Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Alexion Europe SAS, 103-105 rue Anatole France, 92300 Levallois-Perret, FRANCE
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):
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.
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 serogroups A, C, Y, W 135 are recommended in preventing the commonly pathogenic meningococcal serogroups. Vaccine against serogroup B where available is also recommended. Patients must receive vaccination according to current national vaccination 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 information brochure and a patient safety card (see Package Leaflet for a description).
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.
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.
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.
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 serogroups A, C, Y, W 135 are recommended in preventing the commonly pathogenic meningococcal serogroups. Vaccine against serogroup B where available is also recommended (see Meningococcal Infection).
Patients less than 18 years of age must be vaccinated against Haemophilus influenzae and pneumococcal infections, and strictly need to adhere to the national vaccination recommendations for each age group.
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.
Treatment with Soliris should not alter anticoagulant management.
When immunosuppressant and anticholinesterase therapies are decreased or discontinued, patients should be monitored closely for signs of disease exacerbation.
When immunosuppressant therapy is decreased or discontinued, patients should be monitored closely for signs and symptoms of potential NMOSD relapse.
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 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).
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.
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.
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.
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.
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, 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.
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.
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.
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.
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.
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.
No specific study of eculizumab on fertility has been conducted.
Soliris has no or negligible influence on the ability to drive and use machines.
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.
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) 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.
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) |
|---|---|---|---|---|
| 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 influenzae 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 | Basedow’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 | Jaundice | |||
| 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 | Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma- glutamyltransferase increased, 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 24.1.
* 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, Hepatosplenic abscess, Perirectal abscess, Rectal abscess.
b Meningococcal infection includes the following group of PTs: Meningococcal infection, Meningococcal sepsis, Meningitis meningococcal, Neisseria infection.
c ADRs identified in postmarketing reports.
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).
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. Soliris has not been studied in paediatric patients with NMOSD.
No overall differences in safety were reported between elderly (≥65 years) and younger refractory gMG patients (<65 years) (see section 5.1).
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 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 national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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