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 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 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.

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, 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 is rarely associated with thromboembolic complications.

Tabulated list of adverse reactions
Previously Treated Patients (PTPs): A total of 153 patients with severe haemophilia B were observed in phase III clinical studies and an extension study. Adverse events were monitored for a total of 561 subject- years. The total number of exposure days was 26,106 with a median of 165 (range 1 to 528) exposure days per subject.



Previously Untreated Patients (PUPs): A total of 33 patients with severe haemophilia B were observed in one clinical study. Adverse events were monitored for a total of 57.51 subject-years. The total number of exposure days was 2,233 with a median of 76 (range 1 to 137) exposure days per subject.

Table 2 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). The table lists adverse reactions reported in the clinical studies and identified in post-marketing use.

Table 2: Adverse reactions reported for ALPROLIX
MedDRA System Organ Class                                     Adverse reactions              Frequency category Blood and lymphatic system disorders                          Factor IX inhibition              Common1 Immune system disorders                                       Hypersensitivity                  Common1 Anaphylactic reaction             Not known
Anaphylactic shock             Not known
Metabolism and nutrition disorders                            Decreased appetite                Uncommon Nervous system disorders                                      Headache                          Common Dizziness                         Uncommon
Dysgeusia                         Uncommon
Cardiac disorders                                             Palpitations                      Uncommon Vascular disorders                                            Hypotension                       Uncommon Gastrointestinal disorders                                    Paraesthesia oral                 Common Breath odour                      Uncommon
Renal and urinary disorders                                   Obstructive uropathy              Common Haematuria                        Uncommon
Renal colic                       Uncommon
General disorders and administration site conditions          Injection site erythema           Common Fatigue                           Uncommon
Infusion site pain                Uncommon
1
Frequency based on occurrence in PUPs study. Both events of factor IX inhibition and hypersensitivity occurred in a single PUP in Study IV. See Description of selected adverse reactions.

Description of selected adverse reactions
Throughout the clinical study program, one patient (previously untreated) in Study IV developed a low titer factor IX inhibitor associated with hypersensitivity (see section 5.1). In post-marketing experience, factor IX inhibitor development and hypersensitivity (including anaphylaxis) have been observed.

Paediatric population
Frequency, type and severity of adverse reactions in children are expected to be similar as in adults. For extent and age characterisation of the safety database in children see section 5.1.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 https://sideeffects.health.gov.il