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One Year Post Exclusivity Adverse Event Review as Mandated by the Best Pharmaceuticals for Children Act. Dr. Solomon Iyasu Medical Team Leader Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration. Acknowledgements. Office of Drug Safety

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One Year Post Exclusivity Adverse Event Review as Mandated by theBest Pharmaceuticals for Children Act

Dr. Solomon IyasuMedical Team Leader

Division of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research

Food and Drug Administration


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Acknowledgements by the

  • Office of Drug Safety

    DSRCS: DDRE:

    -Laura Governale -Mark Avigan

    -Toni Piazza-Hepp -Jennie Chang

    -Yoon Kong -Susan Lu

    -Aaron Mendelsohn -Carol Pamer

    -Gianna Rigoni -Kathleen Phelan

  • Office of Counter-Terrorism and Pediatric Drug Development

    -Louis Cooper

    -Hari Sachs

    -Jean Temeck


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Outline by the

  • Paroxetine

  • Citalopram

  • Vinorelbine

  • Pravastatin


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Adverse Events Data by theSource 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 by the

  • 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 by the(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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Drug Use Data Sources and Limitations (cont’d) by the

  • Child Health Corporation of America™ (CHCA) Pediatric Health Information System (PHIS)

    • Inpatient data from 26 free-standing children’s hospitals with charge level drug utilization data

    • Data cannot be projected nationally


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Background Drug Information by the

  • Moiety: Paxil®, Paxil CR® (paroxetine)

  • Therapeutic Category: Antidepressant

  • Sponsor: GlaxoSmithKline

  • Adult Indications: Major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder

    • adult dose range: 20-60 mg/day

  • There are NO approved pediatric indications

  • Original market approval: December 1992

  • Pediatric exclusivity granted: June 27, 2002


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Relevant Safety Labeling by the

  • Pregnancy Category C

  • Precautions:

    • Suicide risk inherent in MDD

    • Suicide risk present in co-morbid conditions

    • Activation of mania

    • Seizures

    • Adverse events with abrupt discontinuation

      • agitation, anxiety, dizziness, sensory disturbance, nausea and sweating


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Relevant Safety Labeling by the(cont’d)

Adverse Events

  • Pre-marketing reports:

    • Hypertension, diabetes, dysphagia, nausea/vomiting

  • Post-marketing reports

    • Serotonin syndrome, hepatic dysfunction, anaphylaxis

  • Overdosage

    • hepatic dysfunction


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Drug use trends: Paroxetine by the

  • Second most commonly used SSRI in children.1

  • Both pediatric & adult prescriptions have increased steadily between 1999 and 2003. 1

  • Pediatric Diagnosis (off label): depression, anxiety and obsessive-compulsive disorders 2

  • Pediatric patients account for approximately 3.5 % of total U.S. prescriptions of Paxil® between Jul 2002 – Jun 2003 (1.1 million).1,3*

    1IMS Health, National Prescription Audit Plus, On-Line Source Year Aug 1999 – Jul 2003, Data Extracted Aug 2003

    2IMS Health, National Disease and Therapeutic Index, CD-Rom, Source 3 Year Jul 2000 – Jun 2003

    3AdvancePCS Dimension Rx, On-Line

    *Calculation based on application of proportions of pediatric paroxetine prescriptions in AdvancePCSto IMS Health, National Prescription Audit Plus to estimate number of paroxetine prescriptions dispensed nationwide to pediatric population


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Pediatric Adverse Events in the One-Year Post-Exclusivity Period: Predominant Events (n=127)

  • Psychiatric adverse events (68)

  • Discontinuation Syndrome/Decrease in Dose (7)

  • Maternal Exposures (33)

  • Neurologic events (8)

  • Accidental Ingestion (2)

  • Other (9)


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Pediatric Adverse Events: Deaths Period: Predominant Events (n=127)

10 deaths involving direct pediatric exposures

  • 9 completed suicides

  • 1 case of Stevens Johnson Syndrome; patient also received valproic acid

    3 deaths among patients with prenatal exposure


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Pediatric Adverse Events Period: Predominant Events (n=127)Deaths

  • Prenatal exposures (n=3)

    • Congenital heart disease (36 week premature infant)

    • SIDS* (53 day, morphine withdrawal)

    • Multiple congenital anomaly (possibly a genetic syndrome)

      *sudden infant death syndrome


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Maternal Exposure Period: Predominant Events (n=127)

  • 33 total in utero or breast feeding exposure

    • possible withdrawal syndrome (11)*

    • congenital anomaly (5)*

    • seizures (4)

    • developmental delay or abnormality (4)

    • murmur or congenital heart disease (3)*

    • insufficient weight gain (2)

    • other (4)

      *includes one fatality, previously described


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Neurologic Events (n = 8) Period: Predominant Events (n=127)

  • Extrapyramidal/movement (3)

    • Two involved other medications (ziprasidone, olanzapine) associated with EPS

  • Seizures (3)

    • Two patients had existing seizure disorder

  • Loss of consciousness and hallucinations (1)

    • patient also on amphetamine-dextro-amphetamine

  • Serotonin syndrome (1)


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Pediatric Adverse Events Period: Predominant Events (n=127)(cont’d)

  • Accidental ingestion

    • 2 y/o ingested 6 tablets of paroxetine, recovered without sequellae

    • 2 y/o comatose with ingestion of multiple medications including paroxetine; recovered after an ICU course

  • Other events (9)

    • single occurrence, majority labeled


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Closing Observations: Paroxetine Period: Predominant Events (n=127)

  • Most events labeled or related to labeled events

  • Unlabeled events involve maternal exposure

  • Safety of paroxetine will continue to be monitored


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Citalopram: Non-psychiatric Adverse Events Period: Predominant Events (n=127)Background Drug Information

  • Moiety: Celexa® (citalopram)

  • Therapeutic Category: Antidepressant

  • Sponsor: Forest Pharmaceuticals

  • Adult Indication: Major Depressive Disorder

    • Adult dose range: 20-40 mg/day

  • There are NO approved pediatric indications

  • Original market approval: July 17, 1998

  • Pediatric exclusivity granted: July 9, 2002


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Relevant Safety Labeling Period: Predominant Events (n=127)

  • Pregnancy Category C

  • Excreted in human breast milk

  • Precautions:

    • Any psychoactive agent may impair intellectual or psychomotor functions

    • Seizures: introduce citalopram with care

  • Post-marketing reports and overdose

    • QTc prolongation


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Drug Use Trends: Citalopram Period: Predominant Events (n=127)

  • 4th most commonly used SSRI in children1

  • Both pediatric and adult prescriptions have increased between 1999 and 20031

  • Pediatric patients account for approximately 3.3% (665, 000) of the total U.S. prescriptions of Celexa® during Jul 2002- Jul 20031,2*

  • Pediatric Diagnosis (off label): depressive disorders, obsessive-compulsive disorder and attention deficit disorder3

    1IMS Health, National Prescription Audit Plus, On-Line Source Year Aug 1999 – Jul 2003, Data Extracted Aug 2003

    2AdvancePCS Dimension Rx, On-Line, Jul 2001 – Jun 2003

    3IMS Health, National Disease and Therapeutic Index, CD-Rom, Source 3 Year Jul 2000 – Jun 2003

    *Calculation based on application of proportions of pediatric citalopram prescriptions in AdvancePCSto IMS Health, National Prescription Audit Plus to estimate number of citalopram prescriptions dispensed nationwide to pediatric population


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Pediatric Adverse Events in the One-Year Post Exclusivity Period

  • Total unduplicated reports (n=42)

  • 16 in utero exposures; resulted in unlabeled events and one death

  • 26 children involving direct exposure, 8 unlabeled events, no deaths

    • 16 serious AEs (10 hospitalization, 4 life-threatening, 2 with disability)


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Pediatric Adverse Events by PeriodGender, Age and Exposure

GENDER

In Utero Exposure (n=16)

Direct Exposure (n=26)

Female

11

17

Male

2

9

Unknown

3

0

AGE

0-2 yrs

15

1

2-5 yrs

1

1

6-11 yrs

0

9

12-16 yrs

0

15


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Pediatric Adverse Events: PeriodReasons for Exposure to Citalopram

  • In utero exposures – 16

  • Direct Pediatric Exposure – 26

    • Depression – 13

    • Ingestion of another person’s prescription – 2

    • Other – 5

    • Unknown - 6


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Non-psychiatric Adverse Events: PeriodIn utero exposures (n=16)

  • death (1)

    • SIDS in 4 month old (Autopsy no cause of death)

  • congenital anomalies (7)

    • 3 unrelated kidney malformations

    • 1 eye malformation

    • 1 cardiac defect

    • 1 cleft lip

    • 1 congenital megacolon

  • potential neonatal withdrawal syndrome (5)

  • other (3)

    • myoclonus and otitis (1), delayed head control at one month (1) fetal asphyxia (1)


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Non-psychiatric Adverse Events: PeriodDirect Pediatric Exposures (n=21)

  • Cardiovascular (n= 4)

    • Supraventricular tachycardia in 8 year old (prior history)

    • Prolonged QTc (2)

      • Syncope/seizure in 13 year old; also taking albuterol, cetirizine, montelukast

      • Overdose in 14 year old

    • Arrhythmia in 8 year old with overdose


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Non-psychiatric Adverse Events Period(cont.)

  • Neurological/Special senses (8)

    • Demyelinating spinal lesion in 13 y/o also on methylphenidate and multivitamin

    • Visual field cut in 15 y/o also on Depo Provera (improved after d/c Depo Provera)

    • Cataract in 10 y/o also on risperidone

    • Seizures (5)


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Non-psychiatric Adverse Events Period(cont’d)

  • Serotonin syndrome, also had seizures (2)

  • Syncope (1)

  • False positive drug screen for cocaine on crushed tablet (1)

  • Others (5) involved concomitant medication and/or underlying disease


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Summary: Period Unlabeled Non-psychiatric Adverse Events

  • Involving in utero exposure

  • Demyelinating spinal cord lesion

  • Visual field cut

  • Supraventricular tachycardia


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Concluding Observations: Citalopram Period

  • Updates will be provided at future meetings on the following pediatric adverse events under review

    • Neonatal withdrawal

    • Ophthalmologic malformation

    • QTc prolongation

  • FDA will continue its routine monitoring of adverse events


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Background Drug Information Period

  • Moiety: Navelbine® (vinorelbine)

  • Therapeutic Category: Anti-tumor

  • Sponsor: GlaxoSmithKline

  • Indication:

    • In adults, single agent or combination with cisplatin for first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer.

    • There are NO approved pediatric indications.

  • Pediatric Exclusivity Granted: Aug 15, 2002


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Drug Use Trends: Vinorelbine Period

  • Use in the pediatric population (ages 0-16 years) did not appear in the inpatient Premier (general) hospital network or in the IMS Health, National Disease and Therapeutic IndexTM office-based practice setting between October 2000 and September 2003.

  • CHCATM accounted for 5 discharges in 2001 and 21 discharges in 2002.

  • Diagnosis: chemotherapy encounters, most commonly Hodgkin’s disease.

    Child Health Corporation of AmericaTM:  Pediatric Health Information System (PHIS),

    2001-2002 (


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Adverse Event Reports: Vinorelbine Period08/15/02 - 09/15/03

  • Total raw number of adult and pediatric reports: 495 reports; (181 U.S. and 314 International)

  • Pediatric reports:

    • 3 unduplicated pediatric reports (1 U.S.; 2 Foreign)

    • All with serious outcomes; no deaths

    • Five of the 16 adverse events (MedDra preferred terms) were considered unlabeled.

    • Diagnosis: Rhabdomysarcoma (2), Neuroblastoma (1)


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Adverse Events: Vinorelbine Period

  • 14 year old with rhabdomyosarcoma developed neutropenia, a labeled event and was successfully treated with Neupogen

  • 2 year old with rhabdomyosarcoma developed life threatening adverse events including unlabeled events (epidermolysis, muscle inflammation, somnolence, tachypnea); also on cytoxan

    • hospitalized for 16 days and recovered

  • 6 year old with neuroblastoma developed adverse events including an unlabeled event (muscle spasm); resolved after lowering dose


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Comments Period

  • Labeled and unlabeled adverse events reported

  • The unlabeled events have also been reported in adults and are not unique to pediatrics

  • The FDA will continue its routine monitoring of adverse events in all populations.


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Background Drug Information Period

  • Moiety: Pravachol® (pravastatin)

  • Therapeutic Category: HMG CoA reductase inhibitor (statin)

  • Sponsor: Bristol-Myers Squibb

  • Indications:

    • Adults

      • prevention of coronary and cardiovascular events

      • hyperlipidemia

    • children >8 years

      • heterozygous familial hypercholesterolemia

  • Pediatric Exclusivity Granted: Jul 10, 2002


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Drug Use Trends: Pravastatin Period

  • Total dispensed prescriptions increased by 17.5% between Sept 1999 and Aug 2003 (from 13.4 to 15.8 million per year) 1

  • Pediatricians wrote 47,000 or 0.4% of the total of 15.8 million pravastatin prescriptions during Sept 2002 to Aug 2003 1

    1IMS Health, National Prescription Audit Plus, On-Line Source Year Sept 1999 – Aug 2003, Data Extracted Aug, 2003


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Drug Use Trends: Pravastatin Period(cont’d)

  • An estimated 7,900 prescriptions were dispensed nationwide to pediatric patients (aged 1-16 years) during Aug 2002 to August 2003. 1

    1Calculation based on application of proportions of pediatric pravastatin prescriptions in AdvancePCS Dimension Rx, On-Line Source, Aug 2002 - Aug 2003 to IMS Health, National Prescription Audit Plus, On-Line Source Sept 1999 – Jul 2003, Data Extracted Aug 2003 to estimate number of pravastatin prescriptions dispensed nationwide to pediatric population


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Pediatric Adverse Event Reports: Pravastatin Period07/10/02 - 08/10/03

  • Total number of adult reports:

    • 993 reports (691 US and 302 international)

  • Pediatric reports:

    • No pediatric reports were submitted during this time period.


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Comments Period

  • The FDA will continue its routine monitoring of adverse events in all populations.


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