Special Comments - Neonatal Intensive Care Drug Manual

Special Comments
Bioavailability of oral dispersion is approximately 75% of intact tablets.
Evidence summary
Treatment of gastroesophageal reflux disease (GORD)
NICE Guidelines1
1. Do not offer acid-suppressing drugs, such as proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs), to treat overt regurgitation in infants and children occurring as an isolated symptom.
2. Consider a 4-week trial of a PPI or H2RA for those who are unable to tell you about their symptoms (for example, infants and young children and those with a neurodisability associated with expressive communication difficulties) who have overt regurgitation with 1 or more of the following: unexplained feeding difficulties (for example, refusing feeds, gagging or choking), distressed behaviour, faltering growth.
3. Consider a 4-week trial of a PPI or H2RA for children and young people with persistent heartburn, retrosternal or epigastric pain.
4. Assess the response to the 4-week trial of the PPI or H2RA, and consider referral to a specialist for possible endoscopy if the symptoms: do not resolve or recur after stopping the treatment.
5. When choosing between PPIs and H2RAs, take into account: The availability of age-appropriate preparations, the preference of the parent (or carer), child or young person (as appropriate) and local procurement costs.
6. Offer PPI or H2RA treatment to infants, children and young people with endoscopy-proven reflux oesophagitis, and consider repeat endoscopic examinations as necessary to guide subsequent treatment.
7. Do not offer metoclopramide, domperidone or erythromycin to treat GOR or GORD without seeking specialist advice and taking into account their potential to cause adverse events.
ESPGHAN and NASPGHAN Guidelines2
For healing of erosive esophagitis and relief of GERD symptoms, PPIs are superior to H2RAs. Both medications are superior to placebo. Administration of long-term acid suppression without a diagnosis is inadvisable. When acid suppression is required, the smallest effective dose should be used. Most patients require only once-daily PPI; routine use of twice-daily dose is not indicated. No PPI has been approved for use in infants < 1 year of age and there are special concerns pertaining to prescription of PPIs in infants, as described in the Guideline.
H2RAs exhibit tachyphylaxis or tolerance but PPIs do not. Tachyphylaxis is a drawback to chronic use. H2RAs have a rapid onset of action and, like buffering agents, are useful for on-demand treatment.
Post-operative prophylaxis in congenital oesophageal atresia and tracheoesophageal fistula
In a systematic review by Shawyer et al,3 of 25 articles (1,663 patients for analysis), most were single center studies (92 %) and retrospective (76 %); there were no randomised control trials. The quality of literature regarding anti-reflux medication for GER post EA-TEF repair is poor.
Kierkus et al, studied the pharmacodynamics and safety of oral pantoprazole in neonates, preterm infants and infants aged 1through 11 month. In two open-label studies, neonates and preterm infants (study 1, 1.2 mg/kg [high dose]) and infants 1
through 11 months (study 2,0.6 [low dose] or 1.2 mg/kg [high dose]) received once-daily pantoprazole. Twentyfour- hour dual-electrode pH-metry parameters were compared between predose and steady state (C5 days) (two-sided, paired t test). Treatment was administered for ≤6 weeks. In studies 1 and 2, 21 and 24 patients, respectively, were enrolled for pharmacodynamic evaluation. The high dose provided similar responses in the two studies and improved these parameters significantly: mean gastric pH and percent time gastric pH>4 increased (p<0.05 both
studies), normalized area under the curve (AUC) of gastric H+ activity decreased (p<0.05 study 2), and normalized AUC of esophageal H+ activity decreased (p<0.05 both
studies). The AUC of esophageal pH<4 decreased. Normalized AUC of esophageal H+ activity decreased (p<0.05 both studies), indicating refluxate pH increased, although this was not reflected in any change in mean esophageal pH or reflux index. The normalized AUC of esophageal H+ activity was a more sensitive measure of changes in esophageal pH.
Ward et al, in a multicentre, randomised, open label trial, assessed the PK of pantoprazole granules after single and multiple doses in 40 neonates and preterm infants. Pantoprazole plasma concentration values were highly variable after single and multiple doses. Pantoprazole is primarily metabolized by the CYP2C19 enzyme and to a limited extent by CYP3A4. As such, pantoprazole PK would be expected to vary with the expression of these enzymes. These enzymes are not completely developed at birth and appear to be activated by a mechanism associated with birth that is independent of gestational age. In conclusion, they reported, in preterm infants and neonates, pantoprazole granules for oral suspension were generally safe and well tolerated. Mean exposures with the pantoprazole 2.5 mg dose were slightly higher than those in older children and adults who received 40 mg and, while the half-life was longer, there was no evidence of accumulation following repeated dose administration.
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