Inhaled Isopropyl Alcohol Superior to Oral Ondansetron as an Antiemetic


Astonishing results from a small, well-designed study may have far-reaching implications.

Though ondansetron is viewed by many as the first-line agent for nausea in the emergency department (ED), there is evidence it doesn’t work in noncancer patients (NEJM JW Emerg Med Aug 2014 and Ann Emerg Med 2014; 64:526). An alternative agent, inhaled isopropyl alcohol, has shown promise (NEJM JW Emerg Med Feb 2016 and Ann Emerg Med 2016; 68:1).

In the current trial, 120 adult ED patients with nausea or vomiting who did not require intravenous access were randomized to inhaled isopropyl alcohol plus 4 mg oral ondansetron; inhaled isopropyl alcohol plus oral placebo; or inhaled saline plus 4 mg oral ondansetron. Isopropyl alcohol was provided in the form of a standard alcohol swab. Patients received a single dose of the oral intervention but could sniff alcohol or saline swabs repeatedly. Nausea was measured on a 100-mm visual analog scale at baseline and 30 minutes.

Mean nausea scores decreased by 30 mm in the alcohol/ondansetron group, 32 mm in the alcohol/placebo group, and 9 mm in the saline/ondansetron group. Rescue antiemetic therapy was given to 28%, 25%, and 45% of each group, respectively. Differences between alcohol and saline groups were statistically significant. Patients in the inhaled alcohol groups also had better nausea control at the time of discharge and reported higher satisfaction with nausea treatment. No adverse events occurred. The mechanism of action is currently unknown.

Comment

It is uncommon for us to assign a rating of “Practice Changing” to a small, single-center study, but these results are truly remarkable and are consistent with prior research. For patients not obviously requiring IV therapy, we should treat nausea with repeated inhalations from an isopropyl alcohol swab instead of administering any other drug. And, although this study provides no direct evidence of benefit to patients who do require IV therapy, there would seem to be little downside to trying this simple and safe intervention in that group, too.

Ondansetron in Early Pregnancy Seen Not to Promote Cardiac Birth Defects Overall


A new report provides some reassurance regarding the safety of the antiemetic ondansetron when taken for nausea and vomiting in early pregnancy, researchers say.

In the large retrospective cohort study, use of ondansetron in the first trimester of pregnancy was not associated with an increased risk for cardiac malformations overall.

In a secondary finding, use of the drug was associated with increased risk for oral clefts, although the absolute risk was low.

“These results suggest that ondansetron does not meaningfully increase the risk of congenital malformations, although a small increase in the risk of oral clefts cannot be excluded,” Krista F. Huybrechts, Brigham and Women’s Hospital and Harvard Medical School, Boston, told theheart.org | Medscape Cardiology.

“These results will hopefully provide reassurance to women who experience nausea and vomiting in pregnancy and need to make a risk–benefit trade off regarding treatment,” said Huybrechts, lead author on the study published December 18 in JAMA.

Evidence for the fetal safety of ondansetron, which is often prescribed for nausea and vomiting during pregnancy, is “limited and conflicting,” the researchers note in their article.

They looked at data from the Medicaid Analytic eXtrract (MAX) database of more than 1.8 million pregnancies, including 88,467 (4.9%) with exposure to ondansetron during the first trimester. They focused on cardiac malformations and oral clefts, the main congenital anomalies identified with any consistency in previous studies.

There were 14,577 cardiac abnormalities in 1,727,947 unexposed infants and 835 in 88,467 exposed infants. The adjusted risk difference was −0.8 (95% confidence interval [CI], −7.3 to 5.7 per 10,000 births) and the adjusted relative risk was 0.99 (95% CI, 0.93 to 1.06).

There was a small but statistically significant increased risk for oral clefts with first-trimester exposure to ondansetron (1912 cases in unexposed infants and 124 in exposed infants). The adjusted risk difference was 2.7 (95% CI, 0.2 – 5.2 per 10,000 births) and the adjusted relative risk was 1.24 (95% CI, 1.03 – 1.48).

After multiple adjustments, there was no difference in the risk for cardiac or overall congenital anomalies in infants born to women exposed to ondansetron. The adjusted risk difference was 5.4 (95% CI, −7.3 to 18.2 per 10,000 births) and the adjusted relative risk was 1.01 (95% CI, 0.98 to 1.05).

“The findings were consistent across a broad range of sensitivity analyses,” the authors report.

Although not formally approved for the treatment nausea and vomiting during pregnancy, the drug’s use for this purpose increased from 0.01% in 2000 to 12% in 2013, they point out.

In an accompanying editorial, David M. Haas, MD, Indiana University School of Medicine, Indianapolis, says early and effective safe treatment of nausea and vomiting in pregnancy is “crucial.”

This study provides “important and helpful” information for physicians to use when counseling women about the safety of treatment options, Haas writes.

The study shows clearly that although the adjusted relative risk for oral clefts was “elevated, the absolute risk increase is very low. The multiple adjustments and comparison groups presented, including accounting for the potential baseline risk of nausea and vomiting, demonstrate the robustness of the authors’ conclusions,” he adds.

Helping Pregnant Women and Clinicians Understand the Risk of Ondansetron for Nausea and Vomiting During Pregnancy


Nausea and vomiting during pregnancy (sometimes termed morning sickness) are among the most common medical issue to arise during pregnancy. Most pregnant women experience some form of nausea and vomiting, and prevalence rates are as high as 50% to 80%.1 Conservative measures, such as dietary modifications and avoidance of triggers, often do not control symptoms, so medications and other nondrug therapies are tried.2 Nausea and vomiting is one of the most common indications for prescriptions during pregnancy.3 Because this is a condition mainly of the first trimester, pregnant women and clinicians have concerns about the potential effects these therapies might have on the developing fetus.

In this issue of JAMA, Huybrechts and colleagues4 attempt to clarify associations of a commonly used antiemetic, ondansetron, with fetal congenital malformations. Because these malformations are typically rare, establishing cause and effect of a single drug and an anomaly is extremely difficult. Association studies using robust data sets often provide the best available evidence for establishing risk or safety of a drug. The authors describe some of the limitations of prior association studies and detail how the Medicaid Analytic eXtract (MAX) database is ideally suited to overcome some of these prior limitations. Because the authors have used these data for other pregnancy exposure studies, they are well-suited for the current analysis.

In this study, the authors used data from more than 1.8 million pregnancies, allowing for a large number of analyses and adjustments. Focusing on cardiac malformations and oral clefts (the main congenital anomalies identified with any consistency in prior studies), the authors found no significant association between ondansetron and cardiac abnormalities (14 577 abnormalities among 1 727 947 unexposed infants and 835 abnormalities among 88 467 exposed infants; adjusted risk difference, −0.8; 95% CI, −7.3 to 5.7 per 10 000 births; adjusted relative risk, 0.99, 95% CI; 0.93 to 1.06). They also detected a small but statistically significant increased risk of oral clefts with first-trimester exposure to ondansetron (1912 abnormalities among unexposed infants and 124 abnormalities among exposed infants; adjusted risk difference, 2.7; 95% CI, 0.2 to 5.2 per 10 000 births; adjusted RR, 1.24; 95% CI, 1.03 to 1.48). After multiple adjustments, the authors also found no difference in the risk of cardiac or overall congenital anomalies for infants of women exposed to ondansetron.

According to the American College of Obstetricians and Gynecologists (ACOG)–endorsed treatment algorithm, ondansetron, a serotonin receptor antagonist, is not the first-line drug for treatment of nausea and vomiting.1 However, it is one of the most commonly used agents in practice.3,5 This may be because of its different formulations, including an oral dissolving tablet, and its perceived effectiveness. Thus, it is important that clinicians and pregnant women have accurate safety information about its use during pregnancy.

Treatment of nausea and vomiting can be difficult and must be tailored to the individual patient. Often, a single treatment or combination of treatments that work for one woman will be ineffective for another. In the population studied by Huybrecht et al, 139 932 pregnant women (7.7%) also filled a prescription for promethazine, 52 818 (2.9%) filled a prescription for metoclopramide, and 9036 filled a prescription for pyridoxine (vitamin B6, 0.5%)—3 commonly used agents for nausea and vomiting. According to the treatment algorithm proposed by the ACOG Practice Bulletin, pyridoxine, alone or in combination with doxylamine, is listed as the first-line agent. Ondansetron appears as a third-line option in the algorithm.1

Ondansetron is metabolized by cytochrome P450 (CYP) enzymes that are polymorphic, such as CYP 2D6. Understanding how genetic differences among individuals cause varied responses to the same drug may have implications for prescribing.6 Because there are often genetic-based differences in activity of common drug-metabolizing enzymes, transporters, and receptors among individuals, pharmacogenomics can help guide therapeutic choices in several disease states.7 Further research is needed for ondansetron and other drugs for nausea and vomiting to determine if pharmacogenomic or specific phenotype characteristics can help personalize treatment for improved outcomes.8,9

In the evolving era of personalized medicine, rapidly determining the most effective therapy can have tangible benefits. Women with severe nausea and vomiting have decreased work productivity, more time away from personally fulfilling activities, and may have higher rates of adverse pregnancy outcomes.10,11 Additionally, severe nausea and vomiting was cited as a reason for higher rates of pregnancy termination from the Motherisk project in Canada.12 Thus, early and effective safe treatment of nausea and vomiting is crucial.

The article by Huybrechts and colleagues provides important and helpful information for physicians and other clinicians to use when counseling women about the safety of treatment options. The safety of some other options, such as pyridoxine, has been established.13 The current article documents clearly that while the adjusted relative risk of oral clefts was elevated, the absolute risk increase is very low. The multiple adjustments and comparison groups presented, including accounting for the potential baseline risk of nausea and vomiting, demonstrate the robustness of the authors’ conclusions.

In addition, the authors acknowledge the typical limitations of these types of analyses. Because of the low frequency of congenital anomaly outcomes, randomized trials would need to have enormous sample sizes to detect differences between drug exposures. Thus, observational data are best suited for these studies. One additional relevant limitation of the data set is that prescriptions for the current recommended first-line treatment, pryidoxine (with or without doxylamine), may not have been completely captured. The prescription combination of doxylamine and pyridoxine was approved by the US Food and Drug Administration in 2013, the final year the MAX data were queried. Many women may have obtained these components over-the-counter, and thus the true polypharmacy rates for nausea and vomiting treatment are not accounted for in the data set.

Utilizing a large data set, the study by Huybrechts et al provides some reassurance for obstetricians and other clinicians, as well as for pregnant women regarding the safety of a commonly used medication for nausea and vomiting. The potential risk and safety findings must be weighed with the effectiveness of ondansetron in treating nausea and vomiting and avoiding hyperemesis gravidarum. The analysis also provides additional reassurance of no increased risk of cardiac or total congenital malformations. As clinicians and pregnant women engage in informed, shared decision-making surrounding treatment for nausea and vomiting, the current information is important for contextualizing risks in light of the potential benefits.

Ondansetron in pregnancy and risk of adverse fetal outcomes.


Ondansetron is frequently used to treat nausea and vomiting during pregnancy, but the safety of this drug for the fetus has not been well studied.

METHODS: We investigated the risk of adverse fetal outcomes associated with ondansetron administered during pregnancy. From a historical cohort of 608,385 pregnancies in Denmark, women who were exposed to ondansetron and those who were not exposed were included, in a 1:4 ratio, in propensity-score-matched analyses of spontaneous abortion (1849 exposed women vs. 7396 unexposed women), stillbirth (1915 vs. 7660), any major birth defect (1233 vs. 4932), preterm delivery (1792 vs. 7168), and birth of infants at low birth weight and small for gestational age (1784 vs. 7136). In addition, estimates were adjusted for hospitalization for nausea and vomiting during pregnancy (as a proxy for severity) and the use of other antiemetics.
RESULTS: Receipt of ondansetron was not associated with a significantly increased risk of spontaneous abortion, which occurred in 1.1% of exposed women and 3.7% of unexposed women during gestational weeks 7 to 12 (hazard ratio, 0.49; 95% confidence interval [CI], 0.27 to 0.91) and in 1.0% and 2.1%, respectively, during weeks 13 to 22 (hazard ratio, 0.60; 95% CI, 0.29 to 1.21). Ondansetron also conferred no significantly increased risk of stillbirth (0.3% for exposed women and 0.4% for unexposed women; hazard ratio, 0.42; 95% CI, 0.10 to 1.73), any major birth defect (2.9% and 2.9%, respectively; prevalence odds ratio, 1.12; 95% CI, 0.69 to 1.82), preterm delivery (6.2% and 5.2%; prevalence odds ratio, 0.90; 95% CI, 0.66 to 1.25), delivery of a low-birth-weight infant (4.1% and 3.7%; prevalence odds ratio, 0.76; 95% CI, 0.51 to 1.13), or delivery of a small-for-gestational-age infant (10.4% and 9.2%; prevalence odds ratio, 1.13; 95% CI, 0.89 to 1.44).
CONCLUSIONS: Ondansetron taken during pregnancy was not associated with a significantly increased risk of adverse fetal outcomes.

Source: NEJM

Ondansetron Safe During Pregnancy.


A large Danish study in the New England Journal of Medicine shows no significant association between the antiemetic ondansetron and adverse pregnancy outcomes.

In this retrospective cohort study, ondansetron had been prescribed for nausea and vomiting in almost 2000 of some 600,000 pregnancies. Ondansetron users were no more likely than nonusers to experience spontaneous abortion or stillbirth, or to have preterm delivery, a small-for-getational-age infant, or an infant with a major birth defect.

Source: Journal Watch Women’s Health

 

Ondansetron (Zofran) 32 mg, Single Intravenous (IV) Dose: Updated Safety Communication – Product Removal due to Potential For Serious Cardiac Risks


AUDIENCE: Oncology, Surgery, Health Professional

ISSUE: FDA is notifying health care professionals that the 32 mg, single intravenous (IV) dose of the anti-nausea drug Zofran (ondansetron hydrochloride) will no longer be marketed because of the potential for serious cardiac risks.

BACKGROUND: The 32 mg, single IV dose of Zofran had been used to prevent chemotherapy-induced nausea and vomiting. A previous Drug Safety Communication (DSC), issued on June 29, 2012, communicated that the 32 mg, single IV dose should be avoided due to the risk of a specific type of irregular heart rhythm called QT interval prolongation, which can lead to Torsades de Pointes, an abnormal, potentially fatal heart rhythm.  These drugs are sold pre-mixed in solutions of either dextrose or sodium chloride in plastic containers.

FDA anticipates these products will be removed from the market through early 2013.  FDA does not anticipate that removal of the 32 mg intravenous dose of ondansetron currently sold as pre-mixed injections will contribute to a drug shortage of IV ondansetron, as the 32 mg dose makes up a very small percentage of the current market

RECOMMENDATION: FDA continues to recommend the intravenous regimen of 0.15 mg/kg administered every 4 hours for three doses to prevent chemotherapy-induced nausea and vomiting. Oral dosing of Ondansetron remains effective for the prevention of chemotherapy-induced nausea and vomiting. At this time, there is not enough information available for FDA to recommend an alternative single IV dose regimen.