BENEFIX Powder and solvent for solution for injection Ref.[9440] Active ingredients: Nonacog alfa

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.

Record of use

It is strongly recommended that every time BeneFIX is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product. 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.

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

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.

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

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.

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

Uncommon: Infusion-site cellulitisa

Blood and lymphatic system disorders

Uncommon: Factor IX inhibitionb

Immune system disorders

Common: Hypersensitivity^c

Frequency not known: Anaphylactic reaction*

Nervous system disorders

Very common: Headache^d

Common: Dizziness; Dysgeusia

Uncommon: Somnolence; tremor

Eye disorders

Uncommon: Visual impairmente

Cardiac disorders

Uncommon: Tachycardia^f

Vascular disorders

Common: Phlebitis; flushing^g

Uncommon: Hypotension^h

Frequency not known: Superior vena cava syndromeⁱ; deep vein thrombosis; thrombosis*; thrombophlebitis*

Respiratory, thoracic and mediastinal disorders

Very common: Cough^j

Gastrointestinal disorders

Common: Vomiting; nausea

Skin and subcutaneous tissue disorders

Common: Rash^k; urticaria

Renal and urinary disorders

Uncommon: Renal infarct^l

General disorders and administration site conditions

Very common: Pyrexia

Common: Chest discomfort°; infusion-site reaction6n^; infusion-site painm

Frequency not known: Inadequate therapeutic response*

Investigations

Frequency not known: 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
° 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 plasmaderived 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 national reporting system listed in Appendix V.

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.