Chemical formula: C₂₀H₂₁F₃N₄O Molecular mass: 390.402 g/mol PubChem compound: 6918248
There are no studies of flibanserin in pregnant women to inform whether there is a drug-associated risk in humans. In animals, fetal toxicity only occurred in the presence of significant maternal toxicity including reductions in weight gain and sedation. Adverse reproductive and developmental effects consisted of decreased fetal weight, structural anomalies and increases in fetal loss at exposures greater than 15 times exposures achieved with the recommended human dosage [see Data]. Animal studies cannot rule out the potential for fetal harm.
In the general population (not taking flibanserin), the estimated background risk of major birth defects is 2% to 4% of live births, and the estimated background risk of miscarriage of clinically recognized pregnancies is 15% to 20%.
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.
Flibanserin is excreted in rat milk. It is unknown whether flibanserin is present in human milk, whether flibanserin has effects on the breastfed infant, or whether flibanserin affects milk production. Because of the potential for serious adverse reactions including sedation in a breastfed infant, breastfeeding is not recommended during treatment with flibanserin.
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).
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.
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).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The approved 100 mg flibanserin dosage at bedtime was administered to 2,997 premenopausal women with acquired, generalized HSDD in clinical trials, of whom 1672 received treatment for at least 6 months, 850 received treatment for at least 12 months, and 88 received treatment for at least 18 months.
The data presented below are derived from five 24-week randomized, double-blind, placebo-controlled trials in premenopausal women with acquired, generalized HSDD. In these five trials, the frequency and quantity of alcohol use was not recorded. Three of these trials (Studies 1 through 3) also provided efficacy data. One of these trials (Study 5) did not evaluate the 100 mg bedtime dose.
In four trials, 100 mg flibanserin at bedtime was administered to 1543 premenopausal women with HSDD, of whom 1060 completed 24 weeks of treatment. The clinical trial population was generally healthy without significant comorbid medical conditions or concomitant medications. The age range was 18-56 years old with a mean age of 36 years old, and 88% were Caucasian and 9% were Black.
Serious adverse reactions were reported in 0.9% and 0.5% of flibanserin-treated patients and placebo-treated patients, respectively.
The discontinuation rate due to adverse reactions was 13% among patients treated with 100 mg flibanserin at bedtime and 6% among patients treated with placebo. The following table displays the most common adverse reactions leading to discontinuation in four trials of premenopausal women with HSDD.
Adverse Reactions* Leading to Discontinuation in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD:
| Placebo (N=1556) | Flibanserin (N=1543) | |
|---|---|---|
| Dizziness | 0.1% | 1.7% |
| Nausea | 0.1% | 1.2% |
| Insomnia | 0.2% | 1.1% |
| Somnolence | 0.3% | 1.1% |
| Anxiety | 0.3% | 1% |
* Adverse reactions leading to discontinuation of ≥1% of patients receiving 100 mg flibanserin at bedtime and at a higher incidence than placebo-treated patients.
The table below summarizes the most common adverse reactions reported in four trials of premenopausal women with HSDD. This table shows adverse reactions reported in at least 2% of patients treated with flibanserin and at a higher incidence than with placebo. The majority of these adverse reactions began within the first 14 days of treatment.
Common Adverse Reactions* in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD:
| Placebo (N=1556) | Flibanserin (N=1543) | |
|---|---|---|
| Dizziness | 2.2% | 11.4% |
| Somnolence | 2.9% | 11.2% |
| Nausea | 3.9% | 10.4% |
| Fatigue | 5.5% | 9.2% |
| Insomnia | 2.8% | 4.9% |
| Dry mouth | 1.0% | 2.4% |
* Adverse reactions reported in ≥2% of patients receiving 100 mg flibanserin at bedtime and at a higher incidence than placebo-treated patients.
In four trials in premenopausal women with HSDD treated with 100 mg flibanserin at bedtime, less common adverse reactions (reported in ≥1% but <2% of flibanserin-treated patients and at a higher incidence than with placebo) included:
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.
In five trials of premenopausal women with HSDD, accidental injury was reported in 42/1543 (2.7%) flibanserin-treated patients and 47/1905 (2.5%) placebo-treated patients. Among these 89 patients who experienced injuries, 9/42 (21%) flibanserin-treated patients and 3/47 (6%) placebo-treated patients reported adverse reactions consistent with CNS depression (e.g., somnolence, fatigue, or sedation) within the preceding 24 hours.
In four trials of premenopausal women with HSDD, 1466 patients (43%) reported concomitant use of hormonal contraceptives (HC) at study enrollment. These trials were not prospectively designed to assess an interaction between flibanserin and HC. flibanserin-treated patients who reported HC use had a greater incidence of dizziness, somnolence, and fatigue compared to flibanserin-treated patients who did not report HC use (dizziness 9.9% in HC non-users, 13.4% in HC users; somnolence 10.6% in HC non-users, 12.3% in HC users; fatigue 7.5% in HC non-users, 11.4% in HC users). There were no meaningful differences in the incidence of these adverse reactions in placebo-treated patients who reported or did not report HC use.
One death occurred in a 54 year-old postmenopausal woman treated with 100 mg flibanserin taken at bedtime (flibanserin is not approved for the treatment of postmenopausal women with HSDD). This patient had a history of hypertension and hypercholesterolemia and baseline alcohol consumption of 1-3 drinks daily. She died of acute alcohol intoxication 14 days after starting flibanserin. Blood alcohol concentration on autopsy was 0.289 g/dL. The autopsy report also noted coronary artery disease. A relationship between this patient’s death and use of flibanserin is unknown.
Alcohol and Flibanserin 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 flibanserin 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 flibanserin 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 flibanserin 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 flibanserin or alcohol were administered alone.
In this study, somnolence was reported in 67%, 74%, and 92% of subjects who received flibanserin alone, flibanserin in combination with 0.4 g/kg alcohol, and flibanserin 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 flibanserin 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 flibanserin and alcohol, compared to those who received alcohol alone or flibanserin 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 flibanserin with alcohol, compared to 25-41% of subjects administered alcohol alone and 84% of subjects taking flibanserin alone. Dizziness was reported in 27-40% of subjects administered flibanserin with alcohol, compared to 6-20% of subjects administered alcohol alone and 31% of subjects taking flibanserin alone.
Alcohol Use at Various Time Intervals Before Flibanserin 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 flibanserin 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 flibanserin arm had taken flibanserin 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 flibanserin, subjects administered alcohol alone, and subjects administered flibanserin alone. Three subjects were unable to stand due to feeling dizzy or hypotension; two following alcohol and flibanserin separated by 2 and 6 hours, and one subject who received flibanserin alone.
In this study, somnolence was reported in 35-53% of subjects administered flibanserin and alcohol, compared to 5-8% of subjects taking alcohol alone and 50% of subjects taking flibanserin alone. Dizziness was reported in 5-13% of subjects administered flibanserin and alcohol, compared to 0-3% of subjects taking alcohol alone and 12% of subjects taking flibanserin alone.
Alcohol Use in the Evening Before Bedtime Flibanserin 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 flibanserin 100 mg at bedtime. There were no cases of syncope. Upon rising the following morning, the incidence of hypotension was 23% among subjects administered flibanserin after alcohol, 23% among subjects administered alcohol alone and 36% with flibanserin 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 flibanserin administration until the following morning.
In a pharmacokinetic drug interaction study of 100 mg flibanserin and 200 mg fluconazole (a moderate CYP3A4 inhibitor, moderate CYP2C9 inhibitor, and a strong CYP2C19 inhibitor) in healthy subjects, hypotension or syncope requiring placement supine with legs elevated occurred in 3/15 (20%) subjects treated with concomitant flibanserin and fluconazole compared to no such adverse reactions in subjects treated with flibanserin alone or fluconazole alone. One of these 3 subjects became unresponsive with a blood pressure of 64/41 mm Hg and required transportation to the hospital emergency department where she required intravenous saline. Due to these adverse reactions, the study was stopped. In this study, the concomitant use of flibanserin and fluconazole increased flibanserin exposure 7-fold.
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.
In a pharmacogenomic study of 100 mg flibanserin in subjects who were poor or extensive CYP2C19 metabolizers, syncope occurred in 1/9 (11%) subjects who were CYP2C19 poor metabolizers (this subject had a 3.2 fold higher flibanserin exposure compared to CYP2C19 extensive metabolizers) compared to no such adverse reactions in subjects who were CYP2C19 extensive metabolizers.
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