Marstacimab

Marstacimab has not been studied in patients with moderate or severe renal impairment.

Marstacimab has not been studied in patients with moderate or severe hepatic impairment.

The following patients may be at an increased risk of thromboembolic events with use of this medicinal product:

• patients with a history of coronary artery disease, venous or arterial thrombosis or ischaemic disease,
• patients with known risk factors for thromboembolism, including but not limited to genetic prothrombotic conditions (e.g. Factor V Leiden), patients with prolonged periods of immobilisation, obesity, and smoking,
• patients currently experiencing an acute severe illness with increased tissue factor expression (such as serious infection, sepsis, trauma, crush injuries, cancer).
• patients managed in perioperative setting and/or undergoing surgery. In the perioperative setting, concomitant use of marstacimab with other haemostatic agents can potentially increase the risk of thrombosis.

Marstacimab has not been studied in patients with a history of previous thromboembolic events and there is limited experience in patients with acute severe illness.

The benefits and risks of using marstacimab in patients with a history of thromboembolic events, with known risk factors for thromboembolism, or currently experiencing an acute severe illness should be considered. Patients at risk should be monitored for early signs of thrombosis, and prophylactic measures against thromboembolism should be instituted according to current recommendations and standard of care. Marstacimab prophylaxis should be interrupted if diagnostic findings consistent with thromboembolism occur and patients should be managed as clinically indicated.

The use of anti-tissue factor pathway inhibitor (anti-TFPI) products, including marstacimab, has been associated with the development of thromboembolic complications in patients exposed to additional haemostatic agents (i.e. bypassing agents) in close proximity. Factor VIII and factor IX products and bypassing agents have been safely administered for the treatment of breakthrough bleeds in patients receiving marstacimab. If factor VIII or factor IX products or bypassing agents are indicated in a patient receiving marstacimab prophylaxis, the minimum effective dose according to the product label is recommended. Patients should be informed of and monitored for the occurrence of signs and symptoms of thromboembolic events. In case of suspicion of thromboembolic events, marstacimab should be discontinued and appropriate medical treatment should be initiated.

There are no clinical studies of marstacimab use in pregnant women. Animal reproduction studies have not been conducted with marstacimab. It is not known whether marstacimab can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Marstacimab should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the foetus 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 marstacimab is excreted in human milk. No studies have been conducted to assess the impact of marstacimab on milk production or its presence in breast milk. Human IgG is known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, marstacimab could be used during breast-feeding if clinically needed.

Women of childbearing potential

Women of childbearing potential receiving marstacimab should use effective contraception during, and for at least 1 month after cessation of marstacimab treatment.

Fertility

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

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

Summary of the safety profile

The overall safety profile of marstacimab is based on pooled data from clinical studies. The most serious adverse drug reaction reported from the clinical studies with marstacimab was thrombosis (0.6%).

The most frequently reported adverse reactions after treatment with marstacimab were injection site reactions (ISRs) (11.4%).

Tabulated list of adverse reactions

Safety data in the table below are based on pooled data from the Phase 3 safety and efficacy study (BASIS) and from the patients who rolled over from the BASIS study into the open-label extension (OLE) study. The data from the pivotal Phase 3 study 12-month Active Treatment Phase reflects exposure of 167 male patients with haemophilia A or B with inhibitors (30.5%) or without inhibitors (69.5%) to marstacimab administered once weekly. Of the 167 patients, 135 (80.8%) were adults (18 years of age and older) and 32 (19.2%) were adolescents (12 years up to <18 years). A total of 154 of the 159 patients completing the 12-month treatment period subsequently enrolled in the ongoing OLE study. The median total duration of exposure was 1 225 days (range 28 to 1 659 days).

The table below summarises the adverse reactions reported in patients who received marstacimab prophylaxis. The adverse reactions listed in the table below are presented by system organ class (SOC) and frequency categories, defined using 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) or frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions:

^a Headache includes both headache and migraine.
^b ADR reported in the open-label extension study.
^c see 'Description of selected adverse reactions'.

Description of selected adverse reactions

Injection site reactions

In total, 19 (11.4%) patients treated with marstacimab reported ISRs. The majority of ISRs observed in marstacimab clinical studies were transient and reported as mild to moderate in severity. No occurrences of injection site reaction led to a dose adjustment or drug discontinuation. ISRs include injection site bruising, injection site erythema, injection site haematoma, injection site haemorrhage, injection site induration, injection site oedema, injection site pain, injection site pruritus, and injection site swelling.

Rash

In total, 6 (3.6%) patients treated with marstacimab reported rash.

One patient with severe haemophilia B with inhibitors and a history of allergic reaction to exogenous factor IX experienced severe rash with onset at approximately 9 months. The patient required a prolonged course of oral corticosteroids for resolution and treatment with marstacimab was discontinued.

Paediatric population

The paediatric population studied comprises a total of 32 adolescent patients (from 12 to <18 years of age). The safety profile of marstacimab was overall consistent between adolescents and adults.