Nicotine Poisoning Seizures Darken Cloud Around E-Cigarettes' NRT Potential

FDA for several years has noted opportunity for e-cigarettes and other electric nicotine delivery systems products to help adult smokers switch to a potentially less harmful form of nicotine delivery. "But we’ve also been clear that, even for adults, e-cigarettes are not risk free," says FDA Commissioner Gottlieb and Principal Deputy Commissioner Abernethy. Most seizures reported by youth and young adult e-cigarette users.

Electronic cigarettes' potential for approval as FDA-approved products indicated for smoking cessation takes another hit from reports that some users, mostly youths or young adults, have experienced seizures.

FDA stated in an April 3 alert that for several years it often has noted an opportunity for e-cigarettes and other electric nicotine delivery systems products to help currently addicted adult smokers to completely switch to a potentially less harmful form of nicotine delivery.

"But we’ve also been clear that, even for adults, e-cigarettes are not risk free. While we believe that currently addicted adult smokers who completely switch off of combustible tobacco and onto e-cigarettes have the potential to improve their health, e-cigarettes still pose health risks," said FDA Commissioner Scott Gottlieb and Principal Deputy Commissioner Amy Abernethy in a joint statement.

Gottlieb and Abernethy, both physicians, said the risks include the possible release of some chemicals at higher levels than conventional cigarettes. Seizures or convulsions are known potential side effects of nicotine poisoning and have been reported in scientific literature from to intentional or accidental swallowing of nicotine-containing e-liquids, the said.

"While we believe that currently addicted adult smokers who completely switch off of combustible tobacco and onto e-cigarettes have the potential to improve their health, e-cigarettes still pose health risks." – FDA Commissioner Scott Gottlieb and Principal Deputy Commissioner Amy Abernethy

However, in a review of voluntary adverse event reports for ENDs submitted to the agency and to poison control centers, FDA identified 35 reported cases of seizures following use of e-cigarettes between 2010 and early 2019, with an uptick starting in June 2018.

"While 35 cases may not seem like much compared to the total number of people using e-cigarettes, we are nonetheless concerned by these reported cases," the commissioner and deputy commissioner said.

FDA is seeking more information about seizures following e-cigarette use to identify common risk factors and understand whether any ENDS product attributes such as nicotine content or formulation contribute to seizures.

Gottlieb and Abernethy said not all incidents of seizures potentially linked to nicotine toxicity may be reported, but that 35 cases warrant scientific investigation to determine whether a connection exists. They added that FDA doesn't yet know of a direct relationship between the use of e-cigarettes and a risk of seizure.

FDA Scrutiny Broad And Growing

Even without a conclusive finding linking their use to seizures, ENDS products' outlook for potential approval by FDA as Rx or OTC treatments labeled for smoking cessation and related indications will take a hit from the agency's latest concern.

Nicotine addiction from use of the products by nonsmokers or continued nicotine dependency by former smokers have been a concern at FDA since ENDS became available in the US, and stopping sales of the products to young people, driven largely by firms' marketing flavored nicotine, has been a priority for Gottlieb since he became commissioner in 2017.

According to FDA, most recent data from research show more than 3.6m US middle and high school students in 2018 were current (within the past 30 days) e-cigarette users, up from 1.5m students in 2017. The data also showed youth who used e-cigarettes were using them more frequently and using flavored products more often than in 2017.

"This is particularly troubling given research shows kids using e-cigarettes are more likely to take up combustible cigarettes," said Gottlieb in the agency's April 1 announcement.

Gottlieb, who leaves the agency on April 5, has shined a spotlight on this priority in his last month as commissioner. On April 1, FDA announced a public scientific workshop scheduled for May 15 to discuss the challenges and science on youth tobacco use and addiction and treatment strategies to support cessation. The workshop will follow a public hearing FDA conducted in January to gain perspectives on the topic and has announced funding opportunities to support research on youth tobacco initiation, use and cessation.

In March, FDA proposed ending its current compliance policy for flavored ENDS products, other than tobacco-, mint-, and menthol-flavored products, and to prioritize enforcement of products sold in ways that risk allowing access to minors.

The agency says its expects that the compliance policy changes will end sales of some flavored ENDS products and stringent proof-of-age requirements will be implemented to prevent minors' access to other flavored products that remain available. Additionally, FDA proposed moving up the date for requiring premarket authorization for all flavored ENDS products to August 2021.

Gottlieb, who has met with leading ENDS product firms to encourage effective, voluntary actions to prevent sales to minors, said with the proposed policy, the agency is "putting all manufacturers and retailers on notice: you may be subject to FDA enforcement for selling certain flavored ENDS products without authorization."

Earlier Hits On ENDS' NRT Potential

FDA and the Federal Trade Commissioner previously put the ENDS industry on notice jointly submitted warning letters to 13 manufacturers, distributors and retailers for selling liquid nicotine used in e-cigarettes with labeling and advertising resembling "kid-friendly food products" including juice boxes, candy or cookies, some with cartoon-like imagery. Several warned in May 2018 also were cited for illegally selling the products to minors. (Also see "Smoking Cessation Indication For E-Cigarettes Could Fade Under Cloud Of Nicotine Packaged For Children" - HBW Insight, 1 May, 2018.)

Additionally, in October 2018 FDA warned a Chinese firm about selling liquid nicotine spiked with erectile dysfunction drugs. (Also see "Sales of Drug-Spiked Nicotine Could Sink E-Cigarettes' Smoking Cessation Chances " - HBW Insight, 11 Oct, 2018.)

FDA has backed its encouragement for research on ENDS' use in smoking cessation, though, with separate draft guidances on clinical and nonclinical trials. The clinical trials draft guidance published in February reiterates FDA's expectation for multiple trials to demonstrate an investigational nicotine replacement therapy product with characteristics different from an approved product, such as route of administration, is effective for smoking cessation or reduction in risk of relapse. (Also see "Wider Options In FDA's NRT Clinical Trial Guidance, Approval Path Still Narrow" - HBW Insight, 29 Mar, 2019.)

Its August 2018 nonclinical draft guidance recommends that even before a sponsor for a potential NRT new drug application begin clinical trials, they need results from animal studies which would require years of work. (Also see "FDA Helps E-Cigarettes Navigate NDA Process With Nonclinical Tests Guidance" - HBW Insight, 3 Aug, 2018.)

Meanwhile, researchers in a study published recently in the Journal of the American Medical Association Oncology showing increased ENDS use among cancer patients emphasized that studies are needed on potential health outcomes from long-term use of the products. A high prevalence of ENDS use among current smokers calls into question whether the products are useful for smoking cessation, they stated. (Also see "E-Cigarettes' Appeal For Smoking Cessation Cooled By Risk Questions" - HBW Insight, 20 Feb, 2019.)