Dr. Ron’s Research Review – March 8, 2017

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This week’s research review focuses on nausea and vomiting of pregnancy.

An unpublished 8-Way 1970s trial of medications for NVP has limitations: the final results are not available, data from more than 30% of recruited individuals were not analyzed although the follow up period was only one week. Data integrity is questionable because data from at least one investigator were subsequently excluded for reasons including “data recording in absence of patient visits”. In 2013, the US FDA referred to these results in approving doxylamine and pyridoxine (Diclegis) in the treatment of NVP. But did not mention any of these problems.
Bendectin had originally been approved in 1956 as a three-agent formulation, consisting of 10 mg of dicyclomine (antispasmodic), 10 mg of doxylamine (antihistamine), and 10 mg of pyridoxine (vitamin B6). In the 1970s, dicyclomine was determined to be ineffective, and Bendectin was consequently reformulated as a two-drug combination. Initial reports questioning the safety of Bendectin ignited public fears resulting in a lawsuit. However, studies did not support this. (Slaughter et al., 2014)

Several articles recommend Diclegis for nausea and vomiting in pregnancy, except for this one from Canada, which recommends vitamin B6 alone!
There is limited evidence that doxylamine-pyridoxine is more effective than pyridoxine alone. There is stronger support for the safety of pyridoxine monotherapy than for the combination of doxylamine-pyridoxine during pregnancy, and some conflicting evidence links doxylamine-pyridoxine use to pyloric stenosis and childhood malignancies. (Persaud et al., 2014)

 

Dr. Ron


 

Articles

Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy
            (Persaud et al., 2014) Download
Doxylamine-pyridoxine is the first-line agent for the treatment of nausea and vomiting of pregnancy (NVP) according to Canadian guidelines, and this combination is commonly prescribed to pregnant women. There is limited evidence that doxylamine-pyridoxine is more effective than pyridoxine alone. There is stronger support for the safety of pyridoxine monotherapy than for the combination of doxylamine-pyridoxine during pregnancy, and some conflicting evidence links doxylamine-pyridoxine use to pyloric stenosis and childhood malignancies. The role of doxylamine-pyridoxine as the first-line pharmacological treatment for NVP in Canada should be reconsidered. La combinaison doxylamine-pyridoxine constitue l’agent de première intention à utiliser pour la prise en charge de la nausée et des vomissements de la grossesse (NVG), selon les lignes directrices canadiennes traitant de la question, et cette combinaison est couramment prescrite aux femmes enceintes. Les données qui indiquent que la combinaison doxylamine-pyridoxine est plus efficace que la pyridoxine utilisée seule sont limitées. En fait, les données qui soutiennent l’innocuité de la monothérapie à la pyridoxine pendant la grossesse sont plus solides que les données qui soutiennent celle de la combinaison doxylamine-pyridoxine; de plus, certaines données contradictoires établissent des liens entre la combinaison doxylamine-pyridoxine et les tumeurs malignes de l’enfance et la sténose du pylore. Le rôle de la combinaison doxylamine-pyridoxine à titre de traitement pharmacologique de première intention pour contrer la nausée et les vomissements de la grossesse au Canada devrait être remis en question.

FDA approval of doxylamine-pyridoxine therapy for use in pregnancy.
            (Slaughter et al., 2014) Download
In 1983, the combination-drug product Bendectin (Merrell Dow), consisting of 10 mg of doxylamine succinate and 10 mg of pyridoxine hydrochloride per tablet, was voluntarily withdrawn from the U.S. market. For the next 30 years, there were no med- ications that had been approved by the Food and Drug Adminis- tration (FDA) for the treatment of nausea and vomiting of preg- nancy. Recently, the FDA approved Diclegis (Duchesnay), a product with the same combination of doxylamine and pyridoxine that had been marketed as Bendectin. The Bendectin experience serves as an informative case study of how decisions that are not science- based may affect the marketing and availability of a drug product and lead to adverse public health consequences.


 

8-Way Randomized Controlled Trial of Doxylamine, Pyridoxine and Dicyclomine for Nausea and Vomiting during Pregnancy: Restoration of Unpublished Information.
            (Zhang and Persaud, 2017) Download
OBJECTIVES:  We report information about an unpublished 1970s study ("8-way" Bendectin Study) that aimed to evaluate the relative therapeutic efficacy of doxylamine, pyridoxine, and dicyclomine in the management of nausea and vomiting during pregnancy. We are publishing the trial's findings according to the restoring invisible and abandoned trials (RIAT) initiative because the trial was never published. DESIGN:  Double blinded, multi-centred, randomized placebo-controlled study. SETTING:  14 clinics in the United States. PARTICIPANTS:  2308 patients in the first 12 weeks of pregnancy with complaints of nausea or vomiting were enrolled. INTERVENTIONS:  Each patient was randomized to one of eight arms: placebo, doxylamine/pyridoxine/dicylcomine, doxylamine/pyridoxine, dicylomine/pyridoxine, doxylamine, dicyclomine/pyridoxine, pyridoxine and dicyclomine. Each patient was instructed to take 2 tablets at bedtime and 1 additional tablet in the afternoon or morning if needed, for 7 nights. OUTCOMES:  Reported outcomes included the number of hours of nausea reported by patients, the frequency of vomiting reported by patients and the overall efficacy of medication as judged by physicians. RESULTS:  Data from 1599 (69% of those randomized) participants were analyzed. Based on the available summary data of physician evaluation of symptoms and ignoring missing data and data integrity issues, the proportion of participants who were "evaluated moderate or excellent" was greater in each of the seven active treatment groups when compared with placebo (57%): doxylamine/pyridoxine/dicylcomine (14% absolute difference versus placebo; 95% CI: 4 to 24), doxylamine/pyridoxine (21; 95% CI 11 to 30), dicylomine/pyridoxine (21; 95% CI 11 to 30), doxylamine (20; 95% CI 10 to 29), dicyclomine/pyridoxine (4; 95% CI -6 to 14), pyridoxine (9; 95% CI -1 to 19) and dicyclomine (4; 95% CI -6 to 14). Based on incomplete information, the most common adverse events were apparently drowsiness and fatigue. There is a high risk of bias in these previously unpublished results given the high attrition rate in a 7 day trial, the lack of prespecified outcomes or analyses, and the exclusion of some data because of questionable data integrity. CONCLUSION:  The available information about this "8-way Bendectin" trial indicates it should not be used to support the efficacy of doxylamine, pyridoxine or dicyclomine for the treatment of nausea and vomiting during pregnancy because of a high risk of bias. TRIAL REGISTRATION:  Not registered.

 


References

Persaud, N, J Chin, and M Walker (2014), ‘Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy’, J Obstet Gynaecol Can, 36 (4), 343-48. PubMed: 24798673
Slaughter, SR, et al. (2014), ‘FDA approval of doxylamine-pyridoxine therapy for use in pregnancy.’, N Engl J Med, 370 (12), 1081-83. PubMed: 24645939
Zhang, R and N Persaud (2017), ‘8-Way Randomized Controlled Trial of Doxylamine, Pyridoxine and Dicyclomine for Nausea and Vomiting during Pregnancy: Restoration of Unpublished Information.’, PLoS One, 12 (1), e0167609. PubMed: 28052111