Ilaris 150 mg powder for solution for injection

One vial contains 150 mg of canakinumab*.

After reconstitution, each ml of solution contains 150 mg canakinumab.

* fully human monoclonal antibody produced in mouse hybridoma Sp2/0 cells by recombinant DNA technology

For a full list of excipients, see section 6.1.

Powder for solution for injection.

The powder is white.

Ilaris is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS) in adults, adolescents and children aged 4 years and older with body weight above 15 kg, 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.

Treatment should be initiated and supervised by a specialist physician experienced in the diagnosis and treatment of CAPS.

After proper training in the correct injection technique, patients may self-inject Ilaris if their physician determines that it is appropriate and with medical follow-up as necessary.

Adults, adolescents and children aged 4 years and older

The recommended dose of Ilaris is 150 mg for CAPS patients with body weight > 40 kg and 2 mg/kg for CAPS patients with body weight 15 kg and 40 kg. This is administered every eight weeks as a single dose via subcutaneous injection.

If a satisfactory clinical response (resolution of rash and other generalised inflammatory symptoms) has not been achieved 7 days after treatment start, a second dose of Ilaris at 150 mg or 2 mg/kg can be considered. If a full treatment response is subsequently achieved, the intensified dosing regimen of 300 mg and 4 mg/kg should be maintained. No experience exists for doses > 600 mg every 8 weeks. Clinical experience with dosing at intervals of less than 4 weeks is limited.

Special populations

Paediatric population

Ilaris is not recommended for use in children below 4 years of age or with body weight below 15 kg due to a lack of clinical data.

Elderly

Clinical experience in patients above 65 years is limited, therefore caution is recommended.

Hepatic impairment

Ilaris has not been studied in patients with hepatic impairment.

Renal impairment

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

For instructions on use and handling of the reconstituted solution, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Active, severe infections (see section 4.4).

Serious infections

Ilaris may be 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 Ilaris. Physicians should exercise caution when administering Ilaris to patients with infections, a history of recurring infections, or underlying conditions which may predispose them to infections. Treatment with Ilaris should not be continued or initiated in patients with severe infections requiring medical intervention.

Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported more frequently with Ilaris than with placebo. All infections responded to standard therapy. In canakinumab-treated patients with serious and systemic infections, a physiological inflammatory response was maintained as evidenced by concomitant C-reactive protein (CRP) elevation and fever. A blunted inflammatory response to infections cannot be excluded and increased vigilance is therefore recommended. No unusual or opportunistic infections were reported with Ilaris.

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

PPD (purified protein derivative) skin test

In approximately 12% of CAPS patients tested with a PPD skin test in clinical trials, follow-up testing yielded a positive test result while treated with Ilaris without clinical evidence of a latent or active tuberculosis infection. 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 and appropriate screening tests. Patients must be monitored closely for signs and symptoms of tuberculosis during and after treatment with Ilaris. 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

Neutropenia (absolute neutrophil count [ANC] < 1.5 x 10⁹/l) has been observed commonly with another medicinal product that inhibits IL-1 used in a patient population (rheumatoid arthritis) other than CAPS. Neutropenia was observed commonly in patients with rheumatoid arthritis (not an approved use) who were administered Ilaris subcutaneously in clinical studies. Treatment with Ilaris should not be initiated in patients with neutropenia. It is recommended that neutrophil counts be assessed prior to initiating treatment, after 1 to 2 months, and periodically thereafter while receiving Ilaris. If a patient becomes neutropenic the ANC should be monitored closely and treatment discontinuation should be considered.

Malignancies

The risk for the development of malignancies with anti-interleukin (IL)-1 therapy is unknown. A potential risk cannot be excluded in patients treated with Ilaris.

Hypersensitivity reactions

Cases suggestive of hypersensitivity reactions with Ilaris therapy have been reported in clinical trials. The majority of these events were mild in severity. No anaphylactoid or anaphylactic reactions have been reported. However, the risk of severe hypersensitivity reactions, which is not uncommon for injectable proteins, cannot be excluded (see section 4.3).

Hepatic function

Rare, mild, transient and asymptomatic cases of elevations of serum transaminases or bilirubin have been reported in clinical trials.

Vaccinations

No data are available on the risk of secondary transmission of infection by live (attenuated) vaccines in patients receiving Ilaris. Therefore, live vaccines should not be given concurrently with Ilaris unless the benefits clearly outweigh the risks (see section 4.5).

Prior to initiation of Ilaris therapy, adult and paediatric patients should receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine.

Mutation in NLRP3 gene

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

Interactions between Ilaris 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 Ilaris 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 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 Ilaris. Therefore, live vaccines should not be given concurrently with Ilaris unless the benefits clearly outweigh the risks. Should vaccination with live vaccines be indicated after initiation of Ilaris treatment, the recommendation is to wait for at least 3 months after the last Ilaris injection and before the next one (see section 4.4).

Pregnancy

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 should use effective contraceptives during treatment with Ilaris and for up to 3 months after the last dose. Women who are pregnant or who desire to become pregnant should therefore only be treated after a thorough benefit-risk evaluation.

Lactation

It is unknown whether canakinumab is excreted in human milk. The decision whether to breast-feed during Ilaris 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).

Fertility

Formal studies of the potential effect of Ilaris 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).

The ability to drive and operate machines may be impaired by some symptoms associated with CAPS. Patients who experience vertigo during Ilaris treatment should wait for this to resolve completely before driving or operating machines.

Summary of the safety profile

Approximately 830 subjects have been treated with Ilaris in blinded and open-label clinical trials in patients with CAPS, patients with other diseases, and healthy volunteers. Safety data from 104 CAPS patients is available. A total of 10 serious adverse reactions that were considered by the investigator as related to treatment were reported during the clinical programme in CAPS, of which the most frequent events were infections (3) and vertigo (2). The most frequently reported adverse events included upper respiratory tract infections and nasopharyngitis across all CAPS studies. Dose and duration of treatment have no impact on the type or frequency of adverse events.

A total of 104 adult and paediatric CAPS patients (including FCAS/FCU, MWS, and NOMID/CINCA) have received Ilaris in clinical trials. The safety of canakinumab compared with placebo was investigated in a pivotal phase III trial that consisted of an 8-week, open-label period (Part I), a 24-week, randomised, double-blind and placebo-controlled withdrawal period (Part II), and a 16-week open label period on canakinumab (Part III). All patients were treated with Ilaris 150 mg subcutaneous or 2 mg/kg if body weight was 15 kg and 40 kg.

Adverse reactions are listed according to MedDRA system organ class and frequency category. 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 summary of reported adverse drug reactions from pivotal CAPS clinical trial

Cases suggestive of hypersensitivity reactions with Ilaris therapy have been reported in patients treated with canakinumab in clinical trials. The majority of these events were mild in severity. No anaphylactoid or anaphylactic reactions have been reported.

During clinical trials with canakinumab mean values for hemoglobin increased and decreased for white blood cell, neutrophils and platelets. These changes were potentially due to a decrease in inflammation and not considered to be of clinical relevance.

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.

Paediatric population

Twenty-three paediatric CAPS patients (4-17 years of age) demonstrated similar efficacy and safety to adult patients. Specifically, the overall frequency and severity of infectious episodes in paediatric patients were comparable to that in the adult population. Infection of the upper respiratory tract was the most frequently reported infection.

No case of overdose has been reported.

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

Pharmacotherapeutic group: Interleukin inhibitors, ATC code: L04AC08

This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

Mechanism of action

Canakinumab is a fully 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 neutralises the biological activity of human IL-1 beta by blocking its interaction with IL-1 receptors, thereby preventing IL-1 beta-induced gene activation and the production of inflammatory mediators.

Pharmacodynamic effects

In clinical studies, CAPS patients who have uncontrolled over-production of IL-1 beta show a rapid response to therapy with canakinumab, i.e. laboratory parameters such as high C-reactive protein (CRP) and serum amyloid A (SAA), high neutrophil and platelet counts, and leukocytosis rapidly returned to normal.

Clinical data

The efficacy and safety of canakinumab have been demonstrated in patients with varying degrees of disease severity and different CAPS phenotypes (including FCAS/FCU, MWS, and NOMID/CINCA). Only patients with confirmed NLRP3 mutation were included in the pivotal study.

In the Phase I/II study, treatment with canakinumab had a rapid onset of action, with disappearance or clinically significant improvement of symptoms within one day after dosing. Laboratory parameters such as high CRP and SAA, high neutrophils and platelet counts normalised rapidly within days of canakinumab 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), followed by a 16-week open-label period (Part III). The aim of the study was to assess efficacy, safety, and tolerability 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 of physician'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 of initiation of treatment. Significant improvements were seen in physician's clinical assessment of autoinflammatory 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 assessment of symptoms.

− Part II: In the withdrawal period of the pivotal study, the primary endpoint was defined as the proportion of patients with a disease relapse/flare: none (0%) of the patients randomised to canakinumab 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 and serological response following entry into the open-label canakinumab extension.

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

Sustained efficacy for more than 3 years was observed for the initial four patients with continued administration of canakinumab.

No antibodies to canakinumab have been detected in CAPS patients treated with canakinumab.

Paediatric population

The CAPS trials with canakinumab included a total of 23 paediatric patients with an age range from 4 to 17 years (approximately half of them treated on an mg/kg basis). Overall, the efficacy, safety and tolerability profile of canakinumab in paediatric patients was comparable to adult patients.

The European Medicines Agency has deferred the obligation to submit the results of studies with Ilaris in one or more subsets of the paediatric population in Cryopyrin Associated Periodic Syndromes (CAPS). See section 4.2 for information on paediatric use.

The peak serum canakinumab concentration (C_max) occurred approximately 7 days following single subcutaneous administration of 150 mg in adult CAPS patients. The mean terminal half-life was 26 days. Based on a population pharmacokinetic analysis, the absolute bioavailability of subcutaneous canakinumab was estimated to be 70%. The clearance (CL) and distribution volume (V_ss) of canakinumab varied according to body weight and were estimated to be 0.174 l/day and 6.01 litres, respectively, in a typical CAPS patient of body weight 70 kg. The expected accumulation ratio was 1.3-fold following 6 months of subcutaneous administration of 150 mg canakinumab every 8 weeks. Exposure parameters (such as AUC and C_max) increased in proportion to dose over the dose range of 0.30 to 10.0 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection. There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender or age-related pharmacokinetic differences were observed after correction for body weight.

Paediatric population

Peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of canakinumab 150 mg or 2 mg/kg in paediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults.

Non-clinical data reveal no special hazard for humans based on cross-reactivity, repeated dose, immunotoxicity, reproductive and juvenile toxicity studies performed with canakinumab or a murine anti-murine IL-1 beta antibody.

Since canakinumab binds to marmoset (C. jacchus) and human IL-1 beta with a similar affinity, the safety of canakinumab has been studied in the marmoset. No undesirable effects of canakinumab were seen following twice weekly administration to marmosets for up to 26 weeks or in an embryofoetal developmental toxicity study in pregnant marmosets, at exposure in excess of human clinical levels. In addition, no antibodies to canakinumab were detected in these studies. No non-specific tissue cross-reactivity was demonstrated when canakinumab was applied to normal human tissues.

Formal carcinogenicity studies have not been conducted with canakinumab.

In an embryofoetal development study in marmosets canakinumab showed no maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis.

No undesirable effects of a murine anti-murine IL-1 beta antibody were seen in a complete set of reproductive and juvenile studies in mice. Anti-murine IL-1 beta did not elicit adverse events on foetal or neonatal growth when administered throughout late gestation, delivery and nursing (see section 4.6). The high dose used in these studies was in excess of the maximally effective dose in terms of IL-1 beta suppression and activity.

An immunotoxicology study in mice with a murine anti-murine IL-1 beta antibody showed that neutralising IL-1 beta has no effects on immune parameters and caused no impairment of immune function in mice.

Sucrose

Histidine

Histidine hydrochloride monohydrate

Polysorbate 80

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

36 months

After reconstitution, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

For storage conditions of the reconstituted medicinal product, see section 6.3.

150 mg of powder for solution for injection in a vial (type I glass) with a stopper (coated chlorobutyl rubber) and flip-off cap (aluminium).

Packs containing 1 vial or multipacks containing 4 (4x1) vials.

Not all pack sizes may be marketed.

Instructions for reconstitution

Using aseptic technique, reconstitute each vial of Ilaris at room temperature by slowly injecting 1.0 ml water for injections with a 1 ml syringe and an 18 G x 2 inch (50 mm) needle. Swirl the vial slowly at an angle of about 45° for approximately 1 minute and allow to stand for about 5 minutes. Then gently turn the vial upside down and back again ten times. If possible, avoid touching the rubber stopper with your fingers. Allow to stand for about 15 minutes at room temperature to obtain a clear to opalescent solution. Do not shake. Do not use if particles are present in the solution.

Tap the side of the vial to remove any residual liquid from the stopper. The solution should be free of visible particles and clear to opalescent. The solution should be colourless or may have a slight brownish-yellow tint. If the solution has a distinctly brown discolouration it should not be used. If not used immediately after reconstitution, the solution should be kept at 2°C to 8°C and used within 24 hours.

Instructions for administration

Carefully withdraw the required volume depending on the dose to be administered (0.2 ml to 1.0 ml) and subcutaneously inject using a 27 G x 0.5 inch (13 mm) needle.

The following are suitable injection sites: upper thigh, abdomen, upper arm or buttocks. Broken skin and areas which are bruised or covered by a rash should be avoided. Injection into scar-tissue should be avoided as this may result in insufficient exposure to Ilaris.

Ilaris vials are for single use only.

Disposal

Patients or their caregivers should be instructed on the appropriate procedure for disposal of the vials, syringes and needles in accordance with local requirements.

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

EU/1/09/564/001-002

23.10.2009

16.09.2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

POM