HYMPAVZI Solution for injection Ref.[114436] Active ingredients: Marstacimab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Thromboembolic events

Removal of TFPI inhibition may increase a patient’s coagulation potential and contribute to a patient’s individual, multifactorial risk for thromboembolic events. 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 currently experiencing an acute severe illness with increased tissue factor expression (such as serious infection, sepsis, trauma, crush injuries, cancer).

Marstacimab has not been studied in patients with a history of previous thromboembolic events (see section 5.1) and there is limited experience in patients with acute severe illness.

The use of other anti-tissue factor pathway inhibitor (anti-TFPI) products has been associated with the development of thromboembolic complications in patients exposed to additional haemostatic agents (i.e. bypassing agents) in close proximity. No cases of thromboembolic events were observed in haemophilia patients who had received marstacimab prophylaxis in the clinical studies. Factor VIII and factor IX products have been safely administered for the treatment of breakthrough bleeds in patients receiving marstacimab. If factor VIII or factor IX products are indicated in a patient receiving Hympavzi prophylaxis, the minimum effective dose of factor VIII or factor IX product according to the product label is recommended.

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

Guidance on treating breakthrough bleeds

Factor VIII and factor IX products can be administered for the treatment of breakthrough bleeds in patients receiving Hympavzi. Additional doses of Hympavzi should not be used to treat breakthrough bleeding events. Healthcare professionals should discuss with all patients and/or caregivers about the dose and schedule of clotting factor concentrates to use, if required, while receiving Hympavzi prophylaxis, including using the lowest possible effective dose of clotting factor concentrate. Please refer to the product information for the clotting factor concentrate being used.

Hypersensitivity reactions

Cutaneous reactions of rash and pruritus that may reflect drug hypersensitivity have occurred in marstacimab-treated patients (see section 4.8). If Hympavzi-treated patients develop a severe hypersensitivity reaction, advise patients to discontinue Hympavzi and seek immediate emergency treatment.

Patient with factor inhibitor

In an ongoing clinical study outside the approved indication, in haemophilia patients with inhibitors treated with marstacimab, one (2.9%) patient with severe haemophilia B 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.

Effects of marstacimab on coagulation tests

Marstacimab therapy does not produce clinically meaningful changes in standard measures of coagulation including activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT).

Excipients

Polysorbate content

This medicinal product contains polysorbate 80. Polysorbate 80 may cause hypersensitivity reactions.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 mL, that is to say essentially ‘sodium-free’.

No clinical drug interaction studies with marstacimab have been conducted.

As a monoclonal antibody (mAb), marstacimab is expected to be cleared through catabolic pathways. Thus an impact on its clearance via an interaction with concomitant medicinal products cleared via non-catabolic pathways is unlikely. Indirect effect of a biologic such as marstacimab on the expression of cytochrome P450 enzymes is also not expected.

Women of childbearing potential

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

Pregnancy

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 Hympavzi can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Hympavzi 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).

Breast-feeding

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.

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3). No fertility data are available in humans. Thus, the effect of marstacimab on male and female fertility is unknown.

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

Summary of the safety profile

The most frequently reported adverse reactions after treatment with marstacimab were injection site reactions (ISRs) (11.2%).

Tabulated list of adverse reactions

Safety data in Table 1 are based on pooled data from the Phase 3 safety and efficacy study (BASIS) and its open-label extension (OLE) study (see section 5.1). The data from the pivotal Phase 3 study 12-month active treatment period reflects exposure of 116 male patients with haemophilia A or B without inhibitors to marstacimab administered once weekly. Ninety-seven (83.6%) patients were adults (18 years of age and older) and 19 (16.4%) were adolescents (12 years up to <18 years). At the time of data cut-off, a total of 87 of the 116 patients completing the 12-month treatment period subsequently enrolled in the OLE study. The median duration of exposure was 518.5 days (range 28 to 847 days).

Table 1 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.

Table 1. Adverse reactions:

^a see 'Description of selected adverse reactions'

Description of selected adverse reactions

Injection site reactions

In total, 11.2% of 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 induration, injection site oedema, injection site pain, injection site pruritus, and injection site swelling.

Rash

In the non-inhibitor population, 0.9% of patients reported non-serious rash (Grade 1).

Paediatric population

The paediatric population studied comprises a total of 19 adolescent patients (from 12 to <18 years of age). The safety profile of marstacimab was overall consistent between 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.