Adverse reactions : תופעות לוואי

4.8. Undesirable effects
Tabulated summary of adverse reactions

The following table lists the adverse reactions observed from spontaneous reporting and in clinical trials.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Frequency has been evaluated using the following criteria: very common (1/10), common (1/100, <1/10), uncommon (1/1 000, <1/100), rare (1/10 000, <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).

MedDRA System Organ Class                             Frequency            MedDRA Preferred Term Infections and infestations                                  uncommon          Ear infection Blood and lymphatic system disorders                             common        Factor VIII inhibition1 Immune system disorders                                      not known         Anaphylactic reaction Hypersensitivity2

Nervous system disorders                                     uncommon          Dizziness Tremor
 not known         Loss of consciousness
Syncope
Headache
Paraesthesia


Recombinate Powder for Solution for Injection- BAXIJET ll,   26 2. 2015, RH MedDRA System Organ Class                               Frequency          MedDRA Preferred Term Cardiac disorders                                            not known        Cyanosis Tachycardia

Vascular disorders                                           uncommon         Epistaxis Flushing
Haematoma
Hypotension
Pallor
Peripheral coldness
Respiratory, thoracic and mediastinal                        uncommon         Pharyngolaryngeal pain disorders
 not known        Dyspnea
Cough
Wheezing
Gastrointestinal disorders                                   uncommon         Nausea 
 not known        Vomiting
Abdominal pain
Skin and subcutaneous tissue disorders                       uncommon         Hyperhydrosis Pruritus
Rash
Rash maculo-papular not known        angiooedema
Urticaria
Skin exfoliation
Erythema
Musculoskeletal and connective tissue                        uncommon         Pain in extremity disorders

General disorders and administration site                        common       Shivering conditions
 uncommon         Fatigue
Pyrexia
 not known        Malaise
Injection site reactions
Chest pain
Chest discomfort
Investigations                                               uncommon         Acoustic stimulation tests abnormal


Recombinate Powder for Solution for Injection- BAXIJET ll,   26 2. 2015, RH 1
In the PTP clinical trial (PTP = previously treated patients), none of the 71 subjects developed de novo FVIII antibody, but 22 of 72 evaluable per protocol PUPs (PUP = previously untreated patients) treated with Recombinate did develop FVIII antibodies and the above frequency was based on the PUP data. Of the 22, 10 were high titre ( 5 Bethesda Units) and 12 were low titre (< 5 Bethesda Units).
2
Early signs of hypersensitivity reactions are e.g. urticaria, dyspnea, cough, chest discomfort, wheezing, anaphylaxis, rash, hypotension, pruritus, chills, flushing, pyrexia, cyanosis, tachycardia, vomiting, syncope, headache. Caution is advised in patients with known allergic reactions to constituents of the preparation (See sections 4.3 and 4.4).

Description of selected adverse reactions

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are invariably IgG immunoglobulins directed against the factor VIII procoagulant activity, which are expressed as Bethesda Units (BU) per ml of plasma.

The risk of developing inhibitors is correlated to the exposure to Antihaemophilic factor VIII, this risk being highest within the first 20 exposure days. The reported incidence of inhibitory antibodies in patients with severe haemophilia A who are at high risk for inhibitor development (i.e. PUPs : previously untreated patients) is estimated in studies to be 31 % for Recombinate, which is within the reported range for plasma derived AHF.
Patients treated with Recombinate should be carefully monitored for the development of inhibitory antibodies by clinical observations and laboratory tests.

Paediatric population
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), no age-specific differences in ADRs were noted in the clinical studies.

Notification of suspected adverse reactions
Notification of suspected adverse reactions after market-authorisation has been received is an important practice, as it enables continuous monitoring of the medicinal product’s risk/benefit ration Healthcare professionals are asked to report any suspected adverse reactions to the Ministry of Health according to the National Regulation by using an online form (http://forms.gov.il/globaldata/getsequence/getsequence.aspx? formType = AdversEffectMedic@moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).