PIASKY 340mg injection / infusion solution medication leaflet

Piasky 340 mg solution for injection/infusion

Each 2 mL vial contains 340 mg of crovalimab.

Each mL of solution for injection/infusion contains 170 mg crovalimab.

Crovalimab is a humanised monoclonal antibody produced in Chinese hamster ovary (CHO) cells byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection/infusion (injection/infusion).

Clear to strongly opalescent and almost colourless to brownish-yellow solution. The solution has a pHof approximately 5.8 and an osmolality of approximately 297 mOsm/kg.

Piasky as monotherapy is indicated for the treatment of adult and paediatric patients 12 years of age orolder with a weight of 40 kg and above with paroxysmal nocturnal haemoglobinuria (PNH):

- In patients with haemolysis with clinical symptom(s) indicative of high disease activity.

- In patients who are clinically stable after having been treated with a complement component 5(C5) inhibitor for at least the past 6 months.

Treatment should be initiated under the supervision of a physician experienced in the treatment ofhaematological disorders.

The recommended dosing regimen consists of one loading dose administered by intravenous infusion(on Day 1), followed by four additional weekly loading doses administered by subcutaneous injection(on Days 2, 8, 15, and 22). The maintenance dose starts on Day 29 and is then administered every4 weeks by subcutaneous injection. The doses to be administered are based on the patient’s bodyweight, as shown in Table 1.

For patients switching from treatment with another complement inhibitor, the first intravenous loadingdose of Piasky should be administered at the time of the next scheduled complement inhibitoradministration (see section 4.4 for additional information related to switching between complementcomponent 5 [C5] inhibitor treatments). The administration of the additional subcutaneous loadingdoses and maintenance doses of Piasky will follow as per the schedule shown in Table 1.

Table 1: Piasky dosing regimen based on body weight

Body weight  40 kg to  100 kg  100 kg

Loading Dose

Day 1 1 000 mg (intravenous) 1 500 mg (intravenous)

Day 2, 8, 15, 22 340 mg (subcutaneous) 340 mg (subcutaneous)

Day 29 and Q4Wa thereafter 680 mg (subcutaneous) 1 020 mg (subcutaneous)a Q4W=every 4 weeks

The dosing schedule is allowed to occasionally vary within 2 days of the scheduled administration day(except at Day 1 and Day 2). If this occurs, the subsequent dose should be administered according tothe regular schedule.

Piasky is intended for long-term treatment unless the discontinuation of this medicinal product isclinically indicated (see section 4.4).

If an entire planned dose or part of a planned dose of Piasky is missed, the missing dose or remainderof the planned dose should be administered as soon as possible before the day of the next scheduleddose. The next dose should then be administered on the regular scheduled dosing day. Do not take twodoses or administer more than the prescribed dose on the same day to make up for a missed dose.

Modification of the maintenance dose is required if the patient’s body weight changes by 10% or moreto become consistently greater than or lower than 100 kg during the course of treatment (see Table 1for recommended dose). Accordingly, the patient’s body weight should be monitored periodically andon an ongoing basis, as appropriate.

No dose adjustment is required in patients ≥ 65 years of age, although experience with crovalimab inelderly patients in clinical studies is limited (see section 5.2).

No dose adjustment is recommended for patients with mild, moderate or severe renal impairment (seesection 5.2).

No dose adjustment is recommended for patients with mild hepatic impairment. Crovalimab has notbeen studied in patients with moderate to severe hepatic impairment and no recommendation onposology can be provided (see section 5.2).

No dose adjustment of crovalimab is required in paediatric patients 12 years of age or older with bodyweight ≥ 40 kg. The safety and efficacy of crovalimab in children less than 12 years of age andchildren with body weight < 40 kg have not yet been established. No data are available.

Piasky is administered as an intravenous infusion (first dose) and as a subcutaneous injection(subsequent doses).

Piasky should be prepared for intravenous administration using appropriate aseptic technique. Piaskymust be diluted and administered by a healthcare professional as an intravenous infusion over60 minutes ± 10 minutes (1 000 mg) or 90 minutes ± 10 minutes (1 500 mg). Piasky should not beadministered as an intravenous push or bolus.

For instructions on dilution of the medicinal product before administration, see section 6.6.

The infusion of crovalimab may be slowed or interrupted if the patient develops an infusion relatedreaction. The infusion should be discontinued immediately if the patient experiences a serioushypersensitivity reaction (see section 4.4).

Piasky must be used undiluted and should be prepared using appropriate aseptic technique. It isrecommended to inject Piasky into the abdomen. Within the abdomen, injection sites should be rotatedwith every injection. Injections should never be given into moles, scars, or areas where the skin istender, bruised, red, hard, or not intact.

Administration by the patient and/or caregiver

After proper training in subcutaneous injection technique, the patient may self-administer Piasky orthe caregiver may administer Piasky without healthcare professional (HCP) supervision if the treatingphysician determines that it is appropriate.

Comprehensive instructions for the administration of Piasky are given at the end of the Package

Leaflet.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Patients with unresolved Neisseria meningitidis infection.

- Patients who are not currently vaccinated against Neisseria meningitidis unless they receiveprophylactic treatment with appropriate antibiotics until 2 weeks after vaccination (see section4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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 tomeningococcal infections (septicaemia and/or meningitis). Cases of serious or fatal meningococcalinfections/sepsis have been reported in patients treated with terminal complement inhibitors, which isa known class effect.

Meningococcal infection may become rapidly life-threatening or fatal if not recognised and treatedearly. To reduce the risk of infection, all patients must be vaccinated with a tetravalent meningococcalvaccine at least 2 weeks prior to receiving the first dose of crovalimab. If immediate treatment withcrovalimab is indicated in an unvaccinated patient, the required vaccine should be administered assoon as possible and patients should receive prophylactic antibiotics from the time they startcrovalimab until 2 weeks after vaccination. Vaccines against serogroups A, C, Y, W, and B whereavailable, are recommended to prevent infections with the commonly pathogenic meningococcalserogroups. Patients must maintain up to date vaccinations according to current local guidelines forvaccination 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 forvaccination use. Vaccination may activate the complement system further. As a result, patients withcomplement-mediated diseases, including PNH, may experience transient worsening of signs andsymptoms of their underlying disease, such as haemolysis. Therefore, patients should be closelymonitored for disease symptoms after the recommended vaccination.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be givento the prophylactic use of antibacterial agents based on local guidance. All patients should bemonitored 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 andsymptoms and steps they need to take in seeking medical care immediately. Physicians must discussthe benefits and risks of treatment with Piasky with the patients and provide them with apatient/caregiver guide and a patient card.

Other systemic infections

Due to its mechanism of action, crovalimab must be administered with caution to patients with activesystemic infections. Patients may have increased susceptibility to infections, especially with Neisseriaspp. and other encapsulated bacteria. Vaccinations for the prevention of Streptococcus pneumoniaeand Haemophilus influenzae type b (Hib) infections should be administered according to localguidelines.

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 priorreceiving the first dose of crovalimab. If immediate treatment with crovalimab is indicated in anunvaccinated patient, the required vaccine should be administered as soon as possible and patientsshould receive prophylactic antibiotics from the time they start crovalimab until 2 weeks aftervaccination or according to local standard of care, whichever is longer.

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

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

Type III immune complex reactions

Immune complex formation occurs in patients switching between complement inhibitors which binddifferent 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 C5inhibitor treatment has been cleared from the body (i.e. at least 5.5 half-lives of the previous treatmenthave passed since the last dose) are not at risk of Type III immune complex reactions. Clinical studieswith crovalimab reported adverse events of Type III immune complex mediated reactions (see section4.8).

Signs and symptoms of Type III immune complex reactions observed in clinical studies werearthralgia and other musculoskeletal and connective tissue disorders, rash and other skin andsubcutaneous disorders, pyrexia, asthenia/fatigue, gastrointestinal distress, headache and axonalneuropathy. Type III immune complex reactions may also manifest as renal abnormalities, howeverthis was not observed during clinical studies with crovalimab.

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

Infusion and injection-related reactions

Administration of crovalimab may cause infusion-related reactions or systemic injection-relatedreactions, depending on the route of administration. These may include allergic or hypersensitivityreactions (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, treatmentshould be interrupted and appropriate medical therapy should be administered. In the event of a severeinjection-related reaction after subcutaneous administration or any incidence of serious allergicreaction following intravenous or subcutaneous administration, patients/caregivers should seekimmediate medical attention and appropriate medical therapy should be administered. Patients shouldconfirm 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 beclosely monitored for signs and symptoms of serious intravascular haemolysis, identified by elevatedlactate 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, considerrestarting 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 inloss of crovalimab efficacy. Loss of efficacy and loss of exposure resulting from ADA developmenthas been observed in patients treated with crovalimab in clinical studies. Patients should be routinelymonitored for clinical signs of loss of exposure and efficacy, including serious intravascularhaemolysis. In the event of persistent serious intravascular haemolysis despite compliant treatmentwith crovalimab, patients should be promptly assessed to evaluate the aetiology and the possibility ofthe development of ADAs leading to loss of exposure and efficacy should be considered. Anassessment of the benefits vs risks of continuing crovalimab should be made and a switch to analternative therapy should be considered. Patients/caregivers should be advised to seek immediatemedical 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 complexescomprised of the antibodies bridged by C5 may form when both are present in the circulation. Theseimmune complexes, also referred to as drug-target-drug complexes (DTDCs), can comprise one ormore units of C5 bound to both crovalimab and to another C5 inhibitor and are expected to be clearedwithin approximately 8 weeks (in the case of eculizumab). The immune complexes may be clearedafter a longer duration in the case of switch from C5 inhibitors with an extended half-life such asravulizumab. In some patients, the formation of these complexes results in Type III immune complexreactions (see sections 4.4 and 4.8). In patients switching from another C5 inhibitor therapy, a transientincrease in clearance is observed due to the formation of the immune complexes, leading to a fasterelimination of crovalimab. However, this transient increase in clearance is not clinically relevant anddoes 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 productsinterfering with the metabolising cytochrome P450 (CYP) enzymes, since the clearance pathways ofimmunoglobulins G (IgGs) are distinct from those of small molecules.

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. Basedon its mechanism of action, crovalimab may potentially cause terminal complement inhibition in thefoetal circulation.

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

It is not known whether crovalimab is excreted into human breast milk. Human IgG1 is known to beexcreted 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 therapytaking into account the benefit of breast-feeding for the infant and the benefit of therapy for themother.

No clinical data are available on the effect of crovalimab on human fertility. Animal data fromrepeated-dose toxicity studies showed no effect on male or female reproductive organs (see section5.3).

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

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), upperrespiratory 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 complexmediated reaction (4.0% in patients who switched from treatment with another C5 inhibitor tocrovalimab) and pneumonia (1.5%).

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

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), andone Phase I/II study (COMPOSER, BP39144).

Table 2 lists the adverse reactions that have been reported in association with the use of crovalimab ina pooled analysis of 393 patients enrolled in the Phase III studies, unless otherwise stated. The mediantreatment 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 categoryfor 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 ofdecreasing seriousness.

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

MedDRA system organ class Adverse reactions(MedDRA) Frequency category

Infections and infestations Upper respiratory tractinfection Very common

Respiratory Tract Infection

Common

Urinary Tract Infection

Nasopharyngitis

Septic shock

Uncommon

Bacteraemia

Pyelonephritis

Immune system disorders Type III immune complexmediated reaction* Very common

Hypersensitivity Common

Nervous system disorders Headache Very common

Gastrointestinal Disorders Abdominal pain

Common

Skin and subcutaneous tissuedisorders Rash Common

Musculoskeletal and connectivetissue disorders Arthralgia Common

General disorders and Pyrexia Very commonadministration site conditions

Asthenia

Common

Injection site reaction Uncommon

Injury, poisoning and Infusion related reaction Very commonprocedural complications

Injection-related reaction Common

*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 toanother 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 incidencerates being calculated using these N=201 patients as the denominator. See below.

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 witheculizumab or ravulizumab to crovalimab experienced a Type III immune complex reaction (reportedas 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. Themost common signs and symptoms that were reported were arthralgia and rash, and other symptomsreported 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 fromtreatment with eculizumab or ravulizumab to crovalimab was 1.6 weeks (range: 0.7 - 4.4 weeks), with5.1% of patients (2 of 39) experiencing a Type III immune complex reaction with a time to onset thatexceeded 4 weeks. Most cases of Type III immune complex reaction were transient with a medianduration of 1.7 weeks (range 0.4 - 34.1 weeks). The majority of patients experienced a Grade 1 or 2event (23 of 39 patients), with Grade 3 events affecting 8% (16 of 39) of crovalimab-treated patientswho switched from eculizumab or ravulizumab. Most events resolved with no change in studytreatment with crovalimab.

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

Across two randomised Phase III studies (COMMODORE 1 and COMMODORE 2) and onesingle-arm Phase III study (COMMODORE 3), ADA status was evaluable in 392 patients. Out ofthese 392 patients, 118 (30.1%) were ADA-positive. No differences in the rates of adverse reactionstypically associated with immunogenicity (such as infusion-related reactions, injection site reactions,or hypersensitivity) were observed between ADA-positive and ADA-negative patients (see section5.1).

Immunogenicity leading to loss of exposure and efficacy

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

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

Infusion and Injection-Related Reactions

Across Phase III studies, 10.2% of patients who were treated with crovalimab experienced an infusionrelated 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 aninjection-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%). Themajority 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 ofinfections, particularly infections caused by encapsulated bacteria including Streptococcuspneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae (seesection 4.4).

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

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 appearedsimilar to that observed in adult PNH patients. The adverse reactions associated with crovalimab thatwere reported in paediatric PNH patients are upper respiratory tract infection (16.7%), urinary tractinfection (16.7%), fatigue (16.7%), pyrexia (16.7%), headache (8.3%), infusion-related reaction(8.3%) and injection-related reaction (8.3%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions,and appropriate symptomatic treatment instituted.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, Complement inhibitors, ATC code: L04AJ07

Crovalimab is a recombinant humanised immunoglobulin G1 (IgG1)-based monoclonal antibody thatspecifically binds with high affinity to component 5 (C5) of the complement system, inhibiting itscleavage into C5a and C5b and thus preventing the formation of the membrane attack complex(MAC). Crovalimab causes terminal complement activity inhibition. In patients with PNH, crovalimabinhibits terminal complement-mediated intravascular haemolysis.

In clinical studies with PNH patients, a concentration-dependent inhibition of terminal complementactivity following treatment with crovalimab was observed. Terminal complement activity (CH50 asmeasured by Liposome Immunoassay [LIA]) inhibition was achieved immediately by the end of theinitial crovalimab infusion and was generally sustained through the duration of crovalimab treatment.

Similarly, mean free C5 concentrations decreased to low levels (< 0.0001 g/L) in comparison tobaseline and remained low throughout the treatment period.

Free C5 and CH50 levels were similar between paediatric and adult patients treated with crovalimab.

The safety and efficacy of crovalimab in patients with PNH were evaluated in a non-inferiority

Phase III study (COMMODORE 2, BO42162) and supported by clinical evidence from two additional

Phase III studies (COMMODORE 3, YO42311 and COMMODORE 1, BO42161).

In all Phase III studies, patients were required to be vaccinated against Neisseria meningitidis, eitherwithin 3 years prior to the start of treatment or within 7 days after starting treatment with crovalimab.

Patients vaccinated within 2 weeks prior to initiating crovalimab or after the start of study treatmentreceived appropriate prophylactic antibiotics from the time they started Piasky until at least 2 weeksafter the vaccination (see section 4.4 for warnings and precautions related to serious meningococcalinfection). Patients with a history of Neisseria meningitidis infection in the 6 months prior to screeningand up to the first study drug administration were excluded.

Patients were also excluded if they had a history of allogenic bone marrow transplantation.

Crovalimab was administered in Phase III studies in accordance with the recommended dose describedin section 4.2. Rescue doses of 340 mg of crovalimab administered intravenously were allowed basedon the investigators’ judgement if a patient experienced signs and symptoms of PNH; however, thesestudies were not designed to evaluate the impact of rescue dosing on the efficacy of crovalimab.

Eculizumab was administered per local prescribing information, or in a country without access tocommercial eculizumab (COMMODORE 2), then eculizumab 600 mg was given intravenously onceweekly for the first 4 weeks, followed by 900 mg every 2 weeks thereafter. Rescue doses ofeculizumab were not allowed on study.

The Phase III studies consisted of a primary treatment period of 24 weeks, after which patients had theoption to continue/switch to crovalimab in an extension period.

Study in complement inhibitor-naïve patients with PNH

COMMODORE 2 (Study BO42162)

COMMODORE 2 was a Phase III, randomised, open-label, active-controlled, multicentre clinicalstudy designed to evaluate the efficacy and safety of crovalimab compared to eculizumab in patientswith PNH who were not previously treated with a complement inhibitor. 204 patients (bodyweight  40 kg), were randomised 2:1 to receive either crovalimab (n = 135) or eculizumab (n = 69).

The study additionally enrolled 6 paediatric patients (aged  18 years and with body weight  40 kg)in a descriptive arm to receive crovalimab (see section 5.1). Eligible patients had high disease activityat screening, demonstrated by LDH level  2  upper limit of normal (ULN) and by the presence ofone or more PNH-related signs or symptoms in the past 3 months : fatigue, haemoglobinuria,abdominal pain, shortness of breath (dyspnoea) anaemia (haemoglobin < 10 g/dL), history of a majoradverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packedred blood cell (pRBC) transfusion due to PNH.

Randomisation was stratified by the most recent LDH value (≥ 2 to  4  ULN, or > 4  ULN) and bythe transfusion history (0, > 0 to ≤ 6, or > 6 pRBC units administered within 6 months prior torandomisation); the respective stratification categories were balanced across treatment arms.

Demographics and baseline characteristics of the randomised study population were generallybalanced between the treatment arms and are presented in Table 3.

Table 3: Demographics and baseline characteristics for COMMODORE 2 (randomisedpopulation)

Parameters Crovalimab Eculizumab(N= 135) (N= 69)

Age (years) at PNH diagnosis

Mean (SD) 35.8 (15.5) 37.4 (16.4)

Median (Range) 31.0 (11.5 - 74.7) 32.1 (11.2 - 76.8)

Age (years) at first administration of the study treatment*

Mean (SD) 40.5 (15.2) 41.9 (16.0)

Median (Range) 36.0 (18 - 76) 38.0 (17 - 78)< 18 years (n, %) 0 2 (2.9%)18 - 64 years (n, %) 122 (90.4%) 58 (84.1%)≥ 65 years (n, %) 13 (9.6%) 9 (13.0%)

Weight40 - < 100 kg (n, %) 131 (97.0%) 66 (95.7%)≥ 100 kg (n, %) 4 (3.0%) 3 (4.3%)

Sex

Male (n, %) 77 (57.0%) 35 (50.7%)

Female (n, %) 58 (43.0%) 34 (49.3%)

LDH levels at baseline (x ULN)

Median (Range) 7.0 (2.0 -16.3) 7.7 (2.0 - 20.3)

History of pRBC transfusions in the 12 months prior toscreening

Yes (n, %) 103 (77.4%) 50 (73.5%)pRBC units transfused in the 12 months prior toscreening

Median (Range) 3.8 (0 - 43.5) 3.0 (0 - 41.0)

Total PNH granulocyte clone size (%)

Median (Range) 91.4 (5.8 - 100) 93.6 (6.8 - 99.9)

Total PNH monocyte clone size (%)

Median (Range) 90.9 (42.5 - 99.9) 95.1 (41.5 - 99.9)

Total PNH erythrocytes clone size (%)

Median (Range) 25.3 (3.5 - 96.0) 44.6 (0.1 - 88.9)

Haemoglobin levels at baseline (g/L)

Median (IQR) 85.0 (77.0 - 93.0) 87.0 (81.0 - 97.0)

History of aplastic anaemia

Yes (n, %) 53 (39.3%) 26 (37.7%)

History of myelodysplastic syndrome

Yes (n, %) 6 (4.4%) 6 (8.7%)

History of Major Adverse Vascular Event (MAVE)

Yes (n, %) 21 (15.6%) 10 (14.5%)

Medicinal products at baseline**

Anticoagulants (n, %) 35 (25.9%) 17 (24.6%)

Steroids (n, %) 46 (34.1%) 25 (36.2%)

Immunosuppressive therapy (n, %) 23 (17.0%) 13 (18.8%)

PNH-related signs or symptoms within 3 months prior toscreening

Abdominal Pain 21 (15.6%) 11 (15.9%)

Anaemia 109 (80.7%) 57 (82.6%)

Dysphagia 8 (5.9%) 2 (2.9%)

Erectile Dysfunction 13 (9.6%) 4 (5.8%)

Fatigue 113 (83.7%) 63 (91.3%)

Parameters Crovalimab Eculizumab(N= 135) (N= 69)

Haemoglobinuria 79 (58.5%) 45 (65.2%)

MAVE (including Thrombosis) 9 (6.7%) 5 (7.2%)

Shortness of Breath (Dyspnoea) 29 (21.5%) 14 (20.3%)

Note: IQR = interquartile range.

* Two adolescent patients (both 17 years of age) were randomised into the eculizumab arm prior to theopening of the separate descriptive paediatric arm. Both patients switched to crovalimab in theextension period after completing the primary treatment period; one patient was still < 18 years, whilethe other patient had turned 18 years at the time of first crovalimab treatment. See below “Paediatricpopulation”

**Includes medicinal products that were started prior to initiation of study treatment, and were eitherstopped before or were ongoing at time of initiation of study treatment.

The primary objective of the study was to evaluate the efficacy of crovalimab compared witheculizumab, based on the non-inferiority (NI) assessment of the following co-primary endpoints:haemolysis control, measured by the mean proportion of patients with LDH ≤ 1.5x ULN from Week 5to Week 25; and the proportion of patients who achieved transfusion avoidance, defined as patientswho are pRBC transfusion-free, from baseline through Week 25. Secondary efficacy endpointsincluded the proportion of patients with breakthrough haemolysis, proportion of patients withstabilised haemoglobin, and change in fatigue (measured by the FACIT [Functional Assessment of

Chronic Illness Therapy]-Fatigue scale) from baseline to Week 25.

Crovalimab was non-inferior compared to eculizumab for both co-primary endpoints of haemolysiscontrol and transfusion avoidance and for the secondary endpoints of haemoglobin stabilisation andbreakthrough haemolysis (Figure 1). Figure 2 shows the proportion of patients with LDH ≤ 1.5 ×ULNfrom baseline through Week 25.

Figure 1: Co-primary and secondary endpoint results in (COMMODORE 2, primaryanalysis population)

Note: The triangles indicate the non-inferiority margins, and the circles indicate point estimates. CI =confidence interval;1 One patient randomised to crovalimab did not have post-baseline LDH and was not included in theprimary efficacy analysis.

2 For Transfusion Avoidance and Haemoglobin Stabilisation, difference is calculated as a weighteddifference of crovalimab minus eculizumab. For Breakthrough Haemolysis, difference is calculated asa weighted difference of eculizumab minus crovalimab.3 Odds ratio calculated as odds for crovalimab divided by odds for eculizumab

Figure 2: Proportion of patients with LDH  1.5  ULN from baseline through Week 25, with95% CIs (COMMODORE 2, primary analysis population)

Studies in PNH patients previously treated with complement C5 inhibitor therapy

COMMODORE 1 (Study BO42161) - randomised eculizumab switch patients

COMMODORE 1 was a Phase III, randomised, open-label, active-controlled, multicentre clinicalstudy evaluating the safety, pharmacodynamics, pharmacokinetics and exploratory efficacy ofcrovalimab in patients switching from another complement C5 inhibitor therapy. The primaryobjective of this study was to evaluate safety (see section 4.8). Eighty-nine patients were randomised1:1 to receive either crovalimab (n  45) or eculizumab (n  44). Patients were eligible to enroll intothe randomised arms if they were switching from approved doses of eculizumab and had haemolysiscontrol at screening, defined by LDH level  1.5  ULN. Patients were excluded if they had a Major

Adverse Vascular Event (MAVE) within the 6 months prior to first study drug administration.

Randomisation was stratified by patient transfusion history (whether a patient received a transfusion ofpRBCs within 12 months prior to randomisation).

Demographics and baseline characteristics of the randomised study population were balanced betweenthe treatment arms. The median LDH value at baseline was 1.01 x ULN (range: 0.6-1.7) forcrovalimab and 0.96  ULN (range: 0.7-1.9) for eculizumab. The proportion of patients with a historyof transfusions in the 12 months prior to screening was 22.7% in the crovalimab arm and 25% in theeculizumab arm, with a mean (SD) of 1.6 (3.7) and 2.3 (5.4) units of transfused pRBC in thecrovalimab and eculizumab arms respectively. The baseline median (range) PNH clone sizes for totalerythrocytes, monocytes, and granulocytes for crovalimab arm vs eculizumab arms are as follows:44.6% (2.6 - 100) vs 54.2% (1.3 - 100), 88.6% (13.8 - 100) vs 96.4% (7.6 - 99.9), and 88.1% (5.2 -100), vs 95.7% (7.9 - 99.9), respectively.

Out of 89 randomised patients, efficacy was evaluated in an exploratory fashion in 76 (n=39 forcrovalimab and n=37 for eculizumab) that were enrolled at least 24 weeks before the cut-off date forthe primary analysis. Overall, the results of the exploratory efficacy endpoints showed that patientsswitching to crovalimab from eculizumab maintained disease control. The mean proportion of patientsmaintaining haemolysis control from baseline through Week 25 was 92.9% [95% CI: 86.6, 96.4] forpatients randomised to crovalimab and 93.7% [95% CI: 87.3, 97.0] for patients randomised toeculizumab. Transfusion avoidance was observed in 79.5% [95% CI: 63.1, 90.1] of patientsrandomised to crovalimab and 78.4% [95% CI: 61.3, 89.6] of patients randomised to eculizumab.

COMMODORE 1 (Study BO42161) and COMMODORE 2 (Study BO42162) - clinically stable switchpatients

Supportive data in clinically stable eculizumab switch patients was reported from patients in

COMMODORE 1 (25 efficacy evaluable patients) and COMMODORE 2 (29 efficacy evaluablepatients) that had been treated with eculizumab for at least 24 weeks in the primary treatment periodand had LDH ≤ 1.5 × ULN at switch-to-crovalimab baseline.

Efficacy was evaluated in the patients that had at least 24 weeks of exposure to crovalimab (orotherwise discontinued prior to having reached 24 weeks of treatment). The mean proportion ofclinically stable switch patients maintaining haemolysis control from switch baseline through switch

Week 25 in COMMODORE 1 and COMMODORE 2 was 98.7% [95% CI: 96.2, 99.5] and 95.3%[95% CI: 89.5, 97.9], respectively. Transfusion avoidance was observed in 80.0% [95% CI: 58.70,92.39] and 86.2% [95% CI: 67.43, 95.49] of the clinically stable switch patients, respectively. Theseresults in clinically stable eculizumab switch patients were consistent with the results in randomisedeculizumab switch patients during the primary treatment period of COMMODORE 1.

Furthermore, in the non-randomised arm of COMMODORE 1, of the 19 clinically stable patientsswitching from ravulizumab, 95.8% [95%CI: 89.11, 98.43] maintained haemolysis control and 57.9%[95% CI: 33.97, 78.88] patients were transfusion avoidant from baseline to Week 25.

As with all therapeutic proteins, there is the potential for immune response to crovalimab.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity andspecificity, assay methodology, sample handling, timing of sample collection, concomitant medicinalproducts and underlying disease. For these reasons, comparison of incidence of antibodies tocrovalimab with the incidence of antibodies to other products may be misleading.

In the Phase III study COMMODORE 2, treatment-emergent anti-drug antibodies (ADAs) wereobserved in 35.0% (49/140) of treatment-naïve patients who received crovalimab and 38.2% (26/68)of patients who switched from treatment with another C5 inhibitor to crovalimab. The median time tothe development of first post-baseline ADAs was 16.1 weeks (range: 1.1 to 72.3 weeks), and16.6 weeks (range: 2.1 to 36.3 weeks) in the treatment-naïve patients and patients who werepreviously treated with another C5 inhibitor, respectively. Across Phase III studies, the incidence oftreatment-emergent ADAs was 35.1% (67 patients out of 191) and 25.4% (51 patients out of 201) intreatment-naive and patients who switched from treatment with another C5 inhibitor to crovalimab,respectively.

Across Phase III studies, median concentration time-courses in ADA-positive patients were slightlylower in comparison to ADA-negative patients. Despite this effect, concentrations remained above100 µg/mL (threshold for complete terminal complement inhibition) in more than 80% of

ADA-positive patients. ADA presence was not associated with clinically meaningful impact onpharmacokinetics, pharmacodynamics, and efficacy in most of the patients. However, out of392 patients evaluated for ADA status, partial or complete loss of exposure associated with ADAonset was observed in 23 patients (5.9%); among them, 17 (4.3%) ADA positive patients had a loss ofpharmacological activity (based on CH50 or free C5) coinciding with a loss of exposure, and loss ofefficacy manifested as a sustained loss of haemolysis control in 7 patients (1.8%). There was noevidence for a clinical impact of ADA status on the safety profile of Piasky (see sections 4.4 and 4.8).

Ten paediatric patients (with body weight ≥ 40 kg) treated with crovalimab in COMMODORE 2(n = 7; 13 - 17 years old) and COMMODORE 3 (n = 3; 15 - 17 years old) were evaluable forefficacy.

Nine patients were treatment- naive and 1 patient switched from eculizumab to crovalimab in theextension period. All paediatric patients received the same dosing as adult patients based on bodyweight. All 9 treatment-naive patients achieved haemolysis control (defined as LDH ≤ 1.5 x ULN) by

Week 4 and this was maintained in 7 patients at each visit from baseline to Week 25; the patientswitching from eculizumab to crovalimab maintained haemolysis control through 24 weeks oftreatment in the extension period. Seven out of the 10 paediatric patients achieved transfusionavoidance and haemoglobin stabilisation, and no patients had a breakthrough haemolysis event duringthe 24-week treatment period.

Overall, the treatment effect of crovalimab in paediatric PNH patients was similar to that observed inadult PNH patients.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Piasky in one or more subsets of the paediatric population with PNH (see section 4.2 for informationon paediatric use).

The pharmacokinetics of crovalimab have been characterised both in healthy volunteers and in patientswith PNH. The pharmacokinetics were characterised using non-linear mixed effects pharmacokineticanalysis methods, based on a pooled database composed of 9 healthy volunteers and 210 and211 treatment-naïve patients and patients who switched from previous treatment with another C5inhibitor to crovalimab, respectively.

The concentration-time course of crovalimab is best described using a two-compartment open modelwith first-order elimination and a first order subcutaneous absorption constant. To describe thetransient increase in clearance due to the formation of immune complexes observed in patients whoswitched from treatment with another C5 inhibitor to crovalimab, an additional time-varying clearanceparameter, which decreases exponentially with time, was added. At steady state, exposure is expectedto be similar between treatment naïve and switch patients.

The absorption rate constant was estimated to be 0.126 day-1 [CV%: 38.3]. Following subcutaneousadministration, the bioavailability was estimated at 83.0% [CV%: 116].

The central volume of distribution was estimated to be 3.23 L [CV%: 22.4] and the peripheral volumeof distribution was estimated as 2.32 L [CV%: 70.6].

The small volume of distribution indicates that crovalimab is likely to be distributed mainly in serumand/or in vascular rich tissues.

The metabolism of crovalimab has not been directly studied. IgG antibodies are mainly catabolised bylysosomal proteolysis and then eliminated from or reused by the body.

The clearance was estimated to be 0.0791 L/day [CV%: 20.6]. The terminal half-life of crovalimabwas estimated as 53.1 days [CV%: 39.9], which is longer compared to other humanised IgGantibodies. This long half-life is consistent with the recycling properties of crovalimab.

No pharmacokinetic studies with crovalimab have been conducted in special populations. Bodyweightwas shown to be a significant covariate, with clearances and volumes of distribution increasing andcrovalimab exposure decreasing as bodyweight increases. Therefore, posology of crovalimab is basedon the bodyweight of the patient (see section 4.2).

After inclusion of bodyweight in the model, the population pharmacokinetics analyses in patients with

PNH showed that age (13 - 85 years) and gender did not meaningfully influence the pharmacokineticsof crovalimab. No further dose adjustment is required.

Race/ethnicity was also shown not to have an impact on the pharmacokinetics of crovalimab; however,data are limited in Black patients and therefore not considered conclusive in this population.

No dedicated studies have been conducted to investigate the pharmacokinetics of crovalimab inpatients aged ≥ 65 years, however 46 (10.9%) elderly PNH patients were enrolled in clinical studies,including 35 patients aged 65-74 years, 10 patients aged 75-84 years, and 1 patient aged ≥ 85 years.

The data obtained in PNH clinical studies indicates that exposure in patients aged ≥ 65 years iscomparable to that of younger patients in other age groups, however, due to the limited data in patients≥ 85 years, the pharmacokinetics of crovalimab in those subjects is unknown.

No dedicated studies have been conducted to investigate the pharmacokinetics of crovalimab inpatients with renal impairment, however the data obtained in PNH clinical studies (62 [14.7%] patientswith mild renal impairment, 38 [9%] patients with moderate renal impairment, and 4 [1%] patientswith severe renal impairment) indicate that exposure in patients with mild, moderate, or severe renalimpairment is comparable to that of patients without renal impairment. However, limited data wereobtained for patients with severe renal impairment in PNH clinical studies.

No dedicated studies have been conducted in patients with hepatic impairment, however data obtainedin PNH clinical studies indicate that exposure in patients with mild hepatic impairment (46 [11%] asgraded based on alanine aminotransferase levels) are comparable to that of patients without hepaticimpairment. Limited pharmacokinetic data were available in PNH patients with moderate (0 [0%]) tosevere (1[0.23%]) hepatic impairment, therefore the impact of moderate or severe hepatic impairmenton the pharmacokinetics of crovalimab is unknown and no dose recommendation can be provided (seesection 4.2).

Data obtained in 12 paediatric patients (13-17 years old) in the PNH clinical studies indicates thatexposure in paediatric patients 12 years of age or older with a weight of 40 kg and above was found tobe comparable to that of adult patients.

Non-clinical data revealed no special hazard related to crovalimab treatment for humans based onconventional studies of, repeated dose toxicity (including safety pharmacology endpoints), and toxicityto reproduction and development.

No dedicated studies have been performed to establish the genotoxic potential of crovalimab.

Monoclonal antibodies are not expected to interact directly with DNA or other chromosomal material.

No studies have been performed to establish the carcinogenic potential of crovalimab. Assessment ofavailable evidence related to pharmacodynamic effects and animal toxicology data do not indicatecarcinogenic potential of crovalimab.

Repeated administration of crovalimab to pregnant cynomolgus monkeys during the gestation periodinduced no maternal toxicity and did not affect pregnancy outcome. No effects on the viability, growthand development of the infants were observed during the 6-month postnatal period.

No effects on female or male reproductive organs were observed in cynomolgus monkeys followingrepeated administration of crovalimab for up to 6 months. Separate animal fertility studies have notbeen conducted with crovalimab.

6 PHARMACEUTICAL PARTICULARS

Histidine

Aspartic acid

Arginine hydrochloride

Poloxamer 188

Water for injections

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

Unopened vial3 years.

Prior to administration, unopened vials of Piasky may be stored out of the refrigerator at roomtemperature if needed and then returned to refrigeration. For temperature excursions outside 2 °C -8 °C, the unopened vial can be kept at room temperature (up to 30 °C) in its outer carton for acumulative period of no longer than 7 days. Discard if stored out of the refrigerator at roomtemperature for longer than 7 days.

Diluted solution for intravenous infusion

From a microbiological point of view, unless the method of dilution precludes the risk of microbialcontamination, the diluted solution for intravenous infusion should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user.

If the diluted solution is prepared under controlled and validated aseptic conditions, the medicinalproduct can be stored in the refrigerator at 2 °C to 8 °C and at room temperature (up to 30 ℃).

Detailed storage conditions of the prepared solution for infusion depending on the type of infusionbags used are provided in Table 4.

Table 4: Storage conditions for the solution for infusion prepared using aseptic conditions

Infusion bags Storage conditions

PO/PE/PP Up to 30 days at 2 °C to 8 °C protected from light, and up to 24 hours at roomtemperature (up to 30 °C) under ambient light conditions.

Protect from direct sunlight.

PVC Up to 12 hours at 2 °C to 8 °C protected from light, and up to 12 hours at roomtemperature (up to 30 °C) under ambient light conditions.

Protect from direct sunlight.

polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC)

Undiluted solution for subcutaneous injection

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2-8°C, unless preparation has taken place in controlledand validated aseptic conditions.

If Piasky is transferred from the vial to the syringe under controlled and validated aseptic conditions,the medicinal product in the capped syringe can be stored in the refrigerator at 2 °C to 8 °C for up to14 days protected from light and at room temperature (up to 30 °C) for up to 24 hours at ambient light.

Piasky solution must be protected from direct sunlight.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the diluted solution for intravenous infusion and the undiluted solution forsubcutaneous injection, see section 6.3.

Solution for injection/infusion in a 2 mL single-use vial (Type I glass) with a stopper (rubber) and aseal (aluminium).

Each carton contains one vial.

Piasky vial is for single use only.

Piasky is used diluted for intravenous infusion or undiluted for subcutaneous injection.

Piasky should be inspected visually to ensure there is no particulate matter or discolouration prior toadministration. Piasky is clear to strongly opalescent, and almost colourless to brownish-yellowsolution. Piasky should be discarded if the medicinal product looks cloudy, discoloured or hasparticles in it.

Piasky must be prepared by a healthcare professional under aseptic technique. Piasky solution must bediluted in sodium chloride 9 mg/mL (0.9%) solution for infusion prior to administration. A 0.2 μmin-line filter must be used with the infusion set during administration.

A dedicated infusion line must be used during intravenous administration.

Dilution1. Withdraw the required volume of Piasky from the vial (see Table 5) using a sterilesyringe and dilute into the infusion bag. Multiple vials need to be used to meet therequired volume of Piasky to be added to the infusion bag. Discard any unused portionleft in the vial.

Dilution of Piasky in infusion bags containing sodium chloride 9 mg/mL (0.9%)solution for infusion must be in the range of 4-15 mg/mL (final concentration afterdilution).

Intravenous infusion bags of a volume of 100 mL or 250 mL can be used.

Table 5: Dose example volume determination

Dose Concentration in Volume of Piasky in 0.9%bag sodium chloride Size of infusion bags(mg) (mg/mL) solution* (mL) (mL)1 000 4 5.9 2501 500 6 8.8 2501 000 10 5.9 1001 500 15 8.8 100

* Each 340 mg vial contains a nominal fill volume of 2.0 mL2. Gently mix the infusion bag by slowly inverting the bag. Do not shake.3. Inspect the infusion bag for particles and discard if present.4. Flushing of infusion line is required in order to ensure complete administration of theentire dose.

No incompatibilities have been observed between Piasky and intravenous infusion bags with product-contacting materials made of polyvinyl chloride (PVC), or polyolefins (PO) such as polyethylene (PE)and polypropylene (PP). In addition, no incompatibilities have been observed with infusion sets orinfusion aids with product-contacting materials made of PVC, PE, polyurethane (PU), polybutadiene(PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), or polytetrafluorethylene (PTFE).

For storage conditions of the infusion bags, see section 6.3.

Piasky should be used undiluted and should be prepared using aseptic technique. A syringe, a transferneedle and an injection needle are needed to withdraw Piasky solution from the vial and inject itsubcutaneously.

Each injection is of a volume of 2 mL, corresponding to 340 mg. A 2 mL-size or 3 mL-size syringeshould be used for each injection. A dose of 680 mg is achieved by performing two consecutivesubcutaneous injections of 340 mg. A dose of 1 020 mg is achieved by performing three consecutivesubcutaneous injections of 340 mg.

2 mL or 3 mL syringe

Criteria: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip (in case not locallyavailable, a syringe with Luer Slip tip can be used), sterile, single-use, latex-free and non-pyrogenic.

Transfer needle

Criteria: Stainless steel, sterile, preferably gauge 18 G with single bevel at approximately 45 degreesto reduce risk of needle stick injury, or gauge 21 G standard needle as an alternative, single use, latexfree and non-pyrogenic. A transfer needle without filter is recommended.

Injection needle

Criteria: Hypodermic needle, stainless steel, sterile, gauge 25 G, 26 G or 27 G, length from 9 to13 mm, single use, latex free and non-pyrogenic, preferably including safety needle shield.

Please see section 4.2 for additional information on administration.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

The following points should be strictly adhered to regarding the use and disposal of syringes and othermedicinal sharps:

- Needles and syringes should never be reused or shared with others.

- Place all used needles and syringes into a sharp container (puncture-proof disposable container).

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/24/1848/001

Date of first authorisation: 22 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu