Domperidon biverkningsprofil

Fråga: Barn med avancerat kort tarmsyndrom efter tunntarmsresektion för NEC. Har också mycket dålig tarmmotilitet och vi har testat en del prokinetika utan positiv effekt. Domperidon ej testat och och jag skulle behöva ha hjälp att reda ut biverkningsprofilen, ssk inriktning på kardiologisk biverkan.

Svar: Sammanfattning
Domperidone is a dopamine receptor antagonist. The safety and efficacy of this drug has not been fully evaluated in pediatric patients. Domperidone has been associated with QT-prolongation and a possible increased risk of ventricular arrhythmias. Most data on the risk of arrhythmias have been derived from studies in adults, while data on children are limited. Risk factors for adverse ventricular arrhythmias include electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia), bradycardia and concurrent use of other QT-prolonging drugs.

There have been isolated case reports of extrapyramidal side effects in children following use of domperidone. Elevated prolactin levels were noted in one study.

SvarDomperidone is a dopamine receptor antagonist. The safety and efficacy of this drug has been investigated in a number of studies with limited participants in pediatric patients.

Randomized controlled trials in children

One study included 100 children aged 5-12 years with functional gastrointestinal disorder with predominant pain according to Rome III criteria (1). They were randomized to receive domperidone 10 mg x 3 or placebo for a period of 8 weeks. Dromperidone was found to be more effective than placebo, and none of the patients reported adverse effects.

In a second study, domperidone 0,5 mg/kg was compared with ondansetron and placebo in children aged 1-6 years with acute gastroenteritis (2). A total of 356 children were randomized to a single dose, and the rate of intravenous or nasogastric rehydration was compared between the groups. Domperidone was inferior to ondansetron but better than placebo. A total of 5 out of 119 patients receiving domperidone experienced adverse events; drowsiness, asthenia or irritability (n=2), diarrhea/abdominal pain (n=2), and headache (n=1).

In a third study, 105 children with chronic functional constipation according to Rome II criteria were randomized to treatment with polyethylene glycol (PEG) + domperidone (unknown dose) for 6 months, or PEG+placebo, and followed for 6 months (3). The addition of domperidone did not reduce symptoms. No adverse effects were noted.

A fourth randomized trial compared the efficacy of 8 weeks of therapy with domperidone or placebo in 17 children aged 5 months to 11 years with gastroesophageal reflux (4). Dromperidone resulted in some symptomatic improvement. Four of the eight patients who had received domperidone reported mild self-limiting diarrhea, compared with two of the nine patients who had received placebo. At week 4, the mean prolactin level had risen from 6,3 ng/ml to 41,7 ng/ml for domperidone compared with placebo where the level rose to 10,2 ng/ml. Increased prolactin levels have also been reported in adult clinical trials with an incidence of 0.01%-<0.1% (5). According to the pharmacological database Micromedex, this may increase the risk of neuroendocrinological side effects (i.e., galactorrhea, gynecomastia, amenorrhea).

In a fifth trial, 20 infants with gastroesophageal disease were randomized to treatment with domperidone or 0.8 mg/kg/day or cisapride for 4 weeks (6). Both efficacy and safety in terms of cardiac adverse effects were monitored. In this study, both treatments exhibited a decrease in regurgitation. No overall significant change in QTc-interval was noted for any of the drugs, but one infant given cisapride developed QTc-prolongation (>450 ms).

In a sixth study, 28 children aged 5-17 years with diabetic gastroparesis were randomized to treatment with domperidone (0.9 mg/kg daily) or cisapride (0.8 mg/kg daily) for 8 weeks (7). Domperidone was better than cisapride in terms of improving gastric emptying and dyspeptic symptoms. No adverse effects occurred.

In a seventh study, 80 children aged 1-16 years with gastroesophageal reflux were randomized to treatment with domperidone+antacids, domperidone+alginate, domperidone alone, or placebo, for at duration of 8 weeks (8). There was a reduction of reflux in the first group compared with placebo, but not in the other groups. No patient reported adverse effects.

Uncontrolled, open studies in children

In one study investigating the effect of domperidone on QTc-interval, 40 premature infants received treatment with 1 mg/kg/day for 14 days (9). Overall, no difference in QTc-interval before and after treatment was identified, but two infants exhibited QTc-prolongation and day 7.

In another study, the effect of dromperidone on the QTc-interval was investigated in 31 neonates or infants. ECGs were performed before starting domperidone and at a mean time of 2.5 days after starting the drug (10). The mean daily dosage of domperidone was 1.3 mg/kg/day. In this study, the mean effect on the QTc-interval was +14 ms, which was statistically significant.

In a third study, the effect of dromperidone on the QTc-interval was investigated in22 patients <2 years (median age 8.5 months) (11). Overall, no significant change in QTc was detected after 1 week of daily dosing of domperidone (0,3 mg/kg x 3). However, two patients developed QTc-prolongation >450 ms.

The above studies on QT-interval are difficult to interpret due to the lack of a positive and/or negative control group.

Use of domperidone is contraindicated in patients with underlying cardiac disease, patients with a history of QT interval prolongation or cardiac conduction interval prolongation, significant electrolyte disturbances, or concurrent use of other QT-prolonging drugs because of risks of malignant arrhythmias (12). Factors predisposing to QT-prolongation include electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia), bradycardia and concurrent use of other drugs associated with a risk of QT-prolongation. The summary of product characteristics further states that domperidone should be stopped if there are signs or symptoms of cardiac arrhythmia. According to a review article by Morris AD (13) case–control studies of adult patients identified an association between domperidone and ventricular arrhythmias and sudden cardiac death. When stratified by age, this risk of ventricular arrhythmias and sudden cardiac death was specifically observed in patients older than 60 years. These studies included only adult patients; therefore, according to Morris AD it is difficult to extrapolate the safety risks to the pediatric population.

Other studies in children

In a retrospective review of 230 children with gastroparesis, a total of 33 aged >1–21 years had been treated with domperidone 0.1-0.2 mg/kg x 4, with a maximum dose of 10 mg x 4, for a mean duration of 7.6 months (14). Of the 33 patients, two reported adverse effects; abdominal pain (one patient) and movement disorders (one patient).

Case reports

Extrapyramidal effects in children following treatment with domperidone have been described in three case reports. The first reported a dystonic-type reaction in a 3-year-old boy after receiving oral domperidone 4.2 mg 6 times daily (15). The second describes acute dystonia in a 13-year-old boy treated with domperidone 30 mg/day (16). The third describes extrapyramidal effects in a 4-month-old infant who was receiving domperidone 6 drops 3 times daily (17). Extrapyramidal effects from domperidone are stated to be rare (<0.01%) since it does not cross the blood–brain barrier under normal circumstances (5). It is stated to occur more frequently in neonates and infants compared with adults. Effects reverse spontaneously and completely upon discontinuation of treatment.