Antiemetic Strategy and Adjunctive Treatments

The RCOG table outlines a variety of antiemetics that can be used alone or in combination. The formulary for each region will vary and one should prescribe accordingly.¹

After prescribing an antiemetic, a review of symptoms is required after 24-72 hours. A pragmatic stepwise approach should be followed adding in a further antiemetic if symptoms remain uncontrolled; co-existent use of up to 3 antiemetics from first and second-line options (different drug classes) may be required at which point specialist advice may be sought. When uptitrating antiemetics, add drugs as opposed to replacing them. The symptoms peak between 7 and 9 weeks from the last menstrual period hence additional antiemetics are likely to be required at this point.

Alongside antiemetics, you will also need to consider prescribing:

• Omeprazole/H2 receptor antagonist.
• Laxatives – patients commonly suffer from constipation with antiemetics particularly Ondansetron.
• Thiamine – (100mg TDS) to prevent Wernicke’s encephalopathy in all women with prolonged vomiting >3 weeks/severely reduced dietary intake. Thiamine stores in a previously healthy individual can deplete rapidly and cause symptoms of tachycardia, weakness and decreased deep tendon reflexes within one week without intake.
• Oral nutritional supplements – may supplement an inadequate food intake however may not be tolerated.
• Steroids – discuss with antenatal team if symptoms are not controlled on maximal antiemetics and they remain dehydrated or there is continued weight loss.

Xonvea®: Positioning and Clinical Evidence

Let’s talk more about where Xonvea® (Doxylamine succinate/ Pyridoxine hydrochloride) fits into the clinical picture.

Xonvea® is the only licensed antiemetic for the treatment for nausea and vomiting in pregnancy. The RCOG states that it can be used first line to treat nausea and vomiting however this can be subject to specific, regional formulary rules.

Phase 3 Clinical Trial Data

A phase 3, multicentre, randomised, double-blind, placebo-controlled study was conducted² over a 15-day period in pregnant women (n=131 taking Xonvea® and n=125 taking placebo); 2 doses were taken at bedtime, increased when indicated to the maximum daily dose of 4 tablets daily from day 2-14.

• Inclusion criteria included women aged 18 or over, gestational age 7-14 weeks (mean 9.3 weeks), PUQE score of 6 or above with no response to conservative management.
• Women already on antiemetics or those with chronic co-morbidities were excluded.
• At baseline, the two groups did not differ significantly in terms of demographics and disease characteristics.
• Subjects completed the PUQE score and the global assessment of well-being scale on days 1, 8 and 14.

Efficacy Results

The primary effectiveness endpoint focused on symptom control. Xonvea® was significantly more effective than placebo at reducing NVP symptoms by Day 15 (4.8 point reduction in PUQE score).

The secondary effectiveness endpoints focused on quality of life. Xonvea® patients felt significantly better overall compared to those on placebo, chose to continue treatment after the trial ended and fewer required additional treatment such as dietary modification or alternate therapies.

Safety Profile

This study showed that Xonvea® was an effective and well-tolerated drug. In the Phase 3 clinical trial, the use of Xonvea® was not particularly associated with an increased rate of any adverse effects compared with placebo (all differences were non-significant).

A large amount of data, including two meta-analyses with over 168,000 patients and 18,000 exposures to the doxylamine/pyridoxine combination during first trimester in pregnant women indicates no malformative nor fetal/neonatal toxicity of doxylamine succinate and pyridoxine hydrochloride.³

Use in Breastfeeding

Molecular weight of doxylamine succinate is low enough that passage into breast milk can be expected. Excitement, irritability and sedation have been reported in nursing infants presumably exposed to doxylamine succinate through breast milk. Infants with apnoea or other respiratory syndromes may be particularly vulnerable to the sedative effects of Xonvea® resulting in worsening of their apnoea or respiratory conditions. There are no reports of adverse events in infants presumably exposed to pyridoxine hydrochloride through breast milk. A risk to breastfed infants cannot be excluded hence a risk/benefit assessment needs to be performed.

References:

1. 1. Nelson-Piercy C, Dean C, Shehmar M, et al; Royal College of Obstetricians and Gynaecologists. The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69). BJOG. 2024; 131:e1-e30.
   2. Koren, G., et al. “Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy.” American Journal of Obstetrics & Gynecology, vol. 203, no. 6, 2010, pp. 571.e1–571.e7.
   3. McKeigue, et al. Teratology. 1994. 50: 27-37.

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