In the Journals

Effectiveness of FDA-approved anti-nausea drug during pregnancy questioned

Nav Persaud
Navindra Persaud

An examination appearing in PLOS One of an unpublished study from 2009 suggested that information the FDA used to approve doxylamine-pyridoxine for treatment of nausea and vomiting in pregnant women showed the drug was not effective.

The drug is included in the American College of Obstetricians and Gynecologists’ (ACOG) guidelines as the first-line pharmacological therapies for nausea and vomiting for women who are pregnant.

“Pregnant women should be given accurate information about this and other treatments,” Navindra Persaud, MD, department of family and community medicine, St. Michael’s Hospital in Toronto, told Healio Family Medicine. “Unfortunately, this information [regarding doxylamine-pyridoxine] has not been available to women taking the medication.”

In the DIC-301 trial from 2009, the efficacy of both doxylamine 10 mg and pyridoxine 10 mg taken from two to four times per day vs. placebo in the treatment of nausea and vomiting was assessed in 280 pregnant women matched in a 1:1 ratio. Information from 131 active treatment participants and 125 control participants were analyzed. By study’s end, 101 active treatment participants and 86 control participants provided primary outcome measures. Symptoms were scored by utilizing the 13-point pregnancy unique quantification of emesis scale between baseline and 14 days using an ANCOVA.

Using previously unpublished data obtained from public trial registration information, FDA review documents and study report documents from Health Canada, Persaud and colleagues re-analyzed the data from this study to address differences in prior reports of the trial. They found that there was a 0.73 point improvement (95% CI, 0.21-1.25) in symptoms scores with doxylamine-pyridoxine vs. placebo “when last observation carried forward imputation was used for missing data.” However, they added that this difference was not statistically significant when using different approaches to address the missing data (eg, 0.38; 95% CI, –0.08 to 0.84 using complete data).

Persaud and colleagues also reported that symptom scores plateau after day 10 and “improved substantially” during the 2-week trial in both groups; however, the difference between groups also decreased after the 10th day.

“Both of these findings could be explained by the natural history of the condition, that is, by the resolution of symptoms irrespective of treatment. This natural resolution could account for the lack of clinical important difference between groups,” Persaud and colleagues wrote.

According to Persaud, doxylamine-pyridoxine is still a popular option for pregnant women and approved for use in the U.S. and Canada. He told Healio Family Medicine that four prescriptions for the medication were filled for every five live births in Canada in 2014.

This is not the first time a prior study involving pyridoxine-doxylamine has come under review. Last year, a study also co-authored by Persaud questioned the efficacy of the drugs dicyclomine, pyridoxine, and doxylamine for treating morning sickness. He based the 2017 claim on revisiting a 1970s study that he said was also never published.

“[Doxylamine-pyridoxine] was approved in the 1950s and it seems to be ineffective. There may be other ineffective medications that were approved decades ago and that are being commonly prescribed today,” Persaud said. “We should make information about all medications more easily available to clinicians and patients.”

The multiple findings regarding doxylamine and pyridoxine have impacted his practice, he said.

“I used to prescribe this medication based on clinical practice guidelines and the prescribing of my colleagues. I reluctantly stopped prescribing this medication after carefully reviewing the data from all the studies. I imagine that my colleagues will be reluctant to change their practice just as I was,” Persaud said in the interview. “New information indicating that this medication is effective would make me revisit my decision not to prescribe it. This would include new information about the 2009 clinical trial that would change its interpretation.”

The FDA declined to discuss Persaud’s findings.

“Generally, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health,” Andrea Fischer, FDA spokesperson, told Healio Family Medicine in an interview. “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.”

According to the spokesperson, FDA analyzed all available data when determining the approval, and the FDA’s determination remains unchanged.

ACOG does not plan on revisiting its recommendations in light of this new analysis. Its guidelines are reviewed every 18 to 24 months but ACOG said it would reassess under certain conditions.

“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,” Mark Turrentine, MD, chair of ACOG’s Practice Bulletin Obstetrics Committee, told Healio Family Medicine.

ACOG also cited several studies in explaining its recommendations, and defended its position nothing that patients have suffered when antiemetics have been withdrawn from the market in the past. According to ACOG, the combination of 10 mg of vitamin B6 (pyridoxine) plus 10 mg of doxylamine was also available in the United States from 1958 to 1983, before it was withdrawn from the manufacturer citing “liability costs.” During this time approximately 25% to 30% of all pregnant women received this therapy.

“After the combination was removed from the U.S. market in 1983, use of all antiemetics to treat nausea and vomiting of pregnancy diminished considerably, and hospitalization rates for nausea and vomiting of pregnancy increased,” according to ACOG. - by Janel Miller

Disclosure: Persaud and colleagues report no relevant financial disclosures. Fischer works for the FDA, Turrentine is chair of the ACOG Practice Bulletin Obstetrics Committee.

Nav Persaud
Navindra Persaud

An examination appearing in PLOS One of an unpublished study from 2009 suggested that information the FDA used to approve doxylamine-pyridoxine for treatment of nausea and vomiting in pregnant women showed the drug was not effective.

The drug is included in the American College of Obstetricians and Gynecologists’ (ACOG) guidelines as the first-line pharmacological therapies for nausea and vomiting for women who are pregnant.

“Pregnant women should be given accurate information about this and other treatments,” Navindra Persaud, MD, department of family and community medicine, St. Michael’s Hospital in Toronto, told Healio Family Medicine. “Unfortunately, this information [regarding doxylamine-pyridoxine] has not been available to women taking the medication.”

In the DIC-301 trial from 2009, the efficacy of both doxylamine 10 mg and pyridoxine 10 mg taken from two to four times per day vs. placebo in the treatment of nausea and vomiting was assessed in 280 pregnant women matched in a 1:1 ratio. Information from 131 active treatment participants and 125 control participants were analyzed. By study’s end, 101 active treatment participants and 86 control participants provided primary outcome measures. Symptoms were scored by utilizing the 13-point pregnancy unique quantification of emesis scale between baseline and 14 days using an ANCOVA.

Using previously unpublished data obtained from public trial registration information, FDA review documents and study report documents from Health Canada, Persaud and colleagues re-analyzed the data from this study to address differences in prior reports of the trial. They found that there was a 0.73 point improvement (95% CI, 0.21-1.25) in symptoms scores with doxylamine-pyridoxine vs. placebo “when last observation carried forward imputation was used for missing data.” However, they added that this difference was not statistically significant when using different approaches to address the missing data (eg, 0.38; 95% CI, –0.08 to 0.84 using complete data).

Persaud and colleagues also reported that symptom scores plateau after day 10 and “improved substantially” during the 2-week trial in both groups; however, the difference between groups also decreased after the 10th day.

“Both of these findings could be explained by the natural history of the condition, that is, by the resolution of symptoms irrespective of treatment. This natural resolution could account for the lack of clinical important difference between groups,” Persaud and colleagues wrote.

According to Persaud, doxylamine-pyridoxine is still a popular option for pregnant women and approved for use in the U.S. and Canada. He told Healio Family Medicine that four prescriptions for the medication were filled for every five live births in Canada in 2014.

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This is not the first time a prior study involving pyridoxine-doxylamine has come under review. Last year, a study also co-authored by Persaud questioned the efficacy of the drugs dicyclomine, pyridoxine, and doxylamine for treating morning sickness. He based the 2017 claim on revisiting a 1970s study that he said was also never published.

“[Doxylamine-pyridoxine] was approved in the 1950s and it seems to be ineffective. There may be other ineffective medications that were approved decades ago and that are being commonly prescribed today,” Persaud said. “We should make information about all medications more easily available to clinicians and patients.”

The multiple findings regarding doxylamine and pyridoxine have impacted his practice, he said.

“I used to prescribe this medication based on clinical practice guidelines and the prescribing of my colleagues. I reluctantly stopped prescribing this medication after carefully reviewing the data from all the studies. I imagine that my colleagues will be reluctant to change their practice just as I was,” Persaud said in the interview. “New information indicating that this medication is effective would make me revisit my decision not to prescribe it. This would include new information about the 2009 clinical trial that would change its interpretation.”

The FDA declined to discuss Persaud’s findings.

“Generally, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health,” Andrea Fischer, FDA spokesperson, told Healio Family Medicine in an interview. “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.”

According to the spokesperson, FDA analyzed all available data when determining the approval, and the FDA’s determination remains unchanged.

ACOG does not plan on revisiting its recommendations in light of this new analysis. Its guidelines are reviewed every 18 to 24 months but ACOG said it would reassess under certain conditions.

“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,” Mark Turrentine, MD, chair of ACOG’s Practice Bulletin Obstetrics Committee, told Healio Family Medicine.

PAGE BREAK

ACOG also cited several studies in explaining its recommendations, and defended its position nothing that patients have suffered when antiemetics have been withdrawn from the market in the past. According to ACOG, the combination of 10 mg of vitamin B6 (pyridoxine) plus 10 mg of doxylamine was also available in the United States from 1958 to 1983, before it was withdrawn from the manufacturer citing “liability costs.” During this time approximately 25% to 30% of all pregnant women received this therapy.

“After the combination was removed from the U.S. market in 1983, use of all antiemetics to treat nausea and vomiting of pregnancy diminished considerably, and hospitalization rates for nausea and vomiting of pregnancy increased,” according to ACOG. - by Janel Miller

Disclosure: Persaud and colleagues report no relevant financial disclosures. Fischer works for the FDA, Turrentine is chair of the ACOG Practice Bulletin Obstetrics Committee.