Soliris

Section 2: What you need to know before you use Soliris - Addition of section Soliris contains polysorbate 80

Section 3: How to use Soliris - Minor changes in the dosing table for children and adolescents with PNH and aHUS aged less than 18 years

Section 4: Possible side effects - Removal of the word 'influenzae' to keep only Haemophilus infection and change from Basedow's disease to Grave's disease in Rare side effects. Northern Ireland side effects reporting details removed.

Section 6: What Soliris contains - Included new sentence referring to sodium and polysorbate 80

Local representative of MAH section updated to remove Northern Ireland details.

Package leaflet: Information for the user

Soliris 300 mg concentrate for solution for infusion

Eculizumab

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

-            Keep this leaflet. You may need to read it again.

-            If you have any further questions, ask your doctor, pharmacist or nurse.

-            This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

-            If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1.      What Soliris is and what it is used for

2.      What you need to know before you use Soliris

3.      How to use Soliris

4.      Possible side effects

5.         How to store Soliris

6.         Contents of the pack and other information

1.  What Soliris is and what it is used for

What is Soliris

Soliris contains the active substance eculizumab and it belongs to a class of medicines called monoclonal antibodies. Eculizumab binds to and inhibits a specific protein in the body that causes inflammation and so prevents your body’s systems from attacking and destroying vulnerable blood cells, kidneys, muscles or eye nerves and spinal cord.

What is Soliris used for

Paroxysmal Nocturnal Haemoglobinuria

Soliris is used to treat adults and children patients with a certain type of disease affecting the blood system called Paroxysmal Nocturnal Haemoglobinuria (PNH). In patients with PNH, their red blood cells can be destroyed which can lead to low blood counts (anaemia), tiredness, difficulty in functioning, pain, dark urine, shortness of breath, and blood clots. Eculizumab can block the body’s inflammatory response, and its ability to attack and destroy its own vulnerable PNH blood cells.

Atypical Haemolytic Uremic Syndrome

Soliris is also used to treat adults and children patients with a certain type of disease affecting the blood system and kidney called atypical Haemolytic Uremic Syndrome (aHUS). In patients with aHUS, their kidney and blood cells, including platelets, can be inflamed which can lead to low blood counts (thrombocytopenia and anaemia), reduced or lost kidney function, blood clots, tiredness and difficulty in functioning. Eculizumab can block the body’s inflammatory response, and its ability to attack and destroy its own vulnerable blood and kidney cells.

Refractory Generalized Myasthenia Gravis

Soliris is also used to treat adult and children patients aged 6 years and above with a certain type of disease affecting the muscles and called generalized Myasthenia Gravis (gMG). In patients with gMG, their muscles can be attacked and damaged by the immune system which can lead to profound muscle weakness, impaired mobility, shortness of breath, extreme fatigue, risk for aspiration, and markedly impaired activities of daily living. Soliris can block the body’s inflammatory response, and its ability to attack and destroy its own muscles to improve muscle contraction, thereby reducing symptoms of the disease and impact of the disease on the activities of daily living. Soliris is specifically indicated for patients who remain symptomatic despite treatment with other existing MG therapies.

Neuromyelitis Optica Spectrum Disorders

Soliris is also used to treat adult patients with a certain type of disease that predominantly affects the eye nerves and the spinal cord called Neuromyelitis Optica Spectrum Disorder (NMOSD). In patients with NMOSD, their eye nerve and spinal cord are attacked and damaged by the immune system which can lead to blindness in one or both eyes, weakness or paralysis in the legs or arms, painful spasms, loss of sensation, and markedly impaired activities of daily living. Soliris can block the body’s inflammatory response, and its ability to attack and destroy its own eye nerves and spinal cord, thereby reducing symptoms of the disease and impact of the disease on the activities of daily living.

2.  What you need to know before you use Soliris

Do not use Soliris

-            If you are allergic to eculizumab, proteins derived from mouse products, other monoclonal antibodies, or any of the other ingredients of this medicine (listed in section 6).

-            If you have not been vaccinated against meningococcal infection unless you take antibiotics to reduce the risk of infection until 2 weeks after you have been vaccinated .

-            If you have a meningococcal infection.

Warnings and precautions

Meningococcal and other Neisseria infections alert

Soliris treatment may reduce your natural resistance to infections, especially against certain organisms that cause meningococcal infection (severe infection of the linings of the brain and sepsis) and other Neisseria infections including disseminated gonorrhea.

Consult your doctor before you take Soliris to be sure that you receive vaccination against Neisseria meningitidis, an organism that causes meningococcal infection, at least 2 weeks before beginning therapy, or that you take antibiotics to reduce the risk of infection until 2 weeks after you have been vaccinated. Ensure that your current meningococcal vaccination is up to date. You should also be aware that vaccination may not prevent this type of infection. In accordance with national recommendations, your doctor might consider that you need supplementary measures to prevent infection.

If you are at risk of gonorrhoea, ask your doctor or pharmacist for advice before using this medicine.

Meningococcal infection symptoms

Because of the importance of rapidly identifying and treating certain types of infection in patients who receive Soliris, you will be provided a card to carry with you, listing specific trigger symptoms. This card is named: “Patient Safety Card”.

If you experience any of the following symptoms, you should immediately inform your doctor:  

-          headache with nausea or vomiting

-          headache with a stiff neck or back

-          fever

-          rash

-          confusion

-       severe muscle aches combined with flu-like symptoms

-          sensitivity to light

Treatment for meningococcal infection while travelling

If you are travelling in a remote region where you are unable to contact your doctor or in which you find yourself temporarily unable to receive medical treatment, your doctor can make arrangements to issue, as a preventive measure, a prescription for an antibiotic to counter Neisseria meningitidis that you keep with you. If you experience any of the symptoms amongst those cited above, you should take the antibiotics as prescribed. You should bear in mind that you should see a doctor as soon as possible, even if you feel better after having taken the antibiotics.

Infections

Before starting Soliris, inform your doctor if you have any infections.

Allergic reactions

Soliris contains a protein and proteins can cause allergic reactions in some people.

Children and adolescents

Patients less than 18 years of age must be vaccinated against Haemophilus influenzae and pneumococcal infections

Older people

There are no special precautions needed for the treatment of patients aged from 65 years and over.

Other medicines and Soliris

Tell your doctor or pharmacist if you are using or have recently used or might use any other medicines.

Pregnancy, breast-feeding, and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Women of childbearing potential

The use of effective contraception during treatment and up to 5 months after treatment should be considered in women who are able to get pregnant.

Pregnancy/ Breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Driving and using machines

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

Soliris contains sodium

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicine contains 0.88 g 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 0.67 g 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.

Soliris contains polysorbate 80

This medicine contains 6.6 mg of polysorbate 80 in each vial (30mL vial) which is equivalent to 0.66 mg/kg or less at the maximum dose for adult patients and paediatric patients with body weight more than 10 kg and is equivalent to 1.32 mg/kg or less at the maximum dose for paediatric patients with body weight 5 to <10 kg. Polysorbates may cause allergic reactions. Tell your doctor if you/your child has any known allergies.

3. How to use Soliris

At least 2 weeks before you start treatment with Soliris, your doctor will administer a vaccine against meningococcal infection if it was not previously administered or if your vaccination is outdated. If your child is below the age of vaccination or if you are not vaccinated at least 2 weeks before you start treatment with Soliris, your doctor will prescribe antibiotics to reduce the risk of infection until 2 weeks after you have been vaccinated.

Your doctor will administer a vaccine to your child aged less than 18 years against Haemophilus influenzae and pneumococcal infections according to the national vaccination recommendations for each age group.

Instructions for proper use

The treatment will be given by your doctor or other health care provider by infusing a dilution of the Soliris vial from a drip bag through a tube directly into one of your veins. It is recommended that the beginning of your treatments, called the initial phase, will extend over 4 weeks, followed by a maintenance phase.

If you use this medicine to treat PNH

For adults:

·    Initial Phase:

    Every week for the first four weeks, your doctor will administer an intravenous infusion of diluted Soliris. Each infusion will consist of a dose of 600 mg (2 vials of 30 ml) and will take 25 – 45 minutes (35 minutes ± 10 minutes).

·    Maintenance Phase:

·    In the fifth week, your doctor will administer an intravenous infusion of diluted Soliris at a dose of 900 mg (3 vials of 30 ml) over a 25 – 45 minute (35 minutes ± 10 minutes) period.

·    After the fifth week, your doctor will administer 900 mg of diluted Soliris every two weeks as a long-term treatment.

If you use this medicine to treat aHUS, refractory gMG or NMOSD

For adults:

·    Initial Phase:

Every week for the first four weeks, your doctor will administer an intravenous infusion of diluted Soliris. Each infusion will consist of a dose of 900 mg (3 vials of 30 ml) and will take 25 – 45 minutes (35 minutes ± 10 minutes).

·    Maintenance Phase:

·    In the fifth week, your doctor will administer an intravenous infusion of diluted Soliris at a dose of 1,200 mg (4 vials of 30 ml) over a 25 – 45 minute (35 minutes ± 10 minutes) period.

·    After the fifth week, your doctor will administer 1,200 mg of diluted Soliris every two weeks as a long-term treatment.

Children and adolescents with PNH, aHUS or refractory gMG and who are 40 kg weight and over are treated with the adult dosing.

Children and adolescents with PNH, aHUS or refractory gMG and who are under 40 kg weight require a lower dose based on how much they weigh. Your doctor will calculate this.

For children and adolescents with PNH and aHUS aged less than 18 years:

Body Weight

Initial Phase

Maintenance Phase

30 to <40 kg

600 mg weekly for the first 2 weeks

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

20 to <30 kg

600 mg weekly for the first 2 weeks

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

10 to <20 kg

600 mg single dose at week 1

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

5 to <10 kg

300 mg single dose at week 1

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

Subjects who undergo plasma exchange may receive additional doses of Soliris.

Following each infusion, you will be monitored for about one hour. Your doctor’s instructions should be carefully observed.

If you receive more Soliris than you should

If you suspect that you have been accidentally administered a higher dose of Soliris than prescribed, please contact your doctor for advice.

If you forget an appointment to receive Soliris

If you forget an appointment, please contact your doctor immediately for advice and see section below “If you stop using Soliris”.

If you stop using Soliris for PNH

Interrupting or ending treatment with Soliris may cause your PNH symptoms to come back more severely soon. Your doctor will discuss the possible side effects with you and explain the risks. Your doctor will want to monitor you closely for at least 8 weeks.

The risks of stopping Soliris include an increase in the destruction of your red blood cells, which may cause:

-          A significant fall in your red blood cell counts (anaemia),

-          Confusion or change in how alert you are,

-          Chest pain, or angina,

-       An increase in your serum creatinine level (problems with your kidneys), or

-          Thrombosis (blood clotting).  

If you have any of these symptoms, contact your doctor.  

If you stop using Soliris for aHUS

Interrupting or ending treatment with Soliris may cause your aHUS symptoms to come back. Your doctor will discuss the possible side effects with you and explain the risks. Your doctor will want to monitor you closely.

The risks of stopping Soliris include an increase in the inflammation of your platelets, which may cause:

-          A significant fall in your platelets (thrombocytopenia),

-          A significant rise in destruction of your red blood cells,

-       Decreased urination (problems with your kidneys),

-          An increase in your serum creatinine level (problems with your kidneys),

-          Confusion or change in how alert you are,

-          Chest pain, or angina,

-          Shortness of breath, or

-          Thrombosis (blood clotting).  

If you have any of these symptoms, contact your doctor.  

If you stop using Soliris for refractory gMG

Interrupting or stopping treatment with Soliris may cause your gMG symptoms to come back. Please speak to your doctor before stopping Soliris. Your doctor will discuss the possible side effects and risks with you. Your doctor will also want to monitor you closely.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

If you stop using Soliris for NMOSD

Interrupting or stopping treatment with Soliris may cause your NMOSD to worsen and relapse to happen. Please speak to your doctor before stopping Soliris. Your doctor will discuss the possible side effects and risks with you. Your doctor will also want to monitor you closely.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

4.  Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Your doctor will discuss the possible side effects with you and explain the risks and benefits of Soliris with you prior to treatment.

The most serious side effect was meningococcal sepsis.

If you experience any of the meningococcal infection symptoms (see section 2 Meningococcal and other Neisseria infections alert), you should immediately inform your doctor.

If you are not sure what the side effects below are, ask your doctor to explain them to you.

Very common: may affect more than 1 in 10 people: headache.

Common: may affect up to 1 in 10 people:

·    infection of the lung (pneumonia), common cold (nasopharyngitis), infection of the urinary system (urinary tract infection),

·    low white blood cell count (leukopenia), reduction in red blood cells which can make the skin pale and cause weakness or breathlessness

·    inability to sleep

·    dizziness, high blood pressure

·    upper respiratory tract infection, cough, throat pain (oropharyngeal pain), bronchitis, cold sores (herpes simplex)

·    diarrhea, vomiting, nausea, abdominal pain, rash, hair loss (alopecia), itchy skin (pruritus)

·    pain in the joints (arms and legs), pain in the limbs (arms and legs)

·    fever (pyrexia), feeling tired (fatigue), influenza like illness

·    infusion related reaction

Uncommon: may affect up to 1 in 100 people:

·    severe infection (meningococcal infection), sepsis, septic shock, viral infection, lower respiratory tract infection, stomach flu (gastrointestinal infection), cystitis

·    infection, fungal infection, collection of pus (abscess), type of infection of the skin (cellulitis), influenza, sinusitis, tooth infection (abscess), gum infection

·    relatively few platelets in blood (thrombocytopenia), low level of lymphocytes a specific type of white blood cells (lymphopenia), feeling your heartbeat

·    serious allergic reaction which causes difficulty in breathing or dizziness (anaphylactic reaction), hypersensitivity

·    loss of appetite

·    depression, anxiety, mood swings, sleep disorder

·    tingling in part of the body (paresthesia), shaking, taste disorders (dysgeusia), fainting

·    vision blurred

·    ringing in the ears, vertigo

·    sudden and rapid development of extremely high blood pressure, low blood pressure, hot flush, vein disorder

·    dyspnoea (difficulty breathing), nose bleed, stuffy nose (nasal congestion), throat irritation, runny nose (rhinorrhoea)

·    inflammation of the peritoneum (the tissue that lines most of the organs of the abdomen), constipation, stomach discomfort after meals (dyspepsia), abdominal distension

·    hives, redness of the skin, dry skin, red or purple spots under the skin, increased sweating, inflammation of the skin

·    muscle cramp, muscle aches, back and neck pain, bone pain

·    kidney disorder, difficulties or pain when urinating (dysuria), blood in urine

·    spontaneous penile erection

·    swelling (edema), chest discomfort, feeling of weakness (asthenia), chest pain, infusion site pain, chills

·    increase of liver enzymes, decrease of the proportion of blood volume that is occupied by red blood cells, decrease in the protein in red blood cells that carries oxygen

Rare: may affect up to 1 in 1,000 people:

·    infection by fungi (Aspergillus infection), infection of the joint (arthritis bacterial), Haemophilus infection, impetigo, bacterial sexual transmitted disease (gonorrhea)

·    skin tumor (melanoma), bone marrow disorder

·    destruction of red blood cells (haemolysis), clumping of cells, abnormal clotting factor, abnormal blood clotting,

·    disease with thyroid overactivity (Grave’s disease)

·    abnormal dreams

·    irritation of eye

·    bruise

·    unusual backflow of food from stomach, gum pain

·    yellowing of the skin and/or eyes (jaundice)

·    skin color disorder

·    spasm of mouth muscle, joint swelling 

·    menstrual disorder

·    abnormal leakage of the infused drug out of the vein, infusion site abnormal sensation, feeling hot

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed below:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Soliris

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and vial label after “EXP”. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Soliris vials in the original package may be removed from refrigerated storage for only one single period of up to 3 days. At the end of this period the product can be put back in the refrigerator.

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

After dilution, the product should be used within 24 hours.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6.  Contents of the pack and other information

What Soliris contains

-           The active substance is eculizumab (300 mg/30 ml in a vial corresponding to 10 mg/ml).

-           The other ingredients are:

- sodium phosphate monobasic

- sodium phosphate dibasic

- sodium chloride

- polysorbate 80 (vegetable origin)

Solvent: water for injections

-   Soliris contains sodium and polysorbate 80. See section 2.

What Soliris looks like and contents of the pack

Soliris is presented as a concentrate for solution for infusion (30 ml in a vial – pack size of 1).

Soliris is a clear and colorless solution.

Marketing Authorisation Holder

Alexion Europe SAS

103-105 rue Anatole France

92300 Levallois-Perret

France

Manufacturer

Almac Pharma Services

22 Seagoe Industrial Estate

Craigavon BT63 5QD

United Kingdom

Alexion Pharma International Operations Limited

College Business and Technology Park

Blanchardstown Road North,

Dublin 15

D15 R925

Ireland

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien 

Alexion Pharma Belgium 

Tél/Tel: +32 0 800 200 31 

Lietuva 

UAB AstraZeneca Lietuva 

Tel: +370 5 2660550 

България 

АстраЗенека България ЕООД 

Teл.: +359 24455000 

Luxembourg/Luxemburg 

Alexion Pharma Belgium 

Tél/Tel: +32 0 800 200 31 

Česká republika 

AstraZeneca Czech Republic s.r.o. 

Tel: +420 222 807 111 

Magyarország 

AstraZeneca Kft. 

Tel.: +36 1 883 6500 

Danmark 

Alexion Pharma Nordics AB 

Tlf.: +46 0 8 557 727 50 

Malta 

Alexion Europe SAS 

Tel: +353 1 800 882 840 

Deutschland 

Alexion Pharma Germany GmbH 

Tel: +49 (0) 89 45 70 91 300 

Nederland 

Alexion Pharma Netherlands B.V. 

Tel: +32 (0)2 548 36 67 

Eesti 

AstraZeneca 

Tel: +372 6549 600 

Norge 

Alexion Pharma Nordics AB 

Tlf: +46 (0)8 557 727 50  

Ελλάδα 

AstraZeneca A.E. 

Τηλ: +30 210 6871500 

Österreich 

Alexion Pharma Austria GmbH 

Tel: +41 44 457 40 00 

España 

Alexion Pharma Spain, S.L. 

Tel: +34 93 272 30 05 

Polska 

AstraZeneca Pharma Poland Sp. z o.o. 

Tel.: +48 22 245 73 00 

France 

Alexion Pharma France SAS 

Tél: +33 1 47 32 36 21 

Portugal 

Alexion Pharma Spain, S.L. - Sucursal em Portugal  

Tel: +34 93 272 30 05 

Hrvatska 

AstraZeneca d.o.o. 

Tel: +385 1 4628 000 

România 

AstraZeneca Pharma SRL 

Tel: +40 21 317 60 41  

Ireland 

Alexion Europe SAS 

Tel: +353 1 800 882 840 

Slovenija 

AstraZeneca UK Limited 

Tel: +386 1 51 35 600 

Ísland 

Alexion Pharma Nordics AB 

Sími: +46 0 8 557 727 50 

Slovenská republika 

AstraZeneca AB, o.z. 

Tel: +421 2 5737 7777 

Italia 

Alexion Pharma Italy srl 

Tel: +39 02 7767 9211  

Suomi/Finland 

Alexion Pharma Nordics AB 

Puh/Tel: +46 0 8 557 727 50  

Κύπρος 

Alexion Europe SAS 

Τηλ: +357 22490305 

Sverige 

Alexion Pharma Nordics AB 

Tel: +46 0 8 557 727 50 

Latvija 

SIA AstraZeneca Latvija 

Tel: +371 67377100 

This leaflet was last revised in December 2024.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments.

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Instructions for Use for Healthcare Professionals

Handling Soliris

The following information is intended for medical or healthcare professionals only:

1- How is Soliris supplied?

Each vial of Soliris contains 300 mg of active ingredient in 30 ml of product solution.

2- Before Administration

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

Soliris should be prepared for administration by a qualified healthcare professional using aseptic technique.

·    Inspect visually Soliris solution for particulate matter and discolouration.

·    Withdraw the required 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 (initial concentration divided by 2) by adding the appropriate amount of diluent to the infusion bag. For 300 mg doses, use 30 ml of Soliris (10 mg/ml) and add 30 ml of diluent. For 600 mg doses, use 60 ml of Soliris and add 60 ml of diluent. For 900 mg doses, use 90 ml of Soliris and add 90 ml of diluent. For 1,200 mg doses, use 120 ml of Soliris and add 120 ml of diluent. The final volume of a 5 mg/ml diluted Soliris solution is 60 ml for 300 mg doses, 120 ml for 600 mg doses, 180 ml for 900 mg doses or 240 ml for 1,200 mg doses.

·    Diluents are Sodium chloride 9 mg/ml (0.9%) solution for injection, Sodium chloride 4.5 mg/ml (0.45%) solution for injection or 5% dextrose in Water.

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

·    The diluted solution should be allowed to warm to room temperature [18°C – 25°C] prior to administration by exposure to ambient air.

·    The diluted solution must not be heated in a microwave or with any heat source other than the prevailing room temperature.

·    Discard any unused portion left in a vial.

·    Diluted solution of Soliris may be stored at 2°C – 8°C for up to 24 hours prior to administration.

3- Administration

·    Do not administer Soliris as an intravenous push or bolus injection.

·    Soliris should only be administered via intravenous infusion.

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

The patient 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 four hours in paediatric patients under 18 years of age.

4- Special Handling and Storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect from light. Soliris vials in the original package may be removed from refrigerated storage for only one single period of up to 3 days. At the end of this period the product can be put back in the refrigerator. 

Do not use this medicine after the expiry date which is stated on the carton and vial label after ‘EXP’. The expiry date refers to the last day of that month.

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