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.
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 polysorbate 80 (0.70 mg) in Water for Injection, USP.
CLINICAL PHARMACOLOGY
Kineret® blocks the biologic activity of IL-1 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 rheumatoid arthritis (RA) patients are not sufficient to compete with the elevated amount of locally produced IL-1.
Pharmacokinetics
The absolute bioavailability of Kineret® after a 70 mg SC bolus injection in healthy subjects (n = 11) is 95%.
In subjects with RA, maximum plasma concentrations of 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-life ranged from 4 to 6 hours.
In RA patients, no unexpected accumulation of Kineret® was observed after daily SC 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 SC 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).
Patients With Hepatic Dysfunction: No formal studies have been conducted examining the pharmacokinetics of Kineret® administered subcutaneously in rheumatoid arthritis patients with hepatic impairment.
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® SC 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.
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 .
The treatment response rates did not differ based on gender or ethnic group.
Most clinical responses, both in patients receiving placebo and patients receiving Kineret®, occurred within 12 weeks of enrollment.
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.
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.
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. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day.
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 CLINICAL PHARMACOLOGY, Pharmacokinetics: Patients with Renal Impairment.
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. If particulates or discoloration are observed, the prefilled syringe should not be used.
Administer only one dose (the entire contents of one prefilled glass syringe) per day. Discard any unused portions.
HOW SUPPLIED
Kineret® is supplied in single-use preservative free, prefilled glass syringes with 27 gauge needles. Each prefilled glass syringe contains 0.67 mL (100 mg) of anakinra. Kineret® is dispensed in a 4 x 7 syringe dispensing pack containing 28 syringes (NDC 55513-177-28).
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. Kineret® (anakinra)
WARNINGS
SERIOUS INFECTIONS
KINERET® HAS BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF SERIOUS INFECTIONS (2%) VS. PLACEBO (< 1%). 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.
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). USE OF KINERET® IN COMBINATION WITH TNF BLOCKING AGENTS IS NOT RECOMMENDED.
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