TUESDAY, April 9 (HealthDay News) — A morning-sickness medication that was withdrawn from the market 30 years ago has won U.S. Food and Drug Administration approval under a new name.
In its new form, the drug — formerly called Bendectin and now renamed Diclegis — is the only medication specifically approved to treat the stomach upset many women suffer from during pregnancy.
In the intervening decades between the drug’s withdrawal from the market and its re-approval on Tuesday, the medicine has undergone rigorous scrutiny and is now deemed safe by the FDA.
Obstetricians welcomed the announcement.
“The nausea and vomiting of early pregnancy can range from mild to debilitating,” said Dr. Jennifer Wu, an obstetrician-gynecologist at Lenox Hill Hospital in New York City. “Patients will welcome more options for treatment with the reintroduction of Bendectin.”
Their nausea may not disappear completely, but “it will hopefully decrease to the point that a patient can function,” she added.
Diclegis, which combines vitamin B6 and the antihistamine doxylamine, is a delayed-release pill that’s meant to be taken daily before symptoms set in. Those symptoms are often worse after waking up, hence the name “morning sickness.” But some women are plagued by nausea all day long.
The medication is intended for women whose nausea isn’t “adequately managed through recommended changes in diet and lifestyle,” Dr. Hylton Joffe, director of the Division of Reproductive and Urologic Products in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release.
Morning sickness usually improves after the first trimester. Recommended dietary and lifestyle changes to help beat the nausea include eating several small meals instead of three large meals, eating low-fat bland foods that are easy to digest and avoiding smells that can trigger episodes.
Another expert said the drug’s reintroduction was long overdue.
“This drug should have never been taken off the market in the first place,” said Dr. Keith Eddelman, director of obstetrics at Mount Sinai Medical Center in New York City. “It is not a controversial drug and the data is very convincing.”
- Popular morning sickness drug ‘ineffective,’ study reveals
- ‘Only FDA-approved’ morning sickness drug
- Drug ‘significantly better than placebo’
- ‘Expected difference in PUQE score of 3’
- Placebo just as good as drug?
- What to do when morning sickness strikes
- Nausea Medicine and Morning Sickness: What’s Safe During Pregnancy?
- 3 Anti-Nausea Drugs for Morning Sickness
- FDA-approved morning sickness medication that is proven safe for you and your baby
- Is This Anti-Nausea Pill Safe for Pregnant Women?
Popular morning sickness drug ‘ineffective,’ study reveals
Morning sickness can put a real strain on pregnant mothers. And when diet or non-medicinal treatments fail, a drug that contains doxylamine and pyridoxine is often prescribed. However, the drug’s effectiveness has been called into question.
Share on PinterestMorning sickness can range from mild to debilitating and affects around 80 percent of pregnant mothers.
In 2017, researchers working at the University of Toronto in Canada and the Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, also in Toronto, Canada, reanalyzed a pivotal doxylamine and pyridoxine clinical trial from the 1970s and made a fairly surprising finding: the data had substantial flaws.
Digging even deeper, Dr. Navindra Persaud — from the Department of Family and Community Medicine at St. Michael’s Hospital as well as the Department of Family and Community Medicine at the University of Toronto — and colleagues reanalyzed another clinical trial using an updated version of the drug, this one from 2010.
The recent trial was part of the reason that the Food and Drug Administration (FDA) approved the popular morning sickness drug known as Diclegis.
Commenting on his findings, Prof. Persaud told me, “The medication seems to be ineffective based on the results of this trial. I was shocked to learn this about a commonly prescribed medication.”
The results of Prof. Persaud’s analysis are now published in the journal PLOS ONE.
‘Only FDA-approved’ morning sickness drug
Diclegis is the only drug approved by the FDA for the treatment of morning sickness in pregnancy. According to its manufacturer Duchesnay, it has been prescribed to 33 million women worldwide.
In Canada, where the drug is known as Diclectin, it is prescribed at least once for every two births.
I asked Prof. Persaud why he decided to look into the drug. “I used to prescribe this medication,” he explained. “I was taught to prescribe it. The medication was recommended as the first line medication for nausea and vomiting during pregnancy.”
“When I looked carefully at the clinical practice guidelines that recommended this medication, they did not cite supporting studies. So I tried to find the basis for the recommendations. It was surprisingly difficult to obtain information about this commonly prescribed drug.”
Prof. Navindra Persaud
When the results of the clinical trial were initially published in the American Journal of Obstetrics & Gynecology in 2010, the study authors concluded, “Diclectin is effective and well-tolerated in treating nausea and vomiting of pregnancy.”
Drug ‘significantly better than placebo’
The study involved 261 pregnant women, all of whom completed a 2-week course of daily Dicletin or placebo treatment. As the authors explained in the paper, “Diclectin led to significantly greater improvement in NVP symptoms as compared with placebo.”
This was based on a drop in what is known as the PUQE score. PUQE stands for pregnancy-unique quantification of emesis/nausea, with a score of 3 meaning no symptoms and a score of 15 being the most severe.
Pregnant mothers in the placebo group saw a 3.9 drop in their PUQE score from 8.8 at the start of the study, while those in the treatment group saw a 4.8 point drop down from 9.0.
In addition to the PUQE score, the team also saw a greater improvement in the global assessment of well-being score, less time taken off work, and fewer women seeking alternative treatments when they received the drug.
More pregnant mothers asked to keep taking the drug after the study finished than the placebo.
The key finding remains the PUQE score.
But while the difference seen in the clinical study may be statistically significant, Prof. Persaud uncovered that the results were not in line with what the clinical trial set out to achieve.
‘Expected difference in PUQE score of 3’
Citing the original clinical study report and the FDA review of the study, Prof. Persaud explains that the difference in PUQE score between the drug and the placebo groups was expected to be 3 points — a far cry from the difference reported in the clinical trial.
He told me that ” was surprised that important information about the trial was hidden until now. Although some results were published in 2010, the earlier reports did not mention the fact that a difference of 3 points on the 15-point symptom scale was prespecified as the minimal important difference (or the smallest difference that a patient would deem as important).”
I asked him why he thought the FDA decided to license the drug in light of the results not meeting the expected differences.
“While the review by the FDA was very thorough, the review does not address the fact that the 3-point difference between groups was not found in the trial.”
Prof. Navindra Persaud
In his paper, he explains, “The FDA summary review indicated a ‘small, but statistically significant improvement'” and noted that “although the treatment effect is small, there are no other FDA-approved treatments for nausea and vomiting of pregnancy.”
Placebo just as good as drug?
Commenting on the results of the trial and his reanalysis, Prof. Persaud explained, “In this trial, women given a placebo had large improvements in symptoms over 2 weeks. By the end of the 2-week trial, women given a placebo had symptom scores around 4 and the lowest possible score on the symptom scale is 3.”
“So the results of this study indicate that no studied treatment could have had a substantial benefit over the placebo,” he added.
With millions of women worldwide having taken the drug over the years, could it be the placebo effect that causes the improvement in symptoms?
Explaining his take on the situation, Prof. Persaud said, “We may find that nausea and vomiting during pregnancy may be like the common cold: it is common, it causes substantial suffering, it can occasionally cause serious complications, and it does not have a highly effective treatment.”
So, is it likely that the drug will be withdrawn from the market based on Prof. Persaud’s findings? He doesn’t think so.
“It is very unusual for medications to be removed from the market because of ineffectiveness,” said Prof. Persaud. “Medications are withdrawn when they are found to be harmful after approval but even this is quite rare. So it is unlikely that this medication will be withdrawn.”
What to do when morning sickness strikes
I am no stranger to morning sickness, having endured a seemingly never-ending bout last summer during my second pregnancy. Here is what Prof. Persaud told me about other treatment options.
” ecommended treatments include P6 acupressure, antihistamines such as diphenhydramine, and other nausea treatments such as metoclopramide.” However, he did add the following caveat: “None are proven to be highly effective.”
Prof. Persaud also pointed me in the direction of a 2015 systematic review examining treatments for nausea and vomiting during pregnancy. While some — such as ginger, chamomile, vitamin B-6, and lemon and mint oil — were effective for some women, the ” review found a lack of high-quality evidence to back up any advice on which interventions to use.”
” All of those results should be taken with a grain of salt,” Prof. Persaud said, echoing the review’s findings.
If you are looking for more information about coping with morning sickness, check out our handy guide “Morning sickness: 10 tips to relieve it.”
TUESDAY, Oct. 15 (HealthDay News) — The anti-nausea medication metoclopramide appears to be a safe and effective treatment for morning sickness, Danish researchers report.
More than 40,000 women exposed to metoclopramide while pregnant did not face any increased risk of birth defects or miscarriage, according to a study published Oct. 16 in the Journal of the American Medical Association.
“This is by far the largest study on metoclopramide safety in pregnancy, and as such it expands substantially on the published evidence,” said co-author Dr. Bjorn Pasternak of the Statens Serum Institute in Copenhagen. “It found that metoclopramide use in pregnancy was not associated with increased risk of major adverse outcomes, including major malformations and fetal death, and as such supports what is known about the safety profile of this drug.”
More than half of pregnant women experience nausea and vomiting, usually early in their pregnancy, the study authors noted.
Most women deal with these symptoms with little treatment, but about 10 percent to 15 percent eventually will require medication because they face more serious complications such as dehydration or weight loss.
But many pregnant women have grave concerns regarding any sort of nausea medication because of the horrific birth defects associated with the drug thalidomide, which was used to treat morning sickness in the late 1950s and early 1960s. Thalidomide’s tragic history led to the strengthening of the U.S. Food and Drug Administration (FDA) and the development of regulations regarding medication use during pregnancy.
“There’s a general feeling to take no medications during pregnancy,” said Dr. Siobhan Dolan, associate professor of obstetrics and gynecology at Montefiore Medical Center in New York City and medical adviser to the March of Dimes. “The truth is in the first trimester when the organs are forming we’re cautious about any medication the women take. But there’s a growing appreciation that there can be risks to not treating symptoms like nausea and vomiting.”
Metoclopramide, sold under the brand name Reglan, is one of the most commonly used prescription medications in pregnancy, the authors noted.
Nausea Medicine and Morning Sickness: What’s Safe During Pregnancy?
Anyone who’s ever dealt with morning sickness will tell you: It’s no joke. And now medical experts are shedding a bit more light on the importance of adequately treating pregnancy-induced nausea.
According to Britain’s Royal College of Obstetricians and Gynecologists, four out of five pregnant women experience morning sickness through pregnancy and, despite its name, this affliction can strike all day, every day. Because of this, the group has rolled out new guidelines stressing the importance of proper treatment for morning sickness.
- RELATED: 15 Tips for Dealing with Morning Sickness
“Women with persistent nausea can often feel that there is a lack of understanding of their condition,” Dr. Manjeet Shehmar, the lead author of the guidelines, said, according to the BBC. “They may be unable to eat healthily, have to take time off work, and feel a sense of grief or loss for what they perceive to be a normal pregnancy. It is therefore vital that women with this condition are given the right information and support and are made aware of the therapeutic and alternative therapies available to help them cope.”
According to the guidelines, there’s a lack of understanding about morning sickness. While drug-free therapies like ginger and acupuncture can provide relief, experts believe severe cases of morning sickness may require anti-sickness drugs or even hospital treatment.
Jonathan Schaffir, M.D., an associate professor in the department of Obstetrics and Gynecology at The Ohio State University College of Medicine, says morning sickness ranges from the occasional discomfort to a miserable experience with weight loss, dehydration, and inability to tolerate any food at all. “While the low end of this spectrum may be amenable to non-prescription treatments like bland foods and ginger, the more severe symptoms will usually require some help in the form of medication.”
The American Congress of Obstetricians and Gynecologists agrees that treatment depends on the severity of the case. “If diet and lifestyle changes do not help your symptoms, or if you have severe nausea and vomiting pregnancy, medical treatment may be needed,” the group said in an emailed statement. “If other medical conditions are ruled out, certain medications can be given to treat nausea and vomiting. You and your obstetrician or other members of your health care team can discuss all of these factors to determine the best treatment for your personal situation.”
3 Anti-Nausea Drugs for Morning Sickness
Dr. Schaffir says there are several anti-nausea medications that are used in pregnancy. Here’s some more information about the most common options.
- RELATED: What to Eat For Morning Sickness: The Best Foods and Recipes
Pyridoxine and Doxylamine
“The most extensively studied medication that has been proven safe is a combination of vitamin B6 (pyridoxine) and doxylamine, which is available over the counter as a sleep aid,” Dr. Schaffir says. Your doctor will give instructions for the medicine, but you’ll likely take it two-three times each day. Possible side effects include drowsiness, dry mouth, headaches, dizziness, gastrointestinal issues, muscle pain, and rash.
Dr. Schaffir says that other antihistamines, such as promethazine, are also safe during pregnancy. The prescription drug promethazine is sometimes used to treat nausea and vomiting (and it’s also prescribed for allergies, motion sickness, and sleep regulation). Common side effects include drowsiness, double vision, nervousness, constipation, and hyperactivity, among others.
Promethazine is classified as a category C pregnancy drug. This means that adverse effects have appeared in animal testing, but there haven’t been enough human studies to confirm any complications during pregnancy. Therefore you should only take promethazine while pregnant when the benefits outweigh the risks. You should also avoid taking the drug within two weeks of delivery since it’s been linked to platelet aggregation in the newborn. Talk to your doctor for more information.
- RELATED: When Does Morning Sickness Start and End?
Many women don’t like the sedative effects that nausea medications have, because they become too sleepy to work or take care of other children. A non-sedating medicine that is helpful for nausea in pregnancy is ondansetron. Side effects include headache, dizziness, constipation, and fatigue.
“While used widely with no bad effects, the use of ondansetron in the very early part of pregnancy has come under increased scrutiny lately because of conflicting reports that it may be associated with a small increase in the rate of certain birth defects,” says Dr. Schaffir. “This association has by no means been proven, but because of the uncertainty, many caregivers will avoid this medication until after the first two months of pregnancy.” Regardless, he says that if a woman is unable to keep any food or drink down, then the risk of complications of dehydration and insufficient nutrition may be greater than the risk of using this medication.
- By Zara Husaini Hanawalt
FDA-approved morning sickness medication that is proven safe for you and your baby
Diclegis® is a prescription medicine used to treat nausea and vomiting of pregnancy in women who have not improved with change in diet or other non-medicine treatments.
LIMITATIONS OF USE
It is not known if Diclegis® is safe and effective in women with severe nausea and vomiting of pregnancy, a condition called hyperemesis gravidarum. Women with this condition may need to be hospitalized.
IMPORTANT SAFETY INFORMATION
Diclegis® is intended for use in pregnant women. It is not known if Diclegis® is safe and effective in children under 18 years of age.
Do not take Diclegis® if you:
- are allergic to doxylamine succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any of the ingredients in Diclegis®. Please refer to the Patient Information leaflet for the complete list of ingredients;
- take monoamine oxidase inhibitors (MAOIs). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including Marplan, Nardil, Emsam, Eldepryl, Zelapar, and Parnate.
Before taking Diclegis®, tell your healthcare provider about all of your medical conditions, including if
you: (1) have asthma; (2) have eye problems called increased intraocular pressure or narrow angle glaucoma; (3) have a stomach problem called stenosing peptic ulcer or pyloroduodenal obstruction; (4) have a bladder problem called urinary bladder-neck obstruction; (5) are breastfeeding or plan to breastfeed. Diclegis® can pass into your breast milk and may harm your baby. You should not breastfeed while using Diclegis®.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should you take Diclegis®?
- Talk to your healthcare provider about how much Diclegis® to take and when to take it.
- Take Diclegis® everyday as prescribed by your healthcare provider. Do not stop taking Diclegis® without talking to your healthcare provider first.
- Do not take more than 4 tablets (1 in the morning, 1 in the mid-afternoon, and 2 at bedtime) in 1 day.Take Diclegis® on an empty stomach with a glass of water.
- Take Diclegis® tablets whole.
If you take too much Diclegis® (overdose), you may have the following symptoms: restlessness, dry mouth, the pupils of your eyes become larger (dilated), sleepiness, dizziness, confusion, fast heart rate, seizures, muscle pain or weakness, and sudden and severe kidney problems. If you have these symptoms and they are severe, they may lead to death. Stop taking Diclegis®, call your healthcare provider or go to the nearest hospital emergency room right away. For more information about overdose treatment, call your poison control center at 1-800-222-1222.
What are the possible side effects of Diclegis®?
- The most common side effect of Diclegis® is drowsiness.
- Do not drive, operate heavy machinery, or do other activities that need your full attention unless your healthcare provider says that you may do so.
- Do not drink alcohol, or take other CNS depressants such as cough and cold medicines, certain pain medicines, and medicines that help you sleep while you take Diclegis®. Severe drowsiness can happen or become worse causing falls or accidents.
- Diclegis® may cause an incorrect positive result for urine drug screening tests for methadone, opiates and PCP.
These are not all the possible side effects of Diclegis®. Call your doctor for medical advice about side effects.
Keep Diclegis® and all medicines out of the reach of children. Carefully read the storage instruction as detailed in the Diclegis Patient Information leaflet.
Duchesnay USA encourages you to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088
Is This Anti-Nausea Pill Safe for Pregnant Women?
Deana Brown believes that an anti-nausea drug she took in the first trimester of her pregnancy left her newborn deformed, and she wants GlaxoSmithKline (GSK), its manufacturer, to pay for it.
“GSK’s conduct was tantamount to using expectant mothers and their unborn children as human guinea pigs,” an attorney for Brown alleges in a new lawsuit, filed in October in a U.S. District Court in Idaho.
But is GSK’s drug Zofran actually causing birth defects, or is it just a convenient target in a recurring anxiety over the medications used for morning sickness? Without further research, the answers are still unclear but two things are certain: This isn’t the first time that a drug like Zofran has come under fire, and it won’t be the last.Brown’s daughter was born with amniotic band constriction and teratologic clubfoot deformity, conditions that affect the development of a child’s limbs, hands, and feet. In her lawsuit, Brown’s attorney alleges that GSK, one of the world’s largest drug companies, concealed a known risk of harm related to Zofran, and that “her child would never been injured” if she had been warned of the drug’s alleged side effects.
Brown isn’t alone in her mindset. By Courthouse News’s count, hers is the 193rd Zofran-related lawsuit filed this year alone. As of mid-October, cases like hers are now being consolidated into multidistrict litigation (MDL) in the District Court of Massachusetts, and law firms are rounding up plaintiffs.
But OB/GYNs tell The Daily Beast that the jury is still out on the link between birth defects and Zofran, and that widespread litigation could discourage drug manufacturers from developing necessary morning sickness medication for women who are left with few options.
The Food and Drug Administration (FDA) classifies Zofran as a Category B pregnancy drug, which means that the medication’s safety during pregnancy has been studied in animals but not in humans. The FDA advises, “Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.”
On-label, Zofran is used to treat nausea and vomiting resulting from chemotherapy, but doctors have long prescribed the drug off-label for severe morning sickness. At present, there is only one FDA-approved medication for morning sickness: Diclegis, recently seen on Kim Kardashian’s Instagram, where the reality star promoted the drug without noting its side effects and received an FDA warning as a result.
Although off-label prescription is a common medical practice, drug companies are not allowed to promote products for uses that are not indicated by the FDA. And it is here that GSK has gotten itself into hot water in the past.
In 2012, GSK “agreed to plead guilty and to pay $3 billion to resolve its criminal and civil liability arising from the company’s unlawful promotion of certain prescription drugs,” the Justice Department reported at the time. It was, they added, “the largest healthcare fraud settlement in U.S. history and the largest payment ever by a drug company.” In the settlement agreement, the U.S. claimed that GSK “knowingly promoted the sale and use of Zofran for a variety of conditions other than those for which its use was approved as safe and effective by the FDA (including hyperemesis or pregnancy-related nausea).” The guilty plea was related to other drugs, but this claim was the basis for a portion of the company’s civil liabilities in the settlement.
This allegation is central to Brown’s case, and to many other lawsuits pending against GSK. But the settlement does not necessarily mean that the drug has been proven to cause birth defects.
Dr. Jennifer Gunter, a Bay Area OB/GYN, told The Daily Beast that she herself took Zofran for severe nausea during pregnancy and her son was born with a heart defect, but she doesn’t blame the drug for the outcome.
In a blog post about Zofran litigation, Gunter reviewed the conflicting research on the drug and wrote, “Medications should never be the first line for nausea and vomiting. There are other things to try first, but for some women, like me, these things will fail and then every woman has to decide her individual risk-benefit ratio.”
Gunter also fears the impact that litigation could have on the future of morning sickness medication: “very time some personal injury lawyer decides a potential slight increased risk from a conflicting study means ‘let a jury decide,’ there is a direct negative effect on the willingness of companies to invest in studying morning sickness, and fewer doctors will be willing to prescribe anything except saltine crackers and sympathy.”
Dr. Amy Tuteur, an OB/GYN and author who blogs at The Skeptical OB, largely agreed with Gunter’s assessment, telling The Daily Beast that “Zofran can be a literal lifesaver,” and one that should “be available when other treatments fail.” Women who are “profoundly ill,” Tuteur says, cannot always tolerate Diclegis in treatment for hyperemesis gravidarum (severe vomiting during pregnancy), and might opt to use Zofran instead.
“The evidence linking Zofran to birth defects is limited,” she said. “Nonetheless it should be reserved for those who really need it, and there are some women who really need it.”
Tuteur compared the current furor over Zofran to the widespread litigation around the drug Bendectin in the 1970s and 1980s. The controversy around that drug played out in a strikingly familiar fashion: hundreds of birth defect cases were consolidated into MDL based on unclear evidence. In 1983, under an avalanche of over 300 lawsuits, manufacturer Merrell Dow voluntarily stopped making Bendectin, then the only FDA-approved morning sickness drug on the market.
Hospitalizations for nausea and vomiting during pregnancy (NVP) doubled after use of the drug stopped.
Then, in 1994, large-scale meta analysis later determined that there was no increased risk of birth defects related to Bendectin and now, its active ingredients are—“ironically,” as Tuteur notes—back on the market in the form of Diclegis.
In August of this year, the American College of Obstetricians and Gynecologists (ACOG) updated its morning sickness guidelines and noted that “further studies are warranted” on Zofran use but concluded that evidence that the drug causes birth defects is still not definitive.
“Thus, although some studies have shown an increased risk of birth defects with early ondansetron use, other studies have not and the absolute risk to any fetus is low,” the ACOG update concluded. “As with all medications, the potential risks and benefits should be weighed in each case.”
The FDA reaffirmed Zofran’s classification as a Category B drug in a letter published October 27th, a GSK spokesperson told The Daily Beast. This letter came just two days before Brown’s suit was filed.
“While we cannot comment on any individual case, we believe that the general allegations in the recently filed lawsuits involving Zofran are entirely unfounded,” the spokesperson said in a statement.
“GSK fully respects the right of doctors to assess the health care needs of their patients and apply their own knowledge, training, and experience in deciding whether the therapeutic benefits of a medicine outweigh the potential risks in each patient,” the statement continued.
Asked about the FDA classification of Zofran as a Category B drug, Aimee Wagstaff, an attorney for Brown, alleged that GSK had evidence from its own animal studies of “several concerning trends related to fertility and fetal development” tied to the use of Zofran but continued to “launch and market” the drug anyway.
“If GSK was truly concerned about providing an option for women with severe morning sickness, GSK should actually study the effects of its own drug on pregnant women rather than subjecting unborn children and their families to unknown and untested side effects,” Wagstaff said. “Certainly GSK has the resources to conduct proper clinical trials prior to launching its product, its decision makers just chose not to.”
Correction 11/4/15 8:oo PM: A previous version of this article incorrectly attributed a quote from a 2012 settlement agreement to GSK rather than the U.S. The settlement is now described in greater detail.