2.1 Recommended Dosage

The recommended dosage of ADDYI is 100 mg administered orally once per day at bedtime. ADDYI 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).

2.2 Missed Dose

If a dose of ADDYI 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.

2.3 Discontinuation of ADDYI

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

2.4 Initiation of ADDYI Following Moderate or Strong CYP3A4 Inhibitor Use

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

If initiating a moderate or strong CYP3A4 inhibitor following ADDYI use, start the moderate or strong CYP3A4 inhibitor 2 days after the last dose of ADDYI [see Warnings and Precautions (5.2)].

5.1 Hypotension and Syncope due to an Interaction with Alcohol

Taking ADDYI within two hours after consuming alcohol increases the risk of severe hypotension and syncope. To reduce this risk, counsel patients to wait at least two hours after drinking one or two standard alcoholic drinks before taking ADDYI at bedtime [see Boxed Warning and Adverse Reactions (6.1)]. Patients who drink three or more standard alcoholic drinks should skip their ADDYI dose that evening. One standard alcoholic drink contains 14 grams of pure alcohol and is equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol).

After taking ADDYI at bedtime, advise patients to not use alcohol until the following day.

5.2 Hypotension and Syncope with CYP3A4 Inhibitors

Moderate or Strong CYP3A4 Inhibitors

The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors significantly increases flibanserin concentrations, which can lead to hypotension and syncope [see Adverse Reactions (6.1)]. The concomitant use of ADDYI with a moderate or strong CYP3A4 inhibitor is contraindicated. If the patient requires a moderate or strong CYP3A4 inhibitor, discontinue ADDYI 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 ADDYI 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 ADDYI [see Drug Interactions (7)].

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 [see Drug Interactions (7)].

5.3 Central Nervous System Depression

ADDYI 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 ADDYI once daily at bedtime and placebo, respectively [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. 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 [see Contraindications (4), Warnings and Precautions (5.1, 5.2), Adverse Reactions (6.1), and Drug Interactions (7)].

Patients should not drive or engage in other activities requiring full alertness until at least 6 hours after taking ADDYI and until they know how ADDYI affects them [see Clinical Studies (14.2)].

5.4 Hypotension and Syncope with ADDYI Alone

The use of ADDYI − 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 ADDYI-treated patients and placebo-treated patients, respectively; syncope was reported in 0.4% and 0.2% of ADDYI- treated patients and placebo-treated patients, respectively. The risk of hypotension and syncope is increased if ADDYI is taken during waking hours or if higher than the recommended dose is taken [see Warnings and Precautions (5.1, 5.3), Adverse Reactions (6.1), Drug Interactions (7), and Use in Specific Populations (8.7)]. Consider the benefits of ADDYI 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.

5.5 Syncope and Hypotension in Patients with Hepatic Impairment

The use of ADDYI in patients with any degree of hepatic impairment significantly increases flibanserin concentrations, which can lead to hypotension and syncope. Therefore, the use of ADDYI is contraindicated in patients with hepatic impairment [see Contraindications (4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.6 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth), pruritus, and urticaria have been reported with ADDYI. ADDYI is contraindicated in women with known hypersensitivity to ADDYI or any of its components [see Adverse Reactions (6.2)]. Immediately discontinue ADDYI and initiate appropriate treatment if a hypersensitivity reaction occurs.

5.7 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 [see Nonclinical Toxicology (13.1)]. The clinical significance of these findings is unknown.

6.1 Clinical Trials Experience

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 ADDYI 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 [see Clinical Studies (14)].

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 [see Clinical Studies (14.1)]. One of these trials (Study 5) did not evaluate the 100 mg bedtime dose.

In four trials, 100 mg ADDYI 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 ADDYI-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 ADDYI 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.

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 ADDYI and at a higher incidence than with placebo [see Warnings and Precautions (5.3)].  The majority of these adverse reactions began within the first 14 days of treatment.

Less Common Adverse Reactions

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

•

Anxiety (ADDYI 1.8%; placebo 1.0%),

•

Constipation (ADDYI 1.6%; placebo 0.4%),

•

Abdominal pain (ADDYI 1.5%; placebo 0.9%),

•

Metrorrhagia (ADDYI 1.4%; placebo 1.4%),

•

Rash (ADDYI 1.3%; placebo 0.8%),

•

Sedation (ADDYI 1.3%; placebo 0.2%), and

•

Vertigo (ADDYI 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%) ADDYI-treated patients and 47/1905 (2.5%) placebo-treated patients. Among these 89 patients who experienced injuries, 9/42 (21%) ADDYI-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 ADDYI and HC. ADDYI-treated patients who reported HC use had a greater incidence of dizziness, somnolence, and fatigue compared to ADDYI-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 [see Drug Interactions (7)].

Data from Other Trials

One death occurred in a 54 year-old postmenopausal woman treated with 100 mg ADDYI taken at bedtime (ADDYI is not approved for the treatment of postmenopausal women with HSDD) [see Indications and Usage (1)]. 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 ADDYI. 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 ADDYI is unknown [see Boxed Warning and Warnings and Precautions (5.1)].

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

Hypotension, Syncope, and CNS Depression with Alcohol

Alcohol and ADDYI Administration at the Same Time

The first alcohol interaction study was conducted in 25 healthy subjects (23 men and 2 premenopausal women). The study excluded subjects who drank fewer than five alcoholic drinks per week and those with a history of orthostatic hypotension, or syncope. A single dose of 100 mg ADDYI was administered concurrently with 0.4 g/kg or 0.8 g/kg alcohol in the morning; alcohol was consumed over 10 minutes. Hypotension or syncope requiring therapeutic intervention (ammonia salts and/or placement in supine or Trendelenberg position) occurred in 4 (17%) of the 23 subjects co-administered 100 mg ADDYI and 0.4 g/kg alcohol (equivalent to 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). In these four subjects, all of whom were men, the magnitude of the systolic blood pressure reductions ranged from 28 to 54 mmHg and the magnitude of the diastolic blood pressure reductions ranged from 24 to 46 mmHg. In addition, 6 (25%) of the 24 subjects co-administered 100 mg ADDYI and 0.8 g/kg alcohol (equivalent to four 12 ounce cans of beer containing 5% alcohol content, four 5 ounce glasses of wine containing 12% alcohol content, or four 1.5 ounce shots of 80-proof spirit in a 70 kg person) experienced orthostatic hypotension when standing from a sitting position. The magnitude of the systolic blood pressure reduction 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 ADDYI or alcohol were administered alone.

In this study, somnolence was reported in 67%, 74%, and 92% of subjects who received ADDYI alone, ADDYI in combination with 0.4 g/kg alcohol, and ADDYI in combination with 0.8 g/kg alcohol, respectively. [see Boxed Warning, Warnings and Precautions (5.1, 5.3 and 5.4)].

In the second alcohol interaction study, 96 healthy premenopausal women received a single dose of 100 mg ADDYI concurrently with 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg alcohol (equivalent to one, two or three alcoholic drinks in a 70 kg person, respectively) in the morning. The study excluded subjects with a history of syncope, orthostatic hypotension, hypotensive events, and dizziness, and those with a resting systolic blood pressure less than 110 mmHg or diastolic blood pressure less than 60 mmHg.

In this study, no subjects experienced syncope or hypotension requiring therapeutic intervention. However, subjects who were already hypotensive (blood pressure below 90/60 mmHg) or symptomatic (e.g., dizzy) while in the semi-recumbent position were not permitted to stand for orthostatic measurements, and those with blood pressures below 90/40 mmHg while in the semi-recumbent position had blood pressures repeated until it was deemed safe for them to change position. More subjects had missing or delayed orthostatic measurements (in general, due to hypotension or dizziness) when receiving ADDYI and alcohol, compared to those who received alcohol alone or ADDYI alone. This pattern of missing or delayed orthostatic measurements is concerning for a risk of hypotension and syncope if those subjects had been allowed to stand.

In this study, somnolence was reported in 81-89% of subjects administered ADDYI with alcohol, compared to 25-41% of subjects administered alcohol alone and 84% of subjects taking ADDYI alone. Dizziness was reported in 27-40% of subjects administered ADDYI with alcohol, compared to 6-20% of subjects administered alcohol alone and 31% of subjects taking ADDYI alone. [see Warnings and Precautions (5.1, 5.3, 5.4)].

Alcohol Use at Various Time Intervals Before ADDYI Administration

In a third alcohol interaction study, 64 healthy premenopausal women consumed 0.4 g/kg alcohol (equivalent to 2 alcoholic drinks in a 70 kg person) two, four or six hours prior to receiving ADDYI 100 mg or placebo in the afternoon. The study excluded subjects with a history or presence of orthostatic hypotension, history of hypotension, syncope, or dizziness. Prior to receiving alcohol, the subjects in the ADDYI arm had taken ADDYI for three days to achieve steady state. Syncope occurred in one subject who received alcohol alone. The incidences of orthostatic hypotension and hypotension (blood pressure below 90/60 mmHg) at all time points were similar among subjects administered alcohol before ADDYI, subjects administered alcohol alone, and subjects administered ADDYI alone. Three subjects were unable to stand due to feeling dizzy or hypotension; two following alcohol and ADDYI separated by 2 and 6 hours, and one subject who received ADDYI alone.

In this study, somnolence was reported in 35-53% of subjects administered ADDYI and alcohol, compared to 5-8% of subjects taking alcohol alone and 50% of subjects taking ADDYI alone. Dizziness was reported in 5-13% of subjects administered ADDYI and alcohol, compared to 0-3% of subjects taking alcohol alone and 12% of subjects taking ADDYI alone.

Alcohol Use in the Evening Before Bedtime ADDYI Administration

In another alcohol interaction study, 24 premenopausal women consumed 0.4 g/kg alcohol (equivalent to 2 alcoholic drinks in a 70 kg person) during the evening meal two and a half to four hours prior to taking ADDYI 100 mg at bedtime. There were no cases of syncope. Upon rising the following morning, the incidence of hypotension was 23% among subjects administered ADDYI after alcohol, 23% among subjects administered alcohol alone and 36% with ADDYI alone. No cases of somnolence or dizziness were reported in this study. Conclusions are limited because blood pressure and orthostatic measurements were not taken after ADDYI administration until the following morning.

Hypotension and Syncope with Fluconazole

In a pharmacokinetic drug interaction study of 100 mg ADDYI 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 ADDYI and fluconazole compared to no such adverse reactions in subjects treated with ADDYI 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 ADDYI and fluconazole increased flibanserin exposure 7-fold [see Warnings and Precautions (5.2), Drug Interactions (7) and Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.2), Drug Interactions (7) and Clinical Pharmacology (12.3)].

Syncope in Poor CYP2C19 Metabolizers

In a pharmacogenomic study of 100 mg ADDYI 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 [see Drug Interactions (7), Use in Specific Populations (8.7) and Clinical Pharmacology (12.5)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval of ADDYI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: hypersensitivity reactions, including anaphylaxis, reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth), pruritus, and urticaria.

8.1 Pregnancy

Risk Summary

There are no studies of ADDYI 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 [see Data]. Animal studies cannot rule out the potential for fetal harm.

In the general population (not taking ADDYI), 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 [see Nonclinical Toxicology (13.1)].

8.2 Lactation

Risk Summary

Flibanserin is excreted in rat milk. It is unknown whether flibanserin is present in human milk, whether ADDYI has effects on the breastfed infant, or whether ADDYI affects milk production. Because of the potential for serious adverse reactions including sedation in a breastfed infant, breastfeeding is not recommended during treatment with ADDYI.

8.4 Pediatric Use

ADDYI is not indicated for use in pediatric patients.

8.5 Geriatric Use

ADDYI is not indicated for use in geriatric patients. Safety and effectiveness have not been established in geriatric patients.

8.6 Hepatic Impairment

ADDYI 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 [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)].

8.7 CYP2C19 Poor Metabolizers

CYP2C19 poor metabolizers had increased flibanserin exposures compared to CYP2C19 extensive metabolizers. Additionally, syncope occurred in a subject who was a CYP2C19 poor metabolizer [see Adverse Reactions (6.1) and Clinical Pharmacology (12.5)].  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.

12.1 Mechanism of Action

The mechanism of action of ADDYI in the treatment of premenopausal women with hypoactive sexual desire disorder is not known.

12.2 Pharmacodynamics

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

See Clinical Trials Experience (6.1)

Cardiac Electrophysiology

The effect of ADDYI 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 ADDYI 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, ADDYI 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 ADDYI compared to placebo ranged from 1.7 to 3.2 beats per minute.

12.3 Pharmacokinetics

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 (AUC0-∞) with once-daily dosing of 100 mg of flibanserin was increased 1.4-fold as compared to a single dose.

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) 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%.

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 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.

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 (AUC0-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. ADDYI is contraindicated in patients with hepatic impairment [see Warnings and Precautions (5.5)].

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 (AUC0-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 AUCtau,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 AUCtau,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 (AUC0-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 [see Warnings and Precautions (5.2), Adverse Reactions (6.1) and Drug Interactions (7)].

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 (AUC0-inf) 4.5-fold and Cmax 1.8-fold compared to flibanserin 50 mg alone [see Warnings and Precautions (5.2), Adverse Reactions (6.1) and Drug Interactions (7)].

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 (AUC0-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 [see Drug Interactions (7)].

Moderate CYP3A4 Inhibitor (Grapefruit Juice)

In a study of 26 healthy female subjects, grapefruit juice (240 mL) increased flibanserin 100 mg single dose exposure (AUC0-inf) by 1.4-fold and Cmax 1.1-fold compared to flibanserin 100 mg alone [see Warnings and Precautions (5.2), Adverse Reactions (6.1) and Drug Interactions (7)].

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 [see Adverse Reactions (6.1) and Drug Interactions (7)].

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% [see Drug Interactions (7)].

Moderate CYP3A4 Inducer (Etravirine)

Steady state etravirine, a moderate CYP3A4 inducer, decreased flibanserin exposures by approximately 21% [see Drug Interactions (7)].

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 AUC0-inf by 2.0-fold and Cmax by 1.5-fold, compared to digoxin alone [see Drug Interactions (7)].

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 AUC0-inf of simvastatin, a substrate of CYP3A4, 1.3‑fold and Cmax by 1.2-fold. Flibanserin co-administered with simvastatin increased simvastatin acid AUC0-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 AUC0-inf by 1.09-fold and the EE Cmax by 1.1-fold.  Flibanserin decreased the LNG AUC0-inf by 1.06-fold and did not change the LNG Cmax. [see Adverse Events (6.1), Drug Interactions (7)].

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  AUCt,ss (1.0-fold change) and Cmax (1.0-fold change) but hydroxybupropion AUCt,ss decreased by 9% and Cmax by 11%.

12.5 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 ADDYI and a strong CYP2C19 inhibitor.  In 9 women who were poor metabolizers of CYP2C19, Cmax and AUC0-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 [see Adverse Reactions (6.1) and Use in Specific Populations (8.7)].

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 ADDYI and a strong CYP2C9 inhibitor. In 8 women who were poor metabolizers of CYP2C9, Cmax and AUC0-inf of flibanserin 100 mg once daily decreased 23% and 18%, compared to exposures among 8 extensive metabolizers of CYP2C9.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 (adenoacanthomas 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).

14.1 Studies in Premenopausal HSDD Patients

The efficacy of ADDYI 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 ADDYI 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 ADDYI 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:

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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?”

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

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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.

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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, ADDYI 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 ADDYI 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 ADDYI 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.

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 ADDYI and the percentage of responders with placebo across the three trials was 8-9% for SSEs (29-39% for ADDYI; 21-31% for placebo), 10-13% for FSFI desire domain (43-48% for ADDYI; 31-38% for placebo), and 7-13% for FSDS-R Question 13 (21-34% for ADDYI; 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 ADDYI and the percentage of responders with placebo across the three trials was 10-15% for SSEs (44-48% for ADDYI; 33-36% for placebo), 12-13% for FSFI desire domain (43-51% for ADDYI; 31-39% for placebo), and 9-12% for FSDS-R Question 13 (50-60% for ADDYI; 41-48% for placebo).

14.2 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 ADDYI 100 mg once daily at bedtime or single doses of ADDYI 200 mg at bedtime (two times the maximum recommended dosage) [see Warnings and Precautions (5.3)].