Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most common adverse reactions with ravulizumab are headache (28.2%), upper respiratory tract infection (19.9%), nasopharyngitis (19.5%), diarrhoea (16.9%), pyrexia (16.4%), nausea (13.7%), arthralgia (13.2%), fatigue (13.1%), back pain (12.6%), abdominal pain (11.8%) and dizziness (10.1%). 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 (0.1%).

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 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 infestations   Upper respiratory    Urinary tract infection           Meningococcal infection a, tract infection,                                       Disseminated Gonococcal Nasopharyngitis                                        infection b
Immune system disorders                            Hypersensitivity d                Anaphylactic reaction c Nervous system disorders      Headache
Dizziness
Gastrointestinal disorders    Diarrhoea, Nausea,   Vomiting, Dyspepsia Abdominal pain
Skin and subcutaneous                              Urticaria, Pruritus, Rash tissue disorders
Musculoskeletal and           Arthralgia, Back     Myalgia, Muscle spasms connective tissue disorders   pain
General disorders and          Pyrexia, Fatigue    Influenza like illness, Chills, administration site                                Asthenia conditions
Injury, poisoning and                              Infusion-related reaction procedural complications a
Meningococcal infection includes preferred terms of meningococcal infection, meningococcal sepsis, and encephalitis meningococcal b
Disseminated gonococcal infection includes preferred terms of disseminated gonococcal infection and gonococcal infection c
Estimated from post-marketing experience d
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 reaction reported in paediatric patients was pyrexia (32.3%).

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