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  1. 1. CONTENTS EXECUTIVE SUMMARY............................................................................................................. 2 1 BACKGROUND .................................................................................................................... 2 1.1 Product Formulations and Indications ........................................................................... 2 1.2 Pediatric Filing History.................................................................................................. 2 1.3 Pediatric Labeling .......................................................................................................... 3 2 METHODS AND MATERIALS............................................................................................ 3 2.1 Introduction.................................................................................................................... 3 2.2 AERS Search Criteria .................................................................................................... 4 3 AERS RESULTS FOR ABATACEPT................................................................................... 4 3.1 Crude Counts of All AERS Reports: (Table 1, Figure 1) .............................................. 4 3.2 Case Characteristics From Pediatric Safety Review (Table 2) ...................................... 4 4 DISCUSSION/SUMMARY OF PEDIATRIC CASES.......................................................... 5 4.1 Summary of Adverse Event Reports in Pediatirc Patients (N=7).................................. 5 5 CONCLUSION....................................................................................................................... 7 6 RECOMMENDATIONS........................................................................................................ 7 APPENDIX…….…………………………………………………………………………………..8
  2. 2. EXECUTIVE SUMMARY In accordance with the Pediatric Research Equity Act (PREA), the Division of Pharmacovigilance (DPV) was asked to summarize post-marketing reports of adverse events associated with the use of abatacept in pediatric patients (0-16 years of age) from the Adverse Event Reporting System (AERS) database. Abatacept is a selective T cell costimulation modulator indicated for the treatment of adult rheumatoid arthritis and for juvenile idiopathic arthritis (JIA) in pediatric patients six years of age and older. The AERS database was searched for all reports of adverse events (serious and non-serious) up to the "data lock" date of 07/07/2009; AERS contained 1,795 reports for abatacept. Pediatric reports represent approximately 0.4 % of the total (7/1,795). Seven post-marketing pediatric adverse event cases were identified with the use of abatacept. The reported ages ranged from 7 years to 16 years. Abatacept was used for JIA (a labeled indication) in 4 cases, and in the remaining 4 cases, it was used for off-label indications (psoriasis, uveitis, spondyloarthropathy, and vasculitis).1 The reported events were all single cases precluding a meaningful evaluation of the pediatric risk for these events with abatacept use. Four cases reported labeled events including multiple sclerosis, lymphoma, infection, and dyspnea, and the 3 remaining cases reported unlabeled events including purpura, transaminitis, and uveitis flare. These unlabeled events were either confounded by the concomitant use of other medications or appeared to be disease related. No pediatric deaths were reported with the use of abatacept. Due to the limited number of pediatric cases reported with abatacept, it is difficult to compare the safety profile in pediatric patients to adults. No new safety signals emerged as part of this review. No further labeling changes regarding the pediatric patients are necessary at this time. 1 BACKGROUND 1.1 PRODUCT FORMULATIONS AND INDICATIONS Abatacept is available as a lyophilized powder for intravenous infusion providing 250 mg of abatacept in a 15-mL vial. Abatacept is indicated in adult patients for the treatment of moderate to severe active rheumatoid arthritis. Abatacept is also indicated for moderate to severe active polyarticular juvenile idiopathic arthritis (JIA) in pediatric patients 6 years of age and older.2 1.2 PEDIATRIC FILING HISTORY Abatacept received FDA approval on December 23, 2005. Pediatric approval of abatacept occurred on April 7, 2008. The pediatric approval was based on a three-part study including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). Patients 6 to 17 years of age (n=190) with moderate to severe active polyarticular JIA who had an inadequate response to one or more DMARDs, such as methotrexate (MTX) or TNF antagonists, were treated. The types and frequencies of adverse events were similar to those seen in the abatacept 1 More than one indication for abatacept use was reported in a case. 2 Orencia (abatacept) prescribing information; Bristol Myers Squibb Company, August 2009. 2
  3. 3. trials for adult RA. No new safety signals were observed. Adverse events reported more frequently in the abatacept treated pediatric patients than in the placebo group included infections (45% vs. 44%), gastrointestinal disorders (17% vs. 15%), respiratory disorders (10% vs. 5%), nervous system disorders (5% vs. 3%), musculoskeletal disorders (5% vs. 3%), renal/urinary disorders (5% vs.2%), and vascular disorders (5% vs. 2%). There were no deaths reported during the pediatric study.3 1.3 PEDIATRIC LABELING 4 The pediatric labeling includes the following safety information: ADVERSE REACTIONS Clinical Studies Experience in Juvenile Idiopathic Arthritis In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients. ORENCIA has been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. 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%. 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, and joint wear) were reported during the initial 4 months of treatment with ORENCIA. Of the 190 patients with juvenile idiopathic arthritis treated with 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. 2 METHODS AND MATERIALS 2.1 INTRODUCTION The voluntary or spontaneous reporting of adverse events from healthcare professionals and consumers in the U.S reflects underreporting and also duplicate reporting. For any given report, there is no certainty that the reported suspect product(s) caused the reported adverse event(s). The main utility of a spontaneous reporting system, such as AERS, is to provide signals of potential drug safety issues. Therefore, crude counts from AERS cannot be used to calculate incidence rates or estimates of drug risk for a particular product or used for comparing drug risk between drugs. 3 Hull K. FDA Clinical review of BLA 125118. February 7, 2008. 4 Orencia (abatacept) prescribing information; Bristol Myers Squibb Company, August 2009. 3
  4. 4. 2.2 AERS SEARCH CRITERIA The Adverse Event Reporting System (AERS) database was searched using the drug name abatacept (verbatim and trade name) to obtain crude counts of adverse events associated with the use of abatacept from market approval (December 23, 2005) to the data lock date of July 7, 2009 (Table 1, Figure 1). The AERS search identified seven unique pediatric cases that are summarized in Table 2 and described in more detail in the Discussion section. Three cases were duplicates and are not included in our case series. A graphical comparison by system organ class (SOC) and of the top 25 preferred terms (PT) reported with abatacept use in adults and pediatrics can be found in the Appendix. 3 AERS RESULTS FOR ABATACEPT 3.1 CRUDE COUNTS OF ALL AERS REPORTS: TABLE 1 Table 1: Crude counts1 of AERS Reports from All Sources From Approval Date 12/23/2005 to 07/07/2009 All reports (US)2 Serious3 (US) Death (US) Adults (≥ 17 yrs.) 1,140 (758) 696 (320) 83 (38) Pediatrics (0-16 yrs.) 10 (6) 8 (4) 0 (0) Age unknown (Null values) 645 (622) 116 (93) 9 (6) Total 1,795 (1,386) 820 (417) 92 (44) 1 May include duplicates 2 US counts in parentheses 3 Serious adverse drug experiences per regulatory definition (CFR 314.80) include outcomes of death, life- threatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important medical events. Figure 1: Number of pediatric AERS reports by year from US approval date (12/23/2005) 0 1 0 7 2 0 1 2 3 4 5 6 7 2005 20 06 20 07 200 8 2009 # Peds Reports 3.2 CASE CHARACTERISTICS FROM PEDIATRIC SAFETY REVIEW (TABLE 2) 4
  5. 5. Table 2 : Characteristics of Abatacept Pediatric Cases (December 23, 2005 through July 7, 2009) n=7 Gender Female (4), Male (3) Age 0- 5 years (0) 6-11 years (2) 12-16 years (5) Mean (13 years), Median (14 years), Range (7-16 years) Origin US (3), Foreign (4) Report year 2006 (1), 2008 (4), 2009 (2) Report type Expedited 15-day (5), Periodic (2) Event [n=7] Multiple sclerosis (1), Lymphoma (1), Infection –skin (1), Purpura (1), Dyspnea (1), Transaminitis (1), Uveitis flare (1) Duration of therapy [n=7] Mean (6 months) , Median (3 months), Range (1 day – 19 months) Indication5 [n=7] JIA (4), Uveitis (1), Vasculitis (1), Spondyloarthropathy (1), Psoriasis (1) Outcomes [n=7] Serious (6): Life-Threatening (2), Hospitalization (1), and Other Medically Serious (3) Non-Serious (1) 4 DISCUSSION/SUMMARY OF PEDIATRIC CASES Pediatric reports represent approximately 0.4 % of the total (7/1,795). Seven post-marketing pediatric adverse event cases were identified with the use of abatacept. The reported ages ranged from 7 years to 16 years. Abatacept was used for JIA (a labeled indication) in 4 cases, and in the remaining 4 cases, it was used for off-label indications (psoriasis, uveitis, spondyloarthropathy, and vasculitis).6 The reported events were all single cases precluding a meaningful evaluation of the pediatric risk for these events with abatacept use. Four cases reported labeled events including multiple sclerosis, lymphoma, infection, and dyspnea, and the remaining 3 cases reported unlabeled events including purpura, transaminitis, and uveitis flare. These unlabeled events were either confounded by the concomitant use of other medications or appeared to be disease related. No pediatric deaths were reported with the use of abatacept. Due to the limited number of pediatric cases reported with abatacept, it is difficult to compare the safety profile in pediatric patients to adults (See Appendix). No new safety signals emerged as part of this review. 4.1 SUMMARY OF ADVERSE EVENT REPORTS IN PEDIATRIC PATIENTS (N=7) The 7 pediatric reports are summarized below: 1) Multiple Sclerosis (ISR 5621794, Foreign): A 14 year old male, enrolled in an open-label clinical study with abatacept for the treatment of JIA, was diagnosed with multiple sclerosis and right temporal lobe epilepsy after he received 19 months of abatacept therapy. A pediatric neurologist confirmed these diagnoses with the use of a magnetic resonance imaging (MRI) and 5 Cases may have more than one indication listed. 6 More than one indication for abatacept use was reported in a case. 5
  6. 6. an electroencephalogram (EEG). Concomitant medications included methotrexate, naproxen, and ondansetron which do not contain labeling for multiple sclerosis. Methotrexate and ondansetron are labeled for seizure. Multiple sclerosis is already included in the Adverse Reactions section of the abatacept labeling. Seizure is an unlabeled event for abatacept; however, the seizure in this case was confounded by MS and the concomitant use of other medications labeled for seizures and is unlikely related to abatacept. 2) Lymphoma (ISR 6206481, Foreign): A 16 year old female was diagnosed with lymphomatoid papulosis and then lymphoma approximately 1 month after starting abatacept therapy for vasculitis. The type of lymphoma was not reported. The patient had a skin biopsy six years prior to starting abatacept that diagnosed a possible lymphomatoid papulosis but this diagnosis was not confirmed until shortly after starting abatacept. Prior to starting abatacept, the patient had a 10 year history of treatment with other immunosuppressants including methotrexate, etanercept, adalimumab, infliximab, rituximab, azathioprine, cyclophosphamide, and prednisolone. These concomitant immunosuppressive medications contain labeling for malignancy. Abatacept is labeled for lymphoma. This single case of lymphoma was unlikely related to the use of abatacept given that the patient had a possible diagnosis of lymphomatoid papulosis prior to starting abatacept, a 10 year history of receiving other immunosuppressants prior to abatacept, and a diagnosis of malignancy after receiving only one month of abatacept therapy. 3) Infection – skin (ISR 5124221, Foreign): A 9 year old male was hospitalized with a skin infection and fever after he received approximately 3 months of abatacept therapy for erythrodermic psoriasis. The patient’s cultures were positive for cutaneous staphylococcus. The patient recovered following IV antibiotics and abatacept therapy was continued. Concomitant medication included methotrexate which is labeled for infection. The patient remained on abatacept and methotrexate following recovery and the recurrence of adverse events was not reported. Abatacept is labeled for infection. The contributory role of abatacept and methotrexate in this case could not be excluded. 4) Purpura (ISR 5745419, Domestic): A 15 year old female developed purpura on her legs after receiving approximately 15 months of abatacept therapy for JIA. A biopsy confirmed the diagnosis and the patient was treated with topical steroids. The seriousness of the purpura was reported as mild with no adverse outcome or sequelae. Therapy with abatacept continued without the recurrence of purpura. Concomitant medications include diclofenac and prednisone, which are both labeled for purpura. This single case of purpura is most likely related to the use of diclofenac and prednisone as purpura is associated with their use. The event of purpura is unlikely related to abatacept considering abatacept therapy was continued without incident and the concomitant use of medications labeled for purpura. 5) Dyspnea (ISR 6024565, Domestic): A 7 year old male developed dyspnea and stridor approximately 25 minutes following a trial dose of abatacept for spondyloarthropathy. The same hypersensitivity reaction occurred following a trial dose of infliximab. The patient required epinephrine to recover. Medical history was positive for asthma. Abatacept is labeled for infusion-related reactions and hypersensitivity reactions including dyspnea. 6
  7. 7. 7 6) Transaminitis (ISR 6214146, Foreign): A 14 year old female developed transaminitis after she received approximately 7 months of abatacept therapy for JIA. The transaminitis abated following discontinuation of abatacept. Concomitant medication included diclofenac and omeprazole, which are both labeled for elevated liver tests. Therapy start and end dates were not reported for the concomitant medications. Concomitant use of diclofenac and omeprazole confounded the causality assessment of this single case of transaminitis. 7) Uveitis flare (ISR 5682539, Domestic): A 16 year old female developed a flare of uveitis one day after her first dose of abatacept therapy for the treatment of uveitis. The patient also experienced fatigue, anxiety, and a rash. The patient reported that she may have been experiencing active symptoms of uveitis prior to receiving the first abatacept infusion. This case was coded as non-serious and therapy with abatacept continued. The patient received a second abatacept infusion without any adverse events. This non-serious case of a flare-up of uveitis appears to be disease related rather than drug related. For completeness, this case was included in our case series. 5 CONCLUSION No new safety signals emerged as part of this review. Many of the events reported in pediatric patients are already included in the labeling for abatacept (i.e. multiple sclerosis, malignancy, infections, and dyspnea). The remaining cases that reported unlabeled events were either confounded by the concomitant use of other medications labeled for the events (i.e. purpura and transaminitis) or was a non-serious report that appeared to be disease related (i.e. uveitis flare). The current abatacept label appears to address all of the safety issues discussed in this review. 6 RECOMMENDATIONS • We recommend that no further labeling changes regarding the pediatric patients are necessary at this time.
  8. 8. APPENDIX7 All Preferred Terms in Pediatrics from approval through July 7, 2009 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 0 1 2 3 Anxiety Deposit Eye Drug Ineffective Dyspnoea Erythema Fatigue Feeling Abnormal Headache Hypersensitivity Irritability Lymphoma Lymphomatoid Multiple Sclerosis Off Label Use Pyrexia Rash Skin Haemorrhage Skin Infection Skin Lesion Stridor Temporal Lobe Epilepsy Transaminases Uveitis Purpura PreferredTerms(PT) Number of events in AERS 7 Graphs in Appendix are based on AERS crude counts, duplicates have not been reconciled; more than one event may be reported in a case
  9. 9. Adverse events by MedDRA SOC reported in Pediatrics from approval through July 7, 2009 1 1 1 1 1 1 1 1 2 3 5 0 1 2 3 4 5 6 Eye Immune System Infections Investigations Neoplasms Psychiatric Respiratory Surgical Nervous System General Disorders Skin SystemOrganClass(SOC) Number of events in AERS Page 9
  10. 10. Top 25 Preferred Terms in Adults from approval through July 7, 2009 16 16 16 17 19 20 21 21 22 22 23 23 25 26 27 29 31 32 32 35 37 48 55 59 61 0 10 20 30 40 50 60 70 Anaphylactic Reaction Hypoaesthesia Pain Diarrhoea Cough Blood Pressure Hypersensitivity Oedema Peripheral Arthralgia Back Pain Asthenia Pain In Extremity Vomiting Chest Pain Dizziness Rash Urticaria Pruritus Pyrexia Fatigue Pneumonia Dyspnoea Drug Ineffective Headache Nausea PreferredTerm(PT) Number of Events in AERS Page 10
  11. 11. Page 11 Adverse events by MedDRA SOC reported in adults from approval through July 7, 2009 2 3 5 7 11 16 24 32 34 36 37 45 49 49 70 80 88 123 132 179 181 188 194 255 302 0 50 100 150 200 250 300 350 Social Circumstances Pregnancy Endocrine Surgical Ear Reproductive Hepatobiliary Blood Renal Psychiatric Injury Eye Disorders Immune System Metabolism Cardiac Neoplasms Vascular Disorders Investigations Musculoskeletal Respiratory Skin Nervous System Gastrointestinal Infections General Disorders SystemOrganClass(SOC) Number of Events in AERS

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