ALHEMO Solution for injection Ref.[114497] Active ingredients: Concizumab

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.

Hypersensitivity reactions

Allergic type hypersensitivity reactions have occurred with concizumab within the initial weeks of treatment, including hospitalisation and permanent discontinuation of therapy. Patients should be informed of the signs of acute hypersensitivity reactions.

If symptoms of hypersensitivity occur, the patient should be advised to discontinue the use of Alhemo and contact the physician who should ensure appropriate treatment.

Immunogenicity

Development of neutralising anti-concizumab antibodies, observed in some patients, has not led to loss of efficacy (see section 5.1). However, patients with clinical signs of loss of efficacy (e.g. increase in breakthrough bleeding events) should be evaluated to assess the etiology and other therapeutic options should be considered if neutralising anti-concizumab antibodies are suspected.

Thromboembolic events

Cases of non-fatal arterial and venous thromboembolic events have been reported in the concizumab clinical trials. These cases occurred in patients with multiple risk factors including high or frequent doses of breakthrough bleed treatment (see section 4.8).

Patients treated with concizumab should be informed of and monitored for the occurrence of signs and symptoms of thromboembolic events. In case of suspicion of thromboembolic events, concizumab should be discontinued, and further investigations and appropriate medical treatment should be initiated. There should be careful consideration whether the potential benefit of concizumab treatment outweighs the potential risk in patients considered at high risk of thromboembolic events. This consideration should be re-evaluated periodically.

In conditions in which tissue factor is overexpressed (e.g., advanced atherosclerotic disease, crush injury, cancer or septicaemia), there may be a risk of thromboembolic events or disseminated intravascular coagulation (DIC). In these situations, the potential benefit of treatment with concizumab should be weighed against the risk of these complications.

Effects of concizumab on coagulation tests

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

Excipients

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

This medicinal product contains 0.25 mg of polysorbate 80 in each mL. Polysorbates may cause allergic reactions.

No drug-drug interaction clinical trials have been conducted. A drug-drug interaction toxicity study with rFVIIa in concizumab treated cynomolgus monkeys was conducted. No sign of thrombosis or other adverse findings were observed in normo-coagulant monkeys when adding three consecutive doses of up to 1 mg/kg rFVIIa on top of concizumab at steady state, see section 5.3.

In vitro and ex vivo drug-drug interaction studies were performed with rFVIIa, aPCC, rFVIII or rFIX in blood from haemophilia patients who are on prophylactic treatment with concizumab. These studies did not suggest clinically relevant drug-drug interactions.

For guidance on the use of bypassing agents for treatment of breakthrough bleeding episodes in patients receiving concizumab prophylaxis, see section 4.2.

Women of childbearing potential/contraception in males and females

Women of childbearing potential receiving concizumab should use highly effective contraception during treatment with concizumab and until 7 weeks after end of treatment. The benefits and thromboembolic risks of the type of contraceptives used should be evaluated by the treating physician.

Pregnancy

There are no available data on concizumab use in pregnant women. Animal reproduction studies have not been conducted with concizumab. It is not known whether concizumab can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Concizumab should only be used during pregnancy if the potential benefit for the mother outweighs the potential risk to the foetus.

Breast-feeding

It is unknown whether concizumab is excreted in human milk. Human IgGs are 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, concizumab 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 concizumab on male and female fertility is unknown.

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

Summary of the safety profile

The overall safety profile of concizumab is based on data from clinical trials. The most serious adverse reactions in the clinical trials with concizumab were thromboembolic events (0.9%) and hypersensitivity (0.3%).

Tabulated list of adverse reactions

The following adverse reactions are based on pooled data from the clinical trials NN7415-4159 (phase 1b), NN7415-4310 (phase 2), NN7415-4255 (phase 2), NN7415-4311 (phase 3) and NN7415-4307 (phase 3), in which a total of 320 male patients with haemophilia A with and without inhibitors and haemophilia B with and without inhibitors received at least one dose of concizumab as routine prophylaxis. The patients were exposed for a total of 411 exposure years.

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness, see Table 2.

Table 2. Adverse reactions from pooled clinical trials with concizumab:

Description of selected adverse reactions

Injection site reactions

Injection site reactions were reported across the multiple dose clinical trials. The most frequently reported symptoms were injection site erythema (5.9%), injection site bruising (4.4%) and injection site haematoma (4.1%). The majority were reported as mild.

Paediatric population

78 of the clinical trial participants were adolescents (≥12 to <18 years). The safety profile was similar between adolescent and adult patients and as expected for the age group.

The safety and efficacy of concizumab in children aged below 12 years have not yet been established. No data are available.

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.