当前位置：药品说明书与价格首页 >> 免疫系统 >> 新药推荐 >> Kineret(Anakinra，阿那白滞素注射剂)

Kineret(Anakinra，阿那白滞素注射剂)

2012-03-09 12:31:51 作者：新特药房来源：中国新特药网天津分站浏览次数：946 文字大小：【大】【中】【小】

简介： 英文药名: Kineret (Anakinra) 中文药名: 阿那白滞素注射剂生产厂家: Amgen Inc 药品说明类风湿性关节炎治疗药阿那白滞素（anakinra）商品名: Kineret 结构特点: 本品为重组、非糖基化的人白介素 ...

关键字：Kineret(Anakinra 阿那白滞素注射剂)

英文药名: Kineret (Anakinra)

中文药名: 阿那白滞素注射剂

生产厂家: Amgen Inc

药品说明

类风湿性关节炎治疗药阿那白滞素（anakinra）
商品名: Kineret
结构特点: 本品为重组、非糖基化的人白介素-1受体拮抗剂（IL-1Ra），与天然人IL-1Ra的不同之处在于其N-末端增加了一个蛋氨酸残基。本品由153个氨基酸组成，分子量为17.3kDa。本品采用大肠杆菌表达系统生产。
开发厂商: 美国安进公司研制开发，2001年11月首次在美国上市。　

适应症:
适用于对1个或多个缓解病症的抗风湿性药物（DMARD）治疗无效的18岁及以上中重度活动性类风湿性关节炎（RA）患者，以减轻体征和症状。

药理:
本品竞争性地抑帛IL-1与IL-1Ⅰ型受体（IL-1Rl）相结合，从而阻滞在多个组织和器官中表达的IL-1的生物活性。
炎症刺激诱导IL-1产生，后者可调节各种生理反应包括炎症反应和免疫应答。IL-1具有广泛活性，包括通过诱导蛋白多糖书刊号衰减而降解软骨以及刺激骨吸收。类风湿性关节炎（RA）患者滑膜和滑液中天然产生的IL-1Ra水平不足以对抗局部产生的IL-1量的增加。
11例健康志愿者接受本品70mg，大剂量皮下注射，绝对生物利用度为95%。18例RA患者接受本品临床相关剂量（1-2mg/kg）皮下注射后3-7小时达血药峰值，终末t1-2为4-6小时。RA患者每日接受本品皮下注射，用药24周，未见药物蓄积。
341例患者一日接受本品30、75和150mg，皮下注射，用药24周，药动学分析显示本品的清除率随肌酐清除率升高和体重增加而升高，性别和年龄对平均血浆清除率无显著影响。在严重或末期肾病患者（肌酐清除率低于30ml/min）中，本品的平均血浆清除率下降70％-75％。
在大鼠中进行的毒理学和毒理动力学试验显示本品与甲氨蝶呤合用未见两药清除率或毒理学性质的改变。

临床评价:
在2932例患者中进行了随机双盲安慰剂对照临床研究，为期13周的研究结果显示，本品减轻了大多数患者的炎症和疼痛。
一项疗效研究中，501例患者在接受甲氨蝶呤的基础上随机加用本品或安慰剂治疗。6个月时，本品组达到美国风湿病学会评分中的20％改善（ACR20）的患者为38％，而安慰剂组为22%（P＜0.001）。
一项随机双盲多中心研究中472例患者随机静脉注射本品30、75、150mg或安慰剂，一日1次，连用6-24个月。24周时，本品组健康评价调查表评分下降0.24，安慰剂组下降0.03。在75％的基础骨侵蚀患者中，本品150mg，24周组，31％的患者的进行性关节损害停止，而安慰剂组为16%。研究结束时，本品组14%的患者能够工作和进行日常家务活动，而安慰剂组为6%。
在一项包括419例RA患者的双盲安慰剂对照Ⅱ期临床研究中，接受本品加上1mg/kg甲氨蝶呤皮下注射的患者临床有效率为46％，而单用甲氨蝶呤者为23%。

不良反应:
最常见的不良反应为注射部位反应，通常为轻至中度，表现为发红、肿胀和疼痛。
与安慰剂组相比，本品组严重感染的危险（2%对＜1%）增加。因此，如果患者发生严重感染，应停用本品。
其它不良反应（发生率≥5%且高于安慰剂组）有头痛、恶心、腹泻、鼻窦炎、流感样症状和腹痛。

注意事项:
对大肠杆菌衍生蛋白、本品及其制剂成分过敏者，发生感染的患者禁用。怀孕、哺乳期女、老年人、肾功能不全者慎用。
初步数据显示与单用相比，本品与依那西普（etanercept）合用引起的严重感染和中性粒细胞减少症的发生率较高（分别为7%和3%）。应尽量避免本品与肿瘤坏死因子（TNF）阻断剂合用。
本品可干扰患者对新的抗原如疫苗的正常免疫反应，因此使用本品时接种疫苗无效。

用法用量:
推荐剂量为100mg，一日1次，皮下注射时，在每天的同一时间给药。
可单用或除TNF阻断剂外的DMARD合用。

制剂: 每毫升含本品0.67ml（100mg）。
本品规格有7支包装。

KINERET (anakinra) injection, solution
[Swedish Orphan Biovitrum AB (publ)]

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Kineret safely and effectively. See full prescribing information for Kineret.

Kineret® (anakinra)
For injection, for subcutaneous use
Initial U.S. Approval: 2001

RECENT MAJOR CHANGES

INDICATIONS AND USAGE
Kineret is an interleukin-1 receptor antagonist indicated for reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs) (1)

DOSAGE AND ADMINISTRATION
The recommended dose of Kineret for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. The dose should be administered at approximately the same time every day (2.1)
Physicians should consider a dose of 100 mg of Kineret administered every other day for RA patients who have severe renal insufficiency or end stage renal disease (defined as creatinine clearance < 30 mL/min, as estimated from serum creatinine levels) (2.2)
See full prescribing information for administration instructions (2.3)

DOSAGE FORMS AND STRENGTHS
100 mg/0.67 mL solution for subcutaneous injection (3)

CONTRAINDICATIONS
Known hypersensitivity to E coli-derived proteins, Kineret, or to any component of the product. (4)

WARNINGS AND PRECAUTIONS
Discontinue use if serious infection develops and do not initiate therapy in patients with active infections (5.1)
Use in combination with Tumor Necrosis Factor (TNF) blocking agents is not recommended (5.2)
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported (5.3)
The impact of treatment with Kineret on active and/or chronic infections and the development of malignancies is not known (5.4)
Live vaccines should not be given concurrently with Kineret (5.5)
Neutrophil counts should be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly for 3 months, and thereafter quarterly for a period up to 1 year (5.6)

ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 5%) are injection site reaction, worsening of rheumatoid arthritis, upper respiratory tract infection, headache, nausea, diarrhea, sinusitis, arthralgia, flu like-symptoms, and abdominal pain (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact 1-866-773-5274, FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
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. Use of Kineret in combination with TNF blocking agents is not recommended (7)

USE IN SPECIFIC POPULATIONS
Pediatric use: Not recommended because the prefilled syringes do not permit accurate dosing lower than 100 mg and efficacy could not be demonstrated due to low trial enrollment (8.4)
Geriatric use: Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly (8.5)
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 (8.6)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 09/2011

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Active Rheumatoid Arthritis

Kineret is indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents [see Warnings and Precautions (5.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Active Rheumatoid Arthritis

The recommended dose of Kineret for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day.

2.2 Renal Impairment

Physicians should consider a dose of 100 mg of Kineret administered every other day for RA patients who have severe renal insufficiency or end stage renal disease (defined as creatinine clearance < 30 mL/min, as estimated from serum creatinine levels) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Administration

Instructions on appropriate use should be given by the healthcare provider to the patient or caregiver. Patients or caregivers should not be allowed to administer Kineret until the patient or caregiver has demonstrated a thorough understanding of procedures and an ability to inject the product. After administration of Kineret, it is essential to follow the proper procedure for disposal of syringes and needles. See the “Information for Patients” insert for detailed instructions on the handling and injection of Kineret.

Do not use Kineret beyond the expiration date shown on the carton. Visually inspect the solution for particulate matter and discoloration before administration. There may be trace amounts of small, translucent-to-white amorphous particles of protein in the solution. The prefilled syringe should not be used if the solution is discolored or cloudy, or if foreign particulate matter is present. If the number of translucent-to-white amorphous particles in a given syringe appears excessive, do not use this syringe.

Administer only one dose (the entire contents of one prefilled glass syringe) per day. Discard any unused portions.

3 DOSAGE FORMS AND STRENGTHS

100 mg/0.67 mL solution for subcutaneous injection.

4 CONTRAINDICATIONS

Kineret is contraindicated in patients with known hypersensitivity to E coli-derived proteins, Kineret, or any components of the product [see section Hypersensitivity Reactions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Serious Infections

Kineret has been associated with an increased incidence of serious infections (2%) vs. Placebo (< 1%) in clinical trials. Administration of Kineret should be discontinued if a patient develops a serious infection. Treatment with Kineret should not be initiated in patients with active infections. The safety and efficacy of Kineret in immunosuppressed patients or in patients with chronic infections have not been evaluated.

5.2 Use With TNF Blocking Agents

In a 24-week study of concurrent Kineret and etanercept therapy, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). The combination of Kineret and etanercept did not result in higher ACR response rates compared to etanercept alone [see Clinical Studies (14)]. Use of Kineret in combination with TNF blocking agents is not recommended.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with Kineret. If a severe hypersensitivity reaction occurs, administration of Kineret should be discontinued and appropriate therapy initiated.

The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.

5.4 Immunosuppression

The impact of treatment with Kineret on active and/or chronic infections and the development of malignancies is not known [see Adverse Reactions (6)].

5.5 Immunizations

In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret and placebo treatment groups when the tetanus/diphtheria toxoids vaccine was administered concurrently with Kineret. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be given concurrently with Kineret.

5.6 Neutrophil Count

Patients receiving Kineret may experience a decrease in neutrophil counts. In the placebo-controlled studies, 8% of patients receiving Kineret had decreases in neutrophil counts of at least one World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Nine Kineret-treated patients (0.4%) experienced neutropenia (ANC < 1 x 109/L). This is discussed in more detail in the Adverse Reactions (6): Hematologic Events section. Neutrophil counts should be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly for 3 months, and thereafter quarterly for a period up to 1 year.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

The most serious adverse reactions were:

Serious Infections – [see Warnings and Precautions (5.1)]
Neutropenia, particularly when used in combination with TNF blocking agents

The most common adverse reaction with Kineret is injection-site reactions. These reactions were the most common reason for withdrawing from studies.

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The data described herein reflect exposure to Kineret in 3025 patients, including 2124 exposed for at least 6 months and 884 exposed for at least one year. Studies 1 and 4 [see Clinical Studies (14)] used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis.

Injection-site Reactions:

The most common and consistently reported treatment related adverse event associated with Kineret is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain.

Infections:

In Studies 1 and 4 combined, the incidence of infection was 39% in the Kineret-treated patients and 37% in placebo-treated patients during the first 6 months of blinded treatment. The incidence of serious infections in Studies 1 and 4 was 2% in Kineret-treated patients and 1% in patients receiving placebo over 6 months. The incidence of serious infection over 1 year was 3% in Kineret-treated patients and 2% in patients receiving placebo. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Majority of patients (73%) continued on study drug after the infection resolved. No serious opportunistic infections were reported. Patients with asthma appeared to be at higher risk of developing serious infections when treated with Kineret (8 of 177 patients, 4.5%) compared to placebo (0 of 50 patients, 0%).

In open-label extension studies, the overall rate of serious infections was stable over time and comparable to that observed in controlled trials. In clinical studies and postmarketing experience, cases of opportunistic infections have been observed and included fungal, mycobacterial and bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret alone or in combination with immunosuppressive agents.

In patients who received both Kineret and etanercept for up to 24 weeks, the incidence of serious infections was 7%. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure.

Malignancies:

Among 5300 RA patients treated with Kineret in clinical trials for a mean of 15 months (approximately 6400 patient years of treatment), 8 lymphomas were observed for a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population, based on the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database.9 An increased rate of lymphoma, up to several fold, has been reported in the RA population, and may be further increased in patients with more severe disease activity. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common were breast, respiratory system, and digestive system. There were 3 melanomas observed in Study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known. While patients with RA, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of IL-1 blockers in the development of malignancy is not known.

Hematologic Events:

In placebo-controlled studies with Kineret, 8% of patients receiving Kineret had decreases in total white blood counts of at least one WHO toxicity grade, compared with 2% of placebo patients. Nine Kineret-treated patients (0.4%) developed neutropenia (ANC < 1 x 109/L). 9 % of patients receiving Kineret had increases in eosinophil differential percentage of at least one WHO toxicity grade, compared with 3 % of placebo patients. Of patients treated concurrently with Kineret and etanercept 2% developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy. 2% of patients receiving Kineret had decreases in platelets, all of WHO toxicity grade one, compared to 0% of placebo patients.

Hypersensitivity Reactions:

Hypersensitivity reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported with Kineret.

Immunogenicity:

In Studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positively at one or more timepoints for anti-anakinra antibodies in a highly sensitive, anakinra-binding biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) were seropositive in a cell-based bioassay for antibodies capable of neutralizing the biologic effects of Kineret. Of the 13 patients with available follow-up data, 5 patients remained positive for neutralizing antibodies at the end of the studies. No correlation between antibody development and adverse events was observed.

Antibody assay results are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kineret with the incidence of antibodies to other products may be misleading.

Other Adverse Events:

Table 1 reflects adverse events in Studies 1 and 4, that occurred with a frequency of ≥ 5% in Kineret-treated patients over a 6-month period.

Table 1: Percent of RA Patients Reporting Adverse Events (Studies 1 and 4)
	Placebo	Kineret 100 mg/day
Preferred term	(n = 733)	(n = 1565)

Injection Site Reaction	29%	71%
Worsening of RA	29%	19%
Upper Respiratory Tract Infections	17%	14%
Headache	9%	12%
Nausea	7%	8%
Diarrhea	5%	7%
Sinusitis	7%	7%
Arthralgia	6%	6%
Flu Like Symptoms	6%	6%
Abdominal Pain	5%	5%

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.

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

Pregnancy Category B: Reproductive studies have been conducted with Kineret on rats and rabbits at doses up to 100 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. 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

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 the prefilled syringes do not permit accurate dosing lower than 100 mg. Therefore, Kineret is not recommended for pediatric use.

8.5 Geriatric Use

A total of 752 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 rheumatoid arthritis patients with hepatic impairment.

10 OVERDOSAGE

There have been no cases of overdose reported with Kineret in clinical trials of RA. 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), sodium citrate (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 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL 1RI) 1, which is expressed in a wide variety of tissues and organs.10

IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses.10 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.2 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-1.3,4,5

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.

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/min6), 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 rheumatoid arthritis patients with hepatic impairment.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Kineret has not been evaluated for its carcinogenic potential in animals. Using a standard in vivo and in vitro battery of mutagenesis assays, Kineret did not induce gene mutations in either bacteria or mammalian cells. In rats and rabbits, Kineret at doses of up to 100-fold greater than the human dose had no adverse effects on male or female fertility.

14 CLINICAL STUDIES

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.7 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 2). 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 3.

Most clinical responses, both in patients receiving placebo and patients receiving Kineret, occurred within 12 weeks of enrollment.

Table 2: Percent of Patients with ACR Responses in Studies 1 and 3
a p < 0.05, Kineret versus placebo
b p < 0.01, Kineret versus placebo
c p < 0.001, Kineret versus placebo
	Study 1 (Patients on MTX)		Study 3 (No DMARDs)
				Kineret
Response	Placebo (n = 251)	Kineret 100 mg/day (n = 250)	Placebo (n = 119)	75 mg/day (n = 115)	150 mg/day (n = 115)
ACR20
Month 3	24%	34%a	23%	33%	33%
Month 6	22%	38%c	27%	34%	43%a
ACR50
Month 3	6%	13%b	5%	10%	8%
Month 6	8%	17%b	8%	11%	19%a
ACR70
Month 3	0%	3%a	0%	0%	0%
Month 6	2%	6%a	1%	1%	1%

Table 3: Median ACR Component Scores in Study 1
a Health Assessment Questionnaire; 0 = best, 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
b Visual analog scale; 0 = best, 100 = worst
c Scale 0 to 68
d Scale 0 to 66
		Placebo/MTX		Kineret/MTX 100 mg/day
		(n = 251)		(n = 250)
Parameter (median)		Baseline	Month 6	Baseline	Month 6

Patient Reported Outcomes
	Disability indexa	1.38	1.13	1.38	1.00
	Patient global assessmentb	51.0	41.0	51.0	29.0
	Painb	56.0	44.0	63.0	34.0
Objective Measures
	ESR (mm/hr)	35.0	32.0	36.0	19.0
	CRP (mg/dL)	2.2	1.6	2.2	0.5
Physician's Assessments
	Tender/painful jointsc	20.0	11.0	23.0	9.0
	Physician global assessmentb	59.0	31.0	59.0	26.0
	Swollen jointsd	18.0	10.5	17.0	9.0

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.8 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 4).

Table 4: Mean Radiographic Changes Over 12 Months in Study 1
* Differences and 95% confidence intervals for the differences in change scores between Placebo/MTX and Kineret/MTX
** Based on Wilcoxon rank-sum test
	Placebo/MTX (N = 450)		Kineret 100 mg/day /MTX (N = 449)		Placebo/MTX vs. Kineret/MTX
	Baseline	Change at Month 12	Baseline	Change at Month 12	95% Confidence Interval*	p-value**
TSS	52	2.6	50	1.7	0.9 [0.3, 1.6]	< 0.001
Erosion	28	1.6	25	1.1	0.5 [0.1, 1.0]	0.024
JSN	24	1.1	25	0.7	0.4 [0.1, 0.7]	< 0.001

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).

15 REFERENCES

Hannum CH, Wilcox CJ, Arend WP, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990; 343:336-40.
Van Lent PLEM, Fons AJ, Van De Loo AEM, et al, Major role for interleukin-1 but not for tumor necrosis factor in early cartilage damage in immune complex in mice. J Rheumatol. 1995; 22:2250–2258.
Deleuran BW, Shu CQ, Field M, et al. Localization of interleukin-1 alpha, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis. Br J Rheumatol. 1992; 31:801-809.
Chomarat P, Vannier E, Dechanet J, et al. Balance of IL-1 receptor antagonist/IL-1B in rheumatoid synovium and its regulation by IL-4 and IL-10. J Immunol. 1995; 1432-1439.
Firestein GS, Boyle DL, Yu C, et al. Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum. 1994; 37:644-652.
Cockcroft DW and Gault HM. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41.
Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998; 41:2196-2204.
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.
National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 11 Registries, 1992-1999.
Dinarello CA. Biologic Basis for Interleukin-1 in Disease. Blood 1996; 87:2095-2147.

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. 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 “Information for Patients” insert. While this “Information for Patients” insert 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.

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. 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. Inform patients and their caregivers that the needle cover on the prefilled syringe 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 cautioned 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.

sobi
SWEDISH ORPHAN BIOVITRUM

Manufactured by:
Swedish Orphan Biovitrum AB (publ)
SE-112 76 Stockholm, Sweden
U.S. License No. 1859

Certain manufacturing operations have been performed by other firms.

The product, its production and/or its use may be covered by one or more US Patents, including US Patent Nos. 6,599,873, 6,858,409 and 5,075,222 as well as other patents or patents pending.

3XXXXXX – v13

Patient Information
Kineret®(KIN-eh-ret)
(anakinra)

Read the patient information that comes with Kineret 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 healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Kineret?

Kineret is a medicine that affects your immune system. Kineret can lower the ability of your immune system to fight infections. Serious infections have happened in patients taking Kineret. Taking Kineret may give you a higher chance for getting an infection or make any infection you have worse. You should not start taking Kineret if you have any kind of infection unless your doctor says it is okay.

Before starting Kineret, tell your healthcare provider if you:

think you have an infection
are being treated for an infection
have signs of infection such as fever, chills, or have any open sores on your body
have asthma. Patients with asthma may have a higher risk of getting an infection if they take Kineret.
get a lot of infections or have infections that keep coming back
take other medicines that affect your immune system

If you take other medicines that affect the immune system, such as ENBREL®(etanercept), Humira®(adalimumab), or Remicade®(infliximab) while you are taking Kineret, you could also have an increased risk for getting a serious infection. It is recommended that you do not take these medications (Tumor Necrosis Factor or TNF blocking agents) while taking Kineret.

What is Kineret?

Kineret is an interleukin-1 receptor antagonist (IL-1ra). Kineret is used to reduce the signs and symptoms, and slow down damage to your bones and joints that happens in patients with moderate to severe active Rhematoid Arthritis (RA), but it can also lead to serious side effects because of the effects on your immune system. See “What is the most important information I should know about Kineret?” and “What are the possible side effects with Kineret?”

Kineret is only for adults who have taken other medicines for their RA that have not worked. Kineret can be taken alone or along with other RA medicines except for TNF blocking agents.

Who should not take Kineret?

Do not take Kineret if you have an allergy to:

proteins made from bacterial cells (E coli). Ask your healthcare provider if you are not sure.
any of the ingredients in Kineret. See the end of this leaflet for a complete list of ingredients in Kineret.

What should I tell my healthcare provider before taking Kineret?

Kineret may not be right for you. Tell your healthcare provider about all of your medical conditions, including if you:

have an infection, a history of infections that keep coming back or other conditions that can increase your risk of infections. See “What is the most important information I should know about Kineret?”
have an allergy to rubber or latex. The needle cover on the prefilled syringe contains latex. Do not handle the needle cover if you are allergic to latex.
have kidney problems
are scheduled to receive any vaccines. Patients taking Kineret should not receive live vaccines.

Tell your healthcare provider if you are pregnant, plan to become pregnant, or breastfeeding. Kineret has not been studied in pregnant or nursing women. Kineret should be used during a pregnancy only if needed. It is not known if Kineret will pass into your breast milk. Discuss treatment options with your doctor if you plan on breastfeeding.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Tell your healthcare provider if you take other medicines that affect your immune system. Especially, tell your doctor if you use: ENBREL® (etanercept), Humira® (adalimumab), or Remicade® (infliximab).

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new prescription.

How should I take Kineret?

Kineret is taken by injection under the skin. Your healthcare provider should instruct you on how to inject, how often to inject Kineret, and the correct way to dispose of used syringes.
Take Kineret exactly as your healthcare provider tells you to
If you have a kidney problem your healthcare provider may need to change how often you take your Kineret injections
Inject Kineret at about the same time each day, on a schedule that works best for you
If you miss a dose of Kineret, contact your healthcare provider to find out when to take your next injection
Only you and your healthcare provider can determine how well Kineret is working for you. The time it takes to see improvement in symptoms varies from person to person.

What are the possible side effects of Kineret?

Kineret may cause serious side effects, including:
- Serious Infections. See “What is the most important information I should know about Kineret?” During treatment with Kineret, call your healthcare provider right away if you get an infection, any sign of an infection including a fever, chills, or have any open sores on your body.
- Blood problems. Kineret may cause certain white blood cells called neutrophils to decrease in number (neutropenia). Neutrophils are important in fighting infections. You will need to have blood tests before starting treatment with Kineret, then monthly for three months. After the first three months you will be asked to have your blood tested every three months for up to one year.
- Allergic reactions. If you develop a severe rash or itch, swollen face, or difficulty breathing while taking Kineret, call your doctor right away or seek emergency care immediately.

The most common side effect with Kineret is injection site reactions. These reactions may include redness, swelling, bruising, itching and stinging. Most injection site reactions are mild and last about 2 to 4 weeks.

Other, common side effects include:

-
Upper respiratory infections (including sinus infections)
-
Joint pain
-
Headaches
-
Nausea
-
Diarrhea
-
Abdominal pain
-
Flu-like symptoms
-
Worsening of rheumatoid arthritis

Malignancies.
Patients with rheumatoid arthritis may be at higher risk for lymphoma (a type of cancer).

These are not all of the possible side effects of Kineret. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. For more information, ask your healthcare provider or pharmacist.

How should I store Kineret?

Store Kineret in its original carton in the refrigerator at 36°F to 46°F (2°C to 8°C)
DO NOT FREEZE OR SHAKE Kineret
Keep Kineret away from light
When traveling, make sure you store Kineret at the correct temperature
Safely dispose of Kineret that is out of date or no longer needed

Keep Kineret and all medicines out of the reach of children.

General Information about Kineret

Medicines are sometimes prescribed for conditions that are not mentioned in the patient leaflet. Do not use Kineret for a condition for which it was not prescribed. Do not give Kineret to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about Kineret. If you would like more information about Kineret, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Kineret that is written for health professionals. For more information go to www.kineretrx.com or call 1-866-773-5274.

What are the ingredients in Kineret?

Active ingredients: anakinra

Inactive ingredients: sodium citrate, sodium chloride, disodium EDTA, and polysorbate 80 in Water for Injection, USP

What do I need to know to prepare and give an injection of Kineret?

Each Kineret dose comes in a prefilled glass syringe. There are 7 syringes in each box, one for each day of the week. Use a new syringe each day. Use the Kineret prefilled syringe that matches the day of the week until all 7 are used.

Use each Kineret prefilled syringe only once. Be sure to inject all of the solution in the syringe. If you notice some solution remaining in the syringe, do not re-inject. You should discard the syringe with any remaining solution in the puncture-resistant container. (See “Disposal of Syringes and Supplies”).

If you drop a syringe, do not use the syringe. This is for your safety in case the glass syringe is broken, or the needle is bent or dirty. Dispose of the syringe and replace it with a new one. Take the new syringe from what would be the last day of the week in your current box. For example, if you start on Wednesday, the last day of the week in your series is Tuesday. After using all the remaining syringes in your current box, start your next box.

Setting up for an Injection

Find a clean, flat work surface, such as a table.
Assemble the supplies needed for an injection:
- One alcohol swab
- A dry gauze or cotton ball
- Kineret prefilled syringe
- A puncture-resistant container
Take the carton containing the prefilled syringes of Kineret out of the refrigerator. Remove the prefilled syringe from the box that matches the day of the week. Return the carton containing the remaining prefilled syringes back into the refrigerator.
Check the expiration date on the syringe label. If the expiration date has passed, do not use the syringe. Contact your pharmacist or call 1-866-773-5274 for assistance.
Let the Kineret solution warm to room temperature for 60 to 90 minutes prior to injection. Do not remove the needle cover during this process.
Do not shake the prefilled syringe. If the solution is foamy, allow the prefilled syringe to sit for a few minutes until it clears.
Make sure the solution in the prefilled syringe is clear and colorless. You may see a small amount of tiny particles that are white, or that you can see through. These particles come from the protein in Kineret® and are okay. Do not inject the solution if it is cloudy or discolored, or has large or colored particles. Call your healthcare provider or pharmacist if you have any questions about a Kineret prefilled syringe.
Wash your hands with soap and warm water.

Selecting and preparing the injection site

Choose an injection site. Recommended injection sites include:
- The outer area of the upper arms
- The abdomen (except the two-inch area around the navel)
- The front of the middle thighs
- The upper outer areas of the buttocks
  
  Choose a new site each time you use Kineret. Choosing a new site may help avoid soreness at any one site. Do not inject Kineret into an area that is tender, red, bruised, or hard. Avoid areas with scars or stretch marks. Do not inject close to a vein that you can see under the surface of your skin.
Clean the injection site with an alcohol swab. Let the area dry completely. Injecting through a site that is still moist from an alcohol swab may cause stinging.

Administering the subcutaneous injection

Pick up the prefilled syringe from your flat work surface. Hold the syringe in the hand you will use to inject Kineret. Remove the needle cover. Twisting the needle cover while pulling will help in the removal. Do not touch the needle or allow it to touch any surface. You may notice a small air bubble in the prefilled syringe. You do not have to remove the air bubble. Injecting the solution with the air bubble is harmless.
With your free hand, gently pinch a fold of skin at the cleaned injection site.
Hold the syringe (like a pencil) at a 45 to 90 degree angle to the skin. With a quick, dart-like motion insert the needle into the skin.
After the needle is inserted, gently let go of the skin. Pull the plunger back slightly. If no blood appears in the syringe, slowly push the plunger all the way down to inject Kineret.
If blood comes into the syringe, do not inject Kineret, because the needle has entered a blood vessel. Withdraw the needle. Dispose of the used prefilled syringe in a puncture-resistant container. Prepare a new injection site and use a new prefilled syringe.
When the syringe is empty, pull the needle out of the skin, being careful to keep it at the same angle as inserted.
Place a cotton ball or gauze over the injection site and press for several seconds. Do not use an alcohol swab as it may cause stinging. If there is a little bleeding, you may cover the injection site with a small bandage.

Disposal of the syringe and supplies

The syringes should NEVER be reused. NEVER recap a needle.
Place the used syringe in a puncture-resistant container. A coffee can with a plastic lid or a hard plastic container with a screw-on top may be used. Puncture-resistant containers can also be purchased at your local pharmacy.
Talk to your healthcare provider or pharmacist about how to properly dispose of your used syringes. There may be special local and state laws for disposing of used needles and syringes. Do not throw the disposal container in the household trash. Do not recycle.
The needle cover, alcohol swabs, and other used supplies can be placed in the trash.
Always keep all syringes, injection supplies, and disposal containers out of the reach of children.

sobi
SWEDISH ORPHAN BIOVITRUM

Manufactured by:
Swedish Orphan Biovitrum AB (publ)
SE-112 76 Stockholm, Sweden
License No. 1859

Issue Date: 09/2011

Principal Display Panel - Carton Label

(Seven x 100 mg/0.67 mL Prefilled Glass Syringes) NDC 66658-234-07
sobi

SWEDISH ORPHAN BIOVITRUM
Kineret®
(anakinra)
Single Use Prefilled Glass Syringes
with 27 Gauge Needles
100 mg/0.67 mL
100 mg

For Subcutaneous Use Only
Sterile Solution –No Preservative
Refrigerate at 2° to 8°C (36° to 46°F). Do Not Freeze or Shake.