1. Name Of The Medicinal Product
BeneFIX 250 IU powder and solvent for solution for injection.
BeneFIX 500 IU powder and solvent for solution for injection.
BeneFIX 1000 IU powder and solvent for solution for injection.
2. Qualitative And Quantitative Composition
BeneFIX 250 IU powder and solvent for solution for injection contains nominally 250 IU nonacog alfa (recombinant coagulation factor IX) in each vial of powder for solution for injection. When reconstituted with the accompanying 5 ml water for injection, the product contains approximately 50 IU/ml nonacog alfa.
BeneFIX 500 IU powder and solvent for solution for injection contains nominally 500 IU nonacog alfa (recombinant coagulation factor IX) in each vial of powder for solution for injection. When reconstituted with the accompanying 5 ml water for injection, the product contains approximately 100 IU/ml nonacog alfa.
BeneFIX 1000 IU powder and solvent for solution for injection contains nominally 1000 IU nonacog alfa (recombinant coagulation factor IX) in each vial of powder for solution for injection. When reconstituted with the accompanying 10 ml water for injection, the product contains approximately 100 IU/ml nonacog alfa.
The potency (IU) is determined using the European Pharmacopoeia one-stage clotting assay. The specific activity of BeneFIX is not less than 240 IU/mg protein.
BeneFIX contains recombinant coagulation factor IX, (INN = nonacog alfa). Nonacog alfa is a purified protein that has 415 amino acids in a single chain. It has a primary amino acid sequence that is comparable to the Ala148 allelic form of plasma-derived factor IX, and some post-translational modifications of the recombinant molecule are different from those of the plasma-derived molecule. Recombinant coagulation factor IX is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line.
For excipients, see 6.1.
3. Pharmaceutical Form
Powder and solvent for solution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
4.2 Posology And Method Of Administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.
Posology
The dosage and duration of the substitution therapy depends on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition.
To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised and doses should be calculated taking the factor IX activity, pharmacokinetic parameters such as half-life and recovery, as well as the clinical situation into consideration in order to adjust the dose as appropriate.
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. Factor IX products rarely require to be administered more than once daily.
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. Estimation 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 by an average of 0.7 IU/dl (range from 0.3 to 1.4 IU/dl). Pharmacokinetics have to be assessed regularly in each patient and posology has to be adjusted accordingly.
The required dosage is determined using the following formula:
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For a recovery of 0.7 IU/dl (average increase of factor IX), then:
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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:
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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. 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. Individual patients may vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.
For long-term prophylaxis against bleeding in patients with severe haemophilia B, BeneFIX may be administered. In a clinical study for routine secondary prophylaxis the average dose was 40 IU/kg (range 13 to 78 IU/kg) at intervals of 3 to 4 days. In younger patients, shorter dosage intervals or higher doses may be necessary.
There are insufficient data to recommend the use of BeneFIX in children less than 6 years of age. However, preliminary data in children 6 years or older indicates that even in the absence of factor IX inhibitor, doses in clinical efficacy studies have been increased in several patients. In clinical studies, 57% of the patients increased their doses due to lower than expected recovery or to obtain sufficient therapeutic response or both, some to an average dose of>50 IU/kg. Therefore, close monitoring of factor IX plasma activity should be performed, as well as calculation of pharmacokinetic parameters such as recovery and half-life, as clinically indicated, in order to adjust doses as appropriate. If doses>100 IU/kg have been repeatedly needed during routine prophylaxis or treatment, a switch to another FIX product should be considered.
Patients should be monitored for the development of factor IX inhibitors. If the expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, biological testing should be performed to determine if a factor IX inhibitor is present.
In patients with high levels of inhibitor factor IX therapy may not be effective and other therapeutic options must be considered. Management of such patients should be directed by physicians with experience in the care of patients with haemophilia. See also section 4.4.
Method of Administration
BeneFIX is administered by IV infusion after reconstitution of the lyophilised powder for solution for injection with sterile water for injection (see section 6.6).
The reconstituted solution should be used immediately or within 3 hours.
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.
BeneFIX should be administered at a slow infusion rate. In most of the cases, an infusion rate of up to 4 ml per minute was well tolerated.
4.3 Contraindications
Known history of hypersensitivity to hamster proteins and other constituents of the preparation.
4.4 Special Warnings And Precautions For Use
Activity-neutralizing antibodies (inhibitors) is a very rare event in previously treated patients (PTPs) receiving factor IX-containing products. Since during clinical studies one PTP treated with BeneFIX developed a clinically relevant low responding inhibitor and experience on antigenicity with recombinant factor IX is still limited, patients treated with BeneFIX should be carefully monitored for the development of factor IX inhibitors that should be titrated in Bethesda Units using appropriate biological testing.
Sufficient data have not been obtained from ongoing clinical studies on the treatment of previously untreated patients (PUPs), with BeneFIX.
As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. The product contains traces of hamster proteins. Potentially life-threatening anaphylactic/anaphylactoid reactions have occurred with factor IX products, including BeneFIX. Patients should be informed of early signs of hypersensitivity reactions including difficult breathing, shortness of breath, swelling, hives, itching, tightness of the chest, wheezing, hypotension, and anaphylaxis.
If allergic or anaphylactic-type reactions occur, the administration of BeneFIX has to be discontinued immediately and an appropriate treatment has to be initiated. In some cases, these reactions have progressed to severe anaphylaxis. In the case of shock, the current medical standards for shock treatment should be observed. In case of severe allergic reactions, alternative haemostatic measures should be considered.
There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.
Because of the risk of allergic reactions with factor IX concentrates, the initial administrations of factor IX should, according to the treating physician's judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.
Posology has to be adjusted according to the pharmacokinetics of each patient.
Although BeneFIX contains only factor IX, the risk of thrombosis and disseminated intravascular coagulation (DIC) should be recognised. Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIX should be weighed against the risk of these complications.
There have been reports of agglutination of red blood cells in the tube/syringe with the administration of BeneFIX. So far, no clinical sequelae have been reported in association with this observation. 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.
Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with Factor IX inhibitors and a history of allergic reaction. The safety and efficacy of using BeneFIX for immune tolerance induction has not been established.
In the interest of patients, it is recommended that, whenever possible, every time that BeneFIX is administered to them, the name and batch number of the product is registered.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interactions of recombinant coagulation factor IX products with other medicinal products are known.
4.6 Pregnancy And Lactation
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation only if clearly indicated.
4.7 Effects On Ability To Drive And Use Machines
There are no indications that BeneFIX may impair the ability to drive or operate machines.
4.8 Undesirable Effects
The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience.
Within the organ system classes, adverse reactions are listed under headings of frequency. These frequencies have been estimated on a per-infusion basis and are described using the following categories: uncommon >1/1000, <1/100); rare >1/10,000, <1/1000).
Immune system disorders
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Nervous system disorders
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Gastrointestinal disorders
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General disorders and administration site conditions
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* See additional information below.
Hypersensitivity/allergic reactions
Hypersensitivity or allergic reactions have been infrequently observed in patients treated with factor IX containing products, including BeneFIX. In some cases, these reactions have progressed to severe anaphylaxis. Allergic reactions have occurred in close temporal association with development of factor IX inhibitor (see also 4.4). The aetiology of the allergic reactions to BeneFIX has not yet been elucidated. These reactions are potentially life threatening. If allergic/anaphylactic reactions occur, the administration of BeneFIX should be discontinued at once. In case of severe allergic reactions, alternative haemostatic measures should be considered. The treatment required depends on the nature and severity of side effects (see also 4.4). Due to the production process BeneFIX contains trace amounts of hamster cell proteins. Hypersensitivity responses can occur.
Inhibitor development
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. A clinically relevant, low responding inhibitor was detected in 1 out of 56 BeneFIX patients who had previously received plasma-derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise in inhibitor or anaphylaxis.
There are insufficient data to provide information on inhibitor incidence in PUPs.
Nephrotic syndrome has been reported following high doses of pdFIX to induce immune tolerance in haemophilia B patients with factor IX inhibitors and a history of allergic reactions.
Renal
In a clinical trial, twelve days after a dose of BeneFIX for a bleeding episode, one hepatitis C antibody positive patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX is uncertain. The patient continued to be treated with BeneFIX.
4.9 Overdose
No symptoms of overdose with recombinant coagulation factor IX products have been reported.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic Group: antihaemorrhagic Blood Coagulation Factor IX; ATC Code: B02BD04
BeneFIX contains recombinant coagulation factor IX, (nonacog alfa). Recombinant coagulation factor IX is a single chain glycoprotein with an approximate molecular mass of 55,000 Daltons that is a member of the serine protease family of vitamin K-dependent coagulation factors. Recombinant coagulation factor IX is a recombinant DNA-based protein therapeutic which has structural and functional characteristics comparable to endogenous factor IX. Factor IX is activated by factor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Factor IX activity is absent or greatly reduced in patients with haemophilia B and substitution therapy may be required.
Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
There are insufficient data to recommend the use of BeneFIX in children less than 6 years of age.
5.2 Pharmacokinetic Properties
Infusion of BeneFIX into 56 PTP patients (baseline data) with haemophilia B has shown an in vivo recovery ranging from 15 to 62% (mean 33.7 +/- 10.3%). One International Unit of BeneFIX showed a mean 0.75 IU/dl (range 0.3 to 1.4 IU/dl) increase in the circulating level of factor IX. The biologic half-life ranged from 11 to 36 hours (mean of 19.3 +/- 5.0 hours).
For a subset of the 56 patients, data are available from baseline to 24 months. The pharmacokinetic data for these patients at various time points are shown in the following table:
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