Use of popular morning sickness drug not backed by good evidence: paper
A Canadian doctor is raising more questions about the efficacy of a commonly prescribed drug to treat nausea and vomiting in pregnant women, after finding “many flaws” in a 40-year-old study that helped support the use of the medication in Canada and the United States.
Dr. Nav Persaud, a family physician at St. Michael’s Hospital in Toronto, has been on a long quest to find more information about the pyridoxine-doxylamine drug combination, sold in Canada under the brand name Diclectin. Pyridoxine is a form of vitamin B6 and doxylamine is an antihistamine.
The popular medication, used in half of Canadian pregnancies that result in live births, is the only prescription drug authorized by Health Canada to treat nausea and vomiting in pregnant women. The Society of Obstetricians and Gynaecologists of Canada also recommends Diclectin as a “first line” of treatment for nausea and vomiting during pregnancy due to its “efficacy and safety.”
But the results of a never-before-published clinical trial conducted in the 1970s call into question the benefits of the drug, Dr. Persaud and co-author Dr. Rujun Zhang concluded in a paper published Wednesday in the online journal PLOS ONE.
The trial, conducted at 14 clinics in the United States, enrolled 2,308 patients who were in their first 12 weeks of pregnancy and experiencing nausea and vomiting.
The women were randomly separated into eight groups, one of which received a placebo. The other seven groups received a variety of drugs, including the combination for Diclectin.
The study eventually analyzed data from nearly 1,600 participants, but the final results were never published or made available.
Dr. Persaud found several flaws in the execution and analysis of the clinical trial. Among them:
- A high number of participants did not complete the trial, even though it only lasted one week.
- Some data had to be excluded from the trial after the U.S. Commissioner of Food and Drugs questioned its integrity, partly because the information was being recorded in the patients’ absence.
- Outcome data for 37 per cent of participants in the placebo group was not available.
- The method by which physicians scored symptoms was not clear.
Dr. Persaud said he was unable to contact any of the original researchers involved in the trial, and it appears that most of them have since died.
Although the results of the trial were never published, Health Canada and the U.S. Food and Drug Administration (FDA) used the information collected to approve the drug. The study has also been referenced in support of the use of pyridoxine-doxylamine over the years, Dr. Persaud said.
“I think there is a question about whether this (drug) works at all,” he told CTVNews.ca in a telephone interview.
“As someone who has looked at the information carefully, I wouldn’t conclude after looking at the available information that the medication is effective or that this is a study that I would want to rely on.”
Years after he first started seeking information about pyridoxine-doxylamine from regulatory agencies, Dr. Persaud eventually received 36,000 pages from the FDA and 359 pages from Health Canada – more than 200 of them redacted – through freedom of information requests.
“I was disappointed when I learned about this study,” he said. “I was shocked by some parts of it. I was shocked by the questions about the integrity of the data.”
Under different legislation, called Vanessa’s Law and meant to improve drug safety and transparency, Dr. Persaud was able to receive thousands of additional pages of information about Diclectin from Health Canada. But he had to sign a confidentially agreement, which prevents him from discussing that information publicly until he publishes his analysis of the data.
‘No safety or efficacy issues’: Health Canada
In a written statement to CTV News, Health Canada said it has recently reviewed the safety and effectiveness of Diclectin. The review included scientific and medical literature published up to May, 2015 and found “no new safety or efficacy issues.”
“The available evidence continues to support Diclectin in the treatment of nausea and vomiting during pregnancy,” the agency said.
“It is important to note that since the initial review of evidence that supported Diclectin's approval in Canada, Health Canada re-assessed Diclectin in 1989 and has also reviewed submissions on Diclectin, updated the label as necessary, and continued to monitor its safety profile,” Health Canada said, pointing to a summary of the safety review on its website.
A spokesperson for Duchesnay Inc., the Quebec-based manufacturer of Diclectin, said the safety and efficacy of the drug “have been proven in 16 cohort studies, two meta-analyses, an ecological study, a neurological development study and numerous others.”
In a statement to CTV News, Ron Vaillancourt said that doxylamine succinate and pyridoxine hydrochloride, the two active ingredients in Diclectin, is “the most studied drug combination used in pregnancy.”
“Thus, we have complete confidence in the safety and efficacy of Diclectin and are very proud to provide it as a safe and effective treatment option for women suffering from nausea and vomiting of pregnancy,” Vaillancourt said.
He noted that the drug was also approved by the FDA in 2013 under the name Diclegis, and has been endorsed by the American Congress of Obstetricians and Gynecologists.
Dr. Persaud has previously called for changes to guidelines on Diclectin, after it was discovered that the drug isn't associated with a reduced risk of birth defects, despite previous research claims.
The Society of Obstetricians and Gynaecologists of Canada (SOGC) stands by its guidelines, which recommend doxylamine-pyridoxine combination therapy for management of nausea and vomiting in pregnancy.
“We have abundant evidence that (Diclectin) is safe, and fairly good evidence that it’s effective,” Dr. George Carson, the president of SOGC, told CTV News.
Dr. Carson said that some of the criticism of the 40-year-old clinical trial is valid, but it is “important to remember that the way we do research methodology has improved from the 1970s to now.”
“It does not seem entirely fair to criticize a paper for not meeting standards that did not exist at the time that the work was being done,” he said in an interview.
Dr. Carson said the SOGC’s guidelines on managing nausea and vomiting in pregnancy was based on various research, and did not rely on the older study analyzed by Dr. Persaud.
Jenn Maddan, an Ontario mother of a three-year-old boy who is currently 35 weeks pregnant with her second child, said she has been taking Diclectin throughout both pregnancies, but is not sure how helpful the drug has been.
Maddan has felt so ill that she had to take sick leave from her job.
“I spend every day fighting to make it through the day and not be sick and I am not willing to come off of (Diclectin) at this point to see what my day would look like,” she told CTV News.
She was prescribed drugs other than Diclectin to manage her symptoms, but says they made her even more sick so she stopped taking them.
However, after doing her own research, Maddan said she is “confident” that Diclectin is not doing her any harm.
“My baby is healthy and my son is healthy,” she said.
Other options for pregnant women
Dr. Persaud said the fact that Diclectin is described as the only prescription drug authorized in Canada to help treat pregnancy nausea and vomiting gives a “false impression” that there is something special about the medication.
“The reality is that the actual contents of this medication are similar to other nausea treatments,” he said.
Pregnant women worried about the efficacy of Diclectin have other options backed by “much better evidence,” Dr. Persaud said. Those include metoclopramide and diphenhydramine (commonly known as Benadryl).
Dr. Persaud said Health Canada should make all of its information on Diclectin publicly available, so that health care professionals and pregnant women can make their own informed decisions. He said he has stopped prescribing Diclectin in his own practice, and has heard from several other doctors and health-care practitioners who have done the same.
“The bottom line is, there is no medication that is perfectly safe,” he said. “But if there is no evidence that a medication is effective, we should not use it.”
With files from CTV’s medical specialist Avis Favaro and producer Elizabeth St. Philip