Adverse reactions : תופעות לוואי

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 rarely with recombinant factor IX products 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 is contacted.

There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX products like Refixia is rarely associated with such adverse reactions.

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); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

A total of 115 previously treated male patients with moderate or severe haemophilia B have been exposed to Refixia for a total of 170 patient years in the completed clinical trials.

Table 3      Frequency of adverse reactions in clinical trials
System Organ Class                   Adverse reaction                     Frequency 
Immune system disorders              Hypersensitivity                     Uncommon Anaphylaxis                          Unknown
Inhibitors                           Unknown

Cardiac disorders                    Palpitations                         Uncommon 
Gastrointestinal disorders           Nausea                               Common 
Skin and subcutaneous tissue                 Pruritus*                                    Common disorders

General disorders and                        Fatigue                                      Common administration site conditions               Hot flush                                    Uncommon Injection site reactions**                   Common
*Pruritus includes the terms pruritus and ear pruritus
**Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema and injection site rash.

Previously untreated patients:
In an ongoing trial in previously untreated patients, anaphylaxis has occurred in close temporal association with development of factor IX inhibitors following treatment with Refixia®. The probability of developing inhibitors or an anaphylactic reaction are elevated in the early phases of substitution treatment (see section "Special warnings and precautions").

Description of selected adverse reactions
In an ongoing trial in previously untreated patients, anaphylaxis has occurred in close temporal association with development of factor IX inhibitors following treatment with Refixia. There are insufficient data to provide information on inhibitor incidence in previously untreated patients.

Children and adolescents
Previously treated patients: No differences in the safety profile of Refixia® were detected between previously treated children and adults.
Previously untreated patients: See adverse reactions under "Tabular presentation of adverse reactions" - "Adverse reactions in previously untreated patients".

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: http://sideeffects.health.gov.il.