Summary Safety Review - DICLECTIN (doxylamine and pyridoxine combination) - Assessing Safety in pregnancy
July 15, 2016 - updated July 19, 2016
Diclectin is a drug authorized in Canada to treat nausea and vomiting in pregnancy (i.e. morning sickness). It is a fixed dose-combination product of doxylamine (an antihistamine) and pyridoxine (a form of vitamin B6). The doxylamine/pyridoxine containing products have been used in Canada since 1957. Health Canada has been monitoring the safety of Diclectin and updating the prescribing information as necessary, as it does for all products on the Canadian market.
The safety of Diclectin was recently reviewed by Health Canada as part of its routine health product monitoring. Public interest was also raised by recent media reports on Diclectin.
Health Canada regulates drugs and other health products available to Canadians. Before a therapeutic product is authorized for sale in Canada, the manufacturer must provide evidence of its safety, efficacy and quality, as defined by regulations. Health Canada reviews the evidence to determine whether the risks associated with the product are acceptable in light of its potential benefits. If they are, and if the product has been shown to be effective under specified conditions, it is authorised for sale in Canada.
Authorized use of Diclectin
Diclectin is a drug used to treat nausea and vomiting in pregnancy, which is a very common condition affecting 50%-90% of pregnant women with varying severity and durationFootnote a . Diclectin is currently the only prescription drug authorized in Canada for the treatment of nausea and vomiting in pregnancy.
The current Guidelines issued by the Society of Obstetricians and Gynaecologists of Canada (SOGC)Footnote a recommend Diclectin as a treatment for nausea and vomiting in pregnant women when other measures such as dietary and lifestyle changes have not been effective. According to the SOGC website, the current clinical practice guidelines on the management of nausea and vomiting in pregnancy are being reviewedFootnote b .
Canadian and international regulatory history
In 1975, Diclectin was authorized in Canada as a generic form of Bendectin, a 3-component product: doxylamine, dicyclomine and pyridoxine, which had been marketed in Canada since 1957. Dicyclomine, which decreases muscle spasms in the digestive system, was later excluded from the drug formulation since it was not found to help in treating nausea and vomiting in pregnancy. Since the 1960s, Bendectin was suspected of causing congenital malformations; however, accumulated safety data failed to show an association. Nevertheless, the manufacturer of Bendectin discontinued the product worldwide in 1983 reportedly due to increasing costs from lawsuits. In Canada, the generic product, Diclectin (pyridoxine (B6)/doxylamine), remained available.
In 1989, the then Minister of Health and Welfare Canada requested an independent review of the safety of Diclectin/Bendectin products by an external expert panel. The expert panel confirmed the positive benefit-risk profile for Diclectin and noted that it should continue to be available to Canadian women.
In 1999, the US Food and Drug Administration (FDA) conducted its own review to confirm why Bendectin was removed from the market in 1983. The FDA determined that Bendectin was not discontinued for safety or effectiveness reasons.
In 2013, the US FDA authorized Diclegis (US equivalent to Diclectin) for the treatment of nausea and vomiting in pregnant women as a "Category A drug" (the safest for use in pregnant women). This drug approval was supported by historical and recent data.
Objective of the Safety Review
The objective of this review was to assess available evidence on Diclectin since the 1989 Expert Advisory Panel. The evidence considered Canadian patient reports, scientific and medical literature, and what is known about the use of this medicine both in Canada and internationally. The current strategies to minimize this risk were also considered, including a review of the product information available to health care professionals and patients.
Use of Diclectin in Canada
Health Canada estimates the number of prescriptions for Diclectin to be stable over the last five years at approximately 180,000 new prescriptions per yearFootnote c . During a pregnancy, a woman may require more than one prescription for Diclectin depending on the duration of use. Of note, the number of births in Canada for 2015 is expected to be around 388,000 according to the Statistics Canada websiteFootnote d .
Canadian reports of birth defects/congenital malformations associated with Diclectin use
The Canada Vigilance database was searched for all reports that listed Diclectin since 1975 and found 75 Canadian cases of side effects associated with Diclectin use. Of these, 29 unique cases were considered to be related to the safety review and were further investigated. These included cases reported in infants or neonates as well as cases with events of interest (e.g. spontaneous abortion, congenital impairment, fetal death). Seven cases were assessed as 'possibly associated'Footnote e with Diclectin use while the remaining 22 were classified as unlikely to be associated with Diclectin use or un-assessable (the reports did not have enough information to determine if there was a causal relationship to the drug or whether it was related to natural occurrence). The number of cases reported in Diclectin users is considered to be within the expected incidence (natural occurrence) of major birth defects (3-5%) in newborn babiesFootnote f . No pattern of malformation types or group of malformations was identified in these case reports. The summary of these findings do not indicate a change in the current benefit/risk profile of the product.
The safety review considered the scientific and medical literature published up to May 20, 2015. The potential association between doxylamine/pyridoxine and the risk of birth defects has been extensively studied in numerous types of clinical trials (observational studies, meta-analyses and systematic reviews). Five separate meta-analyses, which combine numerous individual studies, concluded that doxylamine/pyridoxine was not associated with increased risk of birth defectsFootnote g .
While some individual studies reported possible links between doxylamine/pyridoxine use by pregnant women and the occurrence of various birth defects, the majority of the studies did not find a link. There are no identified malformation types or group of malformations that have consistently been reported in the scientific literature to be increased in the populations exposed to doxylamine/pyridoxine combination.
Conclusions and Next Steps
Health Canada has found that Diclectin's benefits continue to outweigh its risks, when used as authorized. The safety information reviewed on Diclectin and birth defects (fetal adverse events) showed no change in the safety profile of Diclectin in pregnant women. The review also concluded that the evidence continues to support Diclectin's safe and effective use for the treatment of nausea and vomiting during pregnancy.
The most recent prescribing information for Diclectin (dated March 2016) continues to reflect the overall knowledge on the safe and effective use of the drug in pregnant women.
Health Canada has shared information on Diclectin externally with third parties, and will continue to make relevant information available as applicable.
Health Canada will continue to monitor the safety of Diclectin as it does for all health products on the Canadian market and will take appropriate and timely action if new health risks are identified. Health Canada will communicate emerging safety information, as necessary, resulting from its post-marketing surveillance program, to health care professionals and consumers, so they can make timely decisions on the risks and benefits.
Full review reports
The full review report for Diclectin is available upon request to the Marketed Health Products Directorate. As with all safety reviews, these reports are subject to redactions of personal and confidential information.
On June 2, 2016, a Scientific Advisory Panel on Diclectin met to consider whether specific study information on Diclectin may be useful to healthcare professionals or patient decision making about the use of the drug. In summary, the panel recommended that no changes to the indicated use of Diclectin are warranted based on the latest available information.
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