Flibanserin

1 INDICATIONS AND USAGE ADDYI is indicated for the treatment of women less than 65 years of age 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 • ADDYI is not indicated in men. • ADDYI is not indicated to enhance sexual performance. ADDYI is indicated for the treatment of women less than 65 years of age 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 ( 1 ): • A co-existing medical or psychiatric condition, • Problems within the relationship, or • The effects of a medication or other drug substance. Limitations of Use: • ADDYI is not indicated in men (1) • ADDYI is not indicated to enhance sexual performance. ( 1 )

2 DOSAGE AND ADMINISTRATION • Recommended dosage is 100 mg taken once daily at bedtime (2.1) • ADDYI is dosed at bedtime because administration during waking hours increases risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression (2.1) • Discontinue ADDYI treatment after 8 weeks if no improvement (2.3) 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 HSDD 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) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Hypotension and syncope [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5) ] • CNS depression [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥2%) are dizziness, somnolence, nausea, fatigue, insomnia, urinary tract infection, anxiety, sinusitis, constipation and dry mouth. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sprout Pharmaceuticals, Inc. at 1-844-746-5745, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 1,672 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) ]. In clinical trials, ADDYI 100 mg once daily at bedtime was administered to 801 postmenopausal women less than 65 years of age with acquired, generalized HSDD, of whom 460 received ADDYI treatment for at least 6 months, and 23 received ADDYI treatment for longer than 6 months. Premenopausal Women The data presented below in Table 1 and Table 2 (left columns) are derived from five 24-week randomized, double-blind, placebo-controlled trials in premenopausal women with acquired, generalized HSDD. In these trials, the frequency and quantity of alcohol use was not recorded. Three of these trials (Studies 1, 2, and 3) also provided efficacy data [see Clinical Studies (14.1) ]. One trial (Study 5) did not evaluate the 100 mg bedtime dose. In four trials in premenopausal women (Studies 1 through 4), 100 mg ADDYI at bedtime was administered to 1543 premenopausal women with HSDD, of whom 1060 completed 24 weeks of treatment. The age range of women enrolled was 18-56 years old with a mean age of 36 years old, and 88% were Caucasian and 9% were Black. In Studies 1 through 4 in premenopausal women, serious adverse reactions were reported in 0.9% and 0.5% of ADDYI-treated patients and placebo-treated patients, respectively. Postmenopausal Women The data presented below in Table 1 and Table 2 (right columns) are derived from two randomized, double-blind, placebo-controlled trials intended to be of 24-week duration in naturally postmenopausal women with acquired, generalized HSDD (Studies 6 and 7). One trial (Study 7) was discontinued prematurely. In these trials, 100 mg ADDYI at bedtime was administered to 801 postmenopausal women less than 65 years of age with HSDD, of whom 460 completed 24 weeks of treatment. The age range of women enrolled was 34-80 years old with a mean age of 56 years old, and 91% were Caucasian, 7% were Black and 94% were less than 65 years of age. The clinical trial population had no significant comorbid medical conditions and were not taking concomitant medications. Serious adverse reactions were reported in 1.5% and 0.7% of ADDYI-treated patients and placebo-treated patients less than 65 years of age, respectively. Adverse Reactions Leading to Discontinuation Table 1 displays the most common adverse reactions leading to discontinuation in six trials of women less than 65 years of age with HSDD that evaluated the ADDYI 100 mg once daily at bedtime dosage by population studied. Table 1 Adverse Reactions Adverse reactions leading to discontinuation of > 1% of patients who received ADDYI 100 mg once daily at bedtime and at a higher incidence than placebo-treated patients in the pooled premenopausal women and postmenopausal women trials. Leading to Discontinuation in Randomized, Double-blind, Placebo-controlled Trials in Women with HSDD (< 65 Years of Age) Adverse Reaction Trials in Premenopausal Women Includes Studies 1-4 Trials in Postmenopausal Women Includes Studies 6 and 7 Placebo (N=1556) ADDYI (N=1543) Placebo (N=797) ADDYI (N=801) Overall 6% 13% 5% 9% Dizziness 0.1% 1.7% 0.3% 0.9% Nausea 0.1% 1.2% 0.3% 0.5% Insomnia 0.2% 1.1% 0.5% 1.4% Somnolence 0.3% 1.1% 0.1% 0.6% Anxiety 0.3% 1% 0.6% 1.2% Most Common Adverse Reactions Table 2 summarizes the most common adverse reactions reported in six trials of women less than 65 years of age 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. Table 2 Common Adverse Reactions Adverse reactions reported in ≥2% of patients who received ADDYI 100 mg once daily at bedtime and at a higher incidence than placebo-treated patients in premenopausal women or postmenopausal women trials. in Randomized, Double-blind, Placebo-controlled Trials in Women with HSDD (<65 Years of Age) Trials in Premenopausal Women Trials in Postmenopausal Women Adverse Reaction Placebo (N=1556) ADDYI (N=1543) Placebo (N=797) ADDYI (N=801) Dizziness 2.2% 11.4% 3.3% 7.9% Somnolence 2.9% 11.2% 1.8% 7.7% Nausea 3.9% 10.4% 3.9% 6.6% Fatigue 5.5% 9.2% 3.9% 3.0% Insomnia 2.8% 4.9% 3.4% 5.7% Dry mouth 1.0% 2.4% 1.3% 2.4% Urinary tract infection 2.4% 2.3% 3.0% 3.2% Anxiety 1.0% 1.8% 1.6% 2.6% Sinusitis 3.5% 2.9% 2.1% 2.5% Constipation 0.4% 1.6% 1.8% 2.5% Less Common Adverse Reactions In six trials in women less than 65 years of age with HSDD treated with ADDYI 100 mg once daily at bedtime, less common adverse reactions (reported in ≥1% but <2% of ADDYI-treated patients and at a higher incidence than with placebo) in the premenopausal population included: abdominal pain, metrorrhagia, rash, sedation, vertigo. In the postmenopausal population, less common adverse reactions included: sleep disorder, bronchitis, edema peripheral, cough, vertigo, palpitations, rash, abnormal dreams. 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. Appendicitis was not reported in trials of postmenopausal women. 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 day. In two trials of postmenopausal women less than 65 years of age with HSDD, accidental injury was reported in 33/801 (4.1%) ADDYI-treated patients and 28/797 (3.5%) placebo-treated patients. Among these 61 patients who experienced injuries, 1/33 (3.0%) ADDYI-treated patients and 3/28 (10.7%) placebo-treated patients reported adverse reactions consistent with CNS depression (e.g., somnolence, fatigue, or sedation) the preceding day. 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. 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 Trendelenburg 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. Dedicated alcohol-interaction studies were not conducted in postmenopausal women. 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 use 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. • Gastrointestinal disorders: vomiting • General disorders and administration site conditions: asthenia, feeling abnormal, feeling drunk, malaise • Nervous system disorders: headache, presyncope, gait disturbance, vision blurred • Psychiatric disorders: brain fog

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 (AUC 0-∞ ) with once-daily dosing of 100 mg of flibanserin was increased 1.4-fold as compared to a single dose. Figure 1 Mean + SD Plasma Flibanserin Concentration-Time Profiles in Healthy Female Subjects Following a Single Oral Dose of 100 mg of Flibanserin (Linear Scale) 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 14 C-radiolabeled flibanserin, 44% of the total 14 C-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 t 1/2 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 (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 [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 (AUC 0-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 (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 [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 (AUC 0-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) ] . Table 4 Drugs That Increase Flibanserin Exposure Coadministered Drug(s) and Dose(s) Dose of ADDYI n Geometric Mean Ratio (90% Confidence Interval) of Pharmacokinetic Parameters of Flibanserin with/without Coadministered Drug No Effect =1.00 Cmax AUC 0-inf Fluconazole 200 mg 100 mg 15 2.2 (1.8 – 2.8) 7.0 (6.0 – 8.2) Ketoconazole 400 mg 50 mg 24 1.8 (1.7 – 2.1) 4.5 (4.0 – 5.1) Itraconazole 200 mg itraconazole dose was not optimal for maximal inhibition of CYP3A4 enzyme. 50 mg 12 1.7 (1.4 – 2.0) 2.6 (2.1 – 3.0) Oral Contraceptives 50 mg 39 1.3 (1.1 – 1.6) 1.4 (1.2 – 1.7) Paroxetine 40 mg 50 mg twice daily 19 1.0 (0.9 – 1.2) 1.0 (0.9 – 1.0) 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 [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 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. [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 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 Coadministered Drug(s) and Dose(s) Dose of ADDYI n Geometric Mean Ratio (90% Confidence Interval) of Pharmacokinetic Parameters of Coadministered Drug with/without Flibanserin No Effect =1.00 Cmax AUC 0-inf Simvastatin 40 mg 50 mg twice daily 12 1.7 (1.4 – 2.0) 2.6 (2.1 – 3.1) Digoxin 0.5 mg 100 mg 24 1.5 (1.3 – 1.6) 2.0 (1.5 – 2.5) Ethinyl estradiol 30 mcg/ Levonorgestrel 150 mcg 100 mg 24 1.1 (1.0 – 1.1) 1.0 (0.9 – 1.0) 1.1 (1.0 – 1.2) 1.0 (0.9 – 1.1) Bupropion 150 mg 100 mg 28 1.0 (0.9 – 1.1) 1.0 (1.0 – 1.1) Figure 1