Flibanserinside effects

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Hypotension and syncope

CNS depression Most common adverse reactions (incidence ≥2%) are dizziness, somnolence, nausea, fatigue, insomnia, urinary tract infection, anxiety, sinusitis, constipation and dry mouth. 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. 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. 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. 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. 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. 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.. 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.. 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. 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 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.

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

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. 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. 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. 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. 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. 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.. 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.. 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. 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 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.

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