Emicizumab interacts in the following cases:
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.
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.
Cases of thrombotic microangiopathy (TMA) were reported from a clinical trial in patients receiving emicizumab prophylaxis when on average a cumulative amount of >100U/kg/24 hours of activated prothrombin complex concentrate (aPCC) for 24 hours or more was administered. Treatment for the TMA events included supportive care with or without plasmapheresis and haemodialysis. Evidence of improvement was seen within one week following discontinuation of aPCC and interruption of emicizumab. This rapid improvement is distinct from the usual clinical course observed in atypical hemolytic uremic syndrome and classic TMAs, such as thrombotic thrombocytopenic purpura. One patient resumed emicizumab following resolution of TMA and continued to be treated safely.
Patients receiving emicizumab prophylaxis should be monitored for the development of TMA when administering aPCC. The physician should immediately discontinue aPCC and interrupt emicizumab therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming emicizumab prophylaxis following complete resolution of TMA on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving emicizumab prophylaxis, see below for dosing guidance on the use of bypassing agents.
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 medications known to be a risk factor for the development of TMA (e.g. ciclosporin, quinine, tacrolimus).
Serious thrombotic events were reported from a clinical trial in patients receiving emicizumab prophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours or more was administered. No cases required anticoagulation therapy. Following discontinuation of aPCC and interruption of emicizumab, evidence of improvement or resolution was seen within one month. One patient resumed emicizumab following resolution of thrombotic event and continued to be treated safely.
Patients receiving emicizumab prophylaxis should be monitored for the development of thromboembolism when administering aPCC. The physician should immediately discontinue aPCC and interrupt emicizumab therapy if clinical symptoms, imaging, and/or laboratory findings consistent with thrombotic events occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming emicizumab prophylaxis following complete resolution of thrombotic events on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving emicizumab prophylaxis, see below for dosing guidance on the use of bypassing agents.
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 receiving emicizumab should use effective contraception during, and for at least 6 months after cessation of emicizumab treatment.
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 influence on the ability to drive and use machines.
The most serious adverse drug reactions (ADRs) reported from the clinical trials with emicizumab were thrombotic microangiopathy (TMA) and thrombotic events, including cavernous sinus thrombosis (CST) and superficial vein thrombosis contemporaneous with skin necrosis.
The most common ADRs reported in ≥10% of patients treated with at least one dose of emicizumab were: injection site reactions (20%), arthralgia (15%) and headache (14%).
In total three patients (0.8%) in the clinical trials receiving emicizumab prophylaxis withdrew from treatment due to ADRs, which were TMA, skin necrosis contemporaneous with superficial thrombophlebitis, and headache.
The following adverse drug reactions (ADRs) are based on pooled data from four phase III clinical trials (adult and adolescent studies [BH29884 – HAVEN 1, BH30071 – HAVEN 3, and BO39182 – HAVEN 4] and a paediatric study BH29992 – HAVEN 2]), in which a total of 373 male patients with haemophilia A received at least one dose of emicizumab as routine prophylaxis. Two hundred and sixty-six (71%) were adults, 47 (13%) were adolescents (≥12 to <18 years), 55 (15%) were children (≥2 to <12 years) and five (1%) were infants and toddlers (1 month to <2 years). The median duration of exposure across the studies was 33 weeks (range: 0.1 to 94.3 weeks).
ADRs from the phase III clinical trials in patients who received emicizumab are listed by MedDRA system organ class. 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).
Summary of adverse drug reactions from pooled HAVEN clinical trials with emicizumab:
Uncommon: Thrombotic microangiopathy
Very common: Headache
Uncommon: Thrombophlebitis superficial, *Cavernous sinus thrombosis
Common: Diarrhoea
Uncommon: Skin necrosis
disorders
Very common: Arthralgia
Common: Myalgia
Very common: Injection site reaction
Common: Pyrexia
* Vascular disorders is a secondary SOC for cavernous sinus thrombosis.
In pooled phase III clinical trials, thrombotic microangiopathy (TMA) events were reported in less than 1% of patients (3/373) 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.
In pooled phase III clinical trials, serious thrombotic events were reported in less than 1% of patients (2/373) 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.
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). 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.
Characterisation of aPCC treatment* in the pooled phase III clinical studies:
| Duration of aPCC treatment | Average cumulative amount of aPCC over 24 hours (U/kg/24 hours)) | ||
|---|---|---|---|
| <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 emicizumab.
a Thrombotic microangiopathy
b Thrombotic event
Injection site reactions (ISRs) were reported very commonly (20%) from clinical trials. All ISRs observed in the emicizumab clinical trials were reported as being non-serious and mild to moderate in intensity, and 95% resolved without treatment. The most commonly reported ISR symptoms were injection site erythema (11%), injection site pain (4%) and injection site pruritus (3%).
The paediatric population studied comprises a total of 107 patients, of which 5 (5%) were infants and toddlers (1 month to less than 2 years of age), 55 (51%) were children (from 2 to less than 12 years of age) and 47 (44%) were adolescents (from 12 to less than 18 years old). The safety profile of emicizumab was overall consistent between infants, children, adolescents, and adults.
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