BEKEMV 300mg concentrate for solution for infusion medication leaflet

BEKEMV 300 mg concentrate for solution for infusion

Eculizumab is a humanised monoclonal (IgG2/4κ) antibody produced in CHO cell line by recombinant

DNA technology.

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

Each mL of solution contains 50 mg sorbitol. Each vial contains 1 500 mg sorbitol.

Each vial contains 3.0 mg of polysorbate 80 (30 mL vial).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear to opalescent, colourless to slightly yellow, pH 5.2 solution.

BEKEMV is indicated in adults and children for the treatment of­ Paroxysmal nocturnal haemoglobinuria (PNH). Evidence of clinical benefit is demonstrated inpatients with haemolysis with clinical symptom(s) indicative of high disease activity, regardlessof transfusion history (see section 5.1).

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

BEKEMV must be administered by a healthcare professional and under the supervision of a physicianexperienced in the management of patients with haematological and 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.

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 BEKEMV administered via a 25 - 45 minute(35 minutes ± 10 minutes) intravenous infusion every week for the first 4 weeks.

* Maintenance phase: 900 mg of BEKEMV administered via a 25 - 45 minute (35 minutes ± 10minutes) intravenous infusion for the fifth week, followed by 900 mg of BEKEMVadministered via a 25 - 45 minute (35 minutes ± 10 minutes) intravenous infusion every14 ± 2 days (see section 5.1).

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 BEKEMV administered via a 25 - 45 minutes(35 minutes ± 10 minutes) intravenous infusion every week for the first 4 weeks.

* Maintenance phase: 1 200 mg of BEKEMV administered via a 25 - 45 minute(35 minutes ± 10 minutes) intravenous infusion for the fifth week, followed by 1 200 mg of

BEKEMV administered via a 25 - 45 minutes (35 minutes ± 10 minutes) intravenous infusionevery 14 ± 2 days (see section 5.1).

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

BEKEMV is contraindicated in children below 2 years of age (see section 4.3).

In paediatric PNH and aHUS patients above 2 years of age and with body weight below 40 kg, the

BEKEMV dosing regimen consists of:

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

Eculizumab has not been studied in patients with PNH who weigh less than 40 kg. The posology ofeculizumab to be used in paediatric patients with PNH weighing less than 40 kg is identical to theweight-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 BEKEMV is required in the setting of concomitant PP/PE/PI (plasmapheresisor plasma exchange, or fresh frozen plasma infusion) as described below:

Type of plasma Most recent Supplemental Timing ofintervention BEKEMV dose BEKEMV supplementaldose with each BEKEMV

PP/PE/PI doseintervention

Plasmapheresis or 300 mg 300 mg per eachplasma plasmapheresis orexchange plasma exchange Within 60 minutessession after each≥ 600 mg 600 mg per each plasmapheresis orplasmapheresis or plasma exchangeplasma exchangesession

Fresh frozen plasma ≥ 300 mg 300 mg per infusion of 60 minutes prior toinfusion fresh frozen plasma each infusion of freshfrozen plasma

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

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

BEKEMV treatment is recommended to continue for the patient’s lifetime, unless the discontinuationof BEKEMV is clinically indicated (see section 4.4).

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

No dose adjustment is required for patients with renal impairment (see section 5.2).

The safety and efficacy of BEKEMV have not been studied in patients with hepatic impairment (seesection 5.2).

BEKEMV should not be administered as an intravenous push or bolus injection. BEKEMV shouldonly be administered via intravenous infusion as described below.

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

The diluted solution of BEKEMV should be administered by intravenous infusion over25 - 45 minutes (35 minutes ± 10 minutes) in adults and 1 - 4 hours in paediatric patients under18 years of age via gravity feed, a syringe-type pump, or an infusion pump. It is not necessary toprotect the diluted solution of BEKEMV from light during administration to the patient.

Patients should be monitored for one hour following infusion. If an adverse event occurs during theadministration of BEKEMV, the infusion may be slowed or stopped at the discretion of the physician.

If the 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.

Hypersensitivity to eculizumab or to any of the excipients listed in section 6.1.

BEKEMV is contraindicated in subjects with hereditary fructose intolerance (HFI). Prior to initiatingtreatment HFI should be excluded on age-appropriate clinical grounds (see section 4.4).

BEKEMV is contraindicated in babies and children below 2 years of age since they may not yet bediagnosed with hereditary fructose intolerance (HFI) (see section 4.4).

BEKEMV 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 receive prophylactictreatment with appropriate antibiotics until 2 weeks after vaccination.

BEKEMV 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 BEKEMV 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 BEKEMV unless the risk of delaying BEKEMV therapy outweighs the risks of developing ameningococcal infection. Patients who initiate BEKEMV treatment less than 2 weeks after receiving atetravalent meningococcal vaccine must receive treatment with appropriate prophylactic antibioticsuntil 2 weeks after vaccination. Vaccines against serogroups A, C, Y, and W 135, are recommended inpreventing the commonly pathogenic meningococcal serogroups. Vaccine against serogroup B whereavailable is also recommended. Patients must receive vaccination according to current nationalvaccination guidelines for vaccination 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) and 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 BEKEMV therapy with patients and provide them with a patientinformation brochure and a patient safety card (see package leaflet for a description).

Other systemic infections

Due to its mechanism of action, BEKEMV 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 BEKEMV may result in infusion reactions or immunogenicity that could causeallergic or hypersensitivity reactions (including anaphylaxis). In clinical trials, 1 (0.9%) refractorygeneralised myasthenia gravis (gMG) patient experienced an infusion reaction which requireddiscontinuation of eculizumab. No PNH or aHUS patients experienced an infusion reaction whichrequired discontinuation of eculizumab. BEKEMV administration should be interrupted in all patientsexperiencing severe infusion reactions and appropriate medical therapy administered.

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

Prior to initiating BEKEMV therapy, it is recommended that PNH and aHUS patients initiateimmunisations according to current immunisation guidelines. Additionally, all patients must bevaccinated against meningococcal infections at least 2 weeks prior to receiving BEKEMV unless therisk of delaying BEKEMV therapy outweighs the risks of developing a meningococcal infection.

Patients who initiate BEKEMV treatment less than 2 weeks after receiving a tetravalentmeningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeksafter vaccination. Vaccines against serogroups A, C, Y and W 135 are recommended in preventing thecommonly pathogenic meningococcal serogroups. Vaccine against serogroup B where available is alsorecommended (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) and TMA (aHUS). Therefore, patients should be closely monitoredfor disease symptoms after recommended vaccination.

Treatment with BEKEMV 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 BEKEMV 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 BEKEMV 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 PNH patients discontinue treatment with BEKEMV 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 discontinues

BEKEMV for at least 8 weeks to detect serious haemolysis and other reactions.

If serious haemolysis occurs after BEKEMV discontinuation, consider the followingprocedures/treatments: blood transfusion (packed red blood cells or RBCs), or exchange transfusion ifthe PNH RBCs are > 50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; orreinstitution of BEKEMV. In PNH clinical studies, 16 patients discontinued the eculizumab treatmentregimen. 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 hospitalisation 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 BEKEMV, 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 BEKEMV.

Severe thrombotic microangiopathy complications post discontinuation can be identified by (i) anytwo, or repeated measurement of anyone, of the following: a decrease in platelet count of 25% or moreas compared to either baseline or to peak platelet count during BEKEMV treatment; an increase inserum creatinine of 25% or more as compared to baseline or to nadir during BEKEMV treatment; or,an increase in serum LDH of 25% or more as compared to baseline or to nadir during BEKEMVtreatment; 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 BEKEMV discontinuation, considerreinstitution of BEKMV treatment, supportive care with PE/PI, or appropriate organ-specificsupportive measures including renal support with dialysis, respiratory support with mechanicalventilation or anticoagulation.

All physicians who intend to prescribe BEKEMV must ensure they are familiar with the physician’sguide to prescribing. Physicians must discuss the benefits and risks of BEKEMV therapy with patientsand provide them with a patient information brochure and a patient safety 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.

Sorbitol

Each mL of this medicinal product contains 50 mg of sorbitol (E420). Patients with hereditary fructoseintolerance (HFI) must not take this medicine. In HFI patients more than 2 years old, a spontaneousaversion for fructose-containing foods develops and may be combined with the onset of symptoms(vomiting, gastro-intestinal disorders, apathy, height and weight retardation). Therefore, a detailedhistory with regards to HFI symptoms has to be taken of each patient prior to receiving BEKEMV. Incase of inadvertent administration and suspicion of fructose intolerance the infusion has to be stoppedimmediately, normal glycaemia has to be re-established and organ function has to be stabilized bymeans of intensive care (see section 4.3).

Babies and children (below 2 years of age) may not yet be diagnosed with HFI. Medicines containingsorbitol/fructose given intravenously may be life threatening and must be contraindicated in thispopulation (see sections 4.2 and 4.3).

BEKEMV vials contain less than 1 mmol of sodium (23 mg) per dose, that is to say essentially“sodium free”. On dilution with 5% glucose solution, the medicinal product is essentially “sodiumfree”.

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicinal productcontains 0.34 g sodium per 180 mL at the maximal dose, equivalent to 17.0% 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 0.18 g sodium per 180 mL at the maximal dose, equivalent to 9.0% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Polysorbate 80

This medicinal product contains 3.0 mg of polysorbate 80 in each vial (30 mL vial) which isequivalent to 0.3 mg/kg or less at the maximum dose for adult patients and paediatric patients withbody weight more than 10 kg and is equivalent to 0.6 mg/kg or less at the maximum dose forpaediatric patients with body weight 5 to < 10 kg. Polysorbates may cause allergic reactions.

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

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) and fresh frozen plasma infusion (PI) have been shown toreduce eculizumab serum levels. A supplemental dose of eculizumab is required in these settings. Seesection 4.2 for guidance in case of concomitant PE, PP or PI 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.

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.

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 benefits and risk analysis isrecommended before starting and during treatment with eculizumab in pregnant women. Should sucha treatment be considered necessary during pregnancy, a close maternal and foetal monitoringaccording to local guidelines 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, BEKEMV should be givento a pregnant woman only if clearly needed.

No effects on the breastfed new-born/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 breast-feeding should be considered along with the mother’sclinical need for eculizumab and any potential adverse effects on the breastfed child from eculizumabor from the underlying maternal condition.

No specific study of eculizumab on fertility has been conducted.

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

Supportive safety data were obtained from 33 clinical studies that included 1 555 patients exposed toeculizumab in complement-mediated disease populations, including PNH, aHUS, refractorygeneralized myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD). Themost common adverse reaction was headache, (occurred mostly in the initial phase of dosing), and themost serious adverse reaction was meningococcal infection.

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)or rare (≥ 1/10 000 to < 1/1 000) frequency with eculizumab, are listed by system organ class andpreferred term. Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

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 (≥ 1/1 000 Rareorgan class common (≥ 1/100 to to < 1/100) (≥ 1/10 000 to < 1/1 000)(≥ 1/10) < 1/10)

Infections and Pneumonia, Meningococcal Aspergillus infectionc,infestations Upper respiratory infectionb, Arthritis bacterialc,tract infection, Sepsis, Genitourinary tract

Bronchitis, Septic shock, gonococcal infection,

Nasopharyngitis, Peritonitis, Haemophilus infection,

Urinary tract Lower respiratory tract Impetigoinfection, infection,

Oral herpes Fungal infection,

Viral infection,

Abscessa,

Cellulitis,

Influenza,

Gastrointestinalinfection,

Cystitis,

Infection,

Sinusitis,

Gingivitis

Neoplasms benign, Malignant melanoma,malignant and Myelodysplasticunspecified syndrome(including cystsand polyps)

Blood and Leucopenia, Thrombocytopenia, Haemolysis*,lymphatic system Anaemia Lymphopenia Abnormal clotting factor,disorders Red blood cellagglutination,

Immune system Anaphylactic reaction,disorders Hypersensitivity

Endocrine Grave’s diseasedisorders

Metabolism and Decreased appetitenutrition disorders

MedDRA system Very Common Uncommon (≥ 1/1 000 Rareorgan class common (≥ 1/100 to to < 1/100) (≥ 1/10 000 to < 1/1 000)(≥ 1/10) < 1/10)

Psychiatric Insomnia Depression, Abnormal dreamsdisorders Anxiety,

Mood swings,

Sleep disorder

Nervous system Headache Dizziness Paraesthesia,disorders Tremour

Dysgeusia ,

Eye disorders Vision blurred Conjunctival irritation

Ear and labyrinth Tinnitus,disorders Vertigo

Cardiac disorders Palpitation

Vascular disorders Hypertension Accelerated Haematomahypertension,

Hypotension,

Hot flush,

Vein disorder

Respiratory, Cough, Dyspnoea,thoracic and Oropharyngeal Epistaxis,mediastinal pain Throat irritation,disorders Nasal congestion,

Rhinorrhoea

Gastrointestinal Diarrhoea, Constipation, Gastroesophageal refluxdisorders Vomiting, Dyspepsia, disease,

Nausea, Abdominal distension Gingival pain

Abdominal pain

Hepatobiliary Jaundicedisorders

Skin and Rash, Urticaria, Skin depigmentationsubcutaneous Pruritus, Erythema,tissue disorders Alopecia Petechiae,

Hyperhidrosis,

Dry skin,

Dermatitis

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

Neck pain

Renal and urinary Renal impairment,disorders Dysuria,

Haematuria

Reproductive Spontaneous penile Menstrual disordersystem and breast erectiondisorders

General disorders Pyrexia, Oedema, Extravasation,and administration Fatigue, Chest discomfort, Infusion site paraesthesia,site conditions Influenza-like Asthaenia, Feeling hotillness Chest pain,

Infusion site pain,

Chills

MedDRA system Very Common Uncommon (≥ 1/1 000 Rareorgan class common (≥ 1/100 to to < 1/100) (≥ 1/10 000 to < 1/1 000)(≥ 1/10) < 1/10)

Investigations Alanine Coombs test positivecaminotransferaseincreased,

Aspartateaminotransferaseincreased,

Gamma-glutamyltransferaseincreased,

Haematocrit decreased,

Haemoglobin decreased

Injury, poisoning Infusion relatedand procedural reactioncomplications

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 version 26.1.

* See ‘Description of selected adverse reactions.’a Abscess includes the following group of preferred terms (PTs): abscess limb, colonic abscess, renal abscess,subcutaneous abscess, 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 reports.

In all clinical studies, 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 with PNH and aHUS. As with all proteins there isa potential for immunogenicity.

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

Cases of thrombotic microangiopathy complication have been reported in the setting of missed ordelayed eculizumab dose in aHUS clinical trials (see section 4.4).

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 PNHpatients. 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 population

No overall differences in safety were reported between elderly (≥ 65 years) and younger refractorygMG patients (< 65 years) (see section 5.1).

Safety data from other clinical studies

Supportive safety data were obtained in 12 completed clinical studies that included 934 patientsexposed to eculizumab in other disease populations other than PNH, aHUS, refractory gMG or

NMOSD. There was an un-vaccinated patient diagnosed with idiopathic membranousglomerulonephropathy who experienced meningococcal meningitis. Adverse reactions reported inpatients with disease other than PNH, aHUS, refractory gMG or NMOSD were similar to thosereported in patients with PNH, aHUS, refractory gMG or NMOSD (see table 1 above). No specificadverse reactions have emerged from these clinical studies.

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.

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

Pharmacotherapeutic group: Complement Inhibitors, ATC code: L04AJ01

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

European Medicines Agency; www.ema.europa.eu.

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

BEKEMV is produced in a CHO cell line and purified by affinity and ion exchange chromatography.

The bulk active substance manufacturing process also includes specific viral inactivation and removalsteps.

Eculizumab, the active substance in BEKEMV, is a terminal complement inhibitor that specificallybinds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5band preventing the generation of the terminal complement complex C5b-9. Eculizumab preserves theearly components 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 BEKEMV treatment.

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

In PNH, chronic administration of BEKEMV 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 treatedwith eculizumab when administered as recommended demonstrated rapid and sustained reduction interminal complement activity. In all aHUS patients, eculizumab serum concentrations ofapproximately 50 - 100 microgram/mL are sufficient for essentially complete inhibition of terminalcomplement activity.

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

Paroxysmal nocturnal haemoglobinuria

The safety and efficacy of eculizumab in PNH patients with haemolysis were assessed in arandomised, 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 characterise 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/microlitrewere randomised 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 medicinal products. Major baseline characteristics werebalanced (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/microlitre received eculizumab over a 52-week period.

Concomitant medicinal products 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/immunosuppressant 16 (36.4) 14 (32.6) 46 (47.4)treatments (%)

Discontinued treatment 10 2 1

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

Q3)) 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)haemolysis resulting in improvements in anaemia as indicated by increased haemoglobin stabilisationand reduced need for RBC transfusions compared to placebo treated patients (see table 3). Theseeffects were 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 lessfatigue and improved health-related quality of life. Because of the study sample size and duration, theeffects of eculizumab on thrombotic events could not be determined. In SHEPHERD study, 96 of the97 enrolled patients completed the study (one patient died following a thrombotic event). A reductionin intravascular haemolysis as measured by serum LDH levels was sustained for the treatment periodand resulted 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 Eculizumab

P-value P-value

N = 44 N = 43 N = 97

Percentage of patients withstabilised haemoglobin0 49 < 0.001 N/Alevels at end of study

PRBC transfused during10 0 < 0.001 0 < 0.001treatment (median)

Transfusion avoidance0 51 < 0.001 51 < 0.001during treatment (%)

LDH levels at end of study2 167 239 < 0.001 269 < 0.001(median, U/L)

LDH AUC at end of study411 822 58 587 < 0.001 -632 264 < 0.001(median, U/L × Day)

Free haemoglobin at end of62 5 < 0.001 5 < 0.001study (median, mg/dL)

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 from10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the sameperiod of 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 × 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 in haemolysisand associated symptoms. At 6 months, patients treated with eculizumab with no history of RBCtransfusion had significantly (p < 0.001) reduced LDH levels (median LDH of 305 U/L; see 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 no historyof transfusion in M07-001

M07-001

Parameter Eculizumab

No transfusion

LDH level at baseline N = 43(median, U/L) 1 447

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) and30 patients in one retrospective study (C09-001r) were used to evaluate the efficacy of eculizumab inthe treatment 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≥ 4 weeks. Complete TMA response was defined as haematologic normalization and a ≥ 25%reduction in serum creatinine sustained in ≥ 2 consecutive measurements for ≥ 4 weeks. Baselinecharacteristics 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 10 (0.26, 236) 48 (0.66, 286)months median (min, max)

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

Number of PE/PI sessions for current clinical 17 (2, 37) 62 (20, 230)

TMA 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 through2 years 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 weresimilar in patients with and without identified mutations in genes encoding complement regulatoryfactor proteins. Reduction in terminal complement activity was observed in all patients aftercommencement of eculizumab. All rates of efficacy endpoints improved or were maintained through2 years of treatment. Complete TMA response was maintained by all responders. When treatment wascontinued for more than 26 weeks, six additional patients achieved and maintained Complete TMAresponse due to a decrease in serum creatinine. No patient required new dialysis with eculizumab.

Renal function, as measured by median eGFR, 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

Normalisation of platelet count

All patients, n (%) 14 (82) 15 (88) 18 (90) 18 (90)(95% CI) (57-96) (64-99) (68-99) (68-99)

Patients with abnormal baseline, n/n 13/15 (87) 13/15 (87) 1/3 (33) 1/3 (33)(%)

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

TMA intervention rate

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

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

P-value P < 0.0001 P < 0.0001 P < 0.0001 P < 0.0001

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

Change in Hgb > 20g/L, n (%) (95% 11 (65) 13 (76) 9 (45) 13 (65)

CI) (38-86) 2 (50-93) (23-68) 3 (41-85)

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

Complete TMA response, n (%) (95% 11(65) 13(76) 5 (25) 11(55)

CI) (38-86) (50-93) (9-49) (32-77)1 At data cut off (20 April 2012)2 Study C08-002: 3 patients received ESA which was discontinued after eculizumab initiation3 Study 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), 0.79 (0.03, 311)median (min, max)

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

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/1.73m2), 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/L byone 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)

Haematologic normalization, n (%) 36 (88)

Median duration of haematologic 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 (%) 37 (90)95% CI 77; 97

Daily TMA intervention rate, median (range)

Before eculizumab 0.63 (0, 1.38)

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

13 weeks 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 haematologic normalization. At the last evaluation, 25 of 41 patients (61%) achievedeGFR improvement of ≥ 15 mL/min/1.73 m2 from baseline.

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) (see tables 3 and 9).

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

P-Value

Mean (SD) Wilcoxon signed Paired t-testrank

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

LDH AUC (U/L × day) -60 634 0.0156 0.0350(72 916)

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

Change from baseline type III RBC clone 1.80 (358.1)size (percent of aberrant cells)

Change from baseline at 12 weeks of 10.5 (6.66) 0.1250 0.0256

PedsQL™ 4.0 generic core scale (patients)

Change from baseline at 12 weeks of 11.3 (8.5) 0.2500 0.0737

PedsQL™ 4.0 generic core scale (parents)

Change from baseline at 12 weeks of

PedsQL™ multidimensional fatigue 0.8 (21.39) 0.6250 0.4687(patients)

Change from baseline at 12 weeks of

PedsQL™ multidimensional fatigue 5.5 (0.71) 0.5000 0.0289(parents)

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 tofirst dose of eculizumab was 1 month (range < 1 to 16 months). The median duration of eculizumabtherapy was 16 weeks (range 4 to 70 weeks) for children < 2 years of age (n = 5) and 31 weeks (range19 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< 2 years (n = 5) 2 to < 12 years <12 years (n = 15)

Efficacy parameter (n = 10)

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

Complete TMA response, n (%) 2 (40) 5 (50) 7 (50)< 2 years (n = 5) 2 to < 12 years <12 years (n = 15)

Efficacy parameter (n = 10)

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 2 (40) 6 (60) 8 (53)improvement≥ 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 TMAmanifestation< 2 months N = 10 > 2 months N = 5(%) (%)

Platelet count normalisation 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 summarises 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 dose0.51 (0.03, 58) 0.56 (0.03,191)(months) median (min, max)

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,110 (19, 146) 91 (19,146)max)

Baseline LDH (U/L) median (min, max) 1 510 (282, 7 164) 1 244 (282, 7 164)

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

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 from88 ± 42 x109/L at baseline to 281 ± 123 x109/L by one week; this effect was maintained through26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x109/L). Renal function, as measured byeGFR, was improved during eculizumab therapy. Nine of the 11 patients who required dialysis atbaseline no longer required dialysis after study day 15 of eculizumab treatment. Responses weresimilar across all ages from 5 months to 17 years of age. In aHUS C10-003, responses to eculizumabwere similar in patients with and without identified mutations in genes encoding complementregulatory factor proteins 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 haematologic normalisation, n (%)14 (78) 18 (82)

Median duration of complete haematologic35 (13, 78) 35 (13, 78)normalisation, weeks (range) 1

Complete TMA response, n (%)

Median duration of complete TMA response, weeks 11 (61) 14 (64)(range)1 40 (13, 78) 37 (13, 78)

TMA event-free status, n (%) 17 (94) 21 (96)95% CI NA 77; 99

Daily TMA intervention rate, median (range)

Before eculizumab treatment, median 0.4 (0, 1.7)

NA

On eculizumab treatment, median 0 (0, 1.01)

NAeGFR 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 (%) 18 (100) 22 (100)95% CI NA 85;1001 Through data cut-off (October 12, 2012), with median duration of eculizumab therapy of 44 weeks (range:1 dose to 88 weeks).

Longer term treatment with eculizumab (median 55 weeks ranging from 1 day 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 22 patients (86%) achieved eGFR improvement of ≥ 15 mL/min/1.73 m2 from baseline. Nopatient required new dialysis with eculizumab.

Pharmacokinetics and active substance metabolism

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.

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.

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 micrograms/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 activity measured by free C5 concentrations of < 0.5 micrograms/mL, is correlatedwith essentially complete blockade of terminal complement activity in PNH and aHUS patients.

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 eculizumab studies showed that gender, race,age (geriatric), or the presence of renal or hepatic impairment function do not influence the PK ofeculizumab.

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 PNH,and aHUS body weight was a significant covariate requiring body weight-based dosing for paediatricpatients.

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.

Acetic acid

Sodium hydroxide

Disodium edetate (EDTA)

Sorbitol (E420)

Polysorbate 80 (E433)

Water for injections

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

3 years

After dilution, chemical and physical in-use stability has been demonstrated for the following:

* Polyolefin IV bags: 14 days at 2°C to 8°C followed by up to 48 hours at 2°C to 8°C or roomtemperature

* PVC IV bags: 48 hours at 2°C to 8°C or room temperature

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°C to 8°C, unless dilution has taken place incontrolled and validated aseptic conditions.

Store in a refrigerator (2°C - 8°C). Do not freeze.

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

BEKEMV vials in the original package may be removed from refrigerated storage for only one singleperiod of up to 7 days. At the end of this period the product can be put back in the refrigerator.

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

Vial (type I glass) with an elastomeric stopper and an aluminium seal with flip-off cap.

Pack size of one vial.

Prior to administration, the BEKEMV solution should be visually inspected for particulate matter anddiscolouration.

Dilution should be performed in accordance with good practices rules, particularly for the respect ofasepsis.

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

Transfer the recommended dose to an infusion bag.

Dilute BEKEMV 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 dosesand 180 mL for 900 mg doses and 240 mL for 1 200 mg doses. The solution should be clear andcolourless.

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 prior to administration byexposure to ambient temperature.

Discard any unused portion left in a vial.

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

Amgen Technology (Ireland) UC

Pottery Road, Dun Laoghaire

Co. Dublin,

A96 F2A8 Ireland

EU/1/23/1727/001

Date of first authorisation: 19 April 2023

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

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