Emergence of Guidelines and Prescribing Trends
Several guidelines supporting the prescribing of cisapride (25–28), domperidone (25–27), and metoclopramide (25–27) to children <2 years old emerged over the years and may be accountable for some of these dramatic changes. The greatest increased number of cisapride prescriptions was observed between 1994 and 1998. A steady increase in domperidone prescriptions in children <2 years was also observed particularly after 2000. The prescribing of metoclopramide decreased during the same period. Figure 4 demonstrates a possible temporal effect in response to these best-known guidelines.
The results from these analyses were presented in full in the GORMET report (18). Following the systematic approach, we did not uncover any new causally related safety issues in children prescribed with these drugs. Only diarrhoea was associated with domperidone prescription in children <2 years old with incidence rate ratio of 1.26 (95% CI 1.08–1.47). The unknown safety signals were, however, in general, associated with concomitant medications and illnesses, and increased dose or duration of prokinetics use.
These data show marked changes in the prescription of cisapride, and then of domperidone in children <2 years old, despite the lack of marketing authorisation for use in this population or good-quality published evidence of efficacy and safety to support these changes. Although we are unable to prove the causes of these changes in this study, the potential drivers are likely to have been a combination of marketing from the companies, publication of articles, and publication of guidelines by professional societies plus societal changes such as expectations of families. A New Zealand study showed similar trends of prescribing for cisapride and suggested delayed response to safety alerts by the general practitioners (GPs)—“this delay was more pronounced with paediatricians when the prescribing practice is already embedded in their routine care” (29). There is a suggestion that clinicians adhere to guidelines poorly (30), but there is no research attempting to link prescription rates to clinical guidelines in the literature. A survey of general paediatricians in Europe (none from the United Kingdom) (31), showed that only a minority follow the most recently published evidence-based guidelines for GOR (4) with self-reported overprescribing of proton pump inhibitors (as defined by the guidelines) in 82% of the respondents; unfortunately, this study did not report their knowledge of the guidelines before the survey and did not ask their reasons for not following the guidelines.
The main limitations of this study are biases and underestimation. The GPRD only records drug prescription, but it is unknown whether the drugs were actually consumed by the patients as prescribed. Many prescriptions of these drugs may have been initiated in the hospitals by paediatricians, neonatologists, or specialist paediatric gastroenterologists; therefore, some early prescriptions would not have been captured in the GPRD. Consequently, the prescribing rates are likely to be an underestimate of the true prescribing. Another limitation of this article is that it presents somewhat older prescribing data (1990–2006). We believe, however, these periods cover the critical time points of the changing guidelines and evidence of prokinetics in children. Moreover, any recent data would not change the temporal trends of the prescribing of cisapride, domperidone, and metoclopramide that we observed in the general practices. This historical evidence may be used to guide future learning and continuing debates in this area.
Cisapride was licensed in the United Kingdom in 1988 for the treatment of GORD in patients >12 years. Cisapride suspension, which would be the form of choice in the prescribing for younger children, became available in the United Kingdom in mid-1992 when we also observed an initial increase in the rates of cisapride prescribing in children. In 1993, a working group of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recommended cisapride to be the first drug treatment in children and infants with GORD following “failed lifestyle changes over 1–2 weeks” (26,32). Despite acknowledging that limited data were available, domperidone and metoclopramide were listed as alternatives in the face of no response to cisapride.
The ESPGHAN guidelines and the introduction of cisapride suspension in 1992 in the United Kingdom were followed by the observed steep increase in the prescribing of cisapride between 1994 and 1998 when the medication became widely available. Reports of prolonged QT intervals and fatal cardiac arrhythmia events among adults taking cisapride treatment, however, soon emerged around 1997.
The profusion of publications and practice guidelines suggesting a benefit from cisapride may have influenced clinicians’ decisions to prescribe cisapride (33). The guidelines on treating reflux with cisapride were based on small, mostly unblinded, clinical trials, which were evaluated qualitatively by a working group within the ESPGHAN (26). The process of drawing up the guidelines, and conflicts of interest were not clearly defined in the published document. There was no evidence of systematic critical evaluation as would be expected now in the United Kingdom in the development of National Institute for Health and Care Excellence or Scottish Intercollegiate Guidelines Network guidelines (34,35). Although drug companies funding underpinning these changes is possible, the legislation preventing open marketing on unlicensed indications would make this route unlikely in Europe. Another factor that may have biased decisions, and which was not openly addressed in many publications of that period, was the disclosure of industry support for individuals in the working group who could influence the final document and its promotion. For paediatricians, and subsequently GPs to react positively to these guidelines was not fully warranted; instead, the guidelines should have been challenged for the lack of evidence.
As part of postmarketing safety monitoring, Janssen Pharmaceutica (Titusville, NJ), which manufactured cisapride and domperidone, issued safety warnings on cisapride in June 1998. This was followed by a reduction in cisapride prescribing rate, suggesting that GPs became more cautious when prescribing cisapride to children. Nevertheless, ESPGHAN and NASPGHAN (North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition) remained openly and largely supportive of the efficacy and safety of cisapride (27,28). The updated 2009 guideline on GORD in infants developed between ESPGHAN and NASPGHAN, however, warns that “potential adverse effects of currently available prokinetic agents outweigh the potential benefits of these medications for the treatment of GORD” (4). It emphasises that there is insufficient evidence of clinical efficacy to justify routine use of bethanechol, metoclopramide, cisapride, or domperidone (4). Unlike the initial ESPGHAN guideline, this report was developed systematically with full disclosure of conflicts of interest.
Accumulating safety evidence from the UK Yellow Card Scheme and other worldwide reports finally prompted the MHRA and the Committee on Safety of Medicines to take action. Marketing authorisation of cisapride in the United Kingdom was suspended on July 28, 2000, and subsequently withdrawn.
Since the withdrawal of cisapride, with less evidence of efficacy and safety, domperidone has become widely prescribed to children for the treatment of GORD symptoms despite the fact that the BNFC does not and never did recommend the use of domperidone in children with GORD symptoms. More than 14 years later, the Paediatric Formulary Committee continues to recognise that domperidone may be used when other interventions have been tried, despite unconvincing evidence of efficacy (8). The data suggest that domperidone prescribing in children rapidly increased in primary care. Prescribing in North America did not go down this route, possibly because the NASPGHAN guidelines never had mentioned domperidone to be an alternative (28).
It is possible that the influx in domperidone prescription was initiated at first to be a replacement for cisapride in which there had been a large increase previously. This would fit with the ESPGHAN guidelines in 1993 and the report published in 1997, which advised that domperidone and metoclopramide may be considered alternatives to cisapride if there was no response to it (25,26). The perceived safety of domperidone with presumed efficacy for the treatment of GORD symptoms in children, however, was most likely the reason for the subsequent rise over the following years. A study in Belgium also observed increasing trend of acid suppressant use in children, which could as well be partly contributed to by the withdrawal of cisapride (36).
Metoclopramide has lost popularity, possibly because of the known extrapyramidal adverse reactions, alongside several early studies showing the superiority of domperidone to metoclopramide (37–40). It is primarily used in older children with nausea and sickness rather than in infants with reflux. Metoclopramide prescriptions may continue to decline in response to a “black box” warning for tardive dyskinesia adverse reactions issued by the Food and Drug Administration on February 29, 2009 (41). The concerns on long-term adverse reactions in children who were affected by the drugs, however, still remain and need further investigation.
The decline in age over time when children had started receiving cisapride and domperidone therapy indicates that paediatricians and/or GPs did react positively to these guidelines. The increasing number of prescriptions per child and longer therapy duration over time suggest that GPs were getting more comfortable prescribing these drugs to children, although this may be a sign that these drugs were not effective and there were continuing symptoms, or may be the children were experiencing a chronic disease and did receive some clinical benefit. For infants with reflux, the reality is that no one knows whether these drugs are of any use and importance. It is possible that they may have a role, but the evidence is presently simply not there (15,16).
The guidelines are probably not all that have contributed to these changes—societal factors such as anxious and more inexperienced parents could be less accepting of having infants with what is for the majority a benign and self-limiting disorder, and chosen to turn to drug treatment for help. The increase in the proportion of infants being treated during the course of the study would be consistent with this. These are only speculations and cannot be explored using these data. Despite these changes in off-label prescribing of prokinetics in children, extensive analyses in GORMET did not reveal any safety signal that may be causally related to the use of cisapride, domperidone, or metoclopramide (18). Our results on safety are also consistent with MHRA's recommendation of reduced dose and duration of domperidone use in adults (6). Our analyses support the development of new well-designed clinical studies to further investigate the efficacy and safety of domperidone use in children <2 for the treatment of GORD.
Off-label drug prescribing may lead to many unknown complications when the efficacy and safety have never been formally assessed in the intended population. Vulnerable populations such as children are affected by this trade, and require more regulated and transparent intervention. More important, the efficacy and safety of the drugs that are widely used off-label, such as domperidone in children, need to be formally assessed in the representative population in a controlled environment to make its use safer.
The authors thank Dr Lesley Wise, who was the Unit Manager at the MHRA for the duration of the study, for her guidance in line with the MHRA's policy. We also thank Ms Anna Shafe, who was an employee of the MHRA at the time this study was started and who contributed to data extraction from the Clinical Practice Research Datalink (previously known as the GPRD) for the study.
1. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr
2. Joint Formulary Committee. British National Formulary. 55th ed.London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2008.
3. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ
4. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr
9. Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr
10. Vandenplas Y, Hegar B. Diagnosis and treatment of gastro-oesophageal reflux
disease in infants and children. J Gastroenterol Hepatol
11. Vandenplas Y, Belli D, Cadranel S, et al. Dietary treatment for regurgitation—recommendations from a working party. Acta Paediatr
12. Ferry GD, Selby M, Pietro TJ. Clinical response to short-term nasogastric feeding in infants with gastroesophageal reflux and growth failure. J Pediatr Gastroenterol Nutr
13. Craig WR, Hanlon-Dearman A, Sinclair C, et al. Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux
in children under two years. Cochrane Database Syst Rev
2004; 4: CD003502.
14. Del Buono R, Wenzl TG, Ball G, et al. Effect of Gaviscon Infant on gastro-oesophageal reflux
in infants assessed by combined intraluminal impedance/pH. Arch Dis Child
15. Augood C, MacLennan S, Gilbert R, et al. Cisapride
treatment for gastro-oesophageal reflux
in children. Cochrane Database Syst Rev
2003; 4: CD002300.
16. Pritchard DS, Baber N, Stephenson T. Should domperidone
be used for the treatment of gastro-oesophageal reflux
in children? Systematic review of randomized controlled trials in children aged 1 month to 11 years old. Br J Clin Pharmacol
17. Hibbs AM, Lorch SA. Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review. Pediatrics
18. Mt-Isa S, Croft NM, Shafe A, et al. Gastro-Oesophageal Reflux
Medicines—Evidence for Trials (GORMET). 2010; London, UK: Medicines and Healthcare Regulatory Agency, Report No.: SDS011.
19. CPRD. The Clinical Practice Research Datalink. http://www.cprd.com
. Published 2013. Accessed June 19, 2013.
20. Joint Formulary CommitteeBritish National Formulary. 39th ed.London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2000.
21. Joint Formulary CommitteeBritish National Formulary. 53rd ed.London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2007.
22. Evans SJ. Pharmacovigilance: a science or fielding emergencies? Stat Med
23. Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf
24. Hill AB. The environment and disease: association or causation? Proc R Soc Med
25. Vandenplas Y, Belli D, Benhamou P, et al. A critical appraisal of current management practices for infant regurgitation and recommendations of a working party. Eur J Pediatr
26. Vandenplas Y, Ashkenazi A, Belli D, et al. A proposition for the diagnosis and treatment of gastro-oesophageal reflux
disease in children: a report from a working group on gastro-oesophageal reflux
disease. Working Group of the European Society of Paediatric Gastro-enterology and Nutrition (ESPGAN). Eur J Pediatr
27. Vandenplas Y, Belli DC, Benatar A, et al. The role of cisapride
in the treatment of pediatric gastroesophageal reflux. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr
28. Shulman RJ, Boyle JT, Colletti RB, et al. The use of cisapride
in children. The North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr
29. de la Porte M, Reith D, Tilyard M. Impact of safety alerts upon prescribing of cisapride
to children in New Zealand. NZ Med J
30. Graham ID, Tetroe J. Some theoretical underpinnings of knowledge translation. Acad Emerg Med
31. Quitadamo P, Papadopoulou A, Wenzl T, et al. European pediatricians’ approach to children with GER symptoms: survey of the implementation of 2009 NASPGHAN-ESPGHAN guidelines. J Pediatr Gastroenterol Nutr
32. Vandenplas Y. Reflux esophagitis in infants and children: a report from the Working Group on Gastro-Oesophageal Reflux
Disease of the European Society of Paediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr
33. Bourke B, Drumm B. Cochrane's epitaph for cisapride
in childhood gastro-oesophageal reflux
. Arch Dis Child
36. De BP, Christiaens T, Stichele RV, et al. Changes in prescription patterns of acid-suppressant medications by Belgian pediatricians: analysis of the national database (1997–2009). J Pediatr Gastroenterol Nutr
37. Agorastos I, Zissis NP, Kaprinis I, et al. Double-blind evaluation of domperidone
in acute vomiting and dyspeptic disorders. J Int Med Res
38. De Loore I, Van Ravensteyn H, Ameryckx L. Domperidone
drops in the symptomatic treatment of chronic paediatric vomiting and regurgitation. A comparison with metoclopramide. Postgrad Med J
1979; 55 (suppl 1):40–42.
39. Haarmann K, Lebkuchner F, Widmann A, et al. A double-blind study of domperidone
in the symptomatic treatment of chronic post-prandial upper gastrointestinal distress. Postgrad Med J
1979; 55 (suppl 1):24–27.
40. Van Outryve M, Lauwers W, Verbeke S. Domperidone
for the symptomatic treatment of chronic post-prandial nausea and vomiting. Postgrad Med J
1979; 55 (suppl 1):33–35.
Keywords:© 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
cisapride; clinical practice guideline; domperidone; gastro-oesophageal reflux; paediatrics