ILARIS 150mg / ml injectible solution medication leaflet

Ilaris 150 mg/ml solution for injection

Ilaris 150 mg solution for injection in pre-filled pen

Ilaris 150 mg/ml solution for injection in vial

Each vial contains 150 mg canakinumab in 1 ml.

Ilaris 150 mg solution for injection in pre-filled pen

Each pre-filled pen contains 150 mg canakinumab in 1 ml.

Canakinumab is a human monoclonal antibody produced in mouse myeloma Sp2/0 cells byrecombinant DNA technology.

The solution for injection contains 0.4 mg/ml polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Solution for injection (injection) in pre-filled pen (SensoReady Pen).

The solution is clear to opalescent and colourless to slightly brownish yellow with a pH ofapproximately 6.5 and osmolality of 350 to 450 mOsm/kg.

Periodic fever syndromes

Ilaris is indicated for the treatment of the following autoinflammatory periodic fever syndromes inadults, adolescents and children aged 2 years and older:

Cryopyrin-associated periodic syndromes

Ilaris is indicated for the treatment of cryopyrin-associated periodic syndromes (CAPS) including:

* Muckle-Wells syndrome (MWS),

* Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurological,cutaneous, articular syndrome (CINCA),

* Severe forms of familial cold autoinflammatory syndrome (FCAS)/familial cold urticaria(FCU) presenting with signs and symptoms beyond cold-induced urticarial skin rash.

Tumour necrosis factor receptor associated periodic syndrome (TRAPS)

Ilaris is indicated for the treatment of tumour necrosis factor (TNF) receptor associated periodicsyndrome (TRAPS).

Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD)

Ilaris is indicated for the treatment of hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinasedeficiency (MKD).

Familial Mediterranean fever (FMF)

Ilaris is indicated for the treatment of Familial Mediterranean Fever (FMF). It is recommended that

Ilaris be given in combination with colchicine, if appropriate.

Ilaris is also indicated for the treatment of:

Still’s disease

Ilaris is indicated for the treatment of active Still’s disease including adult-onset Still’s disease(AOSD) and systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older who haveresponded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) andsystemic corticosteroids. Ilaris can be given as monotherapy or in combination with methotrexate.

Gouty arthritis

Ilaris is indicated for the symptomatic treatment of adult patients with frequent gouty arthritis attacks(at least 3 attacks in the previous 12 months) in whom non-steroidal anti-inflammatory drugs(NSAIDs) and colchicine are contraindicated, are not tolerated, or do not provide an adequateresponse, and in whom repeated courses of corticosteroids are not appropriate (see section 5.1).

For CAPS, TRAPS, HIDS/MKD, FMF and Still’s disease, the treatment is to be initiated andsupervised by a specialist physician experienced in the diagnosis and treatment of the relevantindication.

For gouty arthritis, the physician needs to be experienced in the use of biologics and Ilaris is to beadministered by a healthcare professional.

CAPS: Adults, adolescents and children aged 2 years and older

The recommended starting dose of canakinumab for CAPS patients is:

Adults, adolescents and children ≥ 4 years of age:

* 150 mg for patients with body weight > 40 kg

* 2 mg/kg for patients with body weight ≥ 15 kg and ≤ 40 kg

* 4 mg/kg for patients with body weight ≥ 7.5 kg and < 15 kg

Children 2 to < 4 years of age:

* 4 mg/kg for patients with body weight ≥ 7.5 kg

This is administered every eight weeks as a single dose via subcutaneous injection.

For patients with a starting dose of 150 mg or 2 mg/kg, if a satisfactory clinical response (resolution ofrash and other generalised inflammatory symptoms) has not been achieved 7 days after treatment start,a second dose of canakinumab at 150 mg or 2 mg/kg can be considered. If a full treatment response issubsequently achieved, the intensified dosing regimen of 300 mg or 4 mg/kg every 8 weeks needs tobe maintained. If a satisfactory clinical response has not been achieved 7 days after this increaseddose, a third dose of canakinumab at 300 mg or 4 mg/kg can be considered. If a full treatmentresponse is subsequently achieved, maintaining the intensified dosing regimen of 600 mg or 8 mg/kgevery 8 weeks is to be considered, based on individual clinical judgement.

For patients with a starting dose of 4 mg/kg, if a satisfactory clinical response has not been achieved7 days after treatment start, a second dose of canakinumab 4 mg/kg can be considered. If a fulltreatment response is subsequently achieved, maintaining the intensified dosing regimen of 8 mg/kgevery 8 weeks is to be considered, based on individual clinical judgement.

Clinical experience with dosing at intervals of less than 4 weeks or at doses above 600 mg or 8 mg/kgis limited.

CAPS in adults and children  4 years of age CAPS in children 2-< 4 years of age or 15 kg children  4 years of age  7.5 kg and < 15 kg150 mg or 2 mg/kg 4 mg/kg

Satisfactory clinical Satisfactory clinicalresponse after 7 days? response after 7 days?

No

Yes No Yes

M aintenance dose: Additional dose of Maintenance Additional dose150 mg or 2 mg/kg 150 mg or 2 mg/kg dose 4 mg/kg of 4 mg/kg canevery 8 weeks can be considered every 8 weeks be considered

Satisfactory clinical response after If full treatment7 days? response after 7 days,maintenance dose:8 mg/kg every 8 weeks

Yes No

Maintenance dose: Additional dose of300 mg or 4 mg/kg 300 mg or 4 mg/kg canevery 8 weeks be considered

If full treatment response after7 days, maintenance dose:600 mg or 8 mg/kg every8 weeks

TRAPS, HIDS/MKD and FMF: Adults, adolescents and children aged 2 years and older

The recommended starting dose of canakinumab in TRAPS, HIDS/MKD and FMF patients is:

* 150 mg for patients with body weight > 40 kg

* 2 mg/kg for patients with body weight ≥ 7.5 kg and ≤ 40 kg

This is administered every four weeks as a single dose via subcutaneous injection.

If a satisfactory clinical response has not been achieved 7 days after treatment start, a second dose ofcanakinumab at 150 mg or 2 mg/kg can be considered. If a full treatment response is subsequentlyachieved, the intensified dosing regimen of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) every4 weeks needs to be maintained.

In patients without clinical improvement, it is recommended that the treating physician reconsiderscontinued treatment with canakinumab.

TRAPS, HIDS/MKD and FMF patients TRAPS, HIDS/MKD and FMF patientswith body weight > 40 kg with body weight  7.5 kg and ≤ 40 kg150 mg 2 mg/kg

Satisfactory clinical Satisfactory clinicalresponse after 7 days? response after 7 days?

Yes No Yes No

Maintenance Additional dose of Maintenance Additional dosedose: 150 mg 150 mg can be dose 2 mg/kg of 2 mg/kg canevery 4 weeks considered every 4 weeks be considered

If full treatment response is If full treatment response isachieved, maintenance dose: achieved, maintenance dose:

300 mg every 4 weeks 4 mg/kg every 4 weeks

Still’s disease (SJIA and AOSD)

The recommended dose of canakinumab for patients with Still’s disease with body weight ≥ 7.5 kg is4 mg/kg (up to a maximum of 300 mg) administered every four weeks via subcutaneous injection. Inpatients without clinical improvement, it is recommended that the treating physician reconsiderscontinued treatment with canakinumab.

Gouty arthritis

Management of hyperuricaemia with appropriate urate lowering therapy (ULT) needs to be institutedor optimised. Canakinumab needs to be used as an on-demand therapy to treat gouty arthritis attacks.

The recommended dose of canakinumab for adult patients with gouty arthritis is 150 mg administeredsubcutaneously as a single dose during an attack. For maximum effect, administration of canakinumabas soon as possible after the onset of a gouty arthritis attack is recommended.

It is recommended that patients who do not respond to initial treatment are not re-treated withcanakinumab. In patients who respond and require re-treatment, there needs to be an interval of at least12 weeks before a new dose of canakinumab may be administered (see section 5.2).

If an injection is missed in patients with CAPS, TRAPS, HIDS/MKD, FMF or Still’s disease (AOSDor SJIA), it is to be administered as soon as possible without waiting until the next scheduled dose.

Subsequent doses are to be administered at the recommended intervals.

CAPS, TRAPS, HIDS/MKD and FMF

The safety and efficacy of canakinumab in CAPS, TRAPS, HIDS/MKD and FMF patients under2 years of age have not been established. Currently available data are described in sections 4.8, 5.1 and5.2 but no recommendation on a posology can be made.

SJIA

The safety and efficacy of canakinumab in SJIA patients under 2 years of age have not beenestablished. No data are available.

Gouty arthritis

There is no relevant use of canakinumab in the paediatric population in the indication gouty arthritis.

No dose adjustment is required.

Canakinumab has not been studied in patients with hepatic impairment. No recommendation on aposology can be made.

No dose adjustment is needed in patients with renal impairment. However, clinical experience in suchpatients is limited.

Patient Card

All prescribers of Ilaris shall be familiar with the SmPC and inform the patients/caregivers about the

Patient Card explaining what to do should they experience any symptom of infection or macrophageactivation syndrome (MAS), or in case of vaccinations prior to treatment. The physician will providethe Patient Card to each patient/caregiver.

For subcutaneous use.

The following are suitable injection sites: upper thigh, abdomen, upper arm or buttocks. It isrecommended to select a different injection site each time the product is injected to avoid soreness.

Broken skin and areas which are bruised or covered by a rash must be avoided. Injection into scartissue must be avoided as this may result in insufficient exposure to canakinumab.

Vial

Each vial is for single use in a single patient, for a single dose.

CAPS, TRAPS, HIDS/MKD, FMF and Still’s disease (AOSD and SJIA)

After proper training in the correct injection technique, patients or their caregivers may injectcanakinumab if the physician determines that it is appropriate and with medical follow-up as necessary(see section 6.6).

For instructions on administering the medicinal product, see section 6.6.

Pre-filled pen

The pen must not be shaken.

Each pre-filled pen is for single use in a single patient, for a single dose.

CAPS, TRAPS, HIDS/MKD, FMF and Still’s disease (AOSD and SJIA)

After proper training in the correct injection technique, adult and adolescent patients aged 12 years orolder and weighing above 40 kg, or their caregivers, may inject canakinumab if the physiciandetermines that it is appropriate and with medical follow-up as necessary. Adolescent patients mayrequire the supervision of an adult caregiver to perform self-injection (see section 6.6).

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 numberof the administered product should be clearly recorded.

Canakinumab is associated with an increased incidence of serious infections. Patients must bemonitored carefully for signs and symptoms of infections during and after treatment withcanakinumab (see section 4.8). Physicians need to exercise caution when administering canakinumabto patients with infections, a history of recurring infections, or underlying conditions which maypredispose them to infections.

Treatment of CAPS, TRAPS, HIDS/MKD, FMF and Still’s disease (SJIA and AOSD)

Canakinumab must not be initiated or continued in patients during an active infection requiringmedical intervention.

Treatment of gouty arthritis

Canakinumab must not be administered during an active infection.

Concomitant use of canakinumab with tumour necrosis factor (TNF) inhibitors is not recommendedbecause this may increase the risk of serious infections (see section 4.5).

Isolated cases of unusual or opportunistic infections (including aspergillosis, atypical mycobacterialinfections, herpes zoster) have been reported during canakinumab treatment. The causal relationship ofcanakinumab to these events cannot be excluded.

Tuberculosis screening

In approximately 12% of CAPS patients tested with a PPD (purified protein derivative) skin test inclinical trials, follow-up testing yielded a positive test result while treated with canakinumab withoutclinical 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 riskof reactivation of tuberculosis. Before initiation of therapy, all patients must be evaluated for bothactive and latent tuberculosis infection. Particularly in adult patients, it is recommended that thisevaluation includes a detailed medical history. Appropriate screening tests (e.g. tuberculin skin test,interferon gamma release assay or chest X-ray) are recommended to be performed in all patients (localrecommendations may apply). Patients must be monitored closely for signs and symptoms oftuberculosis during and after treatment with canakinumab. All patients are to be instructed to seekmedical 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 anegative to a positive PPD test, especially in high-risk patients, alternative means of screening for atuberculosis infection can be considered.

Neutropenia and leukopenia

Neutropenia (absolute neutrophil count [ANC] < 1.5 x 109/l) and leukopenia have been observed withmedicinal products that inhibit IL-1, including canakinumab. Treatment with canakinumab is not to beinitiated 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 to2 months. For chronic or repeated therapies, it is also recommended to assess WBC countsperiodically during treatment. If a patient becomes neutropenic or leukopenic, the WBC counts need tobe monitored closely and treatment discontinuation considered.

Malignancy events have been reported in patients treated with canakinumab. The risk for thedevelopment of malignancies with anti-interleukin (IL)-1 therapy is unknown.

Hypersensitivity reactions with canakinumab therapy have been reported. The majority of these eventswere mild in severity. During clinical development of canakinumab in over 2 600 patients, noanaphylactoid 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).

Hepatic function

Transient and asymptomatic cases of elevations of serum transaminases or bilirubin have beenreported in clinical trials (see section 4.8).

No data are available on the risk of secondary transmission of infection by live (attenuated) vaccinesin patients receiving canakinumab. Therefore, live vaccines must not be given concurrently withcanakinumab 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 receiveall vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine(see section 4.5).

Mutation in NLRP3 gene in CAPS patients

Clinical experience in CAPS patients without a confirmed mutation in the NLRP3 gene is limited.

Macrophage activation syndrome in patients with Still’s disease (SJIA and AOSD)

Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop inpatients with rheumatic conditions, in particular Still’s disease. If MAS occurs, or is suspected,evaluation and treatment need to be started as early as possible. Physicians need to be attentive tosymptoms of infection or worsening of Still’s disease, as these are known triggers for MAS. Based onclinical trial experience, canakinumab does not appear to increase the incidence of MAS in Still’sdisease patients, but no definitive conclusion can be made.

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Drug reaction with eosinophilia and systemic symptoms (DRESS) has rarely been reported in patientstreated with Ilaris, predominantly in patients with systemic juvenile idiopathic arthritis (sJIA). Patientswith DRESS may require hospitalization, as this condition may be fatal. If signs and symptoms of

DRESS are present and an alternative aetiology cannot be established, Ilaris must not be re-administered and a different treatment considered.

Polysorbate 80 content

This medicinal product contains 0.4 mg of polysorbate 80 in each 1 ml of solution for injection.

Polysorbates may cause allergic reactions. The patient/caregiver needs to be instructed to tell thedoctor if they or their child have/has any known allergies.

Interactions between canakinumab and other medicinal products have not been investigated in formalstudies.

An increased incidence of serious infections has been associated with administration of another IL-1blocker in combination with TNF inhibitors. Use of canakinumab with TNF inhibitors is notrecommended because this may increase the risk of serious infections.

The expression of hepatic CYP450 enzymes may be suppressed by the cytokines that stimulatechronic inflammation, such as interleukin-1 beta (IL-1 beta). Thus, CYP450 expression may bereversed when potent cytokine inhibitory therapy, such as canakinumab, is introduced. This isclinically relevant for CYP450 substrates with a narrow therapeutic index where the dose isindividually adjusted. On initiation of canakinumab in patients being treated with this type ofmedicinal product, it is recommended that therapeutic monitoring of the effect or of the activesubstance concentration is performed and the individual dose of the medicinal product adjusted asnecessary.

No data are available on either the effects of live vaccination or the secondary transmission ofinfection by live vaccines in patients receiving canakinumab. Therefore, live vaccines must not begiven concurrently with canakinumab unless the benefits clearly outweigh the risks. In casevaccination with live vaccines is indicated after initiation of canakinumab treatment, therecommendation is to wait for at least 3 months after the last canakinumab injection and before thenext one (see section 4.4).

The results of a study in healthy adult subjects demonstrated that a single dose of canakinumab300 mg did not affect the induction and persistence of antibody responses after vaccination withinfluenza or glycosylated protein based meningococcus vaccines.

The results of a 56-week, open label study in CAPS patients aged 4 years and younger demonstratedthat all patients who received non-live, standard of care childhood vaccinations developed protectiveantibody levels.

It is recommended that women use effective contraceptives during treatment with canakinumab andfor 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 donot indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

The risk for the foetus/mother is unknown. It is therefore recommended that women who are pregnantor who desire to become pregnant only be treated after a thorough benefit-risk evaluation.

Animal studies indicate that canakinumab crosses the placenta and is detectable in the foetus. Nohuman data are available, but as canakinumab is an immunoglobulin of the G class (IgG1), humantransplacental transfer is expected. The clinical impact of this is unknown. However, administration oflive vaccines to newborn infants exposed to canakinumab in utero is not recommended for 16 weeksfollowing the mother’s last dose of canakinumab before childbirth. It is recommended that womenwho received canakinumab during pregnancy be instructed to inform the baby’s healthcareprofessional before any vaccinations are given to their newborn infant.

It is unknown whether canakinumab is excreted in human milk. It is therefore recommended that thedecision whether to breast-feed during canakinumab therapy 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 ondevelopment 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 (seesection 5.3).

Ilaris has minor influence on the ability to drive and use machines. Treatment with Ilaris may result indizziness/vertigo or asthenia (see section 4.8). Patients who experience such symptoms during Ilaristreatment need to wait for this to resolve completely before performing tasks that require judgement ormotor skills.

The most frequent adverse reactions were infections predominantly of the upper respiratory tract. Noimpact on the type or frequency of adverse reactions was seen with longer-term treatment.

Hypersensitivity reactions have been reported in patients treated with canakinumab (see sections 4.3and 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 organclass, the adverse reactions are ranked by frequency category with the most common first. Frequencycategories 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); notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 1 Tabulated list of adverse reactions

MedDRA Indications:

System Organ CAPS, TRAPS, HIDS/MKD, FMF, SJIA, gouty arthritis

Class

Very common Respiratory tract infections (including pneumonia, bronchitis, influenza, viralinfection, sinusitis, rhinitis, pharyngitis, tonsillitis, nasopharyngitis, upperrespiratory tract infection)

Ear infection

Cellulitis

Gastroenteritis

Common Vulvovaginal candidiasis

Common Dizziness/vertigo

Very common Upper abdominal pain 1

Uncommon Gastro-oesophageal reflux disease 2

Very common Injection site reaction

Very common Arthralgia 1

Common Musculoskeletal pain 1

Back pain 2

Common Fatigue/asthenia 2

Very common Creatinine renal clearance decreased 1,3

Proteinuria 1,4

Leukopenia 1,5

Common Neutropenia 5

Uncommon Platelet count decreased 51 In SJIA2 In gouty arthritis3 Based on estimated creatinine clearance, most were transient4 Most represented transient trace to 1+ positive urinary protein by dipstick5 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, including321 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 SJIApatients aged 16 to < 20 years, the safety profile of canakinumab was consistent with what wasobserved in SJIA patients less than 16 years of age. The safety profile of canakinumab in AOSDpatients in a randomised, double blind placebo-controlled study (GDE01T) in 36 adult patients (aged22 to 70 years) was similar to what was observed in SJIA patients.

Long-term data and laboratory abnormalities in CAPS patients

During clinical trials with canakinumab in CAPS patients mean values for haemoglobin increased andthose 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 treatedwith 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 morefrequently 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

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 andneutropenia-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 beenidentified 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

In the overall SJIA programme, transient decreased white blood cell (WBC) counts ≤ 0.8 x LLN werereported in 33 patients (16.5%).

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

In the overall SJIA programme, transient decreases in platelet counts (< LLN) were observed in19 patients (9.5%).

ALT/AST

In the overall SJIA programme, high ALT and/or AST > 3 x upper limit of normal (ULN) werereported in 19 patients (9.5%).

Laboratory abnormalities in gouty arthritis patients

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 inthe 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 higherincidence (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 aftercanakinumab treatment in comparative trials in gouty arthritis. In another study, among patients whowere starting on ULT, increases in uric acid were not observed. Uric acid increases were not observedin 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 inaspartate transaminase (AST) of 2.7 U/l and 2.0 U/l, respectively, from baseline to end of study wereseen in the canakinumab-treated groups versus the triamcinolone acetonide-treated group(s), howeverthe incidence of clinically significant changes (≥ 3 x the upper limit of normal) was greater for patientstreated 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 incanakinumab-treated patients compared with a modest decrease of -3.1 mg/dl with triamcinoloneacetonide. 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 thisobservation 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 followinglong-term treatment in this setting was consistent with what has been observed in interventionalstudies in CAPS patients.

There were 80 paediatric CAPS patients (2-17 years of age) who received canakinumab in theinterventional studies. Overall, there were no clinically meaningful differences in the safety andtolerability 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 ofinfectious episodes. Infections of the upper respiratory tract were the most frequently reportedinfection events.

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

There were 102 TRAPS, HIDS/MKD and FMF patients (2-17 years of age) who receivedcanakinumab in a 16-week study. Overall, there were no clinically meaningful differences in the safetyand 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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reported experience with overdose is limited. In early clinical trials, patients and healthy volunteersreceived doses as high as 10 mg/kg, administered intravenously or subcutaneously, without evidenceof acute toxicity.

In case of overdose, it is recommended for the patient to be monitored for any signs or symptoms ofadverse reactions, and appropriate symptomatic treatment instituted immediately.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC08

Canakinumab is a human monoclonal anti-human interleukin-1 beta (IL-1 beta) antibody of the

IgG1/κ isotype. Canakinumab binds with high affinity specifically to human IL-1 beta and neutralisesthe biological activity of human IL-1 beta by blocking its interaction with IL-1 receptors, therebypreventing IL-1 beta-induced gene activation and the production of inflammatory mediators.

CAPS, TRAPS, HIDS/MKD and FMF

In clinical studies, CAPS, TRAPS, HIDS/MKD and FMF patients who have uncontrolled over-production of IL-1 beta show a rapid and sustained response to therapy with canakinumab, i.e.

laboratory parameters such as high C-reactive protein (CRP) and serum amyloid A (SAA), highneutrophil and platelet counts, and leukocytosis rapidly returned to normal.

Still’s disease (SJIA and AOSD)

Adult-onset Still’s disease and systemic juvenile idiopathic arthritis are severe autoinflammatorydiseases, driven by innate immunity by means of pro-inflammatory cytokines, a key one being IL-1-beta.

Common features of SJIA and AOSD include fever, rash, hepatosplenomegaly, lymphadenopathy,polyserositis and arthritis. Treatment with canakinumab resulted in a rapid and sustained improvementof both the articular and the systemic features of SJIA with significant reduction of the number ofinflamed joints, prompt resolution of fever and reduction of acute phase reactants in the majority ofpatients (see Clinical efficacy and safety).

Gouty arthritis

A gouty arthritis attack is caused by urate (monosodium urate monohydrate) crystals in the joint andsurrounding tissue, which trigger resident macrophages to produce IL-1 beta via the “NALP3inflammasome” complex. Activation of macrophages and concomitant over-production of IL-1 betaresults in an acute painful inflammatory response. Other activators of the innate immune system, suchas endogenous agonists of toll-like receptors, may contribute to the transcriptional activation of the IL-1 beta gene, initiating a gouty arthritis attack. Following canakinumab treatment, the inflammatorymarkers CRP or SAA and signs of acute inflammation (e.g. pain, swelling, redness) in the affectedjoint subside rapidly.

CAPS

The efficacy and safety of canakinumab have been demonstrated in a total of 211 adult and paediatricpatients with varying degrees of disease severity and different CAPS phenotypes (including

FCAS/FCU, MWS, and NOMID/CINCA). Only patients with confirmed NLRP3 mutation wereincluded in the pivotal study.

In the Phase I/II study, treatment with canakinumab had a rapid onset of action, with disappearance orclinically significant improvement of symptoms within one day after dosing. Laboratory parameterssuch as high CRP and SAA, high neutrophils and platelet counts normalised rapidly within days ofcanakinumab injection.

The pivotal study consisted of a 48-week three-part multicentre study, i.e. an 8-week open-label period(Part I), a 24-week randomised, double-blind, placebo-controlled withdrawal period (Part II), followedby a 16-week open-label period (Part III). The aim of the study was to assess efficacy, safety, andtolerability of canakinumab (150 mg or 2 mg/kg every 8 weeks) in patients with CAPS.

− Part I: A complete clinical and biomarker response to canakinumab (defined as composite ofphysician’s global assessment on autoinflammatory and on skin disease ≤ minimal and CRP or

SAA values < 10 mg/litre) was observed in 97% of patients and appeared within 7 days ofinitiation of treatment. Significant improvements were seen in physician’s clinical assessment ofautoinflammatory disease activity: global assessment of autoinflammatory disease activity,assessment of skin disease (urticarial skin rash), arthralgia, myalgia, headache/migraine,conjunctivitis, fatigue/malaise, assessment of other related symptoms, and patient’s assessmentof symptoms.

− Part II: In the withdrawal period of the pivotal study, the primary endpoint was defined as theproportion of patients with a disease relapse/flare: none (0%) of the patients randomised tocanakinumab flared, compared with 81% of the patients randomised to placebo.

− Part III: Patients treated with placebo in Part II who flared regained and maintained clinical andserological response following entry into the open-label canakinumab extension.

Table 2 Tabulated summary of efficacy in Phase III trial, pivotal placebo-controlledwithdrawal period (Part II)

Phase III trial, pivotal placebo-controlled withdrawal period (Part II)

Canakinumab Placebo

N=15 N=16 p-valuen(%) n(%)

Primary endpoint (flare)

Proportion of patients with disease flare in Part II 0 (0%) 13 (81%) < 0.001

Inflammatory markers*

C-reactive protein, mg/l 1.10 (0.40) 19.93 (10.50) < 0.001

Serum amyloid A, mg/l 2.27 (-0.20) 71.09 (14.35) 0.002

* mean (median) change from beginning of Part II

Two open-label, uncontrolled, long-term phase III studies were performed. One was a safety,tolerability, and efficacy study of canakinumab in patients with CAPS. The total treatment durationranged from 6 months to 2 years. The other was an open-label study with canakinumab to evaluate theefficacy and safety in Japanese CAPS patients for 24 weeks, with an extension phase up to 48 weeks.

The primary objective was to assess the proportion of patients who were free of relapse at week 24,including those patients whose dose was increased.

In the pooled efficacy analysis for these two studies, 65.6% of patients who had not previously beentreated with canakinumab achieved complete response at 150 mg or 2 mg/kg, while 85.2% of patientsachieved complete response at any dose. Of the patients treated with 600 mg or 8 mg/kg (or evenhigher), 43.8% achieved complete response. Fewer patients aged 2 to < 4 years achieved completeresponse (57.1%) than older paediatric and adult patients. Of the patients who had achieved acomplete response, 89.3% maintained response without relapsing.

Experience from individual patients who achieved a complete response following dose escalation to600 mg (8 mg/kg) every 8 weeks suggests that a higher dose may be beneficial in patients notachieving complete response or not maintaining complete response with the recommended doses(150 mg or 2 mg/kg for patients ≥ 15 kg and ≤ 40 kg). An increased dose was administered morefrequently to patients aged 2 to < 4 years and to patients with NOMID/CINCA symptoms comparedwith FCAS or MWS.

A 6-year observational registry study was conducted to provide data on the long-term safety andeffectiveness of canakinumab treatment in paediatric and adult CAPS patients in routine clinicalpractice. The study included 243 CAPS patients (including 85 patients less than 18 years of age).

Disease activity was rated as absent or mild/moderate in more than 90% of patients at all post-baselinetime points in the study, and median serological markers of inflammation (CRP and SAA) werenormal (< 10 mg/litre) at all post-baseline time points. Although approximately 22% of patientsreceiving canakinumab required dose adjustment, only a small percentage of patients (1.2%)discontinued canakinumab due to lack of therapeutic effect.

The CAPS interventional trials with canakinumab included a total of 80 paediatric patients with an agerange from 2 to 17 years (approximately half of them treated on an mg/kg basis). Overall, there wereno clinically meaningful differences in the efficacy, safety and tolerability profile of canakinumab inpaediatric patients compared to the overall CAPS population. The majority of paediatric patientsachieved improvement in clinical symptoms and objective markers of inflammation (e.g. SAA and

CRP).

A 56-week, open-label study was conducted to assess the efficacy, safety and tolerability ofcanakinumab in paediatric CAPS patients ≤ 4 years of age. Seventeen patients (including 6 patientsunder the age of 2 years) were evaluated, using weight-based starting doses of 2-8 mg/kg. The studyalso evaluated the effect of canakinumab on the development of antibodies to standard childhoodvaccines. No differences in safety or efficacy were observed in patients under the age of 2 yearscompared with patients aged 2 years and above. All patients who received non-live, standard of carechildhood vaccinations (N=7) developed protective antibody levels.

TRAPS, HIDS/MKD and FMF

The efficacy and safety of canakinumab for the treatment of TRAPS, HIDS/MKD and FMF weredemonstrated in a single, pivotal, phase III, 4-part study (N2301) consisting of three separate diseasecohorts.

- Part I: Patients in each disease cohort aged 2 years and older entered a 12-week screening periodduring which they were evaluated for the onset of disease flare.

- Part II: Patients at flare onset were randomised into a 16-week double-blind, placebo-controlledtreatment period during which they received either 150 mg canakinumab (2 mg/kg for patientswith body weight ≤ 40 kg) subcutaneous (s.c.) or placebo every 4 weeks. Patients > 28 days but< 2 years of age were allowed to enter the study directly into an open-arm of Part II as non-randomised patients (and were excluded from the primary efficacy analysis).

- Part III: Patients who completed 16 weeks of treatment and were classified as responders werere-randomised into a 24-week, double-blind withdrawal period during which they receivedcanakinumab 150 mg (2 mg/kg for patients ≤ 40 kg) s.c. or placebo every 8 weeks.

- Part IV: All Part III patients treated with canakinumab were eligible to enter into a 72-weekopen-label treatment extension period.

A total of 185 patients aged 28 days and above were enrolled and a total of 181 patients aged 2 yearsand above were randomised in part II of the study.

The primary efficacy endpoint of the randomised treatment period (Part II) was the proportion ofresponders within each cohort who had resolution of their index disease flare at Day 15 and did notexperience a new flare during the remainder of the 16-week treatment period (defined as completeresponse). Resolution of the index disease flare was defined as having a Physician’s Global

Assessment (PGA) of Disease Activity score < 2 (“minimal or no disease”) and CRP within normalrange (≤ 10 mg/l) or reduction ≥ 70% from baseline. A new flare was defined as a PGA score ≥ 2(“mild, moderate, or severe disease”) and CRP ≥ 30 mg/l. Secondary endpoints, all based on week 16results (end of Part II), included the proportion of patients who achieved a PGA score of < 2, theproportion of patients with serological remission (defined as CRP ≤ 10 mg/l), and the proportion ofpatients with a normalised SAA level (defined as SAA ≤ 10 mg/l).

For the primary efficacy endpoint, canakinumab was superior to placebo for all three disease cohorts.

Canakinumab also demonstrated superior efficacy compared to placebo on the secondary endpoints of

PGA < 2 and CRP ≤ 10 mg/l in all three cohorts. Higher proportions of patients had normalised SAA(≤ 10 mg/l) at week 16 with canakinumab treatment compared to placebo in all three cohorts, with astatistically significant difference observed in TRAPS patients (see Table 3 with study results below).

Table 3 Tabulated summary of efficacy in Phase III trial, pivotal, randomised, placebo-controlled treatment period (Part II)

Phase III trial, pivotal, randomised placebo-controlled treatment period (Part II)

Canakinumab Placebon/N (%) n/N (%) p-value

Primary endpoint (disease flare) - Proportion of patients who had index disease flare resolution atday 15 and did not experience a new flare during the remainder of the 16-week treatment period

FMF 19/31 (61.29) 2/32 (6.25) < 0.0001*

HIDS/MKD 13/37 (35.14) 2/35 (5.71) 0.0020*

TRAPS 10/22 (45.45) 2/24 (8.33) 0.0050*

Secondary endpoints (disease and inflammatory markers)

Physician Global Assessment < 2

FMF 20/31 (64.52) 3/32 (9.38) < 0.0001**

HIDS/MKD 17/37 (45.95) 2/35 (5.71) 0.0006**

TRAPS 10/22 (45.45) 1/24 (4.17) 0.0028**

C-reactive protein ≤ 10 mg/l

FMF 21/31 (67.74) 2/32 (6.25) < 0.0001**

HIDS/MKD 15/37 (40.54) 2/35 (5.71) 0.0010**

TRAPS 8/22 (36.36) 2/24 (8.33) 0.0149**

Serum amyloid A ≤ 10 mg/l

FMF 8/31 (25.81) 0/32 (0.00) 0.0286

HIDS/MKD 5/37 (13.51) 1/35 (2.86) 0.0778

TRAPS 6/22 (27.27) 0/24 (0.00) 0.0235**n=number of responders; N=number of evaluable patients

* indicates statistical significance (one-sided) at the 0.025 level based on Fisher exact test

**Indicates statistical significance (one-sided) at the 0.025 level based on the logistic regression modelwith treatment group and baseline PGA, CRP or SAA respectively, as explanatory variables for eachcohort

Up-titration

In Part II of the study, patients treated with canakinumab who had persistent disease activity receivedan additional dose of 150 mg (or 2 mg/kg for patients ≤ 40 kg) within the first month. This additionaldose could be provided as early as 7 days after the first treatment dose. All up-titrated patientsremained at the increased dose of 300 mg (or 4 mg/kg for patients ≤ 40 kg) every 4 weeks.

In an exploratory analysis of the primary endpoint, it was observed that in patients with an inadequateresponse after the first dose, an up-titration within the first month to a dose of 300 mg (or 4 mg/kg)every 4 weeks further improved flare control, reduced disease activity and normalised CRP and SAAlevels.

Two non-randomised HIDS/MKD patients aged > 28 days but < 2 years were included in the studyand received canakinumab. One patient had resolution of index flare by day 15 after receiving onesingle dose of canakinumab 2 mg/kg, but discontinued treatment after this first dose due to seriousadverse events (pancytopenia and hepatic failure). This patient presented at study entry with a historyof immune thrombocytopenic purpura and an active medical condition of abnormal hepatic function.

The second patient received a starting dose of canakinumab 2 mg/kg and an add-on dose of 2 mg/kg atweek 3, and was up-titrated at week 5 to receive a dose of 4 mg/kg administered every 4 weeks untilthe end of Part II of the study. Resolution of disease flare was achieved by week 5 and the patient hadnot experienced any new flare at the end of Part II of the study (week 16).

Still’s disease (SJIA and AOSD)

SJIA

The efficacy of canakinumab for the treatment of active SJIA was assessed in two pivotal phase IIIstudies (G2305 and G2301). Patients enrolled were aged 2 to < 20 years (mean age of 8.5 years andmean disease duration of 3.5 years at baseline) and had active disease defined as ≥ 2 joints with activearthritis, fever and elevated CRP.

Study G2305

Study G2305 was a randomised, double-blind, placebo-controlled, 4-week study assessing the short-term efficacy of canakinumab in 84 patients randomised to receive a single dose of 4 mg/kg (up to300 mg) canakinumab or placebo. The primary objective was the proportion of patients at day 15 whoachieved a minimum 30% improvement in the paediatric American College of Rheumatology (ACR)response criterion adapted to include absence of fever. Canakinumab treatment improved all paediatric

ACR response scores as compared to placebo at days 15 and 29 (Table 4).

Table 4 Paediatric ACR response and disease status at days 15 and 29

Day 15 Day 29

Canakinumab Placebo Canakinumab Placebo

N=43 N=41 N=43 N=41

ACR30 84% 10% 81% 10%

ACR50 67% 5% 79% 5%

ACR70 61% 2% 67% 2%

ACR90 42% 0% 47% 2%

ACR100 33% 0% 33% 2%

Inactive disease 33% 0% 30% 0%

Treatment difference for all ACR scores was significant (p ≤ 0.0001)

Results for the components of the adapted paediatric ACR which included systemic and arthriticcomponents, were consistent with the overall ACR response results. At day 15, the median changefrom baseline in the number of joints with active arthritis and limited range of motion were -67%and -73% for canakinumab (N=43), respectively, compared to a median change of 0% and 0% forplacebo (N=41). The mean change in patient pain score (0-100 mm visual analogue scale) at day 15was -50.0 mm for canakinumab (N=43), as compared to +4.5 mm for placebo (N=25). The meanchange in pain score among canakinumab treated patients was consistent at day 29.

Study G2301

Study G2301 was a randomised, double-blind, placebo-controlled withdrawal study of flare preventionby canakinumab. The study consisted of two parts with two independent primary endpoints (successfulsteroid taper and time to flare). In Part I (open label) 177 patients were enrolled and received 4 mg/kg(up to 300 mg) canakinumab administered every 4 weeks for up to 32 weeks. Patients in Part II(double-blind) received either canakinumab 4 mg/kg or placebo every 4 weeks until 37 flare eventsoccurred.

Corticosteroid dose tapering:

Of the total 128 patients who entered Part I taking corticosteroids, 92 attempted corticosteroidtapering. Fifty-seven (62%) of the 92 patients who attempted to taper were able to successfully tapertheir corticosteroid dose and 42 (46%) discontinued corticosteroids.

Time to flare:

Patients taking canakinumab in Part II had a 64% reduced risk of a flare event as compared to theplacebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75; p=0.0032). Sixty-three of the 100 patientsentering Part II, whether assigned to placebo or canakinumab, did not experience a flare over theobservation period (up to a maximum of 80 weeks).

Health-related and quality of life outcomes in studies G2305 and G2301

Treatment with canakinumab resulted in clinically relevant improvements in patients’ physicalfunction and quality of life. In study G2305, the Childhood Health Assessment Questionnaire Least

Squares means improvement was 0.69 for canakinumab vs placebo representing 3.6 times the minimalclinically important difference of 0.19 (p=0.0002). The median improvement from baseline to end of

Part I of study G2301 was 0.88 (79%). Statistically significant improvements in the Child Health

Questionnaire-PF50 scores were reported for canakinumab vs placebo in study G2305 (physicalp=0.0012; psychosocial well-being p=0.0017).

Pooled efficacy analysis

Data from the first 12 weeks of canakinumab treatment from studies G2305, G2301 and the extensionstudy were pooled to assess maintenance of efficacy. These data showed similar improvements frombaseline to week 12 in the adapted paediatric ACR responses and its components to those observed inthe placebo controlled study (G2305). At week 12, the adapted paediatric ACR30, 50, 70, 90 and 100responses were: 70%, 69%, 61%, 49% and 30%, respectively and 28% of patients had inactive disease(N=178).

Although limited, evidence from the clinical trials suggests that patients not responding to tocilizumabor anakinra may respond to canakinumab.

Study G2301E1

The efficacy observed in the studies G2305 and G2301 was maintained in the open-label long-termextension study G2301E1. Of the 270 SJIA patients in the study, 147 patients had received treatmentwith canakinumab in studies G2305 or G2301 (Cohort I), and 123 patients were canakinumab-naivepatients (Cohort II). Patients in Cohort I were treated for a median duration of 3.2 years (up to5.2 years), and patients in Cohort II were treated for a median duration of 1.8 years (up to 2.8 years).

In the extension study, all patients received canakinumab 4 mg/kg (up to maximum 300 mg) every4 weeks. In both cohorts, patients who were well-controlled responders (retrospectively defined asadapted paediatric ACR ≥ 90) and who did not require a concomitant corticosteroid were permitted toreduce their canakinumab dose to 2 mg/kg every 4 weeks (62/270; 23%).

Study G2306

Study G2306 was an open-label study to assess maintenance of treatment response with canakinumabdose reduction (2 mg/kg every 4 weeks) or dose interval prolongation (4 mg/kg every 8 weeks) in

SJIA patients who were receiving canakinumab 4 mg/kg every 4 weeks. Seventy five patients aged 2to 22 years who maintained inactive disease status for at least 6 consecutive months (clinicalremission) with canakinumab monotherapy, including patients who were able to maintain inactivedisease status with discontinuation of concomitant corticosteroid and/or methotrexate use for at least4 weeks, were randomised to receive canakinumab 2 mg/kg every 4 weeks (N=38) or canakinumab4 mg/kg every 8 weeks (N=37). After 24 weeks, 71% (27/38) of patients who received the reduceddose (2 mg/kg every 4 weeks) and 84% (31/37) of patients who received the prolonged dosing interval(4 mg/kg every 8 weeks) were able to maintain inactive disease status for 6 months. Of the patients inclinical remission who continued with further dose reduction (1 mg/kg every 4 weeks) or dose intervalprolongation (4 mg/kg every 12 weeks), 93% (26/28) and 91% (30/33) of patients, respectively, wereable to maintain inactive disease status for 6 months. Patients who maintained inactive disease statusfor 6 additional months at this lowest dose regimen were allowed to discontinue canakinumab.

Overall, 33% (25/75) of patients randomised to dose reduction or dose interval prolongation armswere able to discontinue treatment with canakinumab and maintain inactive disease status for6 months. The rate of adverse events in both treatment arms was similar to the rate seen in patientstreated with canakinumab 4 mg/kg every 4 weeks.

AOSD

The efficacy of canakinumab 4 mg/kg (up to maximum 300 mg) administered every 4 weeks in AOSDpatients in a randomised, double-blind placebo-controlled study in 36 patients (22 to 70 years old) wascomparable to that observed in SJIA patients. In study GDE01T, a higher proportion of patients(12/18, 66.7%) in the canakinumab group than in the placebo group (7/17, 41.2%) demonstrated animprovement from baseline in Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28-

ESR) of > 1.2 at week 12, which failed to reach statistical significance (odds ratio 2.86, treatmentdifference [%] 25.49 [95% CI: 9.43, 55.80]). By week 4, 7 of 18 patients (38.9%) treated withcanakinumab had already achieved DAS28-ESR remission versus 2 of 17 patients (11.8%) on placebo.

These data are consistent with the results of a pooled efficacy analysis of 418 SJIA patients whichshowed that the efficacy of canakinumab in a subset of SJIA patients aged 16 to < 20 years (n=34) wasconsistent with the efficacy observed in patients less than 16 years of age (n=384).

Gouty arthritis

The efficacy of canakinumab for the treatment of acute gouty arthritis attacks was demonstrated in twomulticentre, randomised, double-blind, active-controlled studies in patients with frequent goutyarthritis (≥ 3 attacks in the previous 12 months) unable to use NSAIDs or colchicine (due tocontraindication, intolerance or lack of efficacy). The studies were 12 weeks followed by 12-weekdouble-blind extension. A total of 225 patients were treated with subcutaneous canakinumab 150 mgand 229 patients were treated with intramuscular triamcinolone acetonide (TA) 40 mg at study entry,and when experiencing a new attack thereafter. The mean number of gouty arthritis attacks in theprevious 12 months was 6.5. Over 85% of patients had comorbidity, including hypertension (60%),diabetes (15%), ischaemic heart disease (12%), and stage ≥ 3 chronic kidney disease (25%).

Approximately one-third of the patients enrolled (76 [33.8%] in the canakinumab group and 84[36.7%] in the triamcinolone acetonide group) had documented inability (intolerance, contraindicationor lack of response) to use both NSAIDs and colchicine. Concomitant treatment with ULTs wasreported by 42% of patients at entry.

The co-primary endpoints were: (i) gouty arthritis pain intensity (visual analogue scale, VAS) at72 hours post-dose, and (ii) time to first new gouty arthritis attack.

For the overall study population, pain intensity was statistically significantly lower for canakinumab150 mg compared with triamcinolone acetonide at 72 hours. Canakinumab also reduced the risk ofsubsequent attacks (see Table 5).

Efficacy results in a subgroup of patients unable to use both NSAIDs and colchicine and who were on

ULT, failed ULT or had a contraindication to ULT (N=101) were consistent with the overall studypopulation with a statistically significant difference compared to triamcinolone acetonide in painintensity at 72 hours (-10.2 mm, p=0.0208) and in reduction of risk of subsequent attacks (Hazard ratio0.39, p=0.0047 at 24 weeks).

Efficacy results for a more stringent subgroup limited to current users of ULT (N=62) are presented in

Table 5. Treatment with canakinumab induced a reduction of pain and reduced the risk of subsequentattacks in patients using ULT and unable to use both NSAIDs and colchicine, although the observedtreatment difference compared to triamcinolone acetonide was less pronounced than with the overallstudy population.

Table 5 Efficacy for the overall study population and in a subgroup of patients currentlyusing ULT and unable to use both NSAIDs and colchicine

Efficacy endpoint Overall study population; Unable to use both NSAIDs

N=454 and colchicine; on ULT

N=62

Treatment of gouty arthritis attacks as measured by pain intensity (VAS) at 72 h

Least Squares mean estimated -10.7 -3.8difference to triamcinolone acetonide

CI (-15.4, -6.0) (-16.7, 9.1)p-value, 1-sided p < 0.0001* p=0.2798

Risk reduction of subsequent gouty arthritis attacks as measured by time to first new flare(24 weeks)

Hazard ratio to triamcinolone 0.44 0.71acetonide

CI (0.32, 0.60) (0.29, 1.77)p-value, 1-sided p < 0.0001* p=0.2337

* Denotes significant p-value ≤ 0.025

Safety results showed an increased incidence of adverse events for canakinumab compared totriamcinolone acetonide, with 66% vs 53% of patients reporting any adverse event and 20% vs 10% ofpatients reporting an infection adverse event over 24 weeks.

Overall, the efficacy, safety and tolerability profile of canakinumab in elderly patients ≥ 65 years ofage was comparable to patients < 65 years of age.

Patients on urate lowering therapy (ULT)

In clinical studies, canakinumab has been safely administered with ULT. In the overall studypopulation, patients on ULT had a less pronounced treatment difference in both pain reduction andreduction in the risk of subsequent gouty arthritis attacks compared to patients not on ULT.

Antibodies against canakinumab were observed in approximately 1.5%, 3% and 2% of the patientstreated with canakinumab for CAPS, SJIA and gouty arthritis, respectively. No neutralising antibodieswere detected. No apparent correlation of antibody development to clinical response or adverse eventswas observed.

There were no antibodies against canakinumab observed in TRAPS, HIDS/MKD and FMF patientstreated with doses of 150 mg and 300 mg over 16 weeks of treatment. Also, in AOSD no antibodiesagainst canakinumab were observed.

The detection of an immune response is highly dependent on the sensitivity and specificity of theassay used and testing conditions. For these reasons, comparison of the incidence of antibodies againstcanakinumab with the incidence of antibodies against other products may be misleading.

The Marketing Authorisation Holder has completed four Paediatric Investigation Plans forcanakinumab (for CAPS, SJIA, FMF - HIDS/MKD and TRAPS respectively). This productinformation has been updated to include the results of studies with canakinumab in the paediatricpopulation.

The European Medicines Agency has waived the obligation to submit the results of studies withcanakinumab in all subsets of the paediatric population in gouty arthritis (see section 4.2 forinformation on paediatric use).

CAPS

The peak serum canakinumab concentration (Cmax) occurred approximately 7 days following singlesubcutaneous administration of 150 mg in adult CAPS patients. The mean terminal half-life was26 days. Mean values for Cmax and area under the curve extrapolated to infinity (AUCinf) after a singlesubcutaneous dose of 150 mg in a typical adult CAPS patient (70 kg) were 15.9 µg/ml and708 µg*d/ml. The absolute bioavailability of subcutaneously administered canakinumab was estimatedto be 66%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the doserange of 0.30 to 10.0 mg/kg given as intravenous infusion or from 150 to 600 mg as subcutaneousinjection. Predicted steady-state exposure values (Cmin,ss, Cmax,ss, AUC,ss,8w) after 150 mg subcutaneousadministration (or 2 mg/kg, respectively) every 8 weeks were slightly higher in the weight category40-70 kg (6.6 µg/ml, 24.3 µg/ml, 767 µg*d/ml) compared to the weight categories < 40 kg (4.0 µg/ml,19.9 µg/ml, 566 µg*d/ml) and > 70 kg (4.6 µg/ml, 17.8 µg/ml, 545 µg*d/ml). The expectedaccumulation ratio was 1.3-fold following 6 months of subcutaneous administration of 150 mgcanakinumab every 8 weeks.

Canakinumab binds to serum IL-1 beta. The distribution volume (Vss) of canakinumab variedaccording to body weight. It was estimated to be 6.2 litres in a CAPS patient of body weight 70 kg.

The apparent clearance (CL/F) of canakinumab increases with body weight. It was estimated to be0.17 l/d in a CAPS patient of body weight 70 kg and 0.11 l/d in a SJIA patient of body weight 33 kg.

After accounting for body weight differences, no clinically significant differences in thepharmacokinetic properties of canakinumab were observed between CAPS and SJIA patients.

There was no indication of accelerated clearance or time-dependent change in the pharmacokineticproperties of canakinumab following repeated administration. No gender or age-relatedpharmacokinetic differences were observed after correction for body weight.

TRAPS, HIDS/MKD and FMF

Bioavailability in TRAPS, HIDS/MKD and FMF patients has not been determined independently.

Apparent clearance (CL/F) in the TRAPS, HIDS/MKD and FMF population at body weight of 55 kg(0.14 l/d) was comparable to CAPS population at body weight of 70 kg (0.17 l/d). The apparentvolume of distribution (V/F) was 4.96 l at body weight of 55 kg.

After repeated subcutaneous administration of 150 mg every 4 weeks, canakinumab minimalconcentration at week 16 (Cmin) was estimated to be 15.4 ± 6.6 g/ml. The estimated steady state

AUCtau was 636.7 ± 260.2 μg*d/ml.

Still’s disease (SJIA and AOSD)

Bioavailability in SJIA patients has not been determined independently. Apparent clearance per kgbody weight (CL/F per kg) was comparable between the SJIA and CAPS population (0.004 l/d perkg). The apparent volume of distribution per kg (V/F per kg) was 0.14 l/kg. Sparse pharmacokinetics(PK) data in AOSD patients suggest similar PK of canakinumab as compared to SJIA and other patientpopulations.

After repeated administration of 4 mg/kg every 4 weeks the accumulation ratio of canakinumab was1.6 fold in SJIA patients. Steady state was reached after 110 days. The overall predicted mean (±SD)for Cmin,ss, Cmax,ss and AUC,ss4w were 14.7±8.8 μg/ml, 36.5 ± 14.9 μg/ml and 696.1 ± 326.5 μg*d/ml,respectively.

The AUCss4w in each age group was 692, 615, 707 and 742 µg*d/ml for 2-3, 4-5, 6-11, and 12-19 yearsold, respectively. When stratified by weight, a lower (30-40%) median of exposure for Cmin,ss (11.4 vs19 µg/ml) and AUCss (594 vs 880 µg*d/ml) for the lower bodyweight category (≤ 40 kg) vs the higherbodyweight category (> 40 kg) was observed.

Based on the population pharmacokinetic modelling analysis, the pharmacokinetics of canakinumab inyoung adult SJIA patients aged 16 to 20 years were similar to those in patients less than 16 years ofage. Predicted canakinumab steady state exposures at a dose level of 4 mg/kg (maximum 300 mg) inpatients over the age of 20 years were comparable to those in SJIA patients younger than 20 years ofage.

Gouty arthritis population

Bioavailability in gouty arthritis patients has not been determined independently. Apparent clearanceper kg body weight (CL/F per kg) was comparable between the gouty arthritis and CAPS population(0.004 l/d/kg). Mean exposure in a typical gouty arthritis patient (93 kg) after a single subcutaneous150 mg dose (Cmax: 10.8 µg/ml and AUCinf: 495 µg*d/ml) was lower than in a typical 70 kg CAPSpatient (15.9 µg/ml and 708 µg*d/ml). This is consistent with the observed increase in CL/F with bodyweight.

The expected accumulation ratio was 1.1-fold following subcutaneous administration of 150 mgcanakinumab every 12 weeks.

Peak concentrations of canakinumab occurred between 2 to 7 days (Tmax) following singlesubcutaneous administration of canakinumab 150 mg or 2 mg/kg in paediatric patients 4 years of ageand older. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokineticproperties observed in adults. Based on the population pharmacokinetic modelling analysis, thepharmacokinetics of canakinumab in children aged 2 to < 4 years were similar to those in patients4 years of age and older. Subcutaneous absorption rate was estimated to decrease with age andappeared to be fastest in the youngest patients. Accordingly, Tmax was shorter (3.6 days) in younger

SJIA patients (2-3 years) compared to older SJIA patients (12-19 years; Tmax 6 days). Bioavailability(AUCss) was not affected.

An additional pharmacokinetics analysis showed that the pharmacokinetics of canakinumab in6 paediatric CAPS patients under the age of 2 years were similar to the pharmacokinetics in paediatricpatients 2-4 years of age. Based on the population pharmacokinetic modelling analysis, the expectedexposures after a dose of 2 mg/kg were comparable across the CAPS paediatric age groups, but wereapproximately 40% lower in paediatric patients of very low body weight (e.g. 10 kg) than in adultpatients (150 mg dose). This is consistent with the observations of higher exposure in higher bodyweight groups in CAPS patients.

In TRAPS, HIDS/MKD and FMF, exposure parameters (trough concentrations) were comparableacross age groups from 2 to < 20 years old following subcutaneous administration of canakinumab2 mg/kg every 4 weeks.

Pharmacokinetic properties are similar in CAPS, TRAPS, HIDS/MKD, FMF and SJIA paediatricpopulations.

No change in pharmacokinetic parameters based on clearance or volume of distribution were observedbetween elderly patients and adult patients < 65 years of age.

Non-clinical data reveal no special hazard for humans based on conventional studies of cross-reactivity, repeated dose toxicity, immunotoxicity, toxicity to reproduction and development.

Formal carcinogenicity studies have not been conducted with canakinumab.

Mannitol (E 421)

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Vial3 years.

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Store in the original package in order to protect from light.

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Ilaris 150 mg/ml solution for injection is supplied in a single-use vial.

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Once the required volume is withdrawn, recap and remove the withdrawal needle from the syringe andattach a 27 G x 0.5 inch needle (or similar as available on the market) to immediately inject thesolution subcutaneously. Detailed instructions for use are provided in the package leaflet.

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Ilaris 150 mg solution for injection is supplied in a single-use pre-filled pen.

Instructions for administration

After removal of the carton from the refrigerator, the pre-filled pen should be allowed to reach roomtemperature (not above 30°C) over 30 minutes.

Prior to use, a visual inspection of the pre-filled pen is recommended. The liquid needs to be clear toopalescent. Its colour may vary from colourless to slightly brownish yellow. A small air bubble maybe visible, which is normal. Do not use if the liquid contains visible particles or is distinctly brown.

Detailed instructions for use are provided in the package leaflet.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Vial

EU/1/09/564/004

Pre-filled pen

EU/1/09/564/005

Date of first authorisation: 23 October 2009

Date of latest renewal: 06 June 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu