Flibanserin

{{DrugProjectFormSinglePage |authorTag=Martin Nino [1] |genericName=Flibanserin |aOrAn=a |drugClass=tablet for oral administration |indicationType=treatment |indication=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 |hasBlackBoxWarning=Yes |adverseReactions=dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth (incidence ≥2%) |blackBoxWarningTitle=HYPOTENSION AND SYNCOPE IN CERTAIN SETTINGS |blackBoxWarningBody=

• Contraindicated with Alcohol:

The use of Flibanserin tablets and alcohol increases the risk of severe hypotension and syncope. Therefore, alcohol use is contraindicated in patients taking Flibanserin. Before prescribing Flibanserin, 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 Flibanserin about the importance of abstaining from alcohol use. Because of the increased risk of hypotension and syncope due to an interaction with alcohol, Flibanserin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Flibanserin REMS Program.

• Contraindicated with Strong or Moderate CYP3A4 Inhibitors:

The concomitant use of Flibanserin and moderate or strong CYP3A4 inhibitors increases Flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, the use of moderate or strong CYP3A4 inhibitors is contraindicated in patients taking Flibanserin.

• Contraindicated in Patients with Hepatic Impairment:

The use of Flibanserin in patients with hepatic impairment increases Flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, Flibanserin is contraindicated in patients with hepatic impairment. |fdaLIADAdult=======Indications====== Flibanserin tablets are 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.

Limitations of Use

• Flibanserin is not indicated for the treatment of HSDD in postmenopausal women or in men.
• Flibanserin is not indicated to enhance sexual performance.

Dosage

The recommended dosage of Flibanserin is 100 mg administered orally once per day at bedtime. |fdaLIADPed=Flibanserin is not indicated for use in pediatric patients |contraindications=Flibanserin is contraindicated:

• With use of alcohol.
• With concomitant use with moderate or strong CYP3A4 inhibitors.
• In patients with hepatic impairment.

|warnings=======Hypotension and Syncope due to an Interaction with Alcohol====== Alcohol use is contraindicated in patients taking Flibanserin. Before prescribing Flibanserin, the healthcare provider must assess the likelihood of the patient abstaining from alcohol use, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed Flibanserin about the importance of abstaining from alcohol use.

The use of Flibanserin and alcohol increases the risk of severe hypotension and syncope. In a dedicated alcohol interaction study conducted in 25 subjects (23 men and 2 premenopausal women), hypotension or syncope requiring therapeutic intervention (ammonia salts and/or placement in supine or Trendelenburg position) occurred in 4 (17%) of the 23 subjects co-administered Flibanserin 100 mg and 0.4 g/kg alcohol (equivalent of two 12 ounce cans of beer containing 5% alcohol content, two 5 ounce glasses of wine containing 12% alcohol content, or two 1.5 ounce shots of 80-proof spirit in a 70 kg person, consumed over 10 minutes in the morning). In these four subjects, all of whom were men, the magnitude of the systolic blood pressure reductions ranged from about 28 to 54 mmHg and the magnitude of the diastolic blood pressure reductions ranged from about 24 to 46 mmHg. In addition, 6 (25%) of the 24 subjects co-administered Flibanserin 100 mg and 0.8 g/kg alcohol experienced orthostatic hypotension when standing from a sitting position. The magnitude of the systolic blood pressure reductions in these 6 subjects ranged from 22 to 48 mmHg, and the diastolic blood pressure reductions ranged from 0 to 27 mmHg. One of these subjects required therapeutic intervention (ammonia salts and placement supine with the foot of the bed elevated). There were no events requiring therapeutic interventions when Flibanserin or alcohol were administered alone.

Flibanserin is available only through a restricted program under a REMS.

Flibanserin REMS Program

Flibanserin is available only through a restricted program under a REMS called the Flibanserin REMS Program, because of the increased risk of severe hypotension and syncope due to an interaction between Flibanserin and alcohol.

Notable requirements of the Flibanserin REMS Program include the following:

• Prescribers must be certified with the program by enrolling and completing training.
• Pharmacies must be certified with the program and must only dispense to patients pursuant to a prescription from a certified prescriber.

Further information, including a list of qualified pharmacies, is available at www.AddyiREMS.com or 844-746-5745.

Hypotension and Syncope with CYP3A4 Inhibitors

• Moderate or Strong CYP3A4 Inhibitors

The concomitant use of Flibanserin with moderate or strong CYP3A4 inhibitors significantly increases Flibanserin concentrations, which can lead to hypotension and syncope. The concomitant use of Flibanserin with a moderate or strong CYP3A4 inhibitor is contraindicated. If the patient requires a moderate or strong CYP3A4 inhibitor, discontinue Flibanserin at least 2 days prior to starting the moderate or strong CYP3A4 inhibitor. In cases where the benefit of initiating a moderate or strong CYP3A4 inhibitor within 2 days of stopping Flibanserin clearly outweighs the risk of Flibanserin exposure related hypotension and syncope, monitor the patient for signs of hypotension and syncope. Discontinue the moderate or strong CYP3A4 inhibitor for 2 weeks before restarting Flibanserin.

• Multiple Concomitant Weak CYP3A4 Inhibitors

Concomitant use of multiple weak CYP3A4 inhibitors that may include herbal supplements (e.g., ginkgo, resveratrol) or non-prescription drugs (e.g., cimetidine) could also lead to clinically relevant increases in Flibanserin concentrations that may increase the risk of hypotension and syncope.

Central Nervous System Depression

Flibanserin can cause CNS depression (e.g., somnolence, sedation). In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, the incidence of somnolence, sedation or fatigue was 21% and 8% in patients treated with 100 mg Flibanserin once daily at bedtime and placebo, respectively. The risk of CNS depression is increased if Flibanserin is taken during waking hours, or if Flibanserin is taken with alcohol or other CNS depressants, or with medications that increase Flibanserin concentrations, such as CYP3A4 inhibitors.

Patients should not drive or engage in other activities requiring full alertness until at least 6 hours after taking Flibanserin and until they know how Flibanserin affects them.

Hypotension and Syncope with Flibanserin Alone

The use of Flibanserin − without other concomitant medications known to cause hypotension or syncope − can cause hypotension and syncope. In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, hypotension was reported in 0.2% and <0.1% of Flibanserin -treated patients and placebo-treated patients, respectively; syncope was reported in 0.4% and 0.2% of Flibanserin - treated patients and placebo-treated patients, respectively. The risk of hypotension and syncope is increased if Flibanserin is taken during waking hours or if higher than the recommended dose is taken. Consider the benefits of Flibanserin and the risks of hypotension and syncope in patients with pre- existing conditions that predispose to hypotension. Patients who experience pre-syncope should immediately lie supine and promptly seek medical help if the symptoms do not resolve. Prompt medical attention should also be obtained for patients who experience syncope.

Syncope and Hypotension in Patients with Hepatic Impairment

The use of Flibanserin in patients with any degree of hepatic impairment significantly increases Flibanserin concentrations, which can lead to hypotension and syncope. Therefore, the use of Flibanserin is contraindicated in patients with hepatic impairment.

Mammary Tumors in Female Mice

In a 2-year carcinogenicity study in mice, there was a statistically significant and dose-related increase in the incidence of malignant mammary tumors in female mice at exposures 3 and 10 times the recommended clinical dose. No such increases were seen in male mice or in male or female rats. The clinical significance of these findings is unknown. |clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The approved 100 mg Flibanserin dosage at bedtime was administered to 2,997 premenopausal women with acquired, generalized HSDD in clinical trials, of whom 1672 received treatment for at least 6 months, 850 received treatment for at least 12 months, and 88 received treatment for at least 18 months.

Data from Five 24-Week, Randomized, Double-Blind Placebo-Controlled Trials in Premenopausal Women with HSDD

The data presented below are derived from five 24-week randomized, double-blind, placebo-controlled trials in premenopausal women with acquired, generalized HSDD. In these five trials, the frequency and quantity of alcohol use was not recorded. Three of these trials (Studies 1 through 3) also provided efficacy data. One of these trials (Study 5) did not evaluate the 100 mg bedtime dose.

In four trials, 100 mg Flibanserin at bedtime was administered to 1543 premenopausal women with HSDD, of whom 1060 completed 24 weeks of treatment. The clinical trial population was generally healthy without significant comorbid medical conditions or concomitant medications. The age range was 18-56 years old with a mean age of 36 years old, and 88% were Caucasian and 9% were Black.

Serious adverse reactions were reported in 0.9% and 0.5% of Flibanserin-treated patients and placebo-treated patients, respectively.

• Adverse Reactions Leading to Discontinuation

The discontinuation rate due to adverse reactions was 13% among patients treated with 100 mg Flibanserin at bedtime and 6% among patients treated with placebo. TABLE 1 displays the most common adverse reactions leading to discontinuation in four trials of premenopausal women with HSDD.

• Table 1. Adverse Reactions* Leading to Discontinuation in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD

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ADDYI: Flibanserin's Brand name

• Most Common Adverse Reactions

TABLE 2 summarizes the most common adverse reactions reported in four trials of premenopausal women with HSDD. This table shows adverse reactions reported in at least 2% of patients treated with Flibanserin and at a higher incidence than with placebo. The majority of these adverse reactions began within the first 14 days of treatment.

• Table 2. Common Adverse Reactions* in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD

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ADDYI: Flibanserin's Brand name

• Less Common Adverse Reactions

In four trials in premenopausal women with HSDD treated with 100 mg Flibanserin at bedtime, less common adverse reactions (reported in ≥1% but <2% of Flibanserin-treated patients and at a higher incidence than with placebo) included:

• Anxiety (Flibanserin 1.8%; placebo 1.0%),
• Constipation (Flibanserin 1.6%; placebo 0.4%),
• Abdominal pain (Flibanserin 1.5%; placebo 0.9%),
• Metrorrhagia (Flibanserin 1.4%; placebo 1.4%),
• Rash (Flibanserin 1.3%; placebo 0.8%),
• Sedation (Flibanserin 1.3%; placebo 0.2%), and
• Vertigo (Flibanserin 1%; placebo 0.3%).

• Appendicitis

In the five trials of premenopausal women with HSDD, appendicitis was reported in 6/3973 (0.2%) Flibanserin-treated patients, while there were no reports of appendicitis in the 1905 placebo-treated patients.

• Accidental Injury

In five trials of premenopausal women with HSDD, accidental injury was reported in 42/1543 (2.7%) Flibanserin-treated patients and 47/1905 (2.5%) placebo-treated patients. Among these 89 patients who experienced injuries, 9/42 (21%) Flibanserin-treated patients and 3/47 (6%) placebo-treated patients reported adverse reactions consistent with CNS depression (e.g., somnolence, fatigue, or sedation) within the preceding 24 hours.

• Adverse Reactions in Patients Who Reported Hormonal Contraceptive Use

In four trials of premenopausal women with HSDD, 1466 patients (43%) reported concomitant use of hormonal contraceptives (HC) at study enrollment. These trials were not prospectively designed to assess an interaction between Flibanserin and HC. Flibanserin-treated patients who reported HC use had a greater incidence of dizziness, somnolence, and fatigue compared to Flibanserin-treated patients who did not report HC use (dizziness 9.9% in HC non-users, 13.4% in HC users; somnolence 10.6% in HC non-users, 12.3% in HC users; fatigue 7.5% in HC non-users, 11.4% in HC users). There were no meaningful differences in the incidence of these adverse reactions in placebo-treated patients who reported or did not report HC use.

Data from Other Trials

One death occurred in a 54 year-old postmenopausal woman treated with 100 mg Flibanserin taken at bedtime (Flibanserin is not approved for the treatment of postmenopausal women with HSDD). This patient had a history of hypertension and hypercholesterolemia and baseline alcohol consumption of 1-3 drinks daily. She died of acute alcohol intoxication 14 days after starting Flibanserin. Blood alcohol concentration on autopsy was 0.289 g/dL. The autopsy report also noted coronary artery disease. A relationship between this patient’s death and use of Flibanserinis unknown.

• Hypotension, Syncope, and CNS Depression in Studies of Healthy Subjects

• Hypotension, Syncope, and CNS Depression with Alcohol

In a cross-over alcohol interaction study of 100 mg Flibanserin and alcohol in 25 healthy subjects dosed in the morning, somnolence was reported in 67%, 74%, and 92% of subjects who received Flibanserin alone, Flibanserin in combination with 0.4 g/kg ethanol, and Flibanserin in combination with 0.8 g/kg ethanol, respectively. In the group receiving Flibanserin in combination with 0.4 g/kg ethanol, 4/23 (17%) subjects had substantial reductions in blood pressure, resulting in hypotension and/or syncope requiring medical intervention. In the group receiving Flibanserin in combination with 0.8 g/kg ethanol, 6/24 (25%) subjects experienced orthostatic hypotension.

• Hypotension and Syncope with Fluconazole

In a pharmacokinetic drug interaction study of 100 mg Flibanserin and 200 mg fluconazole (a moderate CYP3A4 inhibitor, moderate CYP2C9 inhibitor, and a strong CYP2C19 inhibitor) in healthy subjects, hypotension or syncope requiring placement supine with legs elevated occurred in 3/15 (20%) subjects treated with concomitant Flibanserin and fluconazole compared to no such adverse reactions in subjects treated with Flibanserin alone or fluconazole alone. One of these 3 subjects became unresponsive with a blood pressure of 64/41 mm Hg and required transportation to the hospital emergency department where she required intravenous saline. Due to these adverse reactions, the study was stopped. In this study, the concomitant use of Flibanserin and fluconazole increased Flibanserin exposure 7-fold.

• Syncope with Ketoconazole

In a pharmacokinetic drug interaction study of 50 mg Flibanserin and 400 mg ketoconazole, a strong CYP3A4 inhibitor, syncope occurred in 1/24 (4%) healthy subjects treated with concomitant Flibanserin and ketoconazole, 1/24 (4%) receiving Flibanserin alone, and no subjects receiving ketoconazole alone. In this study, the concomitant use of Flibanserin and ketoconazole increased Flibanserin exposure 4.5-fold.

• Syncope in Poor CYP2C19 Metabolizers

In a pharmacogenomic study of 100 mg Flibanserin in subjects who were poor or extensive CYP2C19 metabolizers, syncope occurred in 1/9 (11%) subjects who were CYP2C19 poor metabolizers (this subject had a 3.2 fold higher Flibanserin exposure compared to CYP2C19 extensive metabolizers) compared to no such adverse reactions in subjects who were CYP2C19 extensive metabolizers. |drugInteractions=TABLE 3 contains clinically significant drug interactions (DI) with Flibanserin.

• Table 3: Clinically Significant Drug Interactions with Flibanserin

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ADDYI: Flibanserin's Brand name

|FDAPregCat=C |useInPregnancyFDA=:*Risk Summary There are no studies of Flibanserin in pregnant women to inform whether there is a drug-associated risk in humans. In animals, fetal toxicity only occurred in the presence of significant maternal toxicity including reductions in weight gain and sedation. Adverse reproductive and developmental effects consisted of decreased fetal weight, structural anomalies and increases in fetal loss at exposures greater than 15 times exposures achieved with the recommended human dosage. Animal studies cannot rule out the potential for fetal harm.

In the general population (not taking Flibanserin), the estimated background risk of major birth defects is 2% to 4% of live births, and the estimated background risk of miscarriage of clinically recognized pregnancies is 15% to 20%.

• Data

• Animal Data

Pregnant rats were administered Flibanserin at doses of 0, 20, 80 and 400 mg/kg/day (3, 15 and 41 times clinical exposures at the recommended human dose based on AUC) during organogenesis. The highest dose was associated with significant maternal toxicity as evidenced by severe clinical signs and marked reductions in weight gain during dosing. In the litters of high-dose dams, there were decreased fetal weights, decreased ossification of the forelimbs and increased number of lumbar ribs, and two fetuses with anophthalmia secondary to severe maternal toxicity. The no adverse effect level for embryofetal toxicity was 80 mg/kg/day (15 times clinical exposure based on AUC).

Pregnant rabbits were administered Flibanserin at doses of 0, 20, 40 and 80 mg/kg/day (4, 8 and 16 times the clinical exposure at the recommended human dose) during organogenesis. Marked decreases in maternal body weight gain (>75%), abortion and complete litter resorption were observed at 40 and 80 mg/kg/day indicating significant maternal toxicity at these doses. Increases in resorptions and decreased fetal weights were observed at ≥ 40 mg/kg/day. No treatment-related teratogenic effects were observed in fetuses at any dose level. The no adverse effect level for maternal and embryofetal effects was 20 mg/kg/day (3-4 times clinical exposure based on AUC).

Pregnant rats were administered Flibanserin at doses of 0, 20, 80 and 200 mg/kg/day (3, 15 and ~ 20 times clinical exposures at the recommended human dose) from day 6 of pregnancy until day 21 of lactation to assess for effects on peri- and postnatal development. The highest dose was associated with clinical signs of toxicity in pregnant and lactating rats. All doses resulted in sedation and decreases in body weight gain during pregnancy. Flibanserin prolonged gestation in some dams in all dose groups and decreased implantations, number of fetuses and fetal weights at 200 mg/kg/day. Dosing dams with 200 mg/kg also decreased pup weight gain and viability during the lactation period and delayed opening of the vagina and auditory canals. Flibanserin had no effects on learning, reflexes, fertility or reproductive capacity of the F1 generation. The no adverse effect level for maternal toxicity and peri/postnatal effects was 20 mg/kg/day. |useInNursing=Flibanserin is excreted in rat milk. It is unknown whether Flibanserin is present in human milk, whether Flibanserin has effects on the breastfed infant, or whether Flibanserin affects milk production. Because of the potential for serious adverse reactions including sedation in a breastfed infant, breastfeeding is not recommended during treatment with Flibanserin. |useInPed=Flibanserin is not indicated for use in pediatric patients. |useInGeri=Flibanserin is not indicated for use in geriatric patients. Safety and effectiveness have not been established in geriatric patients. |useInHepaticImpair=Flibanserin is contraindicated for use in patients with any degree of hepatic impairment. Flibanserin exposure increased 4.5-fold in patients with hepatic impairment, compared to those with normal hepatic function, increasing the risk of hypotension, syncope, and CNS depression. |othersTitle=CYP2C19 Poor Metabolizers |useInOthers=CYP2C19 poor metabolizers had increased Flibanserin exposures compared to CYP2C19 extensive metabolizers. Additionally, syncope occurred in a subject who was a CYP2C19 poor metabolizer. Therefore, increase monitoring for adverse reactions (e.g., hypotension) in patients who are CYP2C19 poor metabolizers. The frequencies of poor CYP2C19 metabolizers are approximately 2–5% among Caucasians and Africans and approximately 2–15% among Asians. |administration=:*Recommended Dosage The recommended dosage of Flibanserin is 100 mg administered orally once per day at bedtime. Flibanserin is dosed at bedtime because administration during waking hours increases the risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression (such as somnolence and sedation).

• Missed Dose

If a dose of Flibanserin is missed at bedtime, instruct the patient to take the next dose at bedtime on the next day. Instruct the patient to not double the next dose.

• Discontinuation of Flibanserin

Discontinue Flibanserin after 8 weeks if the patient does not report an improvement in her symptoms.

• Initiation of Flibanserin Following Moderate or Strong CYP3A4 Inhibitor Use

If initiating Flibanserin following moderate or strong CYP3A4 inhibitor use, start Flibanserin 2 weeks after the last dose of the CYP3A4 inhibitor.

If initiating a moderate or strong CYP3A4 inhibitor following Flibanserin use, start the moderate or strong CYP3A4 inhibitor 2 days after the last dose of Flibanserin.

|overdose=Overdosage of Flibanserin may cause an increase in the incidence or severity of any of the reported adverse reactions. In the event of overdosage, treatment should address the symptoms and supportive measures, as needed. There is no known specific antidote for Flibanserin.

|drugBox={{Drugbox2 | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 437139289 | IUPAC_name = 1-(2-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one | image =fli1.png | image2 =fli2.png

| tradename = Addyi | pregnancy_US = C | legal_US = Rx only | routes_of_administration = Oral

| bioavailability = 33% | protein_bound = ~98% | metabolism = Extensive by liver (mainly by CYP3A4 and CYP2C19) | elimination_half-life = ~11 hours | excretion = Biliary (51%), kidney (44%)

| IUPHAR_ligand = 8182 | CAS_number_Ref =  ^Y | CAS_number = 167933-07-5 | ATC_prefix = G02 | ATC_suffix = CX02 | PubChem = 6918248 | ChemSpiderID_Ref =  ^Y | ChemSpiderID = 5293454 | ChEBI_Ref =  ^N | ChEBI = 90865 | UNII_Ref =  ^Y | UNII = 37JK4STR6Z | KEGG_Ref =  ^Y | KEGG = D02577 | ChEMBL_Ref =  ^Y | ChEMBL = 231068

| C=20 | H=21 | F=3 | N=4 | O=1 | molecular_weight = 390.40 g/mol | smiles = FC(F)(F)c4cc(N3CCN(CCN2c1ccccc1NC2=O)CC3)ccc4 | StdInChI_Ref =  ^Y | StdInChI = 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) | StdInChIKey_Ref =  ^Y | StdInChIKey = PPRRDFIXUUSXRA-UHFFFAOYSA-N }}

|mechAction=The mechanism of action of Flibanserin in the treatment of premenopausal women with hypoactive sexual desire disorder is not known. |PD=:*Receptor Binding: In vitro, Flibanserin demonstrated high affinity for the following serotonin (5-hydroxytryptamine or 5-HT) receptors: agonist activity at 5-HT1A and antagonist activity at 5-HT2A. Flibanserin also has moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors.

• Alcohol Interaction

A randomized, double-blind, single-dose, cross-over, dedicated alcohol interaction study was conducted in 25 healthy subjects (23 men and 2 premenopausal women). In this study, 68%, 16%, 8% and 8% subjects reported a history of drinking 5-6, 7-10, 11-15 and 16-21 drinks per week, respectively. Subjects received one of the following five treatments [Flibanserin and alcohol were administered in the morning and the alcohol was consumed in 10 minutes. Flibanserin is to be only administered at bedtime]:

• 100 mg of Flibanserin alone
• 0.4 g/kg 95% ethanol (equivalent to two 12-ounce cans of beer containing 5% alcohol content, two 5- ounce glasses of wine containing 12% alcohol, or two 1.5-ounce shots of 80 proof spirit in a 70 kg person)
• 0.8 g/kg 95% ethanol (equivalent to four 12-ounce cans of beer containing 5% alcohol content, four 5-ounce glasses of wine containing 12% alcohol, or four 1.5-ounce shots of 80 proof spirit in a 70 kg person)
• 100 mg of Flibanserin in combination with 0.4 g/kg 95% ethanol
• 100 mg of Flibanserin in combination with 0.8 g/kg 95% ethanol

Patients who received Flibanserin with alcohol had a higher incidence of somnolence than patients who received Flibanserin alone or alcohol alone. There were no significant changes in the pharmacokinetics of Flibanserin when administered with or without alcohol.

• Cardiac Electrophysiology

The effect of Flibanserin on the QT interval was evaluated in a randomized, double-blind, placebo- and active- (single dose moxifloxacin) controlled crossover study in 56 healthy men and women. Subjects in the Flibanserin groups received either 50 mg twice a day (equivalent to the daily recommended dosage) or 100 mg three times a day (3 times the daily recommended dosage) administered for 5 days. The time frame for electrocardiogram (ECG) measurements covered maximum plasma concentrations of Flibanserin and relevant metabolites. In this study, Flibanserin did not prolong the QT interval to any clinically relevant extent. The mean increase in heart rate associated with the 100 mg three times a day dose of Flibanserin compared to placebo ranged from 1.7 to 3.2 beats per minute. |PK=Flibanserin showed dose-proportional pharmacokinetics for Cmax after single oral doses of 100 mg to 250 mg (the recommended and 2.5 times the recommended dosage, respectively) in healthy female subjects. Steady state was achieved after 3 days of dosing. The extent of exposure (AUC(0-∞)) with once-daily dosing of 100 mg of Flibanserin was increased 1.4-fold as compared to a single dose.

This image is provided by the National Library of Medicine.

• Absorption

Following oral administration 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) AUC(0-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%.

• Effect of Food

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 AUC(0-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.

• Distribution

Approximately 98% of Flibanserin is bound to human serum proteins, mainly to albumin.

• Elimination

• Metabolism

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.

• Excretion

Flibanserin has a mean terminal half-life of approximately 11 hours.

• Specific Populations

• Hepatic Impairment

Single 50 mg oral doses of Flibanserin were administered to 10 patients with mild hepatic impairment (Child-Pugh score of 6 points), 4 patients with moderate hepatic impairment (Child-Pugh score of 8-9 points), and 14 healthy subjects matched by age, weight, and gender. Systemic Flibanserin exposure (AUC(0-inf)) increased 4.5-fold in patients with mild hepatic impairment, compared to subjects with normal hepatic function, and t1/2 was longer (26 hours compared to 10 hours in matching healthy controls). Due to the small number of patients (n=4) with moderate hepatic impairment enrolled in the study, it is not possible to make conclusions about the quantitative effect of moderate hepatic impairment on Flibanserin exposure. Flibanserin is contraindicated in patients with hepatic impairment.

• Renal Impairment

Single 50 mg oral doses of Flibanserin were administered to 7 patients with mild to moderate renal impairment (GFR 30 to 80 mL/min), 9 patients with severe renal impairment (GFR <30 mL/min, not on dialysis), and 16 healthy subjects matched by age, weight, and gender. Flibanserin exposure (AUC(0-inf)) increased 1.1-fold in patients with mild to moderate renal impairment and 1.2-fold in patients with severe renal impairment, compared to the healthy control subjects.

• Race/Ethnicity

A cross-study comparison between healthy Japanese women and Caucasian women with HSDD showed that Flibanserin exposure was approximately 1.4-fold higher in Japanese women. When the mean Flibanserin exposure in Japanese women was adjusted for weight, the AUC(tau,ss) in Japanese women was 2246 ng*hr/mL, which is comparable to 2080 ng*hr/mL in Caucasian women. The similarity in weight-adjusted AUC(tau,ss) suggests that weight, not race, is the factor contributing to the observed difference in Flibanserin exposure between Japanese and Caucasian women.

• Age

No formal study has been conducted to study the effect of age on Flibanserin exposures.

• Drug Interaction Studies

• Drugs that Increase Flibanserin Exposure

The effects of other drugs on the pharmacokinetics of Flibanserin are presented in TABLE 4 as change relative to Flibanserin administered alone (test/reference).

• Moderate CYP3A4/Moderate CYP2C9/Strong CYP2C19 Inhibitor (Fluconazole)

In a study of 15 healthy female subjects, a fluconazole 400 mg loading dose followed by 200 mg administered once daily for 5 days increased Flibanserin 100 mg single dose exposure (AUC(0-inf)) 7-fold and Cmax 2.2-fold compared to Flibanserin 100 mg alone. Three of 15 subjects (20%) experienced hypotension or syncope from concomitant use of fluconazole and Flibanserin; therefore, the study was stopped early.

• Strong CYP3A4 Inhibitor (Ketoconazole)

In a study of 24 healthy female subjects, ketoconazole 400 mg administered once daily for 5 days following a light breakfast increased Flibanserin 50 mg single-dose exposure (AUC(0-inf)) 4.5-fold and Cmax 1.8-fold compared to Flibanserin 50 mg alone.

• Strong CYP3A4 Inhibitor (Itraconazole)

In a study of 12 healthy male and female subjects, itraconazole 200 mg administered once daily for 4 days following a loading dose of 400 mg increased Flibanserin 50 mg single dose exposure (AUC(0-inf)) 2.6-fold and Cmax 1.7-fold when Flibanserin was given 2 hours after itraconazole on Day 5, compared to exposures with Flibanserin 50 mg alone. The 200 mg itraconazole dose does not maximally inhibit the CYP3A4 enzyme.

• Moderate CYP3A4 Inhibitor (Grapefruit Juice)

In a study of 26 healthy female subjects, grapefruit juice (240 mL) increased Flibanserin 100 mg single dose exposure (AUC(0-inf)) by 1.4-fold and Cmax 1.1-fold compared to Flibanserin 100 mg alone.

• Weak CYP3A4 Inhibitor (Oral Contraceptives)

In a meta-analysis of 17 oral contraceptive users and 91 non-users in Phase 1 studies, the oral contraceptive users had a 1.4-fold higher Flibanserin AUC and 1.3‑fold higher Cmax compared to the non-users.

• Strong CYP2D6 Inhibitor (Paroxetine)

Paroxetine is a strong CYP2D6 inhibitor. In a study of 19 healthy male and female subjects, Flibanserin exposure decreased by approximately 4% when Flibanserin 50 mg twice daily was given with paroxetine compared to Flibanserin alone. Paroxetine was dosed at 20 mg once daily for 3 days followed by 40 mg once daily for 7 days.

• Drugs that Decrease Flibanserin Exposure

• Strong CYP3A4 Inducer (Rifampin)

In a study of 24 healthy female subjects, rifampin 600 mg given once daily for 7 days prior to administration of 100 mg Flibanserin significantly decreased Flibanserin exposure by 95%.

• Moderate CYP3A4 Inducer (Etravirine)

Steady state etravirine, a moderate CYP3A4 inducer, decreased Flibanserin exposures by approximately 21%.

• Table 4 Drugs That Increase Flibanserin Exposure

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ADDYI: Flibanserin's Brand name

• Effects of Flibanserin on Other Drugs

The effects of Flibanserin on the pharmacokinetics of other drugs are presented in Table 5 as change relative to the other drug administered alone (test/reference).

• Digoxin and P-glycoprotein Substrates

A single center, open-label, randomized, two-way crossover study in 24 healthy men and women evaluated the effect of Flibanserin on the pharmacokinetics of digoxin. Flibanserin 100 mg was administered once daily over 5 days followed by a single dose of 0.5 mg digoxin, a P-gp substrate. Flibanserin increased digoxin AUC(0-inf) by 2.0-fold and Cmax by 1.5-fold, compared to digoxin alone.

• Drugs Metabolized by CYP3A4 (Simvastatin)

An open-label, randomized, crossover study in 12 healthy men and women evaluated the effect of Flibanserin 50 mg twice daily for 4 days on the pharmacokinetics of simvastatin 40 mg once daily. Flibanserin increased the AUC(0-inf) of simvastatin, a substrate of CYP3A4, 1.3‑fold and Cmax by 1.2-fold. Flibanserin co-administered with simvastatin increased simvastatin acid AUC(0-inf) by 1.5-fold and Cmax by 1.4-fold.

• Oral Contraceptives

A study in 24 healthy women evaluated the effect of 100 mg Flibanserin once daily for 2 weeks on the pharmacokinetics of a single-dose of ethinyl estradiol (EE) 30 mcg/levonorgestrel (LNG) 150 mcg. Flibanserin increased the EE AUC(0-inf) by 1.09-fold and the EE Cmax by 1.1-fold. Flibanserin decreased the LNG AUC(0-inf) by 1.06-fold and did not change the LNG Cmax.

• Drugs Metabolized by CYP2B6 (Bupropion)

An open-label, randomized, two-period crossover study in 28 healthy women evaluated the effect of Flibanserin on the pharmacokinetics of bupropion. Flibanserin 50 mg twice daily was administered for 2 days followed by 100 mg once daily for 13 days. Bupropion 150 mg twice daily was given for 8 days beginning on Day 6 of Flibanserin treatment. Flibanserin did not change bupropion AUC(t,ss) (1.0-fold change) and Cmax (1.0-fold change) but hydroxybupropion AUC(t,ss) decreased by 9% and Cmax by 11%.

• Table 5 Effects of Flibanserin on Exposure of Other Drugs

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ADDYI: Flibanserin's Brand name

Pharmacogenomics

Patients who are poor metabolizers of CYP2D6, CYP2C9 or CYP2C19 are deficient in CYP2D6, CYP2C9 or CYP2C19 enzyme activity, respectively. Extensive metabolizers have normal functioning CYP enzymes.

• CYP2C19 Poor Metabolizers

A study comparing Flibanserin exposure in CYP2C19 poor metabolizers to CYP2C19 extensive metabolizers was conducted in lieu of a drug interaction study with Flibanserin and a strong CYP2C19 inhibitor. In 9 women who were poor metabolizers of CYP2C19, Cmax and AUC(0-inf) of Flibanserin 100 mg once daily increased 1.5-fold (1.1-2.1) and 1.3-fold (0.9-2.1), compared to exposures among 8 extensive metabolizers of CYP2C19. Flibanserin half-life was increased from 11.1 hours in the extensive metabolizers of CYP2C19 to 13.5 hours in the poor metabolizers of CYP2C19.

The frequencies of poor metabolizers of CYP2C19 are approximately 2–5% among Caucasians and Africans and approximately 2–15% among Asians.

• CYP2D6 Poor Metabolizers

A study comparing Flibanserin exposure in CYP2D6 poor metabolizers to CYP2D6 extensive metabolizers was conducted in addition to a drug interaction study with paroxetine, a strong CYP2D6 inhibitor. In 12 poor metabolizers of CYP2D6, steady state Cmax and AUC of Flibanserin 50 mg twice daily was decreased by 4% and increased by 18%, respectively, compared to exposures among 19 extensive metabolizers, intermediate metabolizers and ultra rapid metabolizers of CYP2D6.

• CYP2C9 Poor Metabolizers

A study comparing Flibanserin exposure in CYP2C9 poor metabolizers to CYP2C9 extensive metabolizers was conducted in lieu of a drug interaction study with Flibanserin and a strong CYP2C9 inhibitor. In 8 women who were poor metabolizers of CYP2C9, Cmax and AUC(0-inf) of Flibanserin 100 mg once daily decreased 23% and 18%, compared to exposures among 8 extensive metabolizers of CYP2C9. |nonClinToxic=:*Carcinogenesis A two-year carcinogenicity study was conducted in CD-1 mice with dietary administration of 0, 10, 80, 200 and 1000/1200 mg/kg/day of Flibanserin. Statistically significant increases in combined mammary tumors (adenoacanthoma and adenocarcinomas) were observed in female mice administered Flibanserin at doses of 200 and 1200 mg/kg/day (exposures, based on AUC, were 3 and 10 times the clinical exposures at the recommended clinical dose). No increases in mammary tumors were observed in male mice. Statistically significant increases were also seen for combined hepatocellular adenomas/carcinomas in female mice treated with Flibanserin 1200 mg/kg/day and for hepatocellular carcinomas in male mice treated with Flibanserin 1000 mg/kg/day (exposures, based on AUC, were 8 times the clinical exposure at the recommended clinical dose).

There were no significant increases in tumor incidence in a two year carcinogenicity study conducted in Wistar rats with dietary administration of 0, 10, 30 and 100 mg/kg/day Flibanserin (up to 5-8 times human exposure at the recommended clinical dose).

• Mutagenesis

Flibanserin was negative for mutagenesis in vitro in Salmonella typhimurium (Ames test) and in Chinese hamster ovary cells. Flibanserin was positive for chromosomal aberrations in cultured human lymphocytes but negative for chromosomal aberrations in vivo in the rat bone marrow micronucleus assay and negative for DNA damage in rat liver in the Comet assay.

• Impairment of Fertility

Female and male rats were administered Flibanserin 14 and 28 days before mating, respectively, to assess for potential effects on fertility and early reproductive performance. Flibanserin slightly increased the duration of the estrus cycle but had no adverse effects on fertility or early embryonic development at doses up to 200 mg/kg/day (~20 times human exposure at the recommended clinical dose).

|clinicalStudies=

Trials in Premenopausal HSDD Patients

The efficacy of Flibanserin for the treatment of HSDD in premenopausal women was established in three 24-week, randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3). The three trials included premenopausal women with acquired, generalized HSDD of at least 6 months duration. In the clinical trials, acquired HSDD was defined as HSDD that developed in patients who previously had no problems with sexual desire. Generalized HSDD was defined as HSDD that was not limited to certain types of stimulation, situations or partners. The patients were treated with Flibanserin 100 mg once daily at bedtime (n = 1187) or placebo (n = 1188). Most of the trial participants were Caucasian (88.6%); the remainder were Black (9.6%) and Asian (1.5%). The mean age of study participants was 36 years old (range 19 to 55 years old); the mean duration in the monogamous, heterosexual relationship was 11 years, and the mean duration of HSDD was approximately 5 years. The completion rate across these three trials was 69% and 78% for the Flibanserin and placebo groups, respectively.

These trials each had two co-primary efficacy endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire:

• The change from baseline to Week 24 in the number of monthly SSEs (i.e., sexual intercourse, oral sex, masturbation, or genital stimulation by the partner). The SSEs were based on patient responses to the following questions: “Did you have a sexual event?” and “Was the sex satisfying for you?”

• Studies 1 and 2 had a different sexual desire endpoint than Study 3:

• In Studies 1 and 2, the sexual desire co-primary endpoint was the change from baseline to Week 24 in the calculated monthly sexual desire score and was based on patient responses to the question: “Indicate your most intense level of sexual desire.” Every day, patients rated their sexual desire level from 0 (no desire) to 3 (strong desire) and recorded their response in an electronic Diary (eDiary). These responses were summed over a 28-day period to yield the calculated monthly sexual desire score, which ranged from 0 to 84.

• In Study 3, the desire domain of the Female Sexual Function Index (FSFI Desire) was the sexual desire co-primary endpoint. The desire domain of the FSFI has two questions. The first question asks patients “Over the past 4 weeks, how often did you feel sexual desire or interest?”, with responses ranging from 1 (almost never or never) to 5 (almost always or always). The second question asks patients “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”, with responses ranging from 1 (very low or none at all) to 5 (very high). The FSFI Desire score was calculated by adding the patient’s responses to these two questions then multiplying that sum by 0.6. The FSFI Desire domain score ranged from 1.2 to 6.

The desire domain of the Female Sexual Function Index (FSFI Desire) was also used as a secondary endpoint in Studies 1 and 2.

The three trials had a secondary endpoint that measured bother (a component of distress) related to sexual desire using Question 13 of the Female Sexual Distress Scale-Revised (FSDS-R). This question asks “How often did you feel: Bothered by low sexual desire?” Patients assessed their sexual distress over a 7-day recall period and responded on a scale of 0 (never) to 4 (always).

The efficacy results from Studies 1, 2, and 3 are summarized in Table 6. In all three trials, Flibanserin resulted in statistically significant improvement compared to placebo in the change from baseline in monthly SSEs at Week 24. In Study 1 and 2, there were no statistically significant differences between Flibanserin and placebo for the eDiary sexual desire endpoint (change in baseline to Week 24). In contrast, in Study 3 there was statistically significant improvement in the change from baseline to Week 24 in sexual desire (using the FSFI Desire Domain) with Flibanserin compared to placebo. The FSFI Desire Domain findings were consistent across all three trials as were the findings for the secondary endpoint that assessed distress using Question 13 of the FSDS-R.

• Table 6 Efficacy Results in Premenopausal HSDD Patients in Studies 1, 2, and 3

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ADDYI: Flibanserin's Brand name

Exploratory analyses were conducted to assess whether the treatment effects varied depending on baseline number of SSEs, FSFI Desire score, and FSDS-R Question 13 distress score. No notable differences were identified among these subgroups.

Supportive analyses were conducted to help interpret the clinical meaningfulness of the observed treatment effects. These analyses defined responders for each efficacy endpoint by anchoring change from baseline to end of treatment with the Patient's Global Impression of Improvement (PGI‑I). The first analysis considered responders to be those who reported being “much improved” or “very much improved.” In this analysis, the absolute difference in the percentage of responders with Flibanserin and the percentage of responders with placebo across the three trials was 8-9% for SSEs (29-39% for Flibanserin; 21-31% for placebo), 10-13% for FSFI desire domain (43-48% for Flibanserin; 31-38% for placebo), and 7-13% for FSDS-R Question 13 (21-34% for Flibanserin; 14-25% for placebo). The second analysis considered responders to be those who reported being at least minimally improved. The absolute difference in the percentage of responders with Flibanserin and the percentage of responders with placebo across the three trials was 10-15% for SSEs (44-48% for Flibanserin; 33-36% for placebo), 12-13% for FSFI desire domain (43-51% for Flibanserin; 31-39% for placebo), and 9-12% for FSDS-R Question 13 (50-60% for Flibanserin; 41-48% for placebo).

Effects on Driving

In a randomized, placebo-controlled, 4-way crossover study in 83 healthy premenopausal female subjects, no adverse effect was detected on measures of driving performance itself or psychomotor performance thought to be important for driving performance when assessed 9 hours following single and multiple doses of Flibanserin 100 mg once daily at bedtime or single doses of Flibanserin 200 mg at bedtime (two times the maximum recommended dosage). |howSupplied= Flibanserin is available as a 100 mg oval, pink, film-coated tablet debossed on one side with “f100” and blank on the other side. Available in bottles of 30 tablets. (NDC 58604-214-30) |storage=Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). |fdaPatientInfo=

• Hypotension and Syncope

Inform patients that Flibanserin can cause severe hypotension and syncope, particularly with alcohol or with moderate or strong CYP3A4 inhibitors. Inform patients that alcohol use and moderate or strong CYP3A4 inhibitors are contraindicated. Counsel patients about the importance of abstaining from alcohol and to ask about drug interactions before starting a new prescription or non-prescription medication or using other products that contain CYP3A4 inhibitors (e.g., grapefruit juice or St. John’s Wort). Advise patients who experience pre-syncope or lightheadedness to lie down and to call for help if symptoms persist.

Flibanserin is available only through a restricted program called the Flibanserin REMS Program. Patients can only obtain Flibanserin from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain Flibanserin.

• CNS Depression

Advise patients that Flibanserin can cause CNS depression, such as somnolence and sedation, and that the risk is increased with other CNS depressants and with certain drug interactions (e.g., hypnotics, benzodiazepines, opioids). The risk is also increased if Flibanserin is taken during waking hours. Advise patients to avoid engaging in activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after the Flibanserin dose and until they know how Flibanserin affects them.

• Nursing Mothers

Advise patients not to breastfeed if they are taking Flibanserin.

• Bedtime Dosing

Advise patients to take only one tablet at bedtime and not to take Flibanserin at any other time of day.

|alcohol=Alcohol use is contraindicated in patients taking Flibanserin. Use of Flibanserin and alcohol increases the risk of severe hypotension and syncope. Before prescribing Flibanserin, the healthcare provider must assess the likelihood of the patient abstaining from alcohol use, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed Flibanserin about the importance of abstaining from alcohol use. |brandNames=ADDYI® }}