PIASKY Solution for injection/infusion Ref.[111488] Active ingredients: Crovalimab

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.

Serious meningococcal infection

Due to its mechanism of action, the use of crovalimab may increase the patient’s susceptibility to meningococcal infections (septicaemia and/or meningitis). Cases of serious or fatal meningococcal infections/sepsis have been reported in patients treated with terminal complement inhibitors, which is a known class effect.

Meningococcal infection may become rapidly life-threatening or fatal if not recognised and treated early. To reduce the risk of infection, all patients must be vaccinated with a tetravalent meningococcal vaccine at least 2 weeks prior to receiving the first dose of crovalimab. If immediate treatment with crovalimab is indicated in an unvaccinated patient, the required vaccine should be administered as soon as possible and patients should receive prophylactic antibiotics from the time they start crovalimab until 2 weeks after vaccination. Vaccines against serogroups A, C, Y, W and B where available, are recommended to prevent infections with the commonly pathogenic meningococcal serogroups. Patients must maintain up to date vaccinations according to current local guidelines for vaccination use. If the patient is being switched from other terminal complement inhibitor treatment, physicians should verify that meningococcal vaccination is current according to local guidelines for vaccination use. Vaccination may activate the complement system further. As a result, patients with complement-mediated diseases, including PNH, may experience transient worsening of signs and symptoms of their underlying disease, such as haemolysis. Therefore, patients should be closely monitored for disease symptoms after the recommended vaccination.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to the prophylactic use of antibacterial agents based on local guidance. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary. Patients should be informed of these signs and symptoms and steps they need to take in seeking medical care immediately. Physicians must discuss the benefits and risks of treatment with Piasky with the patients and provide them with a patient/carer guide and a patient card.

Other systemic infections

Due to its mechanism of action, crovalimab must be administered with caution to patients with active systemic infections. Patients may have increased susceptibility to infections, especially with Neisseria spp. and other encapsulated bacteria. Vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections should be administered according to local guidelines.

If local guidelines mandate vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections, this should be performed at least 2 weeks prior receiving the first dose of crovalimab. If immediate treatment with crovalimab is indicated in an unvaccinated patient, the required vaccine should be administered as soon as possible and patients should receive prophylactic antibiotics from the time they start crovalimab until 2 weeks after vaccination or according to local standard of care, whichever is longer.

If Piasky is administered to patients with active systemic infections, patients should be monitored closely for signs and symptoms of worsening infection. Patients were excluded from clinical studies with crovalimab if they had any active systemic bacterial, viral, or fungal infection within 14 days prior to starting treatment.

Patients should be provided with information from the package leaflet to increase their awareness of the signs and symptoms of potential serious infections.

Type III immune complex reactions

Immune complex formation occurs in patients switching between complement inhibitors which bind different epitopes (see section 4.5). In some patients, the formation of these complexes can result in Type III immune complex mediated reactions, also referred to as Type III immune complex reactions. Patients who have never previously been treated with a C5 inhibitor or patients in whom previous C5 inhibitor treatment has been cleared from the body (i.e. at least 5.5 half-lives of the previous treatment have passed since the last dose) are not at risk of Type III immune complex reactions. Clinical studies with crovalimab reported adverse events of Type III immune complex mediated reactions (see section 4.8).

Signs and symptoms of Type III immune complex reactions observed in clinical studies were arthralgia and other musculoskeletal and connective tissue disorders, rash and other skin and subcutaneous disorders, pyrexia, asthenia/fatigue, gastrointestinal distress, headache and axonal neuropathy. Type III immune complex reactions may also manifest as renal abnormalities, however this was not observed during clinical studies with crovalimab.

Based on time-to-onset for Type III immune complex reactions observed in clinical studies, it is recommended that patients are monitored for the first 30 days after switching from eculizumab or ravulizumab to crovalimab (or vice-versa) for occurrence of the symptoms of Type III immune complex reactions. For mild or moderate Type III immune complex reactions, administration of symptomatic treatment (e.g. topical corticosteroids, antihistamines, antipyretics, and/or analgesics) may be considered. For severe reactions, oral or systemic corticosteroid therapy can be initiated and tapered as clinically indicated.

Infusion and injection-related reactions

Administration of crovalimab may cause infusion-related reactions or systemic injection-related reactions, depending on the route of administration. These may include allergic or hypersensitivity reactions (including anaphylaxis) but also a range of other symptoms such as headache or muscle pain.

In the event of a severe infusion-related reaction after intravenous Piasky administration, treatment should be interrupted and appropriate medical therapy should be administered. In the event of a severe injection-related reaction after subcutaneous administration or any incidence of serious allergic reaction following intravenous or subcutaneous administration, patients/caregivers should seek immediate medical attention and appropriate medical therapy should be administered. Patients should confirm with their healthcare professional whether treatment with Piasky can be continued.

Serious haemolysis after treatment discontinuation in PNH patients

In case of Piasky discontinuation, patients who do not switch to another treatment for PNH must be closely monitored for signs and symptoms of serious intravascular haemolysis, identified by elevated lactate dehydrogenase (LDH) levels, along with sudden decrease in PNH clone size or haemoglobin, or re-appearance of symptoms such as fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), major adverse vascular events (including thrombosis), dysphagia, or erectile dysfunction. If signs and symptoms of haemolysis occur after discontinuation, including elevated LDH, consider restarting appropriate treatment.

Immunogenicity leading to loss of exposure and efficacy

Patients may develop anti-drug antibodies (ADAs) that can interfere with crovalimab exposure. Development of ADAs may lead to loss of crovalimab exposure, which may subsequently result in loss of crovalimab efficacy. Loss of efficacy and loss of exposure resulting from ADA development has been observed in patients treated with crovalimab in clinical studies. Patients should be routinely monitored for clinical signs of loss of exposure and efficacy, including serious intravascular haemolysis. In the event of persistent serious intravascular haemolysis despite compliant treatment with crovalimab, patients should be promptly assessed to evaluate the aetiology and the possibility of the development of ADAs leading to loss of exposure and efficacy should be considered. An assessment of the benefits vs risks of continuing crovalimab should be made and a switch to an alternative therapy should be considered. Patients/caregivers should be advised to seek immediate medical attention if the patient develops signs of worsening PNH. See sections 4.8 and 5.1.

Crovalimab and other C5 inhibitors bind different epitopes on C5 such that immune complexes comprised of the antibodies bridged by C5 may form when both are present in the circulation. These immune complexes, also referred to as drug-target-drug complexes (DTDCs), can comprise one or more units of C5 bound to both crovalimab and to another C5 inhibitor and are expected to be cleared within approximately 8 weeks (in the case of eculizumab). The immune complexes may be cleared after a longer duration in the case of switch from C5 inhibitors with an extended half-life such as ravulizumab. In some patients, the formation of these complexes results in Type III immune complex reactions (see sections 4.4 and 4.8). In patients switching from another C5 inhibitor therapy, a transient increase in clearance is observed due to the formation of the immune complexes, leading to a faster elimination of crovalimab. However, this transient increase in clearance is not clinically relevant and does not require dose adjustment in patients switching from another C5 inhibitor.

No dedicated interaction studies have been conducted.

Crovalimab is not expected to show pharmacokinetic interactions with other medicinal products interfering with the metabolising cytochrome P450 (CYP) enzymes, since the clearance pathways of immunoglobulins G (IgGs) are distinct from those of small molecules.

Pregnancy

There is no data from the use of crovalimab in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Human IgG is known to cross the placenta after first trimester of pregnancy. Based on its mechanism of action, crovalimab may potentially cause terminal complement inhibition in the foetal circulation.

Therefore, the use of Piasky may be considered in pregnant women if the clinical condition of the woman requires treatment with crovalimab.

Breast-feeding

It is not known whether crovalimab is excreted into human breast milk. Human IgG1 is known to be excreted in human milk. A risk to the breastfed infant cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue from Piasky therapy taking into account the benefit of breast-feeding for the infant and the benefit of therapy for the mother.

Fertility

No clinical data are available on the effect of crovalimab on human fertility. Animal data from repeated-dose toxicity studies showed no effect on male or female reproductive organs (see section 5.3).

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

Summary of the safety profile

The most common adverse reactions observed were Type III immune complex mediated reaction (18.9% in patients who switched from treatment with another C5 inhibitor to crovalimab), upper respiratory tract infection (18.6%), pyrexia (13.5%), headache (10.9%) and infusion-related reaction (10.2%). The most common serious adverse reactions observed were Type III immune complex mediated reaction (4.0% in patients who switched from treatment with another C5 inhibitor to crovalimab) and pneumonia (1.5%).

The safety results from the 44 patients in the COMPOSER study where the median treatment duration was 4.69 years (range: 0.4-6.3 years) did not reveal any additional safety concerns associated with long term use of crovalimab.

Tabulated list of adverse reactions

The safety of crovalimab in patients with PNH was evaluated in three Phase III studies, COMMODORE 2 (BO42162), COMMODORE 3 (YO42311), and COMMODORE 1 (BO42161), and one Phase I/II study (COMPOSER, BP39144).

Table 2 lists the adverse reactions that have been reported in association with the use of crovalimab in a pooled analysis of 393 patients enrolled in the Phase III studies, unless otherwise stated. The median treatment duration for crovalimab based on the pooled analysis of 393 patients was 64 weeks (range: 0.1-136.4 weeks).

Adverse reactions are listed by MedDRA system organ class. The corresponding frequency category for each adverse reaction is 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). Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.

Table 2. Summary of adverse reactions occurring in patients treated with Piasky:

^* Type III immune complex mediated reaction (also referred to as Type III immune complex reaction) is limited to patients who switch from another C5 inhibitor to crovalimab or from crovalimab to another C5 inhibitor. The frequency of Type III immune complex reactions is reported for a subset of N=201 patients who switched from treatment with another C5 inhibitor to crovalimab, with incidence rates being calculated using these N=201 patients as the denominator. See below.

Description of selected adverse reactions

Type III immune complex reactions (see sections 4.4 and 4.5)

Across Phase III studies, 19.4% (39 out of 201) of patients who switched from treatment with eculizumab or ravulizumab to crovalimab experienced a Type III immune complex reaction (reported as Type III immune complex mediated reaction). Of these 39 patients, 2 patients experienced a second Type III immune complex reaction after discontinuing crovalimab and switching to ravulizumab. The most common signs and symptoms that were reported were arthralgia and rash, and other symptoms reported include pyrexia, headache, myalgia, abdominal pain, asthenia/fatigue and axonal neuropathy. The median time to onset of a Type III immune complex reaction in patients who switched from treatment with eculizumab or ravulizumab to crovalimab was 1.6 weeks (range: 0.7-4.4 weeks), with 5.1% of patients (2 of 39) experiencing a Type III immune complex reaction with a time to onset that exceeded 4 weeks. Most cases of Type III immune complex reaction were transient with a median duration of 1.7 weeks (range 0.4-34.1 weeks). The majority of patients experienced a Grade 1 or 2 event (23 of 39 patients), with Grade 3 events affecting 8% (16 of 39) of crovalimab-treated patients who switched from eculizumab or ravulizumab. Most events resolved with no change in study treatment with crovalimab.

In the COMPOSER study, among 26 patients who switched from eculizumab to crovalimab, 2 patients each reported 1 adverse event of Type III immune complex reaction. These events were mild/moderate and non-serious. One additional patient developed a mild Type III immune complex reaction after discontinuing crovalimab and switching to a different C5 inhibitor.

Immunogenicity

Across two randomised Phase III studies (COMMODORE 1 and COMMODORE 2) and one single-arm Phase III study (COMMODORE 3), ADA status was evaluable in 392 patients. Out of these 392 patients, 118 (30.1%) were ADA-positive. No differences in the rates of adverse reactions typically associated with immunogenicity (such as infusion-related reactions, injection site reactions, or hypersensitivity) were observed between ADA-positive and ADA-negative patients (see section 5.1).

Immunogenicity leading to loss of exposure and efficacy

Patients may develop ADAs that can interfere with crovalimab exposure. Out of 392 patients evaluated for ADA status, partial or complete loss of exposure associated with ADA onset was observed in 23 patients (5.9%); among them, 17 (4.3%) had a loss of pharmacological activity coinciding with a loss of exposure and with loss of efficacy, manifesting as a sustained loss of haemolysis control in 7 patients (1.8%).

In case of clinical signs of loss of efficacy, prompt evaluation by a healthcare professional should be sought (see section 4.4).

Infusion and Injection-Related Reactions

Across Phase III studies, 10.2% of patients who were treated with crovalimab experienced an infusion related reaction. The most common signs and symptoms that were reported were headache (7.1%), rash (0.8%), dizziness (0.8%), abdominal pain (0.5%), erythema (0.5%), nausea (0.5%), pyrexia (0.5%), and paraesthesia (0.3%). All events reported were Grade 1-2.

Across Phase III studies, 8.4% of patients who were treated with crovalimab experienced an injection-related reaction. The most common signs and symptoms that were reported were headache (2.5%), injection site erythema (1.0%), injection site pain (1.0%), and injection site rash (1.0%). The majority of events were Grade 1-2.

Infections with encapsulated bacteria

Based on its mechanism of action, the use of crovalimab may potentially increase the risk of infections, particularly infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae (see section 4.4).

Across Phase III studies, infections with encapsulated bacteria that were reported were Klebsiella pneumoniae, Klebsiella (not otherwise specified), Haemophilus influenzae and Neisseria subflava, the latter of which caused an adverse event of bacteriaemia in a patient.

Paediatric population

In 12 paediatric PNH patients with body weight ≥40 kg (aged 13-17 years old) included in COMMODORE 1, COMMODORE 2 and COMMODORE 3 studies, the safety profile appeared similar to that observed in adult PNH patients. The adverse reactions associated with crovalimab that were reported in paediatric PNH patients are upper respiratory tract infection (16.7%), urinary tract infection (16.7%), fatigue (16.7%), pyrexia (16.7%), headache (8.3%), infusion-related reaction (8.3%) and injection-related reaction (8.3%).

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.