The content of this evidence review was up-to-date in April 2019. See summaries of product characteristics (SPCs), British national formulary (BNF) or the Medicines and Healthcare products Regulatory Agency (MHRA) or NICE websites for up-to-date information.
Xonvea (Alliance Pharmaceuticals) is a delayed-release tablet containing doxylamine succinate 10 mg (an antihistamine) and pyridoxine hydrochloride 10 mg (vitamin B6). In July 2018, it was granted a marketing authorisation for treating nausea and vomiting of pregnancy in women (aged 18 years or older) who do not respond to conservative management. Doxylamine/pyridoxine is taken every day and not on an as needed basis.
Evidence was from 2 randomised, double-blind, placebo-controlled multicentre trials in the US (Koren et al. 2010 and the DESI study, which was undertaken in 1975 and reported by Zhang et al. 2017). In the key licensing study by Koren et al. (2010), symptoms of nausea and vomiting were evaluated using the Pregnancy unique quantification of emesis (PUQE) score. Small but statistically significant improvements in PUQE scores were seen with doxylamine/pyridoxine compared with placebo at days 3, 4, 5 and 15. The MHRA concluded that the improvements are clinically important for women suffering from nausea and vomiting of pregnancy. The supporting study (the DESI study reported by Zhang et al. 2017) also found that, overall, doxylamine/pyridoxine improved symptoms of nausea and vomiting compared with placebo.
Extensive data suggest that doxylamine/pyridoxine is safe for pregnant women to use, and that it is relatively well tolerated. The results of epidemiological studies designed to detect possible teratogenicity show no association with fetal abnormalities (UK public assessment report).
NICE's guideline on antenatal care for uncomplicated pregnancies and the Royal College of Obstetricians and Gynaecologists' (RCOG) guideline on the management of nausea and vomiting of pregnancy (which predate the availability of doxylamine/pyridoxine in the UK) recommend antihistamines or phenothiazines as first-line medicines. Doxylamine/pyridoxine offers a specifically licensed, but more costly option (on a per tablet basis) for women with symptoms that have not responded to conservative management (for example, ginger, acupressure, and dietary and lifestyle advice). However, there is no evidence to show how the safety and efficacy of doxylamine/pyridoxine compares with current first-line treatment options such as antihistamines and phenothiazines.
The MHRA has advised (personal communication: February 2019) that use of antihistamines or phenothiazines for nausea and vomiting of pregnancy is not off-label because they are not explicitly contraindicated in pregnancy (although their use is cautioned). The exception to this is Buccastem M, which is contraindicated in pregnancy. The MHRA also noted that, because of prescribing hierarchy, the use of other medicines that do not have a specific licence for nausea and vomiting of pregnancy over doxylamine/pyridoxine, which does, would need to be justified.
Although antihistamines and phenothiazines are not specifically licensed for treating nausea and vomiting of pregnancy, their use is established in clinical practice and most have been used in pregnancy without any known adverse effects on the developing baby (UK Teratology Information Service, Treating nausea and vomiting of pregnancy). Product literature for many of these medicines advises caution in pregnancy, which should be discussed with pregnant women before they are prescribed. Some prescribers and women may prefer doxylamine/pyridoxine because it is specifically licensed for use in pregnant women.