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Title: One Year PostExclusivity Adverse Event Review: Ondansetron Pediatric Advisory Committee Meeting Nove


1
One Year Post-Exclusivity Adverse Event Review
Ondansetron Pediatric Advisory Committee
Meeting November 16, 2006
Felicia L. Collins, MD, MPH, FAAPMedical
Officer Pediatric and Maternal Health
Staff Office of New Drugs Center for Drug
Evaluation and Research Food and Drug
Administration
2
Background Drug Information Ondansetron
  • Drug Zofran (ondansetron hydrochloride)
  • Therapeutic Category Serotonin HT3 receptor
    antagonist
  • Sponsor GlaxoSmithKline
  • Original Market Approval January 4, 1991
  • Pediatric Exclusivity Granted December 1, 2004

3
Background Drug Information Ondansetron
  • Indications
  • Prevention of nausea and vomiting associated with
    initial and repeat courses of emetogenic cancer
    chemotherapy, including high dose cisplatin
    chemotherapy induced nausea and vomiting (CINV)
  • Prevention of postoperative nausea and/or
    vomiting PONV

4
Drug Use Trends in Outpatient Settings
Ondansetron
  • 1.6 million dispensed prescriptions for all age
    groups during the 12-month post-exclusivity
    period
  • 107,000 (6.6) were dispensed for the pediatric
    population 0 - 16 years old
  • 11 increase in prescriptions for all age groups
    between the 12-month pre and post-exclusivity
    periods
  • 39 increase for the pediatric population

Verispan, LLC, 2003 2006, Data Extracted
January 2006
5
Drug Use Trends in Outpatient Settings
Ondansetron
  • OB/GYN was the most frequent prescriber specialty
    during the 12-month post-exclusivity period
  • OB/GYN 23 (369,000)
  • Pediatrics 4 (68,000)
  • Malignant neoplasm of the brain was the diagnosis
    most frequently associated with ondansetron use
    in the pediatric population 18 (20,000)

Verispan, LLC, 2003 2006, Data Extracted
January 2006
6
Drug Use Trends in Inpatient Settings
Ondansetron
  • 390,000 discharges associated with ondansetron
    use for all age groups during the 6-month
    post-exclusivity period
  • 12,400 (3.2) for the pediatric population 0 -
    16 years old
  • 2.7 decrease in the discharges associated with
    ondansetron use for all age groups between the
    6-month pre and post-exclusivity periods
  • 7.3 decrease for the pediatric population

Premier Informatics Extracted 2-2-06
7
Pediatric Exclusivity Studies Ondansetron
  • PONV PK study in 1 month to 2 year olds
    51 pediatric surgical patients
    utilized ondansetron prophylactically (24 hour
    observation period)
  • PONV efficacy and safety study in 1 month to 2
    year olds 670 pediatric surgical patients
    utilized ondansetron or placebo prophylactically
    (24 hour observation period)
  • CINV efficacy and safety study in 6 month to 4
    year olds 76 pediatric cancer patients receiving
    moderately to highly emetogenic chemotherapy
    utilized ondansetron prophylactically (24 hour
    observation period)

8
Pediatric Exclusivity Studies PK Study (n51)
  • Design Multi-center, two-arm, single dose (0.1
    mg/kg or 0.2 mg/kg IV)
  • Results Drug clearance was lower and half-life
    was prolonged in patients 1 to 4 months old
    compared to those gt 4 months to 2 years old

9
Pediatric Exclusivity Studies Population PK
Analysis (n127)
  • Design Combined data from PK and CINV studies
  • Results 0.15 mg/kg/dose IV every 4 hours x 3
    doses in cancer patients, aged 6 months to 4
    years, results in systemic exposure levels
    similar to those achieved in older pediatric
    cancer patients at similar doses

10
Pediatric Exclusivity Studies PONV (n670)
  • Design Multi-center, double-blind,
    placebo-controlled, randomized study of a single
    dose of 0.1 mg/kg ondansetron IV administered
    within 5 minutes following anesthesia induction

11
Pediatric Exclusivity Studies PONV Efficacy
  • Endpoints
  • Primary Proportion of patients experiencing at
    least one episode of emesis during the 24 hour
    assessment phase
  • Secondary
  • Time to first emetic episode
  • Time to first rescue medication
  • Incidence of emetic episodes
  • Proportion of patients receiving rescue
    medications
  • Proportion of patients with emetic episodes after
    the receipt of rescue medications

12
PONV Exclusivity Study Efficacy Results
  • Fewer patients experienced at least one emetic
    episode in the drug group (11) compared to the
    placebo group (28)
  • The drug performed better than placebo in 4 of
    the 5 secondary endpoints
  • Time to first emetic episode
  • Incidence of emetic episodes
  • Proportion of patients receiving rescue
    medications
  • Proportion of patients with emetic episodes after
    the receipt of rescue medications

13
Pediatric Exclusivity Studies CINV Efficacy
(n76)
  • Design Multi-center, open-label, 3 doses of 0.15
    mg/kg IV
  • Primary Endpoints
  • Incidence of emesis
  • Proportion of patients who received supplemental
    antiemetic medication during the 24-hour
    assessment period
  • Time to first rescue antiemetic medication
  • Parent/guardian overall satisfaction

14
CINV Exclusivity Study Efficacy Results
  • More than half of the patients had no emetic
    episodes
  • More than half of the patients did not require
    rescue medications
  • 80 of parents/guardian were satisfied with drug
    use

15
Pediatric Exclusivity Studies Safety Results
(n797) (drug group 463, placebo group 334)
  • No deaths
  • 1 of patients had non-fatal serious adverse
    reactions in both the drug (5) and placebo (3)
    groups
  • Drug group convulsions (1), dehydration (1),
    respiratory depression (1), staphylococcal
    infection (1), nodal arrhythmia, hypocapnia,
    hypoxia (1)
  • Placebo group tachycardia (1), bronchospasm (1),
    exacerbated pain (1)

16
Pediatric Exclusivity Study Labeling Changes
  • Clinical Pharmacology Pharmacodynamics
  • Population PK analysis of PK and CINV studies
  • Clinical Studies
  • CINV PONV studies
  • Precautions Pediatric Use
  • Little information available about the use in
    pediatric surgical patients lt1 month old and
    pediatric cancer patients younger than 6 months
    old
  • Slower drug clearance and half-life 2.5 fold
    longer in pediatric patients 1 to 4 months old
    compared to older children gt 4 months to 2 years
    old

17
Pediatric Exclusivity Study Labeling Changes
  • Dosage and Administration
  • CINV in 6 month to 4 year old patients
  • 3 doses of 0.15 mg/kg IV
  • PONV in 1 month to 2 year old patients
  • Single 0.1 mg/kg IV dose for patients weighing 40
    kg or less
  • Single 4 mg dose for patients weighing more than
    40 kg

18
Adverse Event Reports Since Market Approval and
Prior to Pediatric Exclusivity 1/4/91 12/1/04
May include duplicates and unknown ages Crude
count is 18 with 14 unduplicated cases
19
Pediatric Deaths Since Market Approval and Prior
to Pediatric Exclusivity
  • 18 crude count reports
  • 14 unduplicated cases
  • 7 cases excluded due to confounding or
    insufficient information
  • 1 - Erroneous classification of death
  • 1 - Unspecified cause of death in infant with in
    utero exposure
  • 2 - Significant time delay between symptoms
    and/or death and last ondansetron dose (17 hrs,
    12 days)
  • 3 - Complicated underlying medical conditions,
    some with concomitant medications (stage IV
    neuroblastoma with multi-organ failure and
    chemotherapy, medulloblastoma with radiation and
    chemotherapy, idiopathic pneumonitis with
    progressive germ cell disease)

20
Deaths Since Market Approval and Prior to
Pediatric Exclusivity (continued)
  • 7 remaining cases also confounded by complicated
    underlying medical conditions, concomitant
    medications, and/or insufficient details
  • 14 y.o. female with asthma, 1 day s/p scoliosis
    surgery, with decreased RR, BP, SaO2 after
    morphine and 1 hour after 4 mg ondansetron IV
    for nausea (concomitant meds cyclizine,
    albuterol, beclomethasone, terfenadine)
  • 10 y.o. male on chemotherapy for rhabdomyosarcoma
    with dizziness and collapse after 0.15 mg/kg
    ondansetron IV for vomiting (concomitant meds
    methylprednisolone mesna, ifosfamide, etoposide)
  • 9 m.o. male with bone marrow allografts developed
    acidosis, bundle branch block, and cardiac arrest
    with QT prolongation after cisapride and 6 mg
    ondansetron for nausea (concomitant meds
    cyclosporin, ganciclovir, omeprazole, amikacine,
    hydrocortisone, cyclophsphamide, foscarnet,
    alizapride, tienam, and ornidazole)

21
Deaths Since Market Approval and Prior to
Pediatric Exclusivity (continued)
  • 16 y.o. female with disseminated lupus developed
    septic shock or cardiomyopathy 3 days after
    ondansetron IV unknown dose to prevent nausea
    (concomitant meds prednisone, cyclophosphamide,
    mesna, dextropropoxyphene/paracetamol
    combination, furosemide, alizapride,
    ergocalciferol)
  • 2 y.o. male with h/o renal failure and renal
    hypoplasia with unknown cause of death after 17
    days of 3 mg ondansetron po for nausea and
    vomiting (concomitant meds sodium polystyrene
    sulfonate, alfacalcidol, erythropoietin, calcium,
    growth hormone)
  • 11 y.o. female with congenital heart disease on
    antibiotics developed decreased SaO2, headache,
    dizziness, and respiratory failure 1 hour after 4
    mg ondansetron IV for nausea of unknown etiology
    (concomitant meds clarithromycin, cefuroxime.
    PMH allergy to amoxicillin and codeine)
  • 16 y.o. male with end stage cystic fibrosis
    developed decreased SaO2 and arrested minutes
    after 2 mg ondansetron IV for nausea (numerous
    allergies to foods and medications, especially
    antibiotics)

22
Adverse Event Reports During the
Post-Exclusivity Period 12/1/04 1/1/06
May include duplicates and unknown ages
23
Pediatric Death During the Post-Exclusivity
Period (n1, 0 US)
  • 1 death case with insufficient information to
    assess causality
  • 3 year old male with unreported cause of death
    receiving 4 mg ondansetron po (unknown indication
    and duration)

24
Serious Adverse Events During the
Post-Exclusivity Period (n16, 5 US)
  • 1 respiratory case (respiratory depression with
    bradycardia)
  • 2 hepatic cases (1- increased aspartate
    aminotransferase 1- increased
    alanine aminotransferase with ascites)
  • 3 allergic reactions/anaphylaxis cases (1 -
    cyanosis, hypotension, and urticaria 1- dyspnea,
    hypotension, and pruritus 1- anaphylactic shock)
  • 5 neurologic cases (1- dystonia and agitation 1
    - auditory hallucinations, headache, and blurred
    vision 1 - seizure, hypotonia, musculoskeletal
    stiffness, and urinary incontinence 1-
    extrapyramidal reaction, speech impairment,
    clenched jaw 1- seizure and oculogryic crisis)
  • 5 other cases (2 - birth defects, 1- drug
    precipitation in IV, 2 - drug
    ineffectiveness)


Unlabeled events are unlined
25
Unlabeled Serious Adverse Events
  • 1 year old child (gender unspecified) with
    respiratory depression and bradycardia after
    receiving 2 mg ondansetron IV x 1 dose to treat
    an unknown condition (foreign case with very
    little information)
  • 9 year old boy with neuroblastoma experienced
    increased alanine aminotransferase, ascites, and
    pleural effusion after receiving several cancer
    chemotherapy agents and 4 mg ondansetron qd
    (duration and route of administration unknown)
  • Infant (age and gender unspecified) whose mother
    had used ondansetron during pregnancy experienced
    a foot/limb malformation (ondansetron dose,
    duration and route of administration unknown)
  • Infant (age and gender unspecified) whose mother
    had used ondansetron during pregnancy experienced
    tracheomalacia (ondansetron dose, duration, and
    route of administration unknown)


26
Summary Ondansetron
  • This completes the one-year post-exclusivity
    adverse event reporting as mandated by BPCA.
  • FDA recommends routine monitoring of ondansetron
    for adverse events in all populations.
  • Does the Advisory Committee concur?

27
Acknowledgements
  • OSE DGP
  • Ann Corken Mackey Lolita Lopez
  • Lanh Green Ruyi He
  • Rosemary Johann-Liang Joyce Korvick
  • Mark Avigan
  • Michael Evans OCP
  • Laura Governale Suliman Al-Fayoumi
  • Sigal Kaplan Suresh Doddapaneni
  • Toni Piazza-Hepp
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