Safety and historical use

Xonvea is designed specifically for the treatment of NVP and studies indicate no fetal toxicity of Xonvea in pregnant women.1

  • Over 33,000,000 pregnant women between 1956-19832,10
  • 40 years of data in pregnant women2,3
  • 2 meta-analyses involving data from more than 200,000 pregnancies4,5

These data show no significant increase in the risk of birth defects including cardiac defects, limb reduction defects, oral clefts, genital tract malformations and adverse neurodevelopment versus standard care.4-7

The combination of doxylamine succinate and pyridoxine hydrochloride was awarded the highest safety rating for a pregnancy drug at launch in the USA.8,9

History of Xonvea

While it is new to the UK, Xonvea has a well-established safety profile. In Canada, where Xonvea is known as Diclectin, it has been recommended as first-line pharmacotherapy in clinical treatment guidelines since 1979.3

Since 2013 it has also been available in the USA where it is known as Diclegis and is also first line recommended pharmacotherapy in national clinical guidelines.10,12

1956 Bendectin launches (US)

  • Launched in the US as a combination of doxylamine, pyridoxine and dicyclomine.11

1958 Debendox launches (UK)

  • Launched in the UK as a combination of doxylamine, pyridoxine and dicyclomine.11

1979 Diclectin launches (Canada)

  • Launched in the Canada as a combination of doxylamine, pyridoxine and dicyclomine.11

1976 Bendectin (US) Debendox (UK) reformulated

  • A retrospective review demonstrated that dicyclomine did not contribute any benefit to the treatment, so it was removed.
  • The reformulated combination (doxylamine and pyridoxine) was made available in the UK and US.11

1979 Diclectin (Canada) reformulated

  • The reformulated combination (doxylamine and pyridoxine) was made available in Canada. It is still available today and considered standard of care10,12

1983 Bendectin/Debendox globally withdrawn

  • In the late 1970s there were allegations of the potential teratogenicity of the formulation. In 1980 the FDA and a panel of independent experts concluded that the existing data did not show an association between the formulation and human birth defects;13,14 none of the legal cases found an association either. However, the manufacturer ceased production of the formulation in 1983 due to the high legal and liability insurance costs, which were beginning to exceed sales11

2013 Diclegis (US) launches

  • Launched in the US as a combination of doxylamine and pyridoxine.11

2018 Xonvea (UK) launches

  • Launched in the UK as a combination of doxylamine and pyridoxine.1

Fetal safety data

Fetal safety data show no significant increase in the risk of birth defects including cardiac defects, limb reduction defects, oral clefts, genital tract malformations and adverse neurodevelopment versus standard care.4-7

To address the question of potential teratogenicity of doxylamine/pyridoxine combination in humans, two separate meta-analyses were conducted which combined all controlled studies of pregnancy outcome following the use of this product during the first trimester.4,5

  • A systematic analysis of data from 12 cohort and 5 case–control studies (a total of ca. 200,000 patients) calculated the overall summary odds ratio to be 1.01, indicating the absence of any increased risk, with a 95% confidence interval (CI) of 0.66–1.55.8
  • When the two types of studies were separated according to their design, the summary odds ratio was 0.95 (95% CI 0.62–1.45) for cohort studies, and 1.27 (95% CI 0.83–1.94) for case–control studies.8
  • A second meta-analysis was conducted combining data from 16 cohort and 11 case–control studies. The pooled estimate of the relative risk for any malformation at birth in association with exposure to doxylamine/pyridoxine combination in the first trimester was 0.95 (95% CI 0.88–1.04).9

As a group, these studies have shown no differences in the risk of birth defects between those infants whose mothers had taken doxylamine/pyridoxine during the first trimester of pregnancy and those who had not.

In addition to the safety data on malformations and other adverse pregnancy outcomes, doxylamine/pyridoxine combination is one of the few medications that has safety information on the neurodevelopment of children exposed in utero.

Studies indicate no fetal toxicity of Xonvea in pregnant women1

Maternal safety data

There has been vast clinical experience regarding the use of the Xonvea combination (doxylamine/pyridoxine combination) use in pregnancy dating back to 1956.1, 2

Side effects include:

  • Nervous system disorders: somnolence (very common); dizziness (common)
  • Gastrointestinal disorders: dry mouth (common)
  • General disorders and administration site conditions: fatigue (common).

Interactions:

  • Anticholinergic effects of Xonvea may be prolonged and intensified by monoamine oxidase inhibitors (MAOIs) and is therefore not recommended.
  • Concurrent use with central nervous system (CNS) depressants including alcohol, hypnotic sedatives and tranquilizers is not recommended. The combination may result in severe drowsiness.

Warnings and Precautions:

  • Xonvea has anticholinergic properties and, therefore, should be used with caution in patients with: asthma, increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and bladder-neck obstruction.
  • Xonvea contains pyridoxine hydrochloride, a vitamin B6 analog, therefore additional levels from diet and vitamin B6 supplements should be assessed.

In a randomised, double-blind, multicentre placebo controlled trial comparing Xonvea (n=131) versus placebo (n=125) in pregnant women suffering from NVP, the safety profile of Xonvea was consistent with the Summary of Product Characteristics.15

Treatment emergent adverse events1
Variable; n(%) Xonvea (n=131) Placebo (n=125) P value
Somnolence 19(14.5) 15(12) 0.54
Dry mouth 4(3.0) 1(0.8) 0.37
Hypersensitivity 1(0.8) 0(0) >0.99
Dizziness 8(6.0) 8(6.4) 0.94
Headache 17(13) 20(16) 0.51
Loss of consciousness 0(0) 1(0.8) 0.49

There was a 15% increased drop-out rate with those taking placebo vs. Xonvea combination.

A secondary analysis of study DIC-301 sought to evaluate the maternal safety of delayed-release doxylamine/pyridoxine combination in treating NVP compared to placebo, in more detail.16

This analysis demonstrated that doxylamine/pyridoxine combination was well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating NVP. Moreover, doxylamine/pyridoxine use was not associated with an increased rate of any AE over placebo, including CNS depression, gastrointestinal or cardiovascular involvement.

Please read the product’s prescribing information for a full list of the adverse events for this medication.

Prescribing information and adverse events reporting

References:

  1. Xonvea 10 mg/10 mg gastro-resistant tablets Summary of Product Characteristics.
  2. Madjunkova S, Maltepe C, Koren G. The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin®) for the treatment of nausea and vomiting of pregnancy. Pediatr Drugs 2014; 16: 199-211.
  3. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 189, January 2018. Nausea and vomiting of pregnancy. Obstet. Gynecol. 2018;131:e15-e30.
  4. Einarson T, Leeder J, Koren G. A method for meta-analysis of epidemiological studies. Drug Intell Clin Pharma 1988; 22(10):813-824.
  5. McKeigue P, Lamm S, Linn S, Kutcher J. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994; 50(1): 27-37.
  6. Nulman I, Rovet J, Barrera M, et al. Long-term neurodevelopment of children exposed to maternal nausea and vomiting of pregnancy and Diclectin. J Pediatr 2009; 155(1): 45-50, 50.e1-2.
  7. Holmes LB, Teratogen Update: 1983 Bendectin Teratology 83;27:277-8
  8. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
  9. Koren G. The return to the USA of the doxylamine-pyridoxine delayed release combination (Diclegis®) for morning sickness– a new morning for American women. J Popul Ther Clin Pharmacol. 2013;20(2):e161-e162.
  10. Einarson A, Maltepe C, Boskovic R, Koren G. Treatment of nausea and vomiting in pregnancy. Can. Fam. Physician 2007; 53: 2109-2111
  11. Bendectin. Available at: http://www.bendectin.com/en/ [Last accessed October 2018]
  12. SOGC. Clinical practice guidelines. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can. 2002;24(10):817–23.
  13. Federal Register 1980; 807:40-43
  14. Federal Register Vol. 64, No. 152; August 9. 1999. Available at http://www.fda.gov/OHRMS/DOCKETS/98fr/080999e.pdf Last accessed September 2015
  15. Koren G et al. American Journal of Obstetrics & Gynaecology. 2010;203:571.e1–571.e7.
  16. Koren G et al. Demonstration of early efficacy results of the delayed-release combination of doxylamine-pyridoxine for the treatment of nausea and vomiting of pregnancy. BMC Pregnancy and Childbirth (2016) 16:371.