Gastrointestinal Drug (Antisecretory)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although there are no human data for dexlansoprazole, there are data for racemic lansoprazole (see Lansoprazole). These data, combined with the data for the other proton pump inhibitors (PPIs), suggest that the risk of developmental toxicity, including structural anomalies, is low. Human pregnancy experience with three other PPIs (see Lansoprazole, Omeprazole, and Pantoprazole) has not shown a causal relationship with congenital malformations. In some cases, malformations may have been missed because of the design and size of the studies. The carcinogenic and mutagenic data for lansoprazole and other PPIs are a potential concern, but the absence of follow-up studies prevents a risk assessment for exposed offspring. A study showing an association between in utero exposure to gastric acid-suppressing drugs and childhood allergy and asthma requires confirmation. As with all drug therapy, avoidance of dexlansoprazole during pregnancy, especially during the 1st trimester, is the safest course. If dexlansoprazole is required or if inadvertent exposure does occur early in gestation, the known risk to the embryo–fetus for congenital defects appears to be low. Long-term follow-up of offspring exposed during gestation is warranted.
FETAL RISK SUMMARY
Dexlansoprazole is a PPI that blocks gastric acid secretion by a direct inhibitory effect on the gastric parietal cell. It is indicated for healing of all grades of erosive esophagitis for up to 8 weeks, the maintenance of healed erosive esophagitis for up to 6 months, and for the treatment of heartburn associated with nonerosive gastroesophageal reflux disease (GERD) for 4 weeks. Dexlansoprazole is the R-enantiomer of racemic lansoprazole. It is in the same drug class as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. The drug is extensively metabolized to inactive metabolites. Plasma protein binding is about 96%–99% and the elimination half-life is about 1–2 hours (1).
Reproduction studies have been conducted in rabbits. At oral doses about 9 times the maximum recommended human dose, no evidence of fetal harm was observed (1). (See also Lansoprazole.)
Studies for carcinogenicity, mutagenicity, and impairment of fertility were conducted for lansoprazole (see Lansoprazole).
It is not known if dexlansoprazole crosses the human placenta. The molecular weight (about 369) and the elimination half-life suggest that the drug will cross to the embryo–fetus, but the high plasma protein binding might limit the exposure.
A meta-analysis of PPIs in pregnancy was reported in 2009 (2). Based on 1530 exposed compared with 133,410 not exposed pregnancies, the OR for major malformations was 1.12, 95% CI 0.86–1.45. There also was no increased risk for spontaneous abortions (OR 1.29, 95% CI 0.84–1.97) or preterm birth (OR 1.13, 95% CI 0.96–1.33) (2).
A population-based, observational, cohort study formed by linking data from three Swedish national healthcare registers over a 10-year period (1995–2004) was reported in 2009 (3). The main outcome measures were a diagnosis of allergic disease or a prescription for asthma or allergy medications. The drug types included in the study were gastric acid suppressors, including H2-receptor antagonists, prostaglandins, PPIs, combinations for eradication of Helicobacter pylori, and drugs for peptic ulcer and GERD. Of 585,716 children, 29,490 (5.0%) met the diagnosis and 5645 (1%) had been exposed to gastric acid suppression therapy in pregnancy. Of these children, 405 (0.07%) were treated for allergic disease. For developing allergy, the odds ratio (OR) was 1.43, 98% confidence interval (CI) 1.29–1.59, irrespective of the drug, time of exposure during pregnancy, and maternal history of allergy. For developing childhood asthma, but not other allergic diseases, the OR was 1.51, 95% CI 1.35–1.69, irrespective of the type of acid-suppressive drug and the time of exposure in pregnancy. The authors proposed three possible mechanisms for their findings: (a) exposure to increased amounts of allergens could cause sensitization to digestion of labile antigens in the fetus; (b) maternal Th2 cytokine pattern could promote an allergy-prone phenotype in the fetus; and (c) maternal allergen-specific immunoglobulin E could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Several limitations of the study that might have affected their findings were identified, including a general increase in childhood asthma but not necessarily an increase in allergic asthma (3). The study requires confirmation.
Several reports and reviews describing the use of PPIs during human pregnancy have observed no increased risk of developmental toxicity (see Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and Rabeprazole).
BREASTFEEDING SUMMARY
No reports describing the use of dexlansoprazole during human lactation have been located. The molecular weight (about 369) and the elimination half-life (about 1–2 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (about 96%–99%) might limit the amount excreted. The effect of this exposure on a nursing infant is unknown. Because of the carcinogenicity observed in animals with lansoprazole, and the potential for suppression of gastric acid secretion in the nursing infant, the use of dexlansoprazole during lactation is best avoided.
References
1.Product information. Kapidex. Takeda Pharmaceuticals America, 2009.
2.Gill SK, O’Brien L, Einarson TR, Koren G. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol 2009;104:1541–5.
3.Dehlink E, Yen E, Leichtner AM, Hait EJ, Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study. Clin Exp Allergy 2009;39:246–53.