ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ORENCIA 250 mg powder for concentrate for solution for infusion.
2.
Each vial contains 250 mg of abatacept.
Each ml contains 25 mg of abatacept, after reconstitution.
Abatacept is a fusion protein produced by recombinant DNA technology in Chinese hamster ovary
cells.
Excipient: sodium: 0.375 mmol per vial
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
The powder is a white to off-white whole or fragmented cake.
4.
Rheumatoid arthritis
ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe
active rheumatoid arthritis in adult patients who responded inadequately to previous therapy with one
or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a
TNF-alpha inhibitor.
A reduction in the progression of joint damage and improvement of physical function have been
demonstrated during combination treatment with abatacept and methotrexate.
Polyarticular juvenile idiopathic arthritis
ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe
active polyarticular juvenile idiopathic arthritis (JIA) in paediatric patients 6 years of age and older
who have had an insufficient response to other DMARDs including at least one TNF inhibitor.
ORENCIA has not been studied in children under 6 years old.
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and
treatment of rheumatoid arthritis.
If a response to abatacept is not present within 6 months of treatment, the continuation of the treatment
should be reconsidered (see section 5.1).
Adults
To be administered as a 30-minute intravenous infusion at the dose specified in Table 1. Following the
initial administration, ORENCIA should be given 2 and 4 weeks after the first infusion, then
every 4 weeks thereafter.
2
Table 1: Dose of ORENCIA
a
Body Weight of Patient
Dose
Number of Vials
b
< 60 kg
500 mg
2
≥ 60 kg to ≤ 100 kg
750 mg
3
> 100 kg
1,000 mg
4
a
Approximating 10 mg/kg.
b
Each vial provides 250 mg of abatacept for administration.
No dose adjustment is required when used in combination with other DMARDs, corticosteroids,
salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics.
Elderly patients
No dose adjustment is required.
Paediatric patients
Juvenile Idiopathic Arthritis
. The recommended dose of ORENCIA for patients 6 to 17 years of age
with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the
patient’s body weight at each administration. Paediatric patients weighing 75 kg or more should be
administered ORENCIA following the adult dosing regimen, not to exceed a maximum dose of
1,000 mg. ORENCIA should be administered as a 30-minute intravenous infusion. Following the
initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every
4 weeks thereafter.
The safety and efficacy of ORENCIA in children below 6 years of age have not been studied and
therefore, ORENCIA is not recommended for use in children under six years old.
Renal and hepatic impairment
ORENCIA has not been studied in these patient populations. No dose recommendations can be made.
Method of administration
Each vial of ORENCIA 250 mg must be reconstituted with 10 ml of water for injections, using the
silicone-free syringe provided. The reconstituted solution must then be diluted to 100 ml with sodium
chloride 9 mg/ml (0.9%) solution for injection, before administration by intravenous infusion (see
section 6.6).
Hypersensitivity to the active substance or to any of the excipients.
Severe and uncontrolled infections such as sepsis and opportunistic infections (see section 4.4).
Combination with TNF-antagonists
There is limited experience with use of abatacept in combination with TNF-antagonists (see
section 5.1). In placebo-controlled clinical trials, in comparison with patients treated with TNF-
antagonists and placebo, patients who received combination TNF-antagonists with abatacept
experienced an increase in overall infections and serious infections (see section 4.5). Abatacept is not
recommended for use in combination with TNF-antagonists.
While transitioning from TNF-antagonist therapy to ORENCIA therapy, patients should be monitored
for signs of infection (see section 5.1, Study VII).
Allergic reactions
Allergic reactions have been reported uncommonly with abatacept administration in clinical trials,
where patients were not required to be pretreated to prevent allergic reactions (see section 4.8).
Anaphylactic reactions have been reported rarely. Special caution should be exercised in patients with
a history of allergic reactions to abatacept or to any of the excipients. If any serious allergic or
3
anaphylactic reaction occurs, ORENCIA therapy should be discontinued immediately and appropriate
therapy initiated.
Effects on the immune system
Medicinal products which affect the immune system, including ORENCIA, may affect host defences
against infections and malignancies, and affect vaccination responses.
Co-administration of ORENCIA with biologic immunosuppressive or immunomodulatory agents
could potentiate the effects of ORENCIA on the immune system. There is insufficient evidence to
assess the safety and efficacy of ORENCIA in combination with anakinra or rituximab.
Infections
Serious infections, including sepsis and pneumonia, have been reported with abatacept (see
section 4.8). Some of these infections have been fatal. Many of the serious infections have occurred in
patients on concomitant immunosuppressive therapy which in addition to their underlying disease,
could further predispose them to infections. Treatment with ORENCIA should not be initiated in
patients with active infections until infections are controlled. Physicians should exercise caution when
considering the use of ORENCIA in patients with a history of recurrent infections or underlying
conditions which may predispose them to infections. Patients who develop a new infection while
undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA
should be discontinued if a patient develops a serious infection.
No increase of tuberculosis was observed in the pivotal placebo-controlled studies. Nevertheless,
patients should be screened for latent tuberculosis prior to initiating ORENCIA. The available medical
guidelines should also be taken into account.
Anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for
viral hepatitis should be performed in accordance with published guidelines before starting therapy
with ORENCIA.
Treatment with immunosuppressive therapy, such as ORENCIA, may be associated with progressive
multifocal leukoencephalopathy (PML). If neurological symptoms suggestive of PML occur during
ORENCIA therapy, treatment with ORENCIA should be discontinued and appropriate diagnostic
measures initiated.
Malignancies
In the placebo-controlled clinical trials, the frequencies of malignancies in abatacept- and
placebo-treated patients were 1.4% and 1.1%, respectively (see section 4.8). Patients with known
malignancies were not included in these clinical trials. In carcinogenicity studies in mice, an increase
in lymphomas and mammary tumours were noted. The clinical significance of this observation is
unknown (see section 5.3). The potential role of ORENCIA in the development of malignancies,
including lymphoma, in humans is unknown.
Vaccinations
Live vaccines should not be given concurrently with ORENCIA 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 ORENCIA. Insufficient data are available on the effects
of vaccinations in patients receiving ORENCIA. Medicinal products that affect the immune system,
including ORENCIA, may blunt the effectiveness of some immunisations.
It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all
immunizations in agreement with current immunization guidelines prior to initiating ORENCIA
therapy.
Elderly patients
A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received
abatacept in placebo-controlled clinical trials. Similar efficacy was observed in these patients and in
younger patients. The frequencies of serious infection and malignancy relative to placebo among
4
abatacept-treated patients over age 65 were higher than among those under age 65. Because there is a
higher incidence of infections and malignancies in the elderly in general, caution should be used when
treating the elderly (see section 4.8).
Autoimmune processes
There is a theoretical concern that treatment with ORENCIA might increase the risk for autoimmune
processes in adults and children, for example deterioration of multiple sclerosis. In the placebo-
controlled clinical trials, abatacept treatment did not lead to increased autoantibody formation, such as
antinuclear and anti-dsDNA antibodies, relative to placebo treatment (see sections 4.8 and 5.3).
Blood glucose testing
Parenteral medicinal products containing maltose can interfere with the readings of blood glucose
monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The
GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA,
resulting in falsely elevated blood glucose readings on the day of infusion. When receiving
ORENCIA, patients that require blood glucose monitoring should be advised to consider methods that
do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine
dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.
Patients on controlled sodium diet
This medicinal product contains 1.5 mmol (or 34.5 mg) sodium per maximum dose of 4 vials
(0.375 mmol or 8.625 mg sodium per vial). To be taken into consideration when treating patients on a
controlled sodium diet.
Combination with TNF-antagonists
There is limited experience with the use of abatacept in combination with TNF-antagonists (see
section 5.1). While TNF-antagonists did not influence abatacept clearance, in placebo-controlled
clinical trials, patients receiving concomitant treatment with abatacept and TNF-antagonists
experienced more infections and serious infections than patients treated with only TNF-antagonists.
Therefore, concurrent therapy with ORENCIA and a TNF-antagonist is not recommended.
Combination with other medicinal products
Population pharmacokinetic analyses did not detect any effect of methotrexate, NSAIDs, and
corticosteroids on abatacept clearance (see section 5.2).
No major safety issues were identified with use of abatacept in combination with sulfasalazine,
hydroxychloroquine, or leflunomide.
See section 4.4 regarding combination with other medicinal products that affect the immune system
and with vaccinations.
There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo-fetal
development studies no undesirable effects were observed at doses up to 29-fold a human 10 mg/kg
dose based on AUC. In a pre- and postnatal development study in rats limited changes in immune
function were observed at 11-fold a human 10 mg/kg dose based on AUC (see section 5.3). ORENCIA
should not be used in pregnant women unless clearly necessary. Women of child-bearing potential
should use effective contraception during treatment with ORENCIA and up to 14 weeks after the last
dose of abatacept treatment.
Use during lactation
Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in
human milk. Women should not breastfeed while treated with ORENCIA and for up to 14 weeks after
the last dose of abatacept treatment.
5
Fertility
Formal studies of the potential effect of ORENCIA on human fertility have not been conducted.
In rats, abatacept had no undesirable effects on male or female fertility (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed.
Abatacept has been studied in patients with active rheumatoid arthritis in placebo-controlled clinical
trials (1,955 patients with abatacept, 989 with placebo). The trials had either a double-blind,
placebo-controlled period of 6 months (258 patients with abatacept, 133 with placebo) or 1 year
(1,697 patients with abatacept, 856 with placebo). Most patients in these trials were taking
methotrexate (81.9% with abatacept, 83.3% with placebo). Other concomitant medications included:
NSAIDs (83.9% with abatacept, 85.1% with placebo); systemic corticosteroids (74.7% with
abatacept, 75.8% with placebo); non-biological DMARD therapy, most commonly
chloroquine/hydroxychloroquine, leflunomide and/or sulfasalazine (26.9% with abatacept, 32.1% with
placebo); TNF-antagonists, mainly etanercept (9.4% with abatacept, 12.3% with placebo); and
anakinra (1.1% with abatacept, 1.6% with placebo).
In placebo-controlled clinical trials with abatacept, adverse drug reactions (ADRs) were reported
in 52.2% of abatacept-treated patients and 46.1% of placebo-treated patients. The most frequently
reported adverse drug reactions (≥ 5%) among abatacept-treated patients were headache and nausea.
The proportion of patients who discontinued treatment due to ADRs was 3.4% for abatacept-treated
patients and 2.2% for placebo-treated patients.
Listed in Table 2 are adverse drug reactions based on experience in controlled clinical trials in adults
that occurred with greater frequency (difference > 0.2%) in abatacept-treated patients than in
placebo-treated patients. The list is presented by system organ class and frequency, using the
following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency
grouping, undesirable effects are presented in order of decreasing seriousness.
Table 2:
Undesirable Effects in Placebo-Controlled Trials
Investigations
Common
Blood pressure increased, liver function test
abnormal (including transaminases increased)
Uncommon
Blood pressure decreased, weight increased
Cardiac disorders
Uncommon
Tachycardia, bradycardia, palpitations
Blood and lymphatic system
disorders
Uncommon
Thrombocytopenia, leukopenia
Nervous system disorders
Very Common Headache
Common
Dizziness
Uncommon
Paraesthesia
Eye disorders
Uncommon
Conjunctivitis, visual acuity reduced
Ear and labyrinth disorders
Uncommon
Vertigo
6
Respiratory, thoracic and
mediastinal disorders
Common
Cough
Gastrointestinal disorders
Common
Abdominal pain, diarrhoea, nausea, dyspepsia
Uncommon
Gastritis, mouth ulceration, aphthous stomatitis
Skin and subcutaneous tissue
disorders
Common
Rash (including dermatitis)
Uncommon
Increased tendency to bruise, alopecia, dry skin
Musculoskeletal and connective
tissue disorders
Uncommon
Arthralgia, pain in extremity
Infections and infestations
Common
Lower respiratory tract infection (including
bronchitis), urinary tract infection, herpes
simplex, upper respiratory tract infection
(including tracheitis, nasopharyngitis), rhinitis
Uncommon
Tooth infection, infected skin ulcer,
onychomycosis
Neoplasms benign, malignant
and unspecified (incl. cysts and
polyps)
Uncommon
Basal cell carcinoma
Vascular disorders
Common
Hypertension, flushing
Uncommon
Hypotension, hot flush
General disorders and
Common
Fatigue, asthenia
administration site conditions
Uncommon
Influenza like illness
Reproductive system and breast
disorders
Uncommon
Amenorrhea
Psychiatric disorders
Uncommon
Depression, anxiety
ADRs reported in abatacept-treated patients which did not occur with an excess incidence (i.e. the
difference was not > 0.2%) over placebo but were considered to be medically relevant include the
following events:
Common: herpes zoster;
Uncommon: pneumonia, hypersensitivity, pyelonephritis, bronchospasm, urticaria, psoriasis, cystitis,
migraine, throat tightness, dry eye;
Rare: sepsis, bacteraemia.
Additional information
Infections
In the placebo-controlled clinical trials, infections at least possibly related to treatment were reported
in 23.2% of abatacept-treated patients and 19.5% of placebo-treated patients.
7
Serious infections at least possibly related to treatment were reported in 1.8% of abatacept-treated
patients and 1.0% of placebo-treated patients. Serious infections reported in at least one patient treated
with abatacept (0.05% of patients) included the following: pneumonia; bronchitis; cellulitis; acute
pyelonephritis; urinary tract infection; diverticulitis, intestinal abscess; localised infection; skin
abscess; musculoskeletal infections; sepsis; empyema; hepatitis E; and tuberculosis (see section 4.4).
In double blind and open-label clinical trials in 4,149 patients treated with abatacept during
11,658 patient-years, the incidence rate of serious infections was 2.87 per 100 patient -years, and the
annualized incidence rate remained stable.
Malignancies
In placebo-controlled clinical trials, malignancies were reported in 27 of 1,955 abatacept-treated
patients observed during 1,687 patient-years, and in 11 of 989 placebo-treated patients observed
during 794 patient-years.
In double blind and open-label clinical trials in 4,149 patients treated with abatacept during
11,658 patient-years (of which over 1,000 were treated with abatacept for over 5 years), the incidence
rate of malignancy was 1.43 per 100 patient-years, and the annualized incidence rate remained stable.
The incidence rates per 100 patient-years were 0.72 for non-melanomatous skin cancer, 0.59 for solid
malignancies and 0.13 for hematologic malignancies. The most frequently reported organ cancer was
lung cancer (0.17 per 100 patient-years), and the most common hematologic malignancy was
lymphoma (0.06 per 100 patient-years). The incidence rate did not increase for malignancies overall,
by major type (non-melanomatous skin cancer, solid tumors, and hematologic malignancies), or for
individual tumor types in the double blind and open label period compared to the double-blind
experience. The type and pattern of malignancies reported during the open-label period of the trials
were similar to those reported for the double-blind experience.
The incidence rate of observed malignancies was consistent with that expected in an age- and
gender-matched rheumatoid arthritis population (see section 4.4).
Infusion-related reactions
Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in
Studies II, III, and IV (see section 5.1) were more common in the abatacept-treated patients than the
placebo-treated patients (9.8% for abatacept, 6.7% for placebo). The most frequently reported events
with abatacept (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, decreased blood
pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity,
pruritus, rash, and wheezing. Most of these reactions were mild to moderate.
The occurrence of anaphylaxis remained rare between the double blind and long-term open-label
experience. Hypersensitivity was reported uncommonly. Other reactions potentially associated with
hypersensitivity to the medicinal product, such as hypotension, urticaria, and dyspnea, that occurred
within 24 hours of ORENCIA infusion, were uncommon.
Discontinuation due to an acute infusion-related reaction occurred in 0.4% of patients receiving
abatacept and in 0.2% of placebo-treated patients.
Adverse drug reactions in patients with chronic obstructive pulmonary disease (COPD)
In Study IV, there were 37 patients with COPD treated with abatacept and 17 treated with placebo.
The COPD patients treated with abatacept developed adverse drug reactions more frequently than
those treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred more
frequently in abatacept-treated patients than in placebo-treated patients (10.8% vs. 5.9%, respectively);
these included COPD exacerbation, and dyspnea. A greater percentage of abatacept- than
8
placebo-treated patients with COPD developed a serious adverse reaction (5.4% vs. 0%), including
COPD exacerbation (1 of 37 patients [2.7%]) and bronchitis (1 of 37 patients [2.7%]).
Autoimmune processes
Abatacept therapy did not lead to increased formation of autoantibodies, i.e., antinuclear and anti-
dsDNA antibodies, compared with placebo.
The incidence rate of autoimmune disorders remained stable during open-label experience (1.63 per
100 patient -years) compared to the double blind experience (2.07 per 100 patient -years).The most
frequently reported autoimmune-related disorders during the open-label experience were psoriasis,
vasculitis, and Sjogren's syndrome.
Immunogenicity
Antibodies directed against the abatacept molecule were assessed by ELISA assays in 3,985
rheumatoid arthritis patients treated for up to 8 years with abatacept. One hundred and eighty-seven
of 3,877 (4.8%) patients developed anti-abatacept antibodies while on treatment. In patients assessed
for anti-abatacept antibodies after discontinuation of abatacept (> 42 days after last dose), 103 of 1,888
(5.5%) were seropositive.
Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing
antibodies. Twenty-two of 48 evaluable patients showed significant neutralizing activity. The potential
clinical relevance of neutralizing antibody formation is not known.
Overall, there was no apparent correlation of antibody development to clinical response or adverse
events. However, the number of patients that developed antibodies was too limited to make a
definitive assessment. Because immunogenicity analyses are product-specific, comparison of antibody
rates with those from other products is not appropriate.
Safety information related to the pharmacological class
Abatacept is the first selective co-stimulation modulator. Information on the relative safety in a
clinical trial versus infliximab is summarized in section 5.1.
Very common: headache, nausea;
Common: diarrhoea, cough, upper respiratory tract infection, pyrexia, nasopharyngitis, upper
abdominal pain.
ORENCIA has been studied in 190 paediatric patients, 6 to 17 years of age, with polyarticular JIA (see
section 5.1). Adverse reactions (adverse events occurring at a prevalence of at least 5% in the 4 month,
lead-in, open-label period of the study) were similar in type to those seen in adults (Table 2) with the
exception that pyrexia was reported in paediatric patients.
Infections
The types of infections were consistent with those commonly seen in outpatient paediatric populations.
The infections resolved without sequelae. One serious infection (varicella) was reported during the
initial 4 months of treatment with ORENCIA.
Infusion-related reactions
Of the 190 patients with JIA treated with ORENCIA in this study, one (0.5%) patient discontinued due
to non-consecutive infusion reactions, consisting of bronchospasm and urticaria. During Periods A, B,
and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and
were consistent with the types of reactions reported in adults.
Immunogenicity
Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were
assessed by ELISA assays in patients with polyarticular JIA following repeated treatment with
9
ORENCIA. The rate of seropositivity while patients were receiving abatacept therapy was 0.5%
(1/189) during Period A; 13.0% (7/54) during Period B; and 11.4% (17/149) during Period C. For
patients in Period B who were randomized to placebo (therefore withdrawn from therapy for up to
6 months) the rate of seropositivity was 40.7% (22/54). Anti-abatacept antibodies were generally
transient and of low titer. The absence of concomitant methotrexate (MTX) did not appear to be
associated with a higher rate of seropositivity in Period B placebo recipients. The presence of
antibodies was not associated with adverse reactions or infusional reactions, or with changes in
efficacy or serum abatacept concentrations. Of the 54 patients withdrawn from ORENCIA during the
double-blind period for up to 6 months, none had an infusion reaction upon re-initiation of ORENCIA.
Open-label extension period
Upon continued treatment in the open-label extension period, the adverse reactions were similar in
type to those seen in adult patients. One patient was diagnosed with multiple sclerosis while in Period
C (open-label extension).
Doses up to 50 mg/kg have been administered without apparent toxic effect. In case of overdose, it is
recommended that the patient be monitored for any signs or symptoms of adverse reactions and
appropriate symptomatic treatment instituted.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA24
Abatacept is a fusion protein that consists of the extracellular domain of human
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human
immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in Chinese
hamster ovary cells.
Mechanism of action
Abatacept selectively modulates a key costimulatory signal required for full activation of T
lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided by
antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second,
costimulatory signal. A major costimulatory pathway involves the binding of CD80 and
CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes
(signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding to
CD80 and CD86. Studies indicate that naive T lymphocyte responses are more affected by abatacept
than memory T lymphocyte responses.
Studies
in vitro
and in animal models demonstrate that abatacept modulates T lymphocyte-dependent
antibody responses and inflammation.
In vitro
, abatacept attenuates human T lymphocyte activation as
measured by decreased proliferation and cytokine production. Abatacept decreases antigen specific
TNFα, interferon-γ, and interleukin-2 production by T lymphocytes.
Pharmacodynamic effects
Dose-dependent reductions were observed with abatacept in serum levels of soluble
interleukin-2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of
activated synovial macrophages and fibroblast-like synoviocytes in rheumatoid arthritis; rheumatoid
factor, an autoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant of
inflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilage
destruction and tissue remodelling, were decreased. Reductions in serum TNFα were also observed.
10
Clinical efficacy and safety in adult rheumatoid arthritis
The efficacy and safety of abatacept were assessed in randomised, double-blind, placebo-controlled
clinical trials in adult patients with active rheumatoid arthritis diagnosed according to American
College of Rheumatology (ACR) criteria. Studies I, II, III, V, and VI required patients to have at
least 12 tender and 10 swollen joints at randomization. Study IV did not require any specific number
of tender or swollen joints.
In Studies I, II, and V the efficacy and safety of abatacept compared to placebo were assessed in
patients with an inadequate response to methotrexate and who continued on their stable dose of
methotrexate. In addition, Study V investigated the safety and efficacy of abatacept or infliximab
relative to placebo. In Study III the efficacy and safety of abatacept were assessed in patients with an
inadequate response to a TNF-antagonist, with the TNF-antagonist discontinued prior to
randomization; other DMARDs were permitted. Study IV primarily assessed safety in patients with
active rheumatoid arthritis requiring additional intervention in spite of current therapy with
non-biological and/or biological DMARDs; all DMARDs used at enrollment were continued. In Study
VI, the efficacy and safety of abatacept were assessed in methotrexate-naive, Rheumatoid Factor (RF)
and/or anti-Cyclic Citrullinated Peptide 2 (Anti-CCP2)-positive patients with early, erosive
rheumatoid arthritis (≤ 2 years disease duration) who were randomized to receive abatacept plus
methotrexate or methotrexate plus placebo.
Study I patients were randomized to receive abatacept 2 or 10 mg/kg or placebo for 12 months. Study
II, III, IV, and VI patients were randomized to receive a fixed dose approximating 10 mg/kg of
abatacept or placebo for 12 (Studies II, IV, and VI) or 6 months (Study III). The dose of abatacept
was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and
1,000 mg for patients weighing greater than 100 kg. Study V patients were randomized to receive this
same fixed dose of abatacept or 3 mg/kg infliximab or placebo for 6 months. Study V continued for an
additional 6 months with the abatacept and infliximab groups only.
Studies I, II, III, IV, V, and VI evaluated 339, 638, 389, 1,441, 431, and 509 adult patients,
respectively.
Clinical response
ACR response
The percent of abatacept-treated patients achieving ACR 20, 50, and 70 responses in Study II (patients
with inadequate response to methotrexate), Study III (patients with inadequate response to TNF-
antagonist), and Study VI (methotrexate-naive patients) are shown in Table 3.
In abatacept-treated patients in Studies II and III, statistically significant improvement in the
ACR 20 response versus placebo was observed after administration of the first dose (day 15), and this
improvement remained significant for the duration of the studies. In Study VI, statistically significant
improvement in the ACR 20 response in abatacept plus methotrexate-treated patients versus
methotrexate plus placebo-treated patients was observed at 29 days, and was maintained through the
duration of the study. In Study II, 43% of the patients who had not achieved an ACR 20 response
at 6 months developed an ACR 20 response at 12 months.
11
Table 3:
Clinical Responses in Controlled Trials
Percent of Patients
MTX-Naive
Inadequate Response to
MTX
Inadequate Response to
TNF Blocking Agent
Study VI
Study II
Study III
Response Rate
Abatacept
a
+MTX
n = 256
Placebo
+MTX
n = 253
Abatacept
a
+MTX
n = 424
Placebo
+MTX
n = 214
Abatacept
a
+DMARDs
b
n = 256
Placebo
+DMARDs
b
n = 133
ACR 20
Day 15
24%
18%
23%
*
14%
18%
**
5%
Month 6
75%
†
62%
68%
***
40%
50%
***
20%
Month 12
76%
‡
62%
73%
***
40%
NA
d
NA
d
Month 6
53%
‡
38%
40%
***
17%
20%
***
4%
Month 12
57%
‡
42%
48%
***
18%
NA
d
NA
d
ACR 70
Month 6
32%
†
20%
20%
***
7%
10%
**
2%
Month 12
43%
‡
27%
29%
***
6%
NA
d
NA
d
Major Clinical
Response
c
27%
‡
12%
14%***
2%
NA
d
NA
d
DAS28-CRP
Remission
e
Month 6
28%
‡
15%
NA
NA
NA
NA
Month 12
41%
‡
23%
NA
NA
NA
NA
*
p < 0.05, abatacept vs. placebo.
**
p < 0.01, abatacept vs. placebo.
***
p < 0.001, abatacept vs. placebo.
†
p < 0.01, abatacept plus MTX vs. MTX plus placebo
‡
p < 0.001, abatacept plus MTX vs. MTX plus placebo
a
Fixed dose approximating 10 mg/kg (see section 4.2).
b
Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine,
sulfasalazine, leflunomide, azathioprine, gold, and anakinra.
c
Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.
d
After 6 months, patients were given the opportunity to enter an open-label study.
e
DAS28-CRP Remission is defined as a DAS28-CRP score < 2.6
In the open-label extension of Studies I, II, III, and VI durable and sustained ACR 20, 50,
and 70 responses have been observed through 7 years, 5 years, 5 years, and 2 years, respectively, of
abatacept treatment. In study I, ACR responses were assessed at 7 years in 43 patients with 72% ACR
20 responses, 58% ACR 50 responses, and 44% ACR 70 responses. In study II, ACR responses were
assessed at 5 years in 270 patients with 84% ACR 20 responses, 61% ACR 50 responses, and 40%
ACR 70 responses. In study III, ACR responses were assessed at 5 years in 91 patients with 74% ACR
20 responses, 51% ACR 50 responses, and 23% ACR 70 responses. In study VI, ACR responses were
assessed at 2 years in 232 patients with 85% ACR 20 responses, 74% ACR 50 responses, and 54%
ACR 70 responses.
Greater improvements were seen with abatacept than with placebo in other measures of rheumatoid
arthritis disease activity not included in the ACR response criteria, such as morning stiffness.
DAS28 response
Disease activity was also assessed using the Disease Activity Score 28. There was a significant
improvement of DAS in Studies II, III, V, and VI as compared to placebo or comparator.
12
ACR 50
In study VI, a significantly higher proportion of patients in the abatacept plus methotrexate group
(41%) achieved DAS28 (CRP)-defined remission (score < 2.6) versus the methotrexate plus placebo
group (23%) at year 1. The response at Day 365 in the abatacept group was maintained through year 2.
Study V: abatacept or infliximab versus placebo
A randomized, double-blind study was conducted to assess the safety and efficacy of abatacept or
infliximab versus placebo in patients with an inadequate response to methotrexate (Study V). The
primary outcome was the mean change in disease activity in abatacept- treated patients compared to
placebo-treated patients at 6 months with a subsequent double-blind assessment of safety and efficacy
of abatacept and infliximab at 12 months. Greater improvement (p < 0.001) in DAS28 was observed
with abatacept and with infliximab compared to placebo at six months in the placebo-controlled
portion of the trial; the results between the abatacept and infliximab groups were similar. The ACR
responses in Study V were consistent with the DAS28 score. Further improvement was observed at 12
months with abatacept. At 6 months, the incidence of AE of infections were 48.1% (75), 52.1% (86),
and 51.8% (57) and the incidence of serious AE of infections were 1.3% (2), 4.2% (7), and 2.7% (3)
for abatacept, infliximab and placebo groups, respectively. At 12 months, the incidence of AE of
infections were 59.6% (93), 68.5% (113), and the incidence of serious AE of infections were 1.9% (3)
and 8.5% (14) for abatacept and infliximab groups, respectively. The open label period of the study
provided an assessment of the ability of abatacept to maintain efficacy for subjects originally
randomized to abatacept and the efficacy response of those subjects who were switched to abatacept
following treatment with infliximab. The reduction from baseline in mean DAS28 score at day 365
(-3.06) was maintained through day 729 (-3.34) in those patients who continued with abatacept. In
those patients who initially received infliximab and then switched to abatacept, the reduction in the
mean DAS28 score from baseline were 3.29 at day 729 and 2.48 at day 365.
Radiographic response
Structural joint damage was assessed radiographically over a two-year period in Studies II, and VI.
The results were measured using the Genant-modified total Sharp score (TSS) and its components, the
erosion score and joint space narrowing (JSN) score.
In Study II, the baseline median TSS was 31.7 in abatacept-treated patients and 33.4 in placebo-treated
patients. Abatacept/methotrexate reduced the rate of progression of structural damage compared to
placebo/methotrexate after 12 months of treatment as shown in Table 4. The rate of progression of
structural damage in year 2 was significantly lower than that in year 1 for patients randomized to
abatacept (p < 0.0001). Subjects entering the long term extension after 1 year of double blind
treatment all received abatacept treatment and radiographic progression was investigated through year
5. Data were analyzed in an as-observed analysis using mean change in total score from the previous
annual visit. The mean change was, 0.41 and 0.74 from year 1 to year 2 (n=290, 130), 0.37 and 0.68
from year 2 to year 3 (n=293, 130), 0.34 and 0.43 year from 3 to year 4 (n=290, 128) and the change
was 0.26 and 0.29 (n=233, 114) from year 4 to year 5 for patients originally randomized to abatacept +
MTX and placebo + MTX respectively.
Table 4:
Mean Radiographic Changes Over 12 Months in Study II
Parameter
Abatacept/MTX
n = 391
Placebo/MTX
n = 195
P-value
a
Total Sharp score
1.21
2.32
0.012
Erosion score
0.63
1.14
0.029
JSN score
0.58
1.18
0.009
a
Based on non-parametric analysis.
In Study VI, the mean change in TSS at 12 months was significantly lower in patients treated with
abatacept plus methotrexate compared to those treated with methotrexate plus placebo. At 12 months
61% (148/242) of the patients treated with abatacept plus methotrexate and 53% (128/242) of the
13
patients treated with methotrexate plus placebo had no progression (TSS ≤ 0). The progression of
structural damage was lower in patients receiving continuous abatacept plus methotrexate treatment
(for 24 months) compared to patients who initially received methotrexate plus placebo (for 12 months)
and were switched to abatacept plus methotrexate for the next 12 months. Among the patients who
entered the open-label 12 month period, 59% (125/213) of patients receiving continuous abatacept
plus methotrexate treatment and 48% (92/192) of patients who initially received methotrexate and
switched to combination with abatacept had no progression.
Physical function response
Improvement in physical function was measured by the Health Assessment Questionnaire Disability
Index (HAQ-DI) in Studies II, III, IV, V, and VI and the modified HAQ-DI in Study I. The results
from Studies II, III, and VI are shown in Table 5.
Table 5:
Improvement in Physical Function in Controlled Trials
Methotrexate-Naive
Inadequate Response to
Methotrexate
Inadequate Response to
TNF Blocking Agent
Study VI
Study II
Study III
HAQ
c
Disability
Index
Abatacept
a
+MTX
Placebo
+MTX
Abatacept
a
+MTX
Placebo
+MTX
Abatacept
a
+DMARDs
b
Placebo
+DMARDs
b
Baseline (Mean)
1.7
(n=254)
1.7
(n=251)
1.69
(n=422)
1.69
(n=212)
1.83
(n=249)
1.82
(n=130)
Mean Improvement
from Baseline
Month 6
0.85
(n=250)
0.68
(n=249)
0.59
***
(n=420)
0.40
(n=21)
0.45
***
(n=249)
0.11
(n=130)
Month 12
0.96
(n=254)
0.76
(n=251)
0.66
***
(n=422)
0.37
(n=212)
NA
e
NA
e
Proportion of patients
with a clinically
meaningful
improvement
d
Month 6
72%
†
63%
61%
***
45%
47%
***
23%
Month 12
72%
†
62%
64%
***
39%
NA
e
NA
e
***
p < 0.001, abatacept vs. placebo.
†
p < 0.05, abatacept plus MTX vs MTX plus placebo
a
Fixed dose approximating 10 mg/kg (see section 4.2)
.
b
Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine,
sulfasalazine, leflunomide, azathioprine, gold, and anakinra.
c
Health Assessment Questionnaire; 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating,
walking, hygiene, reach, grip, and activities.
d
Reduction in HAQ-DI of ≥ 0.3 units from baseline.
e
After 6 months, patients were given the opportunity to enter into an open-label study.
In Study II, among patients with clinically meaningful improvement at month 12, 88% retained the
response at month 18, and 85% retained the response at month 24. During the open-label periods of
Studies I, II, III, and VI the improvement in physical function has been maintained through 7 years,
5 years, 5 years, and 2 years, respectively.
Health-related outcomes and quality of life
Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies I, II, and
III and at 12 months in Studies I and II. In these studies, clinically and statistically significant
improvement was observed in the abatacept group as compared with the placebo group in
all 8 domains of the SF-36 (4 physical domains: physical function, role physical, bodily pain, general
14
health; and 4 mental domains: vitality, social function, role emotional, mental health), as well as the
Physical Component Summary (PCS) and the Mental Component Summary (MCS). In Study VI,
improvement was observed at 12 months in abatacept plus methotrexate group as compared with the
methotrexate plus placebo group in both PCS and MCS, and was maintained through 2 years.
Study VII: Safety of abatacept in patients with or without washout of previous TNF blocking agent
therapy
A study of open-label abatacept on a background of nonbiologic DMARDs was conducted in patients
with active RA who had an inadequate response to previous (washout for at least 2 months; n=449) or
current (no washout period; n=597) TNF-antagonist therapy (Study VII). The primary outcome,
incidence of AEs, SAEs, and discontinuations due to AEs during 6 months of treatment, was similar
between those who were previous and current TNF-antagonist users at enrollment, as was the
frequency of serious infections.
Paediatric population in polyarticular juvenile idiopathic arthritis
Children and adolescents with moderate to severe active JIA, ages 6 to 17 years with an inadequate
response or intolerance to at least one DMARD, which may have included biologic agents, were
enrolled. The safety and efficacy of ORENCIA were assessed in a three-part study. Period A was a 4-
month open-label lead-in designed to induce an ACR Pedi 30 response. Patients achieving at least a
ACR Pedi 30 response at the end of Period A were randomized into a double-blind, withdrawal phase
(Period B), and received either ORENCIA or placebo for 6 months or until JIA disease flare as defined
in the study. Unless they had discontinued due to safety reasons, all patients who completed, or had a
flare during Period B or were non-responders in Period A were offered entry into Period C, the open-
label extension, which assessed long-term safety and efficacy.
In Period A all patients received 10 mg/kg of abatacept on days 1, 15, 29, 57 and 85 and were assessed
on day 113. During period A, 74% were taking methotrexate (mean dose at study entry,
13.2 mg/m
2
/week) thus, 26% of patients received ORENCIA monotherapy in Period A. Of the
190 patients entering the study, 57 (30%) had previously been treated with anti-TNF therapy.
ACR Pedi 30 responders at the end of Period A were randomized into Period B, the double-blind,
withdrawal phase, to receive either ORENCIA or placebo for 6 months or until JIA flare.
Flare was defined as:
≥ 30% worsening in at least 3 of the 6 polyarticular JIA core set variables
≥ 30% improvement in not more than 1 of the 6 polyarticular JIA core set variables
≥ 2 cm (possible up to 10 cm) of worsening must have been present if the Physician or Parent
Global Assessment was used to define flare
worsening in ≥ 2 joints must have been present if the number of active joints or joints with
limited range of motion was used to define flare
The patients entered in the trial were a mean of 12.4 years of age with mean disease duration of
4.4 years. They had active disease, with baseline mean active joint count of 16 and a mean number of
joints with loss of motion of 16; and elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dl) and
ESRs (mean, 32 mm/h). Their JIA subtypes at disease onset were: Oligoarticular (16%), Polyarticular
(64%; 20% of the total were rheumatoid factor positive), and Systemic (20%).
Of the 190 patients enrolled, 170 completed Period A, 65% (123/190) achieved an ACR Pedi 30
response, and 122 were randomized to Period B. Responses were similar in all subtypes of JIA studied
and for patients with or without methotrexate use. Of the 133 (70%) patients with no prior TNF-
antagonist therapy, 101 (76%) achieved at least an ACR Pedi 30 response; of the 57 patients who had
received prior TNF-antagonist therapy, 22 (39%) achieved at least an ACR Pedi 30 response.
During Period B, the time to disease flare for the patients randomized to placebo was significantly
shorter than for those randomized to abatacept (primary endpoint, p=0.0002; log-rank test).
Significantly more placebo recipients flared during Period B (33/62; 53%) than those maintained on
abatacept (12/60; 20%; chi-square p<0.001). The risk of disease flare for patients continuing on
15
abatacept was less than one third that for placebo-treated patients (hazard ratio estimate=0.31; 95% CI
0.16, 0.59).
Most randomized Period B patients entered Period C (58/60 Period B abatacept recipients; 59/62
Period B placebo recipients), as did 36 of the 47 Period A non-responders (n=153 total patients).
Response rates at the end of Period A, at the end of Period B and after 21 months exposure in Period C
are summarized in Table 6:
Table 6:
Proportion (%) of Polyarticular JIA Patients with ACR Responses or
I
nactive Disease
End of
Period A
(Day 113)
End of Period B
a
(Day 169)
Period C
(Day 589)
Abatacept Abatacept Placebo Abatacept group
in Period B
Placebo group
in Period B
Non-responder in
Period A
n= 190
n= 58
n= 59 n= 51
n= 47
n= 22
ACR30
65
85
68
90
87
73
ACR50
50
79
53
88
83
64
ACR70
28
55
31
75
75
46
ACR90
13
41
15
57
40
18
Inactive
disease
Not
assessed
31
10
43
23
5
a
Day 169 Last Observation Carried Forward (LOCF) for patients treated in Period C
Participants in Period C at day 589 included 51 of the 58 Period B abatacept recipients, 47 of the 59
Period B placebo recipients, and 22 of the 36 Period A non-responders. At the time of database lock
all patients remaining in Period C had received at least 21 months (589 days) of treatment. The median
duration of abatacept treatment in Period C was 898 days (range 56–1,322 days; nearly 32 months).
Fifty-three (35%) of the subjects had received at least 1,020 days (~ 36 months) of abatacept therapy
in Period C. All patients had at least 4 months of prior, open-label abatacept treatment in Period A.
The European Medicines Agency has waived the obligation to submit the results of studies with
ORENCIA in all subsets of the paediatric population from birth to less than 18 years of age with
Rheumatoid arthritis.
5.2 Pharmacokinetic properties
After multiple intravenous infusions (days 1, 15, 30, and every 4 weeks thereafter), the
pharmacokinetics of abatacept in rheumatoid arthritis patients showed dose-proportional increases of
C
max
and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, the mean terminal half-life
was 13.1 days, ranging from 8 to 25 days. The mean distribution volume (Vss) was 0.07 l/kg and
ranged from 0.02 to 0.13 l/kg. The systemic clearance was approximately 0.22 ml/h/kg. Mean
steady-state trough concentrations were approximately 25 μg/ml, and mean C
max
concentrations were
approximately 290 μg/ml. No systemic accumulation of abatacept occurred upon continued repeated
treatment with 10 mg/kg at monthly intervals in rheumatoid arthritis patients.
Population pharmacokinetic analyses 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. Methotrexate, NSAIDs, corticosteroids, and TNF-antagonists were not found to
influence abatacept clearance. No studies were conducted to examine the effects of either renal or
hepatic impairment on the pharmacokinetics of abatacept.
Paediatric population
Population pharmacokinetic analysis of abatacept serum concentration data from patients with JIA 6 to
17 years of age following administration of abatacept 10 mg/kg revealed that the estimated clearance
16
of abatacept, when normalized for baseline body weight, was higher in JIA patients (0.4 ml/h/kg for a
child weighing 40 kg) versus adult rheumatoid arthritis patients. Typical estimates for distribution
volume and elimination half-life were 0.12 l/kg and 11.4 days, respectively, for a child weighing
40 kg. As a result of the higher body-weight normalized clearance and volume of distribution
in JIA
patients, the predicted and observed
systemic exposures of abatacept were lower than that observed in
adults, such that the observed mean (range) peak and trough concentrations were 204 (66 to 595)
μg/ml and 10.6 (0.15 to 44.2) μg/mL, respectively, in patients weighing less than 40 kg, and 229 (58
to 700) μg/ml and 13.1 (0.34 to 44.6) μg/ml, respectively, in patients weighing 40 kg or greater.
5.3 Preclinical safety data
No mutagenicity or clastogenicity was observed with abatacept in a battery of
in vitro
studies. In a
mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary gland
tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours
observed in mice treated with abatacept may have been associated with decreased control of murine
leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term
immunomodulation. In a one-year toxicity study in cynomolgus monkeys, abatacept was not
associated with any significant toxicity. Reversible pharmacological effects consisted of minimal
transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centres in the
spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphological changes was
observed, despite the presence of a virus, lymphocryptovirus, which is known to cause such lesions in
immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the
clinical use of ORENCIA is unknown.
In rats, abatacept had no undesirable effects on male or female fertility. Embryo-foetal development
studies were conducted with abatacept in mice, rats, and rabbits at doses up to 20 to 30 times a
human 10 mg/kg dose and no undesirable effects were observed in the offspring. In rats and rabbits,
abatacept exposure was up to 29-fold a human 10 mg/kg exposure based on AUC. Abatacept was
shown to cross the placenta in rats and rabbits. In a pre- and postnatal development study with
abatacept in rats, no undesirable effects were observed in pups of dams given abatacept at doses up
to 45 mg/kg, representing 3-fold a human 10 mg/kg exposure based on AUC. At a dose of 200 mg/kg,
representing 11-fold a human exposure at 10 mg/kg based on AUC, limited changes in immune
function (a 9-fold increase in the mean T-cell-dependent antibody response in female pups and
inflammation of the thyroid of 1 female pup out of 10 male and 10 female pups evaluated at this dose)
were observed.
Non-clinical studies relevant for use in the paediatric population
Studies in rats exposed to abatacept have shown immune system abnormalities including a low
incidence of infections leading to death (juvenile rats). In addition, inflammation of the thyroid and
pancreas was frequently seen in both juvenile and adult rats exposed to abatacept. Juvenile rats seemed
to be more sensitive to lymphocytic inflammation of thyroid. Studies in adult mice and monkeys have
not demonstrated similar findings. It is likely that the increased susceptibility to opportunistic
infections observed in juvenile rats is associated with the exposure to abatacept before development of
memory responses. The relevance of these results to humans greater than 6 years of age is unknown.
6.
6.1 List of excipients
Maltose
Sodium dihydrogen phosphate monohydrate
Sodium chloride
17
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products. ORENCIA should not be infused concomitantly in the same intravenous line with other
medicinal products.
ORENCIA should NOT be used with siliconised syringes (see section 6.6).
6.3 Shelf life
Unopened vial
: 3 years
After reconstitution
: chemical and physical in-use stability has been demonstrated for 24 hours at
2°C - 8°C. From a microbiological point of view, the reconstituted solution should be diluted
immediately.
After dilution
: when the reconstituted solution is diluted immediately, the chemical and physical
in-use stability of the diluted infusion solution has been demonstrated for 24 hours at 2°C - 8°C. From
a microbiological point of view, the product should be used immediately.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
Store in the original package in order to protect from light.
For storage conditions of the reconstituted product see section 6.3.
6.5 Nature and contents of container
250 mg powder in a vial (Type 1 glass) with a stopper (halobutyl-rubber) and flip off seal (aluminium)
with a silicone-free syringe (polyethylene).
Packs of 1, 2, or 3 vials (each 15 ml) and 1, 2, or 3 silicone-free syringes, respectively.
Not all pack-sizes may be marketed.
6.6 Special precautions for disposal and other handling
Reconstitution and dilution should be performed in accordance with good practices rules, particularly
with respect to asepsis.
Reconstitution
1. Determine the dose and the number of ORENCIA vials needed (see section 4.2).
2. Under aseptic conditions, reconstitute each vial with 10 ml of water for injections, using the
silicone
free-disposable syringe provided with each vial
(see section 6.2) and an 18-21 gauge needle.
- Remove the flip-top from the vial and wipe the top with an alcohol swab.
- Insert the syringe needle into the vial through the centre of the rubber stopper and direct the stream
of water for injections to the glass wall of the vial.
- Do not use the vial if the vacuum is not present.
- Remove the syringe and needle after 10 ml of water for injections have been injected into the vial.
- To minimise foam formation in solutions of ORENCIA, the vial should be rotated with gentle
swirling until the contents are completely dissolved.
Do not shake
. Avoid prolonged or vigorous
agitation.
- Upon complete dissolution of the powder, the vial should be vented with a needle to dissipate any
foam that may be present.
- After reconstitution the solution should be clear and colourless to pale yellow. Do not use if opaque
particles, discolouration, or other foreign particles are present.
18
Dilution
3. Immediately after reconstitution, the product must be further diluted to 100 ml with sodium
chloride 9 mg/ml (0.9%) solution for injection.
- From a 100 ml infusion bag or bottle, withdraw a volume of sodium chloride 9 mg/ml (0.9%)
solution for injection equal to the volume of the reconstituted vials.
- Slowly add the reconstituted ORENCIA solution from each vial to the infusion bag or bottle using
the same
silicone-free disposable syringe provided with each vial
.
- Gently mix. The final concentration of abatacept in the bag or bottle will depend upon the amount of
drug added, but will be no more than 10 mg/ml.
- Any unused portion in the vials must be immediately discarded in accordance with local
requirements.
4. When reconstitution and dilution are performed under aseptic conditions ORENCIA infusion
solution can be used immediately or within 24 hours if stored refrigerated at 2°C to 8°C. Prior to
administration, the ORENCIA solution should be inspected visually for particulate matter and
discolouration. Discard the solution if any particulate matter or discolouration is observed. The entire,
fully diluted ORENCIA 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 to 1.2 μm).
- Do not store any unused portion of the infusion solution for reuse.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Bristol-Myers Squibb Pharma EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
8.
EU/1/07/389/001-003
9.
21/05/2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
19
ANNEX II
A.
MANUFACTURERS OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
20
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Bristol-Myers Squibb Company
6000 Thompson Road, East Syracuse
New York 13057
USA
Lonza Biologics Inc.
101 International Drive
Portsmouth, NH 03801-2815
USA
Name and address of the manufacturer responsible for batch release
Bristol-Myers Squibb S.R.L.
Contrada Fontana del Ceraso
03012 Anagni
Italy
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription. (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH should provide a patient alert card in each pack, the text of which is included in Annex III.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 3.5 presented in
Module 1.8.1 of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is placed on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 8.0 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates
of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
21
In addition, an updated RMP should be submitted:
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the EMEA
22
ANNEX III
LABELLING AND PACKAGE LEAFLET
23
A. LABELLING
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
ORENCIA 250 mg powder for concentrate
for solution for infusion
Abatacept
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 250 mg abatacept.
3.
LIST OF EXCIPIENTS
Excipients: maltose, sodium dihydrogen phosphate monohydrate and sodium chloride
4.
Powder for concentrate
for solution for infusion
1 vial
1 sterile silicone-free syringe
2 vials
2 sterile silicone-free syringes
3 vials
3 sterile silicone-free syringes
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use after reconstitution and dilution
Read the package leaflet before reconstitution and use.
For single use only.
Use the silicone-free disposable syringe included in the package for reconstitution.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
25
Read the package leaflet for the shelf-life of the reconstituted product.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Discard any unused solution.
Bristol-Myers Squibb Pharma EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
EU/1/07/389/001
EU/1/07/389/002
EU/1/07/389/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
26
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
TRAY LABEL
1.
ORENCIA 250 mg powder for concentrate
for solution for infusion
Abatacept
2.
Bristol-Myers Squibb Pharma EEIG
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Use the silicone-free disposable syringe included in the package for reconstitution.
Store in a refrigerator.
Store in the original package in order to protect from light.
27
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
ORENCIA 250 mg powder for concentrate
for solution for infusion
Abatacept
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
250 mg of abatacept
6.
OTHER
Use the silicone-free disposable syringe included in the package for reconstitution.
Bristol-Myers Squibb Pharma EEIG
28
PATIENT ALERT CARD TEXT
Orencia Patient Alert Card
This alert card contains important safety
information that you need to be aware of before
you are given ORENCIA and during treatment
with ORENCIA.
Infections
−
If you develop symptoms suggestive of
infections, such as fever, persistent
cough, weight loss, or listlessness, seek
medical attention immediately.
•
Show this card to any doctor involved in
your treatment.
Infections
ORENCIA increases the risk of getting
infections.
- You should not be treated with ORENCIA
if you have severe infection.
- You should be screened for certain
infections prior to treatment with
ORENCIA, according to relevant guidelines.
Tuberculosis (TB)
: The safety of
ORENCIA in individuals with latent TB is
unknown. You should be screened for TB
prior to ORENCIA treatment. It is very
important that you tell your doctor if you
have ever had TB, or if you have been in
close contact with someone who has had TB.
Hepatitis
: Anti-rheumatic therapies have
been associated with hepatitis B reactivation.
You should be screened for viral hepatitis in
accordance with published guidelines.
Dates of ORENCIA Treatment
:
Start:
____________________
Most recent:
____________________
•
See the ORENCIA package leaflet for
more information.
•
Please make sure you also have a list of all
your other medicines with you at any visit
to a health care professional.
Patient’s Name: ____________________
Doctor’s Name: ____________________
Doctor’s Phone: ____________________
Keep this card with you for 3 months after the
last ORENCIA dose, since side effects may
occur a long time after your last dose of
ORENCIA.
29
B. PACKAGE LEAFLET
30
PACKAGE LEAFLET
:
INFORMATION FOR THE USER
ORENCIA 250 mg powder for concentrate for solution for infusion
Abatacept
Read all of this leaflet carefully before you start using this medicine.
Keep this leaflet. You may need to read it again.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What ORENCIA is and what it is used for
2.
Before you use ORENCIA
3.
How to use ORENCIA
5
How to store ORENCIA
6.
Further information
1.
WHAT ORENCIA IS AND WHAT IT IS USED FOR
ORENCIA is an infusion treatment for adults with moderate to severe rheumatoid arthritis and for
children and adolescents aged 6 to 17 years with polyarticular juvenile idiopathic arthritis. It is used in
combination with a medicine called methotrexate. The active ingredient of ORENCIA, abatacept, is a
protein produced in cell cultures.
Rheumatoid arthritis is a long-term progressive systemic disease that, if untreated, can lead to serious
consequences, such as joint destruction, increased disability and impairment of daily activities. In
people with rheumatoid arthritis the body's own immune system attacks normal body tissues, leading
to pain and swelling of the joints. This can cause joint damage. ORENCIA lessens the immune
system's attack on normal tissues by interfering with the immune cells (called T lymphocytes) that
contribute to the development of rheumatoid arthritis.
ORENCIA is used to treat moderate to severe active rheumatoid arthritis when you do not respond
well enough to treatment with other disease-modifying medicines or with another group of medicines
called TNF blockers.
Polyarticular Juvenile Idiopathic Arthritis
Polyarticular juvenile idiopathic arthritis is a long-term inflammatory disease affecting one or more
joints in children and adolescents.
ORENCIA is used after another group of medicines called TNF blockers. If you do not respond well
enough to these medicines, you will be given ORENCIA with methotrexate to treat your polyarticular
juvenile idiopathic arthritis.
ORENCIA is used to:
- slow down the damage to your joints
- improve your physical function
- improve signs and symptoms of polyarticular juvenile idiopathic arthritis
2.
BEFORE YOU USE ORENCIA
Do not use ORENCIA
If you are allergic
(hypersensitive) to abatacept or any of the other ingredients.
31
If you have any further questions, ask your doctor or pharmacist.
4.
Possible side effects
If you have a severe or uncontrolled infection
, therapy with ORENCIA must not be started.
Having an infection could put you at risk of serious side effects from ORENCIA.
Take special care with ORENCIA
If you experience allergic reactions
such as chest tightness, wheezing, severe dizziness or
lightheadedness, swelling or skin rash
tell your doctor immediately
.
If you have any kind of infection
, including long-term or localised infection, or often get
infections.
It is important you tell your doctor if you have symptoms of infection (e.g.
fever, malaise, dental problems).
ORENCIA also can lower your body's ability to fight
infection and the treatment can make you more prone to getting infections or make any
infection you have worse.
If you have had tuberculosis (TB)
or have symptoms of tuberculosis (persistent cough, weight
loss, listlessness, mild fever)
tell your doctor
. Before you use ORENCIA, your doctor will
examine you for tuberculosis or do a skin test.
If you have viral hepatitis
tell your doctor. Before you use ORENCIA, your doctor may
examine you for hepatitis.
If you have cancer
. Your doctor will have to decide if you can still be given ORENCIA.
If you recently had a vaccination
or are planning to have one. Some vaccines should not be
given while receiving ORENCIA.
Check with your doctor before you receive any vaccines.
It is recommended that patients with polyarticular juvenile idiopathic arthritis, if possible, be
brought up to date with all immunisations in agreement with current immunisation guidelines
prior to starting ORENCIA therapy.
If you are using a blood glucose monitor
to check your blood glucose levels. ORENCIA
contains maltose, which is a type of sugar that can give falsely high blood glucose readings
with certain types of blood glucose monitors. Your doctor may recommend a different method
for monitoring your blood glucose levels.
ORENCIA and older people
ORENCIA can be used by people over 65 with no change in dose. Since the elderly are more
susceptible to infections and cancer, ORENCIA should be used with caution in this patient population.
ORENCIA and children
ORENCIA has not been studied in patients under 6 years of age, therefore ORENCIA is not
recommended in this patient population.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
ORENCIA is not to be used
with biological medicines for rheumatoid arthritis including
adalimumab, etanercept, and infliximab; there is insufficient evidence to recommend co-
administration with anakinra and rituximab.
ORENCIA can be taken
with other medicines commonly used in the treatment of rheumatoid
arthritis, such as steroids or painkillers including non-steroidal anti-inflammatories such as ibuprofen
or diclofenac.
Ask your doctor or pharmacist for advice before taking any other medicine while using ORENCIA.
Pregnancy and breast-feeding
The effects of ORENCIA in pregnancy are not known, so do not use ORENCIA if you are pregnant
unless your doctor specifically recommends it. Pregnancy must be avoided while using ORENCIA.
Your doctor will advise you on adequate contraceptive methods while using ORENCIA and up
to 14 weeks after the last dose. If you become pregnant while using ORENCIA, tell your doctor.
It is not known whether abatacept, the active ingredient, passes into human milk. Y
ou must stop
breast-feeding
if you are being treated with ORENCIA and for up to 14 weeks after the last dose.
32
Driving and using machines
If you are feeling tired or unwell after receiving ORENCIA, you should not drive or operate any
machinery. It is not known if ORENCIA will affect the ability to drive or use machines.
Important information about some of the ingredients of ORENCIA
This medicine contains 1.5 mmol (or 34.5 mg) sodium per maximum dose of 4 vials (0.375 mmol or
8.625 mg sodium per vial). To be taken into consideration by patients on a controlled sodium diet.
3.
HOW TO USE ORENCIA
ORENCIA is supplied as a powder for solution for infusion. This means that before ORENCIA is
given to you, it is first dissolved in water for injections, then further diluted with sodium
chloride 9 mg/ml (0.9%) solution for injection.
The recommended dose of abatacept for adults with rheumatoid arthritis is based on body weight:
Your weight
Dose
Vials
Less than 60 kg
500 mg
2
60 kg - 100 kg
750 mg
3
More than 100 kg
1000 mg
4
For children and adolescents aged 6 to 17 years with polyarticular juvenile idiopathic arthritis who
weigh less than 75 kg, the recommended dose of abatacept is 10 mg/kg. Children weighing 75 kg or
more should be administered ORENCIA following the adult dosing regimen.
How ORENCIA is given to you
ORENCIA is given to you into a vein, usually in your arm, over a period of 30 minutes. This
procedure is referred to as an infusion. Healthcare professionals will monitor you while you receive
your ORENCIA infusion.
How often ORENCIA is given to you
ORENCIA should be given to you again, 2 and then 4 weeks after the first infusion. After that you
will receive a dose every 4 weeks. Your doctor will advise you on the duration of treatment and what
other medications you may continue to take while on ORENCIA.
If you use more ORENCIA than you should
In case this happens, your doctor will monitor you for any signs or symptoms of side effects, and treat
these symptoms if necessary.
If you forget to use ORENCIA
If you miss receiving ORENCIA when you are supposed to, ask your doctor when to schedule your
next dose.
If you stop using ORENCIA
The decision to stop using ORENCIA should be discussed with your doctor.
If you have any further questions on the use of this product,
ask your doctor or pharmacist
.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ORENCIA can cause side effects, although not everybody gets them. The most
common side effects with ORENCIA are headache and nausea. Like all medicines that affect your
immune system, ORENCIA can cause serious side effects, which may need treatment.
Possible serious side effects
include serious infections, malignancies and allergic reactions.
33
Tell your doctor immediately
if you notice any of the following:
Severe rash, hives or other signs of allergic reaction
Trouble breathing or swallowing
Tell your doctor as soon as possible
if you notice any of the following:
Signs of infection such as fever, malaise, dental problems, burning sensation during urination,
painful skin rash, painful skin blisters, coughing
The symptoms described above can be signs of the side effects listed below, all of which have been
observed with ORENCIA in adult clinical trials:
The frequency of possible side effects listed below is defined using the following convention:
very common:
affects more than 1 user in 10
common:
affects 1 to 10 users in 100
uncommon:
affects 1 to 10 users in 1,000
rare:
affects 1 to 10 users in 10,000
very rare:
affects less than 1 user in 10,000
not known:
frequency cannot be estimated from the available data
Very common
side effects
: headache.
Common side effects
: infections of nose, throat and lungs, urinary infections, painful skin blisters
(herpes), rhinitis, dizziness, high blood pressure, flushing, cough, nausea, diarrhoea, upset stomach,
abdominal pain, rash, fatigue, weakness and abnormal liver function tests.
Uncommon
side effects
: tooth infection, infected skin ulcer, nail fungal infection, skin cancer, low
blood platelet count, low blood cell counts, allergic reactions, anxiety, numbness, hives, eye
inflammation, dry eye, reduced vision, palpitation, rapid heart rate, low heart rate, low blood pressure,
hot flush, mouth sores, increased tendency to bruise, hair loss, dry skin, painful joints, pain in the
extremities, flu-like illness, increased weight, infusion-related reactions, depression, absence of
menstruation, migraine, kidney infection, psoriasis, difficulty in breathing and throat tightness.
Rare side effects
: blood stream infection.
Your doctor may also do tests to examine your blood values.
Children and adolescents with polyarticular juvenile idiopathic arthritis
The most frequent side effects are listed below:
Very common side effects
: headache, nausea.
Common side effects
: diarrhoea, cough, infections of nose and throat, fever, upper abdominal pain.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
5.
HOW TO STORE ORENCIA
Keep out of the reach and sight of children.
34
Swollen face, hands, feet
Do not use after the expiry date which is stated on the label and the carton after EXP. The expiry date
refers to the last day of that month.
Store in a refrigerator (2°C - 8°C).
Store in the original package in order to protect from light.
After reconstitution and dilution, the infusion solution is stable for 24 hours in a refrigerator, but for
bacteriological reasons, it is to be used immediately.
Do not use ORENCIA if you notice opaque particles, discolouration or other foreign particles present
in the infusion solution.
6.
FURTHER INFORMATION
What ORENCIA contains
The active substance is abatacept.
Each vial contains 250 mg of abatacept.
After reconstitution, each ml contains 25 mg of abatacept.
The other ingredients are maltose, sodium dihydrogen phosphate monohydrate and sodium
chloride.
What ORENCIA looks like and contents of the pack
ORENCIA powder for concentrate for solution for infusion is a white to off-white powder that can
appear solid or broken into pieces.
ORENCIA is available in packs of either 1, 2 or 3 vials and is supplied with respectively 1, 2 or
3 silicone-free syringes.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Bristol-Myers Squibb Pharma EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
Manufacturer:
Bristol-Myers Squibb S.R.L.
Contrada Fontana del Ceraso
I-03012 Anagni-Frosinone
Italy
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
Belgique/België/Belgien
B
RISTOL
-M
YERS
S
QUIBB
B
ELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
Luxembourg/Luxemburg
B
RISTOL
-M
YERS
S
QUIBB
B
ELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
35
България
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Teл.: + 359 800 12 400
Magyarország
B
RISTOL
-M
YERS
S
QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel.: + 36 1 301 9700
Česká republika
B
RISTOL
-M
YERS
S
QUIBB SPOL
.
S R
.
O
.
Tel: + 420 221 016 111
Malta
B
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YERS
S
QUIBB
S.
R
.
L
.
Tel: + 39 06 50 39 61
Danmark
B
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YERS
S
QUIBB
Tlf: + 45 45 93 05 06
Nederland
B
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YERS
S
QUIBB
BV
Tel: + 31 34 857 42 22
Deutschland
B
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YERS
S
QUIBB
G
MB
H
&
C
O
.
KG
A
A
Tel: + 49 89 121 42-0
Norge
B
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YERS
S
QUIBB
N
ORWAY
L
TD
Tlf: + 47 67 55 53 50
Eesti
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QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel: + 372 6827 400
Österreich
B
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S
QUIBB
G
ESMB
H
Tel: + 43 1 60 14 30
Ελλάδα
B
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YERS
S
QUIBB
A.E.
Τηλ: + 30 210 6074300
Polska
B
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YERS
S
QUIBB
P
OLSKA
S
P
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Z O
.
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Tel.: + 48 22 5796666
España
B
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YERS
S
QUIBB
,
S.A.
Tel: + 34 91 456 53 00
Portugal
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F
ARMACÊUTICA
P
ORTUGUESA
, S.A.
Tel: + 351 21 440 70 00
France
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YERS
S
QUIBB
S
ARL
Tél: + 33 (0)810 410 500
România
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K
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Tel: + 40 (0)21 272 16 00
Ireland
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YERS
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QUIBB
P
HARMACEUTICALS
L
TD
Tel: + 353 (1 800) 749 749
Slovenija
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.
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Tel: + 386 1 236 47 00
Ísland
V
ISTOR HF
Sími: + 354 535 7000
Slovenská republika
B
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QUIBB SPOL
.
S R
.
O
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Tel: + 421 2 59298411
Italia
B
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YERS
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QUIBB
S.
R
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L
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Tel: + 39 06 50 39 61
Suomi/Finland
O
Y
B
RISTOL
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YERS
S
QUIBB
(F
INLAND
)
A
B
Puh/Tel: + 358 9 251 21 230
Κύπρος
BRISTOL-MYERS
SQUIBB
A.E
Τηλ: + 357 800 92666
Sverige
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QUIBB
AB
Tel: + 46 8 704 71 00
Latvija
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YÓGYSZERKERESKEDELMI
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Tel: + 371 67 50 21 85
United Kingdom
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TD
Tel: + 44 (0800) 731 1736
36
Lietuva
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QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Tel: + 370 5 2790 762
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
The following information is intended for medical or healthcare professionals only
Reconstitution and dilution should be performed in accordance with good practices rules, particularly
with respect to asepsis.
Dose selection:
see section 3 ‘How to use ORENCIA’ of the Package Leaflet
Reconstitution of vials:
under aseptic conditions, reconstitute each vial with 10 ml of water for
injections, using the
silicone-free disposable syringe provided with each vial
and an 18-21 gauge
needle. Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe
needle into the vial through the centre of the rubber stopper and direct the stream of water for
injections to the glass wall of the vial. Do not use the vial if a vacuum is not present. Remove the
syringe and needle after 10 ml of water for injections have been injected into the vial. To minimise
foam formation in solutions of ORENCIA the vial should be rotated with gentle swirling until the
contents are completely dissolved.
Do not shake
.
Do not use prolonged or vigorous agitation
. Upon
complete dissolution of the powder, the vial should be vented with a needle to dissipate any foam that
may be present. After reconstitution the solution should be clear and colourless to pale yellow. Do not
use if opaque particles, discolouration, or other foreign particles are present.
Preparation of infusion:
immediately after reconstitution, dilute the product to 100 ml with sodium
chloride 9 mg/ml (0.9%) solution for injection. From a 100 ml infusion bag or bottle, withdraw a
volume of 0.9% sodium chloride injection equal to the volume of the reconstituted ORENCIA vials.
Slowly add the reconstituted ORENCIA solution from each vial to the infusion bag or bottle using the
same
silicone-free disposable syringe provided with each vial
. Gently mix. The final concentration
of abatacept in the bag or bottle will depend upon the amount of drug added, but will be no more than
10 mg/ml.
Administration:
when reconstitution and dilution are performed under aseptic conditions ORENCIA
infusion solution can be used immediately or within 24 hours if stored refrigerated at 2°C to 8°C.
However, for microbiological reasons, it is to be used immediately. Prior to administration, the
ORENCIA solution should be inspected visually for particulate matter and discolouration. Discard the
solution if any particulate matter or discolouration is observed. The entire, fully diluted ORENCIA
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 to 1.2 μm). Do not
store any unused portion of the infusion solution for reuse.
Other medicines:
ORENCIA should not be mixed with other medicines or infused concomitantly in
the same intravenous line with other medicines. No physical or biochemical compatibility studies have
been conducted to evaluate the co-administration of ORENCIA with other agents.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
37
Source: European Medicines Agency
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