Adverse reactions : תופעות לוואי

4.8     Undesirable effects
Summary of the safety profile

The most common adverse reactions with ravulizumab are headache (30%), upper respiratory tract infection (21.1%), nasopharyngitis (20.1%), diarrhoea (18.1%), pyrexia (17.6%), nausea (14.6%), arthralgia (14.1%), back pain (13.5%), fatigue (13.1%), abdominal pain (12.3%), dizziness (10.5%) and urinary tract infection (10.2%). The most serious adverse reactions are meningococcal infection (0.7%) including meningococcal sepsis, encephalitis meningococcal, meningococcal infection (see section 4.4) and disseminated gonococcal infection (0.2%).

Tabulated list of adverse reactions

Table 8 gives the adverse reactions observed from clinical trials and from post-marketing experience.
Adverse reactions are listed by MedDRA System Organ Class (SOC) and frequency, using the following convention: 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); very rare (< 1/10,000); and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 8:       Adverse Drug reactions from clinical trials and postmarketing experience MedDRA System Organ Very common                     Common                  Uncommon Class                     (≥ 1/10)                  (≥ 1/100 to < 1/10)     (≥ 1/1,000 to < 1/100) Infections and            Urinary tract infection a                         Meningococcal infestations              Upper respiratory tract                           infection b, infection,                                        Disseminated
Nasopharyngitis                                   Gonococcal infection c e
Immune system                                       Hypersensitivity        Anaphylactic reaction d disorders
Nervous system            Dizziness, Headache disorders
Gastrointestinal          Diarrhoea, Nausea,        Vomiting, Dyspepsia disorders                 Abdominal pain
Skin and subcutaneous                               Urticaria, Pruritus, tissue disorders                                    Rash
Musculoskeletal and       Arthralgia, Back pain     Myalgia, Muscle connective tissue                                   spasms disorders
General disorders and      Pyrexia, Fatigue         Influenza like illness, administration site                                 Chills, Asthenia conditions
Injury, poisoning and                               Infusion-related procedural                                          reaction complications a
Urinary tract infection is a group term that includes Preferred Terms: Urinary tract infection, Urinary tract infection bacterial, Urinary tract infection enterococcal, and Escherichia urinary tract infection b
Meningococcal infection includes preferred terms of meningococcal infection, meningococcal sepsis, and encephalitis meningococcal c
Disseminated gonococcal infection includes preferred terms of disseminated gonococcal infection and gonococcal infection d
Estimated from post-marketing experience e
Hypersensitivity is a group term for Preferred Term drug hypersensitivity with related causality and Preferred Term hypersensitivity


Description of selected adverse reactions

Meningococcal infection/sepsis/encephalitis
Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical trials, < 1 % of patients developed serious meningococcal infections while receiving treatment with ravulizumab; all were adult patients with PNH or NMOSD who had been vaccinated.
Please refer to section 4.4 for information on prevention and treatment of suspected meningococcal infection. In patients treated with ravulizumab, meningococcal infections have presented as meningococcal sepsis and encephalitis meningococcal. Patients should be informed of the signs and symptoms of meningococcal infection and advised to seek medical care immediately.

Infusion-related reactions
In clinical trials, infusion-related reactions were common (≥1%). These events, which were mild to moderate in severity and transient, included back pain, abdominal pain, muscle spasms, drop in blood pressure, elevation in blood pressure, rigors, limb discomfort, hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ravulizumab.

Immunogenicity
In adult PNH patient studies (N = 475), a paediatric PNH study (N = 13), aHUS studies (N=89), a gMG study (N=86) and an NMOSD study (N = 58), 2 (0.3 %) cases of development of treatment-emergent anti-drug antibody have been reported with ravulizumab (1 adult patient with PNH and 1 adult patient with aHUS). These anti-drug antibodies were transient in nature with low titre and did not correlate with clinical response or adverse events.

Paediatric population
Paroxysmal nocturnal haemoglobinuria (PNH)
In paediatric PNH patients (N=13, aged 9 to 17 years old) enrolled in the paediatric PNH Study (ALXN1210-PNH-304), the safety profile appeared similar to that observed in adult PNH patients. The most common adverse reactions reported in paediatric PNH patients were abdominal pain, nausea, nasopharyngitis and headache, which occurred in 3 patients (23.1%).

Atypical haemolytic uremic syndrome (aHUS)
In paediatric patients with evidence of aHUS (N=34, aged 10 months to less than 18 years) included in ALXN1210-aHUS-312 study, the safety profile of ravulizumab appeared similar to that observed in adult patients with evidence of aHUS. The safety profiles in the different paediatric subsets of age appear similar. The safety data for patient below 2 years of age is limited to four patients. The most common adverse reactions (≥ 20%) reported in paediatric patients were pyrexia, vomiting, diarrhoea, headache, nasopharyngitis, upper respiratory tract infection and abdominal pain.

Generalized myasthenia gravis (gMG)
Ravulizumab has not been studied in paediatric patients with gMG.

Neuromyelitis optica spectrum disorder (NMOSD)
Ravulizumab has not been studied in paediatric patients with NMOSD.
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