Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
The most frequent adverse drug reactions were infections predominantly of the upper respiratory tract. No impact on the type or frequency of adverse drug reactions was seen with longer-term treatment.

Hypersensitivity reactions have been reported in patients treated with canakinumab (see sections 4.3 and 4.4).

Opportunistic infections have been reported in patients treated with canakinumab (see section 4.4).

Tabulated list of adverse reactions
Adverse reactions are listed according to MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency category with the most common first. Frequency categories are defined 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.


ILR API Dec21 V4                         Based on EU SmPC 28.09.2021


Table 1             Tabulated list of adverse reactions
MedDRA             Indications:
System Organ       CAPS, TRAPS, HIDS/MKD, FMF, SJIA, gouty arthritis
Class
Infections and infestations
Very common        Respiratory tract infections (including pneumonia, bronchitis, influenza, viral infection, sinusitis, rhinitis, pharyngitis, tonsillitis, nasopharyngitis, upper respiratory tract infection)
Ear infection
Cellulitis
Gastroenteritis
Urinary tract infection
Common             Vulvovaginal candidiasis
Nervous system disorders
Common             Dizziness/vertigo
Gastrointestinal disorders
Very common        Upper abdominal pain 1
Uncommon           Gastro-oesophageal reflux disease 2
Skin and subcutaneous tissue disorders
Very common        Injection site reaction
Musculoskeletal and connective tissue disorders
Very common        Arthralgia 1
Common             Musculoskeletal pain 1
Back pain 2
General disorders and administration site conditions
Common             Fatigue/asthenia 2
Investigations
Very common        Creatinine renal clearance decreased 1,3
Proteinuria 1,4
Leukopenia 1,5
Common             Neutropenia 5
Uncommon           Platelet count decreased 5
1 In SJIA
2 In gouty arthritis
3 Based on estimated creatinine clearance, most were transient
4 Most represented transient trace to 1+ positive urinary protein by dipstick
5 See further information below


Still’s Disease (SJIA and AOSD)

SJIA pooled analysis and AOSD
A total of 445 SJIA patients aged 2 to < 20 years received canakinumab in clinical trials, including 321 patients aged 2 to < 12 years, 88 patients aged 12 to < 16 years, and 36 patients aged 16 to < 20 years.
A pooled safety analysis of all SJIA patients showed that in the subset of young adult SJIA patients aged 16 to <20 years, the safety profile of canakinumab was consistent with what was observed in SJIA patients less than 16 years of age. The safety profile of canakinumab in AOSD patients in a randomised, double blind placebo-controlled study (GDE01T) in 36 adult patients (aged 22 to 70 years) was similar to what was observed in SJIA patients.


ILR API Dec21 V4                                  Based on EU SmPC 28.09.2021 
Description of selected adverse reactions
Long-term data and laboratory abnormalities in CAPS patients
During clinical trials with canakinumab in CAPS patients mean values for haemoglobin increased and those for white blood cell, neutrophils and platelets decreased.

Elevations of transaminases have been observed rarely in CAPS patients.

Asymptomatic and mild elevations of serum bilirubin have been observed in CAPS patients treated with canakinumab without concomitant elevations of transaminases.
In the long-term, open-label studies with dose escalation, events of infections (gastroenteritis, respiratory tract infection, upper respiratory tract infection), vomiting and dizziness were more frequently reported in the 600 mg or 8 mg/kg dose group than in other dose groups.

Laboratory abnormalities in TRAPS, HIDS/MKD and FMF patients
Neutrophils
Although ≥ Grade 2 reductions in neutrophil count occurred in 6.5% of patients (common) and Grade 1 reductions occurred in 9.5% of patients, the reductions are generally transient and neutropenia-associated infection has not been identified as an adverse reaction.

Platelets
Although reductions in platelet count (≥ Grade 2) occurred in 0.6% of patients, bleeding has not been identified as an adverse reaction. Mild and transient Grade 1 reduction in platelets occurred in 15.9% of patients without any associated bleeding adverse events.

Laboratory abnormalities in SJIA patients
Haematology
In the overall SJIA program, transient decreased white blood cell (WBC) counts < 0.8× lower limit of normal (LLN) were reported in 33 patients (16. 5%).

In the overall SJIA program, transient decreases in absolute neutrophil count (ANC) to less than 1x109/L were reported in 12 patients (6.0%).

In the overall SJIA program, transient decreases in platelet counts ( 3 x upper limit of normal (ULN) were reported in 19 patients (9.5%).

Laboratory abnormalities in gouty arthritis patients
Haematology
Decreased white blood cell counts (WBC) ≤ 0.8 x lower limit of normal (LLN) were reported in 6.7% of patients treated with canakinumab compared to 1.4% treated with triamcinolone acetonide. Decreases in absolute neutrophil counts (ANC) to less than 1 x 109/L were reported in 2% of patients in the comparative trials. Isolated cases of ANC counts < 0.5 x 109/L were also observed (see section 4.4).

Mild (< LLN and > 75 x 109/L) and transient decreases in platelet counts were observed at a higher incidence (12.7%) with canakinumab in the active-controlled clinical studies versus the comparator (7.7%) in gouty arthritis patients.

Uric acid
Increases in uric acid level (0.7 mg/dL at 12 weeks and 0.5 mg/dL at 24 weeks) were observed after canakinumab treatment in comparative trials in gouty arthritis. In another study, among patients who were 

ILR API Dec21 V4                          Based on EU SmPC 28.09.2021 starting on urate lowering therapy (ULT), increases in uric acid were not observed. Uric acid increases were not observed in clinical trials in non-gouty arthritis populations (see section 5.1).

ALT/AST
Mean and median increases in alanine transaminase (ALT) of 3.0 U/L and 2.0 U/L, respectively, and in aspartate transaminase (AST) of 2.7 U/L and 2.0 U/L, respectively, from baseline to end of study were seen in the canakinumab -treated groups versus the triamcinolone acetonide-treated group(s), however the incidence of clinically significant changes (≥3 x the upper limit of normal) was greater for patients treated with triamcinolone acetonide (2.5% for both AST and ALT) compared with canakinumab -treated patients (1.6% for ALT and 0.8% for AST).

Triglycerides
In active-controlled gouty arthritis trials, there was a mean increase in triglycerides of 33.5 mg/dL in canakinumab -treated patients compared with a modest decrease of -3.1 mg/dL with triamcinolone acetonide. The incidence of patients with triglyceride elevations >5 x upper limit of normal (ULN) was 2.4% with canakinumab and 0.7% with triamcinolone acetonide. The clinical significance of this observation is unknown.

Long term data from observational study
A total of 243 CAPS patients (85 paediatric patients aged ≥ 2 to ≤ 17 years and 158 adult patients aged ≥ 18 years) were treated with canakinumab in routine clinical practice in a long-term registry study (mean of 3.8 years of canakinumab exposure). The safety profile of canakinumab observed following long-term treatment in this setting was consistent with what has been observed in interventional studies in CAPS patients.

Paediatric population
There were 80 paediatric CAPS patients (2-17 years of age) who received canakinumab in the interventional studies. Overall, there were no clinically meaningful differences in the safety and tolerability profile of canakinumab in paediatric patients compared to the overall CAPS population (comprised of adult and paediatric patients, N=211) including the overall frequency and severity of infectious episodes. Infections of the upper respiratory tract were the most frequently reported infection events.

Additionally, 6 paediatric patients under the age of 2 years were evaluated in a small open-label clinical study. The safety profile of canakinumab appeared similar to that in patients aged 2 years and above.

There were 102 TRAPS, HIDS/MKD and FMF patients (2-17 years of age) who received canakinumab in a 16-week study. Overall, there were no clinically meaningful differences in the safety and tolerability profile of canakinumab in paediatric patients compared to the overall population.

Elderly population
There is no significant difference in safety profile observed in patients ≥65 years of age.

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 https://sideeffects.health.gov.il