Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency were development of neutralising antibodies to factor VIII (inhibitors), headache and fever.

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).

Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions may be observed.

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

Tabulated summary of adverse reactions
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequency categories are defined 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, undesirable effects are presented in order of decreasing seriousness.

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports MedDRA Standard System                         Adverse reaction                      Frequencya Organ Class
Infections and infestations       Influenza                                            Uncommon Laryngitis                                           Uncommon
Blood and lymphatic system        Factor VIII inhibition                                Uncommon disorders                                                                                (PTPs)d Very common
(PUPs)d
Lymphangitis                                         Uncommon
Immune system disorders            Anaphylactic reaction                                Not known Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports MedDRA Standard System                           Adverse reaction                    Frequencya Organ Class
Hypersensitivityc                                     Not known
Nervous system disorders          Headache                                               Common Dizziness                                            Uncommon
Memory impairment                                    Uncommon
Syncope                                              Uncommon
Tremor                                               Uncommon
Migraine                                             Uncommon
Dysgeusia                                            Uncommon
Eye disorders                     Eye inflammation                                     Uncommon Cardiac disorders                 Palpitations                                         Uncommon Vascular disorders                Haematoma                                            Uncommon Hot flush                                            Uncommon
Pallor                                               Uncommon
Respiratory, thoracic and         Dyspnoea                                             Uncommon mediastinal disorders
Gastrointestinal disorders        Diarrhoea                                            Uncommon Abdominal pain upper                                 Uncommon
Nausea                                               Uncommon
Vomiting                                             Uncommon
Skin and subcutaneous tissue      Pruritus                                             Uncommon disorders                         Rash                                                 Uncommon Hyperhidrosis                                        Uncommon
Urticaria                                            Uncommon
General disorders and             Pyrexia                                                Common administration site conditions    Peripheral oedema                                    Uncommon Chest pain                                           Uncommon
Chest discomfort                                     Uncommon
Chills                                               Uncommon
Feeling abnormal                                     Uncommon
Vessel puncture site haematoma                       Uncommon
Fatigue                                               Not known
Injection site reaction                               Not known
Malaise                                               Not known
Investigations                    Monocyte Count increased                             Uncommon Coagulation factor VIII level decreasedb             Uncommon
Haematocrit decreased                                Uncommon
Laboratory test abnormal                             Uncommon
Injury, poisoning and procedural Post procedural complication                          Uncommon complications                     Post procedural haemorrhage                          Uncommon Procedural site reaction                             Uncommon
 a)    Calculated based on total number of patients who received ADVATE (418).
b)    The unexpected decrease in coagulation factor VIII levels occurred in one patient during continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis was maintained at all times during this period and both plasma factor VIII levels and clearance rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays performed after completion of continuous infusion and at study termination were negative.
c)    ADR explained in the section below.
d)    Frequency is based on studies with all FVIII products which included patients with severe haemophilia A. PTPs=previously treated patients, PUPs=previously untreated patients.


Description of selected adverse reactions
ADRs specific to residues from the manufacturing process
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who were assessed for antibodies to murine IgG, 10 showed a statistically significant upward trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst repeated exposures to the study product.

Hypersensitivity
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and pruritus.

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

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 on line form https://sideeffects.health.gov.il/