# Presentation: 193838

## 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**

## Outline

- busulfan
- losartan
- tamoxifen
- nefazodone
- cetirizine
- quinapril

## 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

## 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 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.

## 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.

## 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.

## 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.

- 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**

## Drug use trends: busulfan

- No pediatric outpatient use according to NPA*Plus* (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 2003
- IMS Health, National Disease and Therapeutic Index, CD-Rom, Years 2000-2002
- AdvancePCS Dimension Rx
- Premier Perspective

## 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.

## 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

## 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

## Drug use trends: losartan

- NPA *Plus* (1998-2002)
- Total dispensed prescriptions increasing
- 10.6 million in 1998; 16.2 million in 2002
- 9.4 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 1998-2002, Data Extracted June 2003

## Pediatric Drug Use Trends: losartan

- NDTI (2001-2003)
- pediatrics represents approximately 1% of the total losartan mentions
- Leading Pediatric Diagnoses in 2001-2003
- Cardiomyopathy
- Essential hypertension, unspecified
- IMS Health, National Disease and Therapeutic Index, CD-Rom, Source 3 Year 4/00 – 3/03

## Pediatric Drug Use Trends: losartan

- Data from AdvancePCS (April 2001- April 2003)
- Cozaar prescriptions dispensed have increased slightly
- Hyzaar prescriptions have remained stable
- Less than .001 percent were for pediatric patients.
- AdvancePCS Dimension Rx

## 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)

## 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.

## 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.** **

## 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.

## Drug 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
- Pediatric specialty:
- 8,000 dispensed prescriptions in 2002
- 5,000 dispensed prescriptions Jan-May 2003.
- IMS Health, National Prescription Audit *Plus*, Years 1998-2002 & Year to Date May 2003,
- Data Extracted Aug 2003

## Drug use trends: tamoxifen

- NDTI (2000-2002)
- 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

## 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

## 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.

## Drug 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 2003
- IMS Health, National Disease and Therapeutic Index , CD-Rom, 3 Year July 2000 – June 2003
- AdvancePCS Dimension Rx, On-Line

## 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

## 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.

## 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

## Drug use trends: cetirizine

- NPA*Plus* (1998-2002)
- 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 1998-2002, Data Extracted June 2003

## Drug use trends: cetirizine

- NDTI First quarter of 2003
- approximately 1⁄2 of mentions for cetirizine were for pediatric patients
- approximately 1⁄4 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

## 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

## 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.

## 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

## 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

## Drug use trends: quinapril

- NPA *Plus* (1998-2002)
- Total dispensed prescriptions for quinapril
- - 10.0 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 1998-2002 & Year to Date June 2003, Data Extracted Sept 2003

## 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

## 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

## 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.**

## 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