4.1. Therapeutic indications

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

BeneFIX can be used for all age groups.

4.2. Posology and method of administration

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

Treatment monitoring

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

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

Posology

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

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

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

On demand treatment

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

The required dose is determined using the following formula:

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

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

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

Degree of haemorrhage/Type of surgical procedure

Factor IX level required (%) or (IU/dL)

Frequency of doses (hours)/Duration of Therapy (days)

Haemorrhage

Early haemarthrosis, muscle bleeding or oral bleeding

20-40

Repeat every 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.

More extensive haemarthrosis, muscle bleeding or haematoma

30-60

Repeat infusion every 24 hours for 3-4 days or more until pain and acute disability are resolved.

Life-threatening haemorrhages

60-100

Repeat infusion every 8 to 24 hours until threat is resolved.

Surgery

Minor:

Including tooth extraction

Major

30-60

80-100

(pre- and postoperative)

Every 24 hours, at least 1 day, until healing is achieved.

Repeat infusion every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor IX activity of 30% to 60% (IU/dL)

Prophylaxis

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

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

Paediatric population

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

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

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

Elderly population

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

Method of administration

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

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

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

Agglutination of red blood cells in the tube/syringe

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

Continuous infusion

Administration by continuous infusion has not been approved and is not recommended (see also sections 4.4 and 6.6).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

Known allergic reaction to hamster proteins.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Patients can affix one of the peel-off labels found on the vial to document the batch number in their diary or for reporting any side effects.

Hypersensitivity

Allergic-type hypersensitivity reactions are possible with BeneFIX. The product contains traces of hamster proteins. Potentially life-threatening anaphylactic/anaphylactoid reactions have occurred with factor IX products, including BeneFIX. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of early signs of hypersensitivity reactions including difficult breathing, shortness of breath, swelling, hives, generalised urticaria, itching, tightness of the chest, bronchospasm, laryngospasm, wheezing, hypotension, blurred vision, and anaphylaxis.

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.

Inhibitors

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 new-born infants, 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).

Cardiovascular events

In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.

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.

Special populations

Sufficient data have not been obtained from clinical studies on the treatment of previously untreated patients (PUPs) with BeneFIX.

Sodium content

After reconstitution, BeneFIX contains 0.2 mmol sodium (4.6 mg) per vial, that is to say essentially 'sodium-free'. Depending on body weight of the patient and posology of BeneFIX, patients could receive multiple vials. This should be taken into consideration if the patient is on a low salt diet.

4.5. Interaction with other medicinal products and other forms of interaction

No interactions of human coagulation factor IX (rDNA) products with other medicinal products have been reported.

4.6. Fertility, 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 breast-feeding only if clearly indicated.

The effect of BeneFIX on fertility has not been established.

4.7. Effects on ability to drive and use machines

BeneFIX has no influence on the ability to drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed and may in some cases progress to severe anaphylaxis (including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.

Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.

Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

There is a potential risk of thromboembolic episodes following the administration of factor IX products, see section 4.4.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100), not known (cannot be estimated from the available data). The table lists adverse reactions reported in the clinical trials of previously treated patients and identified in postmarketing use. The frequencies are based on all causality treatment emergent adverse events in pooled clinical trials with 224 subjects.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class

Very common

≥ 1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1,000 to < 1/100

Frequency not known

(cannot be estimated from the available data)

Infections and infestations

Infusion-site cellulitisa

Blood and lymphatic system disorders

Factor IX inhibitionb

Immune system disorders

Hypersensitivityc

Anaphylactic reaction*

Nervous system disorders

Headached

Dizziness;

Dysgeusia

Somnolence;

tremor

Eye disorders

Visual impairmente

Cardiac disorders

Tachycardiaf

Vascular disorders

Phlebitis; flushingg

Hypotensionh

Superior vena cava syndromei,* ; deep vein thrombosis*;

thrombosis*;

thrombophlebitis*

Respiratory, thoracic and mediastinal disorders

Coughj

Gastrointestinal disorders

Vomiting; nausea

Skin and subcutaneous tissue disorders

Rashk; urticaria

Renal and urinary disorders

Renal infarctl

General disorders and administration site conditions

Pyrexia

Chest discomforto; infusion-site reactionn; infusion-site painm

Inadequate therapeutic response*

Investigations

Inadequate factor IX recovery p, *

* ADR identified post-marketing

a including cellulitis

b low-titer transient inhibitor formation

c including drug hypersensitivity, angioedema, bronchospasm, wheezing, dyspnoea, and laryngospasm

d including migraine, sinus headache

e including scintillating scotoma and blurred vision

f including heart rate increased, sinus tachycardia

g including hot flush, feeling hot, skin warm

h including blood pressure decreased

i superior vena cava (SVC) syndrome in critically ill neonates, while receiving continuous-infusion of BeneFIX through a central venous catheter

j including productive cough

k including rash macular, rash papular, rash maculopapular

l developed in a hepatitis C antibody-positive patient 12 days after a dose of BeneFIX for a bleeding episode.

m including injection site pain, infusion-site discomfort

n including infusion-site pruritus, infusion-site erythema

o including chest pain and chest tightness

p This is a verbatim term. No MedDRA 17.1 PT was retrieved.

Description of selected adverse reactions

Hypersensitivity/allergic reactions

If any suspected hypersensitivity reaction takes place that is thought to be related to the administration of BeneFIX see sections 4.2 and 4.4.

Inhibitor development

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 (see section 4.4).

Paediatric population

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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