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Alexion Pharma UK Ltd

3 Furzeground Way, Stockley Park, Uxbridge, Middlesex, UB111EZ, UK
Telephone: +44 (0)208 744 6600
Fax: +44 (0)800 633 5145
Medical Information Direct Line: 1 800 936 537
Medical Information e-mail: MedicalInformation.UK@alexion.com
Customer Care direct line: 0800 1300 212
Medical Information Facsimile: +44 (0) 1895 549 613
Summary of Product Characteristics last updated on medicines.ie: 11/09/2017
SPC Soliris

When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 11/09/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   14-Aug-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



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

Updated on 30/03/2017 and displayed until 11/09/2017
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   23-Mar-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company


  • 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.
Updated on 28/06/2016 and displayed until 30/03/2017
Reasons for adding or updating:
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   09-Jun-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

New "Date of Revision of the Text".
Updated on 30/09/2015 and displayed until 28/06/2016
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
Date of revision of text on the SPC:   24-Sep-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

In section 4.2 Posology and method of administration:

-The title "Older population" has been replaced with "Elderly"

-The title "Patients with renal impairment" has been replaced with "Renal impairment"

-The title "Patients with hepatic impairment" has been replaced with "Hepatic impairment"


In section 4.3 Contraindications:

-Harmonization between PNH and aHUS wording of the contraindication for Soliris initiation in patients with unresolved Neisseria meningitidis infection and who are not currently vaccinated against Neisseria meningitidis (unless they receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination)


In section 4.4 Special warnings and precautions for use:

-Reference to the serogroup B meningococcal vaccine  has been added

-Reference to tetravalent or conjugated vaccines has been removed

-Harmonization between PNH and aHUS wording of the contraindication for Soliris initiation in patients with unresolved Neisseria meningitidis infection and who are not currently vaccinated against Neisseria meningitidis (unless they receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination)


Updated on 14/04/2015 and displayed until 30/09/2015
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   30-Mar-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Text removed strikethrough
Text added : Red 


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


 

M07-001

Parameter

 

Soliris

No transfusion

LDH level at baseline
(median , U/L)

 

N=43

1447

LDH level at 6 months

(median, U/L)

 

N=36

305

FACIT-Fatigue score at baseline

(median)

 

N=25

32

FACIT-Fatigue score at last available assessment (median)

 

N=31

44


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

Parameter

aHUS Study C10-004 

N = 41

Time from aHUS diagnosis to first study dose until screening in (months),
median ( range min, max)

0.79 (0.03, 311)

Time from current clinical TMA manifestation until first study dose in  (months), median ( range min, max)

0.52 (0.03, 19)

Baseline platelet count (× 109/L), median (,range min, max)

125 (16, 332)

Baseline LDH (U/L), median (,range min, max)

375 (131, 3318)

Baseline eGFR (mL/min/1.73m2), median (range min, max)

10 (6, 53)

 

 

 


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
    

Efficacy Parameter

aHUS Study C10-004

(N = 41)
At 26-weeks

Change in platelet count through week 26 (109/L)

111 (-122, 362)

 

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 

Parameter

1 month to <12 years

(N = 18)

 

 All Patients

(N = 22)

 

Time from aHUS diagnosis until first study dose screening in (months) median (min, max range )

0.51 (0.03, 58)

0.56 (0.03,191)

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

0.23 (0.03, 4)

0.20 (0.03, 4)

Baseline platelet count (x 109/L), median ( min max range)

110 (19, 146)

91 (19,146)

Baseline LDH (U/L) median (min, max range)

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.  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   

Efficacy Parameter

1 month to <12 years

(N = 18)

At 26-weeks

All Patients

(N = 22) 

At 26-weeks



1 Through data cut-off (October 12, 2012), with median duration of Soliris therapy of 44 weeks (range: 1dose to 88 weeks).

Longer term treatment with Soliris (median 55 weeks ranging from 1day to 107 weeks) was associated with an increased rate of clinically meaningful improvements in pediatric and adolescent patients with aHUS. When Soliris treatment was continued for more than 26 weeks, one additional patient (68% of patients 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 eGFR improvement of  15 mL/min/1.73 m2 from baseline. No patient required new dialysis with Soliris.

 

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).

10.     DATE OF REVISION OF THE TEXT

Date:  10 February 2015  30/03/2015

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 17/09/2014 and displayed until 14/04/2015
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Change to joint SPC covering all presentations
Date of revision of text on the SPC:   21-Mar-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



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.

 

 

 

 

 

 

 

 

 

Updated on 17/12/2013 and displayed until 17/09/2014
Reasons for adding or updating:
  • Removal of black triangle
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   10-Sep-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Black triangle has been removed from Soliris
In section 4.8 (undesirable effects), in Table. 1, in 'infections and infestations', in common Aspergillus infection has been added
In section 10 Date of Revision of the text has changed to 10 September 2013
Updated on 31/05/2013 and displayed until 17/12/2013
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   29-Apr-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



 

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:

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Patient Body Weight

Initial Phase

Maintenance Phase

≥40 kg

900 mg weekly x 4

1200 mg at week 5; then 1200 mg every 2 weeks

30 to <40 kg

600 mg weekly x 2

900 mg at week 3; then 900 mg every 2 weeks

20 to <30 kg

600 mg weekly x 2

600 mg at week 3; then 600 mg every 2 weeks

10 to <20 kg

600 mg weekly x 1

300 mg at week 2; then 300 mg every 2 weeks

to <10 kg

300 mg weekly x 1

300 mg at week 2; then 300 mg every 3 weeks

 

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

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MedDRA System Organ Class

 

Very Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Infection and infestations

 

Meningococcal sepsis, Meningococcal meningitis, Sepsis, Septic shock, Pneumonia, Arthritis bacterial, Upper respiratory tract infection, Nasopharyngitis, Bronchitis, Oral Herpes, Gastrointestinal infection, Urinary tract infection, Cystitis, Viral infectioninfectionl

Neisseria infection, Lower respiratory tract infection, Fungal infection, Haemophilus influenzae infection, Abscess, Cellulitis, Influenza, Gingival infection, Infection, Sinusitis, Tooth infection, Impetigo

Neoplasms benign, malignant and unspecified (including cysts and polyps)

 

 

Malignant melanoma, Myelodysplastic syndrome

Blood and lymphatic system disorders

Leukopenia

Thrombocytopenia, Haemolysis*

Coagulopathy, Red blood cell agglutination, Abnormal clotting factor, Anaemia, Lymphopenia

Immune system disorders

 

Anaphylactic reaction

Hypersensitivity

Endocrine disorders

 

 

Basedow’s disease

Metabolism and nutrition disorders

 

 

Anorexia, Decreased appetite

Psychiatric disorders

 

 

Depression, Anxiety, Insomnia, Sleep disorder, Abnormal dreams, Mood swings

Nervous system disorders

Headache

Dizziness, Paraesthesia, Dysgeusia

Syncope, Tremor

Eye disorders

 

 

Vision blurred, Conjunctival irritation

Ear and labyrinth disorders

 

Vertigo

Tinnitus

Cardiac disorders

 

 

Palpitation

Vascular disorders

 

Accelerated hypertension

Hypertension, Hypotension, Haematoma, Hot flush, Vein disorder

Respiratory, thoracic and mediastinal disorders

 

Cough, Nasal congestion, Pharyngolaryngeal pain, Throat irritation

Epistaxis, Rhinorrhoea

Gastrointestinal disorders

 

Diarrhoea, Vomiting, Nausea, Abdominal pain, Constipation, Dyspepsia

Peritonitis, Gastrooesophagal reflux disease, Abdominal distension, Gingival pain

Hepatobiliary disorders

 

 

Jaundice

Skin and subcutaneous tissue disorders

 

Rash, Alopecia, Dry skin, Pruritus

Urticaria, Dermatitis, Erythema, Petechiae, Skin depigmentation, Hyperhidrosis,

Musculoskeletal and connective tissue disorders

 

Arthralgia, Myalgia, Back pain,  Neck pain, Pain in extremity

Trismus, Joint swelling, Muscle spasms, Bone pain

Renal and urinary disorders

 

Dysuria

Renal impairment, Haematuria

Reproductive system and breast disorders

 

Spontaneous penile erection

Menstrual disorder

General disorders and administration site conditions

 

Oedema, Infusion related reaction, Chest discomfort, Pyrexia, Chills, Fatigue, Asthenia

Chest pain, Infusion site paraesthesia, Infusion site pain, Extravasation, Influenza like illness, Feeling hot

Investigations

 

Coombs test positive*

Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Haematocrit decreased, Haemoglobin decreased

*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

 

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P – Value

 

Mean (SD)

Wilcoxon Signed Rank

Paired t-test

Change from baseline at 12 weeks of LDH Value (U/L)

-771 (914)

0.0156

0.0336

LDH AUC
(U/L x Day)

-60,634 (72,916)

0.0156

0.0350

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 clone size (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 (patients)

0.8 (21.39)

0.6250

0.4687

Change from baseline at 12 weeks of PedsQLTM Multidimensional Fatigue (parents)

5.5 (0.71)

0.5000

0.0289

 

 

 

Atypical Haemolytic Uremic Syndrome

 

A total of 15 paediatric patients (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

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Efficacy Parameter

<2 years

(n=5)

2 to <12 years

(n=10)

<12 years

(n=15)

Patients with platelet count normalization, n (%)

4 (80)

10 (100)

14 (93)

Complete TMA response, n (%)

2 (40)

5 (50)

7 (50)

Daily TMA intervention rate, median (range)

    Before eculizumab

    On eculizumab treatment

 

 

1 (0, 2)

<1 (0, <1)

 

 

<1 (0.07, 1.46)

0 (0, <1)

 

 

<1 (0, 2)

0 (0, <1)

Patients with eGFR improvement ≥15 mL/min/1.73 m2, n (%)

2 (40)

6 (60)

8 (53)

 

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

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Duration of current severe clinical TMA manifestation

 

< 2 months
N=10 (%)

>2 months
N=5 (%)

Platelet count normalization

9 (90)

5 (100)

TMA event-free status

8 (80)

3 (60)

Complete TMA response

7 (70)

0

eGFR improvement ≥ 15 mL/min/1.73m2

7 (70)

0*

*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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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