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).

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

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Esperoct. 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.

Tabulated list of adverse reactions

The frequencies of adverse reactions as observed in 270 unique subjects across five prospective, multi-centre clinical studies in previously treated patients (PTPs) with severe haemophilia A (<1% endogenous factor VIII activity) and no history of inhibitors are listed in table 3. The categories of adverse reactions presented in table 3 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 <1,000), very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 3          Frequency of adverse reactions for PTPs*
MedDRA System Organ           Adverse reactions                Frequency Class
Blood and lymphatic system Factor VIII inhibition              Uncommon (PTPs)** disorders
Immune system disorders       Hypersensitivity                 Uncommon Skin and subcutaneous         Rash                             Common tissue disorders              Erythema
Pruritus
General disorders and               Injection site reactions***         Common administration sites conditions
Investigations                      Coagulation factor VIII             Unknown**** level decreased
* PTPs: Previously-treated patients.
** Frequency is based on studies with all factor VIII products which included patients with severe haemophilia A.
*** Preferred terms included in injection site reactions: Injection site reaction, Vessel puncture site haematoma, Infusion site reaction, Injection site erythema, Injection site rash, Vessel puncture site pain, and Injection site swelling.
**** Based on post marketing reports.

Description of selected adverse reactions

Factor VIII inhibitors
One confirmed case of factor VIII inhibitor occurred in an 18 year-old previously treated patient on prophylactic treatment with Esperoct. The patient had a factor VIII gene intron 22 inversion and was at a high risk of developing factor VIII inhibitors.
There is no indication of an increased risk of factor VIII inhibitor development with treatment of Esperoct as compared to other factor VIII products.

Anti-drug antibodies
There was one case of persistent anti-drug antibodies concomitant with the confirmed case of factor VIII inhibitors (see Factor VIII inhibitors). Three patients had transiently positive test results for anti-drug antibodies after administration of Esperoct but no correlation with adverse events could be established.

Anti-PEG antibodies
During the clinical trial programme, thirty-two patients had pre-existing anti-PEG antibodies before administration of Esperoct. Twenty of the 32 patients were negative for anti-PEG antibodies post administration of Esperoct. Eleven patients developed transient low titre anti- PEG antibodies. No correlation with adverse events could be established.
From post-marketing reporting, occurrence of anti-PEG-antibodies has also been observed at time of switching to Esperoct. In some patients anti-PEG antibodies may have been associated with lower than expected level of FVIII activity.

Paediatric population

In the safety profile of Esperoct®, no difference was detected between previously treated children and adolescents and adults.


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 http://sideeffects.health.gov.il which refer the user to an online adverse reaction reporting form, or by entering the following link: http://sideeffects.health.gov.il.