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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?