Ilaris · 4.3 Contraindications · 1

HOS-095472 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most frequent adverse reactions were infections predominantly of the upper respiratory tract. No impact 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 4.3 and 4.4). Opportunistic infections have been reported in patients treated with canakinumab (see section 4.4). Tabulated list of adverse reactions Adverse reactions are listed according to MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency category with the most common first. Frequency categories are defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 10 Table 1 Tabulated list of adverse reactions MedDRA Indications: System Organ CAPS, TRAPS, HIDS/MKD, FMF, SJIA, gouty arthritis Class Infections and infestations Very common Respiratory tract infections (including pneumonia, bronchitis, influenza, viral infection, sinusitis, rhinitis, pharyngitis, tonsillitis, nasopharyngitis, upper respiratory tract infection) Ear infection Cellulitis Gastroenteritis Urinary tract infection Common Vulvovaginal candidiasis Nervous system disorders Common Dizziness/vertigo Gastrointestinal disorders Very common Upper abdominal pain 1 Uncommon Gastro-oesophageal reflux disease 2 Skin and subcutaneous tissue disorders Very common Injection site reaction Musculoskeletal and connective tissue disorders Very common Arthralgia 1 Common Musculoskeletal pain 1 Back pain 2 General disorders and administration site conditions Common Fatigue/asthenia 2 Investigations Very common Creatinine renal clearance decreased 1,3 Proteinuria 1,4 Leukopenia 1,5 Common Neutropenia 5 Uncommon Platelet count decreased 5 1 In SJIA 2 In gouty arthritis 3 B

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HOS-095468 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active, severe infections (see section 4.4).

HOS-095467 · has-indication-information · PDF-Seite 2

Periodic fever syndromes Ilaris is indicated for the treatment of the following autoinflammatory periodic fever syndromes in adults, 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 periodic syndrome (TRAPS). 2 Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD) Ilaris is indicated for the treatment of hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (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 have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic 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 adequate response, and in whom repeated courses of corticosteroids are not appropriate (see section 5.1).

HOS-095470 · has-interaction-information · PDF-Seite 9

Interactions between canakinumab and other medicinal products have not been investigated in formal studies. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Use of canakinumab with TNF inhibitors is not recommended because this may increase the risk of serious infections. The expression of hepatic CYP450 enzymes may be suppressed by the cytokines that stimulate chronic inflammation, such as interleukin-1 beta (IL-1 beta). Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as canakinumab, is introduced. This is clinically relevant for CYP450 substrates with a narrow therapeutic index where the dose is individually adjusted. On initiation of canakinumab in patients being treated with this type of medicinal product, it is recommended that therapeutic monitoring of the effect or of the active substance concentration is performed and the individual dose of the medicinal product adjusted as necessary. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving canakinumab. Therefore, live vaccines must not be given concurrently with canakinumab unless the benefits clearly outweigh the risks. In case vaccination with live vaccines is indicated after initiation of canakinumab treatment, the recommendation is to wait for at least 3 months after the last canakinumab injection and before the next one (see section 4.4). The results of a study in healthy adult subjects demonstrated that a single dose of canakinumab 300 mg did not affect the induction and persistence of antibody responses after vaccination with influenza or glycosylated protein based meningococcus vaccines. The results of a 56-week, open label study in CAPS patients aged 4 years and younger demonstrated that all patients who received non-live, standard of care childhood vaccinations developed protective antibody levels.

HOS-095471 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential / Contraception in males and females It is recommended that women use effective contraceptives during treatment with canakinumab and for up to 3 months after the last dose. 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. It is therefore recommended that women who are pregnant or who desire to become pregnant only be treated after a thorough benefit-risk evaluation. 9 Animal studies indicate that canakinumab crosses the placenta and is detectable in the foetus. No human data are available, but as canakinumab is an immunoglobulin of the G class (IgG1), human transplacental transfer is expected. The clinical impact of this is unknown. However, administration of live vaccines to newborn infants exposed to canakinumab in utero is not recommended for 16 weeks following the mother’s last dose of canakinumab before childbirth. It is recommended that women who received canakinumab during pregnancy be instructed to inform the baby’s healthcare professional before any vaccinations are given to their newborn infant. Breast-feeding It is unknown whether canakinumab is excreted in human milk. It is therefore recommended that the decision 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 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 canakinumab on human fertility have not been conducted. Canakinumab had no effect on male fertility parameters in marmosets (C. jacchus). A murine anti- murine IL-1 beta antibody had no undesirable effects on fertility in male or female mice (see section 5.3).

HOS-095469 · has-warning-information · PDF-Seite 7

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Infections Canakinumab is associated with an increased incidence of serious infections. Patients must be monitored carefully for signs and symptoms of infections during and after treatment with canakinumab (see section 4.8). Physicians need to exercise caution when administering canakinumab to patients with infections, a history of recurring infections, or underlying conditions which may predispose 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 requiring medical 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 recommended because this may increase the risk of serious infections (see section 4.5). Isolated cases of unusual or opportunistic infections (including aspergillosis, atypical mycobacterial infections, herpes zoster) have been reported during canakinumab treatment. The causal relationship of canakinumab to these events cannot be excluded. Tuberculosis screening In approximately 12% of CAPS patients tested with a PPD (purified protein derivative) skin test in clinical trials, follow-up testing yielded a positive test result while treated with canakinumab without clinical evidence of a latent or active tuberculosis infection. It is unknown whether the use of interleukin-1 (IL-1) inhibitors such as canakinumab increases the risk of reactivation of tuberculosis. Before initiation of therapy, all patients must be evaluated for both active and latent tuberculosis infection. Particularly in adult patients, it is recommended that this evaluation 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 (local recommendations may apply). Patients must be monitored closely for signs and symptoms of tuberculosis during and after treatment with canakinumab. All patients are to be instructed to seek medical advice if signs or symptoms suggestive of tuberculosis (e.g. persistent cough, weight loss, subfebrile temperature) appear during canakinumab therapy. In the event of conversion from

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