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

BeneFIX 250 IU powder and solvent for solution for injection contains nominally 250 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 ml (0.234%) sodium chloride solution for injection, each ml of the solution contains approximately 50 IU nonacog alfa.

BeneFIX 500 IU powder and solvent for solution for injection contains nominally 500 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 ml (0.234%) sodium chloride solution for injection, each ml of the solution contains approximately 100 IU nonacog alfa

BeneFIX 1000 IU powder and solvent for solution for injection contains nominally 1000 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 ml (0.234%) sodium chloride solution for injection, each ml of the solution contains approximately 200 IU nonacog alfa

BeneFIX 2000 IU powder and solvent for solution for injection contains nominally 2000 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 ml (0.234%) sodium chloride solution for injection, each ml of the solution contains approximately 400 IU nonacog alfa.

BeneFIX 3000IU powder and solvent for solution for injection contains nominally 3000 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 ml (0.234%) sodium chloride solution for injection, each ml of the solution contains approximately 600 IU nonacog alfa.

The potency (IU) is determined using the European Pharmacopoeia one-stage clotting assay. The specific activity of BeneFIX is not less than 200 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 the full list of excipients, see section 6.1.

Powder and solvent for solution for injection

White/almost white powder and clear and colourless solvent..

Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).

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

Posology

The dose 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. The dose of BeneFIX may differ from that of plasma-derived factor IX products.

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 are 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).

On demand treatment 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, an average of 0.8 IU/dl (range from 0.4 to 1.4 IU/dl) in adult patients (≥ 12 years) (further information in section 5.2).

The required dose is determined using the following formula:

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

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:

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.

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.

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 74 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.

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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. If doses >100 IU/kg have been repeatedly needed during routine prophylaxis or treatment, a switch to another FIX product should be considered.

Monitoring for inhibitors

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 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.

Administration by continuous infusion has not been approved and is not recommended (see also sections 4.4, 4.8 and 6.6). For instructions on reconstitution of the medicinal product before administration, see section 6.6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Known allergic reaction to hamster proteins.

Anaphylactic and hypersensitivity reactions

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, bronchospasm, laryngospasm, wheezing, hypotension, blurred vision, 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 treatment of shock should be observed. In case of severe allergic reactions, alternative haemostatic measures should be considered.

Neutralizing antibodies

Activity-neutralizing antibodies (inhibitors) are an uncommon event in previously treated patients (PTPs) receiving factor IX-containing products. As one PTP treated with BeneFIX developed a clinically relevant low responding inhibitor during clinical studies 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.

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. Preliminary information suggests a relationship may exist between the presence of major deletion mutations in a patient's factor IX gene and an increased risk of inhibitor formation and of acute hypersensitivity reactions. Patients known to have major deletion mutations of the factor IX gene should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product.

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.

Thrombosis

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.

The safety and efficacy of BeneFIX administration by continuous infusion have not been established (see also sections 4.2 and 4.8). There have been post-marketing reports of thrombotic events, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates, while receiving continuous-infusion BeneFIX through a central venous catheter (see also section 4.8).

Nephrotic syndrome

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.

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. So far, no clinical sequelae 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.

Special populations

Sufficient data have not been obtained from ongoing clinical studies on the treatment of previously untreated patients (PUPs), with BeneFIX. Additional safety and efficacy studies in paediatric patients are ongoing in previously treated, minimally treated, and previously untreated paediatric patients. 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.

Record of use

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.

No interaction studies have been performed.

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 breast-feeding only if clearly indicated.

The effect of BeneFIX on fertility has not been established.

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions BeneFIX has no or negligible influence on the ability to drive or use machines.

Summary of the safety profile

The most frequent adverse reactions include headache, dizziness, nausea, injection site reaction, injection site pain and skin-related hypersensitivity reactions. The most significant include: anaphylaxis, cellulitis, phlebitis, and neutralising antibodies. The frequencies of these events are in the uncommon and rare categories.

Tabulated list of adverse reactions

During uncontrolled, open label clinical trials with BeneFIX conducted in PTPs, 113 adverse reactions were reported in 25/65 (38.5%) subjects who received a total of 7573 infusions. Adverse reactions, estimated on a per-infusion basis, were categorized as common ( ≥1/100 to <1/10), uncommon (≥1/1,000 to ≤1/100) or rare (≥1/10,000 to ≤1/1,000). Adverse reactions based on experience from clinical trials and post marketing experience are presented below by system organ class and frequency of occurrence. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* See additional information below.

Description of selected adverse reactions

Hypersensitivity/allergic reactions

Hypersensitivity or allergic reactions have been rarely 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 section 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 section 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 65 BeneFIX patients (including 9 patients participating only in the surgery study) who had previously received plasma-derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise in inhibitor or anaphylaxis..

Nephrotic syndrome has been reported following high doses of plasma-derived factor IX to induce immune tolerance in haemophilia B patients with factor IX inhibitors and a history of allergic reactions.

Renal infarct

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.

Thrombotic events

There have been post-marketing reports of thrombotic events, including life-threatening SVC syndrome in critically ill neonates, while receiving continuous-infusion BeneFIX through a central venous catheter. Cases of peripheral thrombophlebitis and deep venous thrombosis have also been reported; in most of these cases, BeneFIX was administered via continuous infusion, which is not an approved method of administration (see also sections 4.2 and 4.4).

Inadequate therapeutic response and inadequate factor IX recovery

Inadequate therapeutic response and inadequate factor IX recovery have been reported during the post-marketing use of BeneFIX (see also section 4.2).

If any adverse 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.

Paediatric population

Allergic reactions might be experienced more frequently in children than in adults.

There is insufficient data to provide information on inhibitor incidence in PUPs (see also section 5.1).

No case of overdose has been reported.

Pharmacotherapeutic group: Antihaemorrhagic blood coagulation factor IX; ATC code: B02BD09

Mechanism of action

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.

Pharmacodynamic effects

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.

Paediatric population

Efficacy analysis in study 3090A1-301-WW was based on 22 evaluable paediatric subjects on prophylaxis regimen including 4 on-demand patients who shortly changed to prophylaxis. Two patients underwent surgical procedures (circumcision and port-a-catheter insertion). Safety analysis of 25 evaluable patients reflected a safety profile as expected. The only documented serious adverse event related with BeneFIX was reported from the only included PUP, who experienced hypersensitivity and inhibitor development.

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:

AUC_{0 - ∞} = Area Under the Curve

MRT = Mean Residence Time

SD = Standard Deviation

CI = Confidence Interval

A population pharmacokinetic model was developed using data collected in 73 patients aged 7 months to 60 years. The parameters estimated using the final 2-compartment model are shown in Table 2. Infants and children had higher clearance, larger volume of distribution, shorter half-life and lower recovery than adolescents and adults. The terminal phase has not been covered unambiguously due to lack of data beyond 24 hours in paediatric subjects < 6 years of age.

A 28% lower recovery of BeneFIX in comparison to plasma-derived factor IX was shown. Pharmacokinetic parameters of BeneFIX have also been determined after single and multiple intravenous doses in different species. The pharmacokinetic parameters obtained in studies comparing BeneFIX to plasma-derived factor IX were similar to those obtained in human studies. Structural differences of BeneFIX compared with plasma-derived factor IX appear to contribute to the different recovery compared to plasma-derived factor IX.

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.

No investigations on carcinogenicity, fertility impairment and foetal development have been conducted.

Powder

Sucrose

Glycine

L-Histidine

Polysorbate 80

Solvent

Sodium chloride solution

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Only the provided infusion set should be used. Treatment failure can occur as a consequence of human coagulation factor IX adsorption to the internal surfaces of some infusion equipment.

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 powder and solvent for solution for injection: 250 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 500 IU powder and solvent for solution for injection: 500 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 1000 IU powder and solvent for solution for injection: 1000 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 2000 IU powder and solvent for solution for injection: 2000 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 3000 IU powder and solvent for solution for injection: 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.

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

BeneFIX 250 IU powder and solvent for solution for injection: EU/1/97/047/004

BeneFIX 500 IU powder and solvent for solution for injection: EU/1/97/047/005

BeneFIX 1000 IU powder and solvent for solution for injection: EU/1/97/047/006

BeneFIX 2000 IU powder and solvent for solution for injection: EU/1/97/047/007

BeneFIX 3000 IU powder and solvent for solution for injection: EU/1/97/047/008

Date of first authorisation: 27 August 1997

Date of latest renewal: 27 August 2012

20 February 2013

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

BF 4_0