2013年9月3日,单抗药物Ilaris(canakinumab)已获欧盟委员会(EC)批准,用于2岁及以上活动性全身型幼年特发性关节炎(SJIA)患者的治疗。该药是首个获批用于SJIA的IL-1β抑制剂,同时也是唯一获批专门用于SJIA治疗且每月仅需一次的皮下注射药物。
Long-term data and laboratory abnormalities in CAPS patients During clinical trials with Ilaris in CAPS patients mean values for haemoglobin increased and those 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 treated with Ilaris 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 more frequently reported in the 600 mg or 8 mg/kg dose group than in other dose groups. Laboratory abnormalities in SJIA patients Haematology In the overall SJIA program, transient decreased white blood cell (WBC) counts ≤ 0.8 x LLN were reported in 33 patients (16.5%). In the overall SJIA program, transient decreases in absolute neutrophil count (ANC) to less than 1 x 109/l were reported in 12 patients (6.0%). In the overall SJIA program, transient decreases in platelet counts (< LLN) were observed in 19 patients (9.5%). ALT/AST In the overall SJIA program, high ALT and/or AST > 3 x upper limit of normal (ULN) were reported in 19 patients (9.5%). Laboratory abnormalities in gouty arthritis patients Haematology Decreased white blood cell counts (WBC) ≤ 0.8 x lower limit of normal (LLN) were reported in 6.7% of patients treated with Ilaris 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 in the 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 higher incidence (12.7%) with Ilaris 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 after Ilaris treatment in comparative trials in gouty arthritis. In another study, among patients who were starting on ULT, increases in uric acid were not observed. Uric acid increases were not observed in 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 in aspartate transaminase (AST) of 2.7 U/l and 2.0 U/l, respectively, from baseline to end of study were seen in the Ilaris-treated groups versus the triamcinolone acetonide-treated group(s), however the incidence of clinically significant changes (≥ 3 x the upper limit of normal) was greater for patients treated with triamcinolone acetonide (2.5% for both AST and ALT) compared with Ilaris-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 in Ilaris-treated patients compared with a modest decrease of -3.1 mg/dl with triamcinolone acetonide. The incidence of patients with triglyceride elevations > 5 x upper limit of normal (ULN) was 2.4% with Ilaris and 0.7% with triamcinolone acetonide. The clinical significance of this observation is unknown. Paediatric population There were 69 paediatric CAPS patients (2-17 years of age) included in the studies. Overall, there were no clinically meaningful differences in the safety and tolerability profile of Ilaris in paediatric patients compared to the overall CAPS population (comprised of adult and pediatric patients, N=194), including the overall frequency and severity of infectious episodes. Infections of the upper respiratory tract were the most frequently reported infection events. Elderly population There is no significant difference in safety profile observed in patients ≥ 65 years of age. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Reported experience with overdose is limited. In early clinical trials, patients and healthy volunteers received doses as high as 10 mg/kg, administered intravenously or subcutaneously, without evidence of acute toxicity. 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. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC08 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 CAPS 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. SJIA Systemic Juvenile Idiopathic Arthritis is a severe autoinflammatory disease, driven by innate immunity by means of pro-inflammatory cytokines, a key one being IL-1-beta. Common features of SJIA include fever, rash, hepatosplenomegaly, lymphadenopathy, polyserositis and arthritis. Treatment with canakinumab resulted in a rapid and sustained improvement of both the articular and the systemic features of SJIA with significant reduction of the number of inflamed joints, prompt resolution of fever and reduction of acute phase reactants in the majority of patients (see Clinical efficacy and safety). Gouty arthritis A gouty arthritis attack is caused by urate (monosodium urate monohydrate) crystals in the joint and surrounding tissue, which trigger resident macrophages to produce IL-1 beta via the “NALP3 inflammasome” complex. Activation of macrophages and concomitant over-production of IL-1 beta results in an acute painful inflammatory response. Other activators of the innate immune system, such as 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 inflammatory markers CRP or SAA and signs of acute inflammation (e.g. pain, swelling, redness) in the affected joint subside rapidly. Clinical efficacy and safety CAPS The efficacy and safety of Ilaris 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 Ilaris 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 Ilaris 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 Ilaris (150 mg or 2 mg/kg every 8 weeks) in patients with CAPS. − Part I: A complete clinical and biomarker response to Ilaris (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 Ilaris 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 Ilaris extension. Table 2 Tabulated summary of efficacy in Phase III trial, pivotal placebo-controlled withdrawal period (Part II)
In the pooled efficacy analysis for these two studies, 65.6% of patients who had not previously been treated with canakinumab achieved complete response at 150 mg or 2 mg/kg, while 85.2% of patients achieved complete response at any dose. Of the patients treated with 600 mg or 8 mg/kg (or even higher), 43.8% achieved complete response. Fewer patients aged 2 to < 4 years achieved complete response (57.1%) than older paediatric and adult patients. Of the patients who had achieved a complete response, 89.3% maintained response without relapsing. Experience from individual patients who achieved a complete response following dose escalation to 600 mg (8 mg/kg) every 8 weeks suggests that a higher dose may be beneficial in patients not achieving 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 more frequently to patients aged 2 to < 4 years and to patients with NOMID/CINCA symptoms compared with FCAS or MWS. Paediatric population The CAPS trials with Ilaris included a total of 69 paediatric patients with an age range from 2 to 17 years (approximately half of them treated on an mg/kg basis). Overall, there were no clinically meaningful differences in the efficacy, safety and tolerability profile of Ilaris in paediatric patients compared to the overall CAPS population. The majority of paediatric patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g. SAA and CRP). SJIA The efficacy of Ilaris for the treatment of active SJIA was assessed in two pivotal studies (G2305 and G2301). Patients enrolled were aged 2 to < 20 years (mean age of 8.5 years and mean disease duration of 3.5 years at baseline) and had active disease defined as ≥ 2 joints with active arthritis, fever and elevated CRP. Study G2305 Study G2305 was a randomised, double-blind, placebo-controlled, 4-week study assessing the short-term efficacy of Ilaris in 84 patients randomised to receive a single dose of 4 mg/kg (up to 300 mg) Ilaris or placebo. The primary objective was the proportion of patients at day 15 who achieved a minimum 30% improvement in the paediatric American College of Rheumatology (ACR) response criterion adapted to include absence of fever. Ilaris treatment improved all paediatric ACR response scores as compared to placebo at days 15 and 29 (Table 3) Table 3 Paediatric ACR response and disease status at days 15 and 29
Study G2301 Study G2301 was a randomised, double-blind, placebo-controlled withdrawal study of flare prevention by Ilaris. The study consisted of two parts with two independent primary endpoints (successful steroid taper and time to flare). In part I (open label) 177 patients were enrolled and received 4 mg/kg (up to 300 mg) Ilaris administered every 4 weeks for up to 32 weeks. Patients in part II (double-blind) received either Ilaris 4 mg/kg or placebo every 4 weeks until 37 flare events occurred. Corticosteroid dose tapering: Of the total 128 patients who entered part I taking corticosteroids, 92 attempted corticosteroid tapering. Fifty-seven (62%) of the 92 patients who attempted to taper were able to successfully taper their corticosteroid dose and 42 (46%) discontinued corticosteroids Time to flare: Patients taking Ilaris in part II had a 64% reduced risk of a flare event as compared to the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75; p=0.0032). Sixty-three of the 100 patients entering part II, whether assigned to placebo or canakinumab, did not experience a flare over the observation period (up to a maximum of 80 weeks). Health-related and quality of life outcomes in studies G2305 and G2301 Treatment with Ilaris resulted in clinically relevant improvements in patients' physical function and quality of life. In study G2305, the Childhood Health Assessment Questionnaire Least Squares means improvement was 0.69 for Ilaris vs placebo representing 3.6 times the minimal clinically 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 Ilaris vs placebo in study G2305 (physical p=0.0012; psychosocial well-being p=0.0017). Pooled Efficacy Analysis Data from the first 12 weeks of Ilaris treatment from studies G2305, G2301 and the extension study were pooled to assess maintenance of efficacy. These data showed similar improvements from baseline to week 12 in the adapted paediatric ACR responses and its components to those observed in the placebo controlled study (G2305). At week 12, the adapted paediatric ACR30, 50, 70, 90 and 100 responses were: 70%, 69%, 61%, 49% and 30%, respectively and 28% of patients had inactive disease (N=178). The efficacy observed in the studies G2305 and G2301 was maintained in the ongoing, open-label long-term extension study (data available through median of 49 weeks of follow-up). In this study, 25 patients who had a strong ACR response for a minimum of 5 months reduced their Ilaris dose to 2 mg/kg every 4 weeks and maintained a paediatric ACR100 response throughout the time the reduced dose was given (median 32 weeks, 8-124 weeks). Although limited, evidence from the clinical trials suggests that patients not responding to tocilizumab or anakinra, may respond to canakinumab. Gouty arthritis The efficacy of Ilaris for the treatment of acute gouty arthritis attacks was demonstrated in two multicentre, randomised, double-blind, active-controlled studies in patients with frequent gouty arthritis (≥ 3 attacks in the previous 12 months) unable to use NSAIDs or colchicine (due to contraindication, intolerance or lack of efficacy). The studies were 12 weeks followed by 12-week double-blind extension. A total of 225 patients were treated with subcutaneous Ilaris 150 mg and 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 the previous 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 Ilaris group and 84 [36.7%] in the triamcinolone acetonide group) had documented inability (intolerance, contraindication or lack of response) to use both NSAIDs and colchicine. Concomitant treatment with ULTs was reported by 42% of patients at entry. The co-primary endpoints were: (i) gouty arthritis pain intensity (visual analogue scale, VAS) at 72 hours post-dose, and (ii) time to first new gouty arthritis attack. For the overall study population, pain intensity was statistically significantly lower for Ilaris 150 mg compared with triamcinolone acetonide at 72 hours. Ilaris also reduced the risk of subsequent attacks (see Table 4). 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 study population with a statistically significant difference compared to triamcinolone acetonide in pain intensity at 72 hours (-10.2 mm, p=0.0208) and in reduction of risk of subsequent attacks (Hazard ratio 0.39, 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 4. Treatment with Ilaris induced a reduction of pain and reduced the risk of subsequent attacks in patients using ULT and unable to use both NSAIDs and colchicine, although the observed treatment difference compared to triamcinolone acetonide was less pronounced than with the overall study population. Table 4 Efficacy for the overall study population and in a subgroup of patients currently using ULT and unable to use both NSAIDs and colchicine
Elderly population Overall, the efficacy, safety and tolerability profile of Ilaris in elderly patients ≥ 65 years of age was comparable to patients < 65 years of age Patients on urate lowering therapy (ULT) In clinical studies, Ilaris has been safely administered with ULT. In the overall study population, patients on ULT had a less pronounced treatment difference in both pain reduction and reduction in the risk of subsequent gouty arthritis attacks compared to patients not on ULT. Immunogenicity Antibodies against Ilaris were observed in approximately 1.5%, 3% and 2% of the patients treated with Ilaris for CAPS, SJIA and gouty arthritis, respectively. No neutralising antibodies were detected. No apparent correlation of antibody development to clinical response or adverse events was observed. This medicinal product has been authorised for CAPS 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. Paediatric population 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) and Juvenile Idiopathic Arthritis (see section 4.2 for information on paediatric use). The European Medicines Agency has waived the obligation to submit the results of studies with Ilaris in all subsets of the paediatric population in gouty arthritis (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties CAPS Absorption The peak serum canakinumab concentration (Cmax) occurred approximately 7 days following single subcutaneous administration of 150 mg in adult CAPS patients. The mean terminal half-life was 26 days. Mean values for Cmax und AUCinf after a single subcutaneous dose of 150 mg in a typical adult CAPS patient (70 kg) were 15.9 µg/ml and 708 µg*d/ml. The absolute bioavailability of subcutaneously administered canakinumab was estimated to be 66%. Exposure parameters (such as AUC and Cmax) 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 600 mg as subcutaneous injection. Predicted steady-state exposure values (Cmin,ss, Cmax,ss, AUC,ss,8w) after 150 mg subcutaneous administration (or 2 mg/kg, respectively) every 8 weeks were slightly higher in the weight category 40-70 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 expected accumulation ratio was 1.3-fold following 6 months of subcutaneous administration of 150 mg canakinumab every 8 weeks. Distribution Canakinumab binds to serum IL-1 beta. The distribution volume (Vss) of canakinumab varied according to body weight. It was estimated to be 6.2 litres in a CAPS patient of body weight 70 kg. Elimination The apparent clearance (CL/F) of canakinumab increases with body weight. It was estimated to be 0.17 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 the pharmacokinetic properties of canakinumab were observed between CAPS and SJIA patients. 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. SJIA Bioavailability in SJIA patients has not been determined independently. Apparent clearance per kg body weight (CL/F per kg) was comparable between the SJIA and CAPS population (0.004 l/d per kg). The apparent volume of distribution per kg (V/F per kg) was 0.14 l/kg. After repeated administration of 4 mg/kg every 4 weeks the accumulation ratio of canakinumab was 1.6 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 years old, respectively. When stratified by weight, a lower (30-40%) median of exposure for Cmin,ss (11.4 vs 19 µg/ml) and AUCss (594 vs 880 µg*d/ml) for the lower bodyweight category (≤ 40 kg) vs the higher bodyweight category (> 40 kg) was observed. Gouty arthritis population Bioavailability in gouty arthritis patients has not been determined independently. Apparent clearance per 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 subcutaneous 150 mg dose (Cmax: 10.8 µg/ml and AUCinf: 495 µg*d/ml) was lower than in a typical 70 kg CAPS patient (15.9 µg/ml and 708 µg*d/ml). This is consistent with the observed increase in CL/F with body weight. The expected accumulation ratio was 1.1-fold following subcutaneous administration of 150 mg canakinumab every 12 weeks. Paediatric population Peak concentrations of canakinumab occurred between 2 to 7 days (Tmax) 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. Based on the population pharmacokinetic modelling analysis, the pharmacokinetics of canakinumab in children aged 2 to < 4 years were similar to those in patients 4 years of age and older. Subcutaneous absorption rate was estimated to decrease with age and appeared 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. Pharmacokinetic properties are similar in CAPS and SJIA paediatric populations. Elderly population No change in pharmacokinetic parameters based on clearance or volume of distribution were observed between elderly patients and adult patients < 65 years of age. 5.3 Preclinical safety data 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. Plasma concentrations that are well tolerated in animals are in excess of at least 42-fold (Cmax) and 78-fold (Cavg) the plasma concentrations in paediatric CAPS patients (body weight 10 kg) treated with clinical doses of canakinumab up to 8 mg/kg subcutaneously every 8 weeks. Plasma concentrations that are well tolerated in animals exceed at least 62-fold (Cmax) and 104-fold (Cavg) the plasma concentrations in paediatric SJIA patients, treated with up to 4 mg/kg via the subcutaneous route every 4 weeks. 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. 6. Pharmaceutical particulars 6.1 List of excipients Sucrose Histidine Histidine hydrochloride monohydrate Polysorbate 80 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years. 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. 6.4 Special precautions for storage 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 after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 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. 6.6 Special precautions for disposal and other handling Ilaris 150 mg powder for solution for injection is supplied in a single-use vial for individual use. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Instructions for reconstitution Using aseptic technique, reconstitute each vial of Ilaris at room temperature (typically 15°C to 25°C) 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. 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. 7. Marketing authorisation holder Novartis Europharm Limited Frimley Business Park Camberley GU16 7SR United Kingdom 8. Marketing authorisation number(s) EU/1/09/564/001-002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 23 October 2009 Date of latest renewal: 26 October 2014 10. Date of revision of the text 10 October 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu |
Ilaris(Canakinumab Injection)人抗白介素-1β单克隆抗体简介:
2013年9月3日,单抗药物Ilaris(canakinumab)已获欧盟委员会(EC)批准,用于2岁及以上活动性全身型幼年特发性关节炎(SJIA)患者的治疗。该药是首个获批用于SJIA的IL-1β抑制剂,同时也是唯一获批专门 ... 责任编辑:admin |
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