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Prokinetics Prescribing in Paediatrics: Evidence on Cisapride, Domperidone, and Metoclopramide

Mt-Isa, Shahrul*; Tomlin, Stephen; Sutcliffe, Alastair; Underwood, Martin§; Williamson, Paula||; Croft, Nicholas M.; Ashby, Deborah*

Journal of Pediatric Gastroenterology and Nutrition: April 2015 - Volume 60 - Issue 4 - p 508–514
doi: 10.1097/MPG.0000000000000657
Original Articles: Gastroenterology
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Objectives: Domperidone and metoclopramide are prokinetics commonly prescribed off-label to infants and younger children in an attempt to treat gastro-oesophageal reflux symptoms. Another prokinetic drug, cisapride, was used but withdrawn in 2000 in the United Kingdom because of serious arrhythmic adverse events. Medicines and Healthcare Products Regulatory Agency issued safety warnings for domperidone in May 2012 and restricted its indications. We report here national primary care prescribing trends and safety signals of these drugs in children.

Methods: We used data from the General Practice Research Database between 1990 and 2006 for children <18 years. Descriptive statistics and Poisson regressions were performed to characterise prescribing trends. We examined safety signals in nested case–control studies.

Results: The proportion of children <2 years old being prescribed one of the medications doubled during the study period. Prescriptions of domperidone increased 10-fold, mainly following the withdrawal of cisapride in 2000. Prescriptions of metoclopramide did not change significantly. Despite the increase in prescriptions of domperidone, no new safety signals were identified.

Conclusions: These data showed dramatic changes in prescribing of cisapride and domperidone despite the lack of good-quality supporting evidence. It is possible that these prescribing trends were influenced by published guidelines. Even if produced without robust efficacy and safety evidence, published guidelines can influence clinicians and consequently affect prescribing. Therefore, improving the evidence base on prokinetics to inform future guidelines is vital. The lack of new safety signals during this period would support the development of suitable powered clinical studies.

*Imperial Clinical Trials Unit, School of Public Health, Imperial College London

Evelina Children's Hospital, Pharmacy Department, King's Health Partners, Guy's and St Thomas’ NHS Foundation Trust

General and Adolescent Paediatrics Unit, Institute of Child Health, University College London, London

§Warwick Medical School, University of Warwick, Coventry

||Centre for Medical Statistics and Health Evaluation, University of Liverpool, Liverpool

Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.

Address correspondence and reprint requests to Dr Shahrul Mt-Isa, Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London W2 1PG, UK (e-mail: s.mt-isa@imperial.ac.uk).

Received 17 October, 2014

Accepted 27 November, 2014

The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the UK Department of Health or the Medicines and Healthcare Products Regulatory Agency (MHRA).

N.M.C. and D.A. contributed equally to the article.

This study was supported by the MHRA Pharmacoepidemiology Research Programme (grant no. SDS011).

N.M.C. has participated as an investigator in a trial of a treatment of reflux in infants funded by Johnson & Johnson. The other authors report no conflicts of interest.

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What Is Known/What Is New

What Is Known

  • Routine medical records such as Clinical Practice Research Datalink (CPRD) are useful for studying drug prescribing trends.
  • The Medicines Act neither promotes nor prohibits off-label drug prescribing recognising that it may be necessary.
  • A New Zealand study shows increasing trend in cisapride prescriptions (1991–1998) and a rapid decline following safety warnings in 1998.
  • What Is New
  • CPRD is useful in studying emerging safety concerns of informed off-label drug prescribing.
  • Domperidone prescribing in children increases despite no robust efficacy and safety evidence in the population.
  • Published guidelines may have been a major driver in these changes.
  • Formal benefit–risk assessment using CPRD can contribute to the development of guidelines for patient subgroups.

It is a common practice to prescribe off-label drugs to children (1). This is neither promoted nor prohibited by the Medicines Act (1968) because informed use of off-label drugs is necessary to treat sick children (2). In many cases, there is little evidence for efficacy or safety of the drugs when used in this population. More than 50% of medicines used in children in the European Union have never been studied in this population (3).

An example of this is the use of prokinetic drugs in children with gastro-oesophageal reflux (GOR) or GOR disease (GORD). GOR is an involuntary passage of gastric contents into the oesophagus and a common problem in infants (4). GORD is defined as the “reflux of gastric contents causing troublesome symptoms and/or complications” (4). GOR (and GORD) is generally benign and usually resolves between 12 and 24 months of age, but in some cases, a drug treatment is used in an attempt to control worsening or persistence of the symptoms. Prokinetics such as cisapride, domperidone, and metoclopramide have been used to treat GORD symptoms in children, but their licensing indications in children are restricted to nausea and vomiting. Cisapride was withdrawn in July 2000 following cardiac adverse reactions in adults. A drug of similar class, domperidone, emerged as an alternative following the withdrawal. In May 2012, the UK Medicines and Healthcare Products Regulatory Agency (MHRA), however, warned of the small risk of serious ventricular arrhythmia and sudden cardiac death associated with domperidone, with elevated risk in those consuming daily doses of >30 mg (5). The MHRA subsequently revised the contraindications of domperidone and enforced restricted use in May 2014 for adults, while acknowledging that further research is needed in children (6), and later placed it under additional monitoring (Black Triangle) in July 2014 (7). These changes triggered a revision to the off-label use of domperidone for GORD in the UK British National Formulary for Children (BNFC) in October 2014 (8). Other treatment options are available, all with limited evidence of efficacy (9–14).

A Cochrane systematic review on cisapride after its withdrawal concluded that there was no clear evidence that cisapride reduces GORD symptoms, and suggested substantial publication bias towards studies showing positive effect of cisapride (15). A systematic review of domperidone concluded that there is a minimal evidence for efficacy of domperidone in reducing GORD symptoms but few trials were available (16). Systematic reviews of metoclopramide concluded that there may be some benefit against placebo (13), but there is insufficient evidence to support or oppose its use for GORD in infants because few trials were available and mostly were of short duration (17).

Gastro-Oesophageal Reflux Medicines—Evidence for Trials (GORMET) was a study designed to explore the potential of the General Practice Research Database (GPRD) for informing clinical trial design on safety of medicines used off-label in primary care for the treatment of GORD symptoms in children (18). The study population was extracted from approximately 3.6 million active patients from approximately 433 practices participating in GPRD, covering 5.5% of the UK population (http://www.gprd.com in April 2008; http://www.cprd.com on March 29, 2012) (19).

We address chronological changes in prescribing trends of cisapride, domperidone, and metoclopramide in children, as explored in GORMET (18). We consider external factors that may have influenced the trends observed, particularly the emergence of paediatric guidelines on the management of GORD during this critical period. The side effects of these drugs are well documented for adult use but not in children. Therefore, we also looked for signs of any increased clinical events associated with these drugs that may be causally related (safety signals) with their use in children to identify potential safety issues, particularly for younger children in whom the indications were likely to be for GORD.

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METHODS

We used GORMET data from the GPRD for children aged <18 years old between 1990 and 2006, who were prescribed cisapride (N = 1497), domperidone (N = 9319), or metoclopramide (N = 17,985), and had at least 3 months of follow-up data recorded (18). Each child was matched by age and sex to 4 children without any prescription of the 3 drugs. The number of all of the children in GPRD <18 years old, by year, during the same time period was used as the denominator.

We used Poisson regression adjusted for the size of the underlying child population in the GPRD by year to calculate incidence rates (number of new children per million starting prescription in a particular year). We calculated these rates for all of the children initially, and then for the subset of children <2 years old (<2) and for those 2 years old and older (≥2) because of the likely different indications in these 2 age groups. The prescribing would be expected to be somewhat different between these groups of children because prokinetics are likely to be prescribed to children <2 to alleviate GOR/GORD symptoms but prescribing to children ≥2 may be largely because of other reasons such as nausea that result from migraine or chemotherapy and less commonly for symptoms of reflux, which (for natural resolution of the symptoms of GORD during the first 2 years of life) are much less common in this age group. We discuss the trends of prescriptions and the possible influence of paediatric guidelines on GORD.

We hypothesised that side effects listed in the BNFC (20,21) for all of the 3 drugs were known safety signals for children. We calculated the proportional reporting ratios of other drug–event pairs to generate hypotheses of unknown safety signals (22,23). We conducted nested case–control studies for the unknown safety signals, and argued the drug–event causality according to Hill (24).

Ethical approval for this study was obtained from the Independent Scientific Advisory Committee for MHRA database research (project number SDS011).

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RESULTS

Data

Table 1 shows the number of children whose data were used in the analyses. Because GPRD does not record clear diagnosis of GORD, the data extracted contain children prescribed with cisapride, domperidone, and metoclopramide for any indication. The prescription of these drugs is most likely for the treatment of recurrent vomiting because of GORD in children <2. In children ≥2, GORD indication is less common, and these drugs may be prescribed for the licensed indications of nausea and vomiting from various causes including chemotherapy and migraine.

TABLE 1

TABLE 1

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Incidence Rates of Prescribing

There was a small increase in the percentage of all of the children being prescribed 1 of these 3 medications from 0.09% (1990) to 0.11% (2006). Use in those <2 increased markedly from 0.4% to 0.75%, whereas use in those ≥2 decreased from 0.5% to 0.35%.

The annual incidence rates of cisapride (1990–2000) and domperidone (1990–2006) prescription in all of the children increased by 24.6% (95% CI 10.7–38.6) and 7.5% (95% CI 6.8–8.1), respectively, and that of metoclopramide (1990–2006) declined by 4.3% (95% CI 3.4–5.3).

Figure 1 shows the incidence rates per million children by age group and year. There was a dramatic increase in incidence rates in children <2 years old being prescribed domperidone following the withdrawal of cisapride in July 2000. A much smaller increase was observed in those ≥2 years old. The incidence rates in those prescribed with metoclopramide were similar across age groups, with some evidence of a decline.

FIGURE 1

FIGURE 1

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Age at Start of Therapy

The median starting ages in children <2 years old were 6 (interquartile range [IQR] 4–10), 5 (IQR 3–10), and 14 (IQR 9–19) months for cisapride, domperidone, and metoclopramide, respectively. The starting age decreased over time in children <2 years old among those taking cisapride and domperidone, whereas among those taking metoclopramide it did not significantly vary.

The median starting ages in children ≥2 years old were 10 (IQR 5–15), 15 (IQR 11–17), and 14 (IQR 9–16) years for cisapride, domperidone, and metoclopramide, respectively. There were no marked variations in starting age over time for all of the 3 drugs in this group.

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Therapy Amount and Duration

The mean number of prescriptions issued per child <2 years old was generally greater than those issued to children ≥2 years old (Fig. 2). Not only there were more prescriptions, the mean therapy duration was generally longer in the younger group of children than in the older one (Fig. 3). Both trends fit with the indications for chronic GORD symptoms in younger children and the short-term prescribing for licensed indications such as nausea, migraines, and following chemotherapy in older children. Additionally, increasing trends in therapy amount and duration were most pronounced in the domperidone cohorts.

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

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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.

FIGURE 4

FIGURE 4

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Safety Signals

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.

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DISCUSSION

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.

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Acknowledgments

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.

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Keywords:

cisapride; clinical practice guideline; domperidone; gastro-oesophageal reflux; paediatrics

© 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,