After oxidative breakdown, flibanserin (0.01-100 μM; 72 h) can be broken down into two potentially non-toxic degradation products, DP1 and DP2 [1]. Determination of cell viability [1]

In the hippocampus, midbrain, and prefrontal cortex, flibanserin (1, 10, 30 mg/kg; i.p.; single dosage) has unique pharmacological characteristics. The cortex may be more responsive than other brain regions because 5-HT1A receptors are found there [2]. The mesolimbic dopaminergic system and the hypothalamic structures involved in integrating sexual cues associated to sexual motivation are preferentially activated by flibanserin (15, 45 mg/kg; oral; twice daily; 22 days)[3]. Flibanserin (5, 10, 25, and 50 mg/kg; subcutaneous injection; single dosage) reduces anxiety without causing adverse motor effects in a rat ultrasonic vocalization paradigm [4].

Cell viability determination [1]
Cell Types: NHSF cell lin
Tested Concentrations: 0.01, 0.1, 1, 10, 100 μM
Incubation Duration: 72 hrs (hours)
Experimental Results: Cell viability reached 97.91% (DP1) and 96.73% (DP2) at 0.01 μM. Non-toxic at concentrations up to 100 μM (IC50 >100 μM).

Animal/Disease Models: Long Evans female rat (225-250 g) [3]
Doses: 15 mg/kg; 45 mg/kg
Route of Administration: po (oral gavage); twice (two times) daily for 22 days
Experimental Results: Ventral tegmental area The density of activated catecholaminergic neurons increased, but not in the locus coeruleus. After long-term 22-day treatment, Fos expression increased in the medial preoptic area and arcuate nucleus of the hypothalamus, ventral tegmental area, locus coeruleus, and lateral paragigantocellular nucleus.

---

Animal/Disease Models: Infant rat anxiety ultrasonic vocalization model [4]
Doses: 5, 10, 25 and 50 mg/kg
Route of Administration: subcutaneous injection
Experimental Results: Ultrasonic vocalization of infant mice diminished. Shown to be effective within 30 minutes, with no serious motor side effects at active doses.

Absorption, Distribution and Excretion
Flibanserin has an absolute oral availability of 33%.
Elimination via feces (51%) and urine (44%) following a single oral 50 mg dose of flibanserin solution.
Approximately 98% of the drug is bound to human serum proteins, mainly to albumin.
Food increased the extent of absorption and slowed the rate of absorption of a 50 mg dose of flibanserin (one half the recommended dosage). Low-, moderate-, and high-fat meals increased flibanserin AUC0-inf by 1.18-, 1.43-, and 1.56-fold; increased Cmax by 1.02-, 1.13-, and 1.15-fold; and prolonged median Tmax to 1.5, 0.9, 1.8 hours from 0.8 hours under fasted conditions, respectively.
Following oral ministration of a single 100 mg dose of flibanserin in healthy premenopausal women (N=8), mean (SD) Cmax was 419 (206) ng/mL and mean (SD) AUC0-inf was 1543 (511) ng*hr/mL. Median (range) time to reach Cmax was 0.75 (0.75 to 4.0) hours. Absolute bioavailability of flibanserin following oral dosing is 33%.
/MILK/ Flibanserin is excreted in rat milk. It is unknown whether flibanserin is present in human milk, ... .

---

Metabolism / Metabolites
Metabolism is primarily via CYP3A4, slightly CYP2C19. Minimal involvement of CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2D6. At least 35 metabolites of flibanserin are produced, 2 of which reach plasma concentrations as high as parent drug, however they are pharmacologically inactive.
Flibanserin is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C19. Based on in vitro and/or in vivo data, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 contribute minimally to the metabolism of flibanserin. After a single oral solution dose of 50 mg 14C-radiolabeled flibanserin, 44% of the total 14C-flibanserin related radioactivity was recovered in urine, and 51% was recovered in feces. Flibanserin is extensively metabolized to at least 35 metabolites, most of them occurring in low concentrations in plasma. Two metabolites could be characterized that showed plasma concentrations similar to that achieved with flibanserin: 6,21-dihydroxy-flibanserin-6,21-disulfate and 6-hydroxy-flibanserin-6-sulfate. These two metabolites are inactive.

---

Biological Half-Life
≈11 hours
Flibanserin has a mean terminal half-life of approximately 11 hours.

Toxicity Summary
IDENTIFICATION AND USE: Flibanserin (trade name Addyi) is a non-hormonal drug approved for the treatment of generalized hypoactive sexual desire disorder (HSDD) in pre- and postmenopausal women. HUMAN EXPOSURE AND TOXICITY: The adverse event profile of flibanserin is similar to that of other centrally acting drugs. In human exposure studies, the most common reported adverse event was sedation/ drowsiness. Dizziness, nausea, fatigue and somnolence were also reported. Flibanserin can cause CNS depression. The use of flibanserin in patients with hepatic impairment increases flibanserin concentrations, which can cause severe hypotension and syncope. Hypotension and syncope are also an increased risk for patients taking moderate to strong CYP3A4 inhibitors. Concomitant alcohol use also increases the risk of severe hypotension and syncope in patients taking flibanserin. Flibanserin has preferential affinity for serotonin 5-HT(1A), dopamine D(4k), and serotonin 5-HT(2A) receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT(1A) agonist, a very weak partial agonist on dopamine D(4) receptors, and a 5-HT(2A) antagonist. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses. ANIMAL STUDIES: In carcinogenicity studies, mammary tumors were observed in female mice. Hepatocellular carcinomas were reported in female and male mice, however, these effects were only noted in animals exposed to flibanserin at 3-10 x the clinically recommended dose.

---

Hepatotoxicity
In placebo controlled trials, liver test abnormalities were no more common with flibanserin than with placebo treatment, and what abnormalities occurred were mild and resolved spontaneously, usually without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to flibanserin. However, the total clinical experience with flibanserin use has been limited. Many other serotonergic agents, such as the SSRIs, have been implicated in rare instances of clinically apparent liver injury. The latency to onset is typically 1 to 8 weeks and the pattern of enzyme elevations varies, ranging from cholestatic to hepatocellular. Mild signs and symptoms of hypersensitivity (rash, fever, eosinophilia) are common, but usually not prominent. Autoantibody formation is rare. The course is generally self-limited and mild-to-moderate in severity, but fatalities have been reported with some SSRIs. However, flibanserin itself has not been implicated in similar cases.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

---

Protein Binding
~98%, highly bound to proteins (mostly albumin) in serum.

---

Interactions
The concomitant use of Addyi with digoxin, a drug that is transported by P-glycoprotein (P-gp), increases the digoxin concentration. This may lead to digoxin toxicity.
In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various +antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.
The concomitant use of Addyi with CYP3A4 inducers substantially decreases flibanserin exposure compared to the use of Addyi alone. Examples of CYP3A4 inducers: Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapetine, St. John's Wort.
The concomitant use of Addyi with strong CYP2C19 inhibitors may increase flibanserin exposure which may increase the risk of hypotension, syncope, and CNS depression. Examples of strong CYP2C19 inhibitors: Proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals.
For more Interactions (Complete) data for Flibanserin (10 total), please visit the HSDB record page.

[1]. Insights into Flibanserin Oxidative Stress Degradation Pathway: In Silico – In Vitro Toxicity Assessment of Its Degradates. New Journal of Chemistry, 2021.

[2]. A potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors. Br J Pharmacol. 2003 Aug;139(7):1281-8.

[3]. Brain neuronal activation induced by flibanserin treatment in female rats. Psychopharmacology (Berl). 2013 Dec;230(4):639-52.

[4]. Flibanserin has anxiolytic effects without locomotor side effects in the infant rat ultrasonic vocalization model of anxiety. Br J Pharmacol. 2000 Jun;130(4):739-46.

[5]. Flibanserin for hypoactive sexual desire disorder: place in therapy. Ther Adv Chronic Dis. 2017 Jan;8(1):16-25.

Therapeutic Uses
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Flibanserin is included in the database.
Addyi is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to: A co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. Acquired HSDD refers to HSDD that develops in a patient who previously had no problems with sexual desire. Generalized HSDD refers to HSDD that occurs regardless of the type of stimulation, situation or partner. /Included in US product label/
EXPL THER A central problem in the treatment of Parkinson's disease (PD) is the development of motor disturbances like L-DOPA-induced dyskinesia (LID) after long-term treatment. Preclinical and clinical studies demonstrated that serotonin 5-HT(1A) receptor agonists attenuate this disabling motor side effect. The aim of this study was to investigate the ability of flibanserin compared to buspirone to attenuate L-DOPA-sensitized contraversive circling in hemiparkinsonian rats, which is an animal model of LID. Both drugs have a preferential affinity for the serotonin 5-HT(1A) receptors. Buspirone was in comparison because it was expected to have an effect in this model. Unilaterally 6-hydroxydopamine lesioned rats were treated twice daily intraperitoneally (ip) with L-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg) for 21 days (on days 1, 3, 5, 8, 11, 14, 17 and 21). On day 24, L-DOPA-sensitized rats were treated ip 5 min prior to administration of L-DOPA methyl ester and benserazide with either saline (controls), 2.5, 5 and 10 mg/kg buspirone or flibanserin. Acute administration of both flibanserin and buspirone, dose dependently, attenuated the increased contraversive circling. An almost complete inhibition of the turning response was observed at 5 mg/kg buspirone and 10 mg/kg flibanserin. The current preclinical findings further implicate the 5-HT(1A) receptor as a promising therapeutic target for the reduction of LID and predict a potential efficacy of flibanserin in the treatment of LID in PD.

---

Drug Warnings
/BOX WARNING/ The use of Addyi in patients with hepatic impairment increases flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, Addyi is contraindicated in patients with hepatic impairment. Inhibitors are contraindicated in patients taking Addyi.
/BOX WARNING/ The concomitant use of Addyi and moderate or strong CYP3A4 inhibitors increase s flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, the use of moderate or strong CYP3A4 inhibitors is contraindicated in patients taking Addyi.
/BOX WARNING/ The use of Addyi and alcohol increases the risk of severe hypotension and syncope. Therefore, alcohol use is contraindicated in patients taking Addyi. Before prescribing Addyi, assess the likelihood of the patient abstaining from alcohol, taking into account the patient's current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed Addyi about the importance of abstaining from alcohol use. Because of the increased risk of hypotension and syncope due to an interaction with alcohol, Addyi is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Addyi REMS Program.
Addyi can cause CNS depression (e.g., somnolence, sedation). In five 24-week, randomized, placebo controlled, double-blind trials of premenopausal women with hypoactive sexual desire disorder (HSDD), the incidence of somnolence, sedation or fatigue was 21% and 8% in patients treated with 100 mg Addyi once daily at bedtime and placebo, respectively. The risk of CNS depression is increased if Addyi is taken during waking hours, or if Addyi is taken with alcohol or other CNS depressants, or with medications that increase flibanserin concentrations, such as CYP3A4 inhibitors.
For more Drug Warnings (Complete) data for Flibanserin (9 total), please visit the HSDB record page.

C20H21F3N4O

390.41

390.167

167933-07-5

Flibanserin-d4-1;2122830-91-3;Flibanserin hydrochloride;147359-76-0;Flibanserin-d4;2122830-90-2

6918248

White to off-white solid powder

1.292 g/cm3

1.566

3.173

1

6

4

28

550

0

FC(C1C([H])=C([H])C([H])=C(C=1[H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])N2C(N([H])C3=C([H])C([H])=C([H])C([H])=C23)=O)C([H])([H])C1([H])[H])(F)F

PPRRDFIXUUSXRA-UHFFFAOYSA-N

InChI=1S/C20H21F3N4O/c21-20(22,23)15-4-3-5-16(14-15)26-11-8-25(9-12-26)10-13-27-18-7-2-1-6-17(18)24-19(27)28/h1-7,14H,8-13H2,(H,24,28)

3-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl]-1H-benzimidazol-2-one

BIMT 17; BIMT 17BS; EBD 6396; BIMT17; BIMT17BS; EBD-6396; BIMT-17; BIMT-17BS; EBD6396; Flibanserin. trade name: Addyi;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~128.07 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)