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)].

1.2 Cryopyrin-Associated Periodic Syndromes (CAPS)

KINERET is indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID).

1.3 Deficiency of Interleukin-1 Receptor Antagonist (DIRA)

KINERET is indicated for the treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA)

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 Cryopyrin-Associated Periodic Syndromes (CAPS)

The recommended starting dose of KINERET is 1-2 mg/kg for NOMID patients. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation.

Adjust doses in 0.5 to 1 mg/kg increments. Once daily administration is generally recommended, but the dose may be split into twice daily administrations. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.

2.3 Deficiency of Interleukin-1 Receptor Antagonist (DIRA)

The recommended starting dose of KINERET is 1-2 mg/kg daily for patients with DIRA. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation. Adjust doses in 0.5 to 1 mg/kg increments.

Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.

2.4 Renal Impairment

Physicians should consider administration of the prescribed dose of KINERET every other day for 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)].

2.5 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 correctly. The prescribed dose of KINERET should be administered according to the instructions for use and any unused portions discarded. After administration of KINERET it is essential to follow the proper procedure for disposal of syringes and any residual drug. 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.

5.1 Serious Infections

KINERET has been associated with an increased incidence of serious infections (2%) vs. Placebo (< 1%) in clinical trials in RA. Administration of KINERET in RA should be discontinued if a patient develops a serious infection. In KINERET treated NOMID and DIRA patients the risk of a disease flare when discontinuing KINERET treatment should be weighed against the potential risk of continued treatment. 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.

Drugs that affect the immune system by blocking tumor necrosis factor (TNF) have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as KINERET that blocks IL-1 increases the risk of TB or other atypical or opportunistic infections. Health care providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with KINERET.

5.2 Use with TNF Blocking Agents

In a 24-week study of concurrent KINERET and etanercept therapy in RA patients, 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.

KINERET is the recombinant form of IL-1Ra that DIRA patients are lacking. Patients with DIRA may have an increased risk of allergic reactions, particularly in the first several weeks after starting KINERET treatment. Patients should be closely monitored during this time period. If a severe allergic reaction occurs, appropriate treatment should be initiated and discontinuation of KINERET should be considered.

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. Neutrophil counts should therefore 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.

In the placebo-controlled studies, 8% of RA 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 (6.1) section.

In 43 NOMID patients followed for up to 60 months 2 patients experienced neutropenia that resolved over time during continued KINERET treatment. [see Adverse Reactions (6.2)]

6.1 Clinical Studies Experience in RA

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.

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 used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis.

6.2 Clinical Study Experience in NOMID

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.

6.3 Clinical Study Experience in DIRA

The safety data described in this section reflect exposure to KINERET in 9 patients with DIRA treated for up to 10 years in a natural history study (study 17-I-0016). Most patients received a starting dose of 1 to 2 mg/kg/day and thereafter doses were individually adjusted to reach a stable efficacious dose. The highest dose given was 7.5 mg/kg/day. Overall, the safety profile observed in patients with DIRA treated with KINERET was consistent with the safety profile in NOMID patients.

There were 16 serious adverse events (SAEs) reported in 4 out of 9 treated patients. The most common type of SAEs reported (5 events in 2 patients) were infections [see Warnings and Precautions (5.1)].

The most common adverse events in patients with DIRA were upper respiratory tract infections, rash, pyrexia, influenza like illness and gastroenteritis.

There were no permanent discontinuations of KINERET treatment due to AEs.

6.4 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

Hematologic events:

• thrombocytopenia, including severe thrombocytopenia (i.e platelet counts <10x109/L)

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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.

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.

DIRA is an autosomal recessive monogenic autoinflammatory disease caused by mutations in the IL1RN gene leading to loss of secretion of the interleukin-1 receptor antagonist (IL-1Ra). The deficiency of IL-1Ra results in unopposed IL-1α and IL-1β pro-inflammatory signaling causing systemic inflammation with skin and bone involvement.

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.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of KINERET were not conducted. KINERET had no effects on fertility and reproductive performance indices in male and female rats subcutaneous doses up to 200 mg/kg/day (approximately 25 times theMRHD on a mg/kg basis).

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.

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).

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.

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.

14.3 Clinical Studies in DIRA

The safety and efficacy of KINERET were evaluated in a long-term natural history study including 9 DIRA patients (ages 1 month to 9 years at the start of KINERET treatment) treated with KINERET for up to 10 years. All patients had genetically confirmed DIRA. The starting dose of KINERET was 1 to 2 mg/kg/day in the 6 patients for which the dose was reported. The dose was then individually adjusted to reach a stable efficacious dose to control active inflammation. The highest KINERET dose studied was 7.5 mg/kg/day. At the last visit during the first KINERET treatment period, the dose ranged between 2.2 and 6.1 mg/kg/day. Inflammatory remission was defined as achievement of all of the following criteria: CRP ≤ 5 mg/L, no pustulosis, no inflammatory bone disease, and no concomitant glucocorticosteroid use. All 9 patients achieved inflammatory remission while on KINERET treatment.

Storage

KINERET should be stored in the refrigerator at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE OR SHAKE. Protect from light.

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