On June 26, 1998, Janssen Pharmaceutica issued an announcement to physicians and patients that the labeling for cisapride was being changed to reflect increased warnings regarding the association between use of the drugs and adverse cardiac events. Additionally, the list of drugs that potentially could increase the risk of a cisapride-related adverse effect was expanded. The announcement had a major effect on practitioners because of the frequency with which cisapride is used throughout the world. Although well intended, the letter caused confusion as to whether cisapride should be used and if so, what precautions should be taken before or after administering the medication.
In response to the situation, the North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) convened a Committee in August of 1998 to address these and other issues engendered by the new warnings regarding cisapride use (Dr. Allen Mitchell joined the Committee in November of 1998). The purview of the Committee was to develop a medical position statement on the appropriate use of cisapride in infants and children. Members of the Committee included six pediatric gastroenterologists, two pediatric cardiologists, a pediatric pharmacologist, and a pediatric pharmacoepidemiologist. The Committee worked independently but received cooperation from the Janssen U.S.A. staff.
The Cisapride Committee had multiple conference calls. In addition, it performed several literature reviews on the efficacy and safety of cisapride in children. It also reviewed a 150-page report on the efficacy of cisapride; a 150-page report on safety issues, serious arrhythmias, and sudden deaths; and a report of 126 cases of overdoses (prepared by Janssen Pharmaceutica). In addition, the Cisapride Committee held a 2-day meeting in Chicago in September.
Based on its review of the data, the Cisapride Committee developed the following report. The Nominal Group Technique was used to ascertain whether consensus was achieved among the Committee members (1). Consensus was reached on all points. The report was approved by the Executive Council of NASPGN on January 25, 1999. The Committee members addressed the following questions:
1. Does cisapride have a place in pediatric therapy and if so, what is it?
2. Does cisapride cause serious dose-related adverse effects?
3. Can the risk profile for the adverse effects be minimized?
4. If so, how can this be accomplished?
DOES CISAPRIDE HAVE A PLACE IN PEDIATRIC THERAPY AND IF SO, WHAT IS IT?
The Committee recognizes that there are data and practice-based evidence that suggest a role for cisapride as a prokinetic agent in the following conditions or situations: esophagitis, gastroesophageal reflux with heartburn, gastroparesis, dyspepsia, gastroesophageal reflux with failure to thrive, feeding difficulties, gastroesophageal reflux and respiratory disease (e.g., recurrent pneumonia, apnea, asthma, hoarseness, stridor), constipation, pseudo-obstruction, postoperative ileus, distal ileal obstruction syndrome, and as a bowel preparation for colonoscopy.
To assess the data objectively, the Committee reviewed all available published and unpublished reports regarding the use of cisapride in pediatric practice. It was the opinion of the Committee that consideration only should be given to those investigations that had clear and objective outcome criteria and were prospective, randomized, controlled, and published in peer-reviewed journals. Based on these investigations, the Committee determined that cisapride has a place in pediatric therapeutics when used in conditions in which a prokinetic drug is indicated. This evidence comes from controlled clinical studies in children treated for gastroesophageal reflux (2-8). There are limited data regarding its use in other conditions. Three studies support its potential use in constipation, although at doses higher than recommended (see subsequent discussion) (9-11).
A single report suggests it is effective for postoperative ileus in neonates (12). One report suggests that it decreases the incidence of large gastric residual volumes in preterm infants, although the time to achieve full enteral feedings was not different between the cisapride and the control group (13). Another report suggests it is effective for dyspepsia (14).
As a corollary to the question as to whether cisapride is effective, the Committee also examined the issue of whether other drugs are effective for similar conditions for which cisapride has been used. The Committee reviewed all available published reports regarding the use of metoclopramide, bethanechol, and domperidone for gastroenterologic conditions in pediatric practice. Once again, the Committee gave consideration only to those investigations that had clear and objective outcome criteria and were prospective, randomized, controlled, and published in peer-reviewed journals.
It was the opinion of the Committee that the preponderance of data do not support the use of metoclopramide for gastroesophageal reflux in pediatric patients (15-17). One study supports the effectiveness of bethanechol in improving vomiting in infants and children with gastroesophageal reflux (18). The Committee determined that the data were insufficient to assess the usefulness of domperidone (19).
The Committee noted that many of the studies cited above were less than optimal in terms of patient selection (i.e., heterogenous population), duration of study (i.e., too short), lack of clear or objective outcome variables, and attention to drug kinetics (e.g., measurements taken too soon after the drug was administered).
DOES CISAPRIDE CAUSE SERIOUS DOSE-RELATED ADVERSE EFFECTS?
The most serious adverse effects of cisapride are related to its ability to prolong cardiac repolarization. Cisapride can block the rapid component of the delayed rectifying K+ current in myocardium by affecting the IKr channel (20). These changes are related to the cisapride concentration and can result in prolongation of the QTc interval (21). In addition, there are a number of substances capable of increasing cisapride plasma concentrations by interfering with its metabolism by cytochrome P450. Hence, it is possible that certain drug, food, and disease interactions with cisapride may increase the risk of serious ventricular arrhythmias resulting from cisapride (21).
The CYP3A subfamily encompasses up to 40% of the total cytochrome P450 content in the adult liver and small intestine (22). CYP3A7 is the fetal form of CYP3A and accounts for 30% to 50% of total hepatic cytochrome P450. After birth, activity changes from CYP3A7 to CYP3A4, although CYP3A7 can be expressed to some extent in the adult liver.
Both clinical and in vitro data demonstrate that CYP3A4 is responsible for catalyzing the biotransformation of cisapride to its major metabolite, norcisapride. Norcisapride possesses approximately 15% of the prokinetic activity of cisapride and is extensively excreted by renal mechanisms, but has no apparent effect on myocardial conduction (23).
Importantly, CYP3A4 demonstrates significant intersubject variability in both hepatic enzyme content and constitutive activity (up to 10-fold and 20-fold, respectively) (24). CYP3A4 activity in the liver of infants at 1 month of age is approximately 30% of adult activity (25). CYP3A4 activity in infants appears to approach adult values by approximately 6 to 12 months of age (24). It even may exceed adult values between 1 to 4 years of age (24). Thus, it would be anticipated that the developmental pattern of cisapride biotransformation (and plasma clearance) would reflect CYP3A4 ontogeny. Yet, in a study of 100 preterm and term neonates who were given cisapride (0.8 to 1.2 mg/kg/d), steady state plasma concentrations of the drug were similar to those observed in adults taking therapeutic doses of the drug (file data, Janssen Pharmaceutical Research Foundation, 1998). However, the pharmacokinetics of cisapride during the first year of life (e.g., bioavailability and protein-binding characteristics) need to be elucidated fully.
Administration of cisapride with any drug that inhibits CYP3A4, such as the macrolide antibiotics erythromycin and clarithromycin (but not azithromycin) and the azole antifungals (ketoconazole, fluconazole, miconazole, and itraconazole), has the capacity to inhibit cisapride biotransformation and thus, increase cisapride plasma concentrations. The same is theoretically true for conditions associated with decreased CYP3A4 activity (e.g., immaturity or hepatic compromise).
Based on studies of hereditary prolonged QT syndrome, there is a weak relationship between the QTc interval and the risk of death if the interval is mildly prolonged. Between 440 to 500 milliseconds, the risk is unknown. At greater than 500 milliseconds, there is a higher risk and at greater than 600 milliseconds there is a very high risk of death (26). A value of 440 milliseconds marks the limit of the top 2.5% range within the population (27). Other factors are used to increase the predictive value of the risk of a prolonged QTc interval (e.g., family history, T-wave profiles, and history of syncope) (26). Based on molecular studies, prolonged QTc syndrome is a heterogenous disease (28).
The risk associated with a drug-induced prolonged QTc interval is unknown. It is not possible to predict how an individual will respond. It also is possible that a substantial change in the QTc interval before and during drug treatment could be significant, although the absolute number is less than 440 milliseconds.
Data from studies in children suggest that cisapride can increase the QTc interval (29,30). As noted previously, the clinical significance of the increased QTc interval observed in these patients is unclear. In contrast, another study reported no increase in QTc interval as a consequence of cisapride administration (31). Differences between these studies may be related to the higher doses of cisapride used in the study by Khongphattbanayothin et al. (29) and Hill et al. (30). The only patients who demonstrated an arrhythmia were in the report by Hill et al. (30). It is of note that these two patients also were receiving a macrolide antibiotic (see previous and subsequent discussion) (30).
It is recognized that conclusions based solely on adverse effects reports via programs such as MedWatch have limitations. For example, the adverse effects may not be truly attributable to the drug or the number of reports may decrease as the side effects become better known. With these caveats in mind, the Committee reviewed 24 MedWatch reports from the United States (November 1994 through June 1998) regarding potential cisapride-related complications in pediatric patients. There were 14 cardiac arrhythmias and 10 deaths (personal communication, Janssen Pharmaceutica, September 16, 1998). Of the arrhythmias, perhaps two of these could be attributed to cisapride alone. The remainder either did not appear related to cisapride use or likely were due to overdoses or interactions with contraindicated drugs (see below). None of the deaths could be attributed clearly to cisapride use alone.
The committee also reviewed 126 cases of overdoses reported in pediatric patients from both within and outside the United States between 1995 and 1998 (personal communication, Johnson and Johnson, November 11, 1998). In seventeen cases the overdose was approximately 5-fold and in 20 cases it was greater than 10-fold. None of the patients died or had a life-threatening event. In the 24 patients in whom an electrocardiogram was done, seven demonstrated either a prolonged QTc interval or an arrhythmia.
Since the introduction of cisapride in Europe and the United States, it is estimated that up to 140,000,000 courses of therapy have been prescribed (personal communication, Janssen Pharmaceutica, September 16, 1998). The incidence of the congenital long QTc interval associated with genetic defects of IKr channel function is approximately 1:10,000 (32,33). If there were an additive effect between cisapride and the congenital long QTc syndrome, one would expect approximately 14,000 cases of serious ventricular arrhythmias among cisapride-treated subjects. To date, this predicted incidence is not evident from published clinical trials, case reports, or spontaneous adverse event report databases. These issues notwithstanding, it is recommended that the list of contraindications outlined in the current package insert be expanded to include (1) pre-existing cardiac conditions (congenital or acquired) that might predispose the patient to ventricular arrhythmias; (2) intraventricular conduction disturbances; and (3) instances of reduced hepatic function.
There are many drugs that have been shown in vitro or in vivo to have the ability to inhibit CYP3A4 (34). Several of these agents (e.g., erythromycin, clarithromycin, troleandomycin, nefazodone, fluconazole, itraconazole, ketoconazole, indinavir, and ritonavir) have been identified under the "Warnings" statement in the prescribing information for cisapride as having the potential for increasing cisapride plasma concentrations (Janssen Pharmaceutica, June 1998).
Although not contraindicated by the product labeling, theoretically other inhibitors of CYP3A4 could have the potential of producing a similar reaction, although it may not have yet been documented. Because to date many interactions have only been tested in vitro, current information does not enable accurate prediction of the in vivo pharmacokinetic or pharmacodynamic consequences of such theoretical cisapride drug interactions. The extent of CYP3A4 inhibition in vivo and the constitutive activity of CYP3A4 in a given patient cannot be reliably assessed using available clinical methods. Accordingly, when it becomes necessary to administer cisapride with another drug capable of inhibiting CYP3A4 activity, the clinician must be cognizant of the possibility that cisapride plasma concentrations could increase. Such substances that have been tested in vitro include amiodarone, mibefradil, quinine, zafirlukast, fluoxetine, fluvoxamine, saquinavir, diltiazem, methadone, nelfinavir, sertraline, metronidazole, and norfloxacin. Preliminary in vivo data suggest that interactions between cisapride and cimetidine and omeprazole may not be clinically significant (personal communication, Janssen Pharmaceutica, February 8, 1999).
Other drugs that are contraindicated by the product labeling for cisapride are those that prolong the QTc interval via a pharmacodynamic effect (i.e., intrinsic activity on myocardial conduction). These include certain antiarrhythmics, including those of Class IA (e.g., quinidine, procainamide) and Class III (e.g., sotalol), tricyclic antidepressants (e.g., amitriptyline), certain tetracyclic antidepressants (e.g., maprotiline), certain antipsychotic medications (e.g., phenothiazines, sertindole), astemizole, bepridil, sparfloxacin, azole antifungals, erythromycin, clarithromycin, and terodiline.
These lists are not inclusive of all pharmacologic agents that may have the potential to prolong the QTc interval. Thus, the decision to prescribe cisapride must include a complete evaluation of the drug interaction potential based on the complete medication profile in a given patient.
CAN THE RISK PROFILE FOR THE ADVERSE EFFECTS BE MINIMIZED, AND IF SO, HOW?
The Committee believes that with avoidance of contraindicated drugs, patient counseling, and appropriate patient selection and monitoring, the risk for adverse effects from cisapride can be reduced. This can be accomplished with the following guidelines:
1. The most important step that can be taken to minimize the risk of cisapride-associated arrhythmias is to avoid the concomitant administration of contraindicated drugs, particularly the macrolide antibiotics (e.g., erythromycin, clarithromycin) and the azole antifungals, (e.g., fluconazole, itraconazole, miconazole, and ketoconazole).
2. It is recommended that the dose be limited to 0.8 mg/kg/d divided into three to four doses in a 24-hour period. The dose should not exceed the recommended adult dosage of 20 mg 4 times a day. This recommendation is based on studies suggesting an increased risk beyond this dose (29-31).
3. Efforts should be extended in the education of physicians and pharmacists and especially patients and family regarding the appropriate use and contraindications of cisapride. This should include special vigilance about avoiding contraindicated drugs not only at the initiation of therapy but throughout the treatment course.
4. Abnormalities in serum potassium, magnesium, and calcium can increase the risk of an arrhythmia and presumably, more so in the presence of cisapride. Similarly, abnormalities in hepatic synthetic function or renal function can affect cisapride plasma concentrations. Consequently, measurements of serum potassium, magnesium, calcium, liver synthetic function, or renal function tests should be performed when clinically appropriate.
5. Temporary discontinuation should be considered in the presence of acute illnesses such as vomiting or diarrhea that might result in electrolyte abnormalities.
6. This report does not recommend that every patient on cisapride should receive an electrocardiogram. In patients with no identified risk factors there is as yet no evidence that an electrocardiogram performed in patients before or during therapy with cisapride will lower the risk of dangerous arrhythmias. However, it is conceivable that the identification of significant QTc interval prolongation in a patient taking cisapride may have some relevance and may lead a clinician to discontinue the drug. Given the absence of data, the clinician must rely on his or her judgment about the need for an electrocardiogram.
ADDITIONAL ISSUES: RESEARCH
Having reviewed the available data on the efficacy of cisapride and the risk of an adverse cardiac event related to its use, further studies are vitally important. More data are needed on the efficacy of cisapride for the treatment of conditions potentially amenable to therapy with a prokinetic agent. These investigations must (1) be prospective, randomized, controlled, double-blind trials; (2) have clear, objective, and clinically relevant outcome criteria; (3) use cisapride for conditions for which there is presently inadequate treatment; (4) enroll adequate numbers of patients; (5) stratify patients as to severity of disease for which they are being treated; and (6) be of adequate duration to draw clinically relevant conclusions.
More data are needed on the cardiac risks associated with the use of cisapride. Consideration should be given to collecting adverse event data (including electrocardiogram results) in a Registry of Users format. Such a study would be adequately powered to identify patients who are at risk for drug-induced prolonged QTc interval.
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A Medical Position Statement of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition*