One Year Post Exclusivity Adverse Event Monitoring as mandated by the Best Pharmaceuticals for Children Act

1
One Year Post Exclusivity Adverse Event
Monitoringas mandated by theBest
Pharmaceuticals for Children Act
Dr. Solomon IyasuMedical Team Leader Dr.
ShaAvhree Buckman Medical Officer Division of
Pediatric Drug DevelopmentCenter for Drug
Evaluation and Research Food and Drug
Administration
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Outline

• busulfan
• losartan
• tamoxifen
• nefazodone
• cetirizine
• quinapril

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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

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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.

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Drug Use Data Sources and Limitations (contd)

• 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 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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Relevant Pediatric Labeling

• 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.

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Drug 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 (n116 discharges) and 4.9 in 2002 (n247
  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?

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Adverse event reports busulfan3/12/02 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 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 losartan

• 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 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 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

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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

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Pediatric Adverse Event Reports losartan3/14/02
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 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 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 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 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 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 tamoxifen5/16/02
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 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 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
  gt1/3) 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

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Adverse event reports nefazadone6/27/02-7/27/03

• 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 Events6/27/02 7/27/03 N3
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 Crohns 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 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 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 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 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

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Adverse Event Categories cetirizine
N 43 unduplicated reports in pediatric patients.

• 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)

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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 maleconcomitant medications noted
• 8 year old femaleconcomitant medications noted
• In both cases, the condition abated when
  cetirizine was discontinued

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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

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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

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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

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Adverse event reports quinapril6/7/02-7/7/03

• 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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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.

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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