| KINERET® PRESCRIBING INFORMATION |
 |
| |
NOTICE
The following information is intended for use only by residents
of the United States. Countries outside of the United States may have
regulatory requirements or medical practices that are different than
those in the United States and may require reference to different or
additional information. Therefore, this information may not be appropriate
outside of the United States. |
| |
| View Patient Product Information |
| |
|
|
| |
 Download full
US prescribing information |
| |
| You need to have Adobe® Acrobat®
installed to view PDF files. If you do not have Acrobat®
Reader®, you can
download
it for free from the Adobe® website. |
|
 |
| |
| Adobe® Reader®
is a registered trademark of Adobe Systems, Inc. |
|
| |
| |
| 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. |
| |
| Back to top |
| |
| |
| 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.1 |
| |
| 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.2 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-1.3,4,5 |
| |
| 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. |
| |
| Back to top |
| |
| |
| 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.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, hydro-xychloroquine, 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: Infections). |
| |
| 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 1). 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 2. |
| |
| Most clinical responses, both in patients receiving placebo and patients
receiving Kineret®, occurred within 12 weeks of enrollment. |
| |
| Table 1: Percent of Patients with ACR Responses in Studies
1 and 3 |
| |
|
|
Study 1 |
|
Study 3 |
|
(Patients on MTX) |
|
(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) |
|
|
|
| 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% |
|
|
| |
| a p < 0.05, Kineret® versus placebo |
| b p < 0.01, Kineret® versus placebo |
| c p < 0.001, Kineret® versus placebo |
| |
| Back to top |
| |
| Table 2: Median ACR Component Scores in Study 1 |
| |
|
|
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 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 |
| |
| 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). |
| |
| 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 6 months and at 12 months (Table
3). |
| |
| Back to top |
| |
| Table 3: Mean Radiographic Changes Over 12 Months in
Study 1 |
| |
|
|
|
Kineret®
100 mg/day |
Placebo/MTX |
|
Placebo/MTX |
/MTX |
vs. |
|
(N = 450) |
(N = 449) |
Kineret®/MTX |
|
|
|
|
Change at |
|
Change at |
95% Confidence |
|
|
Baseline |
Month 12 |
Baseline |
Month 12 |
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
scores between Placebo/MTX and Kineret®/MTX |
| ** Based on Wilcoxon rank-sum test |
| |
| The disability index of the Health Assessment Questionnaire (HAQ) was
administered monthly for the first six months and quarterly thereafter during
study 1. Health outcomes were assessed by the Short Form-36 (SF-36) questionnaire.
The 1-year data on HAQ in study 1 showed more improvement with Kineret®
than placebo. The physical component summary (PCS) score of the SF-36 also
showed more improvement with Kineret® than placebo but not
the mental component summary (MCS). |
| |
| |
| Kineret® is indicated for the 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). Kineret®
can be used alone or in combination with DMARDs other than Tumor Necrosis
Factor (TNF) blocking agents (see WARNINGS). |
| |
| |
| Kineret® is contraindicated in patients with known hypersensitivity
to E coli-derived proteins, Kineret®, or any components
of the product. |
| |
| Back to top |
| |
| |
| 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. |
| |
| |
| General |
| |
| Hypersensitivity reactions associated with Kineret® administration
are rare. 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. |
| |
| Immunosuppression |
| |
| The impact of treatment with Kineret® on active and/or
chronic infections and the development of malignancies is not known (see
WARNINGS and ADVERSE REACTIONS:
Infections and Malignancies). |
| |
| 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® (see PRECAUTIONS:
Immunosuppression). Therefore, live vaccines should not be
given concurrently with Kineret®.
|
| |
| Back to top |
| |
| Information for Patients |
| |
| If a physician has determined that a patient can safely and effectively
receive Kineret® at home, patients and their caregivers
should be instructed on the proper dosage and administration of Kineret®.
All patients should be provided 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 health care provider. |
| |
| Patients should be informed of the signs and symptoms of allergic and
other adverse drug reactions and advised of appropriate actions. The patient should be informed 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. Patients
and their caregivers should be thoroughly instructed in 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 health care provider. |
| |
| Laboratory Tests |
| |
| 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 1 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:
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. |
| |
| 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 also
WARNINGS: Use with TNF Blocking Agents). 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.
|
| |
| 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. |
| |
| 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. |
| |
| Back to top |
| |
| 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. |
| |
| 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. Pediatric use of Kineret® is 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. |
| |
| 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. |
| |
| Back to top |
| |
| |
| The most serious adverse reactions were: |
| |
- Serious Infections - see WARNINGS
- 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 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).
The majority of ISRs were reported as mild. These typically lasted for 14
to 28 days and were characterized by 1 or more of the following: erythema,
ecchymosis, inflammation, and pain. In studies 1 and 4, 71% of patients
developed an ISR, which was typically reported within the first 4 weeks
of therapy. The development of ISRs in patients who had not previously experienced
ISRs was uncommon after the first month of therapy. |
| |
| Back to top |
| |
| 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, rather than unusual, opportunistic, fungal,
or viral infections. 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%).
Most patients continued on study drug after the infection resolved. |
| |
| 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, rare 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®, treatment
was associated with small reductions in the mean values for total white
blood count, platelets, and absolute neutrophil count (ANC), and a small
increase in the mean eosinophil differential percentage. |
| |
| In all placebo-controlled studies, 8% of patients receiving Kineret®
had decreases in ANC of at least 1 WHO toxicity grade, compared with 2%
of placebo patients. Nine Kineret®-treated patients (0.4%)
developed neutropenia (ANC < 1 x 109/L). Two percent of patients
treated concurrently with Kineret® and etanercept developed
neutropenia (ANC < 1 x 109/L). While neutropenic, one patient
developed cellulitis which recovered with antibiotic therapy. |
| |
| Back to top |
| |
| 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 4 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 4: Percent of RA Patients Reporting Adverse Events
(Studies 1 and 4) |
| |
|
|
|
Kineret® |
|
Placebo |
100 mg/day |
| Preferred term |
(n = 733) |
(n = 1565) |
|
|
|
| Injection Site Reaction |
29% |
71% |
| Worsening of RA |
29% |
19% |
| URI |
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% |
|
|
|
| |
| Back to top |
| |
| |
| 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. |
| |
| |
| 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 health care 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. |
| |
| Back to top |
| |
| |
| 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.
Rx only
|
| |
| Back to top |
| |
| |
| 1. |
|
Hannum CH, Wilcox CJ, Arend WP, et al. Interleukin-1
receptor antagonist activity of a human interleukin-1 inhibitor. Nature.
1990; 343:336-40. |
| 2. |
|
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. |
| 3. |
|
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. |
| 4. |
|
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. |
| 5. |
|
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. |
| 6. |
|
Cockcroft DW and Gault HM. Prediction of creatinine
clearance from serum creatinine. Nephron 1976; 16:31-41. |
| 7. |
|
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. |
| 8. |
|
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. |
| 9. |
|
National Cancer Institute. Surveillance, Epidemiology,
and End Results Database (SEER) Program. SEER Incidence Crude Rates,
11 Registries, 1992-1999. |
|
| |
| This product, its production, and/or its use
may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,599,873
and 5,075,222 as well as other patents or patents pending. |
| |
 |
|
|
|
| |
| |
Manufactured by:
Amgen Manufacturing, Limited,
a subsidiary of Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
© 2001-2006 Amgen Inc. All rights reserved.
Issue Date: 12/15/2006 |
|
| |
| |
| INFORMATION FOR PATIENTS |
|
| |
NOTICE
The following information is intended for use only by residents
of the United States. Countries outside of the United States may have
regulatory requirements or medical practices that are different than
those in the United States and may require reference to different or
additional information. Therefore, this information may not be appropriate
outside of the United States. |
| |
| View Kineret® Prescribing Information |
| |
|
|
| |
|
Download patient product information |
| |
| You need to have Adobe® Acrobat®
installed to view PDF files. If you do not have Acrobat®
Reader®, you can
download
it for free from the Adobe® website. |
|
|
| |
| Adobe® Reader®
is a registered trademark of Adobe Systems, Inc. |
|
| |
|
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.
|
| |
| |
|
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.
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 chance 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®.
|
| |
Kineret® is an interleukin-1 receptor antagonist (IL-1ra).
Kineret® is used to reduce the signs and symptoms, and slow down damage that happens
in patients with moderate to severe active Rhematoid Arthritis (RA), but it can also
lead to serious side effects because of the affects 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.
|
| |
| |
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®.
|
| Back to top |
| |
| |
|
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.
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.
|
| |
| Back to top |
| |
| |
- 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. In clinical studies, most patients
saw their arthritis symptoms improve within 12 weeks of starting 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.
The most common side effect with Kineret® is injection site reaction. These reactions may include redness,
swelling, bruising, itching and stinging. Most injection site reactions are mild and last about 2 to 4 weeks.
Side effects that are rare include:
- Malignancies. Patients with rheumatoid arthritis (RA) may be at higher risk for lymphoma (a type of cancer).
- Allergic reactions. Allergic reactions rarely occur in patients taking Kineret®. If you
develop a severe rash, swollen face or difficulty breathing while taking Kineret®, call your
doctor right away or seek emergency care immediately. Tell your healthcare provider if you have
any side effect that bothers you or that does not go away.
These are not all of the possible side effects of Kineret®. For more information, ask your healthcare provider or pharmacist.
|
| |
| Back to top |
| |
| |
- 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.
|
| |
| Back to top |
| |
| |
|
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 1-866-546-3738.
|
| |
| Back to top |
| |
Active ingredients: anakinra
Inactive ingredients: sodium citrate, sodium chloride, disodium EDTA, and polysorbate 80 in Water for Injection, USP |
| |
| |
|
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.
|
| |
| |
|
- 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-Kineret
(1-866-546-3738) 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.
- Do not use a prefilled syringe if the contents appear discolored or cloudy‚ or if there
are any particles in the syringe. Call your healthcare provider or pharmacist if you have
any questions about the way the solution looks.
- Wash your hands with soap and warm water.
|
| Back to top |
| |
| |
|
- 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 can 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.
|
| |
|
 |
1. |
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.
 |
| 3. |
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. |
| |
| 4. |
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.
|
| |
|
- 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.
|
| |
| Back to top |
| |
| |
|
|
|
|
| |
| |
Manufactured by:
Amgen Manufacturing, Limited,
a subsidiary of Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
© 2001-2006 Amgen Inc. All rights reserved.
Issue Date: 12/15/2006 |
|
