Eculizumab interacts in the following cases:
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.
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.
Administration of eculizumab may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis). In clinical trials, 1 (0.9%) gMG patient experienced an infusion reaction which required discontinuation of eculizumab. No PNH, aHUS or NMOSD patients experienced an infusion reaction which required discontinuation of eculizumab. Eculizumab administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.
Due to its mechanism of action, eculizumab 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.
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.
Human IgG are known to cross the human placental barrier, and thus eculizumab may potentially cause terminal complement inhibition in the foetal circulation. Therefore, eculizumab 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.
Eculizumab has no or negligible influence on the ability to drive and use machines.
Supportive safety data were obtained from 31 completed clinical studies that included 1,503 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 sepsis.
The following list 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.
Adverse Reactions reported in eculizumab clinical trials, including patients with PNH, aHUS, refractory gMG and NMOSD as well as from postmarketing experience:
Common: Pneumonia, Upper respiratory tract infection, Bronchitis, Nasopharyngitis, Urinary tract infection, Oral Herpes
Uncommon: Meningococcal infectionb, Sepsis, Septic shock, Peritonitis, Lower respiratory tract infection, Fungal infection, Viral infection, Abscessa, Cellulitis, Influenza, Gastrointestinal infection, Cystitis, Infection, Sinusitis,
Rare: Aspergillus infectionc, Arthritis bacterialc, Genitourinary tract gonococcal infection, Haemophilus influenzae infection, Impetigo, Gingivitis
Rare: Malignant melanoma, Myelodysplastic syndrome
Common: Leukopenia, Anaemia
Uncommon: Thrombocytopenia, Lymphopenia
Rare: Haemolysis*, Abnormal clotting factor, Red blood cell agglutination, Coagulopathy
Uncommon: Anaphylactic reaction, Hypersensitivity
Rare: Basedow’s disease
Uncommon: Decreased appetite
Common: Insomnia
Uncommon: Depression, Anxiety, Mood swings
Rare: Abnormal dreams, Sleep disorder
Very Common: Headache
Common: Dizziness, Dysgeusia
Uncommon: Paraesthesia, Tremor
Rare: Syncope
Uncommon: Vision blurred
Rare: Conjunctival irritation
Uncommon: Tinnitus, Vertigo
Uncommon: Palpitation
Common: Hypertension
Uncommon: Accelerated hypertension, Hypotension, Hot flush, Vein disorder
Rare: Haematoma
Common: Cough, Oropharyngeal pain
Uncommon: Dyspnoea, Epistaxis, Throat irritation, Nasal congestion, Rhinorrhoea
Common: Diarrhoea, Vomiting, Nausea, Abdominal pain
Uncommon: Constipation, Dyspepsia, Abdominal distension
Rare: Gastroesophageal reflux disease, Gingival pain
Rare: Jaundice
Common: Rash, Pruritus, Alopecia
Uncommon: Urticaria, Erythema, Petechiae, Hyperhidrosis, Dry skin
Rare: Dermatitis, Skin depigmentation
Common: Arthralgia, Myalgia
Uncommon: Muscle spasms, Bone pain, Back pain, Neck pain, Joint swelling, Pain in extremity
Rare: Trismus
Uncommon: Renal impairment, Dysuria, Haematuria
Uncommon: Spontaneous penile erection,
Rare: Menstrual disorder
Common: Pyrexia, Fatigue, Influenza like illness
Uncommon: Edema, Chest discomfort, Asthenia, Chest pain, Infusion site pain, Chills
Rare: Extravasation, Infusion site paraesthesia, Feeling hot
Uncommon: Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Haematocrit decreased, Haemoglobin decreased
Rare: Coombs test positivec
Uncommon: Infusion related reaction
Included Studies: Asthma (C07-002), aHUS(C08-002, C08-003, C10-003, C10-004), Dermatomyositis (C99-006), gMG (C08-001, ECU-MG-301, ECU-MG-302), Neuromyelitis Optica Spectrum Disorder (ECU-NMO-301), 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 21.0.
* 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 eculizumab. Other cases of Neisseria species have been reported including sepsis with Neisseria gonorrhoeae, Neisseria sicca/subflava, Neisseria spp unspecified.
Antibodies to eculizumab 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 eculizumab dose in PNH clinical trials.
Cases of thrombotic microangiopathy complication have been reported in the setting of missed or delayed eculizumab dose in aHUS clinical trials.
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.
Eculizumab has not been studied in paediatric patients with refractory gMG or NMOSD.
No overall differences in safety were reported between elderly (≥65 years) and younger refractory gMG patients (<65 years).
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 list above). No specific adverse reactions have emerged from these clinical studies.
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