VII (tissue factor involved in the extrinsic pathway of coagulation) and also by blood coagulation factor XIa, involved in the intrinsic pathway of coagulation. Activated blood coagulation factor IX in combination with activated blood coagulation factor VIII leads to the activation of blood coagulation factor X, which, in turn, ensures the conversion of prothrombin to thrombin. Thrombin catalyzes the conversion of fibrinogen to fibrin and the formation of a blood clot. Blood coagulation factor IX activity is absent or significantly reduced in patients with hemophilia B, which may require replacement therapy.

Pharmacokinetics

When using Benefix in patients with hemophilia B who had previously received coagulation factor therapy (baseline data), in vivo recovery values were obtained in the range from 15% to 62% (average – 33.7±10.3%). It was shown that the administration of one international unit (IU) of Benefix increases the activity of circulating blood coagulation factor IX by an average of 0.75 IU/dl (variation range – from 0.3 IU/dl to 1.4 IU/dl).

The T_1/2 of nonacog alfa varies from 11 to 36 hours (average – 19.3±5 hours). The recovery of blood coagulation factor IX activity is 28% lower when using Benefix compared to plasma-derived blood coagulation factor IX preparations. It is assumed that this difference in the recovery of blood coagulation factor IX activity is due to their structural differences.

Indications

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

ICD codes

Dosage Regimen

Benefix is administered intravenously as a bolus over several minutes after reconstitution of the lyophilized powder with the supplied water for injections. The rate of administration is determined by the doctor. The administration of Benefix by prolonged infusion has not been studied, so it should not be administered by drip or mixed with infusion solutions or other medicines. Treatment should be initiated under the supervision of a physician experienced in the treatment of hemophilia.

Patients should follow the doctor’s instructions related to the intravenous injection procedures performed by him.

Therapy with any blood coagulation factor IX requires individual dose selection. The doses and duration of replacement therapy depend on the severity of the blood coagulation factor IX deficiency, the location and severity of bleeding, the general condition of the patient and the clinical effect of the therapy. The dose of Benefix may differ from the doses of plasma-derived blood coagulation factor IX preparations.

To ensure the necessary activity of blood coagulation factor IX, careful monitoring of this indicator is recommended (especially during surgical interventions) using appropriate tests. The dose of the drug is calculated based on the activity of blood coagulation factor IX, the pharmacokinetic parameters of the drug, in particular, the half-life and recovery, as well as the clinical situation.

Usually, the use of blood coagulation factor IX preparations more than once a day is not required.

The dose of blood coagulation factor IX is expressed in international units (IU) corresponding to the activity of the WHO standard blood coagulation factor IX. The activity of blood coagulation factor IX in plasma is expressed either as a percentage (relative to normal human plasma values) or in international units (relative to the activity of the international standard for blood coagulation factor IX in plasma).

One international unit (IU) of blood coagulation factor IX activity corresponds to the amount of blood coagulation factor IX contained in 1 ml of plasma from a healthy person. The calculation of the Benefix dose can be based on the data that a dose of blood coagulation factor IX corresponding to 1 IU/kg of body weight increases the level of blood coagulation factor IX in plasma by an average of 0.8±0.2 IU/dl (variation range – from 0.4 IU/dl to 1.4 IU/dl) in adult patients (>15 years). However, the pharmacokinetic parameters of the drug should be assessed for each patient and the dose adjusted accordingly.

The required dose of the drug is calculated using the following formula

Required number of IU of blood coagulation factor IX = Body weight (kg) × Required increase in blood coagulation factor IX activity (% or IU/dl) × Reciprocal of the degree of increase in blood coagulation factor IX activity

Thus, with an average increase in blood coagulation factor IX activity corresponding to 0.8 IU/dl

Required number of IU of blood coagulation factor IX = Body weight (kg) × Required increase in blood coagulation factor IX activity (% or IU/dl) ×1.3 IU/kg/IU/dl

When the hemorrhagic conditions listed below develop, the activity of blood coagulation factor IX in plasma should not fall below the indicated values (in % of normal or in IU/dl) for the corresponding period of time.

When performing major surgical interventions, careful monitoring of replacement therapy is necessary by performing blood coagulation tests (in particular, plasma blood coagulation factor IX activity). The response of individual patients to blood coagulation factor IX therapy may vary due to differences in the degree of in vivo recovery and the half-life of the drug.

Benefix can be used as long-term prevention of bleeding in patients with severe hemophilia B. In a clinical study, the average dose of the drug when used as secondary prophylaxis in patients who had previously received coagulation factor therapy was 40 IU/kg (variation range – from 13 IU/kg to 78 IU/kg) with an administration interval of 3 to 4 days. In younger patients, it may be necessary to shorten the intervals between administrations or increase the dose of the drug.

Use in children (from 6 to 15 years)

In children over 15 years of age, the drug is administered as in adults.

The calculation of the Benefix dose for children aged 6 to 15 years is based on the fact that a dose of blood coagulation factor IX corresponding to 1 IU/kg of body weight in children increases the level of blood coagulation factor IX in plasma by an average of 0.7±0.3 IU/dl (variation range – from 0.2 IU/dl to 2.1 IU/dl). Thus, the drug is used in children using the following scheme

Required number of IU of blood coagulation factor IX = Body weight (kg) × Required increase in blood coagulation factor IX activity (% or IU/dl) ×1.4 IU/kg/IU/dl

It was found that in 57% of children, to achieve the necessary response to therapy, an increase in the dose of the drug is required due to a lower than expected recovery of blood coagulation factor IX activity in plasma; as a result, in some of them the average dose of the drug may be >50 IU/kg. This necessitates careful monitoring of blood coagulation factor IX activity in plasma, as well as calculation of pharmacokinetic parameters, in particular, the degree of recovery and half-life, according to clinical indications, necessary to adjust the drug dose. If repeated administration of the drug in doses >100 IU/kg is necessary for prophylactic or therapeutic purposes, the issue of transferring the patient to therapy with another blood coagulation factor IX preparation should be considered.

Solution Preparation

The drug does not contain preservatives, so the reconstituted solution must be used within 3 hours after preparation.

Store the reconstituted solution for 3 hours after dilution at a temperature not exceeding 30°C (86°F).

If the color of the solution changes or suspended particles appear in it, the solution must be disposed of.

The resulting reconstituted solution of Benefix contains polysorbate-80, which is known to increase the rate of extraction of di-(2-ethoxyethyl) phthalate (DEHP) from polyvinyl chloride (PVC). This must be taken into account when preparing and administering Benefix, including the storage time in a PVC container.

Unused drug residue or materials contaminated with it must be disposed of in accordance with local requirements.

Drug Administration Rules

1. Allow the vial with Benefix lyophilized powder and the pre-filled solvent syringe to warm to room temperature.
2. Remove the plastic flip-off cap from the Benefix vial to expose the central part of the rubber stopper.
3. Wipe the top surface of the vial cap with the supplied alcohol swab or use another antiseptic solution, and let it dry. After cleaning, do not touch the rubber stopper with your hands and do not let it touch any surface.
4. Fold back the lid of the transparent packaging of the adapter for the plastic vial. Do not remove the adapter from the packaging.
5. Place the vial on a flat surface. Holding the adapter packaging, place the adapter on the vial. Press firmly on the packaging until the adapter snaps into place on the top of the vial with the adapter needle inserted into the vial stopper.
6. Attach the plunger rod to the solvent syringe by pressing firmly and turning it.
7. Break off the protective cap of the plastic tip of the solvent syringe at the perforation mark. Do this by alternately bending the cap up and down until the cap breaks off at the perforation mark. Do not touch the inner surface of the cap and the syringe tip. It may be necessary to put the cap back in place (if the administration of the reconstituted Benefix is not carried out immediately); therefore, the cap should be set aside, placing it upside down.
8. Remove the packaging from the adapter and discard it.
9. Place the vial on a flat surface. Connect the syringe with the solution to the vial adapter by inserting the syringe tip into the hole in the adapter, simultaneously pressing and firmly turning the syringe clockwise until it is securely fastened.
10. Slowly press the plunger rod to inject all the solvent into the Benefix vial.
11. With the syringe still connected to the adapter, gently rotate the vial until the powder is dissolved.
12. Before administration, the final solution should be visually checked for particles. The solution should be clear and colorless.

Note: if two or more vials of Benefix are used for one administration, the contents of each vial must be reconstituted according to the instructions above.

1. Making sure that the syringe plunger rod remains in the fully inserted position, turn the vial over. Slowly draw all the solution into the syringe.

If it is necessary to use more than one vial of Benefix, the solvent syringe should be disconnected, leaving the vial adapter in place. Immediately after this, attach a separate Luer lock syringe and draw up all the solution. A separate large Luer lock syringe can be used to extract the reconstituted contents of each vial.

Do not disconnect the syringe from the vial until you are ready to connect the syringe to the next vial.

1. Disconnect the syringe from the vial adapter by gently pulling and turning the syringe counterclockwise. Discard the vial together with the adapter attached to it.

Note: if the solution is not intended for immediate administration, the syringe cap must be carefully put back in place. Do not touch the syringe tip and the inner surface of the cap.

Administration (intravenous injection)

Benefix should be administered using the supplied microinfusion set and the pre-filled solvent syringe or a single sterile disposable plastic syringe with a Luer lock.

1. Connect the syringe to the Luer lock tip of the microinfusion set tubing.
2. Apply a tourniquet and prepare the injection site by thoroughly wiping the skin with the alcohol swab provided in the kit.
3. Insert the needle of the microinfusion set tubing into the vein and remove the tourniquet. Remove all air from the infusion set tubing by drawing it back into the syringe. The reconstituted product should be administered intravenously over several minutes. The physician may adjust the infusion rate recommendations for more comfortable administration.

Discard any unused solution, empty vials, and used needles and syringes in a medical waste disposal container.

Adverse Reactions

To date, no adverse reactions have been reported with the use of Benefix with a frequency from >1/100 to <1/10 (frequent). As a result, all adverse reactions noted with the use of Benefix have been defined as occurring infrequently (with a frequency from >1/1000 to <1/100) or rarely (with a frequency from >1/10,000 to <1/1000). The most significant of these are anaphylaxis, cellulitis, phlebitis, and the formation of neutralizing antibodies.

The following are adverse reactions registered during clinical studies and in the post-marketing period of the drug’s use, categorized by organ systems and frequency of occurrence. Within each frequency category, adverse effects are listed in order of decreasing severity. Frequency was determined based on the number of adverse event cases per number of infusions performed; the following categories were distinguished: infrequent (with a frequency >1/1000 but <1/100) and rare (with a frequency from >1/10,000 to <1/1000).

Nervous system disorders infrequently – dizziness, headache, presyncope, taste perversion; rarely – tremor, somnolence, dysgeusia.

Gastrointestinal system disorders: infrequently – nausea; rarely – vomiting, diarrhea.

General disorders and administration site conditions: infrequently – injection site cellulitis, injection site phlebitis, injection site reactions (including burning and tightness sensation), injection site discomfort, injection site pain; rarely – fever.

Immune system disorders: infrequently – formation of neutralizing antibodies (inhibitors to coagulation factor IX); rarely – hypersensitivity, allergic reactions, including anaphylaxis, laryngospasm, bronchospasm or respiratory distress (dyspnea), wheezing cough, decreased blood pressure, angioedema, laryngeal edema, tachycardia, chest tightness, urticaria, skin rashes, burning sensation in the jaw and skull area, chills (shivering), tingling sensation, facial flushing, lethargy, anxiety, dry cough or sneezing, blurred vision, allergic rhinitis, weakness, anaphylaxis.

Respiratory system disorders infrequently – cough leading to hypoxia.

Other rarely – shivering, photosensitivity reactions.

Laboratory findings :; infrequently – increased AST and ALT activity, increased bilirubin concentration, increased creatine phosphokinase activity, ALP. Transient appearance of inhibitors in low titer was noted. Cyanosis and decreased blood pressure were also noted during post-marketing studies.

Renal and urinary disorders

In a clinical study, one patient with antibodies to the hepatitis C virus experienced a kidney infarction 12 days after administration of Benefix for a hemorrhagic condition.

Thrombotic conditions

During post-marketing use, reports of thrombosis have been received, including life-threatening superior vena cava syndrome in critically ill newborns receiving Benefix as a continuous infusion via a central venous catheter. There were also 6 reports of thrombophlebitis of peripheral veins and deep vein thrombosis, in most of which Benefix was administered by continuous intravenous infusion, which is not a registered method of administration for this drug.

Inadequate response and inadequate recovery of coagulation factor IX activity

During post-marketing use, reports have been received of inadequate response and inadequate recovery of coagulation factor IX activity with the use of Benefix. If any adverse reactions suspected to be associated with the administration of Benefix occur, it is necessary to reduce the infusion rate or stop it.

Contraindications

• Age under 6 years;
• Intolerance to any of the components of the drug, as well as a history of allergic reaction to hamster proteins.

Use in Pregnancy and Lactation

There are limited data on the use of Benefix in pregnant or breastfeeding women. Therefore, the drug should be prescribed only after assessing the risk-to-benefit ratio for the fetus (or child) and the mother.

Pediatric Use

Contraindicated in children under 6 years of age.

Use in children (from 6 to 15 years)

In children over 15 years of age, the drug is administered as in adults.

The calculation of the Benefix dose for children aged 6 to 15 years is based on the fact that a dose of coagulation factor IX corresponding to 1 IU/kg of body weight increases the plasma level of coagulation factor IX in children by an average of 0.7±0.3 IU/dL (range of variation – from 0.2 IU/dL to 2.1 IU/dL). Thus, the drug is used in children according to the following scheme

Required number of IU of coagulation factor IX = Body weight (kg) × Required increase in coagulation factor IX activity (% or IU/dL) × 1.4 IU/kg/IU/dL

It was found that in 57% of children, a dose increase is required to achieve the necessary therapeutic response due to a lower than expected recovery of coagulation factor IX activity in plasma; as a result, in some of them the average dose of the drug may be >50 IU/kg. This necessitates careful monitoring of plasma coagulation factor IX activity, as well as calculation of pharmacokinetic parameters, in particular, recovery and half-life, according to clinical indications, necessary for dose adjustment. If multiple administrations of the drug in doses >100 IU/kg are required for prophylactic or therapeutic purposes, the possibility of switching the patient to therapy with another coagulation factor IX product should be considered.

Special Precautions

In patients previously treated with coagulation factor IX products, the formation of active neutralizing antibodies (inhibitors) is sometimes observed. As with the use of all coagulation factor IX products, patients receiving Benefix should be examined for the presence of coagulation factor IX inhibitors.

Also, if the recovery of coagulation factor IX activity in plasma does not correspond to expected values or if bleeding control cannot be achieved with appropriate doses of the drug, testing for the presence of coagulation factor IX inhibitors (whose titer should be measured in Bethesda units using adequate tests) should be performed.

In patients with high concentrations of inhibitory antibodies to coagulation factor IX, therapy with it may be ineffective. In this case, alternative treatment methods should be considered. Treatment of such patients should be carried out by physicians experienced in the management of patients with hemophilia.

To date, sufficient data on the use of Benefix in patients previously untreated with coagulation factor products have not been accumulated in ongoing clinical studies.

Additional studies of safety and efficacy in children, previously untreated with coagulation factor products and receiving them, including in small amounts, are currently not completed.

Clinical studies of Benefix did not include a sufficient number of patients aged 65 years and older to determine whether their response to treatment differs from that observed in younger patients. As in younger patients, individual adjustment of the Benefix dose is necessary in all cases.

As with the intravenous administration of any protein products, hypersensitivity reactions may develop with the use of Benefix. Due to the specifics of the manufacturing process, Benefix contains trace amounts of hamster proteins, to which hypersensitivity reactions can also develop. Anaphylactic and anaphylactoid reactions have been infrequently reported with the use of coagulation factor IX products, including Benefix. The etiology of allergic reactions to Benefix is not defined, but these reactions can be life-threatening.

These allergic reactions had a close temporal relationship with the appearance of coagulation factor IX inhibitors. Therefore, patients who have experienced allergic reactions should be examined for the presence of inhibitors. It should also be noted that patients characterized by the presence of coagulation factor IX inhibitors may have an increased risk of anaphylactic reactions with subsequent infusions of coagulation factor IX. According to preliminary data, there is a connection between the patient’s expression of a major mutation (deletion) of the coagulation factor IX gene and an increased risk of inhibitor antibody formation, as well as acute hypersensitivity reactions. Therefore, patients identified as carriers of a major mutation (deletion) of coagulation factor IX should be carefully monitored for clinical manifestations of acute hypersensitivity reactions, especially during the initial phase of therapy.

Patients should be informed about the early clinical signs of hypersensitivity reactions, including the appearance of breathing difficulties, development of edema, hives, skin itching, facial “flushing”, chest tightness sensation, chills, bronchospasm, laryngospasm, wheezing, decreased blood pressure, hyperemia, weakness, blurred vision, and anaphylaxis. If an allergic or anaphylactic reaction or anaphylactic shock develops, the administration of Benefix should be stopped immediately and appropriate therapy according to current medical standards should be initiated. In case of severe allergic reactions, the appointment of alternative hemostatic therapy should be considered. Treatment principles depend on the type and severity of side effects.

Due to the risk of developing allergic reactions, the initial administrations of coagulation factor IX concentrates should, at the discretion of the attending physician, be performed under medical supervision in institutions equipped to provide appropriate emergency care. The drug dose should be adjusted based on the individual pharmacokinetic parameters of the patient.

Although Benefix contains only coagulation factor IX, the risk of thrombosis and disseminated intravascular coagulation (DIC) syndrome should also be kept in mind. Since the use of previously used complex coagulation factor IX concentrates was associated with the development of thromboembolic complications, the administration of products containing coagulation factor IX may be potentially dangerous for patients showing signs of fibrinolysis and for patients with DIC syndrome.

Due to the potential risk of thromboembolism, during the administration of such products to patients with liver diseases in the postoperative period or those with an increased risk of thrombosis or DIC syndrome, monitoring for early manifestations of thrombotic conditions using appropriate tests should be carried out, and if they develop, appropriate therapy should be conducted. In each of these situations, the potential benefit of therapy with Benefix and the risk of developing these complications should be weighed.

There are also reports of erythrocyte agglutination in the tubing or syringe during the administration of Benefix. The clinical consequences of this phenomenon have not been determined to date. To reduce the likelihood of agglutination, it is important to limit the entry of blood into the intravenous infusion system and prevent it from entering the syringe. If erythrocyte agglutination occurs in the system or syringe, the consumables used for drug administration (IV infusion set, syringe, and Benefix solution) should be disposed of and administration repeated using a new drug package.

Cases of nephrotic syndrome have been observed in attempts to induce immune tolerance in patients with hemophilia B who produce inhibitors to coagulation factor IX and had a history of allergic reactions. The safety and efficacy of using Benefix for immune tolerance induction have not been established.

Cases of normalization of abnormal thromboplastin time have been reported. No changes were noted with normal thromboplastin time.

Within the specified shelf life, patients may store the drug at room temperature (not exceeding 30°C (86°F)) for 6 months; after which the drug should not be used!

Effect on ability to drive and operate machinery

Studies on the effect of the drug on the ability to drive a car and operate machinery requiring increased concentration have not been conducted. However, due to the possibility of dizziness, caution should be exercised when performing these activities.

Overdose

No cases of Benefix overdose have been described.

Drug Interactions

Drug interaction studies have not been conducted.

Storage Conditions

Keep out of reach of children at a temperature from 2°C (35.6°F) to 8°C (46.4°F). Do not freeze.

Shelf Life

The shelf life of the lyophilizate is 3 years, the solvent is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.