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Doxylamine Succinate–Pyridoxine Hydrochloride (Diclegis) for the Management of Nausea and Vomiting in Pregnancy: an Overview

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Doxylamine Succinate–Pyridoxine Hydrochloride (Diclegis) for the Management of Nausea and Vomiting in Pregnancy: an Overview International Journal of Women’s Health Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Doxylamine succinate–pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview Nina Nuangchamnong Abstract: Nausea and vomiting in pregnancy (NVP) is common and often undertreated, in Jennifer Niebyl part due to fears of adverse effects of medications on the fetus during early pregnancy. In April 2013, the US Food and Drug Administration (FDA) approved doxylamine succinate 10 mg Department of Obstetrics and Gynecology, University of Iowa and pyridoxine hydrochloride (a vitamin B6 analog) 10 mg as a delayed-release combination Hospitals and Clinics, Iowa, IA, USA pill called Diclegis for the treatment of NVP. Diclegis is currently the only medication that is FDA-approved for the indication of NVP. This review addresses the historical context, safety, efficacy, pharmacology, and practical role of doxylamine and pyridoxine for the management of NVP. The reintroduction of this doxylamine–pyridoxine combination pill into the American market fills a therapeutic gap in the management of NVP left by the removal of the same active drugs marketed over 30 years ago in the form of Bendectin. The substantial amount of safety data accumulated over the years makes it one of the few drugs that qualify for FDA Pregnancy Category A status. In the hierarchical approach to pharmacological treatment of NVP, the combination of doxylamine and pyridoxine should thus be first-tier. Keywords: doxylamine, pyridoxine, vitamin B6, nausea, vomiting, pregnancy Introduction Nausea and vomiting in pregnancy (NVP) is common. A recent estimate of the preva- lence of NVP in the US is 70%.1 A recent estimate of the total economic burden in the US in 2012, including drug treatments for mild-to-severe NVP, hospitalizations for hyperemesis gravidarum, time lost from work, and caregiver time, is $1.7 billion.2 Estimates of prevalence and economic burden due to NVP are similarly high in devel- oping countries.3,4 NVP is a spectrum disorder. It is colloquially referred to as “morning sickness”, but in one study only 1.8% of women reported nausea limited to mornings alone, whereas 80% reported nausea lasting all day.5 Only 50% of women experienced relief by 14 weeks’ gestation; 90% of those affected had relief by 22 weeks’ gestation.5 In another study, about 25% of women had nausea alone, and 50% had both nausea and vomiting.6 Although NVP is generally considered part of a healthy pregnancy, the potential negative effect on the pregnant woman’s quality of life is significant.7,8 Approximately 1% of pregnant women develop a severe form of NVP called hype- remesis gravidarum with dehydration, weight loss, and ketonuria. Some cases of Correspondence: Nina Nuangchamnong hyperemesis gravidarum may by avoided by aggressive early treatment of NVP. Department of Obstetrics and Gynecology, University of Iowa The fear of potential teratogenicity necessitates a proven safe pharmacologic Hospitals and Clinics, 200 Hawkins intervention for NVP during the vulnerable period of organogenesis. The period Drive, Iowa, IA 52242, USA Email [email protected] from onset to peak severity of NVP (from 8 to 10 weeks’ gestation)6 overlaps with submit your manuscript | www.dovepress.com International Journal of Women’s Health 2014:6 401–409 401 Dovepress © 2014 Nuangchamnong and Niebyl. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted http://dx.doi.org/10.2147/IJWH.S46653 without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Nuangchamnong and Niebyl Dovepress the period of fetal organogenesis (from 4 to 10 weeks’ pyridoxine hydrochloride, and dicyclomine hydrochloride. gestation). The etiology of NVP is unknown, but there is a After studies showing no benefit of dicyclomine, which is close temporal relationship between peak human chorionic an antispasmodic agent, Bendectin was reformulated in gonadotropin concentrations and peak symptoms of NVP, 1976 to contain only doxylamine and pyridoxine. Bendectin so human chorionic gonadotropin has been considered a became a leading treatment for NVP in the US as well as likely candidate for the emetogenic stimulus arising from the other countries under different trade names. It was known placenta.9 Interestingly, NVP itself has not been observed to as Debendox in the UK and Australia, and as Lenotan be associated with an increased risk of birth defects.10 in Germany, Switzerland, and other countries in Europe, Many dietary and pharmacologic treatment regimens South America, and Africa. In the 1970s, a number of law- are available. The American Congress of Obstetricians suits were filed alleging that Bendectin, like thalidomide, and Gynecologists has published a stepwise algorithm for was responsible for congenital defects. Unlike claims pharmacologic treatment of NVP, recommending pyridox- against thalidomide, however, the claims against Bendectin ine (vitamin B6) and doxylamine as first-line agents when were for multiple defects and biologically implausible. One conservative treatment with dietary and lifestyle changes is of the cases that received widespread publicity alleged that unsuccessful.9 In April 2013, the US Food and Drug Admin- Bendectin use during pregnancy caused unilateral fetal limb istration (FDA) approved Diclegis® (Duchesnay USA Inc., reduction, which is not biologically plausible because limb Rosemont, PA, USA), a combination of delayed-release defects caused by drug exposure would be bilateral. Despite doxylamine succinate and pyridoxine hydrochloride, for the a lack of scientific evidence, the number of lawsuits grew. treatment of NVP. Diclegis is the only antiemetic with FDA In 1983, the manufacturer of Bendectin elected to discon- Pregnancy Category A status, indicating that adequate and tinue production of Bendectin, not because Bendectin was well-controlled studies have failed to demonstrate a risk to hazardous, but because insurance premiums had become the fetus in the first trimester of pregnancy (and there is no untenable.11 evidence of risk in later trimesters). This review addresses While Bendectin was available in the US from 1958 to the historical context, safety, efficacy, pharmacology, and 1983, it is estimated that 25%–30% of all pregnant women practical role of doxylamine and pyridoxine for the manage- received this medication. The 1980 National Ambulatory ment of NVP. Medical Care Survey indicated that Bendectin accounted for 82% of the antiemetic use for NVP that year. After the History of Bendectin discontinuation of Bendectin, hospital admissions for exces- Diclegis is a reincarnation of the drug combination previously sive vomiting in pregnancy doubled from 1980 to 1985, the marketed, and unfairly maligned, in the US under the brand period when Bendectin use declined and ceased in the US. name Bendectin (Merrell Dow Pharmaceuticals, Kansas, Overall antiemetic use for NVP dropped 90% during that MO, USA). Diclegis contains the same active ingredients time, due to the absence of Bendectin and failure of any other as Bendectin and has the same indication. Great effort has antiemetic to fill the void. During that period, birth-defect been put into demonstrating the safety of Diclegis due to rates remained constant (Figure 1).12 previous experience with another drug used for NVP called thalidomide. Thalidomide was never approved or licensed Safety of doxylamine and pyridoxine by the FDA for use in the US, but thousands of pregnant Although Bendectin was withdrawn from the US market due women in the US in the 1950s had access to thalidomide to lawsuits that alleged a teratogenic effect, no other agents through clinical trials and from other countries. The offspring given in pregnancy have more conclusive safety data with of women who used thalidomide for NVP developed major regard to teratogenicity (Table 1).13 Since the withdrawal anomalies, most commonly bilateral limb reductions called of Bendectin from the American market, the FDA has phocomelia. Although the application to the FDA for approval twice indicated, in 1983 and in 1999, that the medication of the drug was withdrawn, the teratogenicity of thalidomide had not been withdrawn from sales due to lack of safety or had a major influence on the development and use of any effectiveness. Teratologic studies in rabbits and rats, as well medication during early pregnancy thereafter.11 as extensive epidemiologic studies, have produced no evi- Bendectin was FDA-approved in 1956 for treatment of dence that exposure to any of the components of Bendectin NVP. The original formulation included doxylamine succinate, in the first trimester of pregnancy causes an increase in 402 submit your manuscript | www.dovepress.com International Journal of Women’s Health 2014:6 Dovepress Dovepress Doxylamine–pyridoxine for NVP 2.00 NVP hospitalizations 1.50 Limb reduction 1.00 deformities 0.50 Bendectin Annual rate normalized to 1974–1976 tablets sold 0.00 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 Year Figure
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