Current Pediatric Indications for Cisapride

For the past few months, the use of cisapride in children has been the subject of renewed controversy and discussions. Cisapride is a gastrointestinal prokinetic agent that acts as a postganglionic serotonin 5-HT4 receptor agonist. It belongs to a subgroup of substitute benzamides and does not possess dopamine receptor blocking or direct cholinergic receptor stimulating properties. The mechanism of action of cisapride may largely be explained by an enhancement of the physiological release of acetylcholine at the level of the myenteric plexus. In contrast with the majority of drugs, the pharmacokinetics, pharmacodynamics, and efficacy of cisapride in children has been very well studied. Indeed, most new drugs are rarely tested in a pediatric population, resulting in suboptimal therapeutic possibilities for this age group. Epidemiology, pathophysiology, natural course and outcome, and treatment differ between adults and children for many diseases. The latter means that recommendations for optimal approach and treatment, and cost–benefit ratio differ for many diseases between adults and children. This is also the case for gastroesophageal reflux disease (GERD). The recent controversy was sparked by the decision of the United States Food and Drug Administration (FDA) to restrict cisapride availability through a protocol-driven limited access program in the United States (1,2). Although this decision is regarded worldwide as a withdrawal of cisapride from the US market, it should be interpreted with caution. In the past, registration for cisapride in the United States was limited to nocturnal heartburn in adults. Thus, in the United States, prescription of cisapride in children has always been off label. Cisapride is the single prokinetic commercially available today that has been shown to coordinate both gastric and intestinal motility and is therefore a unique molecule. It has been shown recently in adults to be effective in the treatment of heartburn after a provocative meal (3). Proton pump inhibitors (PPIs) are more effective in nocturnal heartburn. Moreover, PPIs do not have a QT-prolonging effect, although they are certainly not free of side effects (4). Even in the absence of an approved pediatric indication, Janssen Pharmaceutica, the manufacturer, and the FDA recognized that there are pediatric patients who may need a prokinetic agent, and the decision was taken to make cisapride available to such patients under the limited-access program. It is noteworthy that among populations eligible for this program are neonates and children with severe gastrointestinal motility disorders. As a result of the FDA decision, the Committee for Proprietary Medicinal Products (CPMP), an expert group from the European Agency for the Evaluation of Medicinal Products (EMEA) held several meetings on cisapride but could not reach a consensus. The decision regarding the status of cisapride was referred back to the regulatory approval authorities of the respective governments of the member states. Not unexpectedly, the national decisions are heterogeneous and sometimes quite drastic. In Germany, it was decided that the drug should be completely withdrawn from the market for a period of 1 year, effective July 1, 2000. The United Kingdom (5) and Indonesia soon followed suit, and the approval license of the drug was suspended. In France, its use was very recently restricted to neonates (excluding premature infants) and infants with complicated GERD and GER resistant to usual treatment (“milk-thickening and other medical drugs”; however, the other medical drugs have not been specified). CISAPRIDE AND TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE Infant regurgitation or GERD improves in most cases spontaneously and disappears frequently at approximately 12 months of age. In 69 older children with a median age of 16 months referred to a tertiary center, 12 months of medical therapy (including cisapride) inhibited the reflux definitively in 80% of these children (6). Although the long-term prognosis of most infants with GERD is excellent, there is considerable morbidity during the first year, including failure to thrive, iron-deficiency anemia, and pulmonary complications. Undiagnosed, and thus untreated, GERD in infants can cause esophageal stricture (7). To avoid these complications with long-term (ad vitam) effects, GERD must be treated effectively, and medical treatment is its cornerstone. The major mechanism of GERD in infants and children is increased frequency of transient lower esophageal sphincter relaxations. Other factors, such as refusal to eat, attenuated swallowing, decreased salivation, dysfunctional peristalsis, delayed gastric emptying, and increased gastric postprandial distension, may contribute. Regarding the role of prokinetics, not much has changed since the consensus publications of the ad hoc European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) Working Groups on Gastroesophageal Reflux in 1993, 1997, 1998, and 1999 (8–12). The actual ESPGHAN recommendations are listed in Table 1.TABLE 1: Treatment recommendations for gastroesophageal reflux diseaseBecause there is a striking contradiction in the frequent use of cisapride in preterm infants and the fact that in most countries the drug label mentions that cisapride is contraindicated in this age group, we will discuss the published data in this patient group in more detail. Four placebo-controlled trials in premature newborns with feeding intolerance and GERD were published (13–16). In two of them, cisapride scored no better in gastric emptying times, food intolerance, and weight gain than placebo (13,14). One placebo-controlled study demonstrated that cisapride was more effective than placebo at improving milk food tolerance, gastric aspirates, and vomiting episodes (15). In a trial in preterm infants by McClure et al. (16), cisapride delayed gastric emptying time and tended to prolong whole gastrointestinal transit time in comparison to placebo. However, baseline data were not provided, and there was no standardized volume of food or a standardized evaluation in function of the volume fed. The placebo given was a laxative (hydroxy propyl-methyl cellulose) (16). It may well be that cisapride improves the coordination of motility but does not shorten transit time. The editor of the journal in which this paper was published evaluated the evidence from this trial to emphasize at the end of the paper (16) “The Medicines Control Agency (17) has stated that cisapride is contraindicated in neonates before 36 weeks of gestation until they are 3 months of age. This is in addition to the already existing recommendation not to use it in children under the age of 12 years, although the drug is widely used in this age group.” This is contradicted by the report of Ward et al. (18) and by the NASPGN and ESPGHAN consensus statements (11,12), demonstrating and concluding that cisapride has a certain efficacy in premature newborns, neonates, and children and that the drug is safe in these age groups. In eight uncontrolled studies, cisapride improved one or more variables including gastric emptying, feeding tolerance, mean gastric residue, mean food volume, reflux index, and number and duration of reflux episodes (19–26). Comparative trials in premature infants with GERD and feeding intolerance were not published. The authors of this consensus statement believe that there is substantial evidence demonstrating the efficacy of cisapride in premature newborns with feeding intolerance and GERD. Cisapride improves and relieves wheezing in 65% to 85% of children, while reducing the need for steroids, bronchodilators, or emergency medication (27). In three controlled studies in young children with bronchopulmonary disease, there was generally a positive effect of cisapride treatment (28–30). Controlled studies in children with cystic fibrosis are inconclusive, because they have concentrated on weight gain instead of reflux parameters (unpublished data, Yvan Vandenplas, August 2000). Despite the presence of some negative studies, a critical evaluation of published reports on the efficacy of different prokinetics (cisapride, domperidone, and metoclopramide) concluded that cisapride is the preferred agent that is available commercially today (8–11). Cisapride effectively resolves symptoms and heals mild-to-moderate esophagitis, with an efficacy similar to that of H2-receptor antagonists (31). Most clinical trials on the efficacy of cisapride have demonstrated that at least one of the endpoints changes favorably as a result of the intervention (9–11). The study by Scott et al. (32) is often referred to as evidence that cisapride is not effective in treating GERD-related symptoms. Nevertheless, the findings showed that cisapride brought about a significant improvement of regurgitation and vomiting scores and a significant decrease in the mean duration of upright and supine reflux episodes. Similarly, Cohen et al. (33) showed a significant improvement of some selected pH parameters but no improvement in the global symptoms score. In the published studies on cisapride in children with GERD, the outcome parameters that change significantly differ from study to study, and almost all studies have at least one outcome parameter that does not change (Table 2). A personal unpublished analysis (Y. Vandenplas, July 1999) of the published efficacy for cisapride in pediatric GERD shows an efficacy of 43% for placebo and 58% for cisapride. The difference is statistically significant, showing that cisapride is indeed effective in the treatment of pediatric GERD. However, it also shows that there certainly is a need for more effective prokinetic drugs and that the placebo effect is also significant. A major drawback of most of the published trials is that randomization was performed in first-line intention early, before parental reassurance and dietary manipulation and therefore contravened published therapeutic recommendations (11). This is confirmed by the recent Cochrane review on cisapride in children that analyzed data from seven trials including 236 participants and compared cisapride to placebo in its effect on symptom presence and improvement. It concludes that there is a statistical difference for the parameter symptoms present-absent, but there is no statistically significant difference for symptom change between placebo and cisapride (34). This does not necessarily mean that cisapride is ineffective. It is more likely that this means that the placebo effect in reflux treatment is so large that randomization should be performed only after failure of placebo. The Cochrane review also concludes that cisapride compared with placebo significantly reduces the number and duration of acid reflux episodes, because there was a significant decrease in reflux index, which is the percentage of time that esophageal pH is below 4.0 (34). Another meta-analysis of six trials showed no benefit in the use of cisapride or placebo for reduction of vomiting (35).TABLE 2: Effects of cisapride on GERD in infantsTABLE 2: ContinuedAs a result of these considerations, this Working Group stresses that we recommend cisapride as the drug of choice in chronic and persistent GERD in infants and children who are resistant to reassurance and dietary treatment. For uncomplicated infantile regurgitation, parental reassurance and dietary manipulation are recommended. In reflux esophagitis, the use of H2 receptor antagonists or PPIs, possibly in combination with prokinetics, is advised (Table 1). SAFETY OF CISAPRIDE The side effects of cisapride should be scrutinized in the proper perspective. Reflux disease (in adults) quite seriously affects quality of life (36,37), and medical treatment to achieve symptomatic relief is not discussed in adults. It is not the purpose of this paper to discuss the medical treatment of adult reflux disease. However, in pediatric experience, many handicapped children and premature infants progress perfectly well with cisapride, with or without acid-suppressing drugs, but often relapse after withdrawal of the prokinetic. During the past couple of years, no new risk factors have been identified (Table 3). There is little doubt that cisapride has a QT-prolonging effect (11,12,38–42). Cisapride possesses class III antiarrhythmic properties and prolongs the action potential duration, delaying cardiac repolarization (43), although some studies do not report an increase in QTc (44,45). In a recent multicenter US study, cisapride did not show any significant effect on cardiac electrical function in children without underlying cardiac disease, drug interactions, or electrolyte imbalance (46). In the study by Khoshoo et al. (38), only 2% of infants showed a QT interval above 450 msec. The effect of cisapride on relevant cardiac events such as arrhythmia is dose-and risk factor–related (47). Tahiri (47) reported a prolonged QTc in 3% of control subjects, in 6% of infants with a dose of less than 0.8 mg/kg per day, in 7% with a dose of 0.8 to 1.0 mg/kg per day, and in 15% with a dose of more than 1 mg/kg per day. Arrhythmia and sudden death have been reported at 10-fold overdose and—as documented by Lupoglazoff et al. (48) —a reduction to a normal dose of 0.8 mg/kg per day allowed further treatment without any cardiac effect in a child who received an initially higher dose and had QT prolongation. Tutar et al. (49) confirmed recently that cisapride causes prolongation of ventricular repolarization without causing increased heterogenicity of repolarization (QT dispersion). All patients in the study remained asymptomatic, without dysrhythmia.TABLE 3: Contraindications and precautions for cisapride use in infants and childrenMost symptomatic cardiac side effects were found in combination with one of the known risk factors, which have been published before (Tables 2, 3) (11,12). The increased plasma levels with consumption of grapefruit juice were mentioned before (11,50). A critical analysis of safety data shows that there were two instances of serious ventricular arrhythmia, QT prolongation, or sudden death reported for every million patients treated for a month, of which more than 85% could be related to a known risk factor. We are not aware of any new published or unpublished safety issues. Recent pharmacologic studies could not identify yet unknown drugs that increase cisapride plasma levels (11,51). Although unpublished manuscripts that have been reviewed by the coauthors of this consensus statement, confirm the QT-prolonging effect of cisapride, this effect does not seem to relate to any clinical manifestation or cardiac rhythm disorder (38–42). Among 36,743 cisapride users in Canada and the United Kingdom, cisapride did not appear to be associated with serious rhythm disorders (52). The authors of this large epidemiologic study concluded that “within the limits of precision resulting from a low frequency of outcome in these populations, cisapride was not associated with an increased risk of serious cardiac rhythm disorders when compared with no drug or comparative drugs”(52). The investigators in a retrospective analysis in premature newborns came to the same conclusions (18). According to recent data, gene mutation may be the fundamental culprit (53). Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers (52). According to yet unpublished data in premature infants, the 1999 recommendation of the Working Group to begin cisapride doses in premature newborns at 0.4 mg/kg per day seems justified (41). The recommended dose in term infants and older children is 0.8 mg/kg per day. A calculation on a per kilogram basis in a one-compartment model provides satisfactory results (54). WHAT IF CISAPRIDE IS NO LONGER AVAILABLE? The available data for other prokinetics such as domperidone and metoclopramide do not support their use in GERD in children (9). Cisapride is the only prokinetic that has been related to an enhanced tolerance of oral feeding in premature newborns. Published evidence has shown that domperidone and metoclopramide have rather weak benefit (9), and no new data have become available. Studies comparing cisapride to metoclopramide have shown a statistically significant better outcome for cisapride, including endoscopic assessment, duration of reflux episodes, esophageal clearance, and symptomatic response (55–57). The ability of oral domperidone to increase the pressure of the lower esophageal sphincter or to promote healing of reflux esophagitis has not been demonstrated in placebo-controlled trials (9). The risk–benefit ratio is much better for cisapride than for the other prokinetics. Side-effects such as extrapyramidal symptoms occur quite frequently with other prokinetics, especially metoclopramide (in more than 20% of patients [9]). These side effects are also reported with domperidone, although at a lesser frequency. Intravenous domperidone has even been reported to cause QT prolongation and ventricular fibrillation (58). The association between prone sleeping and sudden infant death syndrome (SIDS) resulted in the change of the prone 30° head-elevated position from a first-line recommendation in the 1993 consensus to fourth-line treatment in the 1997–1998 consensus (8–10). The prone and left lateral position have recently been shown to reduce GER, this time in preterm infants (59). Most studies designed to evaluate the efficacy of positional treatment involve subjects who have only simple, uncomplicated regurgitation and reflux (9). The effect of positional treatment in infants and children with chronic and persistent GERD was not studied. With the introduction of supine sleeping practices in infants, the mortality rate due to SIDS has declined sharply worldwide from 3/1000 to 1/1000 or below. Sleeping on one side a between reduction of GER episodes and of infant mortality by The reduction in infant mortality rate is more than a than the mortality rate to the use of cisapride used without safety therapy is recommended in severe esophagitis, but does not a major mechanism underlying GERD in children. of the side effects of H2 receptor antagonists and PPIs is the of this However, a shows that the of side effects of these drugs is also quite with rhythm effects of blocking of gastric acid and effect on The long-term use of has been shown to be safe in adults to or more and in children for The show a mortality and a failure rate of several percentage In with we can only that the use of with their documented complications and failure will not especially in life or in the course of GERD GERD in infants and children is a motility disorder with some in and clinical course from GERD in prokinetic should be the drugs of choice in certain Cisapride may also result in improvement of feeding tolerance in premature newborns. Cisapride is the prokinetic with the ratio but there is a need for a prokinetic agent with better precautions for use in children to be treated are limited to of of medication such as and and on a basis (11). Cisapride has a better safety than a or the other prokinetic available. Gastroesophageal reflux in infants must be treated effectively because of its association with complications and long-term effects Indeed, most infants with GERD have an uncomplicated and in to 80% of children referred to a tertiary in the improved with medical therapy 12 months, with no need for further treatment (6). We in with Khoshoo et al. that should before the use of an effective drug because of the need for and time for Moreover, an to as a safety can be an effective to the of contraindicated drug and control could further safety the authors of this consensus paper recommend worldwide registration of cisapride for the treatment of severe and persistent GERD and other gastrointestinal motility such as and chronic intestinal will result in less use and thus will increase use of cisapride is for of its and safety must be to the and of other available We that treatment cisapride is recommended for treatment of pediatric ESPGHAN consensus and that has a in pediatric when used in in which a prokinetic drug is NASPGN Although we that more effective drugs will become available in the evidence that cisapride is the prokinetic drug available in the treatment of gastrointestinal disorders such as GERD in premature newborns, infants, and older children. Recent data on the cardiac side effects of cisapride are very The authors of this paper that no of any from any or was used in the of the further that the in this paper their on the as of 2000. ESPGHAN OF CISAPRIDE for and Gastroenterology, and North of of Indonesia Canada of of Indonesia The The of of and United Kingdom for United Kingdom of of of and for and Gastroenterology, and North of The of The authors for critical review and

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