SOLIRIS 300mg perfusive solution concentrate medication leaflet

Soliris 300 mg concentrate for solution for infusion

Eculizumab is a humanised monoclonal (IgG2/4κ) antibody produced in NS0 cell line by recombinant DNAtechnology.

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.

Excipients with known effect: Sodium (5 mmol per vial), polysorbate 80 (6.6 mg per vial)

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear, colorless, pH 7.0 solution.

Soliris 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 clinical symptom(s)indicative of high disease activity, regardless of transfusion history (see section 5.1).

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

- Refractory generalized myasthenia gravis (gMG) in patients aged 6 years and above who are anti-acetylcholine receptor (AChR) antibody-positive (see section 5.1).

Soliris is indicated in adults for the treatment of:

- Neuromyelitis optica spectrum disorder (NMOSD) in patients who are anti-aquaporin-4 (AQP4)antibody-positive with a relapsing course of the disease (see section 5.1).

Soliris must be administered by a healthcare professional and under the supervision of a physicianexperienced in the management of patients with haematological, renal, neuromuscular or neuro-inflammatory 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 recommendation fromthe treating physician. Home infusions should be performed by a qualified healthcare professional.

Paroxysmal Nocturnal Haemoglobinuria (PNH) in adults

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

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

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

atypical Haemolytic Uremic Syndrome (aHUS), refractory generalized Myasthenia Gravis (gMG) and

Neuromyelitis Optica Spectrum Disorder (NMOSD) in adults

The aHUS, refractory gMG and NMOSD dosing regimen for adult patients (≥18 years of age) consists ofa 4 week initial phase followed by a maintenance phase:

* Initial phase: 900 mg of Soliris 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 Soliris administered via a 25 - 45 minute (35 minutes ± 10minutes) intravenous infusion for the fifth week, followed by 1,200 mg of Soliris administered via a25 - 45 minute (35 minutes ± 10 minutes) intravenous infusion every 14 ± 2 days (see section 5.1).

Available data suggest that clinical response is usually achieved by 12 weeks of Soliris treatment.

Discontinuation of the therapy should be considered in a patient who shows no evidence of therapeuticbenefit by 12 weeks.

Paediatric patients in PNH, aHUS, or refractory gMG

Paediatric PNH, aHUS, or refractory gMG patients with body weight ≥ 40 kg are treated with the adultdosing recommendations.

In paediatric PNH, aHUS, and refractory gMG patients with body weight below 40 kg, the Soliris dosingregimen consists of:

Patient Body Initial Phase Maintenance Phase

Weight30 to <40 kg 600 mg weekly for the first 2 900 mg at week 3; then 900 mg every 2 weeksweeks20 to <30 kg 600 mg weekly for the first 2 600 mg at week 3; then 600 mg every 2 weeksweeks10 to <20 kg 600 mg single dose at week 1 300 mg at week 2; then 300 mg every 2 weeks5 to <10 kg 300 mg single dose at week 1 300 mg at week 2; then 300 mg every 3 weeks

Soliris has not been studied in patients with PNH or refractory gMG who weigh less than 40kg. Theposology of Soliris to be used in paediatric patients with PNH or refractory gMG patients weighing lessthan 40 kg is identical to the weight-based dose recommendation provided for paediatric patients withaHUS. Based on the pharmacokinetic (PK)/pharmacodynamic (PD) data available in patients with aHUSand PNH treated with Soliris, this body-weight based dose regimen for paediatric patients is expected toresult in an efficacy and safety profile similar to that in adults. For patients with refractory gMG weighingless than 40 kg this body-weight based dose regimen is also expected to result in an efficacy and safetyprofile similar to that in adults.

Supplemental dosing of Soliris 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 Supplemental Soliris Timing of

Intervention Soliris Dose Dose With Each Supplemental Soliris

PP/PE/PI Intervention Dose

Plasmapheresis or plasma 300 mg 300 mg per eachexchange plasmapheresis orplasma exchange Within 60 minutes aftersession each plasmapheresis or≥600 mg 600 mg per each plasma exchangeplasmapheresis orplasma exchangesession

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

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

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

Most Recent Soliris Supplemental Soliris Dose Timing of Supplemental

Dose Soliris Dose≥ 900 mg 600 mg per IVIg cycle As soon as possible after≤ 600 mg 300 mg per IVIg cycle IVIg cycle

Abbreviation: IVIg = intravenous immunoglobulin

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

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

Soliris is clinically indicated (see section 4.4).

Soliris may be administered to patients aged 65 years and over. There is no evidence to suggest that anyspecial precautions are needed when older people are treated - although experience with Soliris in thispatient population is still limited.

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

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

The safety and efficacy of Soliris in children with refractory gMG aged less than 6 years old have not beenestablished.

The safety and efficacy of Soliris in children with NMOSD aged less than 18 years old have not beenestablished.

Do not administer as an intravenous push or bolus injection. Soliris should only be administered viaintravenous infusion as described below.

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

The diluted solution of Soliris should be administered by intravenous infusion over 25 - 45 minutes (35minutes ± 10 minutes) in adults and 1-4 hours in paediatric patients under 18 years of age via gravity feed,a syringe-type pump, or an infusion pump. It is not necessary to protect the diluted solution of Soliris fromlight during administration to the patient.

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

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

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

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

Soliris 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.

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

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

Due to its mechanism of action, the use of Soliris increases the patient’s susceptibility to meningococcalinfection (Neisseria meningitidis). Meningococcal disease due to any serogroup may occur. To reduce therisk of infection, all patients must be vaccinated at least 2 weeks prior to receiving Soliris unless the riskof delaying Soliris therapy outweighs the risks of developing a meningococcal infection. Patients whoinitiate Soliris 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 revaccinated accordingto current national guidelines for vaccination use.

Vaccination may further activate complement. As a result, patients with complement-mediated diseases,including PNH, aHUS, refractory gMG and NMOSD, may experience increased signs and symptoms oftheir underlying disease, such as haemolysis (PNH), TMA (aHUS), MG exacerbation (refractory gMG) orrelapse (NMOSD). Therefore, patients should be closely monitored for disease symptoms afterrecommended vaccination.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given toofficial guidance on the appropriate use of antibacterial agents. Cases of serious or fatal meningococcalinfections have been reported in Soliris-treated patients. Sepsis is a common presentation ofmeningococcal infections in patients treated with Soliris (see section 4.8). All patients should bemonitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, andtreated with appropriate antibiotics if necessary. Patients should be informed of these signs and symptomsand steps taken to seek medical care immediately. Physicians must discuss the benefits and risks of Soliristherapy with patients and provide them with a Patient guide and a patient card (see Package Leaflet for adescription).

Due to its mechanism of action, Soliris therapy should be administered with caution to patients with activesystemic infections. Patients may have increased susceptibility to infections, especially with Neisseria andencapsulated 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 patients aboutgonorrhoea prevention.

Administration of Soliris may result in infusion reactions or immunogenicity that could cause allergic orhypersensitivity reactions (including anaphylaxis). In clinical trials, 1 (0.9%) refractory gMG patientexperienced an infusion reaction which required discontinuation of Soliris. No PNH, aHUS, refractorygMG or NMOSD paediatric patients experienced an infusion reaction which required discontinuation of

Soliris. Soliris administration should be interrupted in all patients experiencing severe infusion reactionsand appropriate medical therapy administered.

Infrequent antibody responses have been detected in Soliris-treated patients across all clinical studies. In

PNH placebo controlled studies low antibody responses have been reported with a frequency (3.4%)similar to that of placebo (4.8%).

In patients with aHUS treated with Soliris, antibodies to Soliris were detected in 3/100 (3%) by the ECLbridging format assay. 1/100 (1%) aHUS patients had low positive values for neutralizing antibodies.

In a refractory gMG placebo controlled study, none (0/62) of the Soliris treated patients showed antidrugantibody response during the 26 week active treatment, whereas in a refractory gMG extension study, atotal of 3/117 (2.6%) overall were positive for ADAs at any post-baseline visit. Positive ADA resultsappeared to be transient, as positive titers were not observed at subsequent visits, and there were noclinical findings in these patients suggestive of an effect of positive ADA titers.

In a NMOSD placebo controlled study, 2/95 (2.1%) of the Soliris treated patients showed antidrugantibody response post-baseline. Both patients were negative for neutralizing antibodies. Positive ADAsamples were low titer and transient. There has been no observed correlation of antibody development toclinical response or adverse events.

Prior to initiating Soliris therapy, it is recommended that PNH, aHUS, refractory gMG and NMOSDpatients initiate immunizations according to current immunization guidelines. Additionally, all patientsmust be vaccinated against meningococcal infections at least 2 weeks prior to receiving Soliris unless therisk of delaying Soliris therapy outweighs the risks of developing a meningococcal infection. Patients whoinitiate Soliris 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 revaccinated accordingto current national guidelines for vaccination use (see Meningococcal Infection).

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

Vaccination may further activate complement. As a result, patients with complement-mediated diseases,including PNH, aHUS, refractory gMG and NMOSD may experience increased signs and symptoms oftheir underlying disease, such as haemolysis (PNH), TMA (aHUS), MG exacerbation (refractory gMG) orrelapse (NMOSD). Therefore, patients should be closely monitored for disease symptoms afterrecommended vaccination.

Treatment with Soliris should not alter anticoagulant management.

When immunosuppressant and anticholinesterase therapies are decreased or discontinued, patients shouldbe monitored closely for signs of disease exacerbation.

When immunosuppressant therapy is decreased or discontinued, patients should be monitored closely forsigns and symptoms of potential NMOSD relapse.

PNH patients should be monitored for signs and symptoms of intravascular haemolysis, including serumlactate dehydrogenase (LDH) levels. PNH patients receiving Soliris therapy should be similarly monitoredfor intravascular haemolysis by measuring LDH levels, and may require dose adjustment within therecommended 14±2 day dosing schedule during the maintenance phase (up to every 12 days).

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

If PNH patients discontinue treatment with Soliris 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% absolute decreasein PNH clone size (in the absence of dilution due to transfusion) in one week or less; a haemoglobin levelof <5 g/dL or a decrease of >4 g/dL in one week or less; angina; change in mental status; a 50% increasein serum creatinine level; or thrombosis. Monitor any patient who discontinues Soliris for at least 8 weeksto detect serious haemolysis and other reactions.

If serious haemolysis occurs after Soliris discontinuation, consider the following procedures/treatments:blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCsby flow cytometry; anticoagulation; corticosteroids; or reinstitution of Soliris. In PNH clinical studies, 16patients discontinued the Soliris treatment regimen. Serious haemolysis was not observed.

Thrombotic microangiopathy (TMA) complications have been observed as early as 4 weeks and up to 127weeks following discontinuation of Soliris treatment in some patients. Discontinuation of treatment shouldonly be considered if medically justified.

In aHUS clinical studies, 61 patients (21 paediatric patients) discontinued Soliris treatment with a medianfollow-up period of 24 weeks. Fifteen severe thrombotic microangiopathy (TMA) complications in 12patients were observed following treatment discontinuation, and 2 severe TMA complications occurred inan additional 2 patients that received a reduced dosing regimen of Soliris outside of the approved dosingregimen (See Section 4.2). Severe TMA complications occurred in patients regardless of whether theyhad an identified genetic mutation, high risk polymorphism or auto-antibody. Additional serious medicalcomplications occurred in these patients including severe worsening of kidney function, disease-relatedhospitalization and progression to end stage renal disease requiring dialysis. Despite Soliris re-initiationfollowing discontinuation, progression to end stage renal disease occurred in one patient.

If aHUS patients discontinue treatment with Soliris, they should be monitored closely for signs andsymptoms of severe thrombotic microangiopathy complications. Monitoring may be insufficient to predictor prevent severe thrombotic microangiopathy complications in patients with aHUS after discontinuationof Soliris.

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

If severe thrombotic microangiopathy complications occur after Soliris discontinuation, considerreinstitution of Soliris treatment, supportive care with PE/PI, or appropriate organ-specific supportivemeasures including renal support with dialysis, respiratory support with mechanical ventilation oranticoagulation.

Use of Soliris in refractory gMG treatment has been studied only in the setting of chronic administration.

Patients who discontinue Soliris treatment should be carefully monitored for signs and symptoms ofdisease exacerbation.

Use of Soliris in NMOSD treatment has been studied only in the setting of chronic administration and theeffect of Soliris discontinuation has not been characterized. Patients who discontinue Soliris treatmentshould be carefully monitored for signs and symptoms of potential NMOSD relapse.

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

Professionals to prescribing. Physicians must discuss the benefits and risks of Soliris therapy with patientsand 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 stiff neckor sensitivity to light, they should immediately seek medical care as these signs may be indicative ofmeningococcal infection.

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicinal product contains0.88 g sodium per 240 mL at the maximal dose, equivalent to 44.0% of the WHO recommendedmaximum 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 0.67 g sodium per 240 mL at the maximal dose, equivalent to 33.5% of the WHO recommendedmaximum 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 equivalent to0.66 mg/kg or less at the maximum dose for adult patients and paediatric patients with body weight morethan 10 kg and is equivalent to 1.32 mg/kg or less at the maximum dose for paediatric patients with bodyweight 5 to <10 kg. Polysorbates may cause allergic reactions.

No interaction studies have been performed. Based on the potential inhibitory effect of eculizumab oncomplement-dependent cytotoxicity of rituximab, eculizumab may reduce the expected pharmacodynamiceffects 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 systemic exposuresand reduce effectiveness of eculizumab. Closely monitor for reduced effectiveness of eculizumab.

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 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 potentially causeterminal complement inhibition in the foetal circulation. Therefore, Soliris should be given to a pregnantwoman only if clearly needed.

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, thedevelopmental and health benefits of breastfeeding should be considered along with the mother’s clinicalneed for eculizumab and any potential adverse effects on the breastfed child from eculizumab or from theunderlying maternal condition.

No specific study of eculizumab on fertility has been conducted.

Soliris 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, refractory gMG and

NMOSD. The most common adverse reaction was headache, (occurred mostly in the initial phase ofdosing), and the most 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 reactions reported ata very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100) or rare (≥1/10000 to <1/1 000) frequency with eculizumab, are listed by system organ class and preferred term. Withineach 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 postmarketing experience

MedDRA System Very Common Uncommon Rare

Organ Class Common (≥1/100 to <1/10) (≥1/1 000 to <1/100) (≥1/10000 to <1/1000)(≥1/10)

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

Bronchitis, Peritonitis, Lower gonococcal infection,

Nasopharyngitis, respiratory tract Haemophilus infection,

Urinary tract infection, Fungal Impetigoinfection, Oral infection, Viral

Herpes infection, Abscessa,

Cellulitis, Influenza,

Gastrointestinalinfection, Cystitis,

Infection, Sinusitis,

Gingivitis

Neoplasms benign, Malignant melanoma,malignant and Myelodysplastic syndromeunspecified(including cysts andpolyps)

Blood and lymphatic Leukopenia, Thrombocytopenia, Haemolysis*, Abnormalsystem disorders Anaemia Lymphopenia clotting factor, Red bloodcell agglutination,

Immune system Anaphylactic reaction,disorders Hypersensitivity

Endocrine disorders Grave’s disease

Metabolism and Decreased appetitenutrition disorders

Psychiatric disorders Insomnia Depression, Anxiety, Abnormal dreams

Mood swings, Sleepdisorder

Nervous system Headache D izziness Paraesthesia, Tremor,disorders Dysgeusia, Syncope

Eye disorders Vision blurred Conjunctival irritation

Ear and labyrinth Tinnitus, Vertigodisorders

Cardiac disorders Palpitation

Vascular disorders Hypertension Accelerated Haematomahypertension,

Hypotension, Hotflush, Vein disorder

Respiratory, Cough, Dyspnoea, Epistaxis,thoracic and Oropharyngeal pain Throat irritation, Nasalmediastinal congestion,disorders Rhinorrhoea

Gastrointestinal Diarrhoea, Constipation, Gastroesophageal refluxdisorders Vomiting, Nausea, Dyspepsia, Abdominal disease, Gingival pain

Abdominal pain distension

Hepatobiliary Jaundicedisorders

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

Hyperhidrosis, Dryskin, Dermatitis

Musculoskeletal and Arthralgia, Myalgia, Muscle spasms, Bone Trismus, Joint swellingconnective tissue Pain in extremity pain, Back pain, Neckdisorders pain

Renal and urinary Renal impairment,disorders Dysuria, Haematuria

Reproductive system Spontaneous penile Menstrual disorderand breast disorders erection

General disorders Pyrexia, Fatigue, Edema, Chest Extravasation, Infusion siteand administration Influenza-like discomfort, Asthenia, paraesthesia, Feeling hotsite conditions illness Chest pain, Infusionsite pain, Chills

Investigations Alanine Coombs test positivecaminotransferaseincreased, Aspartateaminotransferaseincreased, Gamma-glutamyltransferaseincreased, Haematocritdecreased,

Haemoglobindecreased

Injury, poisoning Infusion-relatedand procedural reactioncomplication

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 paragraph Description of selected adverse reactions.a Abscess includes the following group of 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.cADRs identified in postmarketing reports

In all clinical studies, the most serious adverse reaction was meningococcal sepsis which is a commonpresentation of meningococcal infections in patients treated with Soliris (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 Soliris were detected in 2% of patients with PNH using an ELISA assay, 3% of patientswith aHUS and 2% of patients with NMOSD using the ECL bridging format assay. In refractory gMGplacebo-controlled studies, no antidrug antibodies were observed. As with all proteins there is a potentialfor immunogenicity.

Cases of haemolysis have been reported in the setting of missed or delayed Soliris dose in PNH clinicaltrials (see also Section 4.4).

Cases of thrombotic microangiopathy complication have been reported in the setting of missed or delayed

Soliris dose in aHUS clinical trials (see also Section 4.4).

In children and adolescent PNH patients (aged 11 years to less than 18 years) included in the paediatric

PNH Study M07-005, the safety profile appeared similar to that observed in adult PNH patients. The mostcommon 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 adult aHUSpatients. The safety profiles in the different paediatric subsets of age appear similar.

In paediatric patients with refractory gMG (aged 12 to less than 18 years) included in

Study ECU-MG-303, the safety profile appeared similar to that observed in adult patients with refractorygMG.

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

Supportive safety data were obtained in 12 completed clinical studies 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 from theseclinical studies.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

Pharmacotherapeutic group: Complement Inhibitors, ATC code: L04AJ01

Soliris is a recombinant humanised monoclonal IgG2/4k antibody that binds to the human C5 complementprotein and inhibits the activation of terminal complement. The Soliris antibody contains human constantregions and murine complementarity-determining regions grafted onto the human framework light- andheavy-chain variable regions. Soliris is composed of two 448 amino acid heavy chains and two 214 aminoacid light chains and has a molecular weight of approximately 148 kDa.

Soliris is produced in a murine myeloma (NS0 cell line) expression system and purified by affinity and ionexchange chromatography. The bulk drug substance manufacturing process also includes specific viralinactivation and removal steps.

Eculizumab, the active ingredient in Soliris, is a terminal complement inhibitor that specifically binds tothe 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 opsonization of microorganisms and clearanceof immune complexes.

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

In most PNH patients, eculizumab serum concentrations of approximately 35 microgram/mL are sufficientfor essentially complete inhibition of terminal complement-mediated intravascular haemolysis.

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

In aHUS patients, uncontrolled terminal complement activation and the resulting complement-mediatedthrombotic microangiopathy are blocked with Soliris treatment.

All patients treated with Soliris when administered as recommended demonstrated rapid and sustainedreduction in terminal 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 Soliris resulted in a rapid and sustained reduction in complement-mediated thrombotic microangiopathy.

In refractory gMG patients, uncontrolled terminal complement activation causes membrane attackcomplex (MAC) dependent lysis and C5a-dependent inflammation at the Neuromuscular Junction (NMJ)leading to failure of neuromuscular transmission. Chronic administration of Soliris results in immediate,complete, and sustained inhibition of terminal complement activity (eculizumab serum concentrations ≥116 microgram/ml).

In patients with NMOSD, uncontrolled terminal complement activation caused by autoantibodies against

AQP4 leads to the formation of the MAC and C5a-dependent inflammation which results in astrocytenecrosis and increased permeability of the blood brain barrier, as well as death of the surroundingoligodendrocytes and neurons. Chronic administration of Soliris results in immediate, complete, andsustained inhibition of terminal complement activity (eculizumab serum concentrations ≥ 116microgram/ml).

The safety and efficacy of Soliris in PNH patients with haemolysis were assessed in a randomized,double-blind, placebo-controlled 26 week study (C04-001). PNH patients were also treated with Soliris ina single arm 52 week study (C04-002), and in a long term extension study (E05-001). Patients receivedmeningococcal vaccination prior to receipt of Soliris. In all studies, the dose of eculizumab was 600 mgevery 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for thestudy duration. Soliris was administered as an intravenous infusion over 25 - 45 minutes (35 minutes ± 10minutes). An observational non-interventional Registry in patients with PNH (M07-001) was also initiatedto characterize the natural history of PNH in untreated patients and the clinical outcomes during Soliristreatment.

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/microliter wererandomized to either Soliris (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent aninitial observation period to confirm the need for RBC transfusion and to identify the haemoglobinconcentration (the 'set-point') which would define each patient’s haemoglobin stabilization andtransfusion outcomes. The haemoglobin set-point was less than or equal to 9 g/dL in patients withsymptoms and was less than or equal to 7 g/dL in patients without symptoms. Primary efficacy endpointswere haemoglobin stabilization (patients who maintained a haemoglobin concentration above thehaemoglobin set-point and avoid any RBC transfusion for the entire 26 week period) and bloodtransfusion requirement. Fatigue and health-related quality of life were relevant secondary 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 systemic corticosteroids atbaseline 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 the prior24 months and at least 30,000 platelets/microliter received Soliris over a 52-week period. Concomitantmedications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% ofthe 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 Soliris Soliris

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

Treatments (%) 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 Soliris had significantly reduced (p< 0.001) haemolysisresulting in improvements in anaemia as indicated by increased haemoglobin stabilization and reducedneed for RBC transfusions compared to placebo treated patients (see Table 3). These effects were seenamong patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units;> 25 units). After 3 weeks of Soliris treatment, patients reported less fatigue and improved health-relatedquality of life. Because of the study sample size and duration, the effects of Soliris on thrombotic eventscould not be determined. In SHEPHERD study, 96 of the 97 enrolled patients completed the study (onepatient died following a thrombotic event). A reduction in intravascular haemolysis as measured by serum

LDH levels was sustained for the treatment period and resulted in increased transfusion avoidance, areduced 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 Soliris

N = 44 N = 43 P - Value Soliris

N = 97 P - Value

Percentage of patients withstabilized Haemoglobin levels 0 49 < 0.001 N/Aat end of study

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

Transfusion Avoidance duringtreatment (%) 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, Soliris-treated PNHpatients were enrolled in a long term extension study (E05-001). All patients sustained a reduction inintravascular haemolysis over a total Soliris exposure time ranging from 10 to 54 months. There werefewer thrombotic events with Soliris treatment than during the same period 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 Soliris in PNH patients with no historyof RBC transfusion. These patients had high disease activity as defined by elevated haemolysis (LDH≥1.5x ULN) and the presence of related clinical symptom(s): fatigue, haemoglobinuria, abdominal pain,shortness of breath (dyspnoea), anaemia (haemoglobin <100 g/L), major adverse vascular event (includingthrombosis), dysphagia, or erectile dysfunction.

In the PNH Registry, patients treated with Soliris were observed to have a reduction in haemolysis andassociated symptoms. At 6 months, patients treated with Soliris with no history of RBC transfusion hadsignificantly (p<0.001) reduced LDH levels (median LDH of 305 U/L; Table 4). Furthermore, 74% of thepatients without a history of transfusion and treated with Soliris experienced clinically meaningfulimprovements in FACIT-Fatigue score (i.e., increase by 4 points or more) and 84% in EORTC fatiguescore (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 Soliris

No transfusion

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

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

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

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

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

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 30 patients inone retrospective study (C09-001r) were used to evaluate the efficacy of Soliris in the 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 platelet count ≤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/PI treatments/weekfor at least 8 weeks before the first dose). Patients in both prospective studies were treated with Soliris for26 weeks and most patients enrolled into a long-term, open-label extension study. All patients enrolled inboth prospective studies had an ADAMTS-13 level above 5%.

Patients received meningococcal vaccination prior to receipt of Soliris or received prophylactic treatmentwith appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose of Soliris in adult andadolescent aHUS patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1,200 mg 7 ± 2 dayslater, then 1,200 mg every 14 ± 2 days for the study duration. Soliris was administered as an intravenousinfusion over 35 minutes. The dosing regimen in paediatric patients and adolescents weighing less than40 kg was defined based on a pharmacokinetic (PK) simulation that identified the recommended dose andschedule 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, renal functionand quality of life. TMA-event free status was defined as the absence for at least 12 weeks of thefollowing: decrease in platelet count of > 25% from baseline, PE/PI, and new dialysis. TMA interventionswere defined as PE/PI or new dialysis. Haematologic normalization was defined as normalization ofplatelet counts and LDH levels sustained for ≥2 consecutive measurements for ≥4 weeks. Complete TMAresponse was defined as haematologic normalization and a ≥25% reduction in serum creatinine sustainedin ≥ 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

Soliris Soliris

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 < 1 (<1, 4) 9 (1, 45)manifestation until screening in months,median (min, max)

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

Number of PE/PI sessions in 7 days prior to 6 (0, 7) 2 (1, 3)first 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 Soliris for a minimum of 26 weeks. After completion ofthe initial 26-week treatment period, most patients continued to receive Soliris by enrolling into anextension study. In aHUS Study C08-002A/B, the median duration of Soliris therapy wasapproximately100 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 Soliris. Reduction in terminal complement activity was observed in allpatients after commencement of Soliris. Table 6 summarizes the efficacy results for aHUS Study C08-002A/B. All rates of efficacy endpoints improved or were maintained through 2 years of treatment.

Complete TMA response was maintained by all responders. When treatment was continued for more than26 weeks, two additional patients achieved and maintained Complete TMA response due to normalizationof LDH (1 patient) and a decrease in serum creatinine (2 patients).

Renal function, as measured by eGFR, was improved and maintained during Soliris therapy. Four of thefive patients who required dialysis at study entry were able to discontinue dialysis for the duration of

Soliris treatment, and one patient developed a new dialysis requirement. Patients reported improvedhealth-related quality of life (QoL).

In aHUS Study C08-002A/B, responses to Soliris were similar in patients with and without identifiedmutations in genes encoding complement regulatory factor proteins.

Patients in aHUS study C08-003A/B received Soliris for a minimum of 26 weeks. After completion of theinitial 26-week treatment period, most patients continued to receive Soliris by enrolling into an extensionstudy. In aHUS Study C08-003A/B, the median duration of Soliris therapy was approximately 114 weeks(range: 26 to 129 weeks). Table 6 summarizes the efficacy results for aHUS Study C08-003A/B.

In aHUS Study C08-003A/B, responses to Soliris were similar in patients with and without identifiedmutations in genes encoding complement regulatory factor proteins. Reduction in terminal complementactivity was observed in all patients after commencement of Soliris. All rates of efficacy endpointsimproved or were maintained through 2 years of treatment. Complete TMA response was maintained byall responders. When treatment was continued for more than 26 weeks, six additional patients achievedand maintained Complete TMA response due to a decrease in serum creatinine. No patient required newdialysis with Soliris. Renal function, as measured by median eGFR, increased during Soliris 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 > 11 (65) 13 (76) 9 (45) 13 (65)20g/L, n (%) (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)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). Inorder to qualify for enrolment, patients were required to have a platelet count < lower limit of normalrange (LLN), evidence of haemolysis such as an elevation in serum LDH, and serum creatinine above theupper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to80 years). All patients enrolled in aHUS Study C10-004 had an ADAMTS-13 level above 5%. Fifty-onepercent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of35 patients received PE/PI prior to eculizumab. Table 7 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS C10-004.

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

Parameter

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 firststudy dose (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/1.73m2), median (min, max) 10 (6, 53)

Patients in aHUS Study C10-004 received Soliris for a minimum of 26 weeks. After completion of theinitial 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 Soliris. Soliris reduced signs of complement-mediated TMA activity, asshown 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 by one week; this effect wasmaintained through 26 weeks (mean platelet count (±SD) at week 26: 252 ± 70 x109/L). Renal function, asmeasured by eGFR, was improved during Soliris therapy. Twenty of the 24 patients who required dialysisat baseline were able to discontinue dialysis during Soliris treatment. Table 8 summarizes the efficacyresults for aHUS study C10-004.

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

Efficacy Parameter (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 (%) 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 Soliris therapy of 50 weeks (range: 13weeks to 86 weeks).

Longer term treatment with Soliris (median 52 weeks ranging from 15 to 126 weeks) was associated withan increased rate of clinically meaningful improvements in adult patients with aHUS. When Soliristreatment was continued for more than 26 weeks, three additional patients (63% of patients in total)achieved Complete TMA response and four additional patients (98% of patients in total) achievedhematologic normalization. At the last evaluation, 25 of 41 patients (61%) achieved eGFR improvementof ≥ 15 mL/min/1.73 m2 from baseline.

Data from 139 patients in two prospective controlled studies (Studies C08-001 and ECU-MG-301), andone open-label extension trial (Study ECU-MG-302) were used to evaluate the efficacy of Soliris in thetreatment of patients with refractory gMG.

Study ECU-MG-301 (REGAIN) was a 26-week double-blind, randomized, placebo-controlled, multi-center Phase 3 study of Soliris in patients who had failed previous therapies and remain symptomatic. Onehundred and eighteen (118) of the 125 (94%) patients completed the 26-week treatment period and117 (94%) patients subsequently enrolled in Study ECU-MG-302, an open-label, multi-center long-termsafety and efficacy extension study in which all patients received Soliris treatment.

In Study ECU-MG-301, gMG patients with a positive serologic test for anti-AChR antibodies, MGFA(Myasthenia Gravis Foundation of America) clinical classification class II to IV and MG-ADL total score≥6 were randomized to either Soliris (n = 62) or placebo (n = 63). All patients included in the trial wererefractory gMG patients and met the following predefined criteria:

1) Failed treatment for at least one year with 2 or more immunosuppressant therapies (either incombination or as monotherapy), ie, patients continued to have impairment in activities of daily livingdespite immunosuppressant therapies

OR2) Failed at least one immunosuppressant therapy and required chronic plasma exchange or IVIg tocontrol symptoms, ie, patients require PE or IVIg on a regular basis for the management of muscleweakness at least every 3 months over previous 12 months.

Patients received meningococcal vaccination prior to initiating treatment with Soliris or receivedprophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In Studies ECU-MG-301 and ECU-MG-302, the dose of Soliris in adult refractory gMG patients was 900 mg every 7 ± 2 daysfor 4 weeks, followed by 1200 mg at Week 5± 2 days, then 1,200 mg every 14 ± 2 days for the studyduration. Soliris was administered as an intravenous infusion over 35 minutes.

Table 9 presents the baseline characteristics of the refractory gMG patients enrolled in Study ECU-MG-301.

Table 9: Patient Demographic and Characteristics in Study ECU-MG-301

Soliris (n=62) Placebo (n=63)

Age at MG Diagnosis (years),

Mean (min, max) 38.0 (5.9, 70.8) 38.1 (7.7, 78.0)

Female, n (%) 41 (66.1) 41 (65.1)

Duration of MG (years),

Mean (min, max) 9.9 (1.3, 29.7) 9.2 (1.0, 33.8)

Baseline MG-ADL Score

Mean (SD) 10.5 (3.06) 9.9 (2.58)

Median 10.0 9.0

Baseline QMG Score

Mean (SD) 17.3 (5.10) 16.9 (5.56)

Median 17.0 16.0≥3 Prior Immunosuppressive Therapies*since diagnosis, n (%) 31 (50.0) 34 (54.0)

Number of patients with prior exacerbationssince diagnosis, n (%) 46 (74.2) 52 (82.5)

Number of patients with prior MG crisissince diagnosis, n (%) 13 (21.0) 10 (15.9)

Any prior ventilator support since diagnosis,n (%) 15 (24.2) 14 (22.2)

Any prior intubation since diagnosis (MGFAclass V), n (%) 11 ( 17.7) 9 ( 14.3)

* Immunosuppressant’s included, but are not limited to, corticosteroids, azathioprine, mycophenolate, methotrexate ,cyclosporine, tacrolimus, or cyclophosphamide.

The primary endpoint for Study ECU-MG-301 was the change from baseline in the MG Activities of

Daily Living Profile (MG-ADL - a patient reported outcome measure validated in gMG) total score at

Week 26. The primary analysis of the MG-ADL was a Worst-Rank ANCOVA with a mean rank of 56.6for Soliris and 68.3 for placebo, based on 125 study patients (p=0.0698).

The key secondary endpoint was the change from baseline in the Quantitative MG Scoring System (QMG- a physician reported outcome measure validated in gMG) total score at Week 26. The primary analysisof the QMG was a Worst-Rank ANCOVA with a mean rank of 54.7 for Soliris and 70.7 for placebo,based on 125 study patients (p=0.0129).

Efficacy outcomes for the pre-specified repeated measures analyses of the primary and secondaryendpoints are provided in Table 10.

Table 10: ECU-MG-301 Efficacy Outcomes Change from Baseline to Week 26

Efficacy Soliris Placebo Soliris change p-value (using

Endpoints: Total (n=62) (n=63) relative to placebo repeated measuresscore change (SEM) (SEM) - LS Mean analysis)from baseline at Difference (95%

Week 26 CI)

MG-ADL -4.2 (0.49) -2.3(0.48) -1.9 0.0058(-3.3, -0.6)

QMG -4.6 (0.60) -1.6 (0.59) -3.0 0.0006(-4.6, -1.3)

MGC -8.1 (0.96) -4.8 (0.94) -3.4 0.0134(-6.0, -0.7)

MG-QoL-15 -12.6 (1.52) -5.4 (1.49) -7.2 0.0010(-11.5, -3.0)

SEM= Standard Error of the Mean CI= Confidence Interval, MGC= Myasthenia Gravis Composite, MG-QoL15=

Myasthenia Gravis Quality of Life 15

In Study ECU-MG-301, a clinical responder in the MG-ADL total score was defined as having at least a3-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was 59.7%on Soliris compared with 39.7% on placebo (p=0.0229).

In Study ECU-MG-301, a clinical responder in the QMG total score was defined as having at least a 5-pointimprovement. The proportion of clinical responders at Week 26 with no rescue therapy was 45.2% on Soliriscompared with 19% on placebo (p=0.0018).

Table 11 presents an overview of the patients reporting clinical deterioration and patients requiring rescuetherapy over the 26 weeks.

Table 11: Clinical deterioration and rescue therapy in ECU-MG-301

Variable Statistic Placebo Soliris(N=63) (N=62)

Total number of patients reporting clinical deterioration n (%) 15 (23.8) 6 (9.7)

Total number of patients requiring rescue therapy n (%) 12 (19.0) 6 (9.7)

Of the 125 patients enrolled in ECU-MG-301, 117 patients subsequently enrolled in a long-term extensionstudy (Study ECU-MG-302), in which all received Soliris. Patients that were previously treated with Solirisin Study ECU-MG-301 continued to demonstrate a sustained effect of Soliris on all measures (MG-ADL,

QMG, MGC and MG-QoL15) over an additional 130 weeks of treatment with eculizumab in Study ECU-

MG-302. For patients who received placebo in Study ECU-MG-301 (placebo/eculizumab arm of Study

ECU-MG-302), improvement occurred after initiating treatment with eculizumab and was maintained formore than 130 weeks in Study ECU-MG-302. Figure 1 presents the change from baseline in both MG-ADL(A) and QMG (B) after 26 weeks of treatment in Study ECU-MG-301 and after 130 weeks of treatment (n= 80 patients) in Study ECU-MG-302.

Figure 1: Mean changes from baseline in MG-ADL (1A) and QMG (1B) over Studies ECU-MG-301 and

ECU-MG-302

In Study ECU-MG-302, physicians had the option to adjust background immunosuppressant therapies. Inthis setting, 65.0% of patients decreased their daily dose of at least 1 immunosuppressive therapy (IST);43.6% of patients stopped an existing IST. The most common reason for change in IST therapy wasimprovement in MG symptoms.

Twenty-two (22) (17.6%) elderly refractory gMG patients (> 65 years of age) were treated with Soliris inthe clinical trials. No substantial differences were seen in safety and efficacy related to age.

Data from 143 patients in one controlled study (Study ECU-NMO-301) and from 119 patients whocontinued in one open-label extension trial (Study ECU-NMO-302) were used to evaluate the efficacy andsafety of Soliris in the treatment of patients with NMOSD.

Study ECU-NMO-301 was a double-blind, randomized, placebo-controlled, multi-center, Phase 3 study of

Soliris in patients with NMOSD.

In Study ECU-NMO-301, patients with NMOSD with a positive serologic test for anti-AQP4 antibodies, ahistory of at least 2 relapses in last 12 months or 3 relapses in the last 24 months with at least 1 relapse inthe 12 months prior to screening and an Expanded Disability Status Scale (EDSS) score ≤ 7, wererandomized 2:1 to either Soliris (n = 96) or placebo (n = 47). Patients were permitted to receivebackground immunosuppressant therapies at stable dose during the study, with the exclusion of rituximaband mitoxantrone.

Patients either received meningococcal vaccination at least 2 weeks prior to initiating treatment with

Soliris or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. Inthe eculizumab NMOSD clinical development program, the dose of Soliris in adult patients with NMOSDwas 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg at Week 5 ± 2 days, then 1200 mg every14 ± 2 days for the study duration. Soliris was administered as an intravenous infusion over 35 minutes.

The majority (90.9%) of patients were female. Approximately half were White (49.0%). The median ageat first dose of study drug was 45 years.

Table 12: Patient Disease History and Baseline Characteristics in Study ECU-NMO-301

Placebo Eculizumab Total

Variable Statistic (N = 47) (N = 96) (N = 143)

NMOSD History

Age at NMOSD Initial Mean (SD) 38.5 (14.98) 35.8 (14.03) 36.6 (14.35)

Clinical Presentation Median 38.0 35.5 36.0(years) Min, Max 12, 73 5, 66 5, 73

Time from NMOSD Mean (SD) 6.601 (6.5863) 8.156 (8.5792) 7.645 (7.9894)initial clinical Median 3.760 5.030 4.800presentation to firstdose of study drug Min, Max 0.51, 29.10 0.41, 44.85 0.41, 44.85(years)

Historical Annualized Mean (SD) 2.07 (1.037) 1.94 (0.896) 1.99 (0.943)

Relapse Rate within Median 1.92 1.85 1.9224 months prior to

Screening Min, Max 1.0, 6.4 1.0, 5.7 1.0, 6.4

Baseline characteristics

Baseline EDSS score Mean (SD) 4.26 (1.510) 4.15 (1.646) 4.18 (1.598)

Median 4.00 4.00 4.00

Min, Max 1.0, 6.5 1.0, 7.0 1.0, 7.0

No IST usage atbaseline n (%) 13 (27.7) 21 (21.9) 34 (23.8)

Abbreviations: ARR = adjudicated relapse rate; EDSS = Expanded Disability Status Scale; IST = immunosupressanttherapy; Max = maximum; Min = minimum; NMOSD = neuromyelitis optica spectrum disorder; SD = standarddeviation.

The primary endpoint for Study ECU-NMO-301 was the time to first on-trial relapse as adjudicated by anindependent committee who were blinded to treatment. A significant effect on the time to first adjudicated

On-trial Relapse was observed for eculizumab compared with placebo (relative risk reduction 94%; hazardratio 0.058; p<0.0001) (Figure 2). Soliris-treated patients experienced similar improvement in time to firstadjudicated on-trial relapse with or without concomitant IST treatment.

1.097.9% 96.4% 96.4%0.80.663.2%0.4 51.9%45.4%0.2 Proportion Relapse-Free at48 Weeks (95% CI) (1,2):0.632 (0.468, 0.758) Log rank p-value (3): <0.0001 Placebo0.979 (0.918, 0.995) Hazard ratio (95% CI) (4,5): 0.058 (0.017, 0.197) Eculizumab0.00 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216

Time in Study Period (weeks)

Number at Risk:

Placebo 47 38 30 24 21 16 13 10 9 6 5 5 4 3 3 3 3 1

Eculizumab 96 92 83 78 68 60 58 52 46 41 32 24 22 18 14 8 2 1

Figure 2: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse in

Study ECU-NMO-301 - Full Analysis Set

Note: Patients who did not experience an adjudicated On-trial Relapse were censored at the end of the Study Period.

Stratified analyses are based on four randomization strata:(i) low EDSS at randomization (<=2.0), (ii) high EDSS (>=2.5 to <=7) and treatment naive at randomization, (iii) high

EDSS (>=2.5 to <=7) and continuing on the same IST(s) since last relapse at randomization, (iv) high EDSS (>=2.5to <=7) and changes in IST(s) since last relapse at randomization.1 Based on the Kaplan-Meier product limit method.2 Based on the complementary log-log transformation.3 Based on a stratified log-rank test.4 Based on a stratified Cox proportional hazards model.5 Wald confidence interval.

Abbreviations: CI = confidence interval; EDSS = Expanded Disability Status Scale; IST = immunosuppressive therapy

The adjudicated on-trial annualized relapse rate (ARR) ratio (95% CI) for eculizumab compared withplacebo was 0.045 (0.013, 0.151), representing a 95.5% relative reduction in adjudicated On-trial ARR forpatients treated with eculizumab compared with placebo (p<0.0001) (Table 13).

Proportion Relapse-Free

Table 13: Adjudicated On-trial Annualized Relapse Rate in Study ECU-NMO-301 - Full Analysis

Set

Placebo Eculizumab

Variable Statistic (N = 47) (N = 96)

Total number of relapses Sum 21 3

Total number of patient-years in studyperiod n 52.41 171.32

Rate 0.350 0.016

Adjusted adjudicated ARRa95% CI 0.199, 0.616 0.005, 0.050

Rate ratio(eculizumab/placebo) … 0.045

Treatment effecta 95% CI … 0.013, 0.151p-value … <0.0001a Based on a Poisson regression adjusted for randomization strata and historical ARR in 24 monthsprior to Screening.

Abbreviations: ARR = annualized relapse rate; CI = confidence interval.

Compared to placebo-treated patients, Soliris-treated patients had reduced annualized rates ofhospitalizations (0.04 for Soliris versus 0.31 for placebo), of intravenous corticosteroid administrations totreat acute relapses (0.07 for Soliris versus 0.42 for placebo), and of plasma exchange treatments (0.02 for

Soliris versus 0.19 for placebo).

The distribution of changes from Baseline to End of Study on other secondary endpoints favoredeculizumab treatment over placebo across all neurologic disability (EDSS score [p=0.0597] and mRS[nominal p=0.0154]), functional disability (HAI [nominal p=0.0002]) and quality of life (EQ-5D VAS[nominal p=0.0309] and EQ-5D Index [nominal p= 0.0077]) measures.

The final analysis of Study ECU-NMO-302 demonstrates a significant and clinically meaningful reductionin On-trial ARR (as determined by the treating Physician) on eculizumab treatment, based on the median(min, max) change (-1.825 [-6.38, 1.02], p<0.0001) from historical ARR (24 months prior to screening in

Study ECU-NMO-301).

In Study ECU-NMO-302, physicians had the option to adjust background immunosuppressant therapies. Inthis setting, the most common change in immunosuppressant therapy was decreased immunosuppressanttherapy dose, which occurred in 21.0% of patients. Further, 15.1% of patients stopped an existing IST.

Soliris (eculizumab) has not been studied for the treatment of acute relapses in NMOSD patients.

A total of 7 PNH paediatric patients, with a median weight of 57.2 kg (range of 48.6 to 69.8 kg) and agedfrom 11 to 17 years (median age : 15.6 years), received Soliris 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 a markeddecrease or elimination of blood transfusions, and a trend towards an overall improvement in generalfunction. The efficacy of eculizumab treatment in paediatric PNH patients appears to be consistent withthat observed in adult PNH patients enrolled in PNH pivotal Studies (C04-001 and C04-002) (Table 3 and14).

Table 14: 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 0.0336

Value (U/L)

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

Change from baseline at 12 weeks in

Plasma 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

PedsQLTM4.0 Generic Core scale (patients) 10.5 (6.66) 0.1250 0.0256

Change from baseline at 12 weeks of

PedsQLTM4.0 Generic Core scale (parents) 11.3 (8.5) 0.2500 0.0737

Change from baseline at 12 weeks of

PedsQLTM Multidimensional Fatigue 0.8 (21.39) 0.6250 0.4687(patients)

Change from baseline at 12 weeks of

PedsQLTM Multidimensional Fatigue 5.5 (0.71) 0.5000 0.0289(parents)

A total of 15 paediatric patients (aged 2 months to 12 years) received Soliris 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 Soliris was 14 months (range <1, 110 months). Themedian time from current thrombotic microangiopathy manifestation to first dose of Soliris was 1 month(range <1 to 16 months). The median duration of Soliris therapy was 16 weeks (range 4 to 70 weeks) forchildren < 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 observed inpatients enrolled in aHUS pivotal Studies C08-002 and C08-003 (Table 6). No paediatric patient requirednew dialysis during treatment with Soliris.

Table 15: 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 function witheculizumab treatment (Table 15).

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 16).

Table 16: Efficacy Outcomes in Paediatric Patients in Study C09-001r according to duration ofcurrent severe clinical thrombotic microangiopathy (TMA) manifestation

Duration of current severeclinical 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 Soliris inaHUS Study C10-003.

In Study C10-003, patients who enrolled in the study were required to have a platelet count < lower limitof normal range (LLN), evidence of haemolysis such as an elevation in serum LDH above the upper limitsof normal and serum creatinine level ≥97 percentile for age without the need for chronic dialysis. Themedian patient age was 6.5 years (range: 5 months to 17 years). Patients enrolled in aHUS C10-003 hadan ADAMTS-13 level above 5%. Fifty percent of patients had an identified complement regulatory factormutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 17 summarizesthe key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study C10-003.

Table 17: 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 Soliris for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients elected to continue on chronic dosing. Reduction in terminalcomplement activity was observed in all patients after commencement of Soliris. Soliris reduced signs ofcomplement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26weeks. The mean (±SD) platelet count increased from 88 ± 42 x109/L at baseline to 281 ± 123 x109/L byone week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106x109/L). Renal function, as measured by eGFR, was improved during Soliris therapy. Nine of the 11patients who required dialysis at baseline no longer required dialysis after Study Day 15 of eculizumabtreatment. Responses were similar across all ages from 5 months to 17 years of age. In aHUS C10-003,responses to Soliris were similar in patients with and without identified mutations in genes encodingcomplement regulatory factor proteins or auto-antibodies to factor H.

Table 18 summarizes the efficacy results for aHUS C10-003.

Table 18: 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 hematologic1 35 (13, 78) 35 (13, 78)normalization, weeks (range)

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 (%) 17 (94) 21 (96)95% CI NA 77; 99

Daily TMA Intervention rate, median (range)

NA 0.4 (0, 1.7)

Before eculizumab treatment, median

NA 0 (0, 1.01)

On eculizumab treatment, medianeGFR improvement ≥15 mL/min/ 1.73*m2, n (%) 16 (89) 19 (86)

Change in eGFR ( ≥15 mL/min/1.73*m2) at 26weeks, 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 Soliris therapy of 44 weeks (range: 1 dose to 88weeks).

Longer term treatment with Soliris (median 55 weeks ranging from 1day to 107 weeks) was associatedwith an increased rate of clinically meaningful improvements in paediatric and adolescent patients withaHUS. When Soliris treatment was continued for more than 26 weeks, one additional patient (68% ofpatients in total) achieved Complete TMA Response and two additional patients (91% of patients in total)achieved hematologic normalization. At the last evaluation, 19 of 22 patients (86%) achieved eGFRimprovement of ≥ 15 mL/min/1.73 m2 from baseline. No patient required new dialysis with Soliris.

A total of 11 paediatric patients with refractory gMG received Soliris in study ECU-MG-303. The median(range) body weight of the treated patients was 59.7 kg (37.2 to 91.2 kg) at baseline, and the median(range) age of 15 years (12 to 17 years) at screening. All patients included in the study were patients withrefractory gMG who had one or more of the following:

1. Failed treatment ≥ 1 year with at least 1 IST, defined as: (i) Persistent weakness with impairment ofactivities of daily living, or (ii) Myasthenia gravis exacerbation and/or crisis while on treatment,or (iii) Intolerance to ISTs due to side effect or comorbid condition(s).

2. Require maintenance PE or IVIg to control symptoms (ie, patients who require PE or IVIg on aregular basis for the management of muscle weakness at least every 3 months over the last12 months prior to screening).

The baseline characteristics of the paediatric patients with refractory gMG enrolled in study ECU-MG-303are outlined in Table 19.

Table 19: Patient Demographic and Characteristics in Study ECU-MG-303

Eculizumab (n = 11)

Female n (%) 9 (81.8%)

Duration of MG (time from MG Mean (SD) 3.99 (2.909)diagnosis to first study drug date Median (min, max) 2.90 (0.1, 8.8)[years])

Baseline MG-ADL total score Mean (SD) 5.0 (5.25)

Median (min, max) 4.0 (0, 19)

Baseline QMG total score Mean (SD) 16.7 (5.64)

Median (min, max) 15.0 (10, 28)

MGFA classification at Screening n (%)

IIa 2 (18.2)

IIb 3 (27.3)

IIIa 3 (27.3)

IIIb 0

IVa 3 (27.3)

IVb 0

Patients with prior MG exacerbation n (%)including MG crisis since diagnosis

No 4 (36.4)

Yes 7 (63.6)

Exacerbation 6 (54.5)

MG crisis 3 (27.3)

Chronic IVIg therapy at study entry n (%)

Yes 6 (54.5)

No 5 (45.5)

Number of immunosuppressant n (%)therapies at Baseline 2 (18.2)0 4 (36.4)1 5 (45.5)

Patients with any immunosuppressant n (%)therapiesa at Baseline n (%)

Corticosteroids 8 (72.7)

Azathioprine 1 (9.1)

Mycophenolate mofetil 2 (18.2)

Tacrolimus 3 (27.3)aImmunosuppressant therapies included corticosteroids, azathioprine, cyclophosphamide, cyclosporine,methotrexate, mycophenolate mofetil, or tacrolimus. No patient received cyclosporine, cyclophosphamide, ormethotrexate at Baseline.

Abbreviations: IVIg = intravenous immunoglobulin; max = maximum; MG = myasthenia gravis;

MG-ADL = Myasthenia Gravis Activities of Daily Living profile; MGFA = Myasthenia Gravis Foundation of

America; min = minimum; QMG = Quantitative Myasthenia Gravis score for disease severity; SD = standarddeviation

The primary endpoint of study ECU-MG-303 was the change from baseline in the QMG total score overtime regardless of rescue therapy. Paediatric patients treated with Soliris demonstrated a statisticallysignificant improvement from baseline in QMG total score throughout the Primary Evaluation Treatment

Period of 26 weeks. The results for the primary and main secondary endpoint in study ECU-MG-303 areincluded in Table 20.

The efficacy of Soliris treatment in paediatric patients with refractory gMG was consistent with thatobserved in adult patients with refractory gMG enrolled in the pivotal study ECU-MG-301 (Table 10).

Table 20: Efficacy Outcomes in Study ECU-MG-303

Efficacy Endpoints: Total Score Change from Baseline at LS Mean (SEM)

Week 26 95% CI

QMG -5.8 (1.2)(-8.40, -3.13)na = 10

MG-ADL total score -2.3 (0.6)(-3.63, -1.03)na = 10

MGC total score -8.8 (1.9)(-12.92, -4.70)na = 10an is the number of patients at Week 26

Abbreviations: CI = confidence interval; LS = least squares; MG-ADL = Myasthenia Gravis Activities of Daily

Living profile; MGC = Myasthenia Gravis Composite; QMG = Quantitative Myasthenia Gravis score for diseaseseverity; SEM = standard error of mean; VAS = visual analog scale

In study ECU-MG-303, a clinical responder in the QMG and MG-ADL total scores was defined as havingat least a 5-point improvement and 3-point improvement from baseline, respectively. The proportion ofclinical responders in the QMG and MG-ADL total scores at Week 26 regardless of rescue therapy was 70%and 50%, respectively. The 10 patients who completed their visit at Week 26 achieved improved status of

MGFA Post-Interventional Status (MGFA-PIS) at Week 26. Seven (70%) patients achieved minimalmanifestation of refractory gMG at Week 26.

An event of clinical deterioration (MG crisis) was observed in 1 patient (9.1%) during the

Primary Evaluation Treatment Period requiring rescue therapy (PE) which was administeredbetween the Week 22 and Week 24 study visits. As a result and due to physician decision, thispatient did not have QMG, MG-ADL or other efficacy assessments after Week 20 and did notenter the extension period.Another 2 patients experienced clinical deteriorations (MG crisis)during the Extension Period requiring rescue therapy (PE and IVIg for clinical deterioration inone case and IVIg and 2 supplemental treatments of eculizumab in the second case).

During the entire study period in paediatric patients with refractory gMG (study ECU-MG-303), 4 out of11 patients (36.4%) decreased their daily dose of IST or anticholinesterase therapy due to improved MGsymptoms. An additional patient (9.1%) decreased and subsequently increased their daily dose during the

Extension Period due to improved and worsened MG symptoms respectively and 1 patient started a newcorticosteroid treatment due to worsened MG symptoms.

All patients who completed the Primary Treatment Period (N=10) entered the Extension Period of up to208 weeks of treatment. Only two patients completed the Extension Period. Eight participantsdiscontinued the study during the Extension Period including 4 participants transitioned to eithercommercially available Soliris or Ultomiris or transferred to another ongoing Ultomiris paediatric study.

Patients consistently maintained the response through the study, which was of similar magnitude to thatreported to during the initial treatment period.

Figure 3: Change from Baseline in QMG Total Score (LS Mean and 95% CI) regardless of Rescue

Therapy) during Week 1 to Week 52 Using a Repeated Measures Model

Abbreviations:; LS=Least square; CI=Confidence Interval.

Note: Baseline is defined as the last available assessment value prior to first study drug infusion.

Note: Estimates are based on MMRM that included terms of visit and baseline value.

Mean equal to 0. A compound symmetry covariance structure was used.

The European Medicines Agency has waived the obligation to submit the results of studies with Soliris inone or more subsets of the paediatric population in the treatment of NMOSD (see section 4.2 forinformation on paediatric use).

Pharmacokinetics and Drug 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. Humanantibodies are predominately catabolized by lysosomal enzymes to small peptides and amino acids.

No specific studies have been performed to evaluate the hepatic, renal, lung, or gastrointestinal routes ofexcretion/elimination for Soliris. In normal kidneys, antibodies are not excreted and are excluded fromfiltration by their size.

In 40 patients with PNH, a 1-compartmental model was used to estimate pharmacokinetic parameters aftermultiple doses. Mean clearance was 0.31 ± 0.12 mL/hr/kg, mean volume of distribution was 110.3 ±17.9 mL/kg, and mean elimination half-life was 11.3 ± 3.4 days. The steady state is achieved by 4 weeksusing the PNH adult dosing regimen.

In PNH patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations andmaintenance of trough levels above ≥ 35 microgram/mL results in essentially complete blockade ofhaemolytic activity in the majority of PNH patients.

A second population PK analysis with a standard 1 compartmental model was conducted on the multipledose PK data from 37 aHUS patients receiving the recommended Soliris regimen in studies C08-002A/Band C08-003A/B. In this model, the clearance of Soliris for a typical aHUS patient weighing 70 kg was0.0139 L/hr and the volume of distribution was 5.6 L. The elimination half-life was 297 h (approximately12.4 days).

The second population PK model was applied to the multiple dose PK data from 22 paediatric aHUSpatients receiving the recommended Soliris regimen in aHUS C10-003. The clearance and volume ofdistribution of Soliris are weight dependent, which forms the basis for a weight categorical based doseregimen in paediatric patients (see section 4.2). Clearance values of Soliris in paediatric aHUS patientswere 10.4, 5.3, and 2.2 mL/hr with body weight of 70, 30, and 10 kg, respectively; and the correspondingvolume of distribution values were 5.23, 2.76, and 1.21 L, respectively. The corresponding eliminationhalf-life remained almost unchanged within a range of 349 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. Supplementaldosing is recommended when Soliris is administered to aHUS patients receiving plasma infusion orexchange (see section 4.2).

All aHUS patients treated with Soliris when administered as recommended demonstrated rapid andsustained 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, aHUS, refractory gMG and NMOSD patient populations.

Pharmacodynamic activity measured by free C5 concentrations of <0.5 ug/mL, is correlated withessentially complete blockade of terminal complement activity in PNH, aHUS, refractory gMG and

NMOSD patients.

Dedicated studies have not been conducted to evaluate the pharmacokinetics of Soliris in special patientpopulations identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment.

Population PK (PopPK) analysis on data collected across studies in PNH, aHUS, gMG and NMOSDpatients showed that gender, race, age (geriatric), or the presence of renal or hepatic impairment functiondo not influence the PK of eculizumab.

The pharmacokinetics of eculizumab was evaluated in Study M07-005 in PNH paediatric patients (agedfrom 11 to less than 18 years), in Studies C08-002, C08-003, C09-001r and C10-003 in aHUS paediatricpatients (aged 2 months to less than 18 years), and in Study ECU-MG-303 paediatric patients withrefractory gMG (aged from 12 years to less than 18 years) PopPK analysis showed that for PNH, aHUS,refractory gMG, and NMOSD, body weight was a significant covariate requiring body weight-baseddosing for pediatric patients.

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 renal proximaltubular 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 the course ofthe study was effectively blocked in both female and male mice.

No clear treatment-related effects or adverse effects were observed in reproductive toxicology studies inmice with a surrogate terminal complement inhibitory antibody, which was utilized 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 dysplasia andone case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higherantibody dose (approximately 4 times the maximum recommended human Soliris dose, based on a bodyweight comparison); however, the exposure did not increase foetal loss or neonatal death.

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

Sodium phosphate, monobasic

Sodium phosphate, dibasic

Sodium chloride

Polysorbate 80

Water for injections

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

30 months.

After dilution, the medicinal product should be used immediately. However, chemical and physicalstability has been demonstrated for 24 hours at 2°C - 8°C.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

Soliris vials in the original package may be removed from refrigerated storage for only one single periodof up to 3 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.

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

Pack size of one vial.

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

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

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

Transfer the recommended dose to an infusion bag.

Dilute Soliris to a final concentration of 5 mg/ml by addition to the infusion bag using sodium chloride9 mg/ml (0.9%) solution for injection, sodium chloride 4.5 mg/ml (0.45%) solution for injection, or 5%dextrose 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 the productand diluent.

The diluted solution should be allowed to warm to room temperature prior to administration by exposureto 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.

Alexion Europe SAS103-105 rue Anatole France92300 Levallois-Perret

FRANCE

EU/1/07/393/001

Date of first authorisation : 20 June 2007

Date of latest renewal : 18 June 2012

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

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