An Updated Medical Position Statement of the North American Society for Pediatric Gastroenterology and Nutrition

On January 24, 2000, Janssen Pharmaceutica issued an announcement to physicians and patients that the labeling for cisapride was being changed again to reflect additional information regarding the association between use of the drug and adverse cardiac events in adults. The list of cardiac conditions and agents that potentially could increase the risk of cisapride-related adverse effects was expanded and specific recommendations were made regarding the use of ECG and electrolyte monitoring. Similar to the response to the first letter issued on June 26, 1998, the letter caused confusion as to whether cisapride should be used and if so, what precautions should be taken prior to or after administering the medication. On March 23, 2000 it was announced that Janssen Pharmaceutica would stop marketing cisapride as of July 14, 2000. After that date, the drug will be available through an investigational limited access program (1). Patients who potentially are eligible for the program include those with refractory gastroesophageal reflux (associated with failure to thrive, asthma, bradycardia, apnea, or other serious conditions), pseudo-obstruction, and neonates with feeding intolerance (1). The Committee that had been convened by the North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) in August, 1998 to address these and other issues raised by the initial label changes in June, 1998, met again to reassess the situation. The Committee addressed the question as to whether the newer information should cause the previous consensus statement regarding the efficacy and safety of cisapride to be altered. As previously noted, members of the Committee included six pediatric gastroenterologists, two pediatric cardiologists, a pediatric pharmacologist, and a pediatric pharmacoepidemiologist (2). The Committee worked independently but received cooperation from the Janssen USA staff. The intent was to review any new information regarding cisapride that had become available subsequent to the Committee's previous review that was published in May 1999 (2). The Committee reviewed all U.S. pediatric MedWatch reports regarding cisapride submitted since the previous review (i.e., subsequent to June, 1998). In addition, it reviewed the literature on the efficacy and safety of cisapride in children that was published subsequent to the previous review (2). Based on its review of the updated data, the Cisapride Committee developed the following report. Consensus was reached on all points. The Executive Council of NASPGN officially approved the report in June 2000. EFFICACY As in the previous report by the Committee, consideration was given to those investigations that had clear and objective outcome criteria and were prospective, randomized, controlled, and published in peer-reviewed journals (2). Based on the previously reviewed investigations and the one newer study, the Committee confirms its earlier view that cisapride has a place in pediatric therapeutics when used in conditions where a prokinetic drug is indicated (2,3). This conclusion is based on studies in children treated for gastroesophageal reflux. Data regarding its use in other conditions remains limited. An additional study supports its potential use in constipation (2,4). The role of cisapride for feeding intolerance in preterm infants remains unclear based upon an additional trial (2,5). SAFETY Data from studies in children suggest that cisapride can, in some circumstances, increase the QTc interval although not necessarily above normal limits (2). The most recent data again suggest that prolongation is more likely to occur when the dose exceeds 0.8 mg per kg per day (2,6). In a retrospective study of more than 11,000 preterm infants, no adverse cardiac events were observed (7). However, it is recognized that the retrospective nature of the data may limit its reliability. As noted in the previous Committee statement, the clinical significance of the increased QTc interval observed in these patients continues to be unclear (2). A review of the U.S. pediatric MedWatch reports published since June, 1998 (provided by Janssen Pharmaceutica, February 4, 2000) suggested that none of the 21 adverse cardiac events or 4 deaths could be attributed to cisapride alone. The adverse effects likely were due to other causes (e.g., sepsis), underlying heart disease, the concurrent use of contraindicated drugs, or a ten-fold overdose. Thirteen of these reports were published in a single paper (8). RECOMMENDATIONS Based upon this current updated review, the Committee continues to endorse its previously published statement (2). However, based upon more recent data, the Committee recommends that the list of contraindicated substances be expanded to include prochlorperazine, promethazine, and grapefruit juice. These agents were identified in the most recent letter from Janssen Pharmaceutica (January 24, 2000). The following statements highlight recommendations from the previous consensus statement. 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. With avoidance of contraindicated drugs, patient counseling, appropriate patient selection and monitoring, the risk from cisapride can be reduced. 3. It is recommended that the dose be limited to 0.8 mg per kg per day divided into three to four doses in a 24-hour period. The dose should not exceed the recommended adult dosage of 20 mg four times a day. 4. 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. 5. Measurements of serum potassium, magnesium, calcium, liver synthetic function, or renal function tests should be performed when clinically appropriate. 6. Temporary discontinuation should be considered in the presence of acute illnesses such as vomiting and/or diarrhea that might result in electrolyte abnormalities. 7. This report does not recommend that every patient on cisapride should receive an electrocardiogram (ECG). In patients with no identified risk factors there is as yet no evidence that an ECG 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 ECG. RESEARCH The Committee continues to urge the carrying out of further studies. As noted previously, these investigations must: 1. be prospective, randomized, controlled, double-blind trials; 3. have clear, objective, and clinically relevant outcome criteria; 5. use cisapride for conditions for which there is presently inadequate treatment; 7. enroll adequate numbers of patients; 9. stratify patients as to severity of disease for which they are being treated; 11. be of adequate duration to draw clinically relevant conclusions.