Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The overall safety profile of Hemlibra is based on data from clinical studies and post-marketing surveillance. The most serious adverse drug reactions (ADRs) reported from the clinical studies with Hemlibra were thrombotic microangiopathy (TMA) and thrombotic events, including cavernous sinus thrombosis (CST) and superficial vein thrombosis contemporaneous with skin necrosis (see below and section 4.4).

The most common ADRs reported in ≥ 10% of patients treated with at least one dose of Hemlibra were: injection site reactions (19.4 %), arthralgia (14.2 %) and headache (14.0 %).
In total three patients (0. 7 %) in the clinical studies receiving Hemlibra prophylaxis withdrew from treatment due to ADRs, which were TMA, skin necrosis contemporaneous with superficial thrombophlebitis, and headache.

Tabulated list of adverse drug reactions

The following adverse drug reactions (ADRs) are based on data from post-marketing surveillance and pooled data from five phase III clinical studies (adult and adolescent studies [ BH29884 - HAVEN 1, BH30071 – HAVEN 3, and BO39182 – HAVEN 4], an all-age group study [BO41423 – HAVEN 6], and a paediatric study [BH29992 - HAVEN 2]), in which a total of 444 patients with haemophilia A received at least one dose of Hemlibra as routine prophylaxis (see section 5.1). Three hundred and seven (69.1 %) of the clinical study participants were adults (of which two were female), 61 (13.7 %) were adolescents (≥ 12 to < 18 years), 71 (16.0 %) were children (≥ 2 to < 12 years) and five (1.1 %) were infants and toddlers (1 month to < 2 years). The median duration of exposure across the studies was 32 weeks (range: 0.1 to 94.3 weeks).

ADRs from the phase III clinical studies and post-marketing surveillance are listed by MedDRA system organ class (Table 2). The corresponding frequency categories for each ADR are based on 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) and not known (cannot be estimated from the available data).

Table 2     Summary of adverse drug reactions from pooled HAVEN clinical studies and post- marketing surveillance with Hemlibra

System Organ Class (SOC)                    Adverse reactions                    Frequency (preferred term, MedDRA)

Blood and lymphatic system disorders        Thrombotic microangiopathy           Uncommon Nervous system disorders                    Headache                             Very common Vascular disorders                          Thrombophlebitis superficial         Uncommon Cavernous sinus thrombosisa          Uncommon
Gastrointestinal disorders                  Diarrhoea                            Common Skin and subcutaneous tissue disorders      Skin necrosis                        Uncommon Angioedema                           Uncommon
Urticaria                            Common
Rash                                 Common
Musculoskeletal and connective tissue       Arthralgia                           Very common disorders
Myalgia                              Common
General disorders and administration site   Injection site reaction              Very common conditions
Pyrexia                              Common
Therapeutic response decreasedb      Uncommon a
Vascular disorders is a secondary SOC for cavernous sinus thrombosis.
b
Loss of efficacy (therapeutic response decreased) manifest as an increase in breakthrough bleeding has been reported with neutralising anti-emicizumab antibodies with decreasing emicizumab concentration (see Description of selected adverse drug reactions and sections 4.4 and 5.1).



Description of selected adverse drug reactions

Thrombotic microangiopathy
In pooled phase III clinical studies, TMA events were reported in less than 1 % of patients (3/444) and in 9.7 % of patients (3/31) who received at least one dose of aPCC while being treated with emicizumab. All 3 TMAs occurred when on average a cumulative amount of > 100 U/Kg/24 hours of aPCC for 24 hours or more was administered during a treatment event (see section 4.4). Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity. One patient resumed Hemlibra following resolution of TMA without recurrence.

Thrombotic events

In pooled phase III clinical studies, serious thrombotic events were reported in less than 1% of patients (2/444) and in 6.5% of patients (2/31) who received at least one dose of aPCC while being treated with emicizumab. Both serious thrombotic events occurred when on average a cumulative amount of > 100 U/Kg/24 hours of aPCC for 24 hours or more was administered during a treatment event. One patient resumed Hemlibra following resolution of the thrombotic event without recurrence (see section 4.4).

Characterization of the interaction between emicizumab and aPCC treatment in pivotal clinical studies

There were 82 instances of aPCC treatment* in patients receiving Hemlibra prophylaxis, of which eight instances (10%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; two of the eight instances were associated with thrombotic events and three of the eight instances were associated with TMA (Table 3). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment. Of all instances of aPCC treatment, 68 % consisted of only one infusion < 100 U/kg.

Table 3      Characterisation of aPCC treatment* in the pooled phase III clinical studies 
Average cumulative amount of aPCC over 24 hours
Duration of aPCC                                   (U/kg/24 hours) treatment
<50                      50–100                 >100
<24 hours                        9                        47                      13 24-48 hours                      0                         3                      1b
>48 hours                        1                         1                    7a,a,a,b 
* An instance of aPCC treatment is defined as all doses of aPCC received by a patient, for any reason, until there was a 36-hour treatment-free break. Includes all instances of aPCC treatment excluding those in the first 7 days and those that occurred 30 days after the discontinuation of Hemlibra.
a
Thrombotic microangiopathy b
Thrombotic event

Injection site reactions

Injection site reactions (ISRs) were reported very commonly (19.4 %) from the pooled phase III clinical studies. All ISRs observed in the Hemlibra clinical studies were reported as being non-serious and mild to moderate in intensity, and 94.9 % resolved without treatment. The most commonly reported ISR symptoms were injection site erythema (10.6 %), injection site pain (4.1 %), injection site pruritus (2.9%) and injection site swelling (2.7 %).


Immunogenicity

In the pooled phase III clinical studies with Hemlibra, development of neutralising anti-emicizumab antibodies associated with decreasing emicizumab concentration was uncommon (see section 5.1).
One patient, who developed neutralising anti-emicizumab antibodies with decreasing emicizumab concentration, experienced loss of efficacy (manifest as breakthrough bleeding) after five weeks of treatment and later discontinued Hemlibra treatment (see sections 4.4 and 5.1).

Paediatric population

The paediatric population studied comprises a total of 137 patients, of which 5 (3.6 %) were infants and toddlers (1 month to less than 2 years of age), 71 (51.8 %) were children (from 2 to less than 12 years of age) and 61 (44.5 %) were adolescents (from 12 to less than 18 years old).
The safety profile of Hemlibra was overall consistent between infants, children, adolescents, and adults.

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