A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Kineret Side Effects, and Drug Interactions - Anakinra
Kineret Side Effects, and Drug Interactions - Anakinra
SIDE EFFECTS
The most serious adverse reactions were:
• Serious Infections-see WARNINGS
• Neutropenia, particularly when used in combination
with TNF blocking agents – see WARNINGS
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 2606 patients, including 1812 exposed for at least 6 months and 570 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.
Infections
In Studies 1 and 4 combined, the incidence of infection was
40% in the Kineret -treated patients and 35% in placebo-treated patients. The
incidence of serious infections in studies 1 and 4 was 1.8% in Kineret -treated
patients and 0.6% in placebo-treated patients over 6 months. 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;
Kineret 5% versus placebo <1%. Most patients continued on study drug after
the infection resolved. There were no on-study deaths due to serious infectious
episodes in either study. In a study in which patients were receiving both etanercept
and Kineret for up to 24 weeks, the incidence of serious infections was 7%.
These infections consisted of bacterial pneumonia (2 cases) and cellulitis (2
cases), which recovered with antibiotic treatment.
Malignancies
Twenty-one malignancies of various types were observed in 2531
RA patients treated in clinical trials with KineretTM for up to 50
months. The observed rates and incidences were similar to those expected for
the population studied.
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 blood 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. Six Kineret -treated patients (0.3%) developed neutropenia
(ANC £ 1 x 109/L). Additional patients
treated with Kineret plus etanercept (2/58, 3%) developed ANC £
1 x 10 9/L. While neutropenic, one patient developed cellulitis and
the other patient developed pneumonia. Both patients recovered with antibiotic
therapy.
Immunogenicity
In Study 4, 28% of patients tested positively for anti-Kineret
antibodies at month 6 in a highly sensitive, Kineret -binding biosensor assay.
Of the 1274 subjects with available data, <1% (n = 9) were seropositive in
a cell-based bioassay for antibodies capable of neutralizing the biologic effects
of Kineret . None of these 9 subjects were positive for neutralizing antibodies
at more than 1 time point, and all of these subjects were negative for neutralizing
antibodies by 9 months. No correlation between antibody development and clinical
response or adverse events was observed. The long-term immunogenicity of Kineret
is unknown.
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 3 reflects adverse events in Studies 1 and 4, that occurred
with a frequency of ³ 5% and a higher frequency
in Kineret -treated patients.
Table 3. Percent of RA Patients Reporting Adverse Events (Studies
1 and 4)
|
Preferred Term
|
Placebo (N = 534)
|
Kineret 100 mg/day (N = 1366)
|
|
Injection Site Reaction
|
28 %
|
71 %
|
|
Infection
|
35 %
|
40 %
|
|
URI
|
13 %
|
13 %
|
|
Sinusitis
|
4 %
|
6 %
|
|
Influenza-Like Symptoms
|
4 %
|
5 %
|
|
Other
|
23 %
|
26 %
|
|
Headache
|
9 %
|
12 %
|
|
Nausea
|
6 %
|
8 %
|
|
Diarrhea
|
5 %
|
7 %
|
|
Sinusitis
|
6 %
|
7 %
|
|
Influenza-Like Symptoms
|
5 %
|
6 %
|
|
Pain Abdominal
|
4 %
|
5 %
|
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.
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.
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
The safety and efficacy of Kineret in patients with juvenile
rheumatoid arthritis (JRA) have not been established.
Geriatric Use
A total of 653 patients = 65 years of age, including 135 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.
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