Emicizumab

No dose adjustments are recommended in patients with mild, renal or hepatic impairment. There are limited data available on the use of emicizumab in patients with moderate renal or hepatic impairment. Emicizumab has not been studied in patients with severe renal or hepatic impairment.

There is a possibility for hypercoagulability with rFVIIa or FVIII with emicizumab based on preclinical experiments. Emicizumab increases coagulation potential, therefore the FVIIa or FVIII dose required to achieve hemostasis may be lower than when used without emicizumab prophylaxis.

In case of thrombotic complication, the physician should consider discontinuing rFVIIa or FVIII and interrupt emicizumab prophylaxis as clinically indicated. Further management should be tailored to the individual clinical circumstances.

• Decision about dose modifications should take into account the half-life of medications; specifically, interruption of emicizumab may not have an immediate effect.
• Monitoring using a FVIII chromogenic assay may guide the administration of coagulation factors, and testing for thrombophilic traits may be considered.

Experience with concomitant administration of anti-fibrinolytics with aPCC or rFVIIa in patients receiving emicizumab prophylaxis is limited. However, the possibility of thrombotic events should be considered when systemic anti-fibrinolytics are used in combination with aPCC or rFVIIa in patients receiving emicizumab.

Caution should be used when treating patients who are at high risk for TMA (e.g. have a previous medical history or family history of TMA), or those who are receiving concomitant medicinal products known to be a risk factor for the development of TMA (e.g. ciclosporin, quinine, tacrolimus).

There are no clinical studies of emicizumab use in pregnant women. Animal reproduction studies have not been conducted with emicizumab. It is not known whether emicizumab can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Emicizumab should be used during pregnancy only if the potential benefit for the mother outweighs the potential risk to the fetus taking into account that, during pregnancy and after parturition, the risk for thrombosis is increased and that several pregnancy complications are linked to an increased risk for disseminated intravascular coagulation (DIC).

It is not known whether emicizumab is excreted in human milk. No studies have been conducted to assess the impact of emicizumab on milk production or its presence in breast milk. Human IgG is known to be present in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from emicizumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential/Contraception

Women of childbearing potential receiving emicizumab should use effective contraception during, and for at least 6 months after cessation of emicizumab treatment.

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No fertility data are available in humans. Thus, the effect of emicizumab on male and female fertility is unknown.

Emicizumab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

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

The most common ADRs reported in ≥10% of patients treated with at least one dose of emicizumab were: injection site reactions (19.4%), arthralgia (14.2%) and headache (14.0%).

In total three patients (0.7%) in the clinical studies receiving emicizumab 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 emicizumab as routine prophylaxis. 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 1). 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 1. Summary of adverse drug reactions from pooled HAVEN clinical studies and post-marketing surveillance with emicizumab:

^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).

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. Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity. One patient resumed emicizumab 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 emicizumab following resolution of the thrombotic event without recurrence.

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

There were 82 instances of aPCC treatment* in patients receiving emicizumab 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 2). 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 2. Characterisation of aPCC treatment* in the pooled phase III clinical studies:

^* 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 emicizumab.
^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 emicizumab 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 emicizumab, development of neutralising anti-emicizumab antibodies associated with decreasing emicizumab concentration was uncommon. 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 emicizumab treatment.

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 emicizumab was overall consistent between infants, children, adolescents, and adults.