How effective is the most commonly prescribed drug for nausea during pregnancy?
Not so great, say researchers from St. Michael’s Hospital in Canada. They are questioning the effectiveness of pyridoxine-doxylamine, which is sold under the brand name Diclegis in the United States.
In an published today in the journal PLOS ONE, the research team shared previously unpublished information from a randomized clinical trial conducted in 2009, called DIC-301.
The U.S. Food and Drug Administration (FDA) relied on DIC-301 to approve Diclegis, which has been prescribed to millions of women around the world.
But after obtaining a copy of the manufacturer’s full clinical trial report from Health Canada, the researchers from St. Michael’s said they found evidence that the drug isn’t clinically effective.
The clinical trial report specified that the findings would only be considered clinically important if there was a three-point reduction in symptoms — a threshold that the results didn’t meet.
The clinical trial found that on a 13-point scale, women who took the drug reported reductions in symptoms that were only 0.7 points greater than those who took a placebo.
While that difference is statistically significant, it’s not large enough to be noticeable to patients, Dr. Nav Persaud, MSc, lead investigator and a family physician at St. Michael’s, told Healthline.
“One of the most important things about this study is that it explains exactly why many women who have taken this medication would believe that it works and many of the physicians who have prescribed it would believe that it works,” he said.
“When you look at the symptom scores for women who are given a placebo, they start around 9 on the first day of the study, and by two weeks later, the symptom score is 4 out of 13, and a minimum score on that scale is 3, which would indicate no symptoms,” he added.
In other words, whether women were given a placebo or the drug, they went from having relatively high symptoms at the start of the trial to having low or no symptoms by the end.
The simplest explanation, Persaud said, was that participants’ nausea and vomiting was self-limited, which means it would have resolved without treatment.
He noted that while the clinical trial didn’t show that pyridoxine-doxylamine was effective, it also didn’t find any safety issues associated with the drug.
Drug approval in 2013
Diclegis is manufactured by Duchesnay Inc., a pharmaceutical company that focuses on products for pregnant patients.
The drug had been sold under a different name when it was pulled from the market in 1983 after lawsuits were filed stating the medication caused birth defects.
Advocates for Diclegis say the fears stated in the lawsuits were unfounded.
In the early 2000s, Duchesnay Inc. approached the FDA to obtain approval for Diclegis.
The FDA requested evidence from a clinical trial and approved the drug in 2013, after trial DIC-301 was completed.
“The FDA took into account the totality of the evidence submitted when deciding whether Diclegis could be approved, including data from the more recent phase three, randomized, double-blind, placebo-controlled trial [DIC-301] conducted by the company that owns Diclegis, and other supportive data,” the FDA told Healthline in a written statement.
“Based on the available data, the FDA determined that Diclegis has been shown to be safe and effective for the treatment of nausea and vomiting in pregnant women who do not respond to conservative management,” the statement continued.
Healthline also heard from Fiona Story, senior director of communications at Duchesnay Inc., who stated the safety and efficacy of Diclegis have been demonstrated in multiple studies.
Story said trial DIC-301 was designed in collaboration with the FDA through a special protocol assessment.
“The clinical trial achieved a statistically significant endpoint using the method of analysis requested by the FDA in accordance with all FDA requirements,” Story said.
In response to the comments from the FDA and Story, Persaud drew attention to the discrepancy between the pre-specified threshold for clinical importance and the findings in trial DIC-301.
“A difference of three points on the 13-point symptoms scale was pre-specified as the minimal clinically important difference, but the reported difference was less than 1 point,” Persaud said.
“If it is true that the manufacturer and the FDA agreed on the design of the study, then they both agreed ahead of time that three points was the minimal clinically important difference,” he continued.
In the past, Persaud has also raised concerns about other studies on the efficacy of pyridoxine and doxylamine for treating nausea and vomiting in pregnancy.
For example, he last year calling the methodological integrity of an older trial on pyridoxine and doxylamine into question.
Persaud would like the FDA to revisit its regulatory decision on Diclegis and more clearly articulate its basis for believing the drug is effective.
“It’s one thing to say, as the FDA does, that it’s based on the totality of the evidence,” he said, “but you know, as someone who has taken quite a bit of time to try to sift through all of the evidence for this medication, I actually couldn’t tell you exactly what they mean.”
In its statement to Healthline, the FDA noted that it’s reviewing Persaud’s article.
“The FDA is reviewing the findings of the paper. The FDA remains committed to informing the public in a timely manner when the agency identifies concerns about approved drug products,” the statement read.
Talk to your doctor
Diclegis is currently the first-line pharmacological treatment recommended by the American College of Obstetricians and Gynecologists (ACOG) for nausea and vomiting in pregnancy.
“This month, ACOG released its updated Practice Bulletin ‘Nausea and Vomiting of Pregnancy’ and maintains that vitamin B6 (pyridoxine) alone or vitamin B6 (pyridoxine) plus doxylamine in combination is safe and effective and should be considered first-line pharmacotherapy,” Dr. Mark Turrentine, chair of ACOG’s Committee on Practice Bulletins — Obstetrics, told Healthline.
“If the U.S. Food and Drug Administration, the authors of the original studies, or the drug manufacturer correct or retract any of the evidence used to develop ACOG’s guidance, we will reassess and consider the conclusions at that time,” he added.
In his own clinical practice, Persaud has stopped prescribing Diclegis.
“I used to prescribe it routinely for women who have nausea and vomiting during pregnancy, but I have completely stopped prescribing this medication,” he said.
“And my recommendation [for patients] would be to speak to your healthcare providers about effective treatment for nausea and vomiting during pregnancy. Based on the information that I’ve reviewed, this medication doesn’t seem to be effective,” he added.
According to Persaud, several other drugs are available for the treatment of nausea and vomiting in pregnancy.