FDA批准Ilaris用于治疗冷吡啉相关的周期性综合征 2009年6月18日，诺华公司表示，美国食品药物管理局(FDA)已批准Ilaris用于治疗儿童(年龄≥4岁)和成人冷吡啉相关的周期性综合征(CAPS)，CAPS是一种终身性自身免疫性疾病。Ilaris是一种完全人源化单克隆抗体制剂，其靶向阻断白介素-1β (IL-β)，IL-β是一种CAPS患者体内产生过量的物质。Ilaris已被FDA指定为罕见病治疗药物。 Ilaris适用于治疗2种CAPS：家族性冷自身炎症反应综合征和穆-韦二氏综合征。CAPS是由一种基因突变引起，该基因突变导致患者体内产生过量的IL-β，从而引发持续炎症状态以及由此造成的组织损伤。CAPS患者可出现以下症状：虚弱乏力、皮疹、发热、头痛、关节疼痛和结膜炎。本病的临床表现可始于出生时或婴儿期，每天都可出现，并且可困扰患者终生。该症长期发展可产生严重或可能致命性的后果，包括耳聋、骨关节畸形、致视力下降的中枢神经系统损伤以及致肾衰竭和早期死亡的淀粉样变性。 这次Ilaris获准的依据是来自一项由3部分组成、为期1年的III期研究的结果。这项研究纳入了35例年龄介于9~74岁、疾病严重程度不同的CAPS患者。2009年6月4日发表于《新英格兰医学杂志》的研究结果显示，大多数患者对Ilaris的反应快速、完全且持续。该研究的第2部分比较了每2个月接受Ilaris治疗的患者与服用安慰剂的患者。结果显示，Ilaris组患者无1例（0/15）出现疾病突发，而安慰剂组16例患者中则有13例出现疾病突发(分别为0%对81%，P <0.001)。 在参与研究的患者中，Ilaris通常耐受性良好，除了所有可疑感染增加以外，不良事件无一致模式。2例患者出现严重不良事件：眩晕和下尿路感染。接受Ilaris治疗的患者所报道的最常见不良事件为鼻咽炎、腹泻、流感、头痛和恶心。没有发现长期治疗会影响不良事件的类型或发生频率。 Ilaris的给药方案是每8周一次，静脉注射。 【原产地英文商品名】ILARIS 180mg/vial 【原产地英文药品名】CANAKINUMAB/PF 【中文参考商品译名】ILARIS 180毫克/瓶 【中文参考药品译名】人抗白介素-1β单克隆抗体 【生产厂家中文参考译名】诺华制药 【生产厂家英文名】NOVARTIS PHARMS ILARIS - canakinumab injection  Novartis Pharmaceuticals Corporation ---------- ILARIS® (canakinumab) Injection for Subcutaneous use The following prescribing information is based on official labeling in effect July 2009.HIGHLIGHTS OF PRESCRIBING INFORMATION  These highlights do not include all the information needed to use ILARIS safely and effectively. See full prescribing information for ILARIS.  ILARIS (canakinumab) injection for subcutaneous use Initial U.S. Approval: 2009   INDICATIONS AND USAGE ILARIS is an interleukin-1β blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including: Familial Cold Autoinflammatory Syndrome (FCAS) Muckle-Wells Syndrome (MWS) (1)   DOSAGE AND ADMINISTRATION 150 mg for CAPS patients with body weight greater than 40 kg and 2 mg/kg for CAPS patients with body weight greater than or equal to 15 kg and less than or equal to 40 kg. For children 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. (2.2)   DOSAGE FORMS AND STRENGTHS Sterile, single-use 6-mL, glass vial containing 180 mg of ILARIS as a lyophilized powder for reconstitution. (3)   CONTRAINDICATIONS None. (4)   WARNINGS AND PRECAUTIONS Interleukin-1 blockade may interfere with immune response to infections. Treatment with medications that work through inhibition of IL-1 has been associated with an increased risk of serious infections. ILARIS has been associated with an increased incidence of serious infections. 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. Discontinue treatment with ILARIS if a patient develops a serious infection. Do not initiate treatment with ILARIS in patients with active infection requiring medical intervention. (5.1) Live vaccines should not be given concurrently with ILARIS. Prior to initiation of therapy with ILARIS, patients should receive all recommended vaccinations. (5.3)   ADVERSE REACTIONS The most common adverse reactions reported by patients with CAPS treated with ILARIS are nasopharyngitis, diarrhea, influenza, headache and nausea. (6)  DRUG INTERACTIONS No formal drug interaction studies have been conducted with ILARIS. USE IN SPECIFIC POPULATIONS Pregnancy: No Human data. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. (8.1) Nursing Mothers: Caution should be exercised when administered to a nursing woman. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling     FULL PRESCRIBING INFORMATION 1  INDICATIONS AND USAGE ILARIS (canakinumab) is an interleukin-1β blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including: Familial Cold Autoinflammatory Syndrome (FCAS) Muckle-Wells Syndrome (MWS) 2  DOSAGE AND ADMINISTRATION 2.1  General Dosing Information INJECTION FOR SUBCUTANEOUS USE ONLY. 2.2  Recommended Dose The recommended dose of ILARIS is 150 mg for CAPS patients with body weight greater than 40 kg. For CAPS patients with body weight between 15 kg and 40 kg, the recommended dose is 2 mg/kg. For children 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. ILARIS is administered every eight weeks as a single dose via subcutaneous injection. 2.3  Preparation for Administration Using aseptic technique, reconstitute each vial of ILARIS by slowly injecting 1 mL of preservative-free Sterile Water for Injection with a 1 mL syringe and an 18 G × 2″ needle. Swirl the vial slowly at an angle of about 45° for approximately 1 minute and allow to stand for 5 minutes. Then gently turn the vial upside down and back again ten times. Avoid touching the rubber stopper with your fingers. Allow to stand for about 15 minutes at room temperature to obtain a clear solution. Do not shake. Do not use if particulate matter is present in the solution. Tap the side of the vial to remove any residual liquid from the stopper. The reconstituted solution should be essentially free from particulates, and clear to opalescent. The solution should be colorless or may have a slight brownish-yellow tint. If the solution has a distinctly brown discoloration it should not be used. If not used within 60 minutes of reconstitution, the solution should be stored in the refrigerator at 2 to 8°C (36 to 46°F) and used within 4 hours. Slight foaming of the product upon reconstitution is not unusual. Using a sterile syringe and needle carefully withdrawthe required volume depending on the dose to be administered (0.2 mL to 1 mL) and subcutaneously inject using a 27 G × 0.5″ needle. Injection into scar tissue should be avoided as this may result in insufficient exposure to ILARIS. ILARIS 180-mg powder for solution for injection is supplied in a single-use vial. Any unused product or waste material should be disposed of in accordance with local requirements. 3  DOSAGE FORMS AND STRENGTHS ILARIS is supplied as a 180 mg white lyophilized powder for solution for subcutaneous injection. Reconstitution with 1 mL of preservative-free Sterile Water for Injection is required prior to subcutaneous administration of the drug, resulting in a total volume of 1.2 mL reconstituted solution. The reconstituted ILARIS is a clear to slightly opalescent, colorless to a slight brownish yellow tint, essentially free from particulates, 150 mg/mL solution. 4  CONTRAINDICATIONS None 5  WARNINGS AND PRECAUTIONS 5.1  Serious Infections ILARIS may be associated with an increased risk of serious infections. 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 initiated in patients with active infection requiring medical intervention. Administration of ILARIS should be discontinued if a patient develops a serious infection. Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with ILARIS. The observed infections responded to standard therapy. No unusual or opportunistic infections were reported with ILARIS. In clinical trials, ILARIS has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Taking ILARIS with TNF inhibitors is not recommended because this may increase the risk of serious infections [see Drug Interactions (7.1)]. Drugs that affect the immune system by blocking TNF have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as ILARIS that block IL-1 increases the risk of TB or other atypical or opportunistic infections. Prior to initiating immunomodulatory therapies, including ILARIS, patients should be tested for latent tuberculosis infection. ILARIS has not been studied in patients with a positive tuberculosis screen, and the safety of ILARIS in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ILARIS. Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ILARIS. 5.2  Immunosuppression The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including ILARIS, may result in an increase in the risk of malignancies. 5.3  Immunizations Live vaccines should not be given concurrently with ILARIS [see Drug Interactions (7.2)]. Since no data are available on either the efficacy or on the risks of secondary transmission of infection by live vaccines in patients receiving ILARIS, live vaccines should not be given concurrently with ILARIS. In addition, because ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. No data are available on the effectiveness of vaccinations with inactivated (killed) antigens in patients receiving ILARIS [see Drug Interactions (7.2)]. Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine. (See current recommended immunization schedules at the website of the Centers for Disease Control, http://www.cdc.gov/vaccines/recs/schedules/). 6  ADVERSE REACTIONS The data described herein reflect exposure to ILARIS in 104 adult and pediatric CAPS patients (including 20 FCAS, 72 MWS, 10 MWS/NOMID (Neonatal Onset Multisystem Inflammatory Disorder) overlap, 1 non-FCAS non-MWS, and 1 mis-diagnosed in placebo-controlled (35 patients) and uncontrolled trials). Sixty-two patients were exposed to ILARIS for at least 6 months, 56 for at least 1 year and 4 for at least 3 years. A total of 9 serious adverse reactions were reported for CAPS patients. Among these were vertigo (2 patients), infections (3 patients), including intra-abdominal abscess following appendectomy (1 patient). The most commonly reported adverse reactions associated with ILARIS treatment in the CAPS patients were nasopharyngitis, diarrhea, influenza, headache, and nausea. No impact on the type or frequency of adverse drug reactions was seen with longer-term treatment. One patient discontinued treatment due to potential infection. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1  Clinical Trial Experience Approximately 833 subjects have been treated with ILARIS in blinded and open-label clinical trials in CAPS and other diseases, and healthy volunteers. A total of 15 patients reported serious adverse reactions during the clinical program. Study 1 investigated the safety of ILARIS in an 8-week, open-label period (Part 1), followed by a 24-week, randomized withdrawal period (Part 2), followed by a 16-week, open-label period (Part 3). All patients were treated with ILARIS 150 mg subcutaneously or 2 mg/kg if body weight was greater than or equal to 15 kg and less than or equal to 40 kg (see Table 1). Since all CAPS patients received ILARIS in Part 1, there are no controlled data on adverse events (AEs). Data in Table 1 are for all AEs for all CAPS patients receiving canakinumab. In study 1, no pattern was observed for any type or frequency of adverse events throughout the three study periods. Table 1. Number (%) of Patients with AEs by Preferred Terms, in > 10% of Patients in Parts 1 to 3 of the Phase 3 Trial for CAPS Patients ILARIS N=35 Preferred Term n (%) n % of Patients with Adverse Events 35 (100) Nasopharyngitis 12 (34)  Diarrhea 7 (20) Influenza 6 (17) Rhinitis 6 (17) Nausea 5 (14) Headache 5 (14) Bronchitis 4 (11) Gastroenteritis 4 (11) Pharyngitis 4 (11) Weight increased 4 (11) Musculoskeletal pain 4 (11) Vertigo 4 (11) 6.2  Vertigo Vertigo has been reported in 9 to 14% of patients in CAPS studies, exclusively in MWS patients, and reported as a serious adverse event in two cases. All events resolved with continued treatment with ILARIS. 6.3  Injection Site Reactions In Study 1, subcutaneous injection site reactions were observed in 9% of patients in Part 1 with mild tolerability reactions; in Part 2, one patient each (7%) had a mild or a moderate tolerability reaction and, in Part 3, one patient had a mild local tolerability reaction. No severe injection-site reactions were reported and none led to discontinuation of treatment. 6.4  Immunogenicity A specific biosensor binding assay was used to detect antibodies directed against canakinumab in patients who received ILARIS. None of the 60 CAPS patients who had received ILARIS tested positive for treatment-emergent binding antibodies at the time points tested. Thirty-one of 60 CAPS patients had a duration of exposure to canakinumab >48 weeks. The data obtained in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, underlying disease, and the number of patients tested. For these reasons, comparison of the incidence of antibodies to canakinumab with the incidence of antibodies to other products may be misleading. 7  DRUG INTERACTIONS Interactions between ILARIS and other medicinal products have not been investigated in formal studies. 7.1  TNF-Blocker and IL-1 Blocking Agent An increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors in another patient population. Use of ILARIS with TNF inhibitors may also result in similar toxicities and is not recommended because this may increase the risk of serious infections [see Warnings and Precautions (5.1)]. The concomitant administration of ILARIS with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacological interactions between ILARIS and a recombinant IL-1ra, concomitant administration of ILARIS and other agents that block IL-1 or its receptors is not recommended. 7.2  Immunization 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. It is recommended that, if possible, pediatric and adult patients should complete all immunizations in accordance with current immunization guidelines prior to initiating ILARIS therapy [see Warnings and Precautions (5.3)]. 7.3  Cytochrome P450 Substrates The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as canakinumab, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of canakinumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed. 8  USE IN SPECIFIC POPULATIONS 8.1  Pregnancy Pregnancy Category C Canakinumab has been shown to produce delays in fetal skeletal development when evaluated in marmoset monkeys using doses 23-fold the maximum recommended human dose (MRHD) and greater (based on a plasma area under the time-concentration curve [AUC] comparison). Doses producing exposures within the clinical exposure range at the MRHD were not evaluated. Similar delays in fetal skeletal development were observed in mice administered a murine analog of canakinumab. There are no adequate and well-controlled studies of ILARIS in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Embryofetal developmental toxicity studies were performed in marmoset monkeys and mice. Pregnant marmoset monkeys were administered canakinumab subcutaneously twice weekly at doses of 15, 50 or 150 mg/kg (representing 23- to 230-fold the human dose based on a plasma AUC comparison at the MRHD) from gestation days 25 to 109 which revealed no evidence of embryotoxicity or fetal malformations. There were increases in the incidence of incomplete ossification of the terminal caudal vertebra and misaligned and/or bipartite vertebra in fetuses at all dose levels when compared to concurrent controls suggestive of delay in skeletal development in the marmoset. Since canakinumab does not cross-react with mouse or rat IL-1, pregnant mice were subcutaneously administered a murine analog of canakinumab at doses of 15, 50, or 150 mg/kg on gestation days 6, 11 and 17. The incidence of incomplete ossification of the parietal and frontal skull bones of fetuses was increased in a dose-dependent manner at all dose levels tested. 8.3  Nursing Mothers It is not known whether canakinumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILARIS is administered to a nursing woman. 8.4  Pediatric Use The CAPS trials with ILARIS included a total of 23 pediatric patients with an age range from 4 years to 17 years (11 adolescents were treated subcutaneously with 150 mg, and 12 children were treated with 2 mg/kg based on body weight greater than or equal to 15 kg and less than or equal to 40 kg). The majority of patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g., Serum Amyloid A and C-Reactive Protein). Overall, the efficacy and safety of ILARIS in pediatric and adult patients were comparable. Infections of the upper respiratory tract were the most frequently reported infection. The safety and effectiveness of ILARIS in patients under 4 years of age has not been established [see Pharmacokinetics (12.3)]. 8.5  Geriatric Use Clinical studies of ILARIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6  Patients with Renal Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with renal impairment. 8.7  Patients with Hepatic Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with hepatic impairment. 10  OVERDOSAGE No case of overdose has been reported. In the case of overdose, it is recommended that the subject be monitored for any signs and symptoms of adverse reactions or effects, and appropriate symptomatic treatment be instituted immediately. 11  DESCRIPTION Canakinumab is a recombinant, human anti-human-IL-1β monoclonal antibody that belongs to the IgG1/κ isotype subclass. It is expressed in a murine Sp2/0-Ag14 cell line and comprised of two 447- (or 448-) residue heavy chains and two 214-residue light chains, with a molecular mass of 145157 Daltons when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to the protein backbone at asparagine 298 (Asn 298). The biological activity of canakinumab is measured by comparing its inhibition of IL-1β-dependent expression of the reporter gene luciferase to that of a canakinumab internal reference standard, using a stably transfected cell line. ILARIS is supplied in a sterile, single-use, colorless, 6 mL glass vial with coated stopper and aluminum flip-off cap. Each vial contains 180 mg of canakinumab as a white, preservative-free, lyophilized powder. Reconstitution with 1 mL of preservative-free Sterile Water for Injection is required prior to subcutaneous administration of the drug. The reconstituted canakinumab is a 150 mg/mL solution essentially free of particulates, clear to slightly opalescent, and is colorless or may have a slightly brownish-yellow tint. A volume of up to 1 mL can be withdrawn for delivery of 150 mg/mL canakinumab for subcutaneous administration. Each reconstituted vial contains 180 mg canakinumab, sucrose, L-histidine, L-histidine HCl monohydrate, polysorbate 80 and Sterile Water for Injection. No preservatives are present. 12  CLINICAL PHARMACOLOGY 12.1  Mechanism of Action CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis. The NLRP-3 gene encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/κ isotype. Canakinumab binds to human IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). 12.2  Pharmacodynamics C-reactive protein and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Following ILARIS treatment, CRP and SAA levels normalize within 8 days. 12.3  Pharmacokinetics Absorption The peak serum canakinumab concentration (Cmax) of 16 ± 3.5 μg/mL occurred approximately 7 days after subcutaneous administration of a single, 150-mg dose subcutaneously to adult CAPS patients. The mean terminal half-life was 26 days. The absolute bioavailability of subcutaneous canakinumab was estimated to be 70%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection. Distribution Canakinumab binds to serum IL-1β. Canakinumab volume of distribution (Vss) varied according to body weight and was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg. The expected accumulation ratio was 1.3-fold following 6 months of subcutaneous dosing of 150 mg ILARIS every 8 weeks. Elimination Clearance (CL) of canakinumab varied according to body weight and was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg. 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. Pediatrics Peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of ILARIS 150 mg or 2 mg/kg in pediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults. 13  NONCLINICAL TOXICOLOGY 13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of canakinumab. The mutagenic potential of canakinumab was not evaluated. As canakinumab does not cross-react with rodent IL-1β, male and female fertility was evaluated in a mouse model using a murine analog of canakinumab. Male mice were treated weekly beginning 4 weeks prior to mating and continuing through 3 weeks after mating. Female mice were treated weekly for 2 weeks prior to mating through gestation day 3 or 4. The murine analog of canakinumab did not alter either male or female fertility parameters at subcutaneous doses up to 150 mg/kg. 14  CLINICAL STUDIES The efficacy and safety of ILARIS for the treatment of CAPS was demonstrated in Study 1, a 3-part trial in patients 9 to 74 years of age with the MWS phenotype of CAPS. Throughout the trial, patients weighing more than 40 kg received ILARIS 150 mg and patients weighing 15 to 40 kg received 2 mg/kg. Part 1 was an 8-week open-label, single-dose period where all patients received ILARIS. Patients who achieved a complete clinical response and did not relapse by Week 8 were randomized into Part 2, a 24-week randomized, double-blind, placebo-controlled withdrawal period. Patients who completed Part 2 or experienced a disease flare entered Part 3, a 16-week open-label active treatment phase. A complete response was defined as ratings of minimal or better for physician’s assessment of disease activity (PHY) and assessment of skin disease (SKD) and had serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA) less than 10 mg/L. A disease flare was defined as a CRP and/or SAA values greater than 30 mg/L and either a score of mild or worse for PHY or a score of minimal or worse for PHY and SKD. In Part 1, a complete clinical response was observed in 71% of patients one week following initiation of treatment and in 97% of patients by Week 8 (see Figure 1 and Table 2). In the randomized withdrawal period, a total of 81% of the patients randomized to placebo flared as compared to none (0%) of the patients randomized to ILARIS. The 95% confidence interval for treatment difference in the proportion of flares was 53% to 96%. At the end of Part 2, all 15 patients treated with ILARIS had absent or minimal disease activity and skin disease (see Table 2). In a second trial, patients 4 to 74 years of age with both MWS and FCAS phenotypes of CAPS were treated in an open-label manner. Treatment with ILARIS resulted in clinically significant improvement of signs and symptoms and in normalization of high CRP and SAA in a majority of patients within 1 week. Table 2. Physician’s Global Assessment of Auto-Inflammatory Disease Activity and Assessment of Skin Disease: Frequency Table and Treatment Comparison in Part 2 (Using LOCF, ITT Population) ILARIS Placebo N=15 N=16 Baseline Start of Part 2 (Week 8) End of Part 2 Start of Part 2 (Week 8) End of Part 2 Physician's Global Assessment of Auto-Inflammatory Disease Activity – n (%) Absent 0/31 (0) 9/15 (60) 8/15 (53) 8/16 (50) 0/16 (0)  Minimal 1/31 (3) 4/15 (27) 7/15 (47) 8/16 (50) 4/16 (25) Mild  7/31 (23) 2/15 (13) 0/15 (0)  0/16 (0)  8/16 (50) Moderate 19/31 (61) 0/15 (0)  0/15 (0)  0/16 (0)  4/16 (25) Severe  4/31 (13) 0/15 (0)  0/15 (0)  0/16 (0)  0/16 (0)  Assessment of Skin Disease – n (%) Absent  3/31 (10) 13/15 (87) 14/15 (93) 13/16 (81) 5/16 (31) Minimal  6/31 (19)  2/15 (13)  1/15 (7)   3/16 (19) 3/16 (19) Mild  9/31 (29)  0/15 (0)   0/15 (0)   0/16 (0)  5/16 (31) Moderate 12/31 (39)  0/15 (0)   0/15 (0)   0/16 (0)  3/16 (19) Severe  1/32 (3)   0/15 (0)   0/15 (0)   0/16 (0)  0/16 (0)  Markers of inflammation CRP and SAA normalized within 8 days of treatment in the majority of patients. Normal mean CRP (Figure 1) and SAA values were sustained throughout Study 1 in patients continuously treated with canakinumab. After withdrawal of canakinumab in Part 2 CRP (Figure 1) and SAA values again returned to abnormal values and subsequently normalized after reintroduction of canakinumab in Part 3. The pattern of normalization of CRP and SAA was similar. 16  HOW SUPPLIED/STORAGE AND HANDLING Carton of 1 vial NDC 0078-0582-61 Each 6 mL single-use vial of ILARIS contains a sterile, preservative free, white lyophilized powder containing 180 mg of canakinumab. Each vial is to be reconstituted with 1 mL of preservative-free Sterile Water for Injection in a 150 mg/mL solution. Special Precautions for Storage The unopened vial must be stored refrigerated at 2 to 8°C (36 to 46°F). Do not freeze. Store in the original carton to protect from light. Do not use beyond the date stamped on the label. After reconstitution, ILARIS should be kept from light, and can be kept at room temperature if used within 60 minutes of reconstitution. Otherwise, it should be refrigerated at 2 to 8°C (36 to 46°F) and used within 4 hours of reconstitution. ILARIS does not contain preservatives. Unused portions of ILARIS should be discarded. Keep this and all drugs out of the reach of children. 17  PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling. Patients should be provided the opportunity to read the Patient Information for ILARIS prior to the first treatment and any questions resulting from the patient’s reading of the guide should be discussed. 17.1  Drug Administration Healthcare providers should perform administration of ILARIS by the subcutaneous injection route. 17.2  Infections Patients should be cautioned that ILARIS use has been associated with serious infections. Patients should be counseled to contact their healthcare professional immediately if they develop an infection after starting ILARIS. Treatment with ILARIS should be discontinued if a patient develops a serious infection. Patients should be counseled not to take any IL-1 blocking drug, including ILARIS, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of ILARIS with other IL-1 blocking agents, such as rilonacept and anakinra is not recommended. Patients should be cautioned not to initiate treatment with ILARIS if they have a chronic or active infection, including HIV, Hepatitis B or C. 17.3  Vaccinations Prior to initiation of therapy with ILARIS, physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ILARIS. 17.4  Injection-site Reactions Physicians should explain to patients that a very small number of patients in the clinical trials experienced a reaction at the subcutaneous injection site. Injection-site reactions may include pain, erythema, swelling, pruritus, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Healthcare providers should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician. INFORMATION FOR PATIENTS See patient information leaflet. Patient Information ILARIS® (i-LAHR-us) (canakinumab) Read the Patient Information that comes with ILARIS before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. What is ILARIS? ILARIS is a prescription medicine injected just below the skin (subcutaneous) used in adults and children 4 years and older to treat auto-inflammatory diseases known as Cryopyrin-Associated Periodic Syndromes (CAPS), including: Familial Cold Autoinflammatory Syndrome (FCAS) Muckle-Wells Syndrome (MWS) It is not known if ILARIS is safe or effective in children under 4 years of age. What should I tell my healthcare provider before taking ILARIS? Before you take ILARIS, tell your healthcare provider if you: think you have an infection are being treated for an infection have signs of an infection, such as fever, cough, or flu-like symptoms have a history of infections that keep coming back have or have had HIV, Hepatitis B, or Hepatitis C have an immune system problem. People with these conditions have a higher chance for infections. have tuberculosis (TB), or if you have been in close contact with someone who has or has had tuberculosis are scheduled to receive any immunizations (vaccines). You should not get ‘live vaccines’ if you take ILARIS. are pregnant or planning to become pregnant. It is not known if ILARIS will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking ILARIS. are breastfeeding or planning to breastfeed. It is not known if ILARIS passes into your breast milk. You and your healthcare provider should decide if you will take ILARIS or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Especially tell your healthcare provider if you take: medicines that affect your immune system IL-1 blocking agents such as Kineret® (anakinra), Arcalyst® (rilonacept) Tumor Necrosis Factor (TNF) inhibitors such as Enbrel® (etanercept) Humira® (adalimumab), or Remicade® (infliximab) medicines that can affect enzyme metabolism. Ask your healthcare provider if you are not sure. Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How will I receive ILARIS? Do not receive ILARIS if you have an infection. ILARIS is given by your healthcare provider every 8 weeks. Your healthcare provider may change your dose if needed. What are the possible side effects of ILARIS? ILARIS can cause serious side effects including: serious infections decrease your body’s ability to fight infections (immunosuppression) feeling like you are spinning (vertigo) Call your healthcare provider right away if you have any of these signs of an infection: a fever lasting longer than 3 days a cough that does not go away redness in one part of your body warm feeling or swelling of your skin The most common side effects include: cold symptoms diarrhea flu (influenza) runny nose nausea headache injection site reaction (such as redness, swelling, warmth, itching) Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ILARIS. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of ILARIS Medicines are sometimes prescribed for purposes other than those listed in patient information leaflets. Do not use ILARIS for a condition for which it was not prescribed. This leaflet summarizes the most important information about ILARIS. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ILARIS that was written for health professionals. For more information about ILARIS, call 1-877-452-7471 or visit www.ILARIS.com. What are the ingredients in ILARIS? Active ingredients: canakinumab Inactive ingredients: sucrose, L-histidine, L-histidine HCl monohydrate, polysorbate 80, preservative-free Sterile Water for Injection. What is CAPS Disease? In patients with CAPS, the body produces excessive amounts of a chemical messenger called interleukin-1 beta (IL-1β). This may lead to symptoms such as fever, headache, fatigue, skin rash, painful joints and muscles. In some patients, more severe outcomes such as hearing impairment are observed. Kineret®, Arcalyst®, Enbrel®, Humira®, Remicade® are trademarks of Amgen, Regeneron, Immunex Corporation, Abbott Laboratories, Centocor Ortho Biotech Inc., respectively. REV: JUNE 2009   T2009-82 Manufactured By: Novartis Pharma Stein AG Stein, Switzerland Distributed By: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis PRODUCT PHOTO NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size. The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected over dosage, the drug's identity should be verified by chemical analysis. Ilaris(人抗白介素-1β单克隆抗体canakinumab) 11一般描述： Canakinumab是重组，人抗-人-IL-1β单抗，属IgG1/κ同工型亚类。在鼠类Sp2/0-Ag14细胞株中表达，由两条447-(或448-)残基重链和两条214-残基轻链组成，当去糖基化时分子质量为145157道尔顿。Canakinumab的两条重链均含寡糖链连接至蛋白骨架天冬酰胺298(Asn 298)。 用一株稳定转染细胞株，比较IL-1β-荧光素酶报告基因与一种canakinumab内部参比标准依赖性表达抑制作用的测定Canakinumab的生物学活性。 ILARIS以一种无菌，单次使用，无色，6 mL有涂膜塞和铝制翻转帽玻璃小瓶供应。每只小瓶含180 mg的白色，无防腐剂，冻干粉canakinumab。药物皮下给药前需要用1 mL无防腐剂无菌注射用水配制。配制好的canakinumab是一种150 mg/mL溶液基本上无颗粒，澄明至略微发乳白色，和是无色或可能有略微棕黄色。为皮下给药输送150 mg/mL canakinumab可抽吸至1 mL容积，每配制好的小瓶含180 mg canakinumab，蔗糖， L-组氨酸，L-组氨酸HCL单水化物，聚山梨醇80和无菌注射用水。不存在防腐剂。 1 适应证和用途： ILARIS是白介素-1β阻断剂，适用于治疗成年和儿童4岁和以上隐热蛋白(cryopyrin)-相关周期综合症(CAPS)，包括：家族性冷自发炎症综合症(Familial Cold Autoinflammatory Syndrome, FCAS。 罕见炎症，特征为一般性暴露于冷温度后发热，皮疹和关节痛)；穆-韦二氏综合征(Muckle-Wells Syndrome, MWS，注：特征为家族性淀粉样变性，涉及肾，神经性和原因不明进行性耳聋，和伴肢体关节肌肉疼痛发热性荨麻疹；常染色体显性遗传)。 2 剂量和使用方法： 2.1 一般给药资料 仅为皮下注射。 2.2 推荐剂量 体重>40 kg CAPS患者用150 mg和体重≥15 kg和≤40 kg CAPS患者用2 mg/kg。15至40 kg，反应不佳的儿童剂量可增至3 mg/kg。对CAPS患者体重大于40 kg ILARIS的推荐剂量是150 mg。 对CAPS患者体重15 kg和40 kg间，推荐剂量是2 mg/kg。对于15至40 kg有不充分反应儿童，剂量可增加至3 mg/kg。 ILARIS是作为单次给药通过皮下注射每8周给药。 2.3 为给药配制 用无菌术，配制每小瓶ILARIS通过用1 mL 注射器和一个18 G × 2”针头缓慢注射1 mL的无防腐剂无菌注射用水。在一个角度约45°缓慢旋转小瓶约1分钟和放置5分钟，然后轻轻将小瓶上下倒置十次。避免用手指触橡皮塞。在被室温放置约15分钟得到澄明溶液。不要震荡。在溶液有颗粒物质不要使用。敲打小瓶侧部去掉从塞子来的残留液体。配制好溶液应基本上无颗粒和澄明至略微发乳白色。溶液应无色或可能有略微棕黄色，如溶也有明显棕色变色不应使用。如不在配制60分钟内使用，溶液应贮存在冰箱在2至8° C(36至46° F)和在4小时内使用。配制好产品略微起泡沫并非不寻常。 使用一支无菌注射前和针头小心抽吸需要容积依赖于将给予的剂量(0.2 mL至1 mL)和用1只27 G × 0.5”针头皮下注射。 避免注射如瘢痕组织这可能导致暴露于ILARIS不充分。 ILARIS 180-mg粉为注射溶液在在一只单次使用小瓶内供应。按照当地要求应遗弃任何未使用或废材料。 3 剂型和规格 ILARIS是在以180 mg白色冻干粉为皮下注射溶液供应。皮下给药前，药物需要用1 mL无防腐剂无菌注射用水配制，导致棕容积1.2 mL配制好的溶液。配制好的ILARIS是澄明至略微发乳白色，无色至略微棕黄色，基本上无颗粒，150 mg/mL溶液。 4 禁忌证： 无。 5 警告和注意事项 5.1 严重感染 ILARIS可能伴有严重感染风险增加。当给予ILARIS至有感染患者，复发感染史或所患疾病可能倾向感染时医生应特别小心。有活动性感染需要干预的患者不应开始用ILARIS治疗。如果患者发生严重感染应停止 ILARIS给药。 用ILARIS曾报道感染，占优势是上呼吸道感染，在某些情况严重。观察到感染对标准治疗有反应。用ILARIS 无不寻常或机遇性感染报道。在临床试验中，ILARIS未曾同时给予肿瘤坏死因子(TNF)抑制剂。给予另一种IL-1β阻断剂与TNF抑制剂联用曾伴随严重感染发生率增加。因为可能增加严重感染风险建议ILARIS不要与TNF抑制剂使用[见药物相互作用(7.1)]。 通过阻断TNF影响免疫系统的药物曾伴随潜伏结核(TB)再次激活风险的增加。有可能用药物例如ILARIS阻断IL-1β增加TB或其它不典型或机遇性感染的风险。 开始免疫调解治疗前，包括ILARIS，应检验患者潜伏结核感染。尚未在有阳性结核筛选患者中研究ILARIS，和有潜伏结核感染个体中ILARIS的安全性不清楚。结核筛选检验阳性患者用ILARIS治疗前应用标准医学实践治疗。 卫生保健提供者应跟踪当前CDC指导原则评价和在开始使用ILARIS治疗前治疗可能的潜伏结核感染。 5.2 免疫抑制 不清楚用抗-白介素-1(IL-1)治疗对恶性病发生的影响。 然而，用免疫抑制剂治疗，包括ILARIS，可能导致恶性病风险增加。 5.3 免疫接种 与ILARIS同时不应给予活疫苗[见药物相互作用(7.2)]。因为对或疗效或对在接受ILARIS患者中通过活疫苗继发传播感染的风险均无可供利用发资料，用ILARIS不应同时给予活疫苗。此外，因为ILARIS可能干预对新抗原的正常免疫反应，患者接受ILARIS中免疫接种可能无效。接受ILARIS患者中接种灭活(杀死)抗原的有效性没有可以得到的资料。[见药物相互作用(7.2)]。 因为IL-1β阻断可能干扰对干扰的免疫反应。建议开始用ILARIS治疗前，成年和儿童患者接受所有推荐的免疫接种，如适当，包括肺炎球菌疫苗和灭活的流感疫苗。 6 不良反应 在此描述反映在104例成年和儿童CAPS患者，(包括20例FCAS，72例MWS，10例MWS/NOMID(新生儿发病多系统炎症疾病)重叠，1例非-FCAS非-MWS，和1例误诊在安慰剂-对照(35例患者)和无对照试验暴露于ILARIS的资料。62例患者被暴露至ILARIS至少6个月，56例至少1年和4例至少3年。对CAPS患者报道总共9例严重不良反应。这些其中是眩晕(2例患者)，感染(3例患者)，包括阑尾切除术后腹腔内脓肿(1例患者)。CAPS患者伴ILARIS治疗最常报道的不良反应是鼻咽炎、腹泻、流感、头痛、和恶心。用长期治疗未见对不良反应类型和频数的影响。一例患者由于潜在感染停止治疗。 因为临床试验是在广泛不同条件下进行的，某药临床试验中观察到的不良反应率不能与另一药物临床试验中的发生率直接比较而且可能不反映实践中观察到的发生率。 6.1 临床试验经验 在盲态和开放临床试验在CAPS和其它疾病，和健康志愿者中约833例受试者曾被ILARIS治疗。临床计划期间总共报道15例严重不良反应患者。 研究1在一项8-周，开放阶段(第1部分)，接着一项24-周，随机化撤药阶段(第2部分)，接着一项16-周，开放阶段(第3部分)研究ILARIS的安全性。所有患者用ILARIS 150 mg皮下或如体重是大于或等于15 kg和小于或等于40 kg时2 mg/kg治疗。 6.2 眩晕 CAPS研究中报道9至14%患者眩晕，只是在MWS患者中，和2例报道为严重不良事件。用ILARIS继续治疗所有事件解决。 6.3 注射部位反应 在研究1中，在第1部分观察到9%患者有皮下注射部位反应是轻度可耐受性反应；在第2部分，1例患者各(7%) 有轻度或中度可耐受性反应，而在第3部分，1例患者有轻度局部可耐受性反应。未报道无严重注射部位反应和无导致停止治疗。 ***免疫原性 对接受ILARIS患者中检测用一种特异性生物感受器结合分析针对canakinumab的抗体。60例曾接受ILARIS的CAPS患者，在任何测试时间点均没有检出治疗-出现结合抗体阳性。31/60例CAPS患者暴露于canakinumab时间 >48周。在某种分析得到的数据高度依赖于几种因子包括分析灵敏度和特异性，分析方法学，样品处理，采样时间，同时用药，所患疾病，和被测试患者数。由于这些理由，对canakinumab抗体的发生率与其它产品抗体的发生率的比较可能是误导。 7 药物相互作用 尚未进行正式研究ILARIS和其它医药产品间的相互作用。 7.1 TNF-阻断剂和IL-1阻断药物 在另一患者人群中给予另一种IL-1β阻断剂与TNF抑制剂联用曾伴有严重感染发生率增加和中性粒细胞减少风险增加。使用ILARIS与TNF抑制剂可能也导致相似毒性和因为这可能增加严重感染的风险建议不用[见警告和注意事项(5.1)]。 未曾研究过同时给予ILARIS与其它阻断IL-1β。根据ILARIS和一种重组IL-1ra间药理学相互作用的潜能，建议不要同时给予ILARIS和其它阻断IL-1β或其受体的其它药物。 7.2 免疫接种 在患者接受ILARIS中，没有可以得到的或活疫苗接种的效应或通过活疫苗继发传播感染的资料。所以，不应与ILARIS同时给予活疫苗。建议如可能，儿童和成年患者ILARIS在开始ILARIS治疗前，应完成所有免疫接种符合当前免疫接种指导原则[见警告和注意事项(5.3)]。 7.3 细胞色素P450底物 慢性炎症期间细胞因子水平增加CYP450酶的形成被抑制(如，IL-1)。预计一种分子与IL-1结合，例如canakinumab， CYP450酶的形成可能被正常化。这是临床上对CYP450底物有一狭窄的治疗指数有意义的，其中剂量是个体化调整的(如，华法林)。开始用canakinumab, 在正在用这些类型医药产品治疗的患者，应进行治疗性监测效应或药物浓度和必要时可能需要调整医药产品个体剂量。 8临床药理学 8.1 作用机制 CAPS指罕见遗传综合征一般是NLRP-3内突变引起[即核苷酸结合域[nucleotide-binding domain]，富含亮氨酸家族[leucine rich family](NLR)，热蛋白结构域pyrin domain containing 3]基因(也被称为寒冷诱导自身炎症综合症-1[CIAS1])。CAPS疾患是在一个常染色体结构区模式有男性和女性子代等同受影响遗传。所有疾患特点包括发热，荨麻疹样皮疹，关节痛，肌肉痛，疲劳，和结膜炎。 NLRP-3基因编码隐热蛋白[cryopyrin]，炎性体[inflammasome]的一种重要组分。隐热蛋白调解蛋白酶凋亡蛋白质酶-1[caspase-1]和控制白介素-1 beta (IL-1β)的激活。NLRP-3内突变导致炎性体inflammasome过度活化导致过量释放活化的IL-1β驱动炎症。 Canakinumab是一种人单克隆抗人IL-1β抗体的IgG1/κ同工型。Canakinumab与人IL-1结合和通过阻断它与IL-1β受体的相互作用中和其活性，但它不与IL-1β或IL-1β受体拮抗剂(IL-1ra)结合. 8.2 药效学 C-反应蛋白和血清淀粉样蛋白A(SAA)是炎性疾病活动度的指针，在CAPS患者中升高。CAPS患者中升高的SAA曾伴发系统性淀粉样变的发展。ILARIS治疗后，在8天内CRP和SAA水平正常化。 8.3 药代动力学 吸收 皮下给予单次后150-mg剂量至成年CAPS患者，血清峰canakinumab浓度(Cmax)16 ± 3.5 g/mL出现在接近7 天。平均末端半衰期是26天。皮下canakinumab的绝对生物利用度估计是70%。暴露参数(例如AUC和Cmax)增加与剂量成正比例静脉输注0.30至10 mg/kg剂量范围或当皮下注射从150至300 mg时. 分布 Canakinumab与血清IL-1β结合。Canakinumab分布容积(Vss)按体重变化和在一典型体重70 kg CAPS患者估算是6.01立升。每8周皮下给予150 mg ILARIS的6个月后期望的蓄积比值为1.3-倍。 消除 在一典型体重70 kg的CAPS患者中，Canakinumab的清除率(CL)按体重变化和估算是0.174 L/day。重复给药后canakinumab药代动力学的性质没有加速的清除率或依赖-时间的变化的指示。校正体重后无性别-或年龄相关药代动力学差别。 儿童 在儿童患者中单次皮下给予ILARIS 150 mg或2 mg/kg后2至7天间出现canakinumab峰浓度。末端半衰期范围从22.9至25.7天，相似于在成年中观察到药代动力学的性质。 9临床研究 研究1中，在9至74岁有CAPS的MWS表型患者中一项3-部分试验为CAPS的治疗显示ILARIS的有效性和安全性。试验自始至终, 体重超过40 kg患者接受ILARIS 150 mg和体重超过15至40 kg患者接受2 mg/kg。第1部分是一项8-周开放，单次给药期其中所有患者接受ILARIS。达到完全临床缓解和到8周不复发患者被随机化至第2部分，一项24-周随机化，双盲，安慰剂-对照撤药阶段。完成第2部分或经受疾病复燃进入第3部分，一项16-周开放阳性治疗期。完全缓解被定义为对医生的评估疾病活动度(PHY)和评估皮肤病(SKD) 分等级最小或更好和有血清C-反应蛋白(CRP)水平和血清淀粉样蛋白A(SAA)低于10 mg/L。疾病复燃被定义为CRP和/或SAA值大于30 mg/L和或对PHY计分轻度或更坏或对PHY和SKD计分最小或更坏。 在第1部分，开始治疗后1周观察到71%的患者完全临床缓解而97%患者在8周(见图1和表2)。在随机化撤出阶段，总共81%随机化至安慰剂患者复燃与之比较随机化至ILARIS患者复燃为(0%)。治疗差别的复燃比例的95%可信区间是53%至96%。在第2部分结束时，所有15例用ILARIS治疗患者疾病活动度和皮肤疾病治疗缓解为缺乏或最小(见表2)。 在一项第二试验中，患者年龄4至74岁兼有CAPS的MWS和FCAS表型以开放方式被治疗。用ILARIS治疗导致临床上征象和症状显著改善和大多数患者在1周内高CRP和SAA正常化。 大多数患者中，在治疗的8天内炎症的标志物CRP和SAA正常化。研究1在连续用canakinumab治疗患者中，正常平均CRP(图1)和SAA值是持续始终的。在撤去canakinumab后在第2部分CRP(图1)和SAA值再次返回至异常值而在第3部分阶段再次引入canakinumab后，随后正常化。CRP和SAA正常化的模式相似。