Eculizumab

Interactions

Eculizumab interacts in the following cases:

Human immunoglobulin (IVIg)

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.

Rituximab

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.

Anaphylaxis

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.

Infections

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.

Pregnancy

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.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

Fertility

No specific study of eculizumab on fertility has been conducted.

Effects on ability to drive and use machines

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

Adverse reactions


Summary of the safety profile

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.

List of adverse reactions

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:

Infection and infestations

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

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

Rare: Malignant melanoma, Myelodysplastic syndrome

Blood and lymphatic system disorders

Common: Leukopenia, Anaemia

Uncommon: Thrombocytopenia, Lymphopenia

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

Immune system disorders

Uncommon: Anaphylactic reaction, Hypersensitivity

Endocrine disorders

Rare: Basedow’s disease

Metabolism and nutrition disorders

Uncommon: Decreased appetite

Psychiatric disorders

Common: Insomnia

Uncommon: Depression, Anxiety, Mood swings

Rare: Abnormal dreams, Sleep disorder

Nervous system disorders

Very Common: Headache

Common: Dizziness, Dysgeusia

Uncommon: Paraesthesia, Tremor

Rare: Syncope

Eye disorders

Uncommon: Vision blurred

Rare: Conjunctival irritation

Ear and labyrinth disorders

Uncommon: Tinnitus, Vertigo

Cardiac disorders

Uncommon: Palpitation

Vascular disorders

Common: Hypertension

Uncommon: Accelerated hypertension, Hypotension, Hot flush, Vein disorder

Rare: Haematoma

Respiratory, thoracic and mediastinal disorders

Common: Cough, Oropharyngeal pain

Uncommon: Dyspnoea, Epistaxis, Throat irritation, Nasal congestion, Rhinorrhoea

Gastrointestinal disorders

Common: Diarrhoea, Vomiting, Nausea, Abdominal pain

Uncommon: Constipation, Dyspepsia, Abdominal distension

Rare: Gastroesophageal reflux disease, Gingival pain

Hepatobiliary disorders

Rare: Jaundice

Skin and subcutaneous tissue disorders

Common: Rash, Pruritus, Alopecia

Uncommon: Urticaria, Erythema, Petechiae, Hyperhidrosis, Dry skin

Rare: Dermatitis, Skin depigmentation

Musculoskeletal and connective tissue disorders

Common: Arthralgia, Myalgia

Uncommon: Muscle spasms, Bone pain, Back pain, Neck pain, Joint swelling, Pain in extremity

Rare: Trismus

Renal and urinary disorders

Uncommon: Renal impairment, Dysuria, Haematuria

Reproductive system and breast disorders

Uncommon: Spontaneous penile erection,

Rare: Menstrual disorder

General disorders and administration site conditions

Common: Pyrexia, Fatigue, Influenza like illness

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

Rare: Extravasation, Infusion site paraesthesia, Feeling hot

Investigations

Uncommon: Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Haematocrit decreased, Haemoglobin decreased

Rare: Coombs test positivec

Injury, poisoning and procedural complication

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

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 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.

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.

Eculizumab has not been studied in paediatric patients with refractory gMG or NMOSD.

Elderly population

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

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 list above). No specific adverse reactions have emerged from these clinical studies.

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