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英文药名: Kineret(anakinra for injection) 中文药名: 阿那白滞素注射剂 生产厂家: Amgen Inc
The data described herein reflect an open-label study in 43 NOMID patients exposed to Kineret for up to 60 months adding up to a total exposure of 159.8 patient years. Patients were treated with a starting dose of 1 to 2 mg/kg/day and an average maintenance dose of 3-4 mg/kg/day adjusted depending on the severity of disease. Among pediatric NOMID patients, doses up to 7.6 mg/kg/day have been maintained for up to 15 months. There were 24 serious adverse events (SAEs) reported in 14 of the 43 treated patients. The most common type of SAEs reported were infections [see Warnings and Precautions (5.1)]. Five SAEs were related to lumbar puncture, which was part of the study procedure. There were no permanent discontinuations of study drug treatment due to AEs. Doses were adjusted in 5 patients because of AEs; all were dose increases in connection with disease flares. The reporting frequency of AEs was highest during the first 6 months of treatment. The incidence of AEs did not increase over time, and no new types of AEs emerged. The most commonly reported AEs during the first 6 months of treatment (incidence >10%) were injection site reaction (ISR), headache, vomiting, arthralgia, pyrexia, and nasopharyngitis (Table 2). The most commonly reported AEs during the 60-month study period, calculated as the number of events/patient years of exposure, were arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash. The AE profiles for different age groups <2 years, 2-11 years, and 12-17 years corresponded to the AE profile for patients ≥18 years, with the exception of infections and related symptoms being more frequent in patients <2 years. Infections The reporting rate for infections was higher during the first 6 months of treatment (2.3 infections/patient-year) compared to after the first 6 months (1.7 infections/patient year). The most common infections were upper respiratory tract infection, sinusitis, ear infections, and nasopharyngitis. There were no deaths or permanent treatment discontinuations due to infections. In one patient Kineret administration was temporarily stopped during an infection and in 5 patients the dose of Kineret was increased due to disease flares in connection with infections. Thirteen infections in 7 patients were classified as serious, the most common being pneumonia and gastroenteritis occurring in 3 and 2 patients, respectively. No serious opportunistic infections were reported. The reporting frequency for infections was highest in patients <12 years of age. Hematologic Events After start of Kineret treatment neutropenia was reported in 2 patients. One of these patients experienced an upper respiratory tract infection and an otitis media infection. Both episodes of neutropenia resolved over time with continued Kineret treatment. Injection Site Reactions In total, 17 injection site reactions (ISRs) were reported in 10 patients during the 60-month study period. Out of the 17 ISRs, 11 (65%) occurred during the first month and 13 (76%) were reported during the first 6 months. No ISR was reported after Year 2 of treatment. The majority of ISRs were reported as mild (76% mild, 24% moderate). No patient permanently or temporarily discontinued Kineret treatment due to injection site reactions. Immunogenicity The immunogenicity of Kineret in NOMID patients was not evaluated. Table 2. Most common (>10% of patients) treatment-emergent adverse events during the first 6 months of Kineret treatment
6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Kineret. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepato-biliary disorders: elevations of transaminases, non-infectious hepatitis 7 DRUG INTERACTIONS No drug-drug interaction studies in human subjects have been conducted. Toxicologic and toxicokinetic studies in rats did not demonstrate any alterations in the clearance or toxicologic profile of either methotrexate or Kineret when the two agents were administered together. 7.1 TNF Blocking Agents A higher rate of serious infections has been observed in patients treated with concurrent Kineret and etanercept therapy than in patients treated with etanercept alone [see Warnings and Precautions (5.2)]. Two percent of patients treated concurrently with Kineret and etanercept developed neutropenia (ANC < 1 x 109/L). Use of Kineret in combination with TNF blocking agents is not recommended. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects: Pregnancy Category B: There are no adequate and well-controlled studies of Kineret in pregnant women. Reproductive studies have been performed in rats and rabbits at doses up to 25 times the maximum recommended human dose (on a mg/kg basis at a maternal dose of 200 mg/kg/day) and have revealed no evidence of impaired fertility or harm to the fetus due to Kineret. Because animal reproduction studies are not always predictive of human response, Kineret should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether Kineret is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised if Kineret is administered to nursing women. 8.4 Pediatric Use The NOMID study included 36 pediatric patients: 13 below 2 years, 18 between 2 and 11 years, and 5 between 12 and 17 years of age. A subcutaneous Kineret starting dose of 1–2 mg/kg/day was administered in all age groups. An average maintenance dose of 3–4 mg/kg/day was adequate to maintain clinical response throughout the study irrespective of age but a higher dose was, on occasion, required in severely affected patients. The prefilled syringe does not allow doses lower than 20 mg to be administered. Kineret was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA; ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Kineret for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Kineret is not recommended for pediatric use in Juvenile Rheumatoid Arthritis. 8.5 Geriatric Use A total of 752 RA patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, were studied in clinical trials. No differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 8.6 Renal Impairment This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in patients with hepatic impairment. 10 OVERDOSAGE There have been no cases of overdose reported with Kineret in clinical trials of RA or NOMID. In sepsis trials no serious toxicities attributed to Kineret were seen when administered at mean calculated doses of up to 35 times those given patients with RA over a 72-hour treatment period. 11 DESCRIPTION Kineret (anakinra) is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus. Kineret consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA technology using an E coli bacterial expression system. Kineret is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, clear, colorless-to-white, preservative free solution for daily subcutaneous (SC) administration. The solution may contain trace amounts of small, translucent-to-white amorphous proteinaceous particles. Each prefilled glass syringe contains: 0.67 mL (100 mg) of anakinra in a solution (pH 6.5) containing disodium EDTA (0.12 mg), sodium chloride (5.48 mg), anhydrous citric acid (1.29 mg), and polysorbate 80 (0.70 mg) in Water for Injection, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Kineret blocks the biologic activity of IL-1 alpha and beta by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs. IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from RA patients are not sufficient to compete with the elevated amount of locally produced IL-1. Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID. 12.3 Pharmacokinetics The absolute bioavailability of Kineret after a 70 mg subcutaneous bolus injection in healthy subjects (n = 11) is 95%. In subjects with RA, maximum plasma concentrations of Kineret occurred 3 to 7 hours after subcutaneous administration of Kineret at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of Kineret was observed after daily subcutaneous doses for up to 24 weeks. The influence of demographic covariates on the pharmacokinetics of Kineret was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous injection of Kineret at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated Kineret clearance increased with increasing creatinine clearance and body weight. After adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance. In NOMID patients, at a median SC dose of 3 mg/kg once daily and a median treatment time of 3.5 years, the median (range) steady-state serum exposure of anakinra was Cmax 3628 (655–8511) ng/mL (n=16) and C24h 203 (53–1979) ng/mL (n=16). The median (range) half-life of anakinra was 5.7 (3.1–28.2) hours (n=12). There was no obvious gender difference. Patients With Renal Impairment: The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance < 30 mL/min1), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of Kineret was removed by hemodialysis or continuous ambulatory peritoneal dialysis. Based on these observations, a dose schedule change should be considered for subjects with severe renal insufficiency or end stage renal disease [see Dosage and Administration (2.2)]. Patients with Hepatic Dysfunction: No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in patients with hepatic impairment. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies to evaluate the carcinogenic potential of Kineret were not conducted. Using a standard in vivo and in vitro battery of mutagenesis assays, Kineret did not induce gene mutations in either bacteria or mammalian cells. Kineret had no effects on fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (approximately 25 times the maximum recommended dose). 14 CLINICAL STUDIES 14.1 Clinical Studies in RA The safety and efficacy of Kineret have been evaluated in three randomized, double-blind, placebo-controlled trials of 1790 patients ≥ 18 years of age with active rheumatoid arthritis (RA). An additional fourth study was conducted to assess safety. In the efficacy trials, Kineret was studied in combination with other disease-modifying antirheumatic drugs (DMARDs) other than Tumor Necrosis Factor (TNF) blocking agents (Studies 1 and 2) or as a monotherapy (Study 3). Study 1 involved 899 patients with active RA who had been on a stable dose of methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks. All patients had at least 6 swollen/painful and 9 tender joints and either a C-reactive protein (CRP) of ≥ 1.5 mg/dL or an erythrocyte sedimentation rate (ESR) of ≥ 28 mm/hr. Patients were randomized to Kineret or placebo in addition to their stable doses of MTX. The first 501 patients were evaluated for signs and symptoms of active RA. The total 899 patients were evaluated for progression of structural damage. Study 2 evaluated 419 patients with active RA who had received MTX for at least 6 months including a stable dose (15 to 25 mg/week) for at least 3 consecutive months prior to enrollment. Patients were randomized to receive placebo or one of five doses of Kineret subcutaneous daily for 12 to 24 weeks in addition to their stable doses of MTX. Study 3 evaluated 472 patients with active RA and had similar inclusion criteria to Study 1 except that these patients had received no DMARD for the previous 6 weeks or during the study. Patients were randomized to receive either Kineret or placebo. Patients were DMARD-naïve or had failed no more than 3 DMARDs. Study 4 was a placebo-controlled, randomized trial designed to assess the safety of Kineret in 1414 patients receiving a variety of concurrent medications for their RA including some DMARD therapies, as well as patients who were DMARD-free. The TNF blocking agents etanercept and infliximab were specifically excluded. Concurrent DMARDs included MTX, sulfasalazine, hydroxychloroquine, gold, penicillamine, leflunomide, and azathioprine. Unlike Studies 1, 2 and 3, patients predisposed to infection due to a history of underlying disease such as pneumonia, asthma, controlled diabetes, and chronic obstructive pulmonary disease (COPD) were also enrolled [see Adverse Reactions (6)]. In Studies 1, 2 and 3, the improvement in signs and symptoms of RA was assessed using the American College of Rheumatology (ACR) response criteria (ACR20, ACR50, ACR70). In these studies, patients treated with Kineret were more likely to achieve an ACR20 or higher magnitude of response (ACR50 and ACR70) than patients treated with placebo (Table 3). The treatment response rates did not differ based on gender or ethnic group. The results of the ACR component scores in Study 1 are shown in Table 4. Most clinical responses, both in patients receiving placebo and patients receiving Kineret, occurred within 12 weeks of enrollment. Table 3: Percent of Patients with ACR Responses in Studies 1 and 3
b p < 0.01, Kineret versus placebo c p < 0.001, Kineret versus placebo Table 4: Median ACR Component Scores in Study 1
b Visual analog scale; 0 = best, 100 = worst c Scale 0 to 68 d Scale 0 to 66 A 24-week study was conducted in 242 patients with active RA on background methotrexate who were randomized to receive either etanercept alone or the combination of Kineret and etanercept. The ACR50 response rate was 31% for patients treated with the combination of Kineret and etanercept and 41% for patients treated with etanercept alone, indicating no added clinical benefit of the combination over etanercept alone. Serious infections were increased with the combination compared to etanercept alone [see Warnings and Precautions (5.1)]. In Study 1, the effect of Kineret on the progression of structural damage was assessed by measuring the change from baseline at month 12 in the Total Modified Sharp Score (TSS) and its subcomponents, erosion score, and joint space narrowing (JSN) score.2 Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months and 12 months and scored by readers who were unaware of treatment group. A difference between placebo and Kineret for change in TSS, erosion score (ES) and JSN score was observed at 12 months (Table 5). Table 5: Mean Radiographic Changes Over 12 Months in Study 1
** Based on Wilcoxon rank-sum test The disability index of the Health Assessment Questionnaire (HAQ) was administered monthly for the first six months and quarterly thereafter during Study 1. Health outcomes were assessed by the Short Form-36 (SF-36) questionnaire. The 1-year data on HAQ in Study 1 showed more improvement with Kineret than placebo. The physical component summary (PCS) score of the SF-36 also showed more improvement with Kineret than placebo but not the mental component summary (MCS). 14.2 Clinical Studies in NOMID The efficacy of Kineret was evaluated in a prospective, long-term, open-label and uncontrolled study which incorporated a withdrawal period in a subset of 11 patients. This study included 43 NOMID patients 0.7 to 46 years of age treated for up to 60 months. Patients were given an initial Kineret dose of 1–2.4 mg/kg body weight. During the study, the dose was adjusted by 0.5 to 1 mg/kg increments to a protocol-specified maximum of 10 mg/kg daily, titrated to control signs and symptoms of disease. The maximum dose actually studied was 7.6 mg/kg/day. The average maintenance dose was 3 to 4 mg/kg daily. In general, the dose was given once daily, but for some patients, the dose was split into twice daily administrations for better control of disease activity. NOMID symptoms were assessed with a disease-specific Diary Symptom Sum Score (DSSS), which included the prominent disease symptoms fever, rash, joint pain, vomiting, and headache. In addition, serum amyloid A (SAA), hsCRP, and ESR levels were monitored. Changes in clinical and laboratory parameters from baseline to Months 3 to 6 and from Month 3 (before withdrawal) to the end of the withdrawal period were assessed in the subset of patients who underwent withdrawal. The estimated changes from baseline in DSSS are summarized through Month 60 in Table 6. Results were consistent across all subgroups, including age, gender, presence of CIAS1 mutation, and disease phenotype. Improvements occurred in all individual disease symptoms comprising the DSSS (Table 7), as well as in the serum markers of inflammation. For the 11 patients who went through a withdrawal phase, disease symptoms and serum markers of inflammation worsened after withdrawal and promptly responded to reinstitution of Kineret therapy. Upon withdrawal of treatment, the median time until disease flare criteria were met was 5 days. Table 6. Estimated change from baseline in DSSS in NOMID patients (N=29)
*Mean (SD) seline value was 4.5 (3.2) Table 7. Individual diary key symptom scores by visit (ITT diary population)
Kineret treatment also appeared to be associated with improvement of, or stability in, assessments of other NOMID disease manifestations, such as CNS, audiogram, and visual acuity data, up to Month 60. 15 REFERENCES 1.Cockcroft DW and Gault HM. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41. 2.Sharp JT, Young DY, Bluhm GB, et al. How many joints in the hands and wrists should be included in a score of radiologic abnormalities used to assess rheumatoid arthritis? Arthritis Rheum. 1985; 28:1326-1335. 3.National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 11 Registries, 1992-1999. Close 16 HOW SUPPLIED/STORAGE AND HANDLING Kineret is supplied in single-use preservative free, prefilled glass syringes with 27 gauge needles. Each prefilled glass syringe contains 100 mg of anakinra per 0.67 mL. The full syringe contains 100 mg anakinra. Kineret is dispensed in a 4 x 7 syringe dispensing pack containing 28 syringes (NDC 66658-234-28). Kineret is also dispensed in a 1 x 7 syringe dispensing pack containing 7 syringes (NDC 66658-234-07). Storage Kineret should be stored in the refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE OR SHAKE. Protect from light. Rx only 17 PATIENT COUNSELING INFORMATION Instruct patients and their caregivers on the proper dosage and administration of Kineret and provide all patients with the “Patient information and Instructions for Use” insert. While this Patient Information and Instructions for Use provides information about the product and its use, it is not intended to take the place of regular discussions between the patient and healthcare provider. The ability to inject subcutaneously should be assessed to ensure proper administration of Kineret. The prefilled syringe contains an outer rigid plastic needle shield attached to a grey inner needle cover. Inform patients and their caregivers that the inner needle cover contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex. Thoroughly instruct patients and their caregivers on the importance of proper disposal and caution against the reuse of needles, syringes, and drug product. A puncture-resistant container for the disposal of used syringes should be available to the patient. The full container should be disposed of according to the directions provided by the healthcare provider. Infections: Inform patients that Kineret may lower the ability of their immune system to fight infections. Advise patients of the importance of contacting their doctor if they develop any symptoms of infection. Injection-site reactions: Physicians should explain to patients that almost a quarter of patients in the clinical trial experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, purities, brusing, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Inform patients or their caregivers that the prefilled syringe should be removed from refrigeration and left at room temperature for 30 minutes before injecting. Patients 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. Allergic or other drug reactions: Inform patients about the signs and symptoms of allergic and other adverse drug reactions and the appropriate actions they should take if they experience any of these signs and symptoms. --------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: KINERET 100mg/0.67mL/SYRINGE 28DISP SYRINGES/box 原产地英文药品名: ANAKINRA 中文参考商品译名: KINERET 100毫克/0.67毫升/注射器 28注射器/盒 中文参考药品译名: 阿那白滞素 中文参考化合物名称: 白细胞介素-1的受体拮抗剂 生产厂家中文参考译名: 安进 生产厂家英文名: Amgen | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
