Abatacept (4101)
| Ingredients: |
Abatacept |
| Indications: |
Arthritis, rheumatoid |
| Pregnancy Category: |
C |
| FDA Approved: |
2005- 12- 01 |
| Classes: |
T- cell modulator |
| Brand Names: |
Orencia
-
US
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$4,860.00
(
Rheumatoid Arthritis ;
Orencia Powder for Injection ;
250 mg/vial ;
750 mg at weeks 0, 2, and 4 (initial therapy) ;
28 day supply
)
$4,860.00
(
Rheumatoid Arthritis ;
Orencia Powder for Injection ;
250 mg/vial ;
750 mg/4 weeks (maintenance) ;
84 day supply
)
|
DESCRIPTION
|
| |
Orencia (abatacept) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T- lymphocyte-
associated antigen 4 (CTLA- 4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1
(IgG1). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular
weight of abatacept is 92 kilodaltons.
Orencia is supplied as a sterile, white, preservative- free, lyophilized powder for parenteral administration. Following reconstitution
with 10 ml of sterile water for injection, the solution of Orencia is clear, colorless to pale yellow, with a pH range of
7.0- 8.0. Each single- use vial of Orencia provides 250 mg abatacept, 500 mg maltose, 17.2 mg monobasic sodium phosphate,
and 14.6 mg sodium chloride for administration.
|
CLINICAL PHARMACOLOGY
|
| |
Mechanism of Action
|
| |
Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby
blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes,
implicated in the pathogenesis of rheumatoid arthritis (RA). Activated T lymphocytes are found in the synovium of patients
with RA.
In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines tumor necrosis factor alpha (TNFα),
interferon- γ, and interleukin- 2. In a rat collagen- induced arthritis model, abatacept suppresses inflammation, decreases
anticollagen antibody production, and reduces antigen specific production of interferon- γ.The relationship of these biological
response markers to the mechanisms by which abatacept exerts its effects in RA is unknown.
|
Pharmacodynamics
|
| |
In clinical trials with abatacept at doses approximating 10 mg/ kg, decreases were observed in serum levels of soluble interleukin-
2 receptor (sIL- 2r), interleukin- 6 (IL- 6), rheumatoid factor (RF), C- reactive protein (CRP), matrix metalloproteinase-
3 (MMP3), and tumor necrosis factor alpha (TNFα). The relationship of these biological response markers to the mechanisms
by which abatacept exerts its effects in RA is unknown.
|
Pharmacokinetics
|
| |
The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/ kg IV infusion and in RA patients
after multiple 10 mg/ kg IV infusions (see TABLE 1 ).
| TABLE 1
Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/ kg IV Infusion(s)
|
| |
Healthy Subjects |
RA Patients |
| |
(After 10 mg/ kg Single Dose) |
(After 10 mg/ kg Multiple Doses*) |
| PK Parameter |
n=13 |
n=14 |
| Peak concentration (Cmax ) [µg/ ml]
|
292 (175- 427) |
295 (171- 398) |
| Terminal half- life (T½ ) [days]
|
16.7 (12- 23) |
13.1 (8- 25) |
| Systemic clearance (CL) [ml/ h/ kg] |
0.23 (0.16- 0.30) |
0.22 (0.13- 0.47) |
| Volume of distribution (Vss) [L/ kg] |
0.09 (0.06- 0.13) |
0.07 (0.02- 0.13) |
|
| *
|
Multiple IV infusions were administered at Days 1, 15, 30, and monthly thereafter. |
|
The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple
IV infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2- 10 mg/ kg. At 10 mg/ kg, serum concentration appeared to reach a steady- state by Day 60
with a mean (range) trough concentration of 24 (1- 66) µg/ ml. No systemic accumulation of abatacept occurred upon continued
repeated treatment with 10 mg/ kg at monthly intervals in RA patients.
Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with
increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate
(MTX), nonsteroidal anti- inflammatory drugs (NSAIDs), corticosteroids, and TNF blocking agents did not influence abatacept
clearance.
The pharmacokinetics of abatacept have not been studied in children and adolescents. No formal studies were conducted to examine
the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept.
|
|
CLINICAL STUDIES
|
| |
The efficacy and safety of abatacept were assessed in five randomized, double- blind, placebo- controlled studies in patients
≥ age 18 with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies 1, 2, 3, and 4 required
patients to have at least 12 tender and 10 swollen joints at randomization. Study 5 did not require any specific number of
tender or swollen joints. abatacept or placebo treatment was given intravenously at Weeks 0, 2, and 4 and then every 4 weeks
thereafter.
Study 1 evaluated abatacept as monotherapy in 122 patients with active RA who had failed at least one non- biologic, disease-
modifying, anti- rheumatic drug (DMARD) or etanercept. In Study 2 and Study 3, the efficacy and safety of abatacept were assessed
in patients with an inadequate response to MTX and who were continued on their stable dose of MTX. In Study 4, the efficacy
and safety of abatacept were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking
agent discontinued prior to randomization; other DMARDs were permitted. Study 5 primarily assessed safety in patients with
active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued.Patients
in Study 5 were not excluded for comorbid medical conditions.
Study 1 patients were randomized to receive 1 of 3 doses of abatacept (0.5, 2, or 10 mg/ kg) or placebo ending at Week 8.
Study 2 patients were randomized to receive abatacept 2 or 10 mg/ kg or placebo for 12 months. Study 3, 4, and 5 patients
were randomized to receive a dose of abatacept based on weight range or placebo for 12 months (Studies 3 and 5) or 6 months
(Study 4). The dose of abatacept was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60- 100 kg,
and 1 g for patients weighing greater than 100 kg.
Clinical Response
|
| |
The percent of abatacept- treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies 1,
2, and 4 are shown in TABLE 2 . Abatacept- treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo- treated patients.
Month 6 ACR response rates in Study 2 for the 10 mg/ kg group were similar to the abatacept group in Study 3.
In Studies 3 and 4, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients. In
Studies 2 and 3, ACR response rates were maintained to 12 months in abatacept- treated patients. ACR responses were maintained
up to 3 years in the open- label extension of Study 2.
| TABLE 2
ACR Responses in Placebo- Controlled Trials (Percent of Patients)
|
| |
|
Inadequate Response to DMARDs |
Inadequate Response to MTX |
Inadequate Response to TNF Blocking Agent |
| |
|
Study 1 |
Study 3 |
Study 4 |
| |
|
Abatacept* |
Placebo |
Abatacept† + MTX |
Placebo + MTX |
Abatacept† + DMARDs |
Placebo + DMARDs |
| Response Rate |
n=32 |
n=32 |
n=424 |
n=214 |
n=256 |
n=133 |
| ACR 20
|
| |
Month 3 |
53% |
31% |
62%§ |
37% |
46%§ |
18% |
| |
Month 6 |
NA |
NA |
68%§ |
40% |
50%§ |
20% |
| |
Month 12 |
NA |
NA |
73%§ |
40% |
NA |
NA |
| ACR 50
|
| |
Month 3 |
16% |
6% |
32%§ |
8% |
18%¤ |
6% |
| |
Month 6 |
NA |
NA |
40%§ |
17% |
20%§ |
4% |
| |
Month 12 |
NA |
NA |
48%§ |
18% |
NA |
NA |
| ACR 70
|
| |
Month 3 |
6% |
0 |
13%§ |
3% |
6%¶ |
1% |
| |
Month 6 |
NA |
NA |
20%§ |
7% |
10%¤ |
2% |
| |
Month 12 |
NA |
NA |
29%§ |
6% |
NA |
NA |
| Major Clinical Response‡
|
NA |
NA |
14%§ |
2% |
NA |
NA |
|
| *
|
10 mg/ kg. |
| †
|
Dosing based on weight range (see DOSAGE AND ADMINISTRATION ).
|
| ‡
|
Major clinical response is defined as achieving an ACR 70 response for a continuous 6- month period. |
| §
|
p <0.001, abatacept vs placebo. |
| ¤
|
p <0.01, abatacept vs placebo. |
| ¶
|
p <0.05, abatacept vs placebo. |
|
The results of the components of the ACR response criteria for Studies 3 and 4 are shown in TABLE 3A and TABLE 3B . In abatacept- treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months
than in placebo- treated patients.
| TABLE 3A
Components of ACR Response at 6 Months — Study 3
|
| |
Inadequate Response to MTX |
| |
Abatacept + MTX (n=424) |
Placebo + MTX (n=214) |
| Component (Median) |
Baseline |
Month 6 |
Baseline |
Month 6 |
| Number of tender joints (0- 68) |
28 |
7* |
31 |
14 |
| Number of swollen joints (0- 66) |
19 |
5* |
20 |
11 |
| Pain† |
67 |
27* |
70 |
50 |
| Patient global assessment† |
66 |
29* |
64 |
48 |
| Disability index‡ |
1.75 |
1.13* |
1.75 |
1.38 |
| Physician global assessment† |
69 |
21* |
68 |
40 |
| CRP (mg/ dl) |
2.2 |
0.9* |
2.1 |
1.8 |
|
| *
|
p <0.001, abatacept vs placebo, based on mean percent change from baseline. |
| †
|
Visual analog scale: 0 = best, 100 = worst. |
| ‡
|
Health Assessment Questionnaire 1 : 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip,
and activities.
|
|
| TABLE 3B
Components of ACR Response at 6 Months — Study 4
|
| |
Inadequate Response to TNF Blocking Agent |
| |
Abatacept + DMARDs (n=256) |
Placebo + DMARDs (n=133) |
| Component (Median) |
Baseline |
Month 6 |
Baseline |
Month 6 |
| Number of tender joints (0- 68) |
30 |
13* |
31 |
24 |
| Number of swollen joints (0- 66) |
21 |
10* |
20 |
14 |
| Pain† |
73 |
43‡ |
74 |
64 |
| Patient global assessment† |
71 |
44* |
73 |
63 |
| Disability index§ |
1.88 |
1.38* |
2.00 |
1.75 |
| Physician global assessment† |
71 |
32* |
69 |
54 |
| CRP (mg/ dl) |
3.4 |
1.3* |
2.8 |
2.3 |
|
| *
|
p <0.001, abatacept vs placebo, based on mean percent change from baseline. |
| †
|
Visual analog scale: 0 = best, 100 = worst. |
| ‡
|
p <0.01, abatacept vs placebo, based on mean percent change from baseline. |
| §
|
Health Assessment Questionnaire 1 : 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip,
and activities.
|
|
Abatacept- treated patients experienced greater improvement than placebo- treated patients in morning stiffness.
|
Radiographic Response
|
| |
Structural joint damage was assessed radiographically and expressed as change in Genant- modified Total Sharp Score 2 (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at Month 12 compared to baseline. In Study
3 the baseline median TSS was 31.7 in abatacept- treated patients and 33.4 in placebo- treated patients. The results are shown
in TABLE 4 . Abatacept/ MTX slowed the progression of structural damage compared to placebo/ MTX alone.
| TABLE 4
Mean Radiographic Changes Over 12 Months in Study 3
|
| |
Abatacept/ MTX |
Placebo/ MTX |
Placebo/ MTX — Abatacept/ MTX |
|
| Parameter |
n=391 |
n=195 |
(95% CI) |
p- Value* |
| Total Sharp score |
1.21 |
2.32 |
1.11 (0.35, 1.88) |
0.012 |
| Erosion score |
0.63 |
1.14 |
0.51 (0.08, 0.94) |
0.029 |
| JSN score |
0.58 |
1.18 |
0.60 (0.21, 0.99) |
0.009 |
|
| *
|
Based on non- parametric analysis. |
|
|
Physical Function Response and Health-Related Outcomes
|
| |
Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ- DI). 1, 3 In Studies 2- 5, abatacept demonstrated greater improvement from baseline than placebo in the HAQ- DI. The results from Studies
2 and 3 are shown in TABLE 5 . Similar results were observed in Study 5. During the open- label period of Study 2, the improvement in physical function
has been maintained for up to 3 years.
| TABLE 5
Mean Improvement From Baseline in Health Assessment Questionnaire Disability Index (HAQ- DI) — Inadequate Response to Methotrexate
|
| |
Study 2 |
Study 3 |
| |
Abatacept* + MTX |
Placebo + MTX |
Abatacept† + MTX |
Placebo + MTX |
| HAQ Disability Index |
(n=115) |
(n=119) |
(n=422) |
(n=212) |
| Baseline (mean) |
0.98‡ |
0.97‡ |
1.69¤ |
1.69¤ |
| Mean improvement Year 1 |
0.40ठ|
0.15‡ |
0.66¤§ |
0.37¤ |
|
| *
|
10 mg/ kg. |
| †
|
Dosing based on weight range (see DOSAGE AND ADMINISTRATION ).
|
| ‡
|
Modified Health Assessment Questionnaire 3 : 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and
activities.
|
| §
|
p <0.001, abatacept vs placebo. |
| ¤
|
Health Assessment Questionnaire 1 : 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip,
and activities.
|
|
Health- related quality of life was assessed by the SF- 36 questionnaire 4 at 6 months in Studies 2, 3, and 4 and at 12 months in Studies 2 and 3. In these studies, improvement was observed in the
abatacept group as compared with the placebo group in all 8 domains of the SF- 36 as well as the Physical Component Summary
(PCS) and the Mental Component Summary (MCS).
|
|
INDICATIONS AND USAGE
|
| |
Abatacept is indicated for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural
damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis who have
had an inadequate response to one or more DMARDs, such as methotrexate or TNF antagonists.Abatacept may be used as monotherapy
or concomitantly with DMARDs other than TNF antagonists.
Abatacept should not be administered concomitantly with TNF antagonists. Abatacept is not recommended for use concomitantly
with anakinra.
|
CONTRAINDICATIONS
|
| |
Abatacept should not be administered to patients with known hypersensitivity to abatacept or any of its components.
|
WARNINGS
|
| |
Concomitant Use With TNF Antagonists
|
| |
In controlled clinical trials, patients receiving concomitant abatacept and TNF antagonist therapy experienced more infections
(63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively) (see ADVERSE REACTIONS, Infections ). These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of abatacept with
TNF antagonist; therefore, concurrent therapy with abatacept and a TNF antagonist is not recommended. While transitioning
from TNF antagonist therapy to abatacept therapy, patients should be monitored for signs of infection.
|
|
PRECAUTIONS
|
| |
Hypersensitivity
|
| |
Of 2688 patients treated with abatacept in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions.
Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred
in less than 0.9% of abatacept- treated patients. Appropriate medical support measures for the treatment of hypersensitivity
reactions should be available for immediate use in the event of a reaction (see ADVERSE REACTIONS, Infusion- Related Reactions and Hypersensitivity Reactions ).
|
Infections
|
| |
Physicians should exercise caution when considering the use of abatacept in patients with a history of recurrent infections,
underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop
a new infection while undergoing treatment with abatacept should be monitored closely.Administration of abatacept should be
discontinued if a patient develops a serious infection (see ADVERSE REACTIONS, Infections ). A higher rate of serious infections has been observed in patients treated with concurrent TNF antagonists and abatacept
(see WARNINGS, Concomitant Use With TNF Antagonists ).
Prior to initiating immunomodulatory therapies, including abatacept, patients should be screened for latent tuberculosis infection
with a tuberculin skin test. Abatacept has not been studied in patients with a positive tuberculosis screen, and the safety
of abatacept in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening
should be treated by standard medical practice prior to therapy with abatacept.
|
Immunizations
|
| |
Live vaccines should not be given concurrently with abatacept or within 3 months of its discontinuation. No data are available
on the secondary transmission of infection from persons receiving live vaccines to patients receiving abatacept. The efficacy
of vaccination in patients receiving abatacept is not known. Based on its mechanism of action, abatacept may blunt the effectiveness
of some immunizations.
|
Use in Patients With Chronic Obstructive Pulmonary Disease (COPD)
|
| |
COPD patients treated with abatacept developed adverse events more frequently than those treated with placebo, including COPD
exacerbations, cough, rhonchi, and dyspnea.Use of abatacept in patients with rheumatoid arthritis and COPD should be undertaken
with caution and such patients should be monitored for worsening of their respiratory status (see ADVERSE REACTIONS, Adverse Reactions in Patients With COPD ).
|
Information for the Patient
|
| |
Patients should be provided the abatacept Patient Information leaflet and provided an opportunity to read it prior to each
treatment session. Because caution should be exercised in administering abatacept to patients with active infections, it is
important that the patient’s overall health be assessed at each visit and any questions resulting from the patient’s reading
of the Patient Information be discussed.
|
Immunosuppression
|
| |
The possibility exists for drugs inhibiting T cell activation, including abatacept, to affect host defenses against infections
and malignancies since T cells mediate cellular immune responses. The impact of treatment with abatacept on the development
and course of malignancies is not fully understood (see ADVERSE REACTIONS, Malignancies ). In clinical trials, a higher rate of infections was seen in abatacept- treated patients compared to placebo (see ADVERSE REACTIONS, Infections ).
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
|
| |
In a mouse carcinogenicity study, weekly SC injections of 20, 65, or 200 mg/ kg of abatacept administered each week for up
to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of malignant lymphomas (all doses)
and mammary gland tumors (intermediate- and high- dose in females). The mice from this study were infected with murine leukemia
virus and mouse mammary tumor virus. These viruses are associated with an increased incidence of lymphomas and mammary gland
tumors, respectively, in immunosuppressed mice. The doses used in these studies were 0.8- , 2.0- and 3.0- fold, the human
exposure at 10 mg/ kg, respectively, based on AUC. The relevance of these findings to the clinical use of abatacept is unknown.
In a 1- year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50
mg/ kg (9- fold the human exposure at 10 mg/ kg dose based on AUC). Abatacept was not associated with any significant drug-
related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to
severe lymphoid depletion of germinal centers in the spleen and/ or lymph nodes. No evidence of lymphomas or preneoplastic
morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed
monkeys within the time frame of this study.The relevance of these findings to the clinical use of abatacept is unknown.
No mutagenic potential of abatacept was observed in the in vitro reverse Ames or Chinese hamster ovary/ hypoxanthine guanine phosphoribosyl- transferase (CHO/ HGPRT) forward point mutation
(with or without metabolic activation) assays, and no chromosomal aberrations were observed in human lymphocytes (with or
without metabolic activation) treated with abatacept. In rats, abatacept had no adverse effects on male or female fertility
at doses up to 200 mg/ kg every 3 days (11- fold a human dose based on AUC).
|
Pregnancy Category C
|
| |
Abatacept was found not to be teratogenic in mice at doses up to 300 mg/ kg and in rats and rabbits at doses up to 200 mg/
kg daily (29- fold a human 10 mg/ kg dose based on AUC in rats and rabbits). Rats treated with abatacept every 3 days during
early gestation throughout the lactation period showed no adverse effects in the offspring at doses up to 45 mg/ kg (3- fold
a human 10 mg/ kg dose based on AUC). At a dose of 200 mg/ kg (11- fold a human 10 mg/ kg dose based on AUC), alterations
of immune function consisted of a 9- fold increase in the T- cell dependent antibody response in female pups and inflammation
of the thyroid in one female pup out of 10 males and 10 females evaluated. Whether these findings indicate a risk for development
of autoimmune diseases in humans exposed in utero to abatacept has not been determined. Abatacept was shown to cross the placenta.
Because animal reproduction studies are not always predictive of human response, abatacept should be used during pregnancy
only if clearly needed. There are no adequate and well- controlled studies in pregnant women.
|
Nursing Mothers
|
| |
Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in human milk or absorbed
systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse
reactions in nursing infants from abatacept, possibly including effects on the developing immune system, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
|
Pediatric Use
|
| |
Safety and effectiveness of abatacept in pediatric patients have not been established.
|
Geriatric Use
|
| |
A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received abatacept in clinical
studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but
these numbers are too low to rule out differences. The frequency of serious infection and malignancy among abatacept- treated
patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies
in the elderly population in general, caution should be used when treating the elderly.
|
|
DRUG INTERACTIONS
|
| |
Formal drug interaction studies have not been conducted with abatacept.
Population pharmacokinetic analyses revealed that MTX, NSAIDs, corticosteroids, and TNF blocking agents did not influence
abatacept clearance (see CLINICAL PHARMACOLOGY, Pharmacokinetics ). The majority of patients in RA clinical studies received one or more of the following concomitant medications with abatacept:
MTX, NSAIDs, corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine,
and anakinra.
Concurrent administration of a TNF antagonist with abatacept has been associated with an increased risk of serious infections
and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with abatacept and TNF antagonists
is not recommended (see WARNINGS, Concomitant Use With TNF Antagonists ).
There is insufficient experience to assess the safety and efficacy of abatacept administered concurrently with anakinra, and
therefore such use is not recommended.
|
ADVERSE REACTIONS
|
| |
General
|
| |
The most serious adverse reactions were serious infections and malignancies (see Infections and Malignancies ).The most commonly reported adverse events (occurring in ≥10% of patients treated with abatacept) were headache, upper respiratory
tract infection, nasopharyngitis, and nausea.
The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of abatacept) were
due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection
(1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia
(0.2%), localized infection (0.2%), and bronchitis (0.1%).
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 abatacept in patients with active RA in placebo- controlled studies (1955 patients
with abatacept, 989 with placebo). The studies had either a double- blind, placebo- controlled period of 6 months (258 patients
with abatacept, 133 with placebo) or 1 year (1697 patients with abatacept, 856 with placebo). A subset of these patients received
concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with abatacept, 134 with placebo).
|
Infections
|
| |
In the placebo- controlled trials, infections were reported in 54% of abatacept- treated patients and 48% of placebo- treated
patients. The most commonly reported infections (reported in 5- 13% of patients) were upper respiratory tract infection, nasopharyngitis,
sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a
higher frequency (>0.5%) with abatacept compared to placebo, were rhinitis, herpes simplex, and pneumonia (see PRECAUTIONS, Infections ).
Serious infections were reported in 3.0% of patients treated with abatacept and 1.9% of patients treated with placebo. The
most common (0.2- 0.5%) serious infections reported with abatacept were pneumonia, cellulitis, urinary tract infection, bronchitis,
diverticulitis, and acute pyelonephritis (see PRECAUTIONS, Infections ).
|
Malignancies
|
| |
In the placebo- controlled portions of the clinical trials (1955 patients for a median of 12 months), the overall frequencies
of malignancies were similar in the abatacept- and placebo- treated patients (1.3% and 1.1%, respectively). However, more
cases of lung cancer were observed in abatacept- treated patients (4, 0.2%) than placebo- treated patients (0). In the cumulative
abatacept clinical trials (placebo- controlled and uncontrolled, open- label) a total of 8 cases of lung cancer (0.21 cases
per 100 patient- years) and 4 lymphomas (0.10 cases per 100 patient- years) were observed in 2688 patients (3827 patient-
years). The rate observed for lymphoma is approximately 3.5- fold higher than expected in an age- and gender- matched general
population based on the Surveillance, Epidemiology, and End Results Database. 5 Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma.Other
malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome,
ovarian, prostate, renal, thyroid, and uterine cancers (see PRECAUTIONS, Immunosuppression ). The potential role of abatacept in the development of malignancies in humans is unknown.
|
Infusion-Related Reactions and Hypersensitivity Reactions
|
| |
Acute infusion- related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies 3, 4, and
5 were more common in the abatacept- treated patients than the placebo patients (9% for abatacept, 6% for placebo). The most
frequently reported events (1- 2%) were dizziness, headache, and hypertension.
Acute infusion- related events that were reported in >0.1% and ≤1% of patients treated with abatacept included cardiopulmonary
symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria,
cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild to moderate. Fewer than 1% of abatacept-
treated patients discontinued due to an acute infusion- related event. In controlled trials, 6 abatacept- treated patients
compared to 2 placebo- treated patients discontinued study treatment due to acute infusion- related events.
Of 2688 patients treated with abatacept in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions.
Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred
in less than 0.9% of abatacept- treated patients and generally occurred within 24 hours of abatacept infusion. Appropriate
medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event
of a reaction (see PRECAUTIONS, Hypersensitivity ).
|
Adverse Reactions in Patients With COPD
|
| |
In Study 5, there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with abatacept and 17
COPD patients who were treated with placebo.The COPD patients treated with abatacept developed adverse events more frequently
than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in abatacept- treated
patients compared to placebo- treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and
dyspnea. A greater percentage of abatacept- treated patients developed a serious adverse event compared to placebo- treated
patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]).
|
Other Adverse Reactions
|
| |
Adverse events occurring in 3% or more of patients and at least 1% more frequently in abatacept- treated patients during placebo-
controlled RA studies are summarized in TABLE 6 .
| TABLE 6
Adverse Events Occurring in 3% or More of Patients and at Least 1% More Frequently in Abatacept- Treated Patients During Placebo-
Controlled RA Studies
|
| |
Abatacept |
Placebo |
| Adverse Event (Preferred Term) |
(n=1955)* |
(n=989)† |
| Headache |
18% |
13% |
| Nasopharyngitis |
12% |
9% |
| Dizziness |
9% |
7% |
| Cough |
8% |
7% |
| Back pain |
7% |
6% |
| Hypertension |
7% |
4% |
| Dyspepsia |
6% |
4% |
| Urinary tract infection |
6% |
5% |
| Rash |
4% |
3% |
| Pain in extremity |
3% |
2% |
|
| *
|
Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). |
| †
|
Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). |
|
|
Immunogenicity
|
| |
Antibodies directed against the entire abatacept molecule or to the CTLA- 4 portion of abatacept were assessed by ELISA assays
in RA patients for up to 2 years following repeated treatment with abatacept. Thirty- four of 1993 (1.7%) patients developed
binding antibodies to the entire abatacept molecule or to the CTLA- 4 portion of abatacept. Because trough levels of abatacept
can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients
that had discontinued treatment with abatacept for over 56 days developed antibodies.
Samples with confirmed binding activity to CTLA- 4 were assessed for the presence of neutralizing antibodies in a cell- based
luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies.
No correlation of antibody development to clinical response or adverse events was observed.
The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays,
and 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, timing of sample collection, concomitant
medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept with the incidence
of antibodies to other products may be misleading.
|
|
OVERDOSAGE
|
| |
Abatacept is administered as an IV infusion under medically controlled conditions. Doses up to 50 mg/ kg have been administered
without apparent toxic effect.In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms
of adverse reactions and appropriate symptomatic treatment instituted.
|
DOSAGE AND ADMINISTRATION
|
| |
Abatacept should be administered as a 30- minute IV infusion at the dose specified in TABLE 7 . Following the initial administration, abatacept should be given at 2 and 4 weeks after the first infusion, then every 4
weeks thereafter. Abatacept may be used as monotherapy or concomitantly with disease- modifying, anti- rheumatic drugs (DMARDs)
other than TNF antagonists.
| TABLE 7
Dose of Abatacept
|
| Body Weight of Patient |
Dose |
Number of Vials* |
| <60 kg |
500 mg |
2 |
| 60- 100 kg |
750 mg |
3 |
| >100 kg |
1 g |
4 |
|
| *
|
Each vial provides 250 mg of abatacept for administration. |
|
Preparation and Administration Instructions
|
| |
Use aseptic technique.
Abatacept is provided as a lyophilized powder in preservative- free, single- use vials.Refer to TABLE 7 for the dose and number of abatacept vials required. Each abatacept vial provides 250 mg of abatacept for administration.
The abatacept powder in each vial must be reconstituted with 10 ml of sterile water for injection using ONLY the SILICONE- FREE DISPOSABLE SYRINGE PROVIDED WITH EACH VIAL and an 18- 21 gauge needle. If the abatacept powder is accidentally reconstituted using a siliconized syringe, the solution
may develop a few translucent particles. Discard any solutions prepared using siliconized syringes.
If the SILICONE- FREE DISPOSABLE SYRINGE is dropped or becomes contaminated, use a new SILICONE- FREE DISPOSABLE SYRINGE from inventory.For information on obtaining additional SILICONE- FREE DISPOSABLE SYRINGES , contact Bristol- Myers Squibb 1- 800- Orencia.
During reconstitution, to minimize foam formation in solutions of abatacept, the vial should be rotated with gentle swirling
until the contents are completely dissolved. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Upon complete dissolution
of the lyophilized powder, the vial should be vented with a needle to dissipate any foam that may be present. The solution
should be clear and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are
present.
- 1. To reconstitute the abatacept powder, remove the flip- top from the vial and wipe the top with an alcohol swab. Insert the
syringe needle into the vial through the center of the rubber stopper and direct the stream of sterile water for injection
to the glass wall of the vial. Do not use the vial if the vacuum is not present.Rotate the vial with gentle swirling until
the contents are completely dissolved.
- 2. Upon complete dissolution of the lyophilized powder, the vial should be vented with a needle to dissipate any foam that may
be present. After reconstitution, each milliliter will contain 25 mg (250 mg/ 10 ml).
- 3. The reconstituted abatacept solution must be further diluted to 100 ml as follows. From a 100- ml infusion bag or bottle,
withdraw a volume of 0.9% sodium chloride injection equal to the volume of the reconstituted abatacept vials (for 2 vials
remove 20 ml, for 3 vials remove 30 ml, for 4 vials remove 40 ml). Slowly add the reconstituted abatacept solution from each
vial into the infusion bag or bottle using the same SILICONE- FREE DISPOSABLE SYRINGE PROVIDED WITH EACH VIAL. Gently mix.
The concentration of the fully diluted abatacept solution in the infusion bag or bottle will be approximately 5, 7.5, or 10
mg of abatacept per ml of solution depending on whether 2, 3, or 4 vials of abatacept are used. Any unused portion in the
vials must be immediately discarded.
- 4. Prior to administration, the abatacept solution should be inspected visually for particulate matter and discoloration. Discard
the solution if any particulate matter or discoloration is observed.
- 5. The entire, fully diluted abatacept solution should be administered over a period of 30 minutes and must be administered with
an infusion set and a STERILE, NON- PYROGENIC, LOW- PROTEIN- BINDING FILTER (pore size of 0.2- 1.2 μm).
- 6. The infusion of the fully diluted abatacept solution must be completed within 24 hours of reconstitution of the abatacept
vials. The fully diluted abatacept solution may be stored at room temperature or refrigerated at 2- 8ºC (36- 46ºF) before
use.
- 7. Abatacept should not be infused concomitantly in the same IV line with other agents. No physical or biochemical compatibility
studies have been conducted to evaluate the coadministration of abatacept with other agents.
|
Storage and Stability
|
| |
Abatacept lyophilized powder must be refrigerated at 2- 8°C (36- 46°F). Do not use beyond the expiration date. Protect the
vials from light by storing in the original package until time of use.
|
|
REFERENCES
|
| |
1. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23(2):137- 145.
2. Genant HK, Jiang Y, Peterfy C, Lu Y, Re´dei J, Countryman PJ. Assessment of rheumatoid arthritis using a modified scoring
method on digitized and original radiographs. Arthritis Rheum. 1998;41(9):1583- 1590.
3. Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon NP. Assessment of patient satisfaction in activities of daily living
using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum. 1983;26(11):1346- 1353.
4. Ware JE Jr, Gandek B. Overview of the SF- 36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol. 1998;51(11):903- 912.
5. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EF, Edwards BK (eds). SEER Cancer Statistics
Review, 1975- 2001, National Cancer Institute. Bethesda, MD, http:/ / seer.cancer.gov/ csr/ 1975_2001/ . Accessed 2004.
|
HOW SUPPLIED
|
| |
Orencia lyophilized powder for IV infusion is supplied as an individually packaged, single- use vial with a silicone- free
disposable syringe. The product is available as 250 mg of abatacept in a 15- ml vial.
|
PRODUCT IDENTIFICATION
|
| |
None Available |
PATIENT DRUG CONSULT HANDOUT
|
| |
None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| powder for injection - intravenous - 250 mg -
|
| 1.0 |
$540.00 |
Orencia
Bristol- Myers Squibb
|
00003218710 |
|
|