Doxylamine + pyridoxine

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Articles

Lactation Safety Information

Promethazine
Antihistamine anti-emetic. Available only in combination with pyridoxine as an anti-emetic
No published evidence of safety
Occasional, short-term use considered compatible with breastfeeding. Repeated use may pose a risk of infant sedation
4th March 2019

New Medicines

Xonvea · Moderate-to-severe nausea and vomiting in pregnancy in women who do not adequately respond to conservative management.

Information

Xonvea
New formulation
Alliance Pharmaceuticals
Duchesnay Inc

Development and Regulatory status

Launched
Phase III Clinical Trials
Launched
September 2018
Sep 18 · Launched in the UK; cost for 20 tablets is £28.50 [11].
Jul 18 · Approved by MHRA with brand name Xonvea; launch expected Autumn 2018 [10].
Jun 18 · Recommended for approval by MHRA. UK launch planned for autumn 2018. Following approval in the UK, Alliance then expects to commence the filing of the necessary applications for regulatory approvals for further European territories in advance of launches later in 2019 [9].
Dec 17 · No update available from manufacturer on likely availability in UK [8].
Sep 16 · Alliance Pharma intends to submit marketing authorisations for doxylamine/pyridoxine controlled release via a decentralised procedure in nine other EU countries, including Germany, France and Italy for the treatment of morning sickness in 2018. The company also reported that it expects that the drug will be approved in the UK in early 2017 [7].
Oct 15 · Currently pre-registration in the UK. Licence application filed with the MHRA [6].
Dec 14 · Doxylamine/pyridoxine receives pregnancy category A status in USA indicating that adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters [3].
May 13 · Launched for Morning sickness in USA (PO) [3].
Apr 13 · Filed for approval for Morning sickness in USA [3].

Category

Histamine H1 receptor antagonist/ Vitamin B6 (doxylamine 10mg/pyridoxine 10mg delayed release tablet)
Nausea and vomiting are common in pregnancy, affecting up to 70% to 85% of pregnant women. Most cases are mild and do not require treatment. Nausea and vomiting in pregnancy usually resolves spontaneously within 16 to 20 weeks and is not associated with a poor pregnancy outcome [1].
Moderate-to-severe nausea and vomiting in pregnancy in women who do not adequately respond to conservative management.
Oral

Trial or other data

Dec 15 · Dosing: The recommended starting dose is 2 tablets at bedtime. If symptoms persist, an additional tablet can be taken each morning starting day 3. If these three tablets do not adequately control symptoms on day 3, an additional tablet can be taken each afternoon starting day 4. The maximum recommended daily dose is 4 tablets and the dosing schedule may be adjusted to symptoms. Continued need should be reassessed as the pregnancy progresses and treatment should be tapered down and stopped in conjunction with clinical judgement [2].
Dec 15 · Safety in pregnancy (pyridoxine): A retrospective cohort study failed to link pyridoxine monotherapy with an increase in major malformations (18/458 cases vs. 34/911 controls; RR 1.05, 95% CI 0.60-1.84).[9] Bendectin (known as Debendox in the UK) was widely used in the 1960’s and 1970’s to combat nausea and vomiting of pregnancy. Bendectin contained pyridoxine and the antihistamine doxylamine, and was voluntarily withdrawn from the US market in 1983 by the manufacturer following reports of congenital malformations, although large prospective studies have not demonstrated teratogenicity. The combination is still available in parts of Europe and North America (Canada). High doses of pyridoxine have been found to be neurotoxic in non-pregnant patients and on this basis The Committee on Toxicity of foods in the UK has recommended a safe upper limit of 10mg pyridoxine daily. However, this dose may be ineffective in the treatment of nausea where doses of up to a maximum of 80mg/day may be required. [2,3,5].
Dec 15 · Safety in pregnancy (doxylamine): There is significant clinical experience and >30 years of data for the use of doxylamine succinate and pyridoxine hydrochloride in pregnant women in the US where it is approved for this indication. These data include two meta-analyses involving data from more than 200,000 pregnancies which show no increase in the risk of birth defects between those infants whose mothers had taken doxylamine succinate and pyridoxine hydrochloride during the first trimester and those infants whose mothers had not. Separate analyses for specific defects, including cardiac defects, limb reduction defects, oral clefts, and genital tract malformations, show no increased risk following the use of doxylamine succinate and pyridoxine hydrochloride and no adverse affect on the development of children exposed in utero. The combination of doxylamine succinate and pyridoxine hydrochloride is approved to treat pregnant women with NVP by the US FDA and has a FDA Pregnancy Category A classification, indicating that adequate and well-controlled studies have failed to demonstrate a risk to the foetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters [2,3].
Feb 13 · Positive results from a randomised, open-label PIII trial of doxylamine/pyridoxine for treatment of hyperemesis gravidarum (NCT00293644). The trial enrolled 150 pts in Canada, who had experienced hyperemesis gravidarum in a previous pregnancy. During the first 3 weeks of symptoms, 70% fewer cases of moderate-to-severe nausea and vomiting occurred in the pre-emptive treatment group, compared to the control group (p=0.05). Pre-emptive treatment also decreased the recurrence of hyperemesis gravidarum (p=0.047), compared to the control group [2,3].
Sep 10 · The efficacy and tolerability of Diclectin is demonstrated in a recent randomised, double-blind, multicentre placebo controlled trial (NCT00614445) of pregnant women suffering from NVP. In this randomised, double-blind, multicentre placebo controlled trial studying pregnant women suffering from NVP, women received Diclectin (n = 131) or placebo (n = 125) for 14 days. Diclectin led to significantly greater improvement in NVP symptoms vs. placebo. The change from baseline in the symptom and quality of life domains of the pregnancy unique quantification of emesis (PUQE) score was ─4.8 ± 2.7 vs. ─3.9 ± 2.6 respectively (p = 0.006). Diclectin resulted in a larger improvement in the global assessment of well-being score (2.8 ± 2.8) vs. placebo (1.8 ± 2.2) (p = 0.005). There was a trend toward more time lost from employment (2.37 ± 10.23) in the placebo group versus the Diclectin group (0.92 ± 3.86) (p = 0.06). There was no difference in the occurrence of side effects between women taking Diclectin or placebo.The most common adverse effects are somnolence, dizziness, dry mouth and fatigue [2-4].

Evidence based evaluations