Flibanserin, sold under the brand name Addyi (), is a medication approved for the treatment of pre-menopausal women with
hypoactive sexual desire disorder
Hypoactive sexual desire disorder (HSDD), hyposexuality, or inhibited sexual desire (ISD) is sometimes considered a sexual dysfunction, and is characterized as a lack or absence of sexual fantasies and desire for sexual activity, as judged by a ...
(HSDD). The medication attemps to improve sexual desire, increase the number of satisfying sexual events, and decrease the distress associated with low sexual desire. The most common side effects are
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a ...
, sleepiness,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
, difficulty falling asleep or staying asleep and dry mouth.
Development
Development or developing may refer to:
Arts
*Development (music), the process by which thematic material is reshaped
* Photographic development
*Filmmaking, development phase, including finance and budgeting
* Development hell, when a proje ...
by
Boehringer Ingelheim
C.H. Boehringer Sohn AG & Co. is the parent company of the Boehringer Ingelheim group, which was founded in 1885 by Albert Boehringer (1861–1939) in Ingelheim am Rhein, Germany. As of 2018, Boehringer Ingelheim is one of the world's List of la ...
was halted in October 2010, following a negative evaluation by the US
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA).Spiegel online Pharmakonzern stoppt Lustpille für die Frau 8 October 2010 (in German) The rights to the drug were then transferred to Sprout Pharmaceuticals, which achieved approval of the drug by the US FDA in August 2015.
Addyi is approved for medical use in the US for premenopausal women with HSDD and in Canada for premenopausal and postmenopausal women with HSDD.
HSDD was recognized as a distinct sexual function disorder for more than 30 years, but was removed from the ''
Diagnostic and Statistical Manual of Mental Disorders
The ''Diagnostic and Statistical Manual of Mental Disorders'' (''DSM''; latest edition: ''DSM-5-TR'', published in March 2022) is a publication by the American Psychiatric Association (APA) for the classification of mental disorders using a com ...
hypoactive sexual desire disorder
Hypoactive sexual desire disorder (HSDD), hyposexuality, or inhibited sexual desire (ISD) is sometimes considered a sexual dysfunction, and is characterized as a lack or absence of sexual fantasies and desire for sexual activity, as judged by a ...
among women. The onset of the flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period.
The effectiveness of flibanserin was evaluated in three phase 3 clinical trials. Each of the three trials had two co-primary endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire. Each of the 3 trials also had a secondary endpoint that measured distress related to sexual desire. All three trials showed that flibanserin produced an increase in the number of SSEs and reduced distress related to sexual desire. The first two trials used an electronic diary to measure sexual desire, and did not find an increase. These two trials also measured sexual desire using the Female Sexual Function Index (FSFI) as a secondary endpoint, and an increase was observed using this latter measure. The FSFI was used as the co-primary endpoint for sexual desire in the third trial, and again showed a statistically significant increase.
Supportive analyses based on the patient's perspective of her symptoms at the end of the study showed that improvements in symptoms of HSDD were not only statistically significant but also clinically meaningful to women.
Side effects
The majority of
adverse events
In pharmaceuticals, an adverse event (AE) is any unexpected or harmful medical occurrence that happens to a patient during medical treatment or a clinical trial. Unlike direct side effects, an adverse event does not necessarily mean the medicatio ...
were mild to moderate in severity. The most commonly reported adverse events included
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a ...
,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
sleepiness
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
, and
trouble sleeping
Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
.
Drinking alcohol while on flibanserin may increase the risk of severe
low blood pressure
Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
. The Addyi Prescribing Information was updated in 2019 following the FDA's review of three postmarketing alcohol interaction studies which led to increased understanding of this drug interaction. This new data led to a removal of the contraindication with alcohol and new recommendations on how to safely consume alcohol while receiving Addyi therapy.
Current recommendations are to wait at least two hours after consuming one or two standard alcoholic drinks before taking ADDYI at bedtime or to skip their ADDYI dose if they have consumed three or more standard alcoholic drinks that evening.
Mechanism of action
Activity profile
Flibanserin acts as a
full agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...
in the
frontal cortex
The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betw ...
and the
Dorsal Raphe Nucleus
The dorsal raphe nucleus is one of the raphe nuclei. It is situated in the brainstem at the midline. It has rostral and caudal subdivisions:
* The rostral aspect of the ''dorsal'' raphe is further divided into interfascicular, ventral, ventrolater ...
, but only as a
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...
hippocampus
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
serotonin receptor
5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...
) (Ki = 1 nM in cells, but only 15–50 nM in cortex, hippocampus and dorsal raphe) and, with lower
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Pa ...
, as an
antagonist
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT2A receptor (Ki = 49 nM) and antagonist or very weak
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...
of the D4 receptor (Ki = 4–24 nM, Ki = 8–650 nM). Despite the much greater affinity of flibanserin for the 5-HT1A receptor, and for reasons that are unknown (although it might be caused by the competition with endogenous serotonin), flibanserin occupies the 5-HT1A and 5-HT2A receptors ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'' with similar percentages. Flibanserin also has low affinity for the 5-HT2B receptor (Ki = 89.3 nM) and the 5-HT2C receptor (Ki = 88.3 nM), both of which it behaves as an antagonist of. Flibanserin preferentially activates 5-HT1A receptors in the
prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
, demonstrating regional selectivity, and has been found to increase
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
and
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
levels and decrease
serotonin
Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
levels in the rat prefrontal cortex, actions that were determined to be mediated by activation of the 5-HT1A receptor. As such, flibanserin has been described as a norepinephrine–dopamine disinhibitor (NDDI).
The proposed
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
Neurotra ...
s,
sex steroid
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
s, and other
hormone
A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
s have important
excitatory
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
or
inhibitory
An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a Chemical synapse, postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Inc ...
effects on the sexual response. Among neurotransmitters, excitatory activity is driven by dopamine and norepinephrine, while inhibitory activity is driven by serotonin. The balance between these systems is of significance for a normal sexual response. By modulating serotonin and dopamine activity in certain parts of the brain, flibanserin may improve the balance between these neurotransmitter systems in the regulation of sexual response.
Society and culture
Flibanserin was originally developed as an
antidepressant
Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.
Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
, but was found to have pro-sexual effects and was later repurposed for the treatment of HSDD.
Names
The brand name is Addyi.
Approval process and advocacy
In June 2010, a federal advisory panel to the US
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) unanimously voted against recommending approval of flibanserin, citing an inadequate risk-benefit ratio. The Committee acknowledged the validity of hypoactive sexual desire as a diagnosis, but expressed concern with the drug's side effects and insufficient evidence for efficacy, especially the drug's failure to show a statistically significant effect on the co-primary endpoint of sexual desire. Earlier in the week, a FDA staff report also recommended non-approval of the drug. Ahead of the votes, Boehringer Ingelheim had mounted a publicity campaign to promote the controversial disorder of "hypoactive sexual desire". In 2010 the FDA issued a Complete Response Letter, stating that the
New Drug Application
The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...
could not be approved in its current form. The letter cited several concerns, including the failure to demonstrate a statistical effect on the co-primary endpoint of sexual desire and overly restrictive entry criteria for the two Phase 3 trials. The Agency recommended performing a new Phase 3 trial with less restrictive entry criteria. On 8 October 2010, Boehringer announced that it would discontinue its development of flibanserin in light of the FDA's decision.
Sprout responded to the FDA's cited deficiencies and refiled the NDA in 2013. The submission included data from a new Phase 3 trial and several Phase 1 drug-drug interaction studies. The FDA again refused the application, citing an uncertain risk/benefit ratio. In December 2013, a Formal Dispute Resolution was filed, which contained the requirements of the FDA for further studies. These include two studies in healthy subjects to determine if flibanserin impairs their ability to drive, and to determine if it interferes with other biochemical pathways. The Agency agreed to call a new Advisory Committee meeting to consider whether the risk-benefit ratio of flibanserin was favorable after this additional data was obtained.''FDA seeks more tests on a female Viagra'', by Matthew Perrone, The Detroit Free Press, page 2A Wednesday, 12 February 2014 Sprout expected to resubmit the New Drug Application (NDA) in the 3rd quarter of 2014.
In June 2015, the US FDA Advisory Committee, which includes the Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSRM), recommended approval of the drug by 18–6, with the proviso that measures be taken to inform women of the drug's side effects. On 18 August 2015, the FDA approved Addyi (Flibanserin) for the treatment of premenopausal women with low sexual desire that causes personal distress or relationship difficulties. The approval specified that flibanserin should not be used to treat low sexual desire caused by co-existing psychiatric or medical problems; low sexual desire caused by problems in the relationship; or low sexual desire due to medication side effects.
As of 21 August 2015, '' The Pharmaceutical Journal'' reported that Sprout Pharmaceuticals had not yet made an application to the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
for a marketing authorisation.
Advocacy groups
''Even the Score'', a coalition of women's groups brought together by a Sprout consultant, actively campaigned for the approval of flibanserin. The campaign emphasized that several approved treatments for male sexual dysfunction exist, while no such treatment for women was available. The group successfully obtained letters of support from the President of the
National Organization for Women
The National Organization for Women (NOW) is an American feminist organization. Founded in 1966, it is legally a 501(c)(4) social welfare organization. The organization consists of 550 chapters in all 50 U.S. states and in Washington, D.C. It ...
, the editor of the Journal of Sexual Medicine, and several members of Congress.
Other organizations supporting the approval of flibanserin included the
National Council of Women's Organizations The National Council of Women's Organizations (NCWO) is an American Non-profit organization, non-profit umbrella organization of more than 100 women's organizations. The organization has a membership of more than 11 million women. In 2005, Susan Sca ...
National Consumers League
The National Consumers League, founded in 1899, is an American consumer organization. The National Consumers League is a private, nonprofit advocacy group representing consumers on marketplace and workplace issues. The NCL provides government, bu ...
National Center for Health Research
The National Center for Health Research (NCHR) is a nonpartisan think tank based in Washington, D.C., founded by Dr. Diana Zuckerman, its current president. Originally founded on December 21, 1999 under the name National Research Center for Wome ...
and Our Bodies Ourselves. A representative of PharmedOut said "To approve this drug will set the worst kind of precedent — that companies that spend enough money can force the FDA to approve useless or dangerous drugs." An editorial in
JAMA
''JAMA'' (''The Journal of the American Medical Association'') is a peer-reviewed medical journal published 48 times a year by the American Medical Association. It publishes original research, reviews, and editorials covering all aspects of b ...
noted that, "Although flibanserin is not the first product to be supported by a consumer advocacy group in turn supported by pharmaceutical manufacturers, claims of gender bias regarding the FDA's regulation have been particularly noteworthy, as have the extent of advocacy efforts ranging from social media campaigns to letters from members of Congress".
The Even the Score campaign was managed by Blue Engine Message & Media, a public relations firm, and received funding from Sprout.
Acquisition by Valeant Pharmaceuticals
In August 2015,
Valeant Pharmaceuticals
Bausch Health Companies Inc. is a global, diversified American-Canadian pharmaceutical company. Its global corporate headquarters are located in Laval, Quebec, Canada, and its U.S. headquarters are in Bridgewater, New Jersey. It develops, manufa ...
and Sprout Pharmaceuticals announced that Valeant will acquire Sprout, on a debt-free basis, for approximately $1 billion in cash, plus a share of future profits based upon the achievement of certain milestones.
Reception
The initial response since the 2015 introduction of flibanserin to the U.S. market was slow with 227 prescriptions written during the first three weeks. The slow response may be related to a number of factors: physicians require about 10 minutes of online training to get certified; the medication has to be taken daily and costs about US$400 per month; and questions about the drug's efficacy and need. Prescriptions for the drug continue to be few with less than 4,000 being made as of February 2016.