Annotations The risks and benefits of cisapride in premature neonates, infants, and children

The Medicines Control Agency and the Committee on Safety of Medicines (CSM) recently stated that cisapride is contraindicated in infants born before 36 weeks’ gestation for three months after birth, and that there is insuYcient data to support the use of cisapride in children up to 12 years of age. These statements need qualification. Many believe cisapride to be a safe and useful agent in a variety of intestinal motility disorders especially in premature infants. Furthermore, data seem to support the use of cisapride throughout childhood. The only support the CSM referenced for their first statement was a study showing clinically asymptomatic electrocardiographic increases in the QTc interval to > 450 in seven of 49 neonates, six of whom were born < 33 weeks’ gestation. This gives reason for caution but not contraindication. Concern relates to QTc > 450, which may predispose to arrhythmias and are a risk factor for sudden infant death (SID). Increases in QTc and arrhythmias are more noticeable with high doses of cisapride and when cisapride inactivation is impaired by drugs acting via the cytochrome P450 3A4 system, such as macrolide antibiotics (erythromycin, clarithromycin) and azole antifungals (fluconazole, itraconazole, ketoconazole or miconazole). But with care is cisapride dangerous? Hill and colleagues found the mean (SD) QTc in 35 children on cisapride to be 428 (35) with QTc > 450 in 11 children. However, only two had torsades de pointes and both were taking a macrolide antibiotic. LupoglazoV and colleagues reported seven cases of asymptomatic QTc prolongation with a mean of 486 (450–540) but dosage was high at 1–1.7 mg/kg/day; Levine et al found no change in QTc in children taking 0.8 mg/kg/day. However, we have found that in 17 surgical neonates mean (SD) QTc rose from 373 (31) to 389 (19) (p = 0.03) while taking cisapride 0.6 mg/kg/day orally or 2 mg/kg/day rectally (bioavailabilty = 40%,) but in no patient did the QTc exceed 450 after starting cisapride. In one study of 20 ventilated premature neonates the mean gastric residue after feeds decreased on cisapride and the mean feeding volume increased. Cisapride also reduced the time to the first sustained feed and increased the mean daily net enteral balance in neonates with a prolonged ileus after abdominal surgery. A working group of the European Society of Paediatric Gastroenterology and Nutrition recommended that prokinetic agents such as cisapride have a place in the treatment of gastro-oesophageal reflux (GOR) especially if positional and dietary recommendations fail. Cisapride increases lower oesophageal sphincter pressure and the amplitude and duration of peristaltic waves. Cisapride reduces oesophageal acid exposure, the duration of reflux episodes, the duration of the longest episode, and the number of long lasting episodes. Many of these studies are randomised, double blind, placebo controlled trials. Symptom improvement with cisapride treatment is greater than after postural and dietary treatment alone, and in one study nocturnal cough disappeared completely in 12 of 13 children taking cisapride. In a placebo controlled trial in 137 infants less than 1 year of age with severe GOR, cisapride significantly reduced the frequency and severity of regurgitation. In a double blind, placebo controlled trial in 20 children (aged 75 days to 47 months) with GOR and peptic oesophagitis there was significant histological improvement only in those treated with cisapride. Cisapride is also more eVective than metoclopramide and is useful in children with cystic fibrosis and GOR. 23 In 10 children with encopresis unresponsive to vigorous treatment, symptoms ceased in eight and improved in the other two. In another trial cisapride increased stool frequency from a mean (SD) of 1.4 (0.5) to 6.5 (4.2) stools/week (p < 0.05) and accidents decreased from 2.9 (2.7) to 0.5 (1.2) (p < 0.05) with encopresis disappearing in 65% of cases and improving in 26%. Two further double blind, placebo controlled trials showed cisapride to improve bowel habits in children with chronic idiopathic constipation. 27 Stool frequency was increased from 1.2 (0.6) to 5.1 (1.9) stools/week (p < 0.05), and transit time was decreased from 91 (9) hours to 57 (20) hours (p < 0.05). Cisparide is useful in children with chronic intestinal pseudo-obstruction with those having migrating motor complexes responding best, especially if there is postprandial duodenal hypomotility. A prospective, randomised, controlled study in children after uncomplicated heart surgery found cisapride reduced intestinal transit time. We believe that the case against cisapride as a safe and extremely useful agent in premature neonates and throughout childhood has not been satisfactorily expounded by the CSM. Our practice is to prescribe oral cisapride at 0.6–0.8 mg/kg/day, measuring QTc before and after starting treatment. We accept that cisapride should not be used when the QTc is > 450 or with contraindicated drugs, but we are keen that the CSM should revisit the question of prematurity.