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

2 Outline busulfan losartan tamoxifen nefazodone cetirizine quinapril

3 Adverse Events Data Source and Limitations: AERS Spontaneous and voluntary system –Underreporting –reporting bias –quality of report –cannot estimate true incidence rate of events or exposure risk

4 Drug Use Data Sources and Limitations 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 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.

5 Drug Use Data Sources and 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.

6 Background Drug Information Moiety: busulfan (Busulfex ® ) Therapeutic Category: Antitumor Sponsor: ESP Pharma, Inc. Indication: –approved as a conditioning regimen in combination with cyclophosphamide prior to allogeneic hematopoietic progenitor cell transplantation in CML.

7 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. Relevant Pediatric Labeling

8 Drug use trends: busulfan No pediatric outpatient use according to NPAPlus  ( ), 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 , Data Extracted June 2003 IMS Health, National Disease and Therapeutic Index , CD-Rom, Years AdvancePCS  Dimension Rx Premier Perspective 

9 Adverse event reports: busulfan 3/12/02 – 4/12/03 Total number of adult and pediatric reports: – 103 reports (52 US and 51 international) Pediatric reports: –9 unduplicated pediatric reports including 3 deaths –None of the pediatric adverse events could be attributed to the drug.

10 Background Drug Information Moiety: losartan (Cozaar ® ) Therapy Category: Antihypertensive agent, angiotensin II receptor antagonist Sponsor: Merck & Co., Inc. Indications: –Hypertension; hypertension with left ventricular hypertrophy; nephropathy in type 2 diabetes –There are no approved pediatric indications

11 Background drug information: losartan Relevant safety labeling –boxed warning against use during pregnancy because of its potential to cause injury and death to the developing fetus

12 Drug use trends: losartan NPA Plus  ( ) –Total dispensed prescriptions increasing 10.6 million in 1998; 16.2 million in million for Cozaar and 6.8 million for Hyzaar (losartan and hydrochlorothiazide) –Pediatrics: accounted for 54,000 prescriptions in 2002 IMS Health, National Prescription Audit Plus , Source Year , Data Extracted June 2003

13 Pediatric Drug Use Trends: losartan NDTI  ( ) pediatrics represents approximately 1% of the total losartan mentions –Leading Pediatric Diagnoses in Cardiomyopathy Essential hypertension, unspecified IMS Health, National Disease and Therapeutic Index , CD-Rom, Source 3 Year 4/00 – 3/03

14 Pediatric Drug Use Trends: losartan Data from AdvancePCS (April April 2003) –Cozaar prescriptions dispensed have increased slightly –Hyzaar prescriptions have remained stable –Less than.001 percent were for pediatric patients. AdvancePCS  Dimension Rx

15 Pediatric Adverse Event Reports: losartan 3/14/02 to 4/18/03 Total number of adult and pediatric reports: –298 reports (91 US and 207 international) Pediatric reports: –5 unduplicated pediatric reports –4 reports due to in-utero exposure, one report due to accidental ingestion by a 2 year old. –2 patients died (1 elective abortion, 1 accidental overdose)

16 Pediatric adverse events: losartan All of the events reported in the five pediatric patients are covered in the warning and precautions sections of the label.

17 Background 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.

18 Background 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.

19 Drug use trends: tamoxifen NPA Plus  ( ) –Total dispensed prescriptions for tamoxifen increased gradually until 2001, followed by a slight decrease in in all ages –Approx. 3.8 million in 1998 vs. 4.6 million in 2001 and 4.3 million in 2002 –Pediatric specialty: 8,000 dispensed prescriptions in ,000 dispensed prescriptions Jan-May IMS Health, National Prescription Audit Plus , Years & Year to Date May 2003, Data Extracted Aug 2003

20 Drug use trends: tamoxifen NDTI  ( ) –The proportion of pediatric use (ages 0-16) has been far less than 1% in the 2001 and 2002 –adolescent subgroup, ages 12-16, represented all the drug mentions Only 3,000 mentions in 2001 and 2,000 mentions in 2002 –Diagnoses appear to be exclusively malignant neoplasm of the brain, unspecified. IMS Health, National Disease and Therapeutic Index , CD-Rom, Source 3 Year 6/00 – 5/03

21 Adverse event reports for tamoxifen 5/16/02 – 6/01/03 Total number of adult reports: –369 reports (202 US and 167 international) Pediatric reports: − There were no pediatric adverse event reports

22 Background Drug Information Moiety: nefazodone (Serzone ® ) Therapeutic Category: Antidepressant Sponsor: Bristol-Myers Squibb Indication: −Major Depressive Disorder −There are no approved pediatric indications Relevant Safety Labeling: There is a boxed warning about life-threatening hepatic toxicity.

23 Drug use trends: nefazodone Both pediatric and adult prescriptions declined between 1999 and (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 June 2003) Pediatric Diagnosis: personality disorder, depressive disorder and infantile autism. IMS Health, National Prescription Audit Plus , 8/99 – 7/03, Data Extracted Sept 2003 IMS Health, National Disease and Therapeutic Index , CD-Rom, 3 Year July 2000 – June 2003 AdvancePCS  Dimension Rx, On-Line

24 Adverse event reports: nefazadone 6/27/02-7/27/03 Total number of adult and pediatric reports: −173 reports (131 US and 42 international) Pediatric reports: −3 unduplicated serious pediatric adverse event reports −no pediatric deaths

25 Pediatric Adverse Events 6/27/02 – 7/27/03 N=3 unduplicated pediatric reports 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.

26 Background Drug Information Moiety: cetirizine (Zyrtec ® ) Therapeutic Category: Antiallergic drug Sponsor: Pfizer Inc. Indication: −Allergic rhinitis (seasonal and perennial) and chronic idiopathic urticaria −Approved for use in children down to 6 months of age

27 Drug use trends: cetirizine NPAPlus  ( ) –Total dispensed prescriptions for cetirizine increasing in all age groups -9.3 million in 1998, 25.7 million in 2002 –Pediatric specialty: about 4 million dispensed prescriptions in 2002 IMS Health, National Prescription Audit Plus , Years , Data Extracted June 2003

28 Drug use trends: cetirizine NDTI  First quarter of 2003 –approximately ½ of mentions for cetirizine were for pediatric patients –approximately ¼ of the mentions for cetirizine with pseudoephedrine were for pediatric patients IMS Health, National Disease and Therapeutic Index , CD-Rom, Source 3 Year 4/00 – 3/03

29 Adverse event reports: cetirizine 3/13/02 – 4/13/03 Total number of adult and pediatric reports: –253 reports (141 US and 112 international) Pediatric reports: –43 unduplicated pediatric reports –no pediatric deaths –15 of the top 20 adverse events were unlabeled

30 Adverse Event Categories : cetirizine Medication Errors: 9 (confusion between Zantac and Zyrtec syrup) Psychiatric events: 7 (aggressive behavior, agitation, hallucinations) Seizure: 5 Somnolence: 3 Allergic reaction: 3 Congenital anomaly: 3 Liver injury: 3 (elevated transaminases, hepatitis) Renal impairment: 2 (ARF, IgA nephropathy) Other: 8 (1 case each: accidental overdose, hearing loss, hyperglycemia, hypogammaglobulinemia, pancreatitis, supraventricular tachycardia, tachypnea (newborn), vertigo) N= 43 unduplicated reports in pediatric patients.

31 Hallucinations 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

32 Background Drug Information Moiety: quinapril (Accupril ® ) Therapeutic Category: Antihypertensive Sponsor: Parke-Davis Indication: −Hypertension and adjunctive therapy for heart failure in adults −There are no approved pediatric indications

33 Drug use trends: quinapril NPA Plus  ( ) –Total dispensed prescriptions for quinapril million in 1998 and 15.7 million in 2002 –Pediatric use less than 1% of total prescriptions dispensed IMS Health, National Prescription Audit Plus , Years & Year to Date June 2003, Data Extracted Sept 2003

34 Drug use trends: quinapril NDTI  (May 2001-May 2003) –Proportion of pediatric use was less than 1% of the total population of quinapril mentions during visits to office-based physicians. IMS Health, National Disease and Therapeutic Index , CD-Rom, Source 3 Year 6/00 – 5/03

35 Adverse event reports: quinapril 6/7/02-7/7/03 Total number of adult and pediatric reports: −198 reports (114 US and 84 international) Pediatric reports: −1 unduplicated serious pediatric adverse event report −Congenital anomaly associated with maternal use: One-day old female born with heart malformation after maternal exposure to quinapril. Salbutamol reported as a concomitant medication

36 Conclusion The inherent limitations of AERS make attribution of adverse events to drug use challenging. The FDA will continue its routine monitoring of adverse events in all populations.

37 Acknowledgement Office of Drug Safety –Division of Surveillance, Research and Communication Support Laura Governale Yoon Kong Gianna Rigoni –Division of Drug Risk Evaluation Michael Johnston Kathleen Phelan Robert Pratt Lopa Thambi Joyce Weaver Office of Counterterrorism and Pediatric Drug Development