Adverse reactions : תופעות לוואי

6           ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
•      Increased Risk of Infection with Concomitant Use with TNF Antagonists [see Warnings and Precautions (5.1)]
•      Hypersensitivity [see Warnings and Precautions (5.2)]
•      Infections [see Warnings and Precautions (5.3)]
•      Increased Risk of Adverse Reactions When Used in Patients with Chronic Obstructive Pulmonary Disease (COPD) [see Warnings and Precautions (5.5)]
•      Immunosuppression [see Warnings and Precautions (5.6)] 

•       Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Reactivation in aGVHD Prophylaxis after Hematopoietic Stem Cell Transplant (HSCT) [see Warnings and Precautions (5.7)]
6.1         Clinical Trials Experience
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.


Adverse Reactions in Adult Patients with RA
Adverse Reactions in Adult Patients with RA Treated with Intravenous ORENCIA The data from placebo-controlled studies described herein reflect exposure to ORENCIA administered intravenously in patients with active RA (1955 patients with ORENCIA, 989 with placebo)(Studies I through VI) [see Clinical Studies (14.1)]. The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF antagonist (204 patients with ORENCIA, 134 with placebo).
The concomitant use of ORENCIA with a TNF antagonist is not recommended [see Indications and Usage (1.5)]. The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti- inflammatory drugs (NSAIDs), corticosteroids, TNF antagonist, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.
The most serious adverse reactions were serious infections and malignancies.

The most commonly reported adverse events (occurring in 10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.
The adverse reactions most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1%), 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%).



Most Common Adverse Reactions in Adult Patients with RA Treated with Intravenous ORENCIA
Adverse reactions occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients (intravenous) during placebo-controlled RA studies are summarized in Table 3.

Table 3: Most Common Adverse Reactions* During Placebo-Controlled RA Studies of Intravenous ORENCIA
Intravenous
Placebo
ORENCIA
(n=989)b
(n=1955)a
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% *    Occurred in ≥3% patients and >1% more frequently in ORENCIA-treated patients.
a    Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).
b    Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).

Infections in Adult Patients with RA Treated with Intravenous ORENCIA In the placebo-controlled trials in patients with RA, infections were reported in 54% of intravenous ORENCIA-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 ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia [see Warnings and Precautions (5.3)].
Serious infections were reported in 3% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis [see Warnings and Precautions (5.3)].
Malignancies in Adult Patients with RA Treated with Intravenous ORENCIA In the placebo-controlled portions of the clinical trials (1955 patients treated for RA with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4 cases, 0.2%) than placebo-treated patients (0 cases, 0%). In the cumulative intravenous ORENCIA clinical trials in patients with RA (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 National Cancer Institute’s Surveillance, Epidemiology, and End Results Database. 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 Warnings and Precautions (5.6)]. The potential role of ORENCIA in the development of malignancies in humans is unknown.
Infusion-Related Reactions and Hypersensitivity Reactions in Adult Patients with RA Treated with Intravenous ORENCIA
Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see Clinical Studies (14.1)] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 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 ORENCIA 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 (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events.
In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of anaphylaxis. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Warnings and Precautions (5.2)].
Adverse Reactions in Patients with COPD Treated for RA with Intravenous ORENCIA In Study V [see Clinical Studies (14.1)], there were 37 and 17 patients with chronic obstructive pulmonary disease (COPD) who were treated for RA with ORENCIA and placebo, respectively.
The COPD patients treated with ORENCIA for RA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-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%)]) [see Warnings and Precautions (5.5)].
Adverse Reactions in Methotrexate-Naive Patients with RA Treated with Intravenous ORENCIA Study VI was an active-controlled clinical trial in methotrexate-naive patients [see Clinical Studies (14.1)]. The safety experience in these patients was consistent with the patients in Studies I-V.



Adverse Reactions in Adult Patients with RA Treated with Subcutaneous or Intravenous ORENCIA
The data described below are derived from Study SC-1. Study SC-1 was a randomized, double- blind, double-dummy, non-inferiority study that compared the safety of ORENCIA administered subcutaneously or intravenously in 1457 patients with RA, who received background methotrexate, and experienced an inadequate response to methotrexate (MTX-IR) [see Clinical Studies (14.1)]. The adverse reaction profile in patients treated with subcutaneous ORENCIA was similar to the adverse reaction profile in patients treated with intravenous ORENCIA and consistent with intravenous ORENCIA administered in Studies I-VI.
Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA The overall frequency of injection site reactions in Study SC-1 was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous ORENCIA group and the subcutaneous placebo group (given intravenous ORENCIA), respectively [see Clinical Studies (14.1)]. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation.



Adverse Reactions in Adult Patients with PsA
Adverse Reactions in Adult Patients with PsA Treated with Intravenous or Subcutaneous ORENCIA
The safety of ORENCIA was evaluated in 594 patients with PsA (341 patients on ORENCIA and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials [see Clinical
Studies (14.3)]. Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II). The safety profile was comparable between ORENCIA given intravenously in Study PsA-I and ORENCIA given subcutaneously in Study PsA-II and also consistent with the safety profile of ORENCIA in patients with RA [see Warnings and Precautions (5), Adverse Reactions (6.1)].
Adverse Reactions in Patients with pJIA
Adverse Reactions in Patients with pJIA Treated with Intravenous ORENCIA In general, the adverse events in pediatric patients with polyarticular JIA (pJIA) treated with intravenous ORENCIA were similar in frequency and type to those seen in adult patients with RA treated with intravenous ORENCIA [see Warnings and Precautions (5) and Adverse Reactions (6)].
Study JIA-1 was a three-part study including an open-label extension that assessed the safety of intravenous ORENCIA in 190 pediatric patients, 6 to 17 years of age, with pJIA. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see Clinical Studies (14.2)]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.
A total of 6 serious adverse events [acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare (2), and joint wear] were reported during the initial 4 months of treatment with intravenous ORENCIA.
Of the 190 pediatric patients with pJIA treated with intravenous ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). 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 events reported in adults.
Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment.
Adverse Reactions in Patients Undergoing Unrelated-Donor Hematopoietic Stem Cell Transplantation (HSCT) with Intravenous ORENCIA
The data described herein were from one clinical study of ORENCIA (GVHD-1) for aGVHD prophylaxis in patients 6 years and older with hematologic malignancies who were undergoing unrelated HSCT wherein all patients were receiving calcineurin inhibitor and methotrexate as the standard of care for aGVHD prophylaxis [see Clinical Studies (14.4)]. Two cohorts were studied at 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation:
1) A single-arm cohort of ORENCIA-treated patients (n=43) who underwent 7 of 8 Human leukocyte antigen (HLA)-matched HSCT from unrelated donors (7 of 8 cohort) and
2) A randomized cohort comprised of ORENCIA-treated patients (n=73) and placebo-treated patients (n=69) who underwent 8 of 8 HLA-matched HSCT from unrelated donors (8 of 8 cohort).
Of the 116 patients who received ORENCIA, 27 (23%) were 6 to less than 17 years of age [see Use in Specific Populations (8.4)].
The safety information from the date of first dose of ORENCIA up to Day 225 post- transplantation from this study is presented below. The incidence of adverse reactions was determined based on pooled data of ORENCIA-treated patients from the 2 study cohorts (n=116).
Serious adverse reactions reported in > 5% of patients who received ORENCIA in combination with a calcineurin inhibitor and methotrexate included pyrexia (20%), pneumonia (8%), acute kidney injury (7%), diarrhea (6%), hypoxia (5%), and nausea (5%).
Permanent discontinuation of ORENCIA due to an adverse reaction occurred in two patients (1.7%) due to one case each of pneumonia and allergic reaction.
The most common (≥10%) adverse reactions in the ORENCIA treated patients were anemia, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, epistaxis, CD4 lymphocytes decreased, hypermagnesemia, and acute kidney injury.
Table 4 summarizes the frequency of adverse reactions reported in the study of ORENCIA in GVHD-1.


Table 4:             Adverse Reactions (>10%) in Patients with aGVHD Who Received ORENCIA with a Difference Between Arms of >2% Compared to
Placebo in GVHD-1

7 of 8 Cohort                            8 of 8 Cohort

Adverse Reaction          ORENCIA (+CNI            ORENCIA (+CNI           Placebo (+CNI and and MTX)                 and MTX)                    MTX)
(N=43)                    (N=73)                    (N=69)

All        Grade 3          All      Grade 3        All         Grade 3 Grades       or 4           Grades     or 4         Grades        or 4 (%)        (%)            (%)        (%)           (%)             (%) 
Blood and
Lymphatic System
Disorders

Anemia                   56            56          69            69         57             57 
CD4 lymphocytes
14            14          14            14         9               9 decreased

Vascular Disorders
Hypertension             49            49          43            43         38             38 
General Disorders and Administrative
Site Conditions

Pyrexia                  28            9           19            10         20              4 
Infections and
Infestations

CMV
Reactivation/CMV         26            26          32            32         22             22 Infection
Table 4:                Adverse Reactions (>10%) in Patients with aGVHD Who Received ORENCIA with a Difference Between Arms of >2% Compared to
Placebo in GVHD-1

7 of 8 Cohort                            8 of 8 Cohort

Adverse Reaction           ORENCIA (+CNI             ORENCIA (+CNI           Placebo (+CNI and and MTX)                  and MTX)                    MTX)
(N=43)                    (N=73)                    (N=69)

All       Grade 3          All      Grade 3        All         Grade 3 Grades      or 4           Grades     or 4         Grades        or 4 (%)        (%)            (%)        (%)           (%)             (%) 
Pneumonia                 19             19          12            12         10              9 
Respiratory and
Mediastinal
Disorders

Epistaxis                 12             12          16            16         10             10 
Renal and Urinary
Disorders

Acute kidney injury        9             7           15            15         10             10 
Metabolism and
Nutrition Disorders

Hypermagnesemia            5             5           18            18         10             10 
Clinically relevant adverse reactions in <10% of patients who received ORENCIA in combination with calcineurin inhibitor and methotrexate in Study GVHD-1 included EBV reactivation.

6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be 
influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other abatacept products may be misleading.
Immunogenicity in Adult Patients with RA Treated with Intravenous ORENCIA 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 intravenous ORENCIA. Thirty-four of 1993 (2%) 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 the subset analysis 9 of 154 (6%) patients that had discontinued intravenous ORENCIA treatment 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. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.
No correlation of anti-abatacept antibody development to clinical response or adverse events was observed.
Immunogenicity in Adult RA Patients Treated with Subcutaneous or Intravenous ORENCIA 
Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous ORENCIA administration. The overall immunogenicity frequency to abatacept was 1% (8/725) and 2% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.
Immunogenicity in Adult RA Patients Treated with Subcutaneous ORENCIA Monotherapy 
Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients, who had not previously received ORENCIA or other CTLA4Ig. Patients in this study received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti- abatacept antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.


Immunogenicity in Adult RA Patients After Treatment, Withdrawal, and then Restart of Subcutaneous ORENCIA

Study SC-3 was conducted to investigate the immunogenicity in adult RA patients after treatment, withdrawal (three months) and restart of ORENCIA subcutaneous treatment (patients were treated concomitantly with methotrexate). One hundred sixty-seven patients were enrolled in the first 3- month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 (0%) patients who continued to receive subcutaneous ORENCIA developed anti-abatacept antibodies compared to 7/73 (10%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients who received subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (3%) in the group who received subcutaneous ORENCIA throughout, and 2/73 (3%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months compared to those who remained on subcutaneous therapy, (these results occurred in those who received or did not receive an intravenous loading dose). The safety observed in this study was consistent with that observed in the other studies.
Immunogenicity in Patients with pJIA Treated with Intravenous ORENCIA Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with pJIA following repeated treatment with intravenous ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.
The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy.


Immunogenicity in Patients Treated for Prophylaxis of aGVHD with Intravenous ORENCIA Immunogenicity was assessed in patients undergoing HSCT. Overall, immunogenicity incidence and associated antibody titers were low from the 4-dose intravenous ORENCIA regimen used in this study. Of the 114 immunogenicity evaluable subjects in the ORENCIA groups, none were positive during the ORENCIA treatment period (Day -1 to Day 28 following transplant). During the off-treatment period (Day 29 and up to Day 180 following transplant); 6 of 91 immunogenicity evaluable subjects (6.6%) were positive for CTLA4 and possibly Ig; 4 of the 6 positive subjects were found to have at least one positive sample with neutralization activity. In this study, immunogenicity positive subjects only had ADA positive samples on Day 180 (off-treatment period) and thus due to the timing of the response, the impact on PK, safety, or efficacy could not be determined.


6.3 Postmarketing Experience
Adverse reactions have been reported during the postapproval use of ORENCIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA. Based on the postmarketing experience with ORENCIA, the following adverse reactions have been identified : 
•   Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis)
•   New or worsening psoriasis
•   Non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma)
•   Angioedema reactions [see Warnings and Precautions (5.2)] 

During postmarketing experience with intravenous ORENCIA, systemic infusion reactions were similar to that seen in the clinical trial experience with intravenous ORENCIA with the exception of one case of fatal anaphylaxis [see Warnings and Precautions (5.2)]. Postmarketing reports of systemic injection reactions (e.g., pruritus, throat tightness, dyspnea) have occurred following the use of subcutaneous ORENCIA.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il