Soliris 300 mg concentrate for solution for infusion

2.1 General description

Eculizumab is a humanised monoclonal IgG_2/4κ antibody produced in NS0 cell line by recombinant DNA technology.

2.2 Qualitative and quantitative composition

Each 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 (5.00 mmol per dose (1 vial))

For the full list of excipients, see section 6.1.

Concentrate for Solution for Infusion.

Clear, colorless, pH 7.0 solution.

Soliris (eculizumab) is indicated for the treatment of patients with

- Paroxysmal nocturnal haemoglobinuria (PNH).

Evidence of clinical benefit of Soliris in the treatment of patients with PNH is limited to patients with history of transfusions.

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

Soliris must be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological and/or renal disorders.

Posology

In Paroxysmal Nocturnal Haemoglobinuria (PNH):

The PNH dosing regimen consists of a 4-week initial phase followed by a maintenance phase:

• Initial phase: 600 mg of Soliris administered via a 25 - 45 minute intravenous infusion every week for the first 4 weeks.

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

In Atypical Haemolytic Uremic Syndrome (aHUS):

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

• Initial phase: 900 mg of Soliris via a 25 - 45 minute intravenous infusion every week for the first 4 weeks

• Maintenance phase: 1200 mg of Soliris administered via a 25 - 45 minute intravenous infusion for the fifth week, followed by 1200 mg of Soliris administered via a 25 - 45 minute intravenous infusion every 14 ± 2 days (see Section 5.1).

In paediatric aHUS patients (aged less than 12 years) and adolescent patients (aged 12 years to under 18 years), the Soliris dosing regimen consists of:

Supplemental dosing of Soliris is required in the setting of concomitant PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion):

Method of administration

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

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

The diluted solution of Soliris should be administered by intravenous infusion over 25 – 45 minutes via gravity feed, a syringe-type pump, or an infusion pump. It is not necessary to protect the diluted solution of Soliris from light during administration to the patient.

Patients should be monitored for one hour following infusion. If an adverse event occurs during the administration of Soliris, 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 adolescents and four hours in children aged less than 12 years.

Paediatric Population: For PNH patients, no data is available in paediatric patients. For aHUS patients, the method of administration of Soliris is the same for all age groups.

Elderly: Soliris may be administered to patients aged 65 years and over. There is no evidence to suggest that any special precautions are needed when older people are treated – although experience with Soliris in this patient population is still limited.

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

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

Treatment monitoring:

aHUS patients should be monitored for signs and symptoms of thrombotic microangiopathy (TMA) (See section 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).

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

Do not initiate Soliris therapy (see section 4.4):

in PNH patients:

• with unresolved Neisseria meningitidis infection.

• who are not currently vaccinated against Neisseria meningitidis.

in aHUS patients:

• with unresolved Neisseria meningitidis infection.

• who are not currently vaccinated against Neisseria meningitidis or do not receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

Soliris 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 Soliris increases the patient's susceptibility to meningococcal infection (Neisseria meningitidis). These patients might be at risk of disease by uncommon serogroups (particularly Y, W135 and X), although meningococcal disease due to any serogroup may occur. To reduce the risk of infection, all patients must be vaccinated at least 2 weeks prior to receiving Soliris. Patients less than 2 years of age and those who are treated with Soliris less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Patients must be re-vaccinated according to current medical guidelines for vaccination use. Tetravalent vaccines against serotypes A, C, Y and W135 are strongly recommended, preferably conjugated ones.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Cases of serious or fatal meningococcal infections have been reported in Soliris-treated patients. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary. Patients should be informed of these signs and symptoms and steps taken to seek medical care immediately (see Package Leaflet for a description).

Other Systemic Infections: Due to its mechanism of action, Soliris therapy should be administered with caution to patients with active systemic infections. The overall severity and frequency of infections in Soliris-treated patients was similar to placebo treated patients in clinical studies, although an increase in the number and severity of infections, particularly due to encapsulated bacteria, cannot be excluded. Patients should be provided with information from the Package Leaflet to increase their awareness of potential serious infections and the signs and symptoms of them.

Infusion Reactions: As with all therapeutic proteins, administration of Soliris may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis), though immune system disorders within 48 hours of Soliris administration did not differ from placebo treatment in PNH, aHUS and other studies conducted with Soliris. In clinical trials, no PNH or aHUS patients experienced an infusion reaction which required discontinuation of Soliris. Soliris administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.

Immunogenicity: Infrequent, low titre antibody responses have been detected in Soliris-treated patients across all studies. In placebo controlled studies low titre responses have been reported with a frequency (3.4%) similar to that of placebo (4.8%). No patients have been reported to develop neutralizing antibodies following therapy with Soliris, and there has been no observed correlation of antibody development to clinical response or adverse events.

Immunization: Prior to initiating Soliris therapy, it is recommended that PNH and aHUS patients should initiate immunizations according to current immunization guidelines. Additionally, all patients must be vaccinated against meningococcus at least 2 weeks prior to receiving Soliris. Patients less than 2 years of age and those who are treated with Soliris less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. If available, tetravalent, conjugated vaccines are recommended (see meningococcal infection).

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

Anticoagulant therapy: Treatment with Soliris should not alter anticoagulant management.

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

aHUS Laboratory Monitoring: aHUS patients receiving Soliris therapy should be monitored for thrombotic microangiopathy by measuring platelet counts, serum LDH and serum creatinine, and may require dose adjustment within the 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 Soliris they should be closely monitored for signs and symptoms of serious intravascular haemolysis. Serious haemolysis is identified by serum LDH levels greater than the pre-treatment level, along with any of the following: greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; a haemoglobin level of <5 g/dL or a decrease of >4 g/dL in one week or less; angina; change in mental status; a 50% increase in serum creatinine level; or thrombosis. Monitor any patient who discontinues Soliris for at least 8 weeks to 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 RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of Soliris. In PNH clinical studies, 16 patients discontinued the Soliris treatment regimen. Serious haemolysis was not observed.

Treatment Discontinuation for aHUS: Severe thrombotic microangiopathy complications were observed after Soliris discontinuation in the aHUS clinical studies. If aHUS patients discontinue treatment with Soliris they should be monitored closely for signs and symptoms of severe thrombotic microangiopathy complications.

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 as compared to either baseline or to peak platelet count during Soliris treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during Soliris treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during Soliris treatment; or (ii) any one of the following: a change in mental status or seizures; angina or dyspnoea; or thrombosis.

Monitor any patient who discontinues Soliris for at least 12 weeks to detect severe thrombotic microangiopathy complications.

If severe thrombotic microangiopathy complications occur after Soliris discontinuation, consider reinstitution of Soliris treatment, supportive care with PE/PI, or appropriate organ-specific supportive measures including renal support with dialysis, respiratory support with mechanical ventilation or anticoagulation. In aHUS clinical studies, 18 patients (5 in the prospective studies) discontinued Soliris treatment. Seven (7) severe thrombotic microangiopathy complications were observed following the missed dose in 5 patients and Soliris was re-initiated in 4 of these 5 patients.

Educational guidance: All physicians who intend to prescribe Soliris must ensure they are familiar with the physician's guide to prescribing. Physicians must discuss the benefits and risks of Soliris therapy with patients and provide them with a patient information brochure and a patient safety card.

Patients should be instructed that if they develop fever > 39°C, headache accompanied with fever and/or stiff neck or sensitivity to light, they should immediately seek medical care as these signs may be indicative of meningococcal infection.

Excipients: This medicinal product contains 5.00 mmol sodium per dose (1 vial). It should be taken into consideration by patients on a controlled sodium diet.

No interaction studies have been performed.

Pregnancy:

For Soliris, no clinical data on exposed pregnancies are available.

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

Human IgG are known to cross human placental barrier, and thus eculizumab may potentially cause terminal complement inhibition in the foetal circulation. Therefore, Soliris should be given to a pregnant woman only if clearly needed. Woman of childbearing potential have to use effective contraception during treatment and up to 5 months after treatment.

Breast-feeding:

It is unknown whether eculizumab is excreted into human milk. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, breast-feeding should be discontinued during treatment and up to 5 months after treatment.

No studies on the effects on the ability to drive and use machines have been performed.

a. Summary of the safety profile

Eculizumab for the treatment of PNH was studied in three clinical studies that included 195 eculizumab-treated patients and most of these patients have been enrolled in the E05-001 extension study. There was one pivotal trial comparing the eculizumab-treatment arm to a placebo-treatment arm.

Eculizumab for the treatment of aHUS was studied in 37 patients enrolled in two prospective controlled clinical studies (C08-002A/B and C08-003A/B). Additional safety data were collected in 30 patients in a retrospective study (C09-001r).

The most frequent adverse reactions were:

- Headache, dizziness, nausea and pyrexia each occurring in 5% or more in PNH clinical trials. Most headaches did not persist after the initial administration phase of Soliris.

- Leukopenia occurring in 10% or more in aHUS clinical trials

b. Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in clinical trials in PNH and aHUS. Adverse reactions reported at a very common (1/10) common (1/100 to <1/10) or uncommon (1/1,000 to <1/100) frequency with eculizumab are listed by system organ class and preferred term.

Table 1: Adverse Reactions Reported in 232 patients included in PNH and aHUS clinical trials and in postmarketing reports

*See paragraph. c. Description of selected adverse reactions

c. Description of selected adverse reactions

There was no evidence of an increased incidence of infection across PNH studies with eculizumab as compared to placebo, including serious infections, severe infections or multiple infections.

In all PNH clinical studies the most serious adverse reaction was meningococcal septicaemia in two vaccinated PNH patients (see section 4.4). There were no meningococcal infections or deaths in the aHUS clinical studies. There did not appear to be evidence for an increased risk of other serious infections with eculizumab treatment in the aHUS studies.

Low titres of antibodies were detected in 2% patients with PNH treated with Soliris. As with all proteins there is a potential for immunogenicity.

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

Cases of thrombotic microangiopathy have been reported in the setting of missed or delayed Soliris dose in aHUS clinical trials (see also Section 4.4).

d. Paediatric population

The safety profile in paediatric aHUS patients in the retrospective study C09-001r (N=15, patients ages 2 months to less than 12 years) treated with Soliris appeared similar to that observed in adult/adolescent aHUS patients. The most common (>10%) adverse events reported in paediatric patients were diarrhoea, vomiting, pyrexia, upper respiratory tract infection and headache.

Safety Data From Other Clinical Studies

Supportive safety data were obtained in 11 clinical studies that included 716 patients exposed to eculizumab in six disease populations other than PNH and aHUS. There was an un-vaccinated patient diagnosed with idiopathic membranous glomerulonephropathy who experienced meningococcal meningitis. With regard to other AEs and considering all double-blind, placebo-controlled studies in patients diagnosed with diseases other than PNH (N=526 patients with Soliris; N=221 patients with placebo), AEs reported with Soliris at a frequency of 2% or greater than the frequency reported with placebo were: upper respiratory tract infection, rash, and injury.

No case of overdose has been reported.

Pharmacotherapeutic group: Immunomodulators, ATC code: L04AA25

Soliris is a recombinant humanised monoclonal IgG_2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement. The Soliris antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Soliris is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148kDa.

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

Mechanism of Action

Eculizumab, the active ingredient in Soliris, is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab preserves the early components of complement activation that are essential for opsonization of microorganisms and clearance of immune complexes.

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

In most PNH patients, eculizumab serum concentrations of approximately 35 microgram/ml are sufficient for 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 mediated thrombotic microangiopathy are blocked with Soliris treatment.

All patients treated with Soliris when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In all aHUS patients, eculizumab serum concentrations of approximately 50-100 microgram/ml are sufficient for essentially complete inhibition of terminal complement activity.

In aHUS, chronic administration of Soliris resulted in a rapid and sustained reduction in complement mediated thrombotic microangiopathy.

Clinical efficacy and safety

Paroxysmal Nocturnal Haemoglobinuria

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 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 Soliris. In all studies, the dose of eculizumab was 600 mg every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 – 45 minutes.

In study C04-001 (TRIUMPH) PNH patients with at least 4 transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either Soliris (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the haemoglobin concentration (the "set-point") which would define each patient's haemoglobin stabilization and transfusion outcomes. The haemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Primary efficacy endpoints were haemoglobin stabilization (patients who maintained a haemoglobin concentration above the haemoglobin set-point and avoid any RBC transfusion for the entire 26 week period) and blood transfusion 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 at baseline continued these medications. Major baseline characteristics were balanced (see table 2).

In the non-controlled study C04-002 (SHEPHERD), PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received Soliris over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Baseline characteristics are shown in Table 2.

Table 2: Patient Demographics and Characteristics in C04-001 and C04-002

In TRIUMPH, study patients treated with Soliris had significantly reduced (p< 0.001) haemolysis resulting in improvements in anaemia as indicated by increased haemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see table 3). These effects 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 Soliris treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of Soliris on thrombotic events could not be determined. In SHEPHERD study, 96 of the 97 enrolled patients completed the study (one patient 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, a reduced need for RBC transfusion and less fatigue. See Table 3.

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

* 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 PNH patients were enrolled in a long term extension study (E05-001). All patients sustained a reduction in intravascular haemolysis over a total Soliris exposure time ranging from 10 to 54 months. There were fewer 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.

Atypical Haemolytic Uremic Syndrome

Data from 37 patients in two prospective controlled studies (C08-002A/B and C08-003A/B) and one retrospective study with 30 patients (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 early phase 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 longer term aHUS without apparent evidence of clinical thrombotic microangiopathy manifestations and receiving chronic PE/PI (1 PE/PI treatment every two weeks and no more than 3 PE/PI treatments/week for at least 8 weeks before the first dose). Patients in both prospective studies were treated with Soliris for 26 weeks and most patients enrolled into a long-term, open-label extension study. All patients enrolled in both prospective studies had an ADAMTS-13 level above 5%.

Patients received meningococcal vaccination prior to receipt of Soliris or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose of Soliris in adult and adolescent aHUS patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg 7 ± 2 days later, then 1200 mg every 14 ± 2 days for the study duration. Soliris was administered as an intravenous infusion over 35 minutes. The dosing regimen in paediatric patients and adolescents weighing less than 40 kg was defined based on a pharmacokinetic (PK) simulation that 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 thrombotic microangiopathy (TMA) event-free status in study C08-003A/B. Additional endpoints included TMA intervention rate, hematologic normalization, complete TMA response, changes in LDH, renal function and quality of life. TMA-event free status was defined as the absence for at least 12 weeks of the following: decrease in platelet count of > 25% from baseline, PE/PI, and new dialysis. TMA interventions were defined as PE/PI or new dialysis. Hematologic normalization was defined as normalization of platelet counts and LDH levels sustained for 2 consecutive measurements for 4 weeks. Complete TMA response was defined as hematologic normalization and a 25% reduction in serum creatinine sustained in 2 consecutive measurements for 4 weeks.

Baseline characteristics are shown in Table 4.

Table 4: Patient Demographics and Characteristics in C08-002A/B and C08-003A/B

Patients in aHUS Study C08-002 A/B received Soliris for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive Soliris by enrolling into an extension study. In aHUS C08-002A/B, the median duration of Soliris therapy was approximately 64 weeks (range: 2 weeks to 90 weeks).

A reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of Soliris. Reduction in terminal complement activity was observed in all patients after commencement of SOLIRIS. Table 5 summarizes the efficacy results for aHUS Study C08-002A/B.

Renal function, as measured by eGFR, was improved during Soliris therapy. Four of the five 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 improved health-related quality of life (QOL).

In aHUS C08-002A/B, responses to Soliris were similar in patients with and without identified mutations 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 the initial 26-week treatment period, most patients continued to receive Soliris by enrolling into an extension study. In aHUS Study C08-003A/B, the median duration of Soliris therapy was approximately 62 weeks (range: 26 to 74 weeks). Table 5 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 identified mutations in genes encoding complement regulatory factor proteins. Reduction in terminal complement activity was observed in all patients after commencement of Soliris. No patient required new dialysis with Soliris. Renal function, as measured by median eGFR, increased during Soliris therapy.

Table 5: Efficacy Outcomes in Prospective aHUS Studies C08-002A/B and C08-003A/B

^1.At data cut-off

² Study C08-002: 3 patients received ESA which was discontinued after eculizumab initiation

³ Study C08-003: 8 patients received ESA which was discontinued in 3 of them during eculizumab therapy

Paediatric aHUS population

A total of 15 paediatric patients (ages 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 (rang <1, 110 months). The median time from current thrombotic microangiopathy manifestation to first dose of Soliris was 1 month (range <1 to 16 month). The median duration of Soliris therapy was 16 weeks (range 4 to 70 weeks) for children < 2 years of age (n=5) and 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10).

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

Table 6: Efficacy Results in Paediatric Patients Enrolled in aHUS C009-001r

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 with eculizumab treatment (table 7).

In paediatric patients with longer duration of current severe clinical TMA manifestation prior to eculizumab, there was TMA control with eculizumab treatment. However, renal function was not changed due to prior irreversible kidney damage (Table 7).

Table 7: Efficacy Outcomes in Paediatric Patients in Study C09-001r according to duration of current severe clinical thrombotic microangiopathy (TMA) manifestation

*One patient achieved eGFR improvement after renal transplant

The European Medicines Agency has deferred the obligation to submit the results of studies with Soliris in one or more subsets of the paediatric population in PNH and in aHUS (see section 4.2 for information on paediatric use).

Pharmacokinetics and Drug Metabolism:

Biotransformation: Human antibodies undergo endocytotic digestion in the cells of the reticuloendothelial system. Eculizumab contains only naturally occurring amino acids and has no known active metabolites. Human antibodies are predominately catabolized by lysosomal enzymes to small peptides and amino acids.

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

Pharmacokinetic Parameters:

In 40 patients with PNH, a 1-compartmental model was used to estimate pharmacokinetic parameters after multiple 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-live was 11.3 ± 3.4 days. Based on these data, the onset of steady state is predicted to be approximately 49 – 56 days.

In PNH patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations and maintenance of trough levels above 35 microgram/ml results in essentially complete blockade of haemolytic activity in the majority of PNH patients.

A second population PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 37 aHUS patients receiving the recommended Soliris regimen in studies C08-002A/B and C08-003A/B. In this model, the clearance of Soliris for a typical aHUS patient weighing 70 kg was 0.0139 L/hr and the volume of distribution was 5.6 L. The elimination half-life was 297 h (approximately 12.4 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 a 1 hour intervention and the elimination half-life of eculizumab was reduced to 1.3 hours. Supplemental dosing is recommended when Soliris is administered to aHUS patients receiving plasma infusion or exchange (see section 4.2).

All aHUS patients treated with Soliris when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In aHUS patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations and maintenance of trough levels of approximately 50-100 microgram/ml result in essentially complete blockade of terminal complement activity in all aHUS patients.

Special Populations:

Formal studies have not been conducted to evaluate the pharmacokinetics of Soliris administration in special PNH patient populations based on gender, race, age (paediatric or geriatric), or renal or hepatic impairment.

The pharmacokinetics of Soliris have been studied in aHUS patients with a range of renal impairment and age. There have been no observed differences in pharmacokinetic parameters noted in these subpopulations of aHUS 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 human tissues. C5 expression in the human tissue panel examined in this study is consistent with published reports of C5 expression, as C5 has been reported in smooth muscle, striated muscle, and renal proximal tubular epithelium. No unexpected tissue cross-reactivity was observed.

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 of the study was effectively blocked in both female and male mice.

Animal reproduction studies have not been conducted with eculizumab. No clear treatment-related effects or adverse effects were observed in reproductive toxicology studies in mice with a surrogate terminal complement inhibitory antibody. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose (approximately 4 times the maximum recommended human Soliris dose, based on a body weight 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 of eculizumab or its effect on fertility.

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 in section 6.6.

30 months.

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

Store in a refrigerator (2°C - 8° C).

Do not freeze.

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

For storage conditions 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).

Soliris should be administered by a health care professional. Soliris therapy must not be initiated without prior vaccination against Neisseria meningitidis at least 2 weeks prior to initial administration. Patients less than 2 years of age and those who are treated with Soliris less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination (see section 4.4).

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

Prior to administration, the Soliris solution should be visually inspected for particulate matter and discolouration.

Instructions:

Reconstitution and dilution should be performed in accordance with good practices rules, particularly for the 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 0.9% sodium chloride, 0.45% sodium chloride, or 5% Dextrose in water, as the diluent.

The final volume of a 5 mg/ml diluted solution is 120 ml for 600 mg doses or 180 ml for 900 mg doses. The solution should be clear and colourless.

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

The diluted solution should be allowed to warm to room temperature prior to administration by exposure to ambient air.

Discard any unused portion left in a vial, as the product contains no preservatives.

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

Alexion Europe SAS

25 Boulevard de l'Amiral Bruix

75016 Paris

FRANCE

EU/1/07/393/001

20 June 2007

November 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.