1 One Year Post Exclusivity Adverse Event Monitoring as mandated by the Best Pharmaceuticals for Children Act Dr. Solomon Iyasu Medical Team Leader Dr. ShaAvhree Buckman Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration
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1 One Year Post Exclusivity Adverse Event Monitoring as mandated by the Best Pharmaceuticals for Children Act Dr. Solomon Iyasu Medical Team Leader Dr.
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One Year Post Exclusivity Adverse Event Monitoring
as mandated by theBest Pharmaceuticals for Children Act
Dr. Solomon IyasuMedical Team LeaderDr. ShaAvhree BuckmanMedical OfficerDivision of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research Food and Drug Administration
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OutlineOutline
• busulfan
• losartan
• tamoxifen
• nefazodone
• cetirizine
• quinapril
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Adverse Events Data Adverse Events Data Source and Limitations: Source and Limitations: AERSAERS
• Spontaneous and voluntary system– Underreporting– reporting bias– quality of report– cannot estimate true incidence rate of events or
exposure risk
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Drug Use Data Sources and Drug Use Data Sources and LimitationsLimitations
• IMS Health, National Prescription Audit Plus measures prescriptions dispensed from retail pharmacies but does not provide demographic information on prescription use
• IMS Health, National Disease and Therapeutic Index is a survey based on a sample size of 2000 - 3000 office-based physicians. The small sample size can make these data projections unstable, particularly when use is not prevalent as in the case of the pediatric population.
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Drug Use Data Sources and Drug Use Data Sources and Limitations (cont’d)Limitations (cont’d)
• AdvancePCS is based on a large prescription claims database but data cannot be projected
• Premier, Inc. contains inpatient drug use from 400 acute, short-stay, non-federal hospitals. National projection methodology is available but the ability to make accurate national estimates is selective; drug use cannot be linked to diagnosis or procedure; treatments administered at hospital outpatient clinics not included.
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Background Drug InformationBackground Drug Information
– approved as a conditioning regimen in combination with cyclophosphamide prior to allogeneic hematopoietic progenitor cell transplantation in CML.
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In children, the effectiveness of Busulfan in the treatment of CML has not been specifically studied. An open-label, uncontrolled study evaluated the pharmacokinetics of Busulfan in 24 patients (5 months-16 years) as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic or non-malignant diseases. Based on the results of this study, a suggested dosing guideline in pediatric patients is included in the label.
Drug use trends: busulfanDrug use trends: busulfan• No pediatric outpatient use according to NPAPlus
(1998-2002), NDTI and data received from AdvancePCS.
• Premier, Inc:– accounted for 10.3% of inpatient pediatric use in
2000 (n=116 discharges) and 4.9% in 2002 (n=247 discharges)
IMS Health, National Prescription Audit Plus, Source Year 1998-2002, Data Extracted June 2003IMS Health, National Disease and Therapeutic Index, CD-Rom, Years 2000-2002AdvancePCS Dimension RxPremier Perspective
• All of the events reported in the five pediatric patients are covered in the warning and precautions sections of the label.
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Background Drug InformationBackground Drug Information • Moiety: tamoxifen (Nolvadex®)• Therapeutic Category: Nonsteroidal antiestrogen• Sponsor: AstraZeneca Pharmaceuticals• Indication:
– Adults: treatment of breast cancer in women and men, reduction of incidence of breast cancer in high risk women.
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Background Drug InformationBackground Drug Information • Relevant pediatric labeling:
– Data from a single, uncontrolled multi-center trial of the treatment of girls with McCune-Albright Syndrome and precocious puberty are included on the label. However, the safety and efficacy of tamoxifen for girls 2-10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment.
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Drug use trends: tamoxifenDrug use trends: tamoxifen• NPA Plus (1998-2003)
– Total dispensed prescriptions for tamoxifen increased gradually until 2001, followed by a slight decrease in 2001-2002 in all ages
– Approx. 3.8 million in 1998 vs. 4.6 million in 2001 and 4.3 million in 2002
− Major Depressive Disorder − There are no approved pediatric indications
• Relevant Safety Labeling: There is a boxed warning about life-threatening hepatic toxicity.
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Drug use trends: nefazodoneDrug use trends: nefazodone• Both pediatric and adult prescriptions declined between
1999 and 2003. (NPA Plus)• Nefazodone is one of the least prescribed antidepressants
in pediatric patients. (NPA Plus, NDTI) • Pediatric use declined by more than half (adults >1/3)
since exclusivity was granted. (data received from AdvancePCS July 2002 - June 2003)
• Pediatric Diagnosis: personality disorder, depressive disorder and infantile autism.
IMS Health, National Prescription Audit Plus, 8/99 – 7/03, Data Extracted Sept 2003IMS Health, National Disease and Therapeutic Index , CD-Rom, 3 Year July 2000 – June 2003AdvancePCS Dimension Rx, On-Line
• Congenital hand malformation in an infant born to a mother who was taking nefazodone along with multiple other medications.
• Potential arrhythmia and agitation in a 3 year old with an accidental ingestion, which resolved after induced emesis.
• Biopsy- proven Crohn’s disease and sclerosing cholangitis in a 14 year old female who was taking nefazodone for depression and multiple other medications.
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Background Drug InformationBackground Drug Information
N= 43 unduplicated reports in pediatric patients.N= 43 unduplicated reports in pediatric patients.
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HallucinationsHallucinations• Review conducted in March 2001 by ODS has suggested
probable linkage between use of cetirizine and incidence of this adverse event
• 2 reported cases of hallucinations during the 1 year post-exclusivity period for cetirizine– 3 year old male—concomitant medications noted– 8 year old female—concomitant medications noted– In both cases, the condition abated when cetirizine was
discontinued
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Background Drug InformationBackground Drug Information