DRUGS FOR

VOMITING IN CHILDREN

FROM GUIDELINES TO REAL LIFE

DR SHAILESH MEHTA

M.D.PEDIATRICS

Practicing pediatrician Chandigarh

ANTI EMETICS IN ACUTE GEWHY DO WE USE THEM?

• in order to increase the success rate of oral rehydration therapy

• increase patient comfort or to reduce concerns of parents

• In a survey of randomly selected board-certified emergency physicians, pediatricians and pediatric emergency medicine specialists demonstrated that more than 50% of clinicians report usage of antiemetics across all three specialties despite the acknowledgement that the use of antiemeticsremains controversial in this setting.

Anti-Emetic Drugs1. ANTIHISTAMINES

CyclizinePromethazineDimenhydrinate

2. DOPAMINE RECEPTORANTAGONISTSDomperidoneMetoclopramideProchlorperazine

3. NEUROKININ RECEPTORANTAGONISTSAprepitant

4. ANTIMUSCARINICS

Hyoscine

5. SHT3 RECEPTOR ANTAGONISTS

Ondansetron

Granisteron

6. CANNABINOIDS

Nabitone

CHOICE OF DRUGS-VOMITING IN ACUTE GE

• A drug once considered a wonder drug .

• Is an antihistaminic

• Also used in motion sickness

• It was the most frequently prescribed agent(64.8%), amongst all prescriptions ofantiemetics in a 2002 survey

• No more recommended in vomiting in A.GE

ISSUES WITH PROMETHAZINE• Respiratory depression; over sedation; agitation; hallucinations;

seizures; and dystonic reactions have been reported with promethazine use in children. A wide range of weight-based doses (0.45 to 6.4 mg per kg) were associated with respiratory depression and cardiac arrests

• FDA in late 2004, added a “boxed warning” was added to the labeling for promethazine hydrochloride (Phenergan), including a contraindication for use in children less than two years of age and a strengthened warning with regard to the use in children two years of age or older

Starke PR, Weaver J, Chowdhury BA. Boxed warning added to promethazine labeling for pediatric use. N Engl J Med. 2005;352(25):2653

Kwon KT, Rudkin SE, Langdorf MI: Antiemetic use in pediatric gastroenteritis: a national survey of emergency physicians, pediatricians, and pediatric emergency physicians. Clin. Pediatrics41,641–652 (2002).

VOMITING IN ACUTE GE

• A dopamine antagonist

• Both central and peripheral acting

• Being widely used for children less than 1 year

• However , not recommended by any authority

• The side effects outweigh the benefits if any

METOCLOPRAMIDE WARNING

METOCLOPRAMIDE PRODUCT INSERT

METOCLOPRAMIDE CONTRA INDICATED LESS THAN 1 YRS

OF AGE https://www.gov.uk/drug-safety-update/metoclopramide-risk-

of-neurological-adverse-effects

VOMITING IN ACUTE GE

• A drug which seems to be slightly out of popularity• FDA boxed warning 2004 –PROLONGS QTc interval• IAP TASK FORCE 2004 deemed it to be safest of all

anti emetics in Acute GE• Not included in any systematic review .Poor quality

of evidence to prove its efficacy.• Dopamine D2 antagonist with less CNS side effects.

Alhashimi D, Alhashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents.Cochrane Database Syst Rev 2009

DeCamp LR, Byerley JS, Doshi N, Steiner MJ. Use of antiemeticagents in acute gastroenteritis: a systematic review and meta-analysis.Arch Pediatr Adolesc Med 2008

DOMPERIDONE DROPSNO PRODUCT INSERT

DOMPERIDONE SYRUP

MOST SYSTEMATIC REVIEWS ON ANTIEMETICS USE IN GASTROENTERITIS EXCLUDE THE FOLLOWING DRUGS

• PROMETHAZINE- FDA BLACK BOX WARNING-NOT TO BE USED UNDER 2YEARS OF AGE

• DOMPERIDONE- , 2004, FDA issued a public warning that distributing any INJECTABLE domperidone-containing products is illegal

Sudden Cardiac Death and Ventricular Arrhythmias Associated with Domperidone: Evidence Supporting Health Canada’s WarningSalmaan Kanji, Alyssa Stevenson, Brian HuttonCan J Hosp Pharm. 2014 Jul-Aug; 67(4): 311–312HEALTH CANADA AND NICE ADVOCATE DOMPERIDONE USE AS GALACTAGOGUE ONLY WITH A WARNING NOTE THAT IT HAS POTENTIAL TO CAUSE ARRYTHMIA IN INFANT AND MOTHER

• CYCLIZINE

• HYOSCINE

( ANTIHISTAMINICS AND ANTIMUSCARINICS MORE USEFUL IN LABYRYNTHINE CAUSES OF VOMITING)

VOMITING IN ACUTE GE• Another wonder drug• Scores over any other anti emetic in many systematic

reviews• Superior to metoclopramide in its anti emetic effect• Used 1 month onwards for certain indications

(http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020007s043lbl.pdf)

• 5HT3 receptor antagonist• Not recommended so far for use in acute

gastroenteritis• No serious side effects except increase diarrhoea

RESULT OF LARGEST SYSTEMATIC REVIEW –

COMPARISON BETWEEN VARIOUS LICENSED ANTI EMETICS

• ONDENSETRON VS METOCLOPRAMIDE VS DIMENHYDRINATE VS DEXAMETHASONE

• The Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE searched from 1980 to March 2011

• 1479 PARTICIPANTS , 7 RCT , Age 1yr-18yr• Fedorowicz Z, Jagannath VA, Carter B. Antiemetics for reducing

vomiting related to acute gastroenteritis in children and adolescents.

• Cochrane Database Syst Rev2011;(9):CD005506

CONCLUSIONS• Oral ondansetron increased the proportion of

patients who had ceased vomiting and reduced the number needing intravenous rehydration and immediate hospital admission.

• Proportion of patients with cessation of vomiting in 24 hours was (58%) with IV ondansetron, (17%) placebo and (33%) in the metoclopramide group (P value = 0.039).

• LOW or limited evidence to support the role of Dimenhydrinate or Dexamethasone in gastroenteritis induced vomiting in children and adolescents

METOCLOPROMIDE VS ONDANSETRON

SYSTEMATIC LITERATURE REVIEW TILL 2012

• metoclopramide appears to be less efficacious in the treatment of gastroenteritis induced vomiting and are associated with more adverse events than ondansetron.

• BMC Public Health. 2013; 13(Suppl 3): S9. • The effect of antiemetics in childhood gastroenteritis• Jai K Das, Rohail Kumar,Rehana A Salam, Stephen

Freedman, and Zulfiqar A Bhutta

SOME ISSUES WITH ONDANSETRON• RECOMMENDATIONS ARE THAT IT SHOULD BE USED ONLY IN

POST SURGERY OR POST CHEMOTHERAPY EMESIS

HOWEVER , IN SOME STUDIES , WHERE ONDANSETRON WAS USED TO CONTROL VOMITING DUE TO GASTROENTERITIS, FOLLOWING WERE THE CONCLUSIONSOndansetron to be used as a single dose( if at all to be used) in gastroenteritis as an indication

• TILL DATE IT IS AN OFF LABEL PRESCRIPTION• THE READMISSION RATES AFTER 72HRS ARE SAME IN

PLACEBO VS ONDANSETRON • ONDANSETRON REDUCES THE IMMEDIATE NEED FOR IV

FLUIDS HOWEVER IT INCREASES EPISODES OF DIARRHOEARoslund G, Hepps TS, McQuillen KK: The role of oral ondansetron in children with vomiting

as a result of acute gastritis/gastroenteritis who have failed oral rehydration therapy: a randomized controlled trial. Ann. Emerg. Med.52,22–29 (2008).DeCamp LR, Byerley JS, Doshi N, Steiner MJ.Clin Exp Gastroenterol. 2010; 3: 97–112.Arch Pediatr Adolesc Med. 2008 Sep;162(9):858-65

DILEMMASVOMITING DUE TO ACUTE GASTROENTERITIS

• STUDIES INDICATE DOMPERIDONE AND METOCLOPROMIDE ARE NEITHER SAFE NOR EFFECTIVE NOR RECOMMENDED IN GASTROENTERITIS INDUCED VOMITING IN CHILDREN

• STUDIES INDICATE ONDENSETRON TO BE MOST EFFECTIVE FOR VOMITING IN ACUTE GE BUT NOT APPROVED FOR THIS INDICATION

NOT ALL THAT NICEBoth the American Academy of Pediatrics and NICE guidelines indicate that there is a consensus of opinion that

“antiemetics are not needed for the management of vomiting due to gastroenteritis in children.”

If at all they are used , they are deemed as “off label prescriptions” , and therefore need to be prescribed after an “informed consent”

American Academy of Pediatrics (AAP). Practice parameter: the management of acute gastroenteritis in young children. American academy of Pediatics, Provisional committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Pediatrics 1996;97:424e35.

National Collaborating Centre for Women’s and Children’s Health. Diarrhoea and Vomiting Diagnosis, Assessment and Management in Children Younger than 5 years. London: RCOG Press, 2009

Khanna R, Lakhanpaul M, Burman-Roy S,et al. BMJ2009;25:1009e12

SUNNY 6MONTHS CHILDInformant mother

Recurrent vomits since 2weeks, not sleeping well, accepting feeds but cries during or after feeds.

No fever or loose stools

WT 7KG

NO DEHYDRATION, AF not depressed nor bulging

PLAYFUL

ON COMPLEMENTARY FEEDS AND BREASTFEEDS

GERD

They may “ VOMIT” OR “REGURGITATE” OR “SPIT up” throughout the day. In fact, more than half of all infants under 3 months old have GERD. The most common symptoms of GERD in children are:- Frequent or recurrent vomiting- Frequent or persistent cough/wheezy chest- Refusing to eat or difficulty eating (choking or gagging with feeding)- Crying with feeding- Heartburn, or abdominal pain - Inadequate weight gain

CHOICE OF DRUGS

• DOMPERIDONE ?

• METOCLOPRAMIDE?

• PPI?

• H2RA?

• CISAPRIDE?

• ONDENSETRON?

• PROMETHAZINE?

DOMPERIDONE – POOR EVIDENCE SUPPORTING ITS ROLE IN GERD

• Evidence for the efficacy of domperidone in GER is very poor in older children, infants and neonates as the result of limitations in study design and length of follow-up, and this evidence is too weak to permit recommendations

Tighe M, Afzal NA, Bevan A, Hayen A, Munro A, Beattie RM. Pharmacological treatment of children with gastro-oesophageal reflux. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD008550. DOI: 10.1002/14651858.CD008550.pub2

METOCLOPRAMIDE FOR GERD7RCT – FOUND REDUCTION IN DAILY

SYMPTOMS• A meta-analysis of 7 RCTs of metoclopramide in developmentally healthy children

1 month to 2 years of age with symptoms of GER found that metoclopramidereduced daily symptoms and the RI but was associated with significant side effects.

• Metoclopramide commonly produces adverse side effects in infants and children, particularly lethargy, irritability, gynecomastia, galacctorhea, and extrapyramidal reactions and has caused permanent tardive dyskinesia

Craig WR, Hanlon-Dearman A, Sinclair C, Taback S, Moffatt M.Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years.Cochrane Database Syst Rev. 2004:CD003502

GERD GUIDELINES ESPGHAN 2009

• PROKINETICS- CISAPRIDE, DOMPERIDONE, METOCLOPRAMIDE NOT RECOMMENDED DUE TO INSUFFICIENT EVIDENCE OF THEIR EFFICACY

• ADVERSE EFFECTS OF PROKINETIC AGENTS OUTWEIGH THE BENEFITS IF ANY

GERD GUIDELINES ESPGHAN 2009

• HISTAMINE 2 RECEPTOR ANTAGONISTS (H2RA)

• PROTON PUMP INHIBITORS

BOTH DEEMED SAFE AND EFFECTIVE FOR GERD

HOWEVER PPI APPROVAL IS BEYOND 1 YEAR OF AGE

FDA ON RANITIDINE

The safety and effectiveness of ZANTAC have been established in the age-group of 1 month to 16 years

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018703s067,019675s034,020251s018lbl.pdf

INTROSPECTION• AM I HAVING COMPLETE KNOWLEDGE

ABOUT THE ANTI EMETIC AND ITS SIDE EFFECTS ?

• IS THE DRUG APPROVED FOR USE FOR THE INDICATION I AM USING ?

• AM I DOING JUSTICE TO MY PATIENT ?

SOMETIMESDOING NOTHING IS THE BEST

THINGA BIG BIG THANK YOU