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Global Medical Cures™ | Humira- Pediatric PostMarketing Adverse Event Review
 

Global Medical Cures™ | Humira- Pediatric PostMarketing Adverse Event Review

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Global Medical Cures™ | Humira- Pediatric PostMarketing Adverse Event Review ...

Global Medical Cures™ | Humira- Pediatric PostMarketing Adverse Event Review




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    Global Medical Cures™ | Humira- Pediatric PostMarketing Adverse Event Review Global Medical Cures™ | Humira- Pediatric PostMarketing Adverse Event Review Document Transcript

    • CONTENTS EXECUTIVE SUMMARY............................................................................................................. 2 1 BACKGROUND .................................................................................................................... 2 1.1 Product Formulations and Indications ........................................................................... 2 1.2 Pediatric Filing History.................................................................................................. 2 1.3 Pediatric Malignancy Regulatory History……………………………………………...2 1.4 Pediatric Labeling .......................................................................................................... 3 2 METHODS AND MATERIALS............................................................................................ 4 2.1 Introduction.................................................................................................................... 4 2.2 AERS Search Criteria .................................................................................................... 4 3 AERS RESULTS for Adalimumab ........................................................................................ 5 3.1 Crude Counts of All AERS Reports: Table 1 ................................................................ 5 3.2 Case Characteristics From Pediatric Safety Review (Table 2) ...................................... 6 4 DISCUSSION/Summary Of PEDIATRIC Cases................................................................... 6 4.1 Pediatric Deaths (N= 4).................................................................................................. 6 4.2 Non-Fatal Serious Adverse Events (N=105).................................................................. 7 4.2.1 Serious Infections (N=24).............................................................................................. 7 4.2.2 Malignancies (N=2) ....................................................................................................... 8 4.2.3 Hypersensitivity/Injection Site Reactions (N=7) ........................................................... 8 4.2.4 Disease Flares/Drug Ineffective (N=22)........................................................................ 9 4.2.5 In Utero Exposures (N=34)............................................................................................ 9 4.2.6 Other Serious Miscellaneous Events (N=17)............................................................... 11 5 CONCLUSION..................................................................................................................... 11 6 RECOMMENDATIONS...................................................................................................... 11 APPENDICES............................................................................................................................... 16 APPENDIX I - Pediatric Labeling…………………………………………….…………12 APPENDIX II - Narrative Summary of the Pediatric Death Cases (N=4)…………..…..13 APPENDIX III - Other Serious Miscellaneous Cases (N=17) ………………………….15 APPENDIX IV - Graphical Comparision of Adult and Pediatric Reported Events …….16
    • EXECUTIVE SUMMARY In accordance with the Pediatric Research Equity Act (PREA), the Division of Pharmacovigilance II (DPV II) was asked to summarize post-marketing reports of adverse events associated with the use of adalimumab in pediatric patients (0-16 years of age) from the Adverse Event Reporting System (AERS) database. Adalimumab is a tumor necrosis factor (TNF) blocker indicated for the treatment of juvenile idiopathic arthritis in pediatric patients four years of age and older and for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and plaque psoriasis in adults. The Adverse Event Reporting System (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 42,852 reports for adalimumab. Pediatric reports represent approximately 1% of the total (471/42,852). One hundred and nine serious pediatric adverse event cases were selected for this case series. The reported ages ranged from 1 day to 16 years old. Adalimumab was used for JIA (a labeled indication) in 20 cases, and it was used for off-label pediatric indications in 51 cases (Crohn’s disease-42, ulcerative colitis-3, uveitis-2, psoriasis-2, psoriatic arthritis-1, and vasculitis- 1); the remaining cases reported in utero exposure cases (37). Many of the events reported in pediatric patients are already included in the pediatric labeling for adalimumab (i.e. serious infection, malignancy, hypersensitivity/injection site reactions, and disease flares). The remaining cases that reported unlabeled events were either confounded by concomitant medications and/or underlying disease, or provided insufficient evidence to conclude a causal association between the events and the use of adalimumab therapy. No new safety signals emerged from this review. No labeling changes regarding the pediatric patients are recommended at this time. 1 BACKGROUND PRODUCT FORMULATIONS AND INDICATIONS Adalimumab is supplied in prefilled syringes as a preservative-free, sterile solution for subcutaneous administration in the following configurations: 40 mg/0.8 mL in a single-use prefilled pen, 40 mg/0.8 mL in a single-dose prefilled glass syringe, and 20 mg/0.4 mL in a single-dose prefilled glass syringe. Adalimumab is indicated for the treatment of juvenile idiopathic arthritis in pediatric patients four years of age and older and for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and plaque psoriasis in adults. PEDIATRIC FILING HISTORY Adalimumab received FDA approval on December 31, 2002. Pediatric approval of adalimumab occurred on February 21, 2008. The pediatric approval of adalimumab was based on a double- blind, multicenter, randomized, parallel-group study in 171 children (4 to 17 years old) with polyarticular juvenile idiopathic arthritis (JIA). In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All subjects had signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. The data from the pediatric study provided statistically significant and consistent support for efficacy of adalimumab in children with polyarticular JIA. The safety profile was similar to that 2
    • seen in adults with a few exceptions; elevations in creatine phosphokinase (CPK) and higher rates of immunogenicity and non-serious hypersensitivity reactions were observed in pediatric patients with adalimumab use. There were no deaths in the pediatric study.1 PEDIATRIC MALIGNANCY REGULATORY HISTORY • June 4, 2008 – An Early Communication (EC) about on ongoing safety review of the TNF blockers and pediatric malignancies was posted on the FDA website. 2 FDA requested additional information on the cases of pediatric malignancy from the sponsors of the TNF blockers. In addition, FDA contacted medical experts to assess the potential association between TNF blockers and malignancy. • June 18, 2008 – FDA Advisory Committee meeting on the proposal for Enbrel (etanercept) treatment for pediatric psoriasis. The committee agreed that the data presented was not sufficient to understand the risk vs. benefit with potential for malignancy in pediatric plaque psoriasis. The committee described that further information is needed, perhaps in the form of a pediatric registry.3 • July 25, 2008 – The OSE review of pediatric malignancy concluded that there is an increased risk of lymphoma and other cancers associated with the use of TNF blockers in children and adolescents.4 • September 5, 2008 - Under provisions of FDAAA section 921, the pediatric malignancy safety issue was posted on the FDA website as new safety information identified from the adverse event reporting system (AERS).5 • August 4, 2009 – In the follow-up to the Early Communication on pediatric malignancies with the TNF blockers the FDA announced that it had concluded that there is an increased risk of lymphoma and other cancers associated with the use of the TNF blockers in children and adolescents. The FDA is requiring that new Boxed Warnings be added to the TNF class of drugs for the increased risk of lymphoma and other malignancies in children and adolescents. 6 • August 25, 2009 - Additional denominator and case information was released on the FDA website to help clinicians better understand the data that was used to conclude that there is an increased risk of malignancy in children treated with TNF blockers.7 • October 2009 – Labeling negotiations between the FDA and the sponsors of the TNF blockers to add new Boxed Warnings for the risk of pediatric malignancies are on-going. 1 Siegel, J. Clinical review of BLA 125057; January 7, 2008. 2 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ucm070725.htm 3 http://www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4361m2-Final.pdf 4 Diak P, La Grenade L., Malignancy in Children - FDA Post-marketing safety review. July 2008. 5 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects /ucm085914.htm 6 FDA: Cancer Warnings Required for TNF Blockers. Accessed September 22, 2009. URL: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm 7 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ucm180694.htm 3
    • PEDIATRIC LABELING 8 Please see Appendix I for a complete listing of the relevant pediatric labeling for adalimumab. Below is a brief summary of the pediatric labeling. Warnings • Immunizations should be brought up to date prior to initiating adalimumab therapy in JIA patients. Adverse Reactions • Immunogenicity was identified in 16% of the JIA patients treated with adalimumab. • Juvenile Idiopathic Arthritis Clinical Studies: In general, the adverse reactions in pediatric patients were similar in frequency and type to those seen in adult patients • Pregnancy Category B METHODS AND MATERIALS 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. AERS SEARCH CRITERIA The Adverse Event Reporting System (AERS) database was searched using the drug name adalimumab (verbatim and trade names) to obtain crude counts of adverse events associated with the use of adalimumab from market approval (December 31, 2002) to the data lock date of July 7, 2009 (see Table 1 in Section 3.1). A detailed (case by case) review of the serious9 reports (n=128) reported with the use of adalimumab in pediatric patients was performed. Figure 1 below is a diagram showing the evaluation process for selecting the eligible reports for the case series (n=109), which was used to characterize the post-marketing adverse events associated with the pediatric use of adalimumab. 8 Humira (adalimumab) prescribing information; Abbott, Inc. August 2008. 9 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. 4
    • Figure 1. Diagram of AERS Case Selection for Adalimumab Pediatric Use (12/31/2002-7/7/2009) Serious Reports Meeting AERS Search Criteria (n= 128) Non-duplicated Serious Reports (n=114) Duplicate Reports (n=14) Eligible Serious Reports for Case Series (n=109) Excluded Reports-- adverse event reported prior to initial adalimumab use (n=2) Excluded Reports-- miscoded and no adverse event reported with adalimumab use (n=3) AERS RESULTS FOR ADALIMUMAB CRUDE COUNTS OF ALL AERS REPORTS: TABLE 1 Table 1: Crude counts1 of AERS Reports from All Sources From Approval Date 12/31/2002 to 07/07/2009 All reports (US)2 Serious3 (US) Death (US) Adults (≥ 17 yrs.) 34,240 (27,759) 10,627 (4,410) 1,331 (539) Pediatrics (0-16 yrs.) 471 (412) 128 (79) 4 (2) Age unknown (Null values) 8,141 (6,718) 1,938 (659) 283 (117) Total 42,852 (34,889) 12,693 (5,148) 1,618 (658) 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. 5
    • Figure 1: Number of pediatric AERS reports by year from US approval date (12/31/2002) 10 21 28 3 45 213 151 0 50 100 150 200 250 2003 2004 2005 2006 2007 2008 2009 # Peds Reports CASE CHARACTERISTICS FROM PEDIATRIC SAFETY REVIEW (TABLE 2) Table 2 : Characteristics of Serious Pediatric Cases (December 31, 2002 through July 7, 2009) n=109 Gender [ n= 98] Male: (52) Female: (46) Age [n=109] 0- <1 month (34) 1 month <2 yrs (4) 2-5 yrs (4) 6-11 yrs (13) 12-16 yrs (54) Mean (9 years); Median (12 years); Range (0-16 years) Origin [n=109] US (66), Foreign (43) Report Year [n=109] 2003(1), 2004 (3), 2005 (4), 2006 (3), 2007 (15), 2008 (50), 2009 (33) Report Type [n=109] Expedited 15-day (94), Periodic (13), Direct (2) Time to onset from start of adalimumab therapy [n=55] Mean (5 months) , Median (2 months) Range: (1 day – 3.75 years) Reason for Use [n=108] Crohn’s disease (42), JIA (20), Ulcerative colitis (3)Uveitis (2), Psoriasis (2), Psoriatic arthritis (1), Vasculitis (1) In utero exposure (37) Outcomes10 [n=109] Death (4), Hospitalization (60), Congenital Anomaly (17), Life- Threatening (2), Disability (2), Other Medically Serious (53) DISCUSSION/SUMMARY OF PEDIATRIC CASES PEDIATRIC DEATHS (N= 4) Four pediatric cases reported an outcome of death with exposure to adalimumab. Three of the four cases involved neonates following in utero adalimumab exposure. Respiratory disorders were reported as the cause of death in the three newborn infants. The remaining death case 10 Cases may have more than one outcome reported 6
    • involved a 16 year old who developed respiratory failure secondary to pneumonia. The causality assessments of the pediatric death cases were confounded by the use of concomitant the (i.e. alcohol, tobacco, corticosteroids, cyclosporine, penicillin, and sedation/anesthetic medications drug delivery) and/or underlying disease (i.e. Crohn’s disease, RA), or provi insufficient evidence t rapies ded o conclude a causal association between the events and the use of summary and a causality assessment for each pediatric death case are located in Appendix II. ty 2.1, cy reported s associated with adalimumab use in pediatric patients in the AERS database as of July 7, 2009. . patients to . nd for adalimumab adequately warns of e potential risk of serious infections in pediatric patients. adalimumab therapy. **A narrative NON-FATAL SERIOUS ADVERSE EVENTS (N=105) OPT requested that we specifically address serious infections, malignancies, and hypersensitivi reactions in our review of non-fatal AERS cases. These events are reviewed in sections 4. 4.2.2, and 4.2.3, respectively. For completeness, we have also provided a synopsis of the remaining reported non-fatal serious adverse events including, disease flares, adverse pregnan outcomes, and other miscellaneous events in sections 4.2.4, 4.2.5, and 4.2.6, respectively. A graphical comparison by system organ class (SOC) and the top 25 preferred terms (PT) with adalimumab use in adults and pediatric patients can be found in the Appendix IV. Of note, DPV II was also requested to highlight cases of CPK elevation as approximately 15% of the children in the JIA clinical trial developed mild-to-moderate elevations of CPK.11 However, there were no cases of CPK elevation 1.1.1 SERIOUS INFECTIONS (N=24) Twenty four cases reported serious infections (TB – 3, Staph – 2, Cellulitis – 2, Viral – 2, H Zoster – 1, CMV – 1, C. difficile – 1, pneumonia – 1, Candida – 1, keratitis – 1, Unknown etiology – 9). Of the 24 cases, 15 cases were of U.S. origin and 9 cases were foreign. Serious infections were reported more in males (15) than females (9). The median age of the was 11 years old with an age range of 2 to 16 years. Eleven cases reported the use of concomitant immunosuppressants (methotrexate, 6-MP, azathioprine, mycophenolate, and corticosteroids), which are labeled for infections. Time to onset of infection ranged from 1 day 19 months after initiating adalimumab with a median of 60 days. The reported indications for adalimumab use included Crohn’s disease (11), JIA (8), ulcerative colitis (3), and uveitis (2). Hospitalization was the outcome in 21 cases, 1 case reported life threatening outcomes, and 11 cases reported other serious medically significant events.12 Thirteen patients recovered, 4 patients had not recovered, and in the remaining 7 cases, the patient’s recovery was not reported The contributory role of adalimumab in these 24 serious infection cases could not be excluded given the plausible temporal association and the immunosuppressive pharmacologic mechanism of adalimumab. The risk of serious infections is found in the Boxed Warnings, the Warnings a Precautions, and the Adverse Reactions sections of the adalimumab label. Also included are recommendations for not starting adalimumab during active infection and to stop therapy if the patient develops a serious infection. The pediatric labeling th 11 Humira (adalimumab) package insert, Abbott; February 2008. 12 Cases may have more than one outcome listed. 7
    • 1.1.2 MALIGNANCIES (N=2) Lymphoma was reported in two female pediatric patients. Prior to the diagnosis of malignanc both cases reported an approximately 10 year history of immunosuppressant use (infliximab, etanercept, abatacept, rituximab, anakinra, cyclophosphamide, rituximab, prednisone, and methotrexate), which are labeled for malignancy (non-age specific). In the first case, a 10 year- old developed Hodgkin’s lymphoma stage IIA while receiving adalimumab for 2.4 years and methotrexate for 3.7 years for JIA. Systemic JIA was diagnosed when the patient was 1 year old. The patient received chemotherapy for this newly diagnosed lymphoma but the outcome was n reported. In the second case, the diagnosis of malignancy did not occur while the patient was receiving adalimumab. While receiving abatacept therapy for vasculitis, a 16 year old was diagnosed with lymphomatoid papulosis and lymphoma. Previously, the patient had received 1 months of adalimumab therapy with the last dose of adalimumab given 19 months prior to the diagnosis of lymphoma. Prior use of methotrexate, rituximab, etanercept, infliximab, azathioprine, cyclophosphamide, and prednisolone was also reported. The type of lymphoma not reported y, ot 4 was . The patient received chemotherapy for the lymphoma but the outcome was not e since the medications were given over a 10 year 3 for e TNF blockers). vents.16 reported. In these two cases, it is possible that the lymphomas were associated with any or all of the reported immunosuppressive medications. It is not possible to determine which medication was more likely to be associated with the outcom period, and are all labeled for malignancy. Based on a separate drug class review of the TNF blockers, the FDA has concluded that there is an increased risk of lymphoma and other cancers associated with the use of TNF blockers in children and adolescents.13,14 The Warnings section of the current adalimumab label describes the increased observance of malignancies found in the adult clinical trials of the TNF blockers. The Division of Anesthesia, Analgesia, and Rheumatology Products is currently working with the sponsors to update all the TNF blocker labels to include a Boxed Warning for an increased risk of malignancy in children. The pending changes to the adalimumab label will adequately warn of an increased risk of malignancy in pediatric patients treated with TNF blockers (see Section 1. the regulatory history of the pediatric malignancy safety concern with th 1.1.3 HYPERSENSITIVITY/INJECTION SITE REACTIONS (N=7) Seven cases reported hypersensitivity or injection site reactions. All the reported events occurred within one month of initiating adalimumab therapy and provided a plausible temporal association with adalimumab. The reported events included injection site pain (3), diffuse swelling (2), pyrexia (2), neck swelling (1), head to toe rash (1), difficulty opening mouth (1), weight gain (1), injection site bruising (1), dizziness (1), and nausea (1).15 None of the cases reported events of anaphylaxis or the formation of autoantibodies. Five cases were of U.S. origin and 2 cases were foreign. The cases were reported more often in males (4) than females (3). The median age of the patients was 13 years old with an age range of 5 to 16 years. The reported indications for adalimumab use included Crohn’s disease (5) and JIA (2). Hospitalization was the outcome in 4 cases, 1 case reported disability, and 4 cases reported other serious medically significant e 13 Diak P, La Grenade L., Malignancy in Children - FDA Post-marketing safety review. July 2008. 14 FDA: Cancer Warnings Required for TNF Blockers. Accessed September 22, 2009. URL: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm 15 Cases may have more than one event reported 16 Cases may have more than one outcome listed. 8
    • Three cases reported discontinuation of adalimumab therapy, 3 cases reported continued treatment, and the remaining case did not provide information regarding the continuation of are unexpected with the use of adalimumab and is adequately labeled for the pediatric population. f reports of treated s that the AERS cases of disease flare and drug ineffectiveness were possibly d h ing 4 cases did not t use of provided that immunogenicity could have played a role in the reports of drug ineffectiveness. adalimumab therapy. In these seven cases, it is possible that the adverse events were associated with adalimumab based on the plausible temporal associations reported. Hypersensitivity and injection site reactions included in the pediatric labeling for adalimumab. The risk of these types of reactions is not 1.1.4 DISEASE FLARES/DRUG INEFFECTIVE (N=22) Occurrences of disease flares and reports of drug ineffectiveness are expected in patients with autoimmune diseases such as Crohn’s disease, JIA, and psoriasis. In the JIA clinical trial, 43% o the pediatric patients who received adalimumab without methotrexate experienced disease flare and 37% experienced flares with concomitant methotrexate.17 Disease flare and immunogenicity are included in the pediatric labeling for adalimumab. A possible explanation for the drug ineffectiveness is that the pediatric patients treated with adalimumab developed immunogenicity. Another possibility for the reports of drug ineffectiveness is that the patient did not respond to adalimumab therapy. It is difficult to assess efficacy from postmarketing reports; the main utility of AERS is to provide signals of potential drug safety issues. It appear disease related. Twenty two AERS cases reported disease flares or drug ineffectiveness. Crohn’s disease (18) was the listed indication for adalimumab use in the majority of the cases followed by JIA (2) an psoriasis (2). Crohn’s disease and psoriasis are off-label uses for adalimumab in the pediatric population. Fifteen cases were of U.S. origin and 7 cases were foreign. The cases were reported more often in females (15) than males (7). The median age of the patients was 15 years old wit an age range of 13 years to 16 years. Hospitalization was the outcome in 16 cases and 7 cases reported other serious medically significant events.18 Nine cases reported discontinuation of adalimumab therapy, 9 cases reported continued treatment, and the remain provide information regarding the continuation of adalimumab therapy. Nine cases reported the use of concomitant immunosuppressants (methotrexate, azathioprine, tacrolimus, and corticosteroids). The remaining 13 cases did not report the concomitan immunosuppressants, which can potentially increase the rate of immunogenicity with adalimumab. Immunogenicity has been shown to be higher in JIA patients treated with adalimumab monotherapy (26%) compared to patients receiving concomitant methotrexate (6%).13 In addition, adalimumab patients with antibodies to adalimumab had lower efficacy results than in patients without antibodies.19 Although none of these 22 pediatric cases information regarding the development of antibodies to adalimumab, it is possible 1.1.5 IN UTERO EXPOSURE/ADVERSE PREGNANCY OUTCOMES (N=34) Thirty four cases reported non-fatal adverse pregnancy outcomes with in utero exposure to adalimumab.20 Seventeen cases reported congenital anomalies, which included reports of 17 Humira (adalimumab) package insert, Abbott; February 2008. 18 Cases may have more than one outcome listed. 19 Humira (adalimumab) package insert, Abbott; February 2008. 20 Three additional in utero exposure cases were reported with an outcome of pediatric death (Section 4.1) 9
    • Down’s syndrome (2), hip dysplasia (2), cleft lip (1), ectopic testicle (1), hypospadias (1), inguinal hernia (1), microcephaly (1), cyanosis (1), craniosynostosis (1), hexadactyly (1), sacral dimple (1), atrial septal defect (1), ventricular septal defect (1), bicuspid aortic valve (1), and cardiomegaly (1). Of the remaining 17 cases, the reported adverse pregnancy outcomes included premature baby (8), neonatal infections {herpes encephalitis-1, meningitis-1, RSV-1}(3), in s not , e in 5 cases, gestational diabetes in ablishing as vious OSE dy s due to adalimumab. However, there have been no well-controlled e mab a f non-adalimumab pregnancies) and within the expected range in the general neonatal aspiration (2), neonatal lupus (1), hypoxia (1), apnea (1), and jaundice (1). In utero exposure to adalimumab was reported during preconception in 16 cases, 1st trimester 19 cases, 2nd trimester in 11 cases, 3rd trimester in 8 cases, and the time of exposure wa provided in 8 cases.21 Nine of the 34 cases reported the maternal use of concomitant immunosuppressants (i.e. corticosteroids-6, methotrexate-2, azathioprine-1, and leflunomide-1). The reported indications for maternal use of adalimumab included Crohn’s disease (15), RA (12) ulcerative colitis (2), psoriasis (1), psoriatic arthritis (1), and ankylosing spondylitis (1); 2 cases did not report this information. Twenty six cases were of U.S. origin and 8 cases were foreign. Pertinent maternal medical history reports included tobacco us 2 cases, marijuana use in 2 cases, and alcohol use in 1 case. These cases are difficult to assess due to the confounding factors such as the maternal medical history (i.e. tobacco and alcohol use), underlying autoimmune diseases (i.e. Crohn’s disease and RA), and the use of concomitant immunosuppressants. A significant limitation of AERS data is that the number of pregnant women exposed to adalimumab is unknown. Therefore, est an increased risk compared to the background rate is not attainable due to the lack of a denominator. Overall, no consistent pattern of adverse pregnancy outcomes was observed. Given the confounding factors and the lack of information in many of these cases, there w insufficient evidence to conclude a causal association between the events and the use of adalimumab therapy during pregnancy. A similar conclusion was made in a pre review from February 2005 on pregnancy outcomes with the TNF blockers.22 Adalimumab is Pregnancy Category B. An embryo-fetal perinatal developmental toxicity stu was performed in cynomolgus monkeys at supratherapeutic human dosages and revealed no evidence of harm to the fetuse studies in pregnant women. A disease based pregnancy registry has been established by the Organization of Teratology Information Specialists (OTIS) for medications, including adalimumab, used to treat autoimmune diseases. The conclusions that will be generated, once a sufficient sample size is enrolled in th OTIS registry, may provide meaningful information regarding the reproductive risks of these drugs. As of December 8, 2008, preliminary results from the OTIS registry for the adalimu cohort (n=34) have not shown an increased reproductive risk for spontaneous abortion (5), stillbirth (0), congenital defect (2), and preterm delivery (4). Pregnancy outcomes for the adalimumab cohort were similar to two comparison groups (i.e. a disease-matched group and healthy group o population.23 21 The use of adalimumab may have been reported during multiple trimesters. 22 Kwon H. FDA Outcomes of Pregnancy with infliximab, etanercept, and adalimumab. OSE Post- marketing safety review. February 2005. 23 Johnson D., Jones K., Chambers C. Pregnancy Outcomes in Women Exposed to Adalimumab: OTIS Autoimmune Diseases in Pregnancy Project. Accessed September 22, 2009. http://www.otispregnancy.org 10
    • Given the uncertainty of an association between adalimumab and adverse pregnancy outcomes, the adalimumab label adequately provides caution that adalimumab “should be used during e a ediatric risk for these events with abatacept use. Chest pain, which s unlabeled adverse events in this section that suggested an association to adalimumab. individual miscellaneous cases are displayed along with the labeling status of r maining cases that reported unlabeled events were either d the use of adalimumab therapy (i.e. adverse pregnancy outcomes). g labeling changes for pediatric malignancies, the adalimumab RECOMMENDATIONS No labeling changes regarding the pediatric patients are recommended at this time. pregnancy only if clearly needed.” 1.1.6 OTHER SERIOUS MISCELLANEOUS EVENTS (N=16) There were 16 cases of other serious miscellaneous events (chest pain-3, hypertension-1, dizziness-1, seizure-1, syncope-1, psoriasis-1, purpura-1, increased hepatic enzymes-1, hemoglobin decreased-1, muscle spasms-1, back pain-1, uveitis-1, diabetes mellitus-1, lupus-lik syndrome-1). The miscellaneous events were predominately single case reports precluding meaningful evaluation of the p is already included in the label (non-age specific), was the only event reported more than once. There was no pattern of seriou In Appendix III, the the reported adverse events. CONCLUSION No new safety signals emerged as part of this review. The reported adverse events in AERS fo the pediatric patients appear to be similar to those seen in the JIA clinical trial and in the adult population. Many of the events reported in pediatric patients are already included in the pediatric labeling for adalimumab (i.e. serious infection, malignancy, hypersensitivity/injection site reactions, and disease flares). The re confounded by concomitant medications and/or underlying disease, or provided insufficient evidence to conclude a causal association between the events an With the addition of the pendin label addresses all of the safety issues discussed in this review. 11
    • APPENDIX I Adalimumab Pediatric Labeling24 Warnings: Immunizations - It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. Adverse Reactions: Immunogenicity - In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy. Juvenile Idiopathic Arthritis Clinical Studies: In general, the adverse reactions in pediatric patients were similar in frequency and type to those seen in adult patients [see Warnings and Precautions (5) and other sections under Adverse Reactions (6)]. Important findings and differences from adults are discussed in the following paragraphs. HUMIRA has been studied in 171 pediatric patients, aged 4 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in juvenile idiopathic arthritis patients were generally similar to those commonly seen in outpatient JIA populations. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment. In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash. Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with juvenile idiopathic arthritis exposed to HUMIRA alone; liver function tests (LFT) elevations were more frequent among those treated with the combination of HUMIRA and MTX. In general, these elevations did not lead to discontinuation of HUMIRA treatment. In the juvenile idiopathic arthritis trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption. Pregnancy: Pregnancy Category B - An embryo-fetal perinatal developmental toxicity study has been performed in cynomolgus monkeys at dosages up to 100 mg/kg (266 times human AUC when given 40 mg subcutaneously with methotrexate every week or 373 times human AUC when given 40 mg subcutaneously without methotrexate) and has revealed no evidence of harm to the fetuses due to adalimumab. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed. Pregnancy Registry: To monitor outcomes of pregnant women exposed to HUMIRA, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1-877-311-8972. 24 Humira (adalimumab) prescribing information; Abbott, Inc. August 2008. 12
    • APPENDIX II Narrative Summary of the Pediatric Death Cases through 7/7/09 (n=4) 1) Fetal Distress Syndrome (ISR # 6220490, Foreign): A newborn infant with in utero exposure to adalimumab during the first, second, and third trimesters experienced acute fetal distress and died. The infant was born via Cesarean section at 39 weeks and six days gestation. No congenital malformation or neonatal pathology was found. Ultrasonographies performed at 12 weeks, 25 weeks, 31 weeks, and 36 weeks were unremarkable. Neonatal birth weight was 3700 g, length was 50 cm, sex was female, cranial perimeter was 38 cm, Apgar score at one minute was 0 and at five minutes was 0. The infant was transferred to the NICU. On an unreported date, the infant died of acute fetal distress. The infant's mother received sedation and anesthetic medications during delivery (drug names not reported). The infant’s mother was 25 years old. No maternal medical problems or complications during delivery or postpartum were noted. The infant’s mother had a medical history of smoking 20 cigarettes per day and received adalimumab and corticosteroids for the treatment of Crohn’s disease; both medications were started during the first trimester. Corticosteroids are Pregnancy Category D when used during the first trimester.25 Reviewer’s comment: The mother’s concomitant use of corticosteroids, sedation and anesthetic medications during delivery, and smoking history confounded the causality assessment of this case. 2) Hypoxia (ISR # 4741573, Domestic): A newborn infant with in utero exposure to adalimumab during preconception experienced hypoxia and died. The infant’s mother was 39 years old when she became pregnant. She had discontinued adalimumab therapy for rheumatoid arthritis four months prior to conception. During delivery, the infant’s mother received penicillin to treat a Group B Streptococcal infection. Consequently, the infant’s mother experienced a severe anaphylactic reaction to penicillin and required treatment with epinephrine. Upon delivery the newborn was hypoxic and died. No other case details were reported. Reviewer’s comment: The adverse event in this case was unlikely related to adalimumab given that adalimumab was discontinued four months prior to conception and has a mean terminal half-life of 2 weeks.26 The adverse events reported in this case were likely related to the mother’s anaphylactic reaction to penicillin. 3) Pulmonary Malformation (ISR 5135851, Domestic – OTIS Pregnancy Registry): A newborn infant with in utero exposure to adalimumab during preconception through the first trimester experienced underdeveloped lungs and died. The infant was prematurely born via emergency Cesarean section at 28 weeks gestation. The infant had to be resuscitated and died 8.5 hours after birth. The underdeveloped lungs were reported as a congenital anomaly. The infant’s mother was 22 years old while pregnant and received sedation and anesthetic medications during delivery (drug names not provided). The infant’s mother had a history of tobacco and alcohol use and received adalimumab and calcipotriene solution therapies during the first trimester of the pregnancy for psoriasis. Reviewer’s comment: The concomitant use of alcohol, tobacco, and calcipotriene while pregnant confounded the causality assessment of this case. The patient’s premature birth at 28 weeks provides a plausible explanation for the origin of the underdeveloped lungs and death. 25 Briggs GB, Freeman RK, Summer JY. Drugs in Pregnancy and Lactation. 8th ed. Philadelphia PA: Lippincott Williams & Wilkins; 2008. 26 Humira (adalimumab) package insert, Abbott; February 2008. 13
    • 4) Pneumonia (ISR # 5968876, Foreign): A 16 year old male was diagnosed with interstitial pneumonia, pyrexia, productive cough, and worsening dyspnea after he received approximately 11 months of adalimumab therapy for JIA. The patient was treated with antibiotics while hospitalized; however, his symptoms worsened and he died nine days after being admitted. The patient died from respiratory failure. The etiology of the infection was not determined; cultures were negative with no evidence of fungal infections or tuberculosis. During the hospitalization, the patient experienced laboratory abnormalities associated with macrophage activation syndrome, including increased ferritin, increased liver enzymes, hyperlipidemia, and pancytopenia. The reporting physician felt that the development of macrophage activation syndrome might have served as a contributing factor in the patient’s death. An autopsy was not performed. Concomitant medication included cyclosporine (indication not provided), which is labeled for serious infections. Reviewer’s comment: The causality assessment of the patient’s death in this case was confounded by the use of concomitant medication labeled for infections and the development of macrophage activation syndrome, which is associated with JIA.27 The events of fever and pneumonia were possibly related to adalimumab and cyclosporine. Adalimumab is labeled for the risk of serious infection in the boxed warnings. 27 Villanueva J, Lee S, Giannini EH, Graham T, Passo M, Filipovich A; Grom A. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther. 2005;7(1):R30-37. 14
    • 15 APPENDIX III Table 3. Summary of Other Serious Miscellaneous Cases in AERS through 7/7/09 (n=16) ISRNUM Age (yrs) Gender Indication Adverse Event Labeled Term Cardiac Disorders (4) 6061322 15 Female Crohn’s disease Hypertension Yes 6092504 13 Female Crohn’s disease Chest pain Yes 5754242 12 Female Crohn’s disease Chest pain Yes 6230242 14 Female JIA Chest pain Yes Nervous System Disorders (3) 6078221 12 Male Crohn’s disease Dizziness Yes 6120880 16 Female JIA Seizure28 none 6106232 15 Male JIA Syncope Yes Skin Disorders (2) 5389744 13 Male Crohn’s disease Psoriasis (new-onset) Pending29 5963134 12 Male Not reported Purpura Bruising Investigations (2) 6223731 16 Male Psoriasis Increased hepatic enzymes Yes 5731570 7 Male Crohn’s disease Hemoglobin decreased Pancytopenia Musculoskeletal Disorders (2) 5175238 11 Male JIA Muscle spasms Yes 5994403 16 Male Crohn’s disease Back pain Yes Eye Disorders (1) 4684902 16 Female JIA Uveitis Cataract Metabolism Disorders (1) 5653658 12 Female JIA Diabetes mellitus none Immune System Disorders (1) 5901735 10 Female Crohn’s disease Lupus-like syndrome Yes 28 The patient had uncontrolled diabetes that was reported to be the suspected root cause of the event. 29 Psoriasis will be added to the Adverse Reactions section per FDA’s public communication. Accessed September 22, 2009. URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174474.htm
    • APPENDIX IV30 Top 25 Serious Preferred Terms in Pediatrics from approval through July 7, 2009 2 2 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 5 8 9 10 14 16 26 0 5 10 15 20 25 30 Anaemia Cellulitis CRP Increased Chest Discomfort Diarrhoea Dizziness Headache Hodgkin's stage II RBC Sed Rate Increased Sepsis Abdominal Pain Anaphylactic Reaction Chest Pain Convulsion Dyspnoea Neonatal Aspiration Rash Small For Dates Baby Psoriasis Pyrexia Hodgkin's Disease Drug Ineffective Premature Baby Crohn's Disease Exposure in Pregnancy PreferredTerms(PT) Number of events in AERS 30 Graphs in the Appendix IV are based on AERS crude counts, duplicates have not been reconciled; more than one event may be reported in a case 16
    • Serious adverse events by MedDRA SOC reported in Pediatrics from approval through July 7, 2009 1 3 4 4 4 4 5 5 6 7 7 10 14 14 15 16 18 18 19 26 34 35 40 0 5 10 15 20 25 30 35 40 Psychiatric Social Circumstances Blood Eye Hepatobiliary Immune System Renal Vascular Cardiac Metabolism Surgical Musculoskeletal Nervous System Skin Neoplasms Investigations Congenital, familial & genetic Pregnancy Respiratory Infections Gastrointestinal Injury General Disorders SystemOrganClass(SOC) Number of events in AERS 17
    • 18 Top 25 serious Preferred Terms in Adults from approval through July 7, 2009 218 221 222 224 232 239 240 247 252 253 272 272 280 288 326 333 353 353 367 400 418 446 457 541 614 0 100 200 300 400 500 600 700 Anaemia Urinary Tract Infection Cough Chest Pain Myocardial Infarction Fatigue Malaise Sepsis Crohn'S Disease Weight Decreased Headache Oedema Peripheral Asthenia Abdominal Pain Drug Ineffective Nausea Rheumatoid Arthritis Vomiting Pain Diarrhoea Fall Arthralgia Dyspnoea Pyrexia Pneumonia PreferredTerms(PT) Number of events in AERS
    • 19 Serious adverse events by MedDRA SOC reported in Adults from approval through July 7, 2009 22 64 69 110 122 245 246 381 439 465 539 566 620 763 840 1073 1321 1341 1403 1526 1820 1852 2194 2224 3402 3543 0 500 1000 1500 2000 2500 3000 3500 4000 Congenital, Familial & Genetic Endocrine Social Circumstances Pregnancy Ear Reproductive System Immune System Hepatobiliary Eye Psychiatric Metabolism Renal Blood Surgical Vascular Cardiac Neoplasms Skin Injury Investigations Respiratory Nervous System Musculoskeletal Gastrointestinal General Disorders Infections SystemOrganClass Number of events in AERS