Contents of the package leaflet for the medicine EPYSQLI 300mg concentrate for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT

Epysqli 300 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of 30 ml contains 300 mg of eculizumab (10 mg/ml).

After dilution, the final concentration of the solution to be infused is 5 mg/ml.

Eculizumab is a humanised monoclonal (IgG2/4κ) antibody produced in Chinese hamster ovary (CHO)cell line by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless, pH 7.0 solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Epysqli is indicated in adults and children for the treatment of:

- Paroxysmal nocturnal haemoglobinuria (PNH).

Evidence of clinical benefit is demonstrated in patients with haemolysis with clinicalsymptom(s) indicative of high disease activity, regardless of transfusion history (see section5.1).

- Atypical haemolytic uremic syndrome (aHUS) (see section 5.1).

4.2 Posology and method of administration

Epysqli must be administered by a healthcare professional and under the supervision of a physicianexperienced in the management of patients with haematological or renal disorders.

Home infusion may be considered for patients who have tolerated infusions well in the clinic. Thedecision of a patient to receive home infusions should be made after evaluation and recommendationfrom the treating physician. Home infusions should be performed by a qualified healthcareprofessional.

Posology

Paroxysmal Nocturnal Haemoglobinuria (PNH) in adults

The PNH dosing regimen for adult patients (≥ 18 years of age) consists of a 4-week initial phasefollowed by a maintenance phase:

* Initial phase: 600 mg of Epysqli administered via a 25 - 45 minute (35 minutes ± 10 minutes)intravenous infusion every week for the first 4 weeks.

* Maintenance phase: 900 mg of Epysqli administered via a 25 - 45 minute (35 minutes ± 10minutes) intravenous infusion for the fifth week, followed by 900 mg of Epysqli administeredvia a 25 - 45 minute (35 minutes ± 10 minutes) intravenous infusion every 14 ± 2 days (seesection 5.1).

atypical Haemolytic Uremic Syndrome (aHUS) in adults

The aHUS dosing regimen for adult patients (≥18 years of age) consists of a 4 week initial phasefollowed by a maintenance phase:

* Initial phase: 900 mg of Epysqli administered via a 25 - 45 minute (35 minutes ± 10 minutes)intravenous infusion every week for the first 4 weeks.

* Maintenance phase: 1,200 mg of Epysqli administered via a 25 - 45 minute (35 minutes ± 10minutes) intravenous infusion for the fifth week, followed by 1,200 mg of Epysqli administeredvia a 25 - 45 minute (35 minutes ± 10 minutes) intravenous infusion every 14 ± 2 days (seesection 5.1).

Paediatric patients in PNH or aHUS

Paediatric PNH or aHUS patients with body weight ≥ 40 kg are treated with the adult dosingrecommendations.

In paediatric PNH and aHUS patients with body weight below 40 kg, Epysqli dosing regimen consistsof:

Patient body Initial phase Maintenance phaseweight30 to < 40 kg 600 mg weekly for the 900 mg at week 3; then 900 mg every 2 weeksfirst 2 weeks20 to < 30 kg 600 mg weekly for the 600 mg at week 3; then 600 mg every 2 weeksfirst 2 weeks10 to < 20 kg 600 mg single dose at 300 mg at week 2; then 300 mg every 2 weeksweek 15 to < 10 kg 300 mg single dose at 300 mg at week 2; then 300 mg every 3 weeksweek 1

Epysqli has not been studied in patients with PNH who weigh less than 40kg. The posology of Epysqlito be used in paediatric patients with PNH patients weighing less than 40 kg is identical to the weight-based dose recommendation provided for paediatric patients with aHUS. Based on thepharmacokinetic (PK)/pharmacodynamic (PD) data available in patients with aHUS and PNH treatedwith eculizumab, this body-weight based dose regimen for paediatric patients is expected to result inan efficacy and safety profile similar to that in adults.

Supplemental dosing of Epysqli is required in the setting of concomitant plasmapheresis (PP), plasmaexchange (PE), or fresh frozen plasma infusion (PI) as described below:

Type of plasma Most recent Epysqli Supplemental Epysqli Timing of supplementalintervention dose dose with each PP/PE/PI Epysqli dose

Intervention

Plasmapheresis or 300 mg 300 mg per each Within 60 minutes afterplasma exchange plasmapheresis or plasma each plasmapheresis orexchange session plasma exchange≥ 600 mg 600 mg per eachplasmapheresis or plasmaexchange session

Fresh frozen ≥ 300 mg 300 mg per infusion of 60 minutes prior to eachplasma infusion fresh frozen plasma infusion of fresh frozenplasma

Abbreviations: PP/PE/PI = plasmapheresis/plasma exchange/plasma infusion

Supplemental dose of Epysqli is required in the setting of concomitant intravenous immunoglobulin(IVIg) treatment as described below (see also Section 4.5):

Most recent Epysqli Supplemental Epysqli dose Timing of supplemental Epysqlidose dose≥ 900 mg 600 mg per IVIg cycle As soon as possible after IVIg≤ 600 mg 300 mg per IVIg cycle cycle

Abbreviation: IVIg = intravenous immunoglobulin

Treatment monitoringaHUS patients should be monitored for signs and symptoms of thrombotic microangiopathy (TMA)(see section 4.4 aHUS laboratory monitoring).

Epysqli treatment is recommended to continue for the patient’s lifetime, unless the discontinuation of

Epysqli is clinically indicated (see section 4.4).

Special populations
Elderly

Epysqli may be administered to patients aged 65 years and over. There is no evidence to suggest thatany special precautions are needed when older people are treated - although experience witheculizumab in this patient population is still limited.

Renal impairment

No dose adjustment is required for patients with renal impairment (see section 5.1).

Hepatic impairment

The safety and efficacy of eculizumab have not been studied in patients with hepatic impairment.

Method of administration

Epysqli should not be administered as an intravenous push or bolus injection. Epysqli should only beadministered via intravenous infusion as described below.

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

The diluted solution of Epysqli should be administered by intravenous infusion over 25 - 45 minutes(35 minutes ± 10 minutes) in adults and 1-4 hours in paediatric patients under 18 years of age viagravity feed, a syringe-type pump, or an infusion pump.

Patients should be monitored for one hour following infusion. If an adverse event occurs during theadministration of Epysqli, the infusion may be slowed or stopped at the discretion of the physician. Ifthe infusion is slowed, the total infusion time may not exceed two hours in adults and four hours inpaediatric patients under 18 years of age.

There is limited safety data supporting home-based infusions, additional precautions in the homesetting such as availability of emergency treatment of infusion reactions or anaphylaxis arerecommended.

Infusion reactions are described in sections 4.4 and 4.8 on the SmPC.

4.3 Contraindications

Hypersensitivity to the active substance, CHO cell products or to any of the excipients listed in section6.1.

Eculizumab therapy must not be initiated in patients (see section 4.4):

- with unresolved Neisseria meningitidis infection

- who are not currently vaccinated against Neisseria meningitidis unless they receiveprophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

4.4 Special warnings and precautions for use

Traceability

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

Eculizumab is not expected to affect the aplastic component of anaemia in patients with PNH.

Meningococcal Infection

Due to its mechanism of action, the use of eculizumab increases the patient’s susceptibility tomeningococcal infection (Neisseria meningitidis). Meningococcal disease due to any serogroup mayoccur. To reduce the risk of infection, all patients must be vaccinated at least 2 weeks prior toreceiving eculizumab unless the risk of delaying eculizumab therapy outweighs the risks of developinga meningococcal infection. Patients who initiate eculizumab treatment less than 2 weeks afterreceiving a tetravalent meningococcal vaccine must receive treatment with appropriate prophylacticantibiotics until 2 weeks after vaccination. Vaccines against all available serogroups including A, C,

Y, W 135, and B, are recommended in preventing the commonly pathogenic meningococcalserogroups. Patients must be vaccinated and revaccinated according to current national guidelines forvaccination use.

Vaccination may further activate complement. As a result, patients with complement-mediateddiseases, including PNH and aHUS, may experience increased signs and symptoms of their underlyingdisease, such as haemolysis (PNH) or TMA (aHUS). Therefore, patients should be closely monitoredfor disease symptoms after recommended vaccination.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be givento official guidance on the appropriate use of antibacterial agents. Cases of serious or fatalmeningococcal infections have been reported in eculizumab-treated patients. Sepsis is a commonpresentation of meningococcal infections in patients treated with eculizumab (see section 4.8). Allpatients should be monitored for early signs of meningococcal infection, evaluated immediately ifinfection is suspected, and treated with appropriate antibiotics if necessary. Patients should beinformed of these signs and symptoms and steps taken to seek medical care immediately. Physiciansmust discuss the benefits and risks of eculizumab therapy with patients and provide them with a

Patient guide and a patient card (see Package Leaflet for a description).

Other Systemic Infections

Due to its mechanism of action, eculizumab therapy should be administered with caution to patientswith active systemic infections. Patients may have increased susceptibility to infections, especiallywith Neisseria and encapsulated bacteria. Serious infections with Neisseria species (other than

Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

Patients should be provided with information from the Package Leaflet to increase their awareness ofpotential serious infections and the signs and symptoms of them. Physicians should advise patientsabout gonorrhoea prevention.

Infusion Reactions

Administration of eculizumab may result in infusion reactions or immunogenicity that could causeallergic or hypersensitivity reactions (including anaphylaxis). In clinical trials of the referencemedicinal product, 1 (0.9%) refractory generalised myasthenia gravis (gMG) patient experienced aninfusion reaction which required discontinuation of eculizumab. No PNH or aHUS patientsexperienced an infusion reaction which required discontinuation of eculizumab. Eculizumabadministration should be interrupted in all patients experiencing severe infusion reactions andappropriate medical therapy administered.

Immunogenicity

Anti-eculizumab antibodies may develop during eculizumab treatment. No apparent correlation ofantibody development with clinical response or adverse events has been observed.

Immunisation

Prior to initiating eculizumab therapy, it is recommended that patients initiate immunisationsaccording to current immunisation guidelines. Additionally, all patients must be vaccinated againstmeningococcal infections at least 2 weeks prior to receiving eculizumab unless the risk of delayingeculizumab therapy outweighs the risks of developing a meningococcal infection. Patients who initiateeculizumab treatment less than 2 weeks after receiving a tetravalent meningococcal vaccine mustreceive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccinesagainst all available serogroups including A, C, Y, W 135 and B are recommended in preventing thecommonly pathogenic meningococcal serogroups. Patients must be vaccinated and revaccinatedaccording to current national guidelines for vaccination use (see Meningococcal Infection).

Patients less than 18 years of age must be vaccinated against Haemophilus influenzae andpneumococcal infections, and strictly need to adhere to the national vaccination recommendations foreach age group.

Vaccination may further activate complement. As a result, patients with complement-mediateddiseases, including PNH and aHUS may experience increased signs and symptoms of their underlyingdisease, such as haemolysis (PNH) or TMA (aHUS). Therefore, patients should be closely monitoredfor disease symptoms after recommended vaccination.

Anticoagulant therapy

Treatment with eculizumab should not alter anticoagulant management.

PNH Laboratory Monitoring

PNH patients should be monitored for signs and symptoms of intravascular haemolysis, includingserum lactate dehydrogenase (LDH) levels. PNH patients receiving eculizumab therapy should besimilarly monitored for intravascular haemolysis by measuring LDH levels, and may require doseadjustment within the recommended 14±2 day dosing schedule during the maintenance phase (up toevery 12 days).

aHUS Laboratory MonitoringaHUS patients receiving eculizumab therapy should be monitored for thrombotic microangiopathy bymeasuring platelet counts, serum LDH and serum creatinine, and may require dose adjustment withinthe recommended 14±2 day dosing schedule during the maintenance phase (up to every 12 days).

Treatment Discontinuation for PNH

If patients discontinue treatment with eculizumab they should be closely monitored for signs andsymptoms of serious intravascular haemolysis. Serious haemolysis is identified by serum LDH levelsgreater than the pre-treatment level, along with any of the following: greater than 25 % absolutedecrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; ahaemoglobin level of < 5 g/dL or a decrease of > 4 g/dL in one week or less; angina; change in mentalstatus; a 50 % increase in serum creatinine level; or thrombosis. Monitor any patient who discontinueseculizumab for at least 8 weeks to detect serious haemolysis and other reactions.

If serious haemolysis occurs after eculizumab discontinuation, consider the followingprocedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCsare > 50 % of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution ofeculizumab. In PNH clinical trials, 16 patients discontinued the eculizumab treatment regimen.

Serious haemolysis was not observed.

Treatment Discontinuation for aHUS

Thrombotic microangiopathy (TMA) complications have been observed as early as 4 weeks and up to127 weeks following discontinuation of eculizumab treatment in some patients. Discontinuation oftreatment should only be considered if medically justified.

In aHUS clinical studies, 61 patients (21 paediatric patients) discontinued eculizumab treatment with amedian follow-up period of 24 weeks. Fifteen severe thrombotic microangiopathy (TMA)complications in 12 patients were observed following treatment discontinuation, and 2 severe TMAcomplications occurred in an additional 2 patients that received a reduced dosing regimen ofeculizumab outside of the approved dosing regimen (see section 4.2). Severe TMA complicationsoccurred in patients regardless of whether they had an identified genetic mutation, high riskpolymorphism or auto-antibody. Additional serious medical complications occurred in these patientsincluding severe worsening of kidney function, disease-related hospitalization and progression to endstage renal disease requiring dialysis. Despite eculizumab re-initiation following discontinuation,progression to end stage renal disease occurred in one patient.

If aHUS patients discontinue treatment with eculizumab, they should be monitored closely for signsand symptoms of severe thrombotic microangiopathy complications. Monitoring may be insufficientto predict or prevent severe thrombotic microangiopathy complications in patients with aHUS afterdiscontinuation of eculizumab.

Severe thrombotic microangiopathy complications post discontinuation can be identified by (i) anytwo, or repeated measurement of any one, of the following: a decrease in platelet count of 25% ormore as compared to either baseline or to peak platelet count during eculizumab treatment; an increasein serum creatinine of 25% or more as compared to baseline or to nadir during eculizumab treatment;or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during eculizumabtreatment; or (ii) any one of the following: a change in mental status or seizures; angina or dyspnoea;or thrombosis.

If severe thrombotic microangiopathy complications occur after eculizumab discontinuation, considerreinstitution of eculizumab treatment, supportive care with PE/PI, or appropriate organ-specificsupportive measures including renal support with dialysis, respiratory support with mechanicalventilation or anticoagulation.

Educational materials

All physicians who intend to prescribe eculizumab must ensure they are familiar with the guide for

Healthcare Professionals to prescribing. Physicians must discuss the benefits and risks of eculizumabtherapy with patients and provide them with a Patient guide and a Patient card.

Patients should be instructed that if they develop fever, headache accompanied with fever and/or stiffneck or sensitivity to light, they should immediately seek medical care as these signs may beindicative of meningococcal infection.

Excipients with known effect
Sodium

Once diluted with sodium chloride 9 mg/mL (0.9 %) solution for injection, this medicinal productcontains 0.47 g sodium per 240 mL at the maximal dose, equivalent to 23.4 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Once diluted with sodium chloride 4.5 mg/mL (0.45 %) solution for injection, this medicinal productcontains 0.26 g sodium per 240 mL at the maximal dose, equivalent to 12.8 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Polysorbate 80

This medicinal product contains 6.6 mg of polysorbate 80 in each vial (30mL vial) which is equivalentto 0.66 mg/kg or less at the maximum dose for adult patients and paediatric patients with body weightmore than 10 kg and is equivalent to 1.32 mg/kg or less at the maximum dose for paediatric patientswith body weight 5 to <10 kg. Polysorbates may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Based on the potential inhibitory effect of eculizumab oncomplement-dependent cytotoxicity of rituximab, eculizumab may reduce the expectedpharmacodynamic effects of rituximab.

Plasma exchange (PE), plasmapheresis (PP), fresh frozen plasma infusion (PI) and intravenousimmunoglobulin (IVIg) have been shown to reduce eculizumab serum levels. A supplemental dose ofeculizumab is required in these settings. See Section 4.2 for guidance in case of concomitant PE, PP,

PI, or IVIg treatment.

Concomitant use of eculizumab with intravenous immunoglobulin (IVIg) may reduce effectiveness ofeculizumab. Closely monitor for reduced effectiveness of eculizumab.

Concomitant use of eculizumab with neonatal Fc receptor (FcRn) blockers may lower systemicexposures and reduce effectiveness of eculizumab. Closely monitor for reduced effectiveness ofeculizumab.

4.6 Fertility, pregnancy and lactation

The use of adequate contraception to prevent pregnancy and for at least 5 months after the last dose oftreatment with eculizumab should be considered for women of childbearing potential.

Pregnancy

There are no well-controlled studies in pregnant women treated with eculizumab. Data on a limitednumber of pregnancies exposed to eculizumab (less than 300 pregnancy outcomes) indicate there is noincreased risk of foetal malformation or foetal-neonatal toxicity. However, due to the lack of well-controlled studies, uncertainties remain. Therefore, an individual risk benefit analysis is recommendedbefore starting and during treatment with eculizumab in pregnant women. Should such a treatment beconsidered necessary during pregnancy, a close maternal and foetal monitoring according to localguidelines is recommended.

Animal reproduction studies have not been conducted with eculizumab (see section 5.3).

Human IgG are known to cross the human placental barrier, and thus eculizumab may potentiallycause terminal complement inhibition in the foetal circulation. Therefore, eculizumab should be givento a pregnant woman only if clearly needed.

Breast-feeding

No effects on the breastfed newborn/infant are anticipated as limited data available suggest thateculizumab is not excreted in human breast milk. However, due to the limitations of the available data,the developmental and health benefits of breastfeeding should be considered along with the mother’sclinical need for eculizumab and any potential adverse events on the breastfed child from eculizumabor from the underlying maternal condition.

Fertility

No specific study of eculizumab on fertility has been conducted.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Supportive safety data were obtained from 33 completed clinical trials that included 1,555 patientsexposed to eculizumab in complement-mediated disease populations, including PNH, aHUS, gMG and

Neuromyelitis Optica Spectrum Disorder (NMOSD). The most common adverse reaction washeadache, (occurred mostly in the initial phase of dosing), and the most serious adverse reaction wasmeningococcal infection.

Tabulated list of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in eculizumab completedclinical trials, including PNH, aHUS, refractory gMG and NMOSD studies. Adverse reactionsreported at a 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) or not known (cannot be estimated from the available data) frequencywith eculizumab, are listed by system organ class and preferred term. Within each frequency grouping,adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions reported in eculizumab clinical trials, including patients with PNH, aHUS,refractory gMG and NMOSD as well as from post marketing experience

MedDRA system Very Common Uncommon Rare Not knownorgan class common (≥1/100 to (≥1/1 000 to <1/100) (≥1/10000 to (cannot be(≥1/10) <1/10) <1/1000) estimatedfrom theavailabledata)

Infection Pneumonia, Upper Meningococcal Aspergillusand respiratory tract infectionb, Sepsis, infectionc, Arthritisinfestations infection, Septic shock, bacterialc,

Bronchitis, Peritonitis, Lower Genitourinary tract

Nasopharyngitis, respiratory tract gonococcal

Urinary tract infection, Fungal infection,infection, Oral infection, Viral Haemophilus

Herpes infection, Abscessa, infection,

Cellulitis, Influenza, Impetigo

Gastrointestinalinfection, Cystitis,

Infection, Sinusitis,

Gingivitis

Neoplasms benign, Malignantmalignant and melanoma,unspecified Myelodysplastic(including cysts syndrome

MedDRA system Very Common Uncommon Rare Not knownorgan class common (≥1/100 to (≥1/1 000 to <1/100) (≥1/10000 to (cannot be(≥1/10) <1/10) <1/1000) estimatedfrom theavailabledata)and polyps)

Blood and Leukopenia, Thrombocytopenia, Haemolysis*,lymphatic system Anaemia Lymphopenia Abnormal clottingdisorders factor, Red bloodcell agglutination,

Coagulopathy

Immune system Anaphylactic reaction,disorders Hypersensitivity

Endocrine disorders Grave’s disease

Metabolism and Decreased appetitenutrition disorders

Psychiatric Insomnia Depression, Abnormal dreamsdisorders Anxiety, Moodswings, Sleepdisorder

Nervous system Headache Dizziness Paraesthesia, Tremor,disorders Dysgeusia, Syncope

Eye disorders Vision blurred Conjunctivalirritation

Ear and labyrinth Tinnitus, Vertigodisorders

Cardiac disorders Palpitation

Vascular disorders Hypertension Accelerated Haematomahypertension,

Hypotension, Hotflush, Veindisorder

Respiratory, Cough, Dyspnoea, Epistaxis,thoracic Oropharyngeal pain Throat irritation, Nasaland congestion,mediastinal Rhinorrhoeadisorders

Gastrointestinal Diarrhoea, Constipation, Gastroesophagealdisorders Vomiting, Nausea, Dyspepsia, reflux disease,

Abdominal pain Abdominal distension Gingival pain

Hepatobiliary Alanine Jaundice Liverdisorders aminotransferase injurydincreased, Aspartateaminotransferaseincreased, Gamma-glutamyltransferaseincreased

Skin and Rash, Pruritus, Urticaria, Skinsubcutaneous tissue Alopecia Erythema, depigmentationdisorders Petechiae,

Hyperhidrosis, Dryskin, Dermatitis

Musculoskeletal Arthralgia, Muscle spasms, Trismus, Jointand connective Myalgia, Pain Bone pain, Back swellingtissue disorders in extremity pain, Neck pain

Renal and urinary Renal impairment,disorders Dysuria,

Haematuria

Reproductive Spontaneous penile Menstrual disorder

MedDRA system Very Common Uncommon Rare Not knownorgan class common (≥1/100 to (≥1/1 000 to <1/100) (≥1/10000 to (cannot be(≥1/10) <1/10) <1/1000) estimatedfrom theavailabledata)system and breast erectiondisorders

General disorders Pyrexia, Fatigue, Edema, Chest Extravasation,and administration Influenza-like discomfort, Infusion sitesite conditions illness Asthenia, Chest paraesthesia,pain, Infusion site Feeling hotpain, Chills

Investigations Haematocrit Coombs testdecreased, positivec

Haemoglobindecreased

Injury, poisoning Infusionand procedural relatedcomplication reaction

Included Studies: Asthma (C07-002), aHUS(C08-002, C08-003, C10-003, C10-004), Dermatomyositis (C99-006), refractory gMG (C08-001, ECU-MG-301, ECU-MG-302, ECU-MG-303), Neuromyelitis Optica Spectrum

Disorder (ECU-NMO-301, ECU-NMO-302), IMG (C99-004, E99-004), PNH (C02-001, C04-001, C04-002,

C06-002, C07-001, E02-001, E05-001, E07-001, M07-005, X03-001, X03-001A), Psoriasis (C99-007), RA(C01-004, C97-001, C99-001, E01-004, E99-001), STEC-HUS (C11-001), SLE (C97-002). MedDRA version26.1.

*See paragraph Description of selected adverse reactions.a Abscess includes the following group of PTs: Abscess limb, Colonic abscess, Renal abscess, Subcutaneousabscess, Tooth abscess, Liver abscess, Perirectal abscess, Rectal abscess.b Meningococcal infection includes the following group of PTs: Meningococcal infection, Meningococcal sepsis,

Meningitis meningococcal.c ADRs identified in post marketing reportsd Frequency cannot be estimated from the available postmarketing data.

Description of selected adverse reactions

In all clinical trials, the most serious adverse reaction was meningococcal sepsis which is a commonpresentation of meningococcal infections in patients treated with eculizumab (see section 4.4).

Other cases of Neisseria species have been reported including sepsis with Neisseria gonorrhoeae,

Neisseria sicca/subflava, Neisseria spp unspecified.

Antibodies to eculizumab were detected in patients. As with all proteins there is a potential forimmunogenicity.

Cases of haemolysis have been reported in the setting of missed or delayed eculizumab dose in PNHclinical trials (see also section 4.4).

Cases of thrombotic microangiopathy complication have been reported in the setting of missed ordelayed eculizumab dose in aHUS clinical trials.

Paediatric population

In children and adolescent PNH patients (aged 11 years to less than 18 years) included in thepaediatric PNH Study M07-005, the safety profile appeared similar to that observed in adult patients.

The most common adverse reaction reported in paediatric patients was headache.

In paediatric aHUS patients (aged 2 months to less than 18 years) included in the aHUS studies C08-002, C08-003, C09-001r and C10-003, the safety profile appeared similar to that observed in adultaHUS patients. The safety profiles in the different paediatric subsets of age appear similar.

Other special populations
Elderly

No overall differences in safety were reported between elderly (≥ 65 years) and younger refractorygMG patients (< 65 years) in eculizumab study.

Patients with other diseases

Safety Data from Other Clinical trials

Supportive safety data were obtained in 12 completed clinical trials that included 934 patients exposedto eculizumab in other disease populations other than PNH, aHUS, refractory gMG or NMOSD. Therewas an un-vaccinated patient diagnosed with idiopathic membranous glomerulonephropathy whoexperienced meningococcal meningitis. Adverse reactions reported in patients with disease other than

PNH, aHUS, refractory gMG or NMOSD were similar to those reported in patients with PNH, aHUS,refractory gMG or NMOSD (see Table 1 above). No specific adverse reactions have emerged fromthese clinical trials.

Reporting of suspected adverse reactions

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.

4.9 Overdose

No case of overdose has been reported in any of the clinical studies.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Complement Inhibitors, ATC code: L04AJ01

Eculizumab is a recombinant humanised monoclonal IgG2/4k antibody that binds to the human C5complement protein and inhibits the activation of terminal complement. The eculizumab antibodycontains human constant regions and murine complementarity-determining regions grafted onto thehuman framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 aminoacid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately148 kDa.

Epysqli is produced in a CHO cell line expression system and purified by affinity and ion exchangechromatography. The bulk active substance manufacturing process also includes specific viralinactivation and removal steps.

Epysqli is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu.

Mechanism of action

Eculizumab, the active substance in Epysqli, is a terminal complement inhibitor that specifically bindsto the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b andpreventing the generation of the terminal complement complex C5b-9. Eculizumab preserves the earlycomponents of complement activation that are essential for opsonisation of microorganisms andclearance of immune complexes.

In PNH patients, uncontrolled terminal complement activation and the resulting complement-mediatedintravascular haemolysis are blocked with eculizumab treatment.

In most PNH patients, eculizumab serum concentrations of approximately 35 microgram/mL aresufficient for essentially complete inhibition of terminal complement-mediated intravascularhaemolysis.

In PNH, chronic administration of eculizumab resulted in a rapid and sustained reduction incomplement- mediated haemolytic activity.

In aHUS patients, uncontrolled terminal complement activation and the resulting complement-mediated thrombotic microangiopathy are blocked with eculizumab treatment.

All patients treated with eculizumab when administered as recommended demonstrated rapid andsustained reduction in terminal complement activity. In all aHUS patients, eculizumab serumconcentrations of approximately 50 - 100 microgram/mL are sufficient for essentially completeinhibition of terminal complement activity.

In aHUS, chronic administration of eculizumab resulted in a rapid and sustained reduction incomplement-mediated thrombotic microangiopathy.

Clinical efficacy and safety
Paroxysmal Nocturnal Haemoglobinuria

The safety and efficacy of eculizumab in PNH patients with haemolysis were assessed in arandomized, double-blind, placebo-controlled 26 week study (C04-001). PNH patients were alsotreated with eculizumab in a single arm 52 week study (C04-002), and in a long term extension study(E05-001). Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies,the dose of eculizumab was 600 mg every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 dayslater, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as anintravenous infusion over 25 - 45 minutes (35 minutes ± 10 minutes). An observational non-interventional Registry in patients with PNH (M07-001) was also initiated to characterize the naturalhistory of PNH in untreated patients and the clinical outcomes during eculizumab treatment.

In study C04-001 (TRIUMPH) PNH patients with at least 4 transfusions in the prior 12 months, flowcytometric confirmation of at least 10 % PNH cells and platelet counts of at least 100,000 /microliterwere randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomisation, all patientsunderwent an initial observation period to confirm the need for RBC transfusion and to identify thehaemoglobin concentration (the 'set-point') which would define each patient’s haemoglobinstabilisation and transfusion outcomes. The haemoglobin set-point was less than or equal to 9 g/dL inpatients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Primaryefficacy endpoints were haemoglobin stabilisation (patients who maintained a haemoglobinconcentration above the haemoglobin set-point and avoid any RBC transfusion for the entire 26 weekperiod) and blood transfusion requirement. Fatigue and health-related quality of life were relevantsecondary endpoints.

Haemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of

PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemiccorticosteroids at baseline continued these medications. Major baseline characteristics were balanced(see Table 2).

In the non-controlled study C04-002 (SHEPHERD), PNH patients with at least one transfusion in theprior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period.

Concomitant medications included anti-thrombotic agents in 63 % of the patients and systemiccorticosteroids in 40 % of the patients. Baseline characteristics are shown in Table 2.

Table 2: Patient demographics and characteristics in C04-001 and C04-002

C04-001 C04-002

Parameter Placebo Eculizumab Eculizumab

N = 44 N = 43 N = 97

Mean age (SD) 38.4 (13.4) 42.1 (15.5) 41.1 (14.4)

Gender - Female (%) 29 (65.9) 23 (53.5) 49 (50.5)

History of aplastic anaemia or MDS (%) 12 (27.3) 8 (18.7) 29 (29.9)

Concomitant anticoagulants (%) 20 (45.5) 24 (55.8) 59 (61)

Concomitant steroids/immunosuppressanttreatments (%) 16 (36.4) 14 (32.6) 46 (47.4)

Discontinued treatment 10 2 1

PRBC in previous 12 months (median(Q1,Q3)) 17.0 (13.5, 25.0) 18.0 (12.0,24.0) 8.0 (4.0, 24.0)

Mean Hgb level (g/dL) at setpoint (SD) 7.7 (0.75) 7.8 (0.79) N/A

Pre-treatment LDH levels (median, U/L) 2,234.5 2,032.0 2,051.0

Free haemoglobin at baseline (median, 46.2 40.5 34.9mg/dL)

In TRIUMPH, study patients treated with eculizumab had significantly reduced (p< 0.001) haemolysisresulting in improvements in anaemia as indicated by increased haemoglobin stabilisation andreduced need for RBC transfusions compared to placebo treated patients (see Table 3). These effectswere seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 -25 units; > 25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue andimproved health-related quality of life. Because of the study sample size and duration, the effects ofeculizumab on thrombotic events could not be determined. In SHEPHERD study, 96 of the 97enrolled patients completed the study (one patient died following a thrombotic event). A reduction inintravascular haemolysis as measured by serum LDH levels was sustained for the treatment period andresulted in increased transfusion avoidance, a reduced need for RBC transfusion and less fatigue. See

Table 3.

Table 3: Efficacy outcomes in C04-001 and C04-002

C04-001 C04-002*

Placebo Eculizumab P - Value Eculizumab

N = 44 N = 43 N = 97 P - Value

Percentage of patients withstabilized haemoglobin 0 49 < 0.001 N/Alevels at end of study

PRBC transfused duringtreatment (median) 10 0 < 0.001 0 < 0.001

Transfusion avoidanceduring treatment (%) 0 51 < 0.001 51 < 0.001

LDH levels at end of study(median, U/L) 2,167 239 < 0.001 269 < 0.001

LDH AUC at end of study(median, U/L x Day) 411,822 58,587 < 0.001 -632,264 < 0.001

Free haemoglobin at end ofstudy (median, mg/dL) 62 5 < 0.001 5 < 0.001

FACIT-Fatigue (effect size) 1.12 < 0.001 1.14 < 0.001

* Results from study C04-002 refer to pre- versus post-treatment comparisons.

From the 195 patients that originated in C04-001, C04-002 and other initial studies, eculizumab-treated PNH patients were enrolled in a long term extension study (E05-001). All patients sustained areduction in intravascular haemolysis over a total eculizumab exposure time ranging from 10 to 54months. There were fewer thrombotic events with eculizumab treatment than during the same periodof time prior to treatment.

However, this finding was shown in non-controlled clinical trials.

The PNH registry (M07-001) was used to evaluate the efficacy of eculizumab in PNH patients with nohistory of RBC transfusion. These patients had high disease activity as defined by elevated haemolysis(LDH ≥ 1.5 x ULN) and the presence of related clinical symptom(s): fatigue, haemoglobinuria,abdominal pain, shortness of breath (dyspnoea), anaemia (haemoglobin < 100 g/L), major adversevascular event (including thrombosis), dysphagia, or erectile dysfunction.

In the PNH Registry, patients treated with eculizumab were observed to have a reduction inhaemolysis and associated symptoms. At 6 months, patients treated with eculizumab with no history of

RBC transfusion had significantly (p< 0.001) reduced LDH levels (median LDH of 305 U/L; Table 4).

Furthermore, 74 % of the patients without a history of transfusion and treated with eculizumabexperienced clinically meaningful improvements in FACIT-Fatigue score (i.e., increase by 4 points ormore) and 84 % in EORTC fatigue score (i.e., decrease by 10 points or more).

Table 4: Efficacy outcomes (LDH level and FACIT-Fatigue) in patients with PNH with nohistory of transfusion in M07-001

M07-001

Parameter Eculizumab

No transfusion

LDH level at baseline N=43(median, U/L) 1447

LDH level at 6 months N=36(median, U/L) 305

FACIT-Fatigue score at baseline N=25(median) 32

FACIT-Fatigue score at last available assessment N=31(median) 44

FACIT-Fatigue is measured on a scale of 0-52, with higher values indicating less fatigue

Atypical Haemolytic Uremic Syndrome

Data from 100 patients in four prospective controlled studies, three in adult and adolescent patients(C08-002A/B C08-003A/B, C10-004) one in paediatric and adolescent patients (C10-003) and 30patients in one retrospective study (C09-001r) were used to evaluate the efficacy of eculizumab in thetreatment of aHUS.

Study C08-002A/B was a prospective, controlled, open-label study which accrued patients in the earlyphase of aHUS with evidence of clinical thrombotic microangiopathy manifestations with plateletcount ≤ 150 x 109/L despite PE/PI, and LDH and serum creatinine above upper limits of normal.

Study C08-003A/B was a prospective, controlled, open-label study which accrued patients with longerterm aHUS without apparent evidence of clinical thrombotic microangiopathy manifestations andreceiving chronic PE/PI (≥1 PE/PI treatment every two weeks and no more than 3 PE/PItreatments/week for at least 8 weeks before the first dose). Patients in both prospective studies weretreated with eculizumab for 26 weeks and most patients enrolled into a long-term, open-labelextension study. All patients enrolled in both prospective studies had an ADAMTS-13 level above 5%.

Patients received meningococcal vaccination prior to receipt of eculizumab or received prophylactictreatment with appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose ofeculizumab in adult and adolescent aHUS patients was 900 mg every 7 ± 2 days for 4 weeks, followedby 1,200 mg 7 ± 2 days later, then 1,200 mg every 14 ± 2 days for the study duration. Eculizumab wasadministered as an intravenous infusion over 35 minutes. The dosing regimen in paediatric patientsand adolescents weighing less than 40 kg was defined based on a pharmacokinetic (PK) simulationthat identified the recommended dose and schedule based on body weight (see section 4.2).

Primary endpoints included platelet count change from baseline in study C08-002A/B and thromboticmicroangiopathy (TMA) event-free status in study C08-003A/B. Additional endpoints included TMAintervention rate, haematologic normalization, complete TMA response, changes in LDH, renalfunction and quality of life. TMA-event free status was defined as the absence for at least 12 weeks ofthe following: decrease in platelet count of > 25% from baseline, PE/PI, and new dialysis. TMAinterventions were defined as PE/PI or new dialysis. Haematologic normalization was defined asnormalization of platelet counts and LDH levels sustained for ≥2 consecutive measurements for ≥4weeks. Complete TMA response was defined as haematologic normalization and a ≥25% reduction inserum creatinine sustained in ≥ 2 consecutive measurements for ≥ 4 weeks.

Baseline characteristics are shown in Table 5.

Table 5: Patient Demographics and Characteristics in C08-002A/B and C08-003A/B

Parameter C08-002A/B C08-003A/B

Eculizumab Eculizumab

N = 17 N = 20

Time from first diagnosis until screening in months, 10 (0.26, 236) 48 (0.66, 286)median (min, max)

Time from current clinical TMA manifestation until < 1 (<1, 4) 9 (1, 45)screening in months, median (min, max)

Number of PE/PI sessions for current clinical TMA 17 (2, 37) 62 (20, 230)manifestation, median (min,max)

Number of PE/PI sessions in 7 days prior to first 6 (0, 7) 2 (1, 3)dose of eculizumab, median (min, max)

Baseline platelet count (× 109/L), mean (SD) 109 (32) 228 (78)

Baseline LDH (U/L), mean (SD) 323 (138) 223 (70)

Patients without identified mutation, n (%) 4 (24) 6 (30)

Patients in aHUS Study C08-002 A/B received eculizumab for a minimum of 26 weeks. Aftercompletion of the initial 26-week treatment period, most patients continued to receive eculizumab byenrolling into an extension study. In aHUS Study C08-002A/B, the median duration of eculizumabtherapy was approximately100 weeks (range: 2 weeks to 145 weeks).

A reduction in terminal complement activity and an increase in platelet count relative to baseline wereobserved after commencement of eculizumab. Reduction in terminal complement activity wasobserved in all patients after commencement of eculizumab. Table 6 summarizes the efficacy resultsfor aHUS Study C08-002A/B. All rates of efficacy endpoints improved or were maintained through 2years of treatment. Complete TMA response was maintained by all responders. When treatment wascontinued for more than 26 weeks, two additional patients achieved and maintained Complete TMAresponse due to normalization of LDH (1 patient) and a decrease in serum creatinine (2 patients).

Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. Fourof the five patients who required dialysis at study entry were able to discontinue dialysis for theduration of eculizumab treatment, and one patient developed a new dialysis requirement. Patientsreported improved health-related quality of life (QoL).

In aHUS Study C08-002A/B, responses to eculizumab were similar in patients with and withoutidentified mutations in genes encoding complement regulatory factor proteins.

Patients in aHUS study C08-003A/B received eculizumab for a minimum of 26 weeks. Aftercompletion of the initial 26-week treatment period, most patients continued to receive eculizumab byenrolling into an extension study. In aHUS Study C08-003A/B, the median duration of eculizumabtherapy was approximately 114 weeks (range: 26 to 129 weeks). Table 6 summarizes the efficacyresults for aHUS Study C08-003A/B.

In aHUS Study C08-003A/B, responses to eculizumab were similar in patients with and withoutidentified mutations in genes encoding complement regulatory factor proteins. Reduction in terminalcomplement activity was observed in all patients after commencement of eculizumab. All rates ofefficacy endpoints improved or were maintained through 2 years of treatment. Complete TMAresponse was maintained by all responders. When treatment was continued for more than 26 weeks,six additional patients achieved and maintained Complete TMA response due to a decrease in serumcreatinine. No patient required new dialysis with eculizumab. Renal function, as measured by medianeGFR, increased during eculizumab therapy.

Table 6: Efficacy Outcomes in Prospective aHUS Studies C08-002A/B and C08-003A/B

C08-002A/B C08-003A/B

N=17 N=20

At 26 weeks At 2 years1 At 26 weeks At 2 years1

Normalization ofplatelet count 14 (82) 15 (88) 18 (90) 18 (90)

All patients, n (%) (57-96) (64-99) (68-99) (68-99)(95% CI) 13/15 (87) 13/15 (87) 1/3 (33) 1/3 (33)

Patients with abnormalbaseline, n/n (%)

TMA event-free 15 (88) 15 (88) 16 (80) 19 (95)status, n (%) (95% CI) (64-99) (64-99) (56-94) (75-99)

TMA intervention rate

Daily pre- 0.88 0.88 0.23 0.23eculizumab rate, (0.04, 1.59) (0.04, 1.59) (0.05, 1.09) (0.05, 1.09)median (min, max)

Daily during- 0 (0, 0.31) 0 (0, 0.31) 0 0eculizumab rate,median (min, max) P<0.0001 P<0.0001 P <0.0001 P<0.0001

P-value

CKD improvement by 10 (59) 12 (71) 7 (35) 12 (60)≥1 stage, (33-82) (44-90) (15-59) (36-81)n (%) (95% CI)eGFR change 20 (-1, 98) 28 (3, 82) 5 (-1, 20) 11 (-42, 30)mL/min/1.73 m2:median (range)eGFR improvement 8 (47) 10 (59) 1 (5) 8 (40)≥15 mL/min/1.73 m2, (23-72) (33-82) (0-25) (19-64)n (%) (95% CI)

Change in Hgb > 20g/L, n 11 (65) 13 (76) 9 (45) 13 (65)(%) (95% CI) (38-86) 2 (50-93) (23-68) 3 (41-85)

Haematologic 13 (76) 15 (88) 18 (90) 18 (90)normalization, n (%) (50-93) (64-99) (68-99) (68-99)(95% CI)

Complete TMA 11(65) 13(76) 5 (25) 11(55)response, n (%) (95% (38-86) (50-93) (9-49) (32-77)

CI)1At data cut off (20 April 2012)2Study C08-002: 3 patients received ESA which was discontinued after eculizumab initiation3Study C08-003: 8 patients received ESA which was discontinued in 3 of them during eculizumab therapyaHUS Study C10-004 enrolled 41 patients who displayed signs of thrombotic microangiopathy(TMA). In order to qualify for enrolment, patients were required to have a platelet count < lower limitof normal range (LLN), evidence of haemolysis such as an elevation in serum LDH, and serumcreatinine above the upper limits of normal, without the need for chronic dialysis. The median patientage was 35 (range: 18 to 80 years). All patients enrolled in aHUS Study C10-004 had an ADAMTS-13level above 5%. Fifty-one percent of patients had an identified complement regulatory factor mutationor auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 7 summarizes thekey baseline clinical and disease-related characteristics of patients enrolled in aHUS C10-004.

Table 7: Baseline Characteristics of Patients Enrolled in aHUS Study C10-004

Parameter aHUS Study C10-004

N = 41

Time from aHUS diagnosis to first study dose (months), median(min, max) 0.79 (0.03, 311)

Time from current clinical TMA manifestation until first studydose (months), median (min, max) 0.52 (0.03, 19)

Baseline platelet count (× 109/L), median (min, max ) 125 (16, 332)

Baseline LDH (U/L), median (min, max) 375 (131, 3318)

Baseline eGFR (mL/min/1.73 m2), median (min, max) 10 (6, 53)

Patients in aHUS Study C10-004 received eculizumab for a minimum of 26 weeks. After completionof the initial 26-week treatment period, most patients elected to continue on chronic dosing.

Reduction in terminal complement activity and an increase in platelet count relative to baseline wereobserved after commencement of eculizumab. Eculizumab reduced signs of complement-mediated

TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS

C10-004, mean (±SD) platelet count increased from 119 ± 66 x109/L at baseline to 200 ± 84 x109/Lby one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 252± 70 x109/L). Renal function, as measured by eGFR, was improved during eculizumab therapy.

Twenty of the 24 patients who required dialysis at baseline were able to discontinue dialysis duringeculizumab treatment. Table 8 summarizes the efficacy results for aHUS study C10-004.

Table 8: Efficacy Outcomes in Prospective aHUS Study C10-004

Efficacy Parameter aHUS Study C10-004(N = 41)

At 26-weeks

Change in platelet count through week 26 (109/L) 111 (-122, 362)

Hematologic Normalization, n (%) 36 (88)

Median duration of hematologic normalization, weeks (range)1 46 (10, 74)

Complete TMA response, n (%) 23 (56)

Median duration of complete TMA response, weeks (range)1 42 (6, 74)

TMA Event-free Status, n (%) 95% CI 37 (90)77; 97

Daily TMA Intervention Rate, median (range) Beforeeculizumab 0.63 (0, 1.38)

On eculizumab treatment 0 (0, 0.58)1Through data cut-off (September 4, 2012), with median duration of eculizumab therapy of 50 weeks (range: 13weeks to 86 weeks).

Longer term treatment with eculizumab (median 52 weeks ranging from 15 to 126 weeks) wasassociated with an increased rate of clinically meaningful improvements in adult patients with aHUS.

When eculizumab treatment was continued for more than 26 weeks, three additional patients (63% ofpatients in total) achieved Complete TMA response and four additional patients (98% of patients intotal) achieved hematologic normalization. At the last evaluation, 25 of 41 patients (61%) achievedeGFR improvement of ≥ 15 mL/min/1.73 m2 from baseline.

Paediatric population
Paroxysmal Nocturnal Haemoglobinuria

A total of 7 PNH paediatric patients, with a median weight of 57.2 kg (range of 48.6 to 69.8 kg) andaged from 11 to 17 years (median age: 15.6 years), received eculizumab in study M07-005.

Treatment with eculizumab at the proposed dosing regimen in the paediatric population was associatedwith a reduction of intravascular haemolysis as measured by serum LDH level. It also resulted in amarked decrease or elimination of blood transfusions, and a trend towards an overall improvement ingeneral function. The efficacy of eculizumab treatment in paediatric PNH patients appears to beconsistent with that observed in adult PNH patients enrolled in PNH pivotal Studies (C04-001 and

C04-002) (Table 3 and 9).

Table 9: Efficacy outcomes in paediatric PNH study M07-005

P - Value

Mean (SD) Wilcoxon Signed

Rank Paired t-test

Change from baseline at 12 weeks of LDH -771 (914) 0.0156 0.0336value (U/L)

LDH AUC -60,634 0.0156 0.0350(U/L x Day) (72,916)

Change from baseline at 12 weeks inplasma free haemoglobin (mg/dL) -10.3 (21.13) 0.2188 0.1232

Change from baseline Type III RBC clonesize (Percent of aberrant cells) 1.80 (358.1)

Change from baseline at 12 weeks of

PedsQLTM 4.0 generic core scale 10.5 (6.66) 0.1250 0.0256

Change fr om baseline at 12 weeks of

PedsQLTM 4.0 generic core scale 11.3 (8.5) 0.2500 0.0737

Change f rom baseline at 12 weeks of

PedsQLTM multidimensional fatigue(patients) 0.8 (21.39) 0.6250 0.4687

Change from baseline at 12 weeks of

PedsQLTM multidimensional fatigue(parents) 5.5 (0.71) 0.5000 0.0289

Atypical Haemolytic Uremic Syndrome

A total of 15 paediatric patients (aged 2 months to 12 years) received eculizumab in aHUS Study C09-001r. Forty seven percent of patients had an identified complement regulatory factor mutation or auto-antibody. The median time from aHUS diagnosis to first dose of eculizumab was 14 months (range <1,110 months). The median time from current thrombotic microangiopathy manifestation to first dose ofeculizumab was 1 month (range <1 to 16 months). The median duration of eculizumab therapy was 16weeks (range 4 to 70 weeks) for children < 2 years of age (n=5) and 31 weeks (range 19 to 63 weeks)for children 2 to <12 years of age (n=10).

Overall, the efficacy results for these paediatric patients appeared consistent with what was observedin patients enrolled in aHUS pivotal Studies C08-002 and C08-003 (Table 6). No paediatric patientrequired new dialysis during treatment with eculizumab.

Table 10: Efficacy Results in Paediatric Patients Enrolled in aHUS C09-001r

Efficacy Parameter <2 years 2 to <12 years <12 years(n=5) (n=10) (n=15)

Patients with platelet count 4 (80) 10 (100) 14 (93)normalization, n (%)

Complete TMA response, n (%) 2 (40) 5 (50) 7 (50)

Daily TMA intervention rate, median(range)

Before eculizumab 1 (0, 2) <1 (0.07, 1.46) <1 (0, 2)

On eculizumab treatment <1 (0, <1) 0 (0, <1) 0 (0, <1)

Patients with eGFR improvement 2 (40) 6 (60) 8 (53)≥15 mL/min/1.73 m2, n (%)

In paediatric patients with shorter duration of current severe clinical thrombotic microangiopathy(TMA) manifestation prior to eculizumab, there was TMA control and improvement of renal functionwith eculizumab treatment (Table 10).

In paediatric patients with longer duration of current severe clinical TMA manifestation prior toeculizumab, there was TMA control with eculizumab treatment. However, renal function was notchanged due to prior irreversible kidney damage (Table 11).

Table 11: Efficacy Outcomes in Paediatric Patients in Study C09-001r according to duration ofcurrent severe clinical thrombotic microangiopathy (TMA) manifestation

Duration of current severe clinical

TMA manifestation< 2 months >2 months

N=10 (%) N=5 (%)

Platelet count normalization 9 (90) 5 (100)

TMA event-free status 8 (80) 3 (60)

Complete TMA response 7 (70) 0eGFR improvement ≥ 15 mL/min/1.73m2 7 (70) 0*

*One patient achieved eGFR improvement after renal transplant

A total of 22 paediatric and adolescents patients (aged 5 months to 17 years) received eculizumab inaHUS Study C10-003.

In Study C10-003, patients who enrolled in the study were required to have a platelet count < lowerlimit of normal range (LLN), evidence of haemolysis such as an elevation in serum LDH above theupper limits of normal and serum creatinine level ≥97 percentile for age without the need for chronicdialysis. The median patient age was 6.5 years (range: 5 months to 17 years). Patients enrolled inaHUS C10-003 had an ADAMTS-13 level above 5%. Fifty percent of patients had an identifiedcomplement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior toeculizumab. Table 12 summarizes the key baseline clinical and disease-related characteristics ofpatients enrolled in aHUS Study C10-003.

Table 12: Baseline Characteristics of Paediatric and Adolescents Patients Enrolled in aHUS

Study C10-0031 month to <12 years All Patients

Parameter (N = 18) (N = 22)

Time from aHUS diagnosis until first study dose(months) median (min, max ) 0.51 (0.03, 58) 0.56 (0.03,191)

Time from current clinical TMA manifestationuntil first study dose (months), median ( min, 0.23 (0.03, 4) 0.20 (0.03, 4)max)

Baseline platelet count (x 109/L), median ( min,max) 110 (19, 146) 91 (19,146)

Baseline LDH (U/L) median (min, max ) 1510 (282, 7164) 1244 (282, 7164)

Baseline eGFR (mL/min/1.73 m2), median (min,max) 22 (10, 105) 22 (10, 105)

Patients in aHUS C10-003 received eculizumab for a minimum of 26 weeks. After completion of theinitial 26-week treatment period, most patients elected to continue on chronic dosing. Reduction interminal complement activity was observed in all patients after commencement of eculizumab.

Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in meanplatelet counts from baseline to 26 weeks. The mean (±SD) platelet count increased from 88 ± 42x109/L at baseline to 281 ± 123 x109/L by one week; this effect was maintained through 26 weeks(mean platelet count (±SD) at week 26: 293 ± 106 x109/L). Renal function, as measured by eGFR, wasimproved during eculizumab therapy. Nine of the 11 patients who required dialysis at baseline nolonger required dialysis after Study Day 15 of eculizumab treatment. Responses were similar across allages from 5 months to 17 years of age. In aHUS C10-003, responses to eculizumab were similar inpatients with and without identified mutations in genes encoding complement regulatory factorproteins or auto-antibodies to factor H.

Table 13 summarizes the efficacy results for aHUS C10-003.

Table 13: Efficacy Outcomes in Prospective aHUS Study C10-0031 month to <12 years All Patients

Efficacy Parameter (N = 18) (N = 22)

At 26-weeks At 26-weeks

Complete Hematologic Normalization, n (%)14 (78) 18 (82)

Median Duration of complete hematologicnormalization, weeks (range) 1 35 (13, 78) 35 (13, 78)

Complete TMA response, n (%)11 (61) 14 (64)

Median Duration of complete TMA response, weeks(range)1 40 (13, 78) 37 (13, 78)

TMA Event-Free Status, n (%) 95% 17 (94) 21 (96)

CI NA 77; 99

Daily TMA Intervention rate, median (range) Beforeeculizumab treatment, median NA 0.4 (0, 1.7)

On eculizumab treatment, median NA 0 (0, 1.01)eGFR improvement ≥15 mL/min/ 1.73*m2, n (%) 16 (89) 19 (86)

Change in eGFR (≥15 mL/min/1.73*m2) at 26 weeks,median (range) 64 (0,146) 58 (0, 146)

CKD improvement by ≥1 stage, n (%) 14/16 (88) 17/20 (85)

PE/PI Event-Free Status, n (%) 16 (89) 20 (91)

New Dialysis Event-Free Status, n (%) 95% 18 (100) 22 (100)

CI NA 85;1001Through data cut-off (October 12, 2012), with median duration of eculizumab therapy of 44 weeks (range: 1dose to 88 weeks).

Longer term treatment with eculizumab (median 55 weeks ranging from 1day to 107 weeks) wasassociated with an increased rate of clinically meaningful improvements in paediatric and adolescentpatients with aHUS. When eculizumab treatment was continued for more than 26 weeks, oneadditional patient (68% of patients in total) achieved Complete TMA Response and two additionalpatients (91% of patients in total) achieved hematologic normalization. At the last evaluation, 19 of 22patients (86%) achieved eGFR improvement of ≥ 15 mL/min/1.73 m2 from baseline. No patientrequired new dialysis with eculizumab.

5.2 Pharmacokinetic properties

Pharmacokinetics and active substance metabolism

Biotransformation

Human antibodies undergo endocytotic digestion in the cells of the reticuloendothelial system.

Eculizumab contains only naturally occurring amino acids and has no known active metabolites.

Human antibodies are predominately catabolised by lysosomal enzymes to small peptides and aminoacids.

Elimination

No specific studies have been performed to evaluate the hepatic, renal, lung, or gastrointestinal routesof excretion/elimination for eculizumab. In normal kidneys, antibodies are not excreted and areexcluded from filtration by their size.

Pharmacokinetic parameters

In 40 patients with PNH, a 1-compartmental model was used to estimate pharmacokinetic parametersafter multiple doses. Mean clearance was 0.31 ± 0.12 mL/hr/kg, mean volume of distribution was110.3 ± 17.9 mL/kg, and mean elimination half-life was 11.3 ± 3.4 days. The steady state is achievedby 4 weeks using the PNH adult dosing regimen.

In PNH patients, pharmacodynamic activity correlates directly with eculizumab serum concentrationsand maintenance of trough levels above ≥ 35 microgram/mL results in essentially complete blockadeof haemolytic activity in the majority of PNH patients.

A second population PK analysis with a standard 1 compartmental model was conducted on themultiple dose PK data from 37 aHUS patients receiving the recommended eculizumab regimen instudies C08-002A/B and C08-003A/B. In this model, the clearance of eculizumab for a typical aHUSpatient weighing 70 kg was 0.0139 L/hr and the volume of distribution was 5.6 L. The eliminationhalf-life was 297 h (approximately 12.4 days).

The second population PK model was applied to the multiple dose PK data from 22 paediatric aHUSpatients receiving the recommended eculizumab regimen in aHUS C10-003. The clearance andvolume of distribution of eculizumab are weight dependent, which forms the basis for a weightcategorical based dose regimen in paediatric patients (see section 4.2). Clearance values of eculizumabin paediatric aHUS patients were 10.4, 5.3, and 2.2 mL/hr with body weight of 70, 30, and 10 kg,respectively; and the corresponding volume of distribution values were 5.23, 2.76, and 1.21 L,respectively. The corresponding elimination half-life remained almost unchanged within a range of349 to 378 h (approximately 14.5 to 15.8 days).

The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions.

Plasma exchange resulted in an approximately 50% decline in eculizumab concentrations following a1 hour intervention and the elimination half-life of eculizumab was reduced to 52.4 hours.

Supplemental dosing is recommended when eculizumab is administered to aHUS patients receivingplasma infusion or exchange (see section 4.2).

All aHUS patients treated with eculizumab when administered as recommended demonstrated rapidand sustained reduction in terminal complement activity. In aHUS patients, pharmacodynamic activitycorrelates directly with eculizumab serum concentrations and maintenance of trough levels ofapproximately 50-100 microgram/ml results in essentially complete blockade of terminal complementactivity in all aHUS patients.

PK parameters are consistent across PNH and aHUS patient populations. Pharmacodynamic activitymeasured by free C5 concentrations of < 0.5 microgram/mL, is correlated with essentially completeblockade of terminal complement activity in PNH and aHUS patients.

Special populations

Dedicated studies have not been conducted to evaluate the pharmacokinetics of eculizumab in specialpatient populations identified by gender, race, age (geriatric), or the presence of renal or hepaticimpairment.

Population PK (PopPK) analysis on data collected across studies in PNH and aHUS patients showedthat gender, race, age (geriatric), or the presence of renal or hepatic impairment/function do notinfluence the PK of eculizumab.

Paediatric population

The pharmacokinetics of eculizumab was evaluated in Study M07-005 in PNH paediatric patients(aged from 11 to less than 18 years) and in Studies C08-002, C08-003, C09-001r and C10-003 inaHUS paediatric patients (aged 2 months to less than 18 years). PopPK analysis showed that for PNHand aHUS, body weight was a significant covariate requiring body weight-based dosing for pediatricpatients.

5.3 Preclinical safety data

The specificity of eculizumab for C5 in human serum was evaluated in two in vitro studies.

The tissue cross-reactivity of eculizumab was evaluated by assessing binding to a panel of 38 humantissues. C5 expression in the human tissue panel examined in this study is consistent with publishedreports of C5 expression, as C5 has been reported in smooth muscle, striated muscle, and renalproximal tubular epithelium. No unexpected tissue cross-reactivity was observed.

Animal reproduction studies have not been conducted with eculizumab due to lack of pharmacologicactivity in non-human species.

In a 26 week toxicity study performed in mice with a surrogate antibody directed against murine C5,treatment did not affect any of the toxicity parameters examined. Haemolytic activity during thecourse of the study was effectively blocked in both female and male mice.

No clear treatment-related effects or adverse effects were observed in reproductive toxicology studiesin mice with a surrogate terminal complement inhibitory antibody, which was utilised to assess thereproductive safety of C5 blockade. These studies included assessment of fertility and early embryonicdevelopment, developmental toxicity, and pre and post-natal development.

When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasiaand one case of umbilical hernia were observed among 230 offspring born to mothers exposed to thehigher antibody dose (approximately 4 times the maximum recommended human eculizumab dose,based on a body weight comparison); however, the exposure did not increase foetal loss or neonataldeath.

No animal studies have been conducted to evaluate the genotoxic and carcinogenic potential ofeculizumab.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium dihydrogen phosphate monohydrate

Disodium hydrogen phosphate heptahydrate

Trehalose dihydrate

Polysorbate 80 (E 433)

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Before dilution3 years at 2 °C - 8 °C.

Epysqli may be stored at temperature up to a maximum of 30 °C for a single period of up to 2 months,but not exceeding the original expiry date. At the end of this period the product can be put back in therefrigerator.

After dilution

Chemical and physical in-use stability of the diluted solution has been demonstrated for each diluentas following:

* Sodium chloride 9 mg/ml (0.9 %) solution for injection, sodium chloride 4.5 mg/ml (0.45 %)solution for injection as diluent: 3 months at 2°C to 8°C followed by up to 72 hours at roomtemperature (up to 30°C)

* 5 % glucose in water as diluent: 24 hours at 2°C to 8°C and at room temperature (up to 30°C)after removal from refrigeration

From a microbiological point of view, the infusion solution should be administered immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2 °C - 8 °C, unless dilution has taken place incontrolled and validated aseptic conditions.

6.4 Special precautions for storage

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

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions up to 30 °C before dilution of the medicinal product, see section 6.3.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

30 ml of concentrate in a vial (Type I glass) with a stopper (coated chlorinated butyl rubber), and aseal (aluminium) with flip-off cap (polypropylene).

Pack size of one vial.

6.6 Special precautions for disposal and other handling

Prior to administration, Epysqli solution should be visually inspected for particulate matter anddiscolouration. Do not use if there is evidence of particulate matter or discolouration.

Instructions:

Reconstitution and dilution should be performed in accordance with good practices rules, particularlyfor the respect of asepsis.

Withdraw the total amount of Epysqli from the vial(s) using a sterile syringe.

Transfer the recommended dose to an infusion bag.

Dilute Epysqli to a final concentration of 5 mg/ml by addition to the infusion bag using sodiumchloride 9 mg/ml (0.9 %) solution for injection, sodium chloride 4.5 mg/ml (0.45 %) solution forinjection, or 5 % glucose in water, as the diluent.

The final volume of a 5 mg/ml diluted solution is 60 ml for 300 mg doses, 120 ml for 600 mg doses,180 ml for 900 mg doses and 240 ml for 1,200 mg doses. The solution should be clear and colourless.

Gently agitate the infusion bag containing the diluted solution to ensure thorough mixing of theproduct and diluent.

The diluted solution should be allowed to warm to room temperature (up to 30 °C) prior toadministration by exposure to ambient air.

Discard any unused portion left in a vial.

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

7. MARKETING AUTHORISATION HOLDER

Samsung Bioepis NL B.V.

Olof Palmestraat 102616 LR Delft

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/23/1735/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 May 2023

10. DATE OF REVISION OF THE TEXT

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

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

Leaflet EPYSQLI 300mg concentrate for solution for infusion

General data about EPYSQLI 300mg

Marketing authorisation

Concentrations available for eculizumab