Adverse reactions : תופעות לוואי

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) 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 Very             Common                       Uncommon                   Rare Organ Class   Common           (≥1/100 to <1/10)            (≥1/1,000 to <1/100)       (≥1/10,000 to (≥1/10)                                                                  <1/1,000) Infection and                  Pneumonia, Upper             Meningococcal              Aspergillus infestations                   respiratory tract infection, infectionb, Sepsis, Septic infectionc, Arthritis Bronchitis,                  shock, Peritonitis,        bacterialc,
Nasopharyngitis, Urinary Lower respiratory tract Genitourinary tract tract infection, Oral        infection, Fungal          gonococcal infection, Herpes                       infection, Viral           Haemophilus infection, Abscessa,       influenzae infection,
Cellulitis, Influenza,     Impetigo,
Gastrointestinal infection, Cystitis,
Infection, Sinusitis,
Gingivitis
Neoplasms                                                                              Malignant melanoma, benign, malignant                                                                      Myelodysplastic and unspecified                                                                        syndrome (including cysts and polyps)
Blood and                      Leukopenia,                  Thrombocytopenia,        Haemolysis*, lymphatic system               Anaemia                      Lymphopenia              Abnormal clotting disorders                                                                            factor, Red blood cell agglutination,
Coagulopathy
Immune system                                               Anaphylactic reaction, disorders                                                   Hypersensitivity Endocrine                                                                            Basedow’s disease disorders
Metabolism and                                              Decreased appetite nutrition disorders


Psychiatric                  Insomnia                    Depression, Anxiety,        Abnormal dreams disorders                                                Mood swings, Sleep disorder
Nervous system Headache Dizziness                        Paraesthesia, Tremor, disorders                                                Dysgeusia, Syncope Eye disorders                                            Vision blurred              Conjunctival irritation Ear and labyrinth                                        Tinnitus, Vertigo disorders
Cardiac disorders                                        Palpitation

Vascular                     Hypertension                Accelerated              Haematoma disorders                                                hypertension, Hypotension, Hot flush,
Vein disorder
Respiratory,                 Cough, Oropharyngeal        Dyspnoea, Epistaxis, thoracic and                 pain                        Throat irritation, Nasal mediastinal                                              congestion, Rhinorrhoea disorders
Gastrointestinal             Diarrhoea, Vomiting,        Constipation,               Gastroesophageal disorders                    Nausea, Abdominal pain      Dyspepsia, Abdominal        reflux disease, distension                  Gingival pain
Hepatobiliary                                                                        Jaundice disorders
Skin and                     Rash, Pruritus, Alopecia    Urticaria, Erythema,        Skin depigmentation subcutaneous                                             Petechiae,
tissue disorders                                         Hyperhidrosis, Dry skin, Dermatitis
Musculoskeletal              Arthralgia, Myalgia, Pain   Muscle spasms, Bone         Trismus, Joint and connective               in extremity                pain, Back pain, Neck       swelling tissue disorders                                         pain
Renal and urinary                                        Renal impairment, disorders                                                Dysuria, Haematuria Reproductive                                             Spontaneous penile          Menstrual disorder system and breast                                        erection disorders
General disorders            Pyrexia, Fatigue, Influenza Edema, Chest                Extravasation, and                          like illness                discomfort, Asthenia,       Infusion site administration                                           Chest pain, Infusion site   paraesthesia, Feeling site conditions                                          pain, Chills                hot Investigations                                           Alanine                     Coombs test positivec aminotransferase increased, Aspartate aminotransferase increased, Gamma- glutamyltransferase increased, Haematocrit decreased, Haemoglobin decreased
Injury, poisoning            Infusion related reaction and procedural complication
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.

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.

Soliris has not been studied in paediatric patients with NMOSD.

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com