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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

• 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.

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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.

Relevant Pediatric LabelingRelevant Pediatric Labeling

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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

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Adverse event reports: Adverse event reports: busulfanbusulfan

3/12/02 – 4/12/033/12/02 – 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.

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Background Drug InformationBackground 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

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Background drug information: Background drug information: losartanlosartan

• Relevant safety labeling– boxed warning against use during pregnancy

because of its potential to cause injury and death to the developing fetus

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Drug use trends: losartanDrug 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

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Pediatric Drug Use Trends: Pediatric Drug Use Trends: losartanlosartan

• 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

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Pediatric Drug Use Trends: Pediatric Drug Use Trends: losartanlosartan

• 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

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Pediatric Adverse Event Reports: Pediatric Adverse Event Reports: losartanlosartan

3/14/02 to 4/18/033/14/02 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)

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Pediatric adverse events: losartanPediatric adverse events: losartan

• 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

– 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

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Drug use trends: tamoxifenDrug 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

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Adverse event reports for tamoxifenAdverse event reports for tamoxifen5/16/02 – 6/01/035/16/02 – 6/01/03

• Total number of adult reports:– 369 reports (202 US and 167 international)

• Pediatric reports:− There were no pediatric adverse event reports

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Background Drug InformationBackground 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.

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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

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Adverse event reports: nefazadoneAdverse event reports: nefazadone6/27/02-7/27/036/27/02-7/27/03

• 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

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Pediatric Adverse EventsPediatric Adverse Events6/27/02 – 7/27/036/27/02 – 7/27/03

N=3 unduplicated pediatric reportsN=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.

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Background Drug InformationBackground 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

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Drug use trends: cetirizineDrug use trends: cetirizine

• NPAPlus (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

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Drug use trends: cetirizineDrug 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

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Adverse event reports: cetirizine Adverse event reports: cetirizine 3/13/02 – 4/13/033/13/02 – 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

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Adverse Event Adverse Event CategoriesCategories: cetirizine: 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.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

• 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

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Drug use trends: quinaprilDrug 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

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Drug use trends: quinaprilDrug 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

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Adverse event reports: quinaprilAdverse event reports: quinapril6/7/02-7/7/036/7/02-7/7/03

• 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

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ConclusionConclusion

• 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.

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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