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 and may in some cases progress to severe anaphylaxis (including shock).
Development of antibodies to mouse and hamster protein with related hypersensitivity reactions may occur.

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Kovaltry. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.


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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Frequency of adverse drug reactions in clinical trials
MedDRA                                   Adverse reactions               Frequency System Organ Class
Blood and lymphatic system disorders     Lymphadenopathy                 uncommon FVIII inhibitor            very common (PUPs)* uncommon (PTPs)*
Immune system disorders                       Hypersensitivity           uncommon Psychiatric disorders                         Insomnia                   common Nervous system disorders                      Headache,                  common 
Dizziness                  common

Dysgeusia                  uncommon
Cardiac disorders                             Palpitation,               uncommon Sinus tachycardia          uncommon
Vascular disorders                            Flushing                   uncommon Gastrointestinal disorders                    Abdominal pain,            common 
Abdominal discomfort       common

Dyspepsia                  common
Skin and subcutaneous tissue disorders        Pruritus,                  common 
Rash***,                   common

Urticaria                  common
Dermatitis allergic        uncommon

General disorders and administration          Pyrexia,                   Common site conditions injection site reactions   common
**
Chest discomfort           uncommon
* Frequency is based on studies with all FVIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients **includes injection site extravasation, hematoma, infusion site pain, pruritus, swelling *** rash, rash erythematous, rash pruritic, rash vesicular

Description of selected adverse reactions

A total of 236 (193 PTPs, 43 PUPs/MTPs) patients constituted the pooled safety population in the three phase III studies in previously treated patients (PTPs), previously untreated patients (PUPs) and minimal treated patients (MTPs); LEOPOLD I, LEOPOLD II, LEOPOLD Kids studies. The median time on clinical trial for pooled safety population was 558 days (range 14 to 2436 days) with a median of 183 exposure days (EDs) (range 1 to 1230 EDs).



•    The most frequently reported adverse reactions in the pooled population were pyrexia, headache and, rash.

•     The most frequently reported adverse reactions in the PTPs were related to potential hypersensitivity reactions, including headache, pyrexia, pruritus, rash and abdominal discomfort.
•     The most frequently reported adverse reaction in PUPs/MTPs was FVIII inhibitor.


Immunogenicity
The immunogenicity of Kovaltry was evaluated in PTPs and PUPs/MTPs.
During clinical trials with Kovaltry in approximately 200 pediatric and adult patients diagnosed with severe hemophilia A (FVIII:C < 1%) with previous exposure to factor VIII concentrates ≥ 50 ED, one case of transient low titer inhibitor (peak titer 1.0 BU/mL) occurred in a 13 year old PTP after 549 EDs. The Factor VIII recovery was normal (2.7 IU/dL per IU/kg).

Paediatric population
In the clinical studies no age-specific differences in ADR were observed except for FVIII inhibitor in PUPs/MTPs.

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
 https://sideeffects.health.gov.il/