Addyi – Analysis of the Potential Safety Signal

The following article is an opinion piece written by Martti Ahtola. The views and opinions expressed in this article are those of the author and do not necessarily reflect the official position of Technology Networks.

It was reported that the Food and Drug Administration (FDA) is looking into an adverse event spike for Sprout’s product Addyi. These reports were based on a potential safety signal identified from FDA Adverse Event Reporting System (FAERS). The number of reported adverse events linked to Addyi in FAERS increased by 500% from 2019 to 2020. While the increase seems large, FDA will most likely not confirm this as a valid signal of new information about the benefit–risk profile of Addyi, based on our analysis of the underlying data.

Addyi (flibanserin) is used to treat decreased sexual desire in women who have not gone through menopause and who have never had low sexual desire in the past. Addyi is a serotonin 1A receptor agonist and a serotonin 2A receptor antagonist, but the mechanism by which the drug improves sexual desire and related distress is not known. Addyi is dosed at bedtime to help decrease the risk of adverse events (AE) occurring due to possible hypotension, syncope, and central nervous system depression. The most common adverse reactions associated with the use of Addyi are dizziness, sleepiness, nausea, fatigue, insomnia, and dry mouth.

Addyi went through a controversial approval in 2015. In its assessment of the medicine, FDA required additional tests to be performed and raised several issues related to the application, for example:

·         Numerically small treatment differences compared to placebo, which did not clearly outweigh the risks

·         A clinically significant interaction with alcohol causing hypotension and syncope, including concerns that the study enrolled mostly men

·         Events of central nervous system depression (e.g., somnolence), some of which appeared temporally associated with accidental injury

According to assessment documentation, during the assessment process FDA received more than two dozen letters about Addyi from various groups and individuals, including advocacy organizations, clinicians, researchers, and members of Congress. According to FDA, most letters requested that Addyi would be approved or that FDA gave Addyi careful consideration in the context of limited treatment options for women with sexual dysfunction compared to the options available to men. Apparently, some of these letters had also alleged that this inequality of treatment options reflects gender bias at the FDA, and that the FDA was holding drugs intended to treat female sexual dysfunction to more stringent standards of approval.

Addyi was approved by the FDA in August 2015, and it has had a rollercoaster of a time on the market in the past six years. This includes an immediate $1 billion buyout by Valeant, disappointing early sales figures, lawsuit for bad marketing by Sprout shareholders, Valeant going through scandals unrelated to Addyi, Valeant handing back the product to Sprout for 6% royalties, relaunching of the product, new labeling requirements and a warning for incorrect marketing from the FDA. It is also good to point out that since Addyi's launch, other products for the treatment of decreased sexual desire have been approved by the FDA.

In 2019, Sprout relaunched the product with a 50 % price drop and a new marketing campaign with a good budget for Google Ads, social media and apparently a marketing team that is not afraid to push their product. The marketing campaign has a very simple message: if you have lost your libido, Addyi is for you. Unfortunately, the message has been sometimes delivered without the required warnings about the contraindications and potentially dangerous side effects.

When Valeant was leading the original launch of Addyi in 2016, they were struggling with low numbers of prescriptions, caused by lack of awareness from potential patients and the prescribers but there were also difficulties to get certified to prescribe the medicine; the process required the doctors to fax their certification to a single location in the US.

Now the Addyi website prominently advertises the telemedicine service for diagnosis, prescription and mail delivery of the medicine. While this service likely increased the number of patients significantly, it is also probably one of the main sources for the adverse event reports from the patients.

We downloaded and reviewed the quarterly FAERS data for 2020. 148 of the 175 cases were reported during Q4 of 2020. We discovered that most of the cases in the 500% spike came from one sender: Sprout itself.

The cases have near sequential FAERS case IDs and sender IDs, so this is likely a result of a batch upload of the annual periodic adverse experience report. The timing of sending these cases would be in line with the time of launch. According to 21 CFR 314.80, three years after the approval of the drug the frequency of periodic adverse experience reports changes from quarterly to annual. The annual report is due within 60 days of the approval date anniversary.

Importantly, the product relaunch in 2019 likely contributed to an increase in patients and logically total number of AEs which is why there was not a spike in the case numbers already in October 2019.

Looking at the Addyi cases for Q4 2020, 143 out of the 148 (97%) cases are from consumers. In comparison, for Viagra (Q2 2020) 24% of adverse event reports were from consumers. We are speculating that most of these cases for Addyi are coming in through the online prescription service on their website.

It is great to see FDA is picking up on potential safety signals and considering regulatory action due to a spike in adverse events, highlighting the importance of post-marketing pharmacovigilance. One of the articles about the spike in adverse event numbers lightly downplayed the significance of the increase as most of the reports came from consumers. However, in an ideal situation, both the pharmaceutical companies and the authorities receive unfiltered, immediate, and detailed feedback from the patients.

While this is not a complete analysis, we believe the 500% spike may not necessarily be a reason for caution. FDA will assess the potential signal and if it would be validated then it would go through further assessment for its potential impact on the benefit–risk profile. The result of signal assessment can be a requirement to adjust the labeling of the product (for example additional warnings or limitations for the usage) or additional safety activities or limitations to the indication of the product.