Title: One Year PostExclusivity Adverse Event Review: Ondansetron Pediatric Advisory Committee Meeting Nove
1One 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
2Background 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
3Background 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
4Drug 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
5Drug 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
6Drug 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
7Pediatric 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)
8Pediatric 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
9Pediatric 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
10Pediatric 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
11Pediatric 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
12PONV 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
13Pediatric 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
14CINV 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
15Pediatric 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)
16Pediatric 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
17Pediatric 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
18Adverse 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
19Pediatric 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)
20Deaths 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)
21Deaths 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)
22Adverse Event Reports During the
Post-Exclusivity Period 12/1/04 1/1/06
May include duplicates and unknown ages
23Pediatric 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)
24Serious 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
25Unlabeled 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)
26Summary 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?
27Acknowledgements
- 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