Nonacog alfa Other names: Recombinant coagulation factor IX

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

Allergic-type hypersensitivity reactions are possible with nonacog alfa. The product contains traces of hamster proteins. Potentially life-threatening anaphylactic/anaphylactoid reactions have occurred with factor IX products, including nonacog alfa. 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.

Although nonacog alfa 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 nonacog alfa should be weighed against the risk of these complications.

The safety and efficacy of nonacog alfa administration by continuous infusion have not been established. 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 nonacog alfa through a central venous catheter.

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 is not available. Therefore, factor IX should be used during pregnancy if clearly indicated.

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 breastfeeding is not available. Therefore, factor IX should be used during breast-feeding only if clearly indicated.

The effect of nonacog alfa on fertility has not been established.

Nonacog alfa 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. 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.

List of adverse reactions

The list 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 listed adverse reactions were 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.

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 nonacog alfa 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 nonacog alfa 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

Inhibitor development

A clinically relevant, low responding inhibitor was detected in 1 out of 65 nonacog alfa patients (including 9 patients participating only in the surgery study) who had previously received plasmaderived products. This patient was able to continue treatment with nonacog alfa with no anamnestic rise in inhibitor or anaphylaxis.

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.