kineret
Manufacturer: Amgen
DESCRIPTION
Kineret® (anakinra) is a recombinant, nonglycosylated form of the humaninterleukin-1 receptor antagonist (IL-1Ra) kineret. Kineret® differs from nativehuman IL-1Ra in that it has the addition of a single methionine residue at itsamino terminus kineret. Kineret® consists of 153 amino acids and has a molecularweight of 17.3 kilodaltons kineret. It is produced by recombinant DNA technology usingan E coli bacterial expression system kineret.
Kineret® is supplied in single use prefilled glass syringes with 27 gaugeneedles as a sterile, clear, colorless-to-white, preservative-free solutionfor daily subcutaneous (SC) administration kineret. Each prefilled glass syringe contains:0.67 mL (100 mg) of anakinra in a solution (pH 6.5) containing sodium citrate(1.29 mg), sodium chloride (5.48 mg), disodium EDTA (0.12 mg), and polysorbate80 (0.70 mg) in Water for Injection, USP kineret.
CLINICAL PHARMACOLOGY
Kineret® blocks the biologic activity of IL-1 by competitively inhibitingIL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressedin a wide variety of tissues and organs kineret. 1
IL-1 production is induced in response to inflammatory stimuli and mediatesvarious physiologic responses including inflammatory and immunological responses kineret. IL-1 has a broad range of activities including cartilage degradation by itsinduction of the rapid loss of proteoglycans, as well as stimulation of boneresorption kineret. 2 The levels of the naturally occurring IL-1Ra in synovium and synovialfluid from rheumatoid arthritis (RA) patients are not sufficient to competewith the elevated amount of locally produced IL-1 kineret. 3,4,5 Pharmacokinetics
The absolute bioavailability of Kineret® after a 70 mg SC bolus injectionin healthy subjects (n = 11) is 95% kineret. In subjects with RA, maximum plasma concentrationsof Kineret® occurred 3 to 7 hours after SC administration of Kineret®at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-liferanged from 4 to 6 hours kineret. In RA patients, no unexpected accumulation of Kineret®was observed after daily SC doses for up to 24 weeks kineret. The influence of demographic covariates on the pharmacokinetics of Kineret®was studied using population pharmacokinetic analysis encompassing 341 patientsreceiving daily SC injection of Kineret® at doses of 30, 75, and 150 mgfor up to 24 weeks kineret. The estimated Kineret® clearance increased with increasingcreatinine clearance and body weight kineret. After adjusting for creatinine clearanceand body weight, gender and age were not significant factors for mean plasmaclearance kineret. Patients With Renal Impairment: The mean plasma clearance of Kineret® insubjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinineclearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, respectively kineret. In severe renal insufficiency and end stage renal disease (creatinine clearance< 30 mL/min 6 ), mean plasma clearance declined by 70% and 75%, respectively kineret. Less than 2.5% of the administered dose of Kineret® was removed by hemodialysisor continuous ambulatory peritoneal dialysis kineret. Based on these observations, adose schedule change should be considered for subjects with severe renal insufficiencyor end stage renal disease (see DOSAGE AND ADMINISTRATION ) kineret. Patients With Hepatic Dysfunction: No formal studies have been conducted examiningthe pharmacokinetics of Kineret® administered subcutaneously in rheumatoidarthritis patients with hepatic impairment kineret.
CLINICAL STUDIES
The safety and efficacy of Kineret® have been evaluated in three randomized,double-blind, placebo-controlled trials of 1790 patients >/= 18 years ofage with active rheumatoid arthritis (RA) kineret. An additional fourth study was conductedto assess safety kineret. In the efficacy trials, Kineret® was studied in combinationwith other disease-modifying antirheumatic drugs (DMARDs) other than Tumor NecrosisFactor (TNF) blocking agents (studies 1 and 2) or as a monotherapy (study 3) kineret.
Study 1 involved 899 patients with active RA who had been on a stable doseof methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks kineret. All patientshad 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 kineret. Patients were randomized to Kineret® or placebo in addition totheir stable doses of MTX kineret. The first 501 patients were evaluated for signs andsymptoms of active RA kineret. The total 899 patients were evaluated for progressionof structural damage kineret. Study 2 evaluated 419 patients with active RA who had received MTX for at least6 months including a stable dose (15 to 25 mg/week) for at least 3 consecutivemonths prior to enrollment kineret. Patients were randomized to receive placebo or oneof five doses of Kineret® SC daily for 12 to 24 weeks in addition to theirstable doses of MTX kineret. Study 3 evaluated 472 patients with active RA and had similar inclusion criteriato study 1 except that these patients had received no DMARD for the previous6 weeks or during the study kineret. 7 Patients were randomized to receive either Kineret®or placebo kineret. Patients were DMARD-na[iuml ]ve or had failed no more than 3 DMARDs kineret. Study 4 was a placebo-controlled, randomized trial designed to assess the safetyof Kineret® in 1414 patients receiving a variety of concurrent medicationsfor their RA including some DMARD therapies, as well as patients who were DMARD-free kineret. The TNF blocking agents etanercept and infliximab were specifically excluded kineret. Concurrent DMARDs included MTX, sulfasalazine, hydroxychloroquine, gold, penicillamine,leflunomide, and azathioprine kineret. Unlike studies 1, 2 and 3, patients predisposedto infection due to a history of underlying disease such as pneumonia, asthma,controlled diabetes, and chronic obstructive pulmonary disease (COPD) were alsoenrolled (see ADVERSE REACTIONS : Infections ) kineret. In studies 1, 2 and 3, the improvement in signs and symptoms of RA was assessedusing the American College of Rheumatology (ACR) response criteria (ACR 20 ,ACR 50 , ACR 70 ) kineret. In these studies, patients treated with Kineret® weremore likely to achieve an ACR 20 or higher magnitude of response (ACR 50 andACR 70 ) than patients treated with placebo (Table 1) kineret. The treatment responserates did not differ based on gender or ethnic group kineret. The results of the ACRcomponent scores in study 1 are shown in Table 2 kineret. Most clinical responses, both in patients receiving placebo and patients receivingKineret®, occurred within 12 weeks of enrollment kineret. Table 1: Percent of Patients with ACR Responses in Studies 1 and 3 Study 1(Patients on MTX) Study 3 (No DMARDs)
Kineret® Kineret®
Placebo 100 mg/day Placebo 75 mg/day 150 mg/day
Response (n = 251) (n = 250) (n = 119) (n = 115) (n = 115)
ACR 20
Month 3 24% 34% a 23% 33% 33%
Month 6 22% 38% c 27% 34% 43% a
ACR 50
Month 3 6% 13% b 5% 10% 8%
Month 6 8% 17% b 8% 11% 19% a
ACR 70
Month 3 0% 3% a 0% 0% 0%
Month 6 2% 6% a 1% 1% 1%
a p < 0.05, Kineret® versus placebo
b p < 0.01, Kineret® versus placebo
c p < 0.001, Kineret® versus placebo
Table 2: Median ACR Component Scores in Study 1 Placebo/MTX
(n = 251) Kineret®/MTX
100 mg/day
(n= 250)
Parameter (median) Baseline Month 6 Baseline Month 6
Patient Reported Outcomes
Disability index a 1.38 1.13 1.38 1.00
Patient global assessment b 51.0 41.0 51.0 29.0
Pain b 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 joints c 20.0 11.0 23.0 9.0
Physician global assessment b 59.0 31.0 59.0 26.0
Swollen joints d 18.0 10.5 17.0 9.0
a Health assessment questionnaire; 0 = best, 3 = worst; includes eight categories:dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities kineret.
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 methotrexatewho were randomized to receive either etanercept alone or the combination ofKineret® and etanercept kineret. The ACR 50 response rate was 31% for patients treatedwith the combination of Kineret® and etanercept and 41% for patients treatedwith etanercept alone, indicating no added clinical benefit of the combinationover etanercept alone kineret. Serious infections were increased with the combinationcompared to etanercept alone (see WARNINGS ) kineret.
In study 1, the effect of Kineret® on the progression of structural damagewas assessed by measuring the change from baseline at month 12 in the TotalModified Sharp Score (TSS) and its subcomponents, erosion score, and joint spacenarrowing (JSN) score kineret. 8 Radiographs of hands/wrists and forefeet were obtainedat baseline, 6 months and 12 months and scored by readers who were unaware oftreatment group kineret. A difference between placebo and Kineret® for change inTSS, erosion score (ES) and JSN score was observed at 6 months and at 12 months(Table 3) kineret. Table 3: Mean Radiographic Changes Over 12 Months in Study 1 Placebo/MTX
(N = 450) Kineret® 100 mg/day/MTX
(N = 449) Placebo/MTX
vs kineret.
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
*Differences and 95% confidence intervals for the differences in change scoresbetween Placebo/MTX and Kineret®/MTX
**Based on Wilcoxon rank-sum test
The disability index of the Health Assessment Questionnaire (HAQ) was administeredmonthly for the first six months and quarterly thereafter during study 1 kineret. Healthoutcomes were assessed by the Short Form-36 (SF-36) questionnaire kineret. The 1-yeardata on HAQ in study 1 showed more improvement with Kineret® than placebo kineret. The physical component summary (PCS) score of the SF-36 also showed more improvementwith Kineret® than placebo but not the mental component summary (MCS) kineret.
INDICATIONS AND USAGE
Kineret® is indicated for the reduction in signs and symptoms and slowingthe progression of structural damage in moderately to severely active rheumatoidarthritis, in patients 18 years of age or older who have failed 1 or more diseasemodifying antirheumatic drugs (DMARDs) kineret. Kineret® can be used alone or incombination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents(see WARNINGS ) kineret.
CONTRAINDICATIONS
Kineret® is contraindicated in patients with known hypersensitivity to Ecoli -derived proteins, Kineret®, or any components of the product kineret.
WARNINGS
KINERET® HAS BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF SERIOUS INFECTIONS(2%) VS kineret. PLACEBO (< 1%) kineret. ADMINISTRATION OF KINERET® SHOULD BE DISCONTINUEDIF A PATIENT DEVELOPS A SERIOUS INFECTION kineret. TREATMENT WITH KINERET® SHOULDNOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS kineret. THE SAFETY AND EFFICACYOF KINERET® IN IMMUNOSUPPRESSED PATIENTS OR IN PATIENTS WITH CHRONIC INFECTIONSHAVE NOT BEEN EVALUATED kineret.
IN A 24-WEEK STUDY OF CONCURRENT KINERET® AND ETANERCEPT THERAPY, THE RATEOF SERIOUS INFECTIONS IN THE COMBINATION ARM (7%) WAS HIGHER THAN WITH ETANERCEPTALONE (0%) kineret. THE COMBINATION OF KINERET® AND ETANERCEPT DID NOT RESULT INHIGHER ACR RESPONSE RATES COMPARED TO ETANERCEPT ALONE kineret. (see CLINICAL STUDIES) kineret. CONCURRENT THERAPY WITH KINERET® AND ETANERCEPT IS NOT RECOMMENDED kineret.
PRECAUTIONS
General
Hypersensitivity reactions associated with Kineret® administration are rare kineret. If a severe hypersensitivity reaction occurs, administration of Kineret®should be discontinued and appropriate therapy initiated kineret.
Immunosuppression
The impact of treatment with Kineret® on active and/or chronic infectionsand the development of malignancies is not known (see WARNINGS and ADVERSE REACTIONS: Infections and Malignancies ) kineret. Immunizations
No data are available on the effects of vaccination in patients receiving Kineret® kineret. Live vaccines should not be given concurrently with Kineret® kineret. No data areavailable on the secondary transmission of infection by live vaccines in patientsreceiving Kineret® (see PRECAUTIONS : Immunosuppression ) kineret. Since Kineret®interferes with normal immune response mechanisms to new antigens such as vaccines,vaccination may not be effective in patients receiving Kineret® kineret. Information for Patients
If a physician has determined that a patient can safely and effectively receiveKineret® at home, patients and their caregivers should be instructed onthe proper dosage and administration of Kineret® kineret. All patients should beprovided with the "Information for Patients" insert kineret. While this "Informationfor Patients" insert provides information about the product and its use,it is not intended to take the place of regular discussions between the patientand healthcare provider kineret. Patients should be informed of the signs and symptoms of allergic and otheradverse drug reactions and advised of appropriate actions kineret. Patients and theircaregivers should be thoroughly instructed in the importance of proper disposaland cautioned against the reuse of needles, syringes, and drug product kineret. A puncture-resistantcontainer for the disposal of used syringes should be available to the patient kineret. The full container should be disposed of according to the directions providedby the healthcare provider kineret. Laboratory Tests
Patients receiving Kineret® may experience a decrease in neutrophil counts kineret. In the placebo-controlled studies, 8% of patients receiving Kineret® haddecreases in neutrophil counts of at least 1 World Health Organization (WHO)toxicity grade compared with 2% in the placebo control group kineret. Nine Kineret®-treatedpatients (0.4%) experienced neutropenia (ANC < 1 ? 10 9 /L) kineret. This is discussedin more detail in the ADVERSE REACTIONS : Hematologic Events section kineret. Neutrophilcounts should be assessed prior to initiating Kineret® treatment, and whilereceiving Kineret®, monthly for 3 months, and thereafter quarterly for aperiod up to 1 year kineret.
Drug Interactions
No drug-drug interaction studies in human subjects have been conducted kineret. Toxicologicand toxicokinetic studies in rats did not demonstrate any alterations in theclearance or toxicologic profile of either methotrexate or Kineret® whenthe two agents were administered together kineret. In a study in which patients withactive RA were treated for up to 24 weeks with concurrent Kineret® and etanercepttherapy, a 7% rate of serious infections was observed, which was higher thanthat observed with etanercept alone (0%) (see also WARNINGS ) kineret. Two percent ofpatients treated concurrently with Kineret® and etanercept developed neutropenia(ANC < 1 ? 10 9 /L) kineret.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Kineret® has not been evaluated for its carcinogenic potential in animals kineret. 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. In ratsand rabbits, Kineret® at doses of up to 100-fold greater than the humandose had no adverse effects on male or female fertility kineret.
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