Article

The Safety of Higher Than Standard Dose of Doxylamine-Pyridoxine (Diclectin®) for Nausea and Vomiting of Pregnancy

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Abstract

A delayed-release combination of doxylamine-pyridoxine (D-P) (Diclectin) is the only approved antiemetic medication for use in pregnancy in Canada. The standard recommended dose is up to 4 tablets a day, regardless of body weight or severity of symptoms. The objective of this study was to determine the incidence of adverse maternal and fetal effects and pregnancy outcome in 225 women taking Diclectin at the recommended (n = 123) or higher than recommended (n = 102) doses. In this observational, prospective study, one-third (33.6%) of women reported having adverse effects (sleepiness, tiredness, and/or drowsiness) temporally related to the medication. There was no association between the dose per kg and rates of reported maternal adverse effects with doses ranging from 0.1 mg/kg to 2.0 mg/kg (1-12 tablets). Nausea and vomiting of pregnancy (NVP) was reported as severe by the majority (75.8%) of women. Mean birth weight (BW) was 3,400 g and gestational age (GA) 39 weeks. Multivariate analysis revealed that only prepregnancy weight and GA predicted lower BW, not the dose of D-P or the severity of NVP. There were two pregnancies with major malformation, a finding that is consistent with the rates of birth defects in the general population. It was concluded that the higher than standard dose of Diclectin, when calculated per kg of body weight, does not affect either the incidence of maternal adverse effects or pregnancy outcome. If needed, Diclectin can be given at doses higher than 4 tablets/day to normalize for body weight or optimize efficacy.

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... As there is very large variability in the severity of NVP, and in its response to pharmacotherapy, the third clinical pharmacology challenge this dissertation addressed is the pharmacokinetics of doxylamine succinate and pyridoxine hydrochloride after Diclectin® administration. Diclectin® is the pharmacotherapy of choice for the treatment of NVP in Canada as it is approved by Health Canada for use in pregnancy 32,33 . ...
... However, is has also been determined that the efficacy of Diclectin ® depends on optimal dosing: a study conducted in 68 pregnant women experiencing moderate to severe NVP concluded that Diclectin ® dosing should be given according to body weight, time and severity of NVP symptoms in order to be most effective 32 . Although the standard recommended dose is up to 4 tablets a day, a study was conducted comparing 123 pregnant women at recommended standard doses and 102 pregnant women higher than recommended doses 33 . This study revealed that higher than standard doses up to 12 tablets a day, when calculated per kg of body weight, do not affect either the incidence of maternal adverse effects or pregnancy outcome, and were found to be more efficacious 33 . ...
... Although the standard recommended dose is up to 4 tablets a day, a study was conducted comparing 123 pregnant women at recommended standard doses and 102 pregnant women higher than recommended doses 33 . This study revealed that higher than standard doses up to 12 tablets a day, when calculated per kg of body weight, do not affect either the incidence of maternal adverse effects or pregnancy outcome, and were found to be more efficacious 33 . ...
... In 1983 the manufacturer voluntarily removed the drug from the market due to litigations and false allegations regarding teratogenic effects. Consequently, there was a 2–3-fold increase in the rate of hospitalization due to NVP.9,35,36 Many case control and cohort studies, with over 170,000 exposures have demonstrated the safety of the combination of doxylamine and pyridoxine, and although it is no longer commercially available in the United States, many compounding pharmacies will prepare the combination on request.7 Women will also take a combination of doxylamine succinate (ie, Unisom®) and a vitamin B6 tablet for the same effect. ...
... A limited number of case series and one study from Motherisk which included 176 women exposed to ondansetron in the 1st trimester, failed to find an association between exposure in first trimester and increased risk for major malformations.38,42,43 Although it may help with reducing symptoms, IV ondansetron was not found to be more effective than promethazine.36,38 Because of cost and paucity of data regarding use in pregnancy, this drug should be reserved for when other forms of therapy prove ineffective. ...
... Phenothiazines such as chlorpromazine, perphenazine, prochlorperazine, promethazine, and trifluoperzaine, have shown to be superior to placebo in the treatment of severe NVP.36,38,39 The aggregate of data has failed to find an increase for adverse effects in babies whose mothers took phenothiazines during pregnancy.38 ...
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Nausea and vomiting of pregnancy (NVP) is a common medical condition in pregnancy with significant physical and psychological morbidity. Up to 90% of women will suffer from NVP symptoms in the first trimester of pregnancy with up to 2% developing hyperemesis gravidarum which is NVP at its worst, leading to hospitalization and even death in extreme cases. Optimal management of NVP begins with nonpharmacological approaches, use of ginger, acupressure, vitamin B6, and dietary adjustments. The positive impact of these noninvasive, inexpensive and safe methods has been demonstrated. Pharmacological treatments are available with varying effectiveness; however, the only drug marketed specifically for the treatment of NVP in pregnancy is Diclectin(®) (vitamin B6 and doxylamine). In addition, the Motherisk algorithm provides a guideline for use of safe and effective drugs for the treatment of NVP. Optimal medical management of symptoms will ensure the mental and physical wellbeing of expecting mothers and their developing babies during this often stressful and difficult time period. Dismissing NVP as an inconsequential part of pregnancy can have serious ramifications for both mother and baby.
... Doses of doxylamine range from 12.5 to 25 mg twice daily or 12.5 mg twice a day with 25 mg at bedtime. Pyridoxine dose range from 10 to 25 mg three to four times daily (109,110). Higher doses have been studied, but they do not improve NVP and were associated with a higher hospitalization rates for rehydration (110). Preemptive antinausea medication has been reported to be more efficacious than therapy after symptoms of NVP (111). ...
... Pyridoxine dose range from 10 to 25 mg three to four times daily (109,110). Higher doses have been studied, but they do not improve NVP and were associated with a higher hospitalization rates for rehydration (110). Preemptive antinausea medication has been reported to be more efficacious than therapy after symptoms of NVP (111). ...
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... Women with HG who had had terminations were three times more likely to report that their health care providers were uncaring or did not realise how sick they were (Poursharif et al 2007). Factors found to be associated with hospitalisation in women in Canada with NVP were more frequent vomiting, use of more antiemetic agents, being primigravida, feeling depressed due to NVP, having an obstetrician as a primary caregiver and NVP having an adverse effect on the partner's life (Atanackovic et al 2001). While women with HG often feel isolated and misunderstood by family, friends and HCPs (Swallow 2010, O'Hara 2013, Sykes et al 2013, social support is protective for NVP. ...
... Pregnancy sickness is often regarded as a first-trimester only problem, but HG is known to last for longer. The duration data are difficult to interpret due to variance in the definitions of NVP and HG between studies but symptoms of HG lasting until birth are widely reported (Gadsby et al 1993, Atanackovic et al 2001, Mullin et al 2012, O'Hara 2013. There is no correlation between the week of starting antiemetics and the week in which they were stopped. ...
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Objective: Hyperemesis gravidarum (HG) has a high recurrence rate so women are likely to suffer from it in a subsequent pregnancy. A lack of awareness in the first pregnancy can compound the condition and delay treatment. We aimed to examine how subsequent pregnancies differ and to explore what factors determine whether a woman has more or fewer hospital admissions. Design: A self-selected internet-based survey. Setting: Participants were all recruited principally through social media and UK-based. Sample: One hundred and seventy-two women who had had at least two HG pregnancies within the past ten years. Methods: Internet survey platform Survey Monkey. Main outcome measures: Questions were mostly asked using Likert-type scales with the option for additional free text responses. Results: Overall, the number of hospital admissions were lower in the later pregnancy. Women attributed this to having earlier access to antiemetics, more support with domestic duties and a reluctance to be separated from their children. Where admissions were higher, it was due to the added stress of child care and/or worse underlying symptoms, meaning women opting to be admitted as rehydration was the only thing which gave relief. Conclusions: Women are advised to start antiemetic treatment earlier in their next pregnancy and put in place sources of support to help with child care. Hospitals could improve services by providing rapid rehydration day units.
... [8] Intravenous rehydration and thiamine may be needed together with antiemetic drugs (doxylamine, methoclopramide and chlorpromazine) in the treatment of hyperemesis gravidarum. [4,9] In our study, we studied whether there is difference between early period complications and perinatal outcomes of pregnant women who were treated with methoclopramide and dimenhydrinate during first trimester. ...
... The pregnant women hospitalized in the clinic for pregnancy nausea-emesis and HG were had rehydration treatment by 0.9% NaCl and 10% dextrose solution. [3,5,6,9] Vitamin complex (Bemiks C) was applied by intravenous administration once a day. Dimenhydrinate and metoclopramide were used in the treatment since they are widely used in the treatment of nausea and emesis during pregnancy, [1,3] reliable, [2,4] effective, [7] cost-efficient and easily accessible. ...
Article
Objective Metoclopramide and dimenhydrinate are used commonly in the treatment of nausea-emesis and hyperemesis gravidarum during the first trimester. Methods This retrospective study included 233 pregnant women who were diagnosed as hyperemesis gravidarum during first trimester between July 4, 2005 and May 27, 2009 at the Clinic of Obstetrics and Gynecology, Simav State Hospital (Simav, Kütahya, Turkey). The pregnant women were separated into groups according to their metoclopramide or dimenhydrinate use. The pregnant women included in the study were chosen from the pregnant women who were healthy and had singleton pregnancy. Results While 113 pregnant women were treated by metoclopramide and 120 pregnant women by dimenhydrinate. Spontaneous abortion was found as 6.2% in the pregnant women who used metoclopramide and as 4.2% who used dimenhydrinate, and stillbirth rate was 1.8 and 0.8%, respectively. Low birth weight rates were 8.0% in metoclopramide group and 5.8% in dimenhydrinate group, and preterm labor rates were 5.3% and 5.0%, respectively. Conclusion We have found that there was no difference between the pregnant women who used metoclopramide and dimenhydrinate in terms of early period complications and perinatal outcomes. Keywords Nausea, emesis, pregnancy, first trimester.
... One observational, prospective study of the delayed-release combination of doxylamine and pyridoxine showed that higher-than-standard doses, when calculated per kilogram of body weight, do not affect either the incidence of maternal adverse effects or pregnancy outcome. 19 One prospective cohort study of motherchild pairs was conducted to determine the effects of NVP and its treatment with Diclectin on child neurodevelopment, and found no adverse effect on children's cognitive abilities upon follow-up at ages 3-7 years. 20 ...
... One study showed that if the patient has a higher body mass index, she may take up to eight to 12 tablets a day without increasing maternal adverse effects, fetal risks, degree of tiredness, or birth defects. 19 Dosing of the delayed-release combination of doxylamine and pyridoxine (Diclectin or Diclegis) is timed so that onset of action is most likely to occur in the early morning, when NVP symptoms are commonly at their peak. The half-life of doxylamine in the delayed-release tablet is 11.7 hours, and the half-life of pyridoxal 5′-phosphate (an active metabolite of pyridoxine) is 56 hours. ...
Article
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Nausea and vomiting in pregnancy (NVP) is common and often undertreated, in 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 and pyridoxine hydrochloride (a vitamin B6 analog) 10 mg as a delayed-release combination 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.
... Another observational, prospective study showed the improved effectiveness of appropriate dosing of Diclectin Ò using more than four tablets per day based on the severity of NVP symptoms and adjustment for body weight. No increase in adverse events or adverse pregnancy outcomes for the higher than standard dose of Diclectin Ò were observed [75]. ...
... An observational, prospective study was conducted in Canada with the objective to determine the incidence of adverse maternal and fetal effects and pregnancy outcome in 225 women taking Diclectin Ò at the recommended (1-4 tablets) (n = 123) or higher than recommended (5-12 tablets) (n = 102) doses. The results showed that higher than standard dose of Diclectin Ò , when calculated per kilogram of body weight, did not affect either the incidence of maternal adverse effects or adverse pregnancy outcomes [75]. ...
Article
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Nausea and vomiting of pregnancy (NVP) affects up to 85 % of all pregnancies. Effective treatment can greatly improve a woman's quality of life, reduce the risk for maternal and fetal complications, and reduce healthcare costs. Unfortunately, many women receive either no pharmacological treatment or are recommended therapies for which fetal safety and efficacy have not been established. First-line treatment of NVP, as recommended by several leading healthcare and professional organizations, is the combination of doxylamine and pyridoxine. This combination, formulated as a 10 mg/10 mg delayed-release tablet, was approved by the US Food and Drug Administration (FDA) for the treatment of NVP in April 2013 under the brand name Diclegis(®), and has been on the Canadian market since 1979, currently under the brand name Diclectin(®). The efficacy of Diclegis(®)/Diclectin(®) has been demonstrated in several clinical trials, and, more importantly, studies on more than 200,000 women exposed to doxylamine and pyridoxine in the first trimester of pregnancy have demonstrated no increased fetal risk for congenital malformations and other adverse pregnancy outcomes. The present review aims to present the scientific evidence on the effectiveness and fetal safety of Diclegis(®)/Diclectin(®) for the treatment of NVP to justify its use as first-line treatment for NVP.
... However, it is important to adjust the schedule according to the pattern of NVP in a particular individual. Higher-than-standard doses of pyridoxine/doxylamine have been studied in pregnancy with some women requiring up to 120 mg (12 tablets) a day with no apparent increased of maternal or fetal risks 26 . ...
Article
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Objective: Nausea and vomiting of pregnancy is a common disease that affects many women suffering from mild to severe symptoms. Amongst the different treatments, a fixed dose combination of doxylamine and pyridoxine has been proven safe and effective although the mechanism of action is not well established. There are different pharmaceutical dosage forms in the European market. The objective of this study was to compare the characteristics of a capsule formulation, Cariban® and a tablet formulation, Xonvea® to evaluate the potential impact of their release profiles on their onset of action. Materials and methods: 10 mg/10 mg of doxylamine succinate/pyridoxine hydrochloride capsules (Cariban®) and tablets (Xonvea®) were used as reference materials. Appearance, mass, composition, and in vitro dissolution profiles were compared. Bibliographic data from 4 pharmacokinetic studies of Xonvea® and 1 pharmacokinetic study of Cariban® was reviewed. Results: In vitro dissolution studies showed significant differences in dissolution profiles of tablets and capsules. The later exhibiting some release of both drug substances in acid conditions followed by a non-complete release after a total of 3 hours while the tablets demonstrated gastro-resistant properties and rapid API release in about 20-30 minutes after the acid stage. Comparison of PK data showed greater Cmax for pyridoxine. Conclusions: At pH 6.8, complete and faster release of the fixed dose combination for Xonvea® gastro-resistant tablets compared to Cariban® capsules could possibly explain the greater Cmax observed in vivo for the tablet's formulation. This could translate into faster onset of action and relief of nausea for pregnant women taking the tablets vs. the capsules.
... 18 En 2002, Laura Magee y Paolo Mazzotta publican un análisis de la evidencia sobre la eficacia y seguridad de los agentes farmacológicos utilizados para el tratamiento de la NVP, incluyendo en su estudio el análisis de los fármacos antihistamínicos, entre ellos el uso de doxilamina y piridoxina, volviendo a citar los dos metaanálisis previamente reportados, así como el metaanálisis publicado por Seto y colaboradores en 1997, quienes encuentran un riesgo para el uso de antihistamínicos y desarrollo de malformaciones congénitas de 0.76 (IC95% de 0.60 a 0.94). 19 En 2003, Jewell & Young publican una revisión sistemática de la evidencia en la biblioteca Cochrane, con la finalidad de identificar en forma exhaustiva todos los ensayos clínicos publicados sobre la eficacia y seguridad de los diferentes tratamientos existentes para la náusea y el vómito en las fases tempranas del embarazo. Para el caso de la doxilamina y la piridoxina identifican sólo un total de tres ensayos clínicos (Greiger 1959, McGuiness 1971 y Wheatley www.medigraphic.org.mx ...
Article
More than 80% of the pregnant women, in one moment of the gestation have nausea and vomiting, than can produce important complications like deshydratation, hospital internment, and affectation of the quality of life. There are controversies about the safety of the combination of doxylamine + pyridoxine for the treatment of the nausea and vomiting of pregnancy (NVP). Objective: To evaluate the efficacy and safety of the combination of doxylamine + pyridoxine for the treatment of NVP using the methodological tool of a systematic review. Materials and methods: For the systematic review we include case-control studies, cohort's studies, and controlled trials, performed in pregnant women with NVP and that were treatment with doxylamine + pyridoxine. We considered the number of congenital defects as the principal outcome variable. We made the systematic review using the following data bases: PubMed (1966 to may 2009), Embase (1988 to may 2009), LILACS (1990 to may 2009), ARTEMISA (review of the 11ª edition to December 2004), Cochrane controlled trials register, Bandolier y DARE. The statistical analysis was made with the calculation of relative risk (RR) and 95% confidence interval (CI 95%) with the Mantel-Hanezel model. Results: There was no risk increase of congenital defects in children born of women with NVP treated with the combination of doxylamine + pyridoxine. The RR identified for all congenital defects was 0.97(IC95% de 0.92 a 1.02), p = 0.168; for cardiovascular defects the RR was 0.92 (CI95% 0.80-1.05), for neural tube defects the RR was 0.99 (CI95% 0.78-1.26), and for urinary defects the RR was 0.99 (CI95% 0.8-1.20). The administration of doxylamine + pyridoxine reduced the risk of NVP persistence with a RR of 0.55 (CI95% 0.41-0.74), p
... However, a review of the safety of doxylamine/pyridoxine taken in doses as high as 5 to 12 tablets a day has been reported. 32 Preemptive treatment in multipara with a high risk of recurrence of severe NVP has been evaluated. 43 Doxylamine/pyridoxine treatment reduced the duration and severity of NVP in women at increased risk of NVP who took the medication at the onset of pregnancy. ...
Article
Objectives: To review the evidence-based management of nausea and vomiting of pregnancy and hyperemesis gravidarum. Evidence: MEDLINE and Cochrane database searches were performed using the medical subject headings of treatment, nausea, vomiting, pregnancy, and hyperemesis gravidarum. The quality of evidence reported in these guidelines has been described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on Preventative Health Care. Benefits: Nausea and vomiting of pregnancy has a profound effect on women's health and quality of life during pregnancy as well as a financial impact on the health care system, and its early recognition and management is recommended. COST: Costs, including hospitalizations, additional office visits, and time lost from work, may be reduced if nausea and vomiting in pregnancy is treated early. Recommendations:
... Thus, the use of a higher drug dosage, as in our study, can be expected to achieve better control of symptoms. Atanackovic and co-workers [15] reported the safety of a higher than standard dose of Diclectin, with doses ranging from 0.1 to 2.0 mg/kg (1-12 tablets Diclectin per day). Their findings are in accordance with our study, showing significant lack of adverse effects among mothers and exposed infants. ...
Article
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Background: Diclectin® (pyridoxine 10 mg and doxylamine 10 mg) has traditionally been used to treat nausea and vomiting of pregnancy (NVP); however, this drug is unavailable in many countries. Objectives: To evaluate the efficacy and safety of a simple bi-daily treatment regimen with the combination of pyridoxine (50 mg twice daily) and doxylamine (25–50 mg) as an alternative treatment for NVP. methods: A prospective case-controlled observational study of mother-infant pairs was conducted between February 2008 and December 2010. All women who contacted the Beilinson Teratology Information Service (BELTIS) regarding treatment of NVP were eligible for inclusion. Using data on NVP severity, treatment efficacy and outcomes, we compared the two groups of women: those treated with the combination of pyridoxine and doxylamine (treatment group, n=29) and those treated with metoclopramide (control group, n=29). results: Moderate to severe symptoms were present in 97% of the treatment group women vs. 69% of control group women (P < 0.01). Despite increased symptom severity in the treatment group, the combination regimen was efficacious: 20/29 (69%) vs. 18/25 (72%) in the treatment vs. control women respectively (P = 0.65). There were no congenital anomalies in the treatment group. Follow-up was normal for all infants. conclusions: Bi-daily combination therapy with pyridoxine and doxylamine for NVP is safe, has comparable efficacy to metoclopramide, and is a treatment alternative in countries where Diclectin is not available. Despite symptoms warranting counseling by a teratology information service, more than a third of women do not take the suggested treatment.
... Various trials failed to confirm this report of any malformations, [24] even with higher dose [25] and thus doxylamine with pyridoxine is most extensively used drug to treat NVPs today. ...
Article
Nausea and vomiting are common symptoms experienced by 50– 90% of women’s in early pregnancy. ‘Morning sickness’ is a misnomer frequently used to describe nausea and vomiting in pregnancy (NVP), although the symptoms may persist the whole day and/or night. Pregnant women experience these symptoms mainly in the first trimester between 6 and 12 weeks of gestation, few of them continue till 20 weeks of gestation while in few others it continues throughout the pregnancy. The problem peaks at 9-week gestation, and approximately 60% of NVPs resolve by the end of first trimester. In a very small minority of these patients, the symptoms become severe leading to dehydration, weight loss, excessive vomiting, and mandate hospital admission; this condition is known as Hyperemesis Gravidarum. Fairweather D.V proposed the most widely used definition of Hyperemesis Gravidarum (HG). He defined HG based on the symptoms, vomiting exceeding three times a day with significant ketonurea or weight loss more than or equal to 5% of pre pregnancy weight, electrolytic imbalance or fluid depletion, and onset occurs at 4 to 8 weeks of pregnancy till 14 to 16 weeks. Nausea and vomiting in pregnancy is of multifarious etiology (fluctuating levels of progesterone, estrogens, Thyroid Stimulating Hormone (TSH), slow peristaltic movement of Gastrointestinal (GI) tract); however, the exact mechanism remains still unclear. Given the uncertainty in treatment of NVPs, both patients and healthcare practitioners often fear the use of antiemetic medications in pregnancy due to the potential risk to fetus and mother. The manifestation of nausea and vomiting in pregnancy is different among each woman, so its management should be tailored similarly. An early treatment of nausea and vomiting is important and beneficial since it prevents a more severe form of occurring, or a possible hospitalization, and prevents both emotional and psychological problems. It is very important for the women and the healthcare providers to understand that a safe and effective NVP treatment benefits both fetus and mother, thus all the treatment options should be open and considered. Nonetheless, given the widespread prevalence of nausea and vomiting, its adverse effects and effects on psychological conditions of pregnant women, it is necessary to be treated effectively and safely during embryonic and fetal developmental stages. First trimester exposure is important to be assessed to monitor the teratogenic potential of the drug; however, randomized control trials are rarely conducted for pregnant women for ethical reasons. Whereas the epidemiological studies done are observational and lack population strength to establish safety and risk involved. This review will mainly focus on pharmacological drugs used in treatment of NVP, and explore their safety and efficacy and evidence based practice. There have been many studies examining the safety of drugs used in NVPs and few of them are covered in this review. The dietary, lifestyle modifications, and nonpharmacological approaches are not covered in this section.
... In Canada, the doxylamine succinate-pyridoxine hydrochloride combination (Diclectin®) has been available since 1979 [17], with a large number of studies corroborating the initial FDA evaluation of its efficacy and safety [18][19][20]. The present study had a placebo arm, as symptoms of NVP tend to subside spontaneously in most women by the end of the first trimester [1]. ...
Article
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Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy Clinical Trial Registration No: NCT00614445 .
... 18 En 2002, Laura Magee y Paolo Mazzotta publican un análisis de la evidencia sobre la eficacia y seguridad de los agentes farmacológicos utilizados para el tratamiento de la NVP, incluyendo en su estudio el análisis de los fármacos antihistamínicos, entre ellos el uso de doxilamina y piridoxina, volviendo a citar los dos metaanálisis previamente reportados, así como el metaanálisis publicado por Seto y colaboradores en 1997, quienes encuentran un riesgo para el uso de antihistamínicos y desarrollo de malformaciones congénitas de 0.76 (IC95% de 0.60 a 0.94). 19 En 2003, Jewell & Young publican una revisión sistemática de la evidencia en la biblioteca Cochrane, con la finalidad de identificar en forma exhaustiva todos los ensayos clínicos publicados sobre la eficacia y seguridad de los diferentes tratamientos existentes para la náusea y el vómito en las fases tempranas del embarazo. Para el caso de la doxilamina y la piridoxina identifican sólo un total de tres ensayos clínicos (Greiger 1959, McGuiness 1971 y Wheatley www.medigraphic.org.mx ...
... The inverse association between vitamin B-12 and birth length in our study therefore requires replication in future studies. Similar to most previous observational (20,22,29,43) or intervention (44,45) studies, we did not find any significant associations between maternal vitamin B-6 status and birth weight or gestational age-related outcomes. In one clinical trial, vitamin B-6 supplementation was associated with reduced birth weight of offspring compared with placebo (46). ...
Article
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Maternal folate, vitamin B-12, and vitamin B-6 concentrations during pregnancy have been shown to influence birth outcomes, but the evidence is inconclusive. We aimed to examine the associations of maternal B-vitamin status with gestational age, birth weight, and length in a birth cohort study in Singapore. Maternal blood samples (n = 999) collected during weeks 26-28 of gestation were assayed for plasma folate, vitamin B-12, and vitamin B-6 concentrations. Birth weight and gestational age data were obtained from hospital records, and other anthropometric variables were measured within 72 h after birth. Relations between B-vitamin status and birth outcomes were assessed by linear or logistic regression with adjustment for potential confounders. Median (IQR) plasma concentrations were 34.4 (24.5-44.6) nmol/L for folate, 209 (167-258) pmol/L for vitamin B-12, and 61.8 (25.9-113) nmol/L for vitamin B-6. We found that higher plasma folate concentrations were associated with a longer gestational age (0.12 wk per SD increase in folate; 95% CI: 0.02, 0.21) and tended to be associated with lower risk of all preterm birth (delivery at <37 wk of gestation; OR: 0.79; 95% CI: 0.63, 1.00) and spontaneous preterm birth (OR: 0.76; 95% CI: 0.56, 1.04). Overall, concentrations of maternal folate, vitamin B-12, and vitamin B-6 were not independently associated with birth weight or being born small for gestational age (SGA; birth weight <10th percentile for gestational age). Higher maternal folate concentrations during late pregnancy were associated with longer gestational age and tended to be associated with a lower risk of preterm birth in this multiethnic Asian population. In contrast, the results of our study suggested little or no benefit of higher folate concentrations for reducing the risk of SGA or of higher vitamin B-6 and vitamin B-12 concentrations for reducing the risk of preterm birth or SGA. © 2015 American Society for Nutrition.
... 40 The effectiveness and safety of Diclectin have been documented in a large number of studies. [44][45][46] The pharmacokinetics of Diclectin was compared between pregnant and nonpregnant women and no difference was found in the apparent clearances of doxylamine and pyridoxal 5'-phosphate (the active metabolite of vitamin B 6 ) between the two groups. Therefore, the scientists concluded that there was no pregnancy-induced effect in the apparent clearances of either doxylamine or pyridoxal 5'-phosphate in women during the first trimester of pregnancy, despite the existence of nausea and vomiting. ...
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Nausea and vomiting in pregnancy can have serious adverse effects on the quality of a woman's life, affecting her occupational, social, and domestic functioning, and her general well-being; therefore, it is very important to treat this condition appropriately and effectively. Evidence-based algorithms support the use of oral pyridoxine alone or combined with doxylamine as first-line treatment. Promethazine or dimenhydrinate, known as a second-line treatment, should be added to the first-line treatment or should be added only to pyridoxine according to different algorithms. In most of the world, there is a lack of approved medicines using this combination approach known as the first-line treatment. Therefore, compounding pharmacists should supply the demand by compounding 10-mg pyridoxine hydrochloride and 10-mg doxylamine succinate slow-release capsules. Since transdermal promethazine does not exist world wide, and, since this medicine has significant added values compared to the oral/rectal dosage forms, compounding pharmacists should offer physicians transdermal promethazine as a second-line therapy in nausea and vomiting in pregnancy. This review summarizes the nausea and vomiting in pregnancy problems and discusses the compounding opportunities that exist in this common and wide-spread pathology in order to improve a woman's quality of life.
... < 0.01). Women whose peak PUQE scores were in the severe range [13,14,19] had median WB score of 1.5/10, those with moderate PUQE scores [7][8][9][10][11][12] had median WB scores of 5/10, and those with mild symptoms (PUQE < or equal to 6) had median WB scores of 7.5/10. ...
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. To determine whether the initiation of treatment (preemptive treatment) before the symptoms of nausea and vomiting of pregnancy (NVP) versus when the symptoms begin can improve the outcome in patients at a high risk for recurrence of severe NVP. . Prospective, randomized controlled trial. . Preemptive therapy conferred a significant reduction in HG as compared to the previous pregnancy ( = 0.047). In the preemptive arm, there were 2.5-fold fewer cases of moderate-severe cases of NVP than those in the control group (15.4% versus 39.13%) in the first 3 weeks of NVP ( = 0.05). In the preemptive group, significantly more women had their NVP resolved before giving birth (78.2% versus 50%) ( < 0.002). . Preemptive treatment with antiemetics is superior to the treatment that starts only when the symptoms have already occurred in decreasing the risk of severe forms of NVP.
... 25 Doses of 50-510 mg/ day taken during the first trimester have not been associated with adverse fetal outcomes. 24,26,27 In addition, pyridoxine supplementation has been used therapeutically to suppress prolactin secretion and inhibit lactation, 28 though its efficacy has not been demonstrated consistently. [29][30][31][32] Vitamin B12 ...
Article
The water-soluble vitamins B6, B12 and C play important roles in maternal health as well as fetal development and physiology during gestation. This systematic review evaluates the risks and benefits of interventions with vitamins B6, B12 and C during pregnancy on maternal, neonatal and child health and nutrition outcomes. Relevant publications were identified by searching PubMed, Popline and Web of Science databases. Meta-analyses were conducted for outcomes where results from at least three controlled trials were available. Potential benefits of vitamin B6 supplementation were reduction in nausea and vomiting, improvement in dental health, and treatment of some cases of anaemia. In meta-analysis based on three small studies, vitamin B6 supplementation had a significant positive effect on birthweight (d = 217 g [95% confidence interval (CI) 130, 304]). Interventions with vitamin C alone or combined with vitamin E did not systematically reduce the incidence of pre-eclampsia, premature rupture of membranes, or other adverse pregnancy outcomes. In meta-analyses, vitamins C and E increased the risk of pregnancy-related hypertension (relative risk 1.10 [95% CI 1.02, 1.19]). Effects of vitamin B6 or C intervention on other neonatal outcomes, including preterm birth, low birthweight, and perinatal morbidity and mortality, were not significant. Data on child health outcomes were lacking. Despite the prevalence of vitamin B12 deficiency amongst populations with limited intake of animal source foods, no intervention trials have evaluated vitamin B12 supplementation before or during pregnancy. In conclusion, existing evidence does not justify vitamin C supplementation during pregnancy. Additional studies are needed to confirm positive effects of vitamin B6 supplementation on infant birthweight and other outcomes. While vitamin B12 supplementation may reduce the incidence of neural tube defects in the offspring based on theoretical considerations, research is needed to support this hypothesis.
... This dosage can be adjusted for severity of symptoms and/or maternal BMI. If the patient has a higher BMI, she may take up to 8–12 tablets a day without increasing maternal adverse effects, fetal risk, degree of tiredness, and birth defects [51]. These higher doses appear to be more efficacious. ...
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NVP occurs in 50-90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with any combination of signs and symptoms. It is appropriate to take the pregnancy-related versus nonpregnancy-related approach when determining the cause of nausea and vomiting but other causes should be considered. The most common etiologies for NVP include the hormonal changes associated with pregnancy, the physiologic changes in the gastrointestinal tract, and a genetic predisposition. Up to 10% of women will require pharmacotherapy to treat the symptoms of NVP despite conservative measures. ACOG currently recommends that a combination of oral pyridoxine hydrochloride and doxylamine succinate be used as first-line treatment for NVP if pyridoxine monotherapy does not relieve symptoms. A review of NVP and early pharmacotherapeutic management is presented due to the fact that NVP is largely undertreated, and investigations into the safe and effective pharmacotherapies available to treat NVP are lacking.
... Antiemetic agents and supposed dosage in hyperemesis gravidarum, adapted from references [13,62,98] ...
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Up to 90% of pregnant women experience nausea and vomiting. When prolonged or severe, this is known as hyperemesis gravidarum (HG), which can, in individual cases, be life threatening. In this article the aetiology, diagnosis and treatment strategies will be presented based on a selective literature review. Treatment strategies range from outpatient dietary advice and antiemetic drugs to hospitalization and intravenous (IV) fluid replacement in persistent or severe cases. Alternative methods, such as acupuncture, are not yet evidence based but sometimes have a therapeutic effect. In most cases, the condition is self limiting and subsides by around 20 weeks gestation. More severe forms require medical intervention once other organic causes of nausea and vomiting have been excluded. In addition, a psychosomatic approach is often helpful. In view of its potential complexity, general practitioners and obstetricians should be well informed about HG and therapy should be multimodal.
... The safety profile of both of these agents is very good. [85,112,113] If a woman needs relief from occasional retching and/or vomiting, phenothiazines will reliably stop vomiting episodes, and most professional association guidelines recommend adding phenothiazines first for women who need relief from vomiting. [92,110,114] Phenothiazines taken orally or used as a rectal suppository can be helpful for breakthrough vomiting, but because they are associated with significant sedation, women may not feel comfortable taking them. ...
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Nausea and vomiting in pregnancy is a continuum that ranges from mild discomfort to significant morbidity. Systematic assessment with the use of the Pregnancy-Unique Quantification of Emesis/Nausea (PUQE) index and timely treatment using evidence-based protocols can decrease the time that many women spend using treatment recommendations that are inadequate. This article reviews the epidemiology of nausea and vomiting in pregnancy, use of the PUQE index, and the evidence for specific nonpharmacologic and pharmacologic treatment regimens. A protocol for clinical management is presented.
... A single 25-mg dose of the antihistamine doxylamine (Unisom) tablet taken at night can be used in combination with vitamin B 6 (10-25 mg 3 times daily). 9 Acupressure was found in 6 of 7 randomized trials to be effective for relieving morning sickness. 10 Acupressure wristbands are readily available over the counter, and many women fi nd them a less expensive alternative to acupuncture. ...
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Women are the largest consumers of healthcare, and this extends to their utilization of complementary and alternative medicine (CAM). Researchers have attempted to uncover the reasons why women turn to CAM in general and to botanical medicine in particular. Desire to have personal control over their health has been cited as the strongest motive for women to use herbal medicine. Second was dissatisfaction with conventional treatment and its disregard for a holistic approach, as well as concerns about the side effects of medications.' These concerns may explain, in part, the fact that many women use herbal remedies during pregnancy. A survey of 578 pregnant women in the eastern United States reported that 45% of respondents had used herbal medicines, and a survey of 588 women in Australia revealed that 36% had used at least 1 herbal product during pregnancy. Women probably feel comfortable using herbal remedies because of their perceived safety, easy access, and the widespread availability of information about them (ie, Internet, magazines, books). While it is true that many botanicals are mild in both treatment effects and side effects, the data regarding safety during pregnancy are very limited. Given the small sample sizes in clinical trials studying botanicals in pregnant women, only large differences in measures of pregnancy outcomes would likely be detected. For example, if an herb were thought to increase the rate of spontaneous abortion from 6% to 7%, a sample size of more than 19000 women would be needed. It is highly unlikely that there will be any studies of a botanical (or drug) with this large a sample size. So when addressing the safety of an herb during pregnancy, we must look at the totality of the evidence, which includes traditional and contemporary use, animal studies, pharmacological studies, and clinical trial data, when available. Survey data tell us that women often do not share their use of herbal remedies with their healthcare providers due to fear of offending providers or to the belief that clinicians will be ignorant about their use. Practitioners should maintain an open and respectful demeanor when counseling pregnant and nursing women about the use of botanical medicines, and they should know how to access unbiased and authoritative information sources, so they may reliably answer questions on inadvertent exposures and provide guidance on herbal products that might be beneficial.
... We used 2 groups of women to compare the endpoints, with data collected in the same fashion. These groups were 1) disease-matched women suffering from depression but taking other nonteratogenic antidepressants and 2) women exposed to other nonteratogenic drugs (specifically, sumatriptin [15], dextromethorphan [16], diclectin [17], and clarithromycin [18]). They were also compared for age, smoking, and alcohol use and matched for time of call, because reported spontaneous abortions rates are probably higher when women call earlier in pregnancy. ...
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Trazodone and nefazodone are phenylpiperazine antidepressants. Currently, there are no adequate, well-controlled studies on the fetal safety of these drugs. Our primary objective was to determine whether the use of trazodone or nefazodone during pregnancy is associated with an increased risk for major malformations. Secondary outcomes of interest included rates of spontaneous and therapeutic abortions, rates of premature labour, and birth weight. Pregnant women from 5 centres who had been exposed to these drugs (n = 147) were enrolled in the study during their first trimester. We compared the women with 2 groups of women who took either other antidepressant drugs (n = 147) or nonteratogenic drugs (n = 147). All the women were followed up after delivery to ascertain pregnancy outcome and the health of the baby. We have completed 147 follow-ups. There were 121 (82.4%) live births, 20 (13.6%) spontaneous abortions, and 6 (4%) therapeutic abortions. Of the live births, there were 2 (1.6%) major malformations. In all cases, drug exposure occurred during the first trimester, with 52 (35%) of the women using these drugs throughout pregnancy. The mean gestational age at birth was 38 weeks (SD 4.2), and the mean birth weight was 3306.34 g (SD 655). We found no statistically significant differences among the 3 groups in any of the endpoints of interest that we examined. Of the sample, 58 women were exposed to trazodone, and 89 were exposed to nefazodone. Our results suggest that these drugs do not increase the rates of major malformations above the baseline rate of 1% to 3%.
Article
Objective: We aimed to research the effects of Dimenhydrinate (DMH) and Ondansetron, used during pregnancy, on the organs of young rats in postnatal period in terms of histopathologically. Material and Methods: In the study, 30 Wistar-Albino type female rats have been used. The rats have been divided into three groups: group 1 (control, n: 10), group 2 (DMH, n: 10) and group 3 (ondansetron, n: 10). We kept them together for pregnancy starting from the first day of pregnancy, a dose of 115 mg/kg/day intramuscular DMH (group 2) and 10 mg/kg/day intraperitoneally ondansetron (group 3) have been given to pregnant rats for a week. As for the control group (group 1), a dose of intramuscular 0.9% NaCl has been given for the same period of time. After birth, the numbers of babies have been ascertained. Brain, lung, heart, liver and kidney tissues have been taken from the babies of each group during their newborn, lactation and adulthood periods. After histologic tissue follow-up methods, the preparates have been painted with Haematoxylin-Eosin (H&E) and then evaluated underlight microscope. Results: There was no significant difference between the controls and experiment groups in point of histopathological change on the organs of the young rats. Conclusion: It has been concluded that DMH and ondansetron treatment during pregnancy period has no histopathological effect on the organs of the young rats.
Article
Of all pregnant women, 50-80% suffers from nausea and vomiting of pregnancy (NVP), also known as morning sickness-although symptoms may persist throughout the whole day. Usually limited to the first trimester, NVP may continue for the entire pregnancy. NVP may range from mild discomfort to severe vomiting and nausea, weight loss, dehydration and metabolic compromise. In severe cases, NVP can be fatal. NVP poses a serious socioeconomic burden, as 25% of women suffering from NVP miss work as a result of their symptoms. The pathogenesis of NVP has been attributed to multiple factors such as elevated levels of prostaglandin levels (by relaxing the gastroesophageal sphincter), gastric dysrhythmia, vitamin B6 deficiency, and hyperolfaction. The chapter discusses the diet manipulations and treatment that can curb NVP, along with some complementary treatment options, such as acupuncture and acupressure, hypnosis, and the consumption of ginger. First- and second-generation antihistamines, especially Doxylamine in combination with vitamin B6 are a safe and effective treatment for NVP. Dopamine antagonists are also widely used for treatment of NVP, especially in countries where Benedictine is unavailable. Apart from these, pyridoxine, thiamine, serotonin antagonists, and glucocorticoids can be used to treat NVP; their pharmacology and toxicology are explained in the chapter.
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Doxylamine (succinate), a monoethanolamine derivative, is an antihistamine with pronounced sedative and antimuscarinic effects. Well absorbed after oral administration, it has subsequently been used in the short-term treatment of .... .
Article
Background & Aims: Due to the importance of a suitable treatment for nausea and vomiting during pregnancy and reducing maternal and fetal complications, and the beneficial effect of Ondansetron in the treatment of nausea and vomiting compared with promethazine, this study was performed. Methods: In this case-control study, 60 pregnant women under 20 weeks of gestation with hyperemesis gravidarum were compared. The subjects were randomly assigned to two groups after excluding patients with a multiple pregnancy, non-viable pregnancy, and underlying diseases that cause nausea. One group received Ondansetron and another received promethazine. After 48 hours, responses and side effects were assessed using 2 questionnaires. Finally, response to treatment and side effects of the two drugs were compared. Results: Although the response to treatment with Ondansetron was obviously better than promethazine, this was not statistically significant. The only clear side effect of promethazine was drowsiness. Conclusion: The response to Ondansetron was good, and there are no reports, in the literature, of it having any adverse effects on the fetus. Moreover, untreated conditions may be followed by many maternal and fetal complications. Therefore, it is better to use Ondansetron in the first course of hospitalization. Although, due to the limited sample size in this study, more studies with larger sample sizes are recommended in order to obtain more accurate results.
Article
Nausea and vomiting of pregnancy (NVP) affects up to 80% of all women to some degree during their pregnancies. Diclectin (doxylamine and pyridoxine [vitamin B6]) has been on the Canadian market for many years and is indicated as the drug of choice for the treatment of NVP. However, some women choose not to treat NVP with pharmacologic measures, perhaps due to a persistent fear of teratogenic risk. The objective of this study was to determine the factors that influence a woman’s decision not to treat NVP with pharmacologic measures. Fifty-nine women recruited from the Motherisk Nausea and Vomiting Helpline completed a questionnaire. All were informed that Diclectin was considered safe for use during pregnancy. At a follow-up telephone call, 34% were not using any pharmacologic treatment, and of those who were taking the drug, 26% were using less than the recommended dose. Reasons cited for not using the medication were insufficient safety data, preference for non-pharmacologic methods, and being made to feel uncomfortable by the physician. Of the women who did use Diclectin, the most convincing reassuring information that it was safe to use came from friends and family. Many other factors play a large role in a women’s decision making.
Article
Studies in the general population have proposed links between nutrition and depression, but less is known about the perinatal period. Depletion of nutrient reserves throughout pregnancy and delayed postpartum repletion could increase the risk of perinatal depression. We examined the relationships of plasma folate and vitamin B12 concentrations during pregnancy with perinatal depression. At 26th-28th weeks of gestation, plasma folate and vitamin B12 were measured in women from the GUSTO mother-offspring cohort study in Singapore. Depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3-month postpartum. EPDS scores of ≥15 during pregnancy or ≥13 at postpartum were indicative of probable depression. Of 709 women, 7.2% (n = 51) were identified with probable antenatal depression and 10.4% (n = 74) with probable postnatal depression. Plasma folate concentrations were significantly lower in those with probable antenatal depression than those without (mean ± SD; 27.3 ± 13.8 vs 40.4 ± 36.5 nmol/L; p = 0.011). No difference in folate concentrations was observed in those with and without probable postnatal depression. In adjusted regression models, the likelihood of probable antenatal depression decreases by 0.69 for every unit variation (increase) in folate (OR = 0.69 per SD increase in folate; 95% CI: 0.52, 0.94). Plasma vitamin B12 concentrations were not associated with perinatal depression. Lower plasma folate status during pregnancy was associated with antenatal depression, but not with postnatal depression. Replication in other studies is needed to determine the direction of causality between low folate and antenatal depression. NCT01174875.
Article
Most bioequivalence (BE) studies are conducted in males with the assumption that variability in pharmacokinetics is similar between the sexes. The purpose of this single-center, reference replicate study was to determine the effect of sex on the pharmacokinetics and BE of doxylamine-pyridoxine 10 mg-10 mg delayed-release tablets. Healthy males (n = 12) and non-pregnant females (n = 12) were administered two tablets, and blood sampling was conducted from 1 hour pre-dose until 72 hours post-dose. After 21 days, dose administration and blood sampling were re-conducted. All analytes were measured using liquid chromatography-tandem mass-spectrometry. Pharmacokinetic parameters were calculated for each study period using standard, non-compartmental methods, and differences were assessed using ANOVA. BE testing was conducted using the relative 90% confidence interval for the AUC0-t for each analyte. Females had significantly larger AUC0-t for doxylamine, 1,550 ng h/mL (coefficient of variance [CV = 19%]) versus 1,272 ng h/mL (CV = 21%; P ≤ .05), and pyridoxine, 35 ng h/mL, (CV = 43%) versus 25 ng h/mL (CV = 31%; P ≤ .05) compared to males. A higher Cmax for doxylamine was observed in females, 107 ng/mL (CV = 16%), compared to males, 86 ng/mL (CV = 15%) (P ≤ .05). BE testing did not demonstrate bioequivalence between males and females. Pharmacokinetic differences observed between the sexes have implications for future BE studies using doxylamine-pyridoxine.
Article
The US FDA approval in April 2013 of Diclegis®, the doxylamine-pyridoxine combination for morning sickness, is a major milestone, particularly since it is indicated for use in pregnancy and the FDA has labeled it a pregnancy category A drug the strongest evidence of fetal safety. After thirty years of being orphaned from an FDA- labeled drug for the most common medical condition in pregnancy, American women and their health care providers have a therapeutic solution that is likely to positively impact millions of women each year. This review highlights the milestones of this antiemetic agent over the last 40 years.
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Vomiting of pregnancy is a physiological symptom of the first trimester and is a frequent reason for consultation in emergency as well as hospitalization in the severe forms (Hyperemesis gravidarum). Though strong the aversion usually developed against the hospitalized patients for H. gravidarum may be, it is important to understand the distress of these women with a symptom difficult to endure, which often reflects a psychical conflict with respect to their pregnancy. The gynecologist must be the somatic doctor who deals with the symptom and its sometimes disastrous clinical consequences, whereas the psychologist or the psychiatrist plays a fundamental role in this pathology. Indeed, he will lead the patient to work on how she feels her pregnancy, to give it a place in her personal history and to understand her contradictory feelings with regard to this pregnancy.
Article
Diclectin (pyridoxine 10 mg and doxylamine 10 mg) has traditionally been used to treat nausea and vomiting of pregnancy (NVP); however, this drug is unavailable in many countries. To evaluate the efficacy and safety of a simple bi-daily treatment regimen with the combination of pyridoxine (50 mg twice daily) and doxylamine (25-50 mg) as an alternative treatment for NVP. A prospective case-controlled observational study of mother-infant pairs was conducted between February 2008 and December 2010. All women who contacted the Beilinson Teratology Information Service (BELTIS) regarding treatment of NVP were eligible for inclusion. Using data on NVP severity, treatment efficacy and outcomes, we compared the two groups of women: those treated with the combination of pyridoxine and doxylamine (treatment group, n=29) and those treated with metoclopramide (control group, n=29). Moderate to severe symptoms were present in 97% of the treatment group women vs. 69% of control group women (P < 0.01). Despite increased symptom severity in the treatment group, the combination regimen was efficacious: 20/29 (69%) vs. 18/25 (72%) in the treatment vs. control women respectively (P = 0.65). There were no congenital anomalies in the treatment group. Follow-up was normal for all infants. Bi-daily combination therapy with pyridoxine and doxylamine for NVP is safe, has comparable efficacy to metoclopramide, and is a treatment alternative in countries where Diclectin is not available. Despite symptoms warranting counseling by a teratology information service, more than a third of women do not take the suggested treatment.
Article
Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied. To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population. Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight. The mean DOX-AUC0→∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0→∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0→∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%. There was a 2.1-fold variability in the DOX-AUC0→∞ and 6.5-fold variability in the PLP-AUC0→∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.
Article
To evaluate the effectiveness of Diclectin (doxylamine succinate 10 mg-pyridoxine hydrochloride 10 mg, delayed-release preparation) as compared with placebo for nausea and vomiting of pregnancy. A randomized, double-blind, multicenter placebo controlled trial studying pregnant women suffering from nausea and vomiting of pregnancy, analyzed by intention to treat. Women received Diclectin (n = 131) or placebo (n = 125) for 14 days. Nausea and vomiting of pregnancy symptoms were evaluated daily using the pregnancy unique quantification of emesis scale. Diclectin use resulted in a significantly larger improvement in symptoms of nausea and vomiting of pregnancy compared with placebo based on both the pregnancy unique quantification of emesis score (-4.8 ± 2.7 vs -3.9 ± 2.6; P = .006) and quality of life. After the trial, 64 (48.9%) women receiving Diclectin asked to continue compassionate use of their medication, as compared with 41 (32.8%) of placebo-treated women (P = .009). Diclectin delayed release formulation of doxylamine succinate and pyridoxine hydrochloride is effective and well tolerated in treating nausea and vomiting of pregnancy.
Article
With up to 80% of pregnant women experiencing nausea and vomiting of pregnancy (NVP), it is critical to have a graded scale of its severity as a guide for appropriate treatment. In 2002 we introduced the Pregnancy-Unique Quantification of Emesis (PUQE) scoring system, which assessed the severity of nausea and vomiting in pregnancy (NVP) based on three physical symptoms: nausea, vomiting, and retching over the previous 12 hours. We present here validation of an extension of the original PUQE, by assessing NVP over 24 hours. This extension is deemed more clinically relevant, because assessment of symptoms over only 12 hours may encompass sleeping hours and hence may not adequately capture the length and severity of the symptoms. In this study we assessed the external validity of the new PUQE-24 by examining its ability to evaluate several characteristics associated with NVP: (a) ability to take multivitamin supplements; (b) rates of hospitalization and emergency room visits for severe symptoms; (c) sleep patterns; (d) liquid intake; and (e) the woman's self-rated well-being scores. Data collected prospectively from 315 women counselled via the Motherisk NVP line were used for the validation. PUQE-24 showed strong correlation with all parameters examined except for sleep patterns and hydration status. The well-being score, however, correlated significantly with hydration status. Capturing 24 hours rather than 12 hours of symptoms may better direct management of NVP and predict its outcome.
Article
The delayed-release combination of doxylamine succinate and pyridoxine hydrochloride was the most commonly used antiemetic (Bendectin) approved by FDA for nausea and vomiting of pregnancy (NVP) until its removal of the market in 1983. The drug is widely used today in Canada (Diclectin). The pharmacokinetics of Diclectin has never been described in humans. To compare the pharmacokinetics of Diclectin to oral solutions of its two components. A randomized, cross over, open label design, comparing the pharmacokinetics of Diclectin to those of the oral solutions of the two components in 18 healthy adult, non pregnant women of childbearing age. Diclectin exhibited similar oral bioavailability to those of the oral solutions. In contrast, the time-to-peak, (Tmax), reflecting the rate of absorption, was 3-6 times longer for the two components of the delayed-release drug confirming its delayed-release characteristics. The pharmacokinetic profile of Diclectin well explains its documented delayed efficacy.
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Ayurveda, the traditional Indian medical system, is receivingincreasing attention worldwide. A retrospective study was conducted to determine the effectiveness ofAyurvedic constitution-based diets on weight loss patterns of obese adults. DESIGN, SETTING, SUBJECTS, AND INTERVENTION: Records of 200 obese adults, both male and female, who had completed 3 months of the diet therapy at Ayurvedic clinics, were examined and data collated. Techniques used included a checklist of personality traits, physical signs, and food likes and dislikes to determine the dosha. Based on the predominant doshas, diets were prescribed and closely monitored for a period of 3 months. Records of height and weight and chest, abdominal, waist, arm, and thigh circumferences noted initially and after each month for the period of 3 months were obtained. Among the 200 subjects, 55 (27.5%) were vatta-, 83 (41.5%) were pitta-, and 62 (31.0%) were kapha-predominant. At the beginning, kapha and pitta people were heavier than vatta people. After the 3 months of therapy, the pitta group lost the most weight (9.84%). The decrease in all the anthropometric measurements was higher in pitta and kapha people than in vatta individuals. Hence, diets based on Ayurvedic constitution may prove useful in promoting weight loss. Though these promising findings support traditional Indian Ayurvedic scriptures, more closely controlled trials are needed to substantiate these findings.
Article
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Nausea and vomiting of pregnancy (NVP) can range from morning sickness to moderate NVP to hyperemesis gravidarum (HG). If it is left unmanaged, health plans may pay for expensive unproven outpatient therapies that are not necessary for treatment of simple morning sickness or moderate NVP. Meanwhile, patients with serious hyperemesis gravidarum whose treatment is delayed may suffer needlessly, ending up with multiple hospitalizations or emergency room (ER) visits. Two expensive, heavily marketed outpatient therapies with scant supportive evidence in the treatment of NVP have recently emerged and some health plans are providing coverage without a thorough review of the medical evidence or cost implications. Health plans may have an opportunity to save a significant amount and to improve member satisfaction by utilizing evidence-based knowledge of pharmacologic interventions that are driven, in order, by known safety, proven efficacy, and cost effectiveness.
Article
Question: One of my patients suffers from a moderate-to-severe form of morning sickness. She responded only partially to doxylamine and pyridoxine (Dicletin), and I wish to try adding another medication. What should my priority be? Answer: An algorithm used by Motherisk to manage thousands of patients takes a hierarchical approach to this condition. This approach is evidence based with regard to fetal safety as well as efficacy.
Article
Our purpose was to determine the extent to which nausea and vomiting of pregnancy affects a woman's quality of life (QOL), ability to function, and health care resource use. Study Design: We conducted an observational, multicenter, prospective cohort study by gathering data on the symptoms, QOL, and health care resource use from women who have nausea and vomiting of pregnancy. All 8 domains of health measured by the Short Form-36 QOL survey were limited by patient symptoms. This limitation manifested itself as patient-time loss from work and other normal activities, unpaid caregiver-time loss from work, and use of health care resources (eg, hospitalization). All types of time loss were correlated to severity of symptoms. Nausea and vomiting of pregnancy can severely reduce a woman's QOL and ability to function. The degree of limitation is associated with the severity of symptoms.
Article
The differential diagnosis of nausea and vomiting is extensive and the underlying cause can be difficult to diagnose. Treatment of nausea and vomiting also can be unsatisfactory because the available pharmacotherapy does not correct the fundamental underlying pathophysiologic abnormalities. In contrast, the diagnosis of nausea and vomiting of pregnancy generally is straightforward. Almost 80% of women have some degree of nausea in the first trimester of pregnancy, and the diagnosis of pregnancy is established easily by the patient or physician. The spectrum varies from mild nausea to hyperemesis gravidarum. Various treatment approaches are addressed.
Article
(1) To quantify rates of suboptimal use of pyridoxine hydrochloride-doxylamine (Diclectin); and (2) to study responses to optimal doses of Diclectin in women previously taking a suboptimal dose. Women who called the Motherisk NVP helpline, and were taking only Diclectin (vitamin B6 10 mg and doxylamine 10 mg), were enrolled in the study and assessed for the severity of nausea and vomiting of pregnancy (NVP) with the Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system. Their Diclectin doses were subsequently increased according to body weight and individual symptoms. A follow-up phone call occurred within 1 to 3 weeks after the intervention, at which time the overall PUQE score was repeated, along with individual scoring of symptoms of nausea, vomiting, and retching. Sixty-eight women were enrolled and completed the study. Despite moderate to severe NVP, defined by the validated PUQE scoring system, most women (50/68) were receiving 2 tablets a day of Diclectin instead of the recommended dose of 4 tablets a day. Following a mean doubling of the dose to 4 tablets a day, there was a significant decrease in length of nausea (from 4 to 3 hours, P < 0.001), frequency of vomiting (from mean 1.6 to 1.3 a day, P = 0.02), and overall PUQE score (from mean 7.5 to 6.1, P < 0.001). Women suffering from NVP are often given subtherapeutic doses of Diclectin. Women should receive a dosage according to their body weight and severity of their symptoms.
Article
The primary objective of our study was to examine the safety and the secondary objective was to examine the effectiveness of ginger for nausea and vomiting of pregnancy (NVP). Pregnant women who called the Motherisk Program who were taking ginger during the first trimester of pregnancy were enrolled in the study. The women were compared with a group of women who were exposed to nonteratogenic drugs that were not antiemetic medications. The women were followed up to ascertain the outcome of the pregnancy and the health of their infants. They were also asked on a scale of 0 to 10 how effective the ginger was for their symptoms of NVP. We were able to ascertain the outcome of 187 pregnancies. There were 181 live births, 2 stillbirths, 3 spontaneous abortions, and 1 therapeutic abortion. The mean birth weight was 3542+/-543 g, the mean gestational age was 39+/-2 weeks, and there were three major malformations. There were no statistical differences in the outcomes between the ginger group and the comparison group with the exception of more infants weighing less than 2500 g in the comparison group (12 vs 3, P < or =.001). There were a total of 66 completed effectiveness scores with the mean score of 3.3+/-2.9 SD. These results suggest that ginger does not appear to increase the rates of major malformations above the baseline rate of 1% to 3% and that it has a mild effect in the treatment of NVP.
Article
Nausea and vomiting of pregnancy (NVP) affects up to 80% of all women to some degree during their pregnancies. Diclectin (doxylamine and pyridoxine [vitamin B6]) has been on the Canadian market for many years and is indicated as the drug of choice for the treatment of NVP. However, some women choose not to treat NVP with pharmacologic measures, perhaps due to a persistent fear of teratogenic risk. The objective of this study was to determine the factors that influence a woman's decision not to treat NVP with pharmacologic measures. Fifty-nine women recruited from the Motherisk Nausea and Vomiting Helpline completed a questionnaire. All were informed that Diclectin was considered safe for use during pregnancy. At a follow-up telephone call, 34% were not using any pharmacologic treatment, and of those who were taking the drug, 26% were using less than the recommended dose. Reasons cited for not using the medication were insufficient safety data, preference for non-pharmacologic methods, and being made to feel uncomfortable by the physician. Of the women who did use Diclectin, the most convincing reassuring information that it was safe to use came from friends and family. Many other factors play a large role in a women's decision making.
Article
Nausea and vomiting of pregnancy (NVP) affects 80% of pregnancies. Its severe form, hyperemesis gravidarum (HG), results in dehydration, electrolyte imbalance, the need for hospitalisation and can, rarely, be fatal. This was a prospective, open-labelled, controlled, interventional study to evaluate the effectiveness of pre-emptive treatment of NVP symptoms in women who experienced severe NVP or HG in their previous pregnancy. Twenty-five women who reported severe symptoms of NVP with or without HG in their previous pregnancy were recruited and counselled to commence the use of antiemetics as soon as they became aware of the present pregnancy, and no later than the beginning of symptoms. They were followed-up prospectively through the index pregnancy for symptoms of NVP, and were counselled continuously as to how to modify antiemetic doses based on symptoms. A comparison group consisted of randomly selected women also counselled by us for NVP, who had also had severe NVP in the previous pregnancy, but who did not call before a planned pregnancy and thus could not be offered pre-emptive therapy. The recruited women commenced pre-emptive drug therapy for NVP before conception or up to 7 weeks' gestation, before the appearance of NVP symptoms in all cases. In comparison to the previous pregnancy, only eight of these 18 women experienced a HG again in the index pregnancy (P = 0.01). The majority of study the women had an improvement in severity of NVP symptoms compared to the previous pregnancy. In the comparison group (n = 35), symptoms in the index pregnancy remained severe in 28 cases (80%), decreased to moderate in six (16.6%) and decreased to mild in five cases (13.9%). There were five cases of HG in the previous pregnancy and three in the index pregnancy. The pre-emptive group was improved significantly compared to the control group (P = 0.01). Pre-emptive symptom management appears to be effective in preventing severe NVP in general, and HG in particular. Women who have experienced severe NVP in a previous pregnancy may benefit from taking antiemetics before, or immediately at the start of symptoms in a subsequent pregnancy.
Article
The management and treatment of gastrointestinal ailments in pregnant women requires special attention and expertise, since the safety of the mother, fetus and neonate remains the primary focus. Nausea and vomiting during pregnancy is common, as is symptomatic gastroesophageal reflux disease. Peptic ulcer disease occurs less frequently and with fewer complications. Gastroenterologists and obstetricians should be familiar with safe treatment options for these conditions, because they can profoundly impair the quality of life of pregnant women. During pregnancy, constipation can develop de novo, or chronic constipation can increase in severity. Given the array of therapies for constipation, physicians must apprise themselves of drugs that are safe for both mother and fetus. Management of acute, self-limited diarrhea should focus on supportive therapy, dietary changes and maintenance of hydration. Treatment of chronic diarrhea should be considered in the context of therapy for the underlying disorder. Inflammatory bowel disease and irritable bowel syndrome present a unique therapeutic challenge--to control the disease while minimizing toxicity to the fetus and mother. Initiation and alteration of medical therapy for gastrointestinal disorders during pregnancy must be undertaken after discussion with the patient's obstetrician.
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The symptoms of nausea and vomiting in pregnancy were described by 363 pregnant women who kept daily symptom diaries. All delivered a single live baby. The majority of information collected was prospective, with the median day from last menstrual period to initial interview by the study midwife being day 57. It was found that 80% of women had symptoms, 28% experienced nausea only, while 52% had nausea and vomiting. The mean number of days from last menstrual period to onset and cessation of symptoms was 39 and 84, respectively, and 40% of women's symptoms ended abruptly. Cessation of symptoms occurred at approximately the same day from the last menstrual period whether they had begun early or later, severely or mildly [corrected]. The median total number of hours of nausea per pregnancy in those 292 women experiencing symptoms was 56, with peak symptoms occurring in the ninth week. Eighty five per cent of women experienced days with two episodes of nausea. Fifty three per cent of episodes of vomiting occurred between 06.00 hours and 12.00 hours. The symptom complex can be defined as episodic daytime pregnancy sickness. Among the study population, 206 women were in paid employment. Seventy three of these women (35%) spent a mean of 62 hours away from their paid work because of symptoms of nausea and vomiting, showing the socioeconomic significance of this condition. The detailed information gathered should help in the investigation of the aetiology of nausea and vomiting during pregnancy.
Article
Despite evidence of fetal safety, most antiemetics are contraindicated in pregnancy. We summarise a risk-benefit analysis of the literature on safety and effectiveness of pharmacotherapy and nontraditional therapy for nausea and vomiting of pregnancy (NVP) to provide evidence-based guidelines on the management of NVP. The medical literature was scanned for controlled studies on the human teratogenicity and effect of various antiemetics in pregnant women. Data were pooled based on drug/therapy class and summarised to determine relative risk with 95% confidence interval (for malformations and failure rates for NVP) and homogeneity (chi-square test). Evidence from controlled trials has demonstrated the safety and efficacy of the following drugs for the treatment of varying degrees of NVP: doxylamine/pyridoxine+/-dicycloverine (dicyclomine), antihistamine H1 receptor antagonists, and phenothiazines (as a group). However, pooled data for doxylamine/pyridoxine+/-dicycloverine, H1 antagonists and phenothiazines were not homogeneous. Other therapies, such as pyridoxine alone, metoclopramide, ondansetron and the corticosteroids may be beneficial in managing NVP. However, limited efficacy studies and the paucity of well-controlled safety studies may limit the use of some of these agents among patients not responsive to first-line agents. Well-controlled safety and effectiveness trials in patients with NVP are lacking for nonpharmacological treatments (e.g. acupressure). NVP can be managed safely and effectively. Further trials must be conducted in order to determine the true effectiveness of certain agents in patients with NVP.
Article
Nausea and vomiting of pregnancy is the most common condition in pregnancy and affects up to 80% of all pregnant women. There are a large number of pharmacological agents that are effective for the treatment of nausea and vomiting associated with conditions such as motion sickness and gastrointestinal conditions; however, their use in pregnancy is limited by the lack of sufficient data on their potential teratogenic effects. The efficacy of the delayed-release combination of doxylamine and pyridoxine (Bendectin, Diclectin) has been shown in several randomized, controlled trials. The present review aims to refute the unsubstantiated beliefs that Diclectin is unsafe when used in the treatment of nausea and vomiting of pregnancy.