Soliris

Manufacturer name change and address update:

Alexion Pharma International Operations Limited

College Business and Technology Park

Blanchardstown Road North

Dublin 15,

D15 R925

Ireland

Update in line with QRD update v10.1 and EC Guideline on ‘Excipients in the labelling and package leaflet of medicinal product for human use’:

Section 2 What you need to know before you use Soliris – update to section ‘Soliris contains sodium’

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicine contains 0.88g sodium (main component of cooking/table salt) in 240 mL at the maximal dose. This is equivalent to 44 % of the recommended maximum daily dietary intake of sodium for an adult. You should take this into consideration if you are on a controlled sodium diet.

Once diluted with sodium chloride 4.5 mg/mL (0.45%) solution for injection, this medicine contains 0.67g sodium (main component of cooking/table salt) in 240 mL at the maximal dose. This is equivalent to 33.5 % of the recommended maximum daily dietary intake of sodium for an adult. You should take this into consideration if you are on a controlled sodium diet.

Section 6 Contents of the pack and other information – text revision date – November 2022

4.4 Special warnings and precautions for use – addition of ‘Traceability’ statement and Sodium content expression in line with QRD update v10.1:

Traceability

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

(...)

Sodium content

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicinal product contains 0.88 g sodium per 240 mL at the maximal dose, equivalent to 44.0% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Once diluted with sodium chloride 4.5 mg/mL (0.45%) solution for injection, this medicinal product contains 0.67 g sodium per 240 mL at the maximal dose, equivalent to 33.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

5.2    Pharmacokinetic properties - update to section title 'Pharmacokinetic/pharmacodynamic relationship(s)' in line with QRD update v10.1

10 Date of revision of the text – 10 November 2022

Update to the SmPC resulted from the review of final clinical study report ECU-NMO-302, a phase III, open-label, extension trial of ECU-NMO-301 to evaluate the safety and efficacy of eculizumab in subjects with neuromyelitis optica spectrum disorder (NMOSD).

Update to Section 5.1 - Pharmacodynamic properties:

(...)

The final analysis of Study ECU-NMO-302 demonstrates a significant and clinically meaningful reduction in 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. In this setting, the most common change in immunosuppressant therapy was decreased immunosuppressant therapy dose, which occurred in 21.0% of patients. Further, 15.1% of patients stopped an existing IST.

(...)

Update to Section 10 - Date of revision of the text:

01 September 2022

Update to ADR reporting details for the inclusion of 'Northern Ireland' as per latest QRD AppendixV

Update to ADR reporting details for the inclusion of 'Northern Ireland' as per latest QRD AppendixV

SmPC updated following approval of 'home infusion' addition as an alternative infusion setting for all approved indications

Changes due to regulatory procedures EMEA/H/C/000791/II/0105 (NMOSD)  & IAIN/0106 (MAH address change).  The European Commission Decision was 26August2019.    

Following approval of procedures EMEA/H/C/000791/II/0105 (NMOSD) & IAIN/0106 (MAH address change).   The European Commission Decision was 26August2019.    

Following approval of procedures EMEA/H/C/000791/II/0105 (NMOSD) & IAIN/0106 (MAH address change).  The European Commission Decision was 26August2019.   

In section 4.4 newly inserted the following.

Sepsis is a common presentation of meningococcal infections in patients treated with Soliris (see section 4.8).  

Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

Physicians should advise patients about gonorrhoea prevention.

In section 4.5 newly inserted the following.

Chronic intravenous human immunoglobulin (IVIg) treatment may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as eculizumab and thereby decrease serum eculizumab concentrations. Drug interaction studies have not been conducted with eculizumab in patients treated with IVIg.

In section 4.8 newly inserted the following.

Other cases of Neisseria species have been reported including sepsis with Neisseria gonorrhoeae, Neisseria sicca/subflava, Neisseria spp unspecified.

In section 10 the date is amended to state September 2018.  

In section 4.6 (Fertility, pregnancy and lactation), the information has been updated due to new data available

In section 5.3 (Preclinical safety data) the information has been updated due to new data available

Section 4.1: New therapeutic indication added. Refractory generalized myasthenia gravis (gMG) in patients who are anti-acetylcholine receptor (AChR) antibody-positive.

Section 4.2: New section added for gMG under the Posologya nd administration. New sentence added: Soliris has not been studied in paediatric patients with refractory gMG.

Section 4.4: (Special Warnings and Precautionf or use): New information on gMG added here. Also new section updated to include: Immunosuppressant and anticholinesterase therapies.

Section 4.8: (Undesirable effects), updated summary of safety profile and update to tabulated list of adverse reactions.

Section 5.1: (Pharmacodynamics properties), added new information on gMG and information about the gMG patients. Added results from clinicnal studies ECU-MG-301 and ECU-MG-302.

Section 5.2: (Pharmacokinetic properties), added new information about the PK parameters observed in the refractory gMG population.

Section 10: Date of Revision of text - 14 August 2017

• Section 4.2: Posology and method of administration. Table heading, Plasma replaced with PE/PI
• Section 4.4: Special warning and precaution for use.
  • Under the Meningococcal Infection section; Following sentence deleted 'These patients might be at risk of disease by uncommon serogroups (such as X), although meningococcal'.
  • 'Outweigh' changed to 'Outweighs'
  • 'Patients who are treated with' has been changed to 'Patients who initiate'
  • 'Serotypes' replaced with 'Serogroups'
  • Patients must be vaccinated or revaccinated has been changed to 'Patient must receive vaccination' 
  • New Paragraph added: 'Vaccination may further activate complement. As a result, patients with complement-mediated diseases, including PNH and aHUS, may experience increased signs and symptoms of their underlying disease, such as haemolysis (PNH) or TMA (aHUS). Therefore, patients should be closely monitored for disease symptoms after recommended vaccination'.
  • Under Immunization section: meningococcus replaced with meningococcal infection
  • 'Patients who are treated with' has been changed to 'Patients who initiate'
  • 'Serotypes' replaced with 'Serogroups'
  • New Paragraph added: 'Vaccination may further activate complement. As a result, patients with complement-mediated diseases, including PNH and aHUS, may experience increased signs and symptoms of their underlying disease, such as haemolysis (PNH) or TMA (aHUS). Therefore, patients should be closely monitored for disease symptoms after recommended vaccination'.
• Section 4.8: Undesirable Effects
  • Summary of safety profile: new sentence added: 'Supportive safety data were obtained from 28 completed clinical studies that included 1,284 patients exposed to eculizumab in ten disease populations, including PNH and aHUS'.
  • Tabulated list of Adverse Reactions: Paragraph reworded as: 'Table 1 gives the adverse reactions observed from spontaneous reporting and in eculizumab completed clinical trials,  including PNH and aHUS studies. Adverse reactions reported at a very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000) frequency with eculizumab are listed by system organ class and preferred term. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness'.
  • Update to Table 1 introduction: 'Adverse Reactions reported in 3021,284 patients included in PNH and aHUS overall eculizumab clinical trials and in, including PNH and aHUS patients as well as from postmarketing experience'
  • Updated list on Table 1: New list of Common, Uncommon and Rare added to SmPC.
  • Patients with other diseases: Paragraph deleted: 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. New Sentence added: 'ADRs reported in patients with disease other than PNH or aHUS, were similar to those reported in patients with PNH or aHUS (see table 1 above). No specific ADRs have emerged from these clinical studies'.
  • Reporting of suspected adverse events: Added in HPRA PV reporting system: 'Ireland: HPRA Pharmacovigilance, Website: www.hpra.ie; E-mail: medsafety@hpra.ie'.
• Section 5.1: Pharmacodynamic properties - Under Mechanism of action section: 'ml' replaced with 'mL'
• Section 5.2: Pharmacokinetic properties - Under Pharmacokinetics Parameters: 'ml' replaced with 'mL'
  • Special Populations - PNH section reworded as: 'Formal Dedicated studies have not been conducted to evaluate the pharmacokinetics of Soliris administration in special PNH patient populations based on identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment'.
• Section 10: Date of Revision of Text: 23 March 2017.

4.1         Therapeutic indication

Soliris is indicated in adults and children 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 demonstrated in patients with history of transfusions 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).

4.4       Special warnings and precautions for use

Treatment Discontinuation for aHUS

Severe thrombotic microangiopathy complications were observed after Soliris discontinuation in the aHUS clinical studies. Thrombotic microangiopathy (TMA) complications have been observed as early as 4 weeks and up to 127 weeks following discontinuation of eculizumab Soliris treatment in some patients. Discontinuation of treatment should only be considered if medically justified.

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

If aHUS patients discontinue treatment with Soliris, they should be monitored closely for signs and symptoms of severe thrombotic microangiopathy complications. Monitoring may be insufficient to predict or prevent severe thrombotic microangiopathy complications in patients with aHUS after discontinuation of Soliris.

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. 

Educational materials

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.

4.8       Undesirable effects

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).

5.1       Pharmacodynamic properties

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 Soliris was administered as an intravenous infusion over 25 – 45 minutes. An observational non-interventional Registry in patients with PNH (M07-001) was also initiated to characterize the natural history of PNH in untreated patients and the clinical outcomes during Soliris treatment.

The PNH registry (M07-001) was used to evaluate the efficacy of Soliris in PNH patients with no history of 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 (including thrombosis), dysphagia, or erectile dysfunction.

In the PNH Registry, patients treated with Soliris were observed to have a reduction in haemolysis and associated symptoms. At 6 months, patients treated with Soliris with no history of RBC transfusion had significantly (p<0.001) reduced LDH levels (median LDH of 305 U/L; Table 4). Furthermore, 74% of the patients treated with Soliris experienced clinically meaningful improvements in FACIT-Fatigue score (i.e., increase by 4 points or more) and 84% in EORTC fatigue score (i.e., decrease by 10 points or more).

Table 4: Efficacy Outcomes (LDH level and FACIT-Fatigue) in Patients with PNH with No History of Transfusion in M07-001

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

Table 45: Patient Demographics and Characteristics in C08-002A/B and C08-003A/B

Table 56: Efficacy Outcomes in Prospective aHUS Studies C08-002A/B and C08-003A/B

¹ .At data cut -off (20 April 2012)

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

⁴ At data cut off (20 April 2012)

aHUS Study C10-004  enrolled 41 patients who displayed signs of thrombotic microangiopathy (TMA).  In order to qualify for enrolment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of haemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis.  The median patient age was 35 (range: 18 to 80 years).  All patients enrolled in aHUS Study C10-004   had an ADAMTS-13 level above 5%.  Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody.  A total of 35 patients received PE/PI prior to eculizumab.  Table 67 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS C10-004.

Table 67:  Baseline Characteristics of Patients Enrolled in aHUS Study C10-004

Patients in aHUS Study C10-004 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. Through data cut off, the median duration of Soliris therapy was approximately 50 weeks (range: 13 weeks to 86 weeks).

Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of Soliris. Soliris reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS C10-004, mean (±SD)  platelet count increased from 119 ± 66 x109/L at baseline to 200 ± 84 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 252 ± 70 x109/L). Renal function, as measured by median eGFR, was improved during Soliris therapy. Twenty of the 24 patients who required dialysis at study entry baseline were able to discontinue dialysis for the duration of  during Soliris treatment. Table 78 summarizes the efficacy results for aHUS study C10-004.

Table 78: Efficacy Outcomes in Prospective for aHUS Study C10-004
    

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

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

Table 89: Efficacy Outcomes in Paediatric PNH Study M07-005

Table 910: Efficacy Results in Paediatric Patients Enrolled in aHUS C09-001r

Table 1011: Efficacy Outcomes in Paediatric Patients in Study C09-001r according to duration of current severe clinical thrombotic microangiopathy (TMA) manifestation

Table 1112:  Baseline Characteristics of Paediatric and Adolescents Patients Enrolled in aHUS Study C10-003 

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.  Through data cutoff, the median duration of Soliris therapy was approximately 44 weeks (range: 1 dose to 88 weeks). 

Reduction in terminal complement activity was observed in all patients after commencement of Soliris.   Soliris reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks.  The mean (±SD)   platelet count increased from 88 ± 42 x109/L at baseline to 281 ± 123 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x109/L). Renal function, as measured by median eGFR, was improved during Soliris therapy.  Nine of the 11 patients who required dialysis at  study entry were able to discontinue dialysis for the duration of Soliris  baseline no longer required dialysis after Study dDay 15 of eculizumab treatment.  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 encoding complement regulatory factor proteins or auto-antibodies to factor H. 

Table 1213 summarizes the efficacy results for aHUS C10-003.

Table 1213:       Efficacy Outcomes in Prospective for aHUS Study C10-003   

The updated SmPC is a combined one for PNH and aHUS indications with updated data from studies.

In 4.2 Posology and method of administration:

·         The instructions for frozen plasma infusions have changed from units to infusion.

·         Heading Changes as below:

1.       Elder Population changed to Older Population

2.        Renal Impairment changed to Patients with renal impairment

3.       Hepatic Treatment changed to Patients with hepatic treatment

·         Method of administration:  There is addition of information for aHUS of the time period of infusion  as  by intravenous infusion over 25 – 45 minutes in adults and 1-4 hours in paediatric patients via gravity feed, a syringe-type pump, or an infusion pump

In 4.4 Special warnings and precautions for use:

Immunogenicity- Information on antibody response in aHUS patients added.

In 4.8 Undesirable effects:

1. Summary of the safety profile updated

2.  No. of patients updated in Table 1: Adverse Reactions reported in 302 patients included in PNH and aHUS clinical trials and in post marketing reports with amendments to adverse events in the table as below:

- Infection and infestations: Meningococcal meningitis, Sepsis, Septic shock, Pneumonia, Gastrointestinal infection, Cystitis changed to Uncommon (≥1/1,000 to <1/100)

- Blood and lymphatic system disorders: Leukopenia changed to Common (≥1/100 to <1/10)

- Metabolism and nutrition disorders: Decreased appetite changed to Common (≥1/100 to <1/10)

- Nervous system disorders: Paraesthesia changed to Uncommon (≥1/1,000 to <1/100)

- Vascular disorders: Hypotension changed to Common (≥1/100 to <1/10) and Accelerated hypertension changed to Uncommon (≥1/1,000 to <1/100)

- Respiratory, thoracic and mediastinal disorders: Rhinorrhoea changed to Common (≥1/100 to <1/10) and Throat irritation changed to Uncommon (≥1/1,000 to <1/100)

- Skin and subcutaneous tissue disorders: Dry skin changed to Uncommon (≥1/1,000 to <1/100)

- Musculoskeletal and connective tissue disorders: Muscle spasms, Bone pain changed to Common (≥1/100 to <1/10)

- Renal and urinary disorders: Dysuria changed to Uncommon (≥1/1,000 to <1/100)

- Reproductive system and breast disorders: Spontaneous penile erection changed to Uncommon (≥1/1,000 to <1/100)

- General disorders and administration site conditions: Infusion related reaction removed from Common (≥1/100 to <1/10) and Influenza like illness changed to Common (≥1/100 to <1/10)

- Injury, poisoning and procedural complication: Infusion related reaction added to Uncommon (≥1/1,000 to <1/100)

Description of selected adverse reactions has now information on aHUS patients added to the PNH information.

Paediatric population has added information about the aHUS studies C08-002, C08-003 and C10-003

Reporting of suspected adverse reactions has information on where reports can be provided to in Alexion.

In 5.1 Pharmacodynamic properties has added information about the aHUS studies C08-002, C08-003 and C10-003 and C10-004  for TMA study

In 10 DATE OF REVISION OF THE TEXT – 21 March 2014

Appendix V – change of address details for Alexion UK, Ireland and Malta.

4.1       Therapeutic indication

Soliris is indicated in adults and children 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).

4.2       Posology and method of administration

Posology

Adult Patients:

In Paroxysmal Nocturnal Haemoglobinuria (PNH):

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

Paediatric Population

The safety and efficacy of Soliris in children with PNH aged less than 18 years  have  not yet been established. No data are available.

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 administered via a 25 – 45 minute intravenous infusion every week for the first 4 weeks.

PediatricPaediatric patients:

Paediatric PNH andn paediatric aHUS patients with body weight ≥ 40kg are treated with the adult dosing recommendations, respectively.

In pediatricpaediatric PNH and aHUS patients with body weight below 40 kg, the Soliris dosing regimen consists of:

Soliris has not been studied in patients with PNH who weigh less than 40kg. The posology of Soliris for PNH patients less than 40kg weight is based on the posology used for patients with aHUS and who weigh less than 40kg.

For adults and paediatric aHUS patients supplementalSupplemental dosing of Soliris is required in the setting of concomitant PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion):

4.4       Special warnings and precautions for use

Other Systemic Infections

Due to its mechanism of action, Soliris therapy should be administered with caution to patients with active systemic infections. Patients may have increased susceptibility to infections, especially with encapsulated bacteria. 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.

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 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 Meningococcal infectionInfection).

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.

4.6     Fertility, pregnancy and lactation

Woman Women of childbearing potential

Woman Women of childbearing potential have to use effective contraception during treatment and up to 5 months after treatment.

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 the 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.

4.8         Undesirable effects

Summary of the safety profile

The most common or serious adverse reactions were headache (occurred mostly in the initial phase), leukopenia, and the most serious adverse reaction was meningococcal infection.

Table 1: Adverse Reactions Reported reported in 239232 patients included in PNH and aHUS clinical trials and in postmarketing reports

*See paragraph Description of selected adverse reactions

Paediatric population

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 most common adverse reaction reported in paediatric patients was headache.

In aHUS patients, theThe safety profile in adolescents (patients aged 12 years to less than 18 years) is consistent with that observed in adults. In infantinfants and children aHUS patients (aged 2 months to less than 12 years) included in the retrospective study C09-001r001 r, the safety profile is( appeared similar to that observed in adult/adolescent aHUS patients. The most common (>10%) adverse reactions reported in paediatric patients were diarrhoea, vomiting, pyrexia, upper respiratory tract infection and headache.

5.1       Pharmacodynamic properties

Mechanism of action

In PNH patients, uncontrolled terminal complement activation and the resulting complement mediatedcomplement-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 mediatedcomplement-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

Paediatric aHUS population

Paroxysmal Nocturnal Haemoglobinuria

A total of 7 PNH paediatric patients, with a median weight of 57.2 kg (range of 48.6 to 69.8 kg) and aged from 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 associated with a reduction of intravascular haemolysis as measured by serum LDH level. It also resulted in a marked decrease or elimination of blood transfusions, and a trend towards an overall improvement in general function. The efficacy of eculizumab treatment in paediatric PNH patients appears to be consistent with that observed in adult PNH patients enrolled in PNH pivotal Studies (C04-001 and C04-002) (Table 3 and 6).

Table 6: Efficacy Outcomes in Paediatric PNH Study M07-005

Atypical Haemolytic Uremic Syndrome

A total of 15 paediatric patients (agedages 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).  The median 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) 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 6Table 5).  No paediatric patient required new dialysis during treatment with Soliris.

Table 67: Efficacy Results in Paediatric Patients Enrolled in aHUS C09-001r

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 Table 8).

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 8).

Table 78: 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).

5.2     Pharmacokinetic properties

Special Populations

PNH

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. 

PediatricPaediatric patients

The pharmacokinetics of eculizumab was evaluated in Study M07-005 including 7 PNH ediatricpaediatric patients (aged from 11 to less than 18 years).

Weight was a significant covariate resulting in a lower eculizumab clearance 0.0105 L/h in the adolescent patients. Dosing for paediatric patients <40 kg is based on paediatric patients with aHUS.

aHUS

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.

10.     DATE OF REVISION OF THE TEXT

18/06/2012

29/04/2013