Perspective

FDA orders label change allowing some alcohol use with flibanserin

The FDA on Thursday issued a safety labeling change order to Sprout Pharmaceuticals for the serotonin receptor agonist flibanserin, ordering a modification to the boxed warning that states alcohol use is contraindicated when taking the drug.

The revised boxed warning for the drug, indicated for premenopausal women with acquired, generalized hypoactive sexual desire disorder, will now state that women should discontinue drinking alcohol at least 2 hours before taking flibanserin (Addyi) at bedtime or skip the flibanserin dose that evening. The change comes after an FDA review of postmarketing studies, including one required when flibanserin was approved in August 2015, as well as other data.

“The FDA helps ensure that the most current safety information about the use of prescription drugs is accurately reflected in product labeling, giving health care professionals and patients confidence that they are able to make the most informed treatment decisions,” Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research’s Office of New Drugs, said in the release. “We recognize that women want access to treatments for female sexual dysfunction, and we are committed to helping ensure approved therapies are safe and effective when taken as indicated and to supporting the development of new therapeutic options for female sexual dysfunction.”

Hypotension, syncope risks

At the time of approval, the FDA reviewed data that included several concerning cases of severe hypotension and syncope when flibanserin and alcohol were taken together. As a result, the label initially approved for flibanserin included a boxed warning that states women prescribed the drug must avoid alcohol. The FDA also required a risk evaluation and mitigation strategy (REMS), which requires that health care professionals who prescribe flibanserin and pharmacies that dispense the drug must be certified with the flibanserin REMS program and that patients must be counseled about the risks for hypotension and syncope. In addition, the FDA required Sprout to further study the interaction between flibanserin and alcohol after approval.

“Based on the results of postmarketing studies, the FDA determined that changes must be made to Addyi’s labeling to clarify that there is still a concern about consuming alcohol close in time to taking Addyi, but that it does not have to be avoided completely,” the FDA stated in the release. “Specifically, the boxed warning, contraindication, warnings and precautions, and adverse reactions sections of labeling are being updated to reflect that women should discontinue drinking alcohol at least 2 hours before taking Addyi at bedtime or to skip the Addyi dose that evening. Women should not consume alcohol at least until the morning after taking Addyi at bedtime.”

Disagreement over labeling

The FDA noted in the release that it is requiring Sprout to make the label changes because the agency was not able to reach an agreement with the company, which was continuing to request removal of the boxed warning and contraindication about alcohol completely from the product labeling.

After a review of available data, the FDA determined that a complete removal of the alcohol warning “was not acceptable for the protection of public health.”

“We work diligently with companies to make labeling updates but occasionally are unable to reach agreement,” Beitz said in the release. “In those rare cases, such as with Addyi today, we have important authorities to compel companies to make safety labeling changes that are critical for the safe use of an approved product. We are taking this action because it is our responsibility to help protect the safety of those who take prescription medicines, which includes helping to ensure that patients are provided access to the most up-to-date information about the drugs they take.”

In the FDA-required postmarketing trial in women who took flibanserin and drank alcohol at the same time, there were missing or delayed blood pressure measurements from when the women were first lying down to when they stood up that are critical in determining the risk for hypotension and syncope, according to the agency.

There were no reports of syncope or hypotension needing intervention among women in the trial; however, the FDA stated that safety precautions built into the trial did not allow for an adequate assessment of this risk.

“For example, women with low blood pressure while lying down or with symptoms that could be related to low blood pressure, such as dizziness, were not permitted to stand up to have blood pressure measurements taken or had to have repeated blood pressure measurements while lying down until they were high enough for the women to safely stand up,” the FDA stated in the release. “As a result, the data collected had missing or delayed blood pressure measurements from these women while standing.”

Many more women had missing or delayed blood pressure measurements when they took flibanserin and alcohol together compared with when they received alcohol alone or flibanserin alone, the FDA stated.

The pattern of the missing or delayed measurements provides further evidence of an interaction between flibanserin and alcohol that can increase the risk for hypotension and syncope. Given these results, the FDA determined that the boxed warning and contraindication continue to be warranted.

“Women at home will not have the safety measures that were included in this trial or necessarily have access to immediate assistance if they were to experience severe hypotension or syncope, which can lead to serious outcomes including falls, accidents and bodily harm,” the FDA stated in the release.

Alcohol timing, reduced risk

In other postmarketing trials, results showed that the risks for severe hypotension and syncope were reduced when women who consumed up to two alcoholic drinks waited at least 2 hours before taking flibanserin. The FDA found those results sufficient to support a modification to the boxed warning and contraindication.

Flibanserin 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. The drug is taken once daily at bedtime to help decrease the risk for adverse events occurring due to possible hypotension, syncope and central nervous system depression, such as sleepiness and sedation. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

In a review assessing trials of flibanserin published in JAMA Internal Medicine and reported by Healio.com, researchers found that the treatment increased the number of satisfying sexual events by less than one each month. Results showed that, between participants who received 100 mg flibanserin and placebo, the pooled mean difference for change in mean satisfying sexual events from baseline was 0.49 (95% CI, 0.32-0.67). In addition, the mean difference for eDiary desire score was 1.63 (95% CI, 0.45-2.82) and the mean difference for Female Sexual Function Index desire was 0.27 (95% CI, 0.17-0.38).

The most common adverse reactions associated with the use of flibanserin are dizziness, somnolence, nausea, fatigue, insomnia and dry mouth. – by Regina Schaffer

For more information:

FDA. FDA orders important safety labeling changes for Addyi. April 11, 2019. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm635847.htm.

Disclosure: Beitz is director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research’s Office of New Drugs.

The FDA on Thursday issued a safety labeling change order to Sprout Pharmaceuticals for the serotonin receptor agonist flibanserin, ordering a modification to the boxed warning that states alcohol use is contraindicated when taking the drug.

The revised boxed warning for the drug, indicated for premenopausal women with acquired, generalized hypoactive sexual desire disorder, will now state that women should discontinue drinking alcohol at least 2 hours before taking flibanserin (Addyi) at bedtime or skip the flibanserin dose that evening. The change comes after an FDA review of postmarketing studies, including one required when flibanserin was approved in August 2015, as well as other data.

“The FDA helps ensure that the most current safety information about the use of prescription drugs is accurately reflected in product labeling, giving health care professionals and patients confidence that they are able to make the most informed treatment decisions,” Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research’s Office of New Drugs, said in the release. “We recognize that women want access to treatments for female sexual dysfunction, and we are committed to helping ensure approved therapies are safe and effective when taken as indicated and to supporting the development of new therapeutic options for female sexual dysfunction.”

Hypotension, syncope risks

At the time of approval, the FDA reviewed data that included several concerning cases of severe hypotension and syncope when flibanserin and alcohol were taken together. As a result, the label initially approved for flibanserin included a boxed warning that states women prescribed the drug must avoid alcohol. The FDA also required a risk evaluation and mitigation strategy (REMS), which requires that health care professionals who prescribe flibanserin and pharmacies that dispense the drug must be certified with the flibanserin REMS program and that patients must be counseled about the risks for hypotension and syncope. In addition, the FDA required Sprout to further study the interaction between flibanserin and alcohol after approval.

“Based on the results of postmarketing studies, the FDA determined that changes must be made to Addyi’s labeling to clarify that there is still a concern about consuming alcohol close in time to taking Addyi, but that it does not have to be avoided completely,” the FDA stated in the release. “Specifically, the boxed warning, contraindication, warnings and precautions, and adverse reactions sections of labeling are being updated to reflect that women should discontinue drinking alcohol at least 2 hours before taking Addyi at bedtime or to skip the Addyi dose that evening. Women should not consume alcohol at least until the morning after taking Addyi at bedtime.”

PAGE BREAK

Disagreement over labeling

The FDA noted in the release that it is requiring Sprout to make the label changes because the agency was not able to reach an agreement with the company, which was continuing to request removal of the boxed warning and contraindication about alcohol completely from the product labeling.

After a review of available data, the FDA determined that a complete removal of the alcohol warning “was not acceptable for the protection of public health.”

“We work diligently with companies to make labeling updates but occasionally are unable to reach agreement,” Beitz said in the release. “In those rare cases, such as with Addyi today, we have important authorities to compel companies to make safety labeling changes that are critical for the safe use of an approved product. We are taking this action because it is our responsibility to help protect the safety of those who take prescription medicines, which includes helping to ensure that patients are provided access to the most up-to-date information about the drugs they take.”

In the FDA-required postmarketing trial in women who took flibanserin and drank alcohol at the same time, there were missing or delayed blood pressure measurements from when the women were first lying down to when they stood up that are critical in determining the risk for hypotension and syncope, according to the agency.

There were no reports of syncope or hypotension needing intervention among women in the trial; however, the FDA stated that safety precautions built into the trial did not allow for an adequate assessment of this risk.

“For example, women with low blood pressure while lying down or with symptoms that could be related to low blood pressure, such as dizziness, were not permitted to stand up to have blood pressure measurements taken or had to have repeated blood pressure measurements while lying down until they were high enough for the women to safely stand up,” the FDA stated in the release. “As a result, the data collected had missing or delayed blood pressure measurements from these women while standing.”

Many more women had missing or delayed blood pressure measurements when they took flibanserin and alcohol together compared with when they received alcohol alone or flibanserin alone, the FDA stated.

The pattern of the missing or delayed measurements provides further evidence of an interaction between flibanserin and alcohol that can increase the risk for hypotension and syncope. Given these results, the FDA determined that the boxed warning and contraindication continue to be warranted.

PAGE BREAK

“Women at home will not have the safety measures that were included in this trial or necessarily have access to immediate assistance if they were to experience severe hypotension or syncope, which can lead to serious outcomes including falls, accidents and bodily harm,” the FDA stated in the release.

Alcohol timing, reduced risk

In other postmarketing trials, results showed that the risks for severe hypotension and syncope were reduced when women who consumed up to two alcoholic drinks waited at least 2 hours before taking flibanserin. The FDA found those results sufficient to support a modification to the boxed warning and contraindication.

Flibanserin 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. The drug is taken once daily at bedtime to help decrease the risk for adverse events occurring due to possible hypotension, syncope and central nervous system depression, such as sleepiness and sedation. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

In a review assessing trials of flibanserin published in JAMA Internal Medicine and reported by Healio.com, researchers found that the treatment increased the number of satisfying sexual events by less than one each month. Results showed that, between participants who received 100 mg flibanserin and placebo, the pooled mean difference for change in mean satisfying sexual events from baseline was 0.49 (95% CI, 0.32-0.67). In addition, the mean difference for eDiary desire score was 1.63 (95% CI, 0.45-2.82) and the mean difference for Female Sexual Function Index desire was 0.27 (95% CI, 0.17-0.38).

The most common adverse reactions associated with the use of flibanserin are dizziness, somnolence, nausea, fatigue, insomnia and dry mouth. – by Regina Schaffer

For more information:

FDA. FDA orders important safety labeling changes for Addyi. April 11, 2019. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm635847.htm.

Disclosure: Beitz is director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research’s Office of New Drugs.

    Perspective
    Sheryl Kingsberg

    Sheryl Kingsberg

    The FDA’s recommended revised box warning appears to take into account a number of discussions between Sprout Pharmaceuticals and the FDA, which the FDA made public in their labeling order to Sprout last week.

    The goal of the FDA is to make sure that the safety and health of patients is a priority and always taken into account. However, not treating is also not benign. Hypoactive sexual desire disorder is a recognized sexual dysfunction that affects millions of women, and pharmacologic treatment, including Addyi, has been shown to be effective in some although not all women.

    The FDA’s approval of Addyi, based on clinical trials comparing Addyi with placebo, required — and it appears may still require — a risk evaluation and mitigation strategies (REMS) program. As we know, REMS programs are designed to help reduce occurrences or severity of certain serious risks, by informing and supporting safe use conditions that are described in a medication's FDA-approved prescribing information for both patients and providers. As with all FDA-approved drugs, the contraindications section of prescription drug labeling must describe situations in which the drug should not be used because the risk of use may outweigh the possible therapeutic benefit of the drug. While the updated labeling for Addyi has not yet been released, FDA’s recommended new labeling is different from current labeling, which states alcohol use is contraindicated and that patients being considered to be prescribed Addyi should be assessed regarding their likelihood of abstaining from alcohol and that prescribers are required to counsel patients prescribed Addyi about the importance of abstaining from alcohol. It appears in new labeling, based on additional alcohol interaction studies in premenopausal women, the FDA has advised that Addyi should only be used 2 hours after discontinuing alcohol due to reported interaction between alcohol and Addyi when taken at the same time.

    This revised labeling will be less prohibitive for prescriber/patient discussions, although prescribers must still talk with their patients because of the drug’s boxed warning. It is always important to have a conversation with patients about medications — REMS or not — about when to take them, how to take them and if it provides a benefit. I hope that the revised label will encourage prescribers and patients to have this conversation. I am encouraged by the FDA's continued recognition that women deserve safe and effective pharmacologic options for HSDD.

    • Sheryl Kingsberg, PhD
    • Chief, Division of Behavioral Medicine, Obstetrics and Gynecology
      University Hospitals Cleveland Medical Center
      Professor of Reproductive Biology and Psychiatry
      Case Western Reserve University School of Medicine

    Disclosures: Kingsberg reports she was an investigator and testified before an FDA advisory committee 2015 for flibanserin approval. She has received consulting fees from Sprout and Valeant and continues to conduct clinical research on flibanserin. She currently serves as a consultant or scientific advisory board member for AMAG, Daré, Duchesney, Emotional Brain, Endoceutics, GTx, IVIX, Lupin, Materna, Palatin Technologies, Pfizer, Strategic Science Technologies, and TherapeuticsMD.