Ilaris 150mg powder for solution for injection Ref.[2607] Active ingredients: Canacinumab

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 × 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:

# Solicited through physician questionnaires
* All events resolved despite continued treatment with Ilaris.

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.

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