(Quetiapine Fumarate) and Seroquel XR Safety and Drug Utilization
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De partme nt of He alth and Human Se rvice s Public He alth Se rvice Food and Drug Administration Ce nte r for Drug Evaluation and Re se arch Office of Surve illance and Epide miology Pe diatric Postmark e ting Pharmacovigilance and Drug Utilization Re vie w Date : February 19, 2016 Safe ty Evaluator: Vicky Chan, P harmD, BCP S Division of P harmacovigilance I Drug Us e Analys t: Travis Ready, P harmD Division of Epidemiolog y II Te am Le ade r: Ida-Lina Diak, P harmD, MS Division of P harmacovigilance I Te am Le ade r: Rajdeep Gill, P harmD Division of Epidemiolog y II De puty Dire ctor Grace Chai, PharmD For Drug Utilization: Division of Epidemiolog y II Acting De puty Divis ion Cindy Kortepeter, P harmD Dire ctor: Division of P harmacovigilance I Divis ion Dire ctor: Robert L. Levin, MD Division of P harmacovigilance I Product Name (s ): Seroquel (quetiapine fumarate), Seroquel XR (quetiapine fumarate, extended release) Pe diatric Labe ling Approval Date : April 30, 2013 Application Type /Numbe r: NDA # 020639, 022047, 022172 Applicant/Spons or: AstraZeneca OSE RCM #: 2015-1960 **This docume nt contains proprie tary drug use data obtained by FDA unde r contract. The drug use data/information cannot be re le as ed to the public/non-FDA pe rs onnel without contractor approval obtaine d through the FDA/CDER Office of Surveillance and Epide miology.** Reference ID: 3890159 TA B L E O F C O NTENTS Executive Summary................................................................................................................. 3 1 Introduction ..................................................................................................................... 4 1.1 Pediatr ic Regulator y History ...................................................................................... 4 1.2 Highlights of Labele d Safety Issues, ........................................................................... 5 Pediatric Use ....................................................................................................................... 7 1.3 Previous OSE Post-Marketing Safety Reviews............................................................ 8 2 Drug utilization data......................................................................................................... 9 2.1 Methods and Materials ............................................................................................... 9 2.1.1 Determining Settings of Care .............................................................................. 9 2.1.2 Data Sources Used .............................................................................................10 2.2 Results .....................................................................................................................10 2.2.1 Patient Data for Quetiapine ................................................................................10 2.2.2 Prescriber Spec ia lty ...........................................................................................11 2.2.3 Diagnoses Associated w ith Use ..........................................................................12 3 Postmarket adverse event Reports ....................................................................................13 3.1 Methods and Materials ..............................................................................................13 3.1.1 FDA Adverse Event Reporting System (FAER S) Search Strategy .......................13 3.1.2 Inclus ion Cr iter ia ...............................................................................................14 3.2 Results .....................................................................................................................14 3.2.1 Tota l number of FAERS reports by Age .............................................................14 3.2.2 Selection of Serious Pediatric Cases in FAERS ...................................................15 3.2.3 Characteristics of Pediatric Case Series ..............................................................16 3.3 Summary of Fatal Pediatric Adverse Event Cases (N=16) ..........................................18 3.4 Summary of Non-Fata l Pediatric Serious Adverse Event Cases (N=62) ......................19 3.4.1 Psychiatr ic Dis orders (n=35) ..............................................................................19 3.4.2 Eye Disor ders (n=7) ...........................................................................................21 3.4.3 Gastrointestina l ( GI) and Hepatic Disor ders (n=6) ..............................................22 3.4.4 Pulmonary/Respirator y/Vascular Dis orders (n=4) ...............................................24 3.4.5 Nervous Syste m Dis orders (n=3) ........................................................................25 3.4.6 Musculoske letal D isor ders (n=2) ........................................................................25 3.4.7 Miscellaneous Dis orders (n=5) ...........................................................................25 4 Discussion ......................................................................................................................26 5 Conc lus ion......................................................................................................................27 6 Recommendations ...........................................................................................................27 7 References ......................................................................................................................27 8 Appendices .....................................................................................................................29 8.1 Appendix A. Drug Utilization Database Descriptions ................................................29 8.2 Appendix B. FDA Adverse Event Reporting Syste m (FAERS) ...................................30 8.3 Appendix C. FAERS Case Numbers, FAERS Version Numbers And Manufacturer Control Numbers For The Pediatric Case Series With Quetia pine (N=78) ...................31 8.4 Appendix D. Fatal Case Narratives ............................................................................33 8.5 Appendix E Suicide Injury Deaths and Rates per 100,000 for Ages 0-24 years old, 2014 ………………………………………………………………………………………….40 Reference ID: 3890159 EXECUTIVE SUMMARY In accordance with the Food and Drug Administration Amendments Act P ediatric Research Equity Act, the Office of Surveillance and Epidemiolo gy (OSE) evaluated postmarketing adverse event reports with a serious outcome and drug utilizat ion data for Seroquel and Seroquel XR (quetiapine fumarate) in pediatric patients. This review was triggered by the pediatric study of quetiapine for the indication of bipolar depression. Quetiapine fumarate was first approved in 1997. Seroquel is indicated for the treatment of schizophrenia; bipolar I disorder manic episodes; and bipolar disorder, depressive episodes. Seroquel XR is indicated for the treatment of schizophrenia; bipolar I disorder, manic or mixed episodes; bipolar disorder, depressive episodes; and major depressive disorder, adjunctive therapy with antidepressants. The approved pediatric labeling is for schizophrenia in adolescents (13-17 years) and bipolar mania in children and adolescents (10-17 years). The Food and Drug Administration Adverse Event Reporting System database was searched for all reports of adverse events received from August 1, 2011 through July 31, 2015. The Division of P harmacovigilance (DP V) focused on the serious pediatric reports with unlabeled events. DP V included 78 pediatric cases with serious, unlabeled events reported with quetiapine use in the case series. There were no new safety signals identified, no increased severity or frequency of any labeled adverse events, and there were no deaths directly associated with quetiapine. There were 16 fatal cases and 62 non-fatal cases from August 1, 2011 through July 31, 2015. More than half (n=9) of the fatal cases did not report a cause of death. The remaining 7 fatal cases that reported a cause of death were all due to multiple drug overdoses, except for 1 case that reported “cerebral death” in a 14-year-old female with a recent history of elevated valproate and alcohol blood levels. Almost half of the 62 non-fatal cases reported overdose, self-injur ious behavior, suicidal ideation, or suicidal attempt. According to the Center for Disease Control and P revention, suicide is the third leading cause of death for youths between the ages of 10 and 24 years. P oisoning is among the top three methods used in suicides of young people. A history of depression or other mental illness is among several risk factors that can put a young person at risk for suicide. The drug utilizat ion data showed that pediatric patients aged 0-17 years accounted for about 7% of total use during each 12-month period analyzed with approximately 168,000 patients during the 12-month period ending July 2012, increasing to about 184,000 patients during the 12-month period ending July 2015 in the outpatient retail pharmacy setting. A slight increase in the use of quetiapine in older pediatric patients aged 10 – 17 years was observed, whereas the use in younger pediatric patients aged 0-9 years showed minor fluctuations. P sychiatry specialists were the top prescribers of quetiapine, followed by nurse practitioner and family practice. Among pediatric patients aged 10-17 years, Affective P sychoses NEC/NOS was the only diagnosis mentioned in association with the use