Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active, severe infections (see section 4.4).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Canakinumab is associated with an increased incidence of serious infections. Therefore patients should be monitored carefully for signs and symptoms of infections during and after treatment with canakinumab. Physicians should exercise caution when administering canakinumab to patients with infections, a history of recurring infections, or underlying conditions which may predispose them to infections.
Canakinumab should not be initiated or continued in patients during an active infection requiring medical intervention.
Canakinumab should not be administered during an active infection. Concomitant use of canakinumab with tumour necrosis factor (TNF) inhibitors is not recommended because this may increase the risk of serious infections (see section 4.5).
Isolated cases of unusual or opportunistic infections (including aspergillosis, atypical mycobacterial infections, herpes zoster) have been reported during canakinumab treatment. The causal relationship of canakinumab to these events cannot be excluded.
In approximately 12% of CAPS patients tested with a PPD (purified protein derivative) skin test in clinical trials, follow-up testing yielded a positive test result while treated with canakinumab without clinical evidence of a latent or active tuberculosis infection.
It is unknown whether the use of interleukin-1 (IL-1) inhibitors such as canakinumab increases the risk of reactivation of tuberculosis. Before initiation of therapy, all patients must be evaluated for both active and latent tuberculosis infection. Particularly in adult patients, this evaluation should include a detailed medical history. Appropriate screening tests (e.g. tuberculin skin test, interferon gamma release assay or chest X-ray) should be performed in all patients (local recommendations may apply). Patients must be monitored closely for signs and symptoms of tuberculosis during and after treatment with canakinumab. All patients should be instructed to seek medical advice if signs or symptoms suggestive of tuberculosis (e.g. persistent cough, weight loss, subfebrile temperature) appear during canakinumab therapy. In the event of conversion from a negative to a positive PPD test, especially in high-risk patients, alternative means of screening for a tuberculosis infection should be considered.
Neutropenia (absolute neutrophil count [ANC] <1.5 × 109/l) and leukopenia have been observed with medicinal products that inhibit IL-1, including canakinumab. Treatment with canakinumab should not be initiated in patients with neutropenia or leukopenia. It is recommended that white blood cell (WBC) counts including neutrophil counts be assessed prior to initiating treatment and again after 1 to 2 months. For chronic or repeated therapies, it is also recommended to assess WBC counts periodically during treatment. If a patient becomes neutropenic or leukopenic, the WBC counts should be monitored closely and treatment discontinuation should be considered.
Malignancy events have been reported in patients treated with canakinumab. The risk for the development of malignancies with anti-interleukin (IL)-1 therapy is unknown.
Hypersensitivity reactions with canakinumab therapy have been reported. The majority of these events were mild in severity. During clinical development of canakinumab in over 2,600 patients, no anaphylactoid or anaphylactic reactions attributable to treatment with canakinumab were reported. However, the risk of severe hypersensitivity reactions, which is not uncommon for injectable proteins, cannot be excluded (see section 4.3).
Transient and asymptomatic cases of elevations of serum transaminases or bilirubin have been reported in clinical trials (see section 4.8).
No data are available on the risk of secondary transmission of infection by live (attenuated) vaccines in patients receiving canakinumab. Therefore, live vaccines should not be given concurrently with canakinumab unless the benefits clearly outweigh the risks (see section 4.5).
Prior to initiation of canakinumab therapy it is recommended that adult and paediatric patients receive all vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine (see section 4.5).
Clinical experience in CAPS patients without a confirmed mutation in the NLRP3 gene is limited.
Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular Still’s disease. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible. Physicians should be attentive to symptoms of infection or worsening of Still’s disease, as these are known triggers for MAS. Based on clinical trial experience, canakinumab does not appear to increase the incidence of MAS in Still’s disease patients, but no definitive conclusion can be made.
Interactions between canakinumab and other medicinal products have not been investigated in formal studies.
An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Use of canakinumab with TNF inhibitors is not recommended because this may increase the risk of serious infections.
The expression of hepatic CYP450 enzymes may be suppressed by the cytokines that stimulate chronic inflammation, such as interleukin-1 beta (IL-1 beta). Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as canakinumab, is introduced. This is clinically relevant for CYP450 substrates with a narrow therapeutic index where the dose is individually adjusted. On initiation of canakinumab in patients being treated with this type of medicinal product, therapeutic monitoring of the effect or of the active substance concentration should be performed and the individual dose of the medicinal product adjusted as necessary.
No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving canakinumab. Therefore, live vaccines should not be given concurrently with canakinumab unless the benefits clearly outweigh the risks. Should vaccination with live vaccines be indicated after initiation of canakinumab treatment, the recommendation is to wait for at least 3 months after the last canakinumab injection and before the next one (see section 4.4).
The results of a study in healthy adult subjects demonstrated that a single dose of canakinumab 300 mg did not affect the induction and persistence of antibody responses after vaccination with influenza or glycosylated protein based meningococcus vaccines.
The results of a 56-week, open label study in CAPS patients aged 4 years and younger demonstrated that all patients who received non-live, standard of care childhood vaccinations developed protective antibody levels.
Women should use effective contraceptives during treatment with canakinumab and for up to 3 months after the last dose.
There is a limited amount of data from the use of canakinumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). The risk for the foetus/mother is unknown. Women who are pregnant or who desire to become pregnant should therefore only be treated after a thorough benefit-risk evaluation.
Animal studies indicate that canakinumab crosses the placenta and is detectable in the foetus. No human data are available, but as canakinumab is an immunoglobulin of the G class (IgG1), human transplacental transfer is expected. The clinical impact of this is unknown. However, administration of live vaccines to newborn infants exposed to canakinumab in utero is not recommended for 16 weeks following the mother’s last dose of canakinumab before childbirth. Women who received canakinumab during pregnancy should be instructed to inform the baby’s healthcare professional before any vaccinations are given to their newborn infant.
It is unknown whether canakinumab is excreted in human milk. The decision whether to breast-feed during canakinumab therapy should therefore only be taken after a thorough benefit-risk evaluation.
Animal studies have shown that a murine anti-murine IL-1 beta antibody had no undesirable effects on development in nursing mouse pups and that the antibody was transferred to them (see section 5.3).
Formal studies of the potential effect of canakinumab on human fertility have not been conducted. Canakinumab had no effect on male fertility parameters in marmosets (C. jacchus). A murine anti- murine IL-1 beta antibody had no undesirable effects on fertility in male or female mice (see section 5.3).
Ilaris has minor influence on the ability to drive and use machines. Treatment with Ilaris may result in dizziness/vertigo or asthenia (see section 4.8). Patients who experience such symptoms during Ilaris treatment should wait for this to resolve completely before driving or operating machines.
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).
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.
Table 1. Tabulated list of adverse reactions:
Indications: CAPS, TRAPS, HIDS/MKD, FMF, SJIA, gouty arthritis
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
Common: Dizziness/vertigo
Very common: Upper abdominal pain1
Uncommon: Gastro-oesophageal reflux disease2
Very common: Injection site reaction
Very common: Arthralgia1
Common: Musculoskeletal pain1, Back pain2
Common: Fatigue/asthenia2
Very common: Creatinine renal clearance decreased1,3, Proteinuria1,4, Leukopenia1,5
Common: Neutropenia5
Uncommon: Platelet count decreased5
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
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.
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.
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.
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.
In the overall SJIA programme, transient decreased white blood cell (WBC) counts ≤0.8 x LLN were reported in 33 patients (16.5%).
In the overall SJIA programme, transient decreases in absolute neutrophil count (ANC) to less than 1 × 109/l were reported in 12 patients (6.0%).
In the overall SJIA programme, transient decreases in platelet counts (< LLN) were observed in 19 patients (9.5%).
In the overall SJIA programme, high ALT and/or AST >3 x upper limit of normal (ULN) were reported in 19 patients (9.5%).
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 × 109/l were reported in 2% of patients in the comparative trials. Isolated cases of ANC counts <0.5 × 109/l were also observed (see section 4.4).
Mild (< LLN and >75 × 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.
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 starting on 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).
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).
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.
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.
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.
There is no significant difference in safety profile observed in patients ≥65 years of age.
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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