Transcript Ondansetron in the Treatment of Acute Gastroenteritis

Ondansetron in the Treatment of
Acute Gastroenteritis in the
Pediatric Population
Sapna N. Patel
UCSF School of Pharmacy
Febuary 2008
Patient GM
o GM is a 4-year male that presents to the
ED with nausea, vomiting and complaints
that his “tummy hurts”
o GM’s mother states that the symptoms
started early am and have not improved
o GM’s mother states that he hasn’t eaten or
drank anything since early am
Background
 Acute gastroenteritis is one of the most
common illnesses in childhood
 3.7 million physician visits annually
 20% of all outpatient visits in children <5
years
 Significant morbidity in the pediatric
population
 Mainly of viral origin
 Sx: nausea, vomiting, fever, abdominal
cramps, anorexia, malaise
Background (cont)
 First line treatment is oral rehydration
 Traditional antiemetics lack documentation of evidence of
efficacy and/or are limited by ADRs
Alternatives
Reason for Low Use
Promethazine
Respiratory depression potential,
should not be used in children <2 years
Prochlorperazine:
Increased rates of EPS effects
Trimethobenzamide
Removed from market-lack of
documentation of efficacy
Metoclopramide
Limited evidence for use, and potential
for EPS
Meclizine
Not studied for indication
Ondansetron Pharmacology
Ondansetron (Zofran®): Increasing popularity
for “off-label” use for gastroenteritis
FDA indicated to prevent N/V in
chemotherapy
Evaluated as an antiemetic for adjunctive
treatment to aid oral rehydration process
Pathogenesis of vomiting may be due to
release of 5-HT that acts on vagal afferent
nerve receptors
Ondansetron: 5-HT receptor antagonist
Exerts its effects on nerves that stimulate
vomiting center
Trial #1 :Oral Ondansetron for
Gastroenteritis in a Pediatric ED
 Objective: Determine if single oral dose of
ondansetron would improve N/V sxs in children
 Study Design: Monocenter, prospective,
randomized, double-blind, placebo-controlled
 Methods: Patients randomized to Ondansetron
ODT (n=104) or placebo (n=107) X 1, followed by
1-hour oral rehydration treatment
 Primary Endpoint: # children who vomited while
receiving oral rehydration
 Secondary Endpoints: mean # vomiting
episodes, # patients treated with IV rehydration or
hospitalized
Trial #1(cont)
 Results:
Treatment group
Primary endpoint: Less likely to vomit (14% vs.
35%, RR=0.40, 95% CI, 0.26-0.61, p<0.001)
Secondary Endpoint: Less mean vomiting
episodes/child (0.18 vs. 0.65, p<0.001)
Secondary Endpoint: Less likely to receive IV
rehydration (14% vs. 31%; RR=0.46; 95% CI, 0.260.79, p=.002)
Secondary Endpoint: 12% reduction in ED stay
(p=0.02)
Safety: More episodes of diarrhea vs. placebo (1.4 vs.
0.5, p<0.001), no additional AE noted
Trial #1: (cont)
Author’s Conclusions:
Single dose of Ondansetron
decreases vomiting and aids with oral
rehydration
Administration may be useful in ED
setting
No clinically significant adverse
effects
Trial #1 (cont)
Pros
Cons
Randomized, Double-blind,
Inclusion Criteria of
Placebo-controlled
diarrheal episodes ≠ CDC
recommendations
Clear definition of vomiting
Use of unvalidated
episode (outcomes)
dehydration scale
Controlled for physician
Evaluated low-risk patients
variability
Use of weight-based
Short evaluation period
dosing
Good patient retention
Manufacturer sponsored
Trial #2: Ondansetron Decreases
Vomiting Assoc. w/Acute Gastroenteritis
 Objective: Evaluate efficacy of ondansetron for
treatment of vomiting in children with acute
gastroenteritis
 Study Design: Monocenter, randomized, doubleblind, placebo-controlled
 Methods: Patients with ≥ 3 vomiting episodes
randomized to receive either IV ondansetron (n=54)
or placebo (n=53)
 Primary Endpoints: Frequency of vomiting
episodes after drug tx, need for hospitalization
 Secondary Endpoints (main): Duration of vomiting
sxs after drug tx, # & duration diarrhea sxs,
frequency of return visits
Trial #2: (cont)
 Results
Treatment group:
Complete cessation of vomiting (70% vs.
51%, p=0.04)
Hospital admission: not statistically significant
Diarrhea episodes: not statistically significant
Median vomiting episodes after drug tx: not
statistically significant
Safety: No significant difference observed
between 2 groups
Trial #2: (cont)
Author’s Conclusions:
 IV ondansetron reduces vomiting
in children with acute gastroenteritis
 Safety and low cost of
ondansetron suggests valuable role
in pediatric gastroenteritis
Trial #2 (cont)
Pros
Cons
Randomized, Double-blind,
Placebo-controlled
Inclusion criteria: eliminates
very low-risk patients
Limited enrollment time
Hospital admission based
on institution-specific
guidelines
Clear definition of vomiting Subjective identification of
episode (outcomes)
higher risk patients
Use of weight-based dosing Least cost-effective form of
ondansetron used
Good patient retention
Subjective monitoring:
caregiver recall
Clinical Trial Discussion
Recent trials discussed represent “off-label”
use of ondansetron for gastroenteritis
Trials highlight ondansetron use as an
adjunct to oral rehydration
Consider use in children with mild to
moderate dehydration who cannot tolerate
oral rehydration therapy
Additional trials needed to assess use in
children with severe dehydration
Ondansetron: Safety Profile
Low incidence of ADRs reported in trials
Common ADRs: Headache, Fatigue,
Diarrrhea, Dizziness
Two trials discussed stated significant
increased frequency of diarrhea episodes
Metabolism by cyp-450 (CYP3A4,
CYP2D6, CYP1A2),system-no data
showing adjustment of similarly
metabolized drugs
GM’s Progress
 In the ED, GM was given Ondansetron ODT
4mg X 1 dose and oral rehydration therapy X
1 hour and discharged following no further
vomiting episodes
 GM’s mother was instructed to give
Pedialyte® at home as tolerated until
symptoms resolve
 GM’s mother was also instructed to
encourage GM to eat
 GM’s symptoms had completely resolved late
the following day
References
 PharmacistsLetter.com. Ondansetron (Zofran) in Children with Viral
Gastroenteritis. [Online] Available
http://www.pharmacistsletter.com/(S(2pgdkg454034v5fcziaedgrw))/pl/detaildocu
ments/230804.pdf?cs=&s=PL, August 16, 2007.
 King CK, Glass R, Bresee JS, Duggan C. Managing Acute Gastroenteritis
Among Children Oral Rehydration, Maintenance, and Nutritional Therapy.
MMWR 52;16:1-16.
 Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D. A
Randomized Clinical Trial Comparing Oral Ondansetron With Placebo in
Children With Vomiting From Acute Gastroenteritis. Ann of Emerg Med
2002;39:397-404.
 Micromedex Drugdex Evaluations-Ondansetron, copyright 2006 by Thomson
MICROMEDEX.
 Freedman SB, Alder M, Seshadri R, Powell EC. Oral Ondansetron for
Gastroenteritis in a Pediatric Emergency Department. N Engl J Med
354;16:1698-705.
 Reeves JJ, Shannon MW, Fleisher GR. Ondansetron Decreases Vomiting
Associated with Acute Gastroenteritis: A Randomized, Controlled Trial.
Pediatrics 2002;109:e62.
 Zofran.com. Prescribing Information. [Online] Available
http://us.gsk.com/products/assets/us_zofran_tablets.pdf, September 4, 2007.
Any Questions?