4.1. Therapeutic indications

Soliris is indicated in adults and children for the treatment of:

- Paroxysmal nocturnal haemoglobinuria (PNH).

Evidence of clinical benefit is demonstrated in patients with haemolysis with clinical symptom(s) indicative of high disease activity, regardless of transfusion history (see section 5.1).

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

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

Soliris is indicated in adults for the treatment of:

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

4.2. Posology and method of administration

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

Home infusion may be considered for patients who have tolerated infusions well in the clinic. The decision of a patient to receive home infusions should be made after evaluation and recommendation from the treating physician. Home infusions should be performed by a qualified healthcare professional.

Posology

Paroxysmal Nocturnal Haemoglobinuria (PNH) in adults

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

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

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

atypical Haemolytic Uremic Syndrome (aHUS), refractory generalized Myasthenia Gravis (gMG) and Neuromyelitis Optica Spectrum Disorder (NMOSD) in adults

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

• Initial phase: 900 mg of Soliris administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion every week for the first 4 weeks.

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

Refractory gMG

Available data suggest that clinical response is usually achieved by 12 weeks of Soliris treatment. Discontinuation of the therapy should be considered in a patient who shows no evidence of therapeutic benefit by 12 weeks.

Paediatric patients in PNH, aHUS, or refractory gMG

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

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

Patient 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

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

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

Type of Plasma Intervention

Most Recent Soliris Dose

Supplemental Soliris Dose With Each PP/PE/PI Intervention

Timing of Supplemental Soliris Dose

Plasmapheresis or plasma exchange

300 mg

300 mg per each plasmapheresis or plasma exchange session

Within 60 minutes after each plasmapheresis or plasma exchange

≥600 mg

600 mg per each plasmapheresis or plasma exchange session

Fresh frozen plasma infusion

≥300 mg

300 mg per infusion of fresh frozen plasma

60 minutes prior to each infusion of fresh frozen plasma

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

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

Most Recent Soliris Dose

Supplemental Soliris Dose

Timing of Supplemental Soliris Dose

≥ 900 mg

600 mg per IVIg cycle

As soon as possible after IVIg cycle

≤ 600 mg

300 mg per IVIg cycle

Abbreviation: IVIg = intravenous immunoglobulin

Treatment monitoring

aHUS patients should be monitored for signs and symptoms of thrombotic microangiopathy (TMA) (see section 4.4 aHUS laboratory monitoring).

Soliris treatment is recommended to continue for the patient's lifetime, unless the discontinuation of Soliris is clinically indicated (see section 4.4).

Elderly

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

Renal impairment

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

Hepatic impairment

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

Paediatric population

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

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

Method of administration

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

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

The diluted solution of Soliris should be administered by intravenous infusion over 25 – 45 minutes (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.

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

There is limited safety data supporting home-based infusions, additional precautions in the home setting such as availability of emergency treatment of infusion reactions or anaphylaxis are recommended. Infusion reactions are described in Sections 4.4 and 4.8 on the SmPC.

4.3. Contraindications

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

Soliris therapy must not be initiated in patients (see section 4.4):

- with unresolved Neisseria meningitidis infection

- who are not currently vaccinated against Neisseria meningitidis unless they receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

4.4. Special warnings and precautions for use

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.

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

Meningococcal Infection

Due to its mechanism of action, the use of Soliris increases the patient's susceptibility to meningococcal infection (Neisseria meningitidis). Meningococcal disease due to any serogroup may occur. To reduce the risk of infection, all patients must be vaccinated at least 2 weeks prior to receiving Soliris unless the risk of delaying Soliris therapy outweighs the risks of developing a meningococcal infection. Patients who initiate Soliris treatment less than 2 weeks after receiving a tetravalent meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against all available serogroups including A, C, Y, W 135 and B, are recommended in preventing the commonly pathogenic meningococcal serogroups. Patients must be vaccinated and revaccinated according to current national guidelines for vaccination use.

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

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

Other Systemic Infections

Due to its mechanism of action, Soliris therapy should be administered with caution to patients with active systemic infections. Patients may have increased susceptibility to infections, especially with Neisseria and encapsulated bacteria. Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

Patients should be provided with information from the Package Leaflet to increase their awareness of potential serious infections and the signs and symptoms of them. Physicians should advise patients about gonorrhoea prevention.

Infusion Reactions

Administration of Soliris may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis). In clinical trials, 1 (0.9%) refractory gMG patient experienced an infusion reaction which required discontinuation of Soliris. No PNH, aHUS, refractory gMG or NMOSD paediatric patients experienced an infusion reaction which required discontinuation of Soliris. Soliris administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.

Immunogenicity

Infrequent antibody responses have been detected in Soliris-treated patients across all clinical studies. In PNH placebo controlled studies low antibody responses have been reported with a frequency (3.4%) similar to that of placebo (4.8%).

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

In a refractory gMG placebo controlled study, none (0/62) of the Soliris treated patients showed antidrug antibody response during the 26 week active treatment, whereas in a refractory gMG extension study, a total of 3/117 (2.6%) overall were positive for ADAs at any post-baseline visit. Positive ADA results appeared to be transient, as positive titers were not observed at subsequent visits, and there were no clinical findings in these patients suggestive of an effect of positive ADA titers.

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

Immunization

Prior to initiating Soliris therapy, it is recommended that PNH, aHUS, refractory gMG and NMOSD patients initiate immunizations according to current immunization guidelines. Additionally, all patients must be vaccinated against meningococcal infections at least 2 weeks prior to receiving Soliris unless the risk of delaying Soliris therapy outweighs the risks of developing a meningococcal infection. Patients who initiate Soliris treatment less than 2 weeks after receiving a tetravalent meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against all available serogroups including A, C, Y, W 135 and B are recommended in preventing the commonly pathogenic meningococcal serogroups. Patients must be vaccinated and revaccinated according to current national guidelines for vaccination use (see Meningococcal Infection).

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

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

Anticoagulant therapy

Treatment with Soliris should not alter anticoagulant management.

Immunosuppressant and anticholinesterase therapies

Refractory gMG

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

Neuromyelitis Optica Spectrum Disorder

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

PNH Laboratory Monitoring

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

aHUS Laboratory Monitoring

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

Treatment Discontinuation for PNH

If PNH patients discontinue treatment with Soliris they should be closely monitored for signs and symptoms of serious intravascular haemolysis. Serious haemolysis is identified by serum LDH levels greater than the pre-treatment level, along with any of the following: greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; a haemoglobin level of <5 g/dL or a decrease of >4 g/dL in one week or less; angina; change in mental status; a 50% increase in serum creatinine level; or thrombosis. Monitor any patient who discontinues Soliris for at least 8 weeks to detect serious haemolysis and other reactions.

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

Treatment Discontinuation for aHUS

Thrombotic microangiopathy (TMA) complications have been observed as early as 4 weeks and up to 127 weeks following discontinuation of 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.

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.

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

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.

Treatment discontinuation for refractory gMG:

Use of Soliris in refractory gMG treatment has been studied only in the setting of chronic administration. Patients who discontinue Soliris treatment should be carefully monitored for signs and symptoms of disease exacerbation.

Treatment discontinuation for NMOSD:

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

Educational materials

All physicians who intend to prescribe Soliris must ensure they are familiar with the guide for Healthcare Professionals to prescribing. Physicians must discuss the benefits and risks of Soliris therapy with patients and provide them with a Patient guide and a Patient card.

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

Excipients with known effect

Sodium

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.

Polysorbate 80

This medicinal product 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.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Based on the potential inhibitory effect of eculizumab on complement-dependent cytotoxicity of rituximab, eculizumab may reduce the expected pharmacodynamic effects of rituximab.

Plasma exchange (PE), plasmapheresis (PP), fresh frozen plasma infusion (PI) and intravenous immunoglobulin (IVIg) have been shown to reduce eculizumab serum levels. A supplemental dose of eculizumab is required in these settings. See Section 4.2 for guidance in case of concomitant PE, PP, PI, or IVIg treatment.

Concomitant use of eculizumab with intravenous immunoglobulin (IVIg) may reduce effectiveness of eculizumab. Closely monitor for reduced effectiveness of eculizumab.

Concomitant use of eculizumab with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab. Closely monitor for reduced effectiveness of eculizumab.

4.6. Fertility, pregnancy and lactation

The use of adequate contraception to prevent pregnancy and for at least 5 months after the last dose of treatment with eculizumab should be considered for women of childbearing potential.

Pregnancy

There are no well-controlled studies in pregnant women treated with eculizumab. Data on a limited number of pregnancies exposed to eculizumab (less than 300 pregnancy outcomes) indicate there is no increased risk of foetal malformation or foetal-neonatal toxicity. However, due to the lack of well-controlled studies, uncertainties remain. Therefore, an individual risk benefit analysis is recommended before starting and during treatment with eculizumab in pregnant women. Should such a treatment be considered necessary during pregnancy, a close maternal and foetal monitoring according to local guidelines is recommended.

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

Human IgG are known to cross the human placental barrier, and thus eculizumab may potentially cause terminal complement inhibition in the foetal circulation. Therefore, Soliris should be given to a pregnant woman only if clearly needed.

Breast-feeding

No effects on the breastfed newborn / infant are anticipated as limited data available suggest that eculizumab is not excreted in human breast milk. However, due to the limitations of the available data, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for eculizumab and any potential adverse effects on the breastfed child from eculizumab or from the underlying maternal condition.

Fertility

No specific study of eculizumab on fertility has been conducted.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Supportive safety data were obtained from 33 clinical studies that included 1,555 patients exposed to eculizumab in complement-mediated disease populations, including PNH, aHUS, refractory gMG and NMOSD. The most common adverse reaction was headache, (occurred mostly in the initial phase of dosing), and the most serious adverse reaction was meningococcal infection.

Tabulated list of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in eculizumab completed clinical trials, including PNH, aHUS, refractory gMG and NMOSD studies. Adverse reactions reported at a very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000) or not known (cannot be estimated from the available data) 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.

Table 1: Adverse Reactions reported in eculizumab clinical trials, including patients with PNH, aHUS, refractory gMG and NMOSD as well as from postmarketing experience

MedDRA System Organ Class

Very Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1 000 to <1/100)

Rare

(≥1/10000 to <1/1000)

Not known (cannot be estimated from the available data)

Infection and infestations

Pneumonia, Upper respiratory tract infection, Bronchitis, Nasopharyngitis, Urinary tract infection, Oral Herpes

Meningococcal infectionb, Sepsis, Septic shock, Peritonitis, Lower respiratory tract infection, Fungal infection, Viral infection, Abscessa, Cellulitis, Influenza, Gastrointestinal infection, Cystitis, Infection, Sinusitis, Gingivitis

Aspergillus infectionc, Arthritis bacterialc, Genitourinary tract gonococcal infection, Haemophilus infection, Impetigo

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

Malignant melanoma, Myelodysplastic syndrome

Blood and lymphatic system disorders

Leukopenia, Anaemia

Thrombocytopenia, Lymphopenia

Haemolysis*, Abnormal clotting factor, Red blood cell agglutination, Coagulopathy

Immune system disorders

Anaphylactic reaction, Hypersensitivity

Endocrine disorders

Grave's disease

Metabolism and nutrition disorders

Decreased appetite

Psychiatric disorders

Insomnia

Depression, Anxiety, Mood swings, Sleep disorder

Abnormal dreams

Nervous system disorders

Headache

Dizziness

Paraesthesia, Tremor, Dysgeusia, Syncope

Eye disorders

Vision blurred

Conjunctival irritation

Ear and labyrinth disorders

Tinnitus, Vertigo

Cardiac disorders

Palpitation

Vascular disorders

Hypertension

Accelerated hypertension, Hypotension, Hot flush, Vein disorder

Haematoma

Respiratory, thoracic and mediastinal disorders

Cough, Oropharyngeal pain

Dyspnoea, Epistaxis, Throat irritation, Nasal congestion, Rhinorrhoea

Gastrointestinal disorders

Diarrhoea, Vomiting, Nausea, Abdominal pain

Constipation, Dyspepsia, Abdominal distension

Gastroesophageal reflux disease, Gingival pain

Hepatobiliary disorders

Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased

Jaundice

Liver injuryd

Skin and subcutaneous tissue disorders

Rash, Pruritus, Alopecia

Urticaria, Erythema, Petechiae, Hyperhidrosis, Dry skin, Dermatitis

Skin depigmentation

Musculoskeletal and connective tissue disorders

Arthralgia, Myalgia, Pain in extremity

Muscle spasms, Bone pain, Back pain, Neck pain

Trismus, Joint swelling

Renal and urinary disorders

Renal impairment, Dysuria, Haematuria

Reproductive system and breast disorders

Spontaneous penile erection

Menstrual disorder

General disorders and administration site conditions

Pyrexia, Fatigue, Influenza-like illness

Edema, Chest discomfort, Asthenia, Chest pain, Infusion site pain, Chills

Extravasation, Infusion site paraesthesia, Feeling hot

Investigations

Haematocrit decreased, Haemoglobin decreased

Coombs test positivec

Injury, poisoning and procedural complication

Infusion-related reaction

Included Studies: Asthma (C07-002), aHUS(C08-002, C08-003, C10-003, C10-004), Dermatomyositis (C99-006), refractory gMG (C08-001, ECU-MG-301, ECU-MG-302, ECU-MG-303), Neuromyelitis Optica Spectrum Disorder (ECU-NMO-301, ECU-NMO-302), IMG (C99-004, E99-004), PNH (C02-001, C04-001, C04-002, C06-002, C07-001, E02-001, E05-001, E07-001, M07-005, X03-001, X03-001A), Psoriasis (C99-007), RA (C01-004, C97-001, C99-001, E01-004, E99-001), STEC-HUS (C11-001), SLE (C97-002). MedDRA version 26.1.

*See paragraph Description of selected adverse reactions.a Abscess includes the following group of PTs: Abscess limb, Colonic abscess, Renal abscess, Subcutaneous abscess, Tooth abscess, Liver abscess, Perirectal abscess, Rectal abscess.b Meningococcal infection includes the following group of PTs: Meningococcal infection, Meningococcal sepsis, Meningitis meningococcal.

c ADRs identified in postmarketing reports

d Frequency cannot be estimated from the available postmarketing data.

Description of selected adverse reactions

In all clinical studies, the most serious adverse reaction was meningococcal sepsis which is a common presentation of meningococcal infections in patients treated with Soliris (see section 4.4).

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

Antibodies to Soliris were detected in 2% of patients with PNH using an ELISA assay, 3% of patients with aHUS and 2% of patients with NMOSD using the ECL bridging format assay. In refractory gMG placebo-controlled studies, no antidrug antibodies were observed. As with all proteins there is a potential for immunogenicity.

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

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

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 paediatric aHUS patients (aged 2 months to less than 18 years) included in the aHUS studies C08-002, C08-003, C09-001r and C10-003, the safety profile appeared similar to that observed in adult aHUS patients. The safety profiles in the different paediatric subsets of age appear similar.

In paediatric patients with refractory gMG (aged 12 to less than 18 years) included in Study ECU-MG-303, the safety profile appeared similar to that observed in adult patients with refractory gMG.

Elderly population

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

Patients with other diseases

Safety Data from Other Clinical Studies

Supportive safety data were obtained in 12 completed clinical studies that included 934 patients exposed to eculizumab in other disease populations other than PNH, aHUS, refractory gMG or NMOSD. There was an un-vaccinated patient diagnosed with idiopathic membranous glomerulonephropathy who experienced meningococcal meningitis. Adverse reactions reported in patients with disease other than PNH, aHUS, refractory gMG or NMOSD were similar to those reported in patients with PNH, aHUS, refractory gMG or NMOSD (see Table 1 above). No specific adverse reactions have emerged from these clinical studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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